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Ruthenium catalyzed hydrogen-borrowing amine alkylation reactions
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Ruthenium catalyzed hydrogen-borrowing amine alkylation reactions
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Content
RUTHENIUM CATALYZED HYDROGEN-BORROWING AMINE ALKYLATION
REACTIONS
by
Anju Nalikezhathu
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
May 2023
Copyright 2023 Anju Nalikezhathu
ii
Dedication
To my Mother, Father, Brother and Husband.
iii
Acknowledgements
I would like to thank my advisor, Prof. Travis J. Williams for his guidance and constant
support during the last five years. His endless enthusiasm for chemistry motivated me to work hard
and face difficult obstacles in my PhD journey. As an international student, I am thankful to Travis
and his wife Sarah for inviting me to celebrate July 4
th
, Thanksgiving, and Christmas with them
every year. I am lucky to have an advisor who is insightful, wise, friendly, and supportive.
I would like to express gratitude to my screening, qualification, and defense committee
members: Professors G. K. Surya Prakash, Noah Malmstadt, Barry C. Thompson, Chao Zhang,
Shaama Mallikarjun Sharada, and Ralf Haiges. I am also grateful to Prof. Prakash for his support
during my job search.
A special thank you to former and current Williams’ group members: Dr. Jeff Celaje, Dr.
Valeriy Cherepakhin, Dr. Zhiyao Lu, Dr. Carlos Navarro, Adrian Tam, Van Do, Long Zhang,
Yuhao Chen, Rice Rander, Justin Lim, Alex Maertens, Talya Kapenstein, Lisa Kalm, Paul
Lauridson, and Steffanie Sun. Especially I am grateful to Valeriy Cherepakin for his excellent
mentorship. His constructive feedbacks and motivation helped me to understand my own potentials
and improve problem solving skills. Jeff Celaje who discovered the ruthenium complex that I
utilized for developing all my hydrogen-borrowing methodologies deserve a great appreciation. A
big thank you to Adriane Tam for being the best mentee and supporting me inside and outside of
lab. I wish all the best for her PhD journey.
Thanks to all Loker Hydrocarbon Reseatch Institute and the Chemistry Department Staff:
David Hunter, Dr. Robert Aniszfeld, Carole Phillips, Jessy May, Michele Dea, Magnolia Benitez,
Allan Kershaw, Dr. Frank Devlin, Michael, Nonezyan, and Eric McClure for their help and advice.
iv
Next, I would like to thank USC organizations, Women in Science and Engineering (WiSE)
and Graduate Student Government (GSG), for their support.
Professors and friends at my undergraduate institution, IISER TVM deserve great
appreciation for giving proper guidance and career orientation which helped me to pursue my PhD
at USC.
Much gratitude must be given to my batchmates Swetha Erukala, Pratyusha Das,
Shubhangi Aggarwal, Raktim Sen and my friends, Sulyab Thottungal, Irshad Ahammed, and all
Ellendale family members for their support and love.
I am so happy to thank my husband, Vishnu who joined with me in the halfway of my PhD
journey. Thank you for standing with me during the hard times and making me stronger.
Above all, my wholehearted thank you to my parents and brother for their endless support
and love. It’s my parents’ support and unconditional love that motivated me to chase my dreams
and pursue my higher education in USA. I love you so much!
v
Table of Contents
Dedication ................................................................................................................. ii
Acknowledgements .................................................................................................. iii
List of Tables ............................................................................................................. x
List of Schemes ........................................................................................................ xi
List of Figures ........................................................................................................ xiv
Abbreviations ........................................................................................................ xxii
Abstract ................................................................................................................ xxiii
Chapter 1. C-N Bond Formation Through Hydrogen-Borrowing ............................. 1
1.1 Introduction ........................................................................................................................... 1
1.2. Other Methods for C-N Bond Formation ............................................................................. 2
1.2.1. Amination of Alkyl Halides .......................................................................................... 2
1.2.2. Reductive Amination ..................................................................................................... 3
1.2.3. Coupling of Amines with Aryl Halides ......................................................................... 3
1.2.4. Hydroamination ............................................................................................................. 6
1.3. Application of Hydrogen-Borrowing Reaction .................................................................... 6
1.3.1 (S)-Rivastigmine ............................................................................................................. 6
1.3.2 NPS R-568 ...................................................................................................................... 7
1.3.3. Noranabasamine ............................................................................................................ 8
1.3.4. Cinnarizine................................................................................................................... 10
1.3.5. Nafetifine ..................................................................................................................... 10
1.3.6. Piribedil ....................................................................................................................... 11
1.3.7. Pyrilamine .................................................................................................................... 12
1.3.8. Saccharide Sensor ........................................................................................................ 12
1.3.9. Tigan and Itopride ....................................................................................................... 13
1.3.10. GlyT1 Inhibitor .......................................................................................................... 13
1.3.11. Pharmaceutically Relevant Intermediates ................................................................. 14
1.4. Reactivity of a Solvent and Base free Ruthenium Catalyst ............................................... 17
1.4.1. Design and Synthesis of Catalysts ............................................................................... 17
1.4.2. Scope of the Reaction .................................................................................................. 18
1.4.3. Mechanism................................................................................................................... 20
vi
1.5. Conclusion .......................................................................................................................... 25
1.6. References .......................................................................................................................... 27
Chapter 2. Ruthenium Catalyzed Tandem Amine Alkylation/Pictet-Spengler
Reaction to Access Tetrahydro-β-Carbolines ..........................................................32
2.1. Introduction ........................................................................................................................ 32
2.2. Optimization of Individual Steps in the Tandem Sequence ............................................... 34
2.2.1. Coupling of Tryptamine and Benzyl Alcohol ............................................................. 34
2.2.2. Cyclization of N-Benzylidinetryptamine to Tetrahydro-β-Carbolines ........................ 35
2.3. Optimization of the Tandem Sequence and Substrate Scope for Reactions from
Tryptamine ................................................................................................................................ 35
2.3.1. Optimization ................................................................................................................ 35
2.3.2. Substrate Scope............................................................................................................ 36
2.4. Optimization of the Tandem Sequence and Substrate Scope for Reactions from N-
Benzyltryptamine ...................................................................................................................... 37
2.4.1 Optimization ................................................................................................................. 37
2.4.2. Substrate Scope............................................................................................................ 38
2.4.3. Alcohols that are Bad Coupling Partners .................................................................... 39
2.4.4. Tandem PSR with Aliphatic Alcohols ......................................................................... 40
2.5. Deprotection of 2.6 to Free Amine 2.5............................................................................... 41
2.6. Other Catalyst Screening for Tandem PSR ........................................................................ 42
2.7. Mechanism for the Tandem Sequence ............................................................................... 43
2.8. Reaction of Tryptamine with Diols to Access Tetracyclic Alkaloids ................................ 46
2.8.1. Screening of Acid Catalysts ........................................................................................ 46
2.8.2. Exploring other Strategies to Access Tetracyclic Alkaloids ....................................... 48
2.9. Exploring Other Amine Substrates in Tandem PSR .......................................................... 50
2.10. Conclusion ........................................................................................................................ 53
2.11. References ........................................................................................................................ 54
Chapter 3. Synthesis of 1,4-Diazacycles from Diamines and Diols ........................58
3.1. Introduction ........................................................................................................................ 58
3.2. Optimization of the Homopiperazine Synthesis................................................................. 61
3.3. Substrate Scope .................................................................................................................. 62
3.3.1. Synthesis of Piperazines .............................................................................................. 62
3.3.2. Synthesis of 1,4-Diazepanes ........................................................................................ 63
vii
3.3.3. Reactions with Chiral Reagents ................................................................................... 67
3.4. Screening of Other Catalysts .............................................................................................. 69
3.5. Catalytic Poisoning ............................................................................................................ 70
3.6. Pharmaceutical Applications .............................................................................................. 72
3.7. Conclusion .......................................................................................................................... 72
3.8. References .......................................................................................................................... 74
Chapter 4. N-Alkylation of Guanidine Compounds by Hydrogen-Borrowing
Catalysis ...................................................................................................................77
4.1. Introduction ........................................................................................................................ 77
4.2. Substrate Scope .................................................................................................................. 80
4.2.1. N-Alkylation of Triazabicyclodecene with Primary Aliphatic Alcohols .................... 80
4.2.2. N-Alkylation of Triazabicyclodecene with Secondary Alcohols ................................ 81
4.2.3. N-Alkylation of Triazabicyclodecene with Benzylic Alcohols ................................... 82
4.2.4. Reaction in the Prescence of Multiple Nucleophilic and Electrophilic Centers .......... 82
4.2.5. N-Alkylation of 2-Aminobenzimidazole ..................................................................... 84
4.2.6. Reaction of Other Guanidine Substrates ..................................................................... 85
4.2.7. Cyclization of Guanidines with Diols ......................................................................... 87
4.3 Summary ............................................................................................................................. 88
4.4. References .......................................................................................................................... 90
Chapter 5. Miscellaneous Experiments ...................................................................92
5.1 Heterocycles from Amine/Diol Coupling ........................................................................... 92
5.2 N-Methylation by Hydrogen-Borrowing ............................................................................. 93
5.3. Iron Catalyzed Synthesis of N-Heterocycles ...................................................................... 94
5.4. Reference ............................................................................................................................ 96
Chapter 6. Experimental and Spectral Data .............................................................98
6.1. General Procedure .............................................................................................................. 98
6.2. Chapter 2 Experimental and Spectral Data ........................................................................ 99
6.2.1. Reactivity of Ruthenium Complex in the Coupling of Tryptamine and Benzyl
Alcohol .................................................................................................................................. 99
6.2.2. Catalyst Screening for the Pictet-Spengler Cyclization ............................................ 103
6.2.3. Substrate Scope for the Tandem Pictet-Spengler Cyclization from Tryptamine ...... 104
viii
6.2.4. Substrate Scope for the Tandem Pictet-Spengler Cyclization from N-
Benzyltryptamine................................................................................................................. 110
6.2.5. Tandem PSR with CF3COOH as the Acid Catalyst .................................................. 123
6.2.6. Tandem PSR with Aliphatic Alcohols ....................................................................... 123
6.2.7. Studies to Probe the Mechanism of Reactions Starting from Tryptamine ................ 125
6.2.8. Studies to Probe the Mechanism of Reactions Starting from N-Benzyltryptamine .. 128
6.2.9. H/D Scrambling Experiment to Probe the Equilibrium between N-
Benzylidenetryptamine and N-Benzyltryptamine ............................................................... 134
6.2.10. Reaction of Tryptamine with 1,4-Butanediol .......................................................... 138
6.2.11. Reaction of Tryptamine with 1,5-Pentanediol ......................................................... 142
6.2.12. Exploring Other Strategies to Access Tetracyclic Alkaloids .................................. 143
6.2.13. NMR Spectra ........................................................................................................... 147
6.2.14. References ............................................................................................................... 170
6.3. Chapter 3 Experimental and Spectral Data ...................................................................... 172
6.3.1. Optimization of the Homopiperazine Synthesis ........................................................ 172
6.3.2. Synthesis of Diamine Substrates ............................................................................... 174
6.3.3. Substrate Scope.......................................................................................................... 189
6.3.4. Other Interesting Substrates through Diamine-Diol Coupling .................................. 202
6.3.5. Three Carbon Diamine/Two Carbon Diol Coupling Vs Two Carbon
Diamine/Three Carbon Diol Coupling ................................................................................ 206
6.3.6. Intramolecular Vs Intermolecular Cyclization .......................................................... 207
6.3.7. Synthesis of 9-Membered Diazacycles ...................................................................... 208
6.3.8. Scope Limitation........................................................................................................ 211
6.3.9 Reaction of Complex C4 with Ethylenediamine ........................................................ 213
6.3.10. Reaction of Three Carbon Diamine with Diols ....................................................... 215
6.3.11. Catalyst Screening ................................................................................................... 217
6.3.12. Exploring Synthesis of Dilazep and Homofenazine ................................................ 218
6.3.13. Homocoupling of Amino Alcohols to Access Diazacycles ..................................... 227
6.3.14. Cross-coupling of Amino Alcohols to Access Diazacycles .................................... 227
6.3.15. Reaction of Diamines with Allylic Alcohols, and α,β-Unsaturated Carbonyl
Compounds .......................................................................................................................... 229
6.3.16. NMR Spectra ........................................................................................................... 230
6.3.17. Crystal Description .................................................................................................. 265
ix
6.3.18. References ............................................................................................................... 269
6.4. Chapter 4 Experimental and Spectral Data ...................................................................... 271
6.4.1. General Procedure ..................................................................................................... 271
6.4.2. Substrate Scope.......................................................................................................... 271
6.4.3. References ................................................................................................................. 309
x
List of Tables
Table 2.1. Coupling of Benzyl Alcohol with Tryptamine............................................................ 34
Table 2.2. Screening of Lewis acid Catalysts. ............................................................................. 35
Table 2.3. Optimization of the Tandem Sequence. ...................................................................... 36
Table 2.4. Substrate Scope for Tandem Pictet-Spengler Reaction of Tryptamine with Benzylic
Alcohols. ....................................................................................................................................... 37
Table 2.5. Optimization of Tandem Pictet-Spengler Reaction of N-Benzyltryptamine with
Benzylic Alcohols. ........................................................................................................................ 38
Table 2.6. Substrate Scope for the Tandem Sequence. ................................................................ 39
Table 2.7. Optimization of Tandem PSR with Aliphatic Alcohols. ............................................. 41
Table 2.8. Screening of Catalysts for N-Benzyl Deprotection of 2.6........................................... 42
Table 2.9. Substituting MgSO4 for In(OTf)3 in the Tandem Sequence. ...................................... 45
Table 2.10. Screening of Bronsted Acid Catalysts....................................................................... 47
Table 2.11. Screening of Solvents. ............................................................................................... 47
Table 2.12. Coupling of Homoveratrylamine with Alcohols. ...................................................... 52
Table 2.13. Coupling of N-Benzylhomoveratrylamine with Alcohols. ....................................... 53
Table 3.1. Optimization of the Homopiperazine Synthesis. ........................................................ 61
Table 3.2. Substrate Scope for Piperazine Synthesis. .................................................................. 63
Table 3.3. Substrate Scope. .......................................................................................................... 66
Table 3.4. Reaction of 3.1b with 1,3-Propanediol. ...................................................................... 68
Table 5.1. Reaction of Amines with Diols. .................................................................................. 93
Table 5.2. Methylation of Amines. .............................................................................................. 94
Table 5.3. Screening of Iron Sources and Diamines for Piperazine Synthesis. ........................... 95
Table 6.2.1. Tandem Pictet Spengler Reaction with CF3COOH as the Acid Catalyst. ............. 123
Table 6.2.2. Optimization Studies for One Step Synthesis of Harmicine. ................................. 140
Table 6.2.3. Coupling of Monoprotected Diols with Tryptamine. ............................................. 145
Table 6.2.4. Coupling of Dihydropyran with Tryptamine. ........................................................ 146
Table 6.3.1. Synthesis of Simple Diamine Substrates................................................................ 175
Table 6.3.2. Synthesis of Substituted Diamine Substrates. ........................................................ 179
Table 6.3.3. Synthesis of Substituted Diimines and Diamines. ................................................. 186
Table 6.3.4. Coupling between 3.1c and Ethylene Glycol. ........................................................ 207
Table 6.3.5. Coupling between 3.1c and 1,3-Propanediol. ........................................................ 208
Table 6.3.6. Reaction of N,N’-Dibenzylethylenediamine and 1,5-Pentaneanediol. ................... 209
Table 6.3.7: Screening of Different Hydrogen-Borrowing Catalysts for 1,4-Diazepane
Synthesis. .................................................................................................................................... 217
Table 6.3.8. Reaction of Phenothiazine 3.35 with Acryloyl Chloride. ...................................... 224
Table 6.3.9. Reaction of 3.39 with Amines. ............................................................................... 224
Table 6.3.10. Reaction of 3.35 with 1,3-Dihalopropane. ........................................................... 226
Table 6.3.11. Homocoupling of Amino Alcohols. ..................................................................... 227
Table 6.3.12. Cross-coupling of Amino Alcohols. .................................................................... 228
xi
List of Schemes
Scheme 1.1. N-Alkylation by Hydrogen-Borrowing. ..................................................................... 2
Scheme 1.2. Alkylation of Amines with Halides. .......................................................................... 2
Scheme 1.3. Reductive Amination. ................................................................................................ 3
Scheme 1.4. Buchwald-Hartwig Amination. .................................................................................. 4
Scheme 1.5. Ullman Amine Synthesis. .......................................................................................... 5
Scheme 1.6. Multi-Component Petasis Reaction. .......................................................................... 5
Scheme 1.7. Hydroamination of Alkene. ....................................................................................... 6
Scheme 1.8. Synthesis of (S)-Rivastigmine. .................................................................................. 7
Scheme 1.9. Synthesis of NPS R-568. ........................................................................................... 8
Scheme 1.10. Synthesis of Noranabasamine. ................................................................................. 9
Scheme 1.11. Synthesis of Cinnarizine. ....................................................................................... 10
Scheme 1.12. Synthesis of Nafetifine........................................................................................... 10
Scheme 1.13. Synthesis of Piribedil. ............................................................................................ 11
Scheme 1.14. Synthesis of Catalyst C3. ....................................................................................... 12
Scheme 1.15. Synthesis of Pyrilamine. ........................................................................................ 12
Scheme 1.16. Synthesis of a Saccharide Sensor 1.13................................................................... 13
Scheme 1.17. Synthesis of Tigan and Itopride. ............................................................................ 13
Scheme 1.18. Scale-up Preparation of Pharmaceutical Intermediate 1.14. .................................. 14
Scheme 1.19. Role of Amino Alcohol 1.17 in the Synthesis of API 1.18. .................................. 15
Scheme 1.20. N-Methylation Routes to Amino Alcohol 1.17. ..................................................... 15
Scheme 1.21. Previous Route to Intermediate 1.22. ..................................................................... 16
Scheme 1.22. Hydrogen-Borrowing Route to Intermediate 1.22. ................................................ 16
Scheme 1.23. Synthesis of Complex C4 and C5.......................................................................... 18
Scheme 1.24. Scope of C4 catalyzed Reaction between Amines and Alcohols. ......................... 20
Scheme 1.25. Proposed Mechanism for C4 Catalyzed Amine/Alcohol Coupling....................... 21
Scheme 1.26. Precatalyst Activation and Death. .......................................................................... 24
Scheme 2.1. Proposed Mechanisms for the Tandem Sequence. .................................................. 43
Scheme 2.2. Deuterium Labeling Experiment. ............................................................................ 45
Scheme 2.3. Reaction of Tryptamine with Diols in the Presence of In(OTf)3. ............................ 46
Scheme 2.4. One-Step Synthesis of Harmicine. ........................................................................... 48
Scheme 2.5. Proposed Mechanism for the Reaction of Tryptamine with 1,4-Butanediol. .......... 49
Scheme 2.6. Synthesis of Compound B. ..................................................................................... 49
Scheme 2.7. Cyclization of Compound B. .................................................................................. 50
Scheme 2.8. Proposed Synthetic Strategy to Tetracyclic Alkaloid from DHP. .......................... 50
Scheme 3.1. Synthesis of 1,4-Diazepane A) from Three Carbon Diamine and Two Carbon Diol
B) from Two Carbon Diamine and Three Carbon Diol. ............................................................... 64
Scheme 3.2. Synthesis of Complex 3.12. ..................................................................................... 71
Scheme 3.3. Pharmaceutical Application: Synthesis of Cyclizine and Homochlorcyclizine. ..... 72
Scheme 4.1. Previous Work and Proposed Strategy for N-Alkylation of Guanidines. ................ 79
Scheme 4.2. Substrate Scope for the Reaction of TBD with Primary Aliphatic Alcohols. ......... 81
Scheme 4.3. Substrate Scope for the Reaction of TBD with Secondary Alcohols. ..................... 81
xii
Scheme 4.4. Substrate Scope for the Reaction of TBD with Benzyl Alcohols. ........................... 82
Scheme 4.5. Reaction of TBD with Alcohols Bearing an Amino Group.
a
.................................. 83
Scheme 4.6. Reaction of TBD with Alcohols Bearing Multiple Electrophilic Centers. .............. 84
Scheme 4.7. Substrate Scope for the Reaction of 2-Aminobenzimidazole with Alcohols. ......... 85
Scheme 4.8. Reaction that Shows the Effect of 2-Guanidinibenzimidazole on Catalyst
Poisoning....................................................................................................................................... 85
Scheme 4.9. Reaction of Guanidine 4.15 with Benzaldehyde. .................................................... 86
Scheme 4.10. Reaction of Guanidine 20 with Benzyl Alcohol.
a
.................................................. 87
Scheme 4.11. Reaction of Guanidine 21 with Benzyl Alcohol. ................................................... 87
Scheme 4.12. Cyclization of Guanidine 4.20 with Ethylene Glycol. ........................................... 88
Scheme 4.13. Cyclization of Guanidine 4.26 with Ethylene Glycol. ........................................... 88
Scheme 4.14. Cyclization of Guanidine 4.20 with 1,3-Propanediol. ........................................... 88
Scheme 6.2.1. Proposed Mechanism for the Reaction of N-benzyltryptamine with
Benzoquinone. ............................................................................................................................ 124
Scheme 6.2.2. Reaction of 2.4 and 2.5 to Probe the Mechanism of Tandem PSR Sequence
Starting from Tryptamine. .......................................................................................................... 125
Scheme 6.3.1. Synthesis of 3.1n................................................................................................. 183
Scheme 6.3.2. Synthesis of 3.1o. ................................................................................................ 184
Scheme 6.3.3. Synthesis of 3.1p................................................................................................. 185
Scheme 6.3.4. Synthesis of 1,4-Diazacycles. ............................................................................. 189
Scheme 6.3.5. Coupling between Substituted Diamine and Substituted Diol............................ 201
Scheme 6.3.6. Coupling between N,N’-Dibenzylethylenediamine and 1,4-Butanediol. ........... 202
Scheme 6.3.7. Coupling between N,N’-Dibenzylethylenediamine and 1,2-
Benzenedimethanol. .................................................................................................................... 204
Scheme 6.3.8. 1,4-Diazepane Synthesis from Two Carbon Diol Vs Three Carbon Diol .......... 207
Scheme 6.3.9. Reaction of N,N’-Dibenzyl-1,3-propanediamine and 1,4-Butanediol. ............... 208
Scheme 6.3.10. Reactions to Probe the Scope Limitation Factor. ............................................. 212
Scheme 6.3.11. Coupling between N-Methylethylenediamine (3.13c) and Ethylene Glycol
(3.4a). .......................................................................................................................................... 215
Scheme 6.3.12. Previous Route to Dilazep. ............................................................................... 219
Scheme 6.3.13. Retrosynthesis of Dilazep through Hydrogen-Borrowing Strategy. ................. 219
Scheme 6.3.14. Synthesis of 3-Hydroxypropyl 3,4,5-trimethoxybenzoate. ............................... 220
Scheme 6.3.15. Reaction of Homopiperazine with 3-Hydroxypropyl 3,4,5-
trimethoxybenzoate. .................................................................................................................... 220
Scheme 6.3.16. Reported Synthesis of Homofenazine. .............................................................. 221
Scheme 6.3.17. Retrosynthetic Strategy 1 to Access Homofenazine. ........................................ 222
Scheme 6.3.18. Retrosynthetic Strategy 2 to Access Homofenazine. ........................................ 223
Scheme 6.3.19. Proposed Synthetic Route 3 to Access Homofenazine. .................................... 226
Scheme 6.3.20. Reaction of N,N’-Dibenzylpropanediamine with allyl alcohol, and methyl
vinyl ketone. ................................................................................................................................ 229
Scheme 6.4.1. Reaction of TBD with n-Butanol. ....................................................................... 271
Scheme 6.4.2. Reaction of TBD with 1-Octanol. ....................................................................... 272
Scheme 6.4.3. Reaction of TBD with 1-Hexadecanol................................................................ 274
xiii
Scheme 6.4.4. Reaction of TBD with Cyclobutanemethanol. .................................................... 275
Scheme 6.4.5. Reaction of TBD with 1-Adamantanemethanol. ................................................ 277
Scheme 6.4.6. Reaction of TBD with Furfuryl Alcohol. ............................................................ 278
Scheme 6.4.7. Reaction of TBD with Cyclopentanol. ............................................................... 280
Scheme 6.4.8. Reaction of TBD with Cyclohexanol.................................................................. 281
Scheme 6.4.9. Reaction of TBD with 2-Butanol. ....................................................................... 283
Scheme 6.4.10. Reaction of TBD with Benzyl Alcohol............................................................. 284
Scheme 6.4.11. Reaction of TBD with Benzyl Alcohol............................................................. 286
Scheme 6.4.12. Reaction of TBD with 1-Phenylethanol. ........................................................... 287
Scheme 6.4.13. Reaction of TBD with 1-(4-Methylphenyl)ethanol. ......................................... 289
Scheme 6.4.14. Reaction of TBD with 1-(4-Methoxyphenyl)ethanol. ...................................... 291
Scheme 6.4.15. Reaction of TBD with 3-(Methylamino)propan-1-ol. ...................................... 292
Scheme 6.4.16. Reaction of TBD with 2-Aminobenzyl Alcohol. .............................................. 293
Scheme 6.4.17. Reaction of TBD with 2,3-Butanediol. ............................................................. 294
Scheme 6.4.18. Reaction of TBD with 3-Chloro-1,2-propanediol............................................. 296
Scheme 6.4.19. Reaction of TBD with 8-Chloro-1-octanol. ...................................................... 297
Scheme 6.4.20. Reaction of 2-Aminobenzimidazole with n-Butanol. ....................................... 298
Scheme 6.4.21. Reaction of 2-Aminobenzimidazole with Cyclopentanol. ................................ 299
Scheme 6.4.22. Reaction of 2-Aminobenzimidazole with Cyclohexanol. ................................. 300
Scheme 6.4.23. Reaction of 2-Aminobenzimidazole with Benzyl Alcohol. .............................. 301
Scheme 6.4.24. Reaction of Guanidine 4.15 with Benzaldehyde. ............................................. 302
Scheme 6.4.25. Reaction of Guanidine 4.19 with Benzyl Alcohol. ........................................... 303
Scheme 6.4.26. Reaction of Guanidine 4.20 with Benzyl Alcohol. ........................................... 304
Scheme 6.4.27. Cyclization of Guanidine 4.20 with Ethylene Glycol. ...................................... 305
Scheme 6.4.28. Cyclization of Guanidine 4.20 with 1,3-Propanediol. ...................................... 307
xiv
List of Figures
Figure 1.1. Noranabasamine and plant derived alkaloids .............................................................. 8
Figure 1.2.
13
C NMR of the coupling of benzyl alcohol-d1 and n-hexylamine at 110 °C (A)
after 2 h stirring and (B) after 24 h stirring under neat reaction conditions. The deuterated
carbons appear as 3-line patterns immediately upfield of the corresponding nondeuterated
singlets. ......................................................................................................................................... 22
Figure 2.1. A) Proposed synthesis of THBCs. B) Examples of pharmaceutically relevant
THBCs. ......................................................................................................................................... 33
Figure 2.2. List of alcohols that didn’t show tandem PSR product
a
. ........................................... 40
Figure 2.3. A) Other amine-alkylation catalysts with the condition used for screening. ............. 43
Figure 3.1. Examples of 1,4-diazacycles in drugs. ...................................................................... 59
Figure 3.2. Previous work and proposed hydrogen borrowing strategy to access 1,4-
diazacycles. ................................................................................................................................... 60
Figure 3.3. Thermal ellipsoid plot of 3.3k. Counter ions and hydrogens are omitted for clarity. 65
Figure 3.4.
1
H NMR spectrum of reaction of 3.1b and 1,3-propanediol with 3 mol % C4 at
110
o
C in neat condition for 44 h after passing through a silica column in hexanes: ethyl
acetate (80:20). .............................................................................................................................. 68
Figure 3.5. LC-QTOF spectrum of reaction of 3.1b and 1,3-propanediol with 3 mol % C4 at
110
o
C in neat condition for 44 h after passing through a silica column in hexanes: ethyl
acetate (80:20). which shows desired product (3.5b') peaks at 335.2526 (M+H)
+
. .................... 69
Figure 3.6. Thermal ellipsoid plots of complex 3.12 Counter ions and hydrogens are omitted
for clarity. ...................................................................................................................................... 71
Figure 4.1. Representative examples of important compounds with guanidine moiety. ............. 78
Figure 4.2. Guanidine substrates. ................................................................................................. 86
Figure 4.3. Guanidine substrates screened in the coupling with ethylene glycol. ....................... 88
Figure 5.1. Structure of ruthenium complex C4. ......................................................................... 92
Figure 6.2.1.
1
H NMR spectrum of the crude reaction mixture for the coupling of tryptamine
and benzyl alcohol at 110 °C in neat, closed flask conditions; 2.3 is observed as product.
Peaks at 4.63 and 1.55 correspond to benzyl alcohol. ................................................................ 100
Figure 6.2.2.
1
H NMR spectrum of the crude reaction mixture for the coupling of tryptamine
and benzyl alcohol under a stream of N2 gas at 110 °C in neat, open flask conditions; 2.3 and
2.4 are observed as products. ...................................................................................................... 101
Figure 6.2.3.
1
H NMR of the crude reaction mixture for the coupling of tryptamine and
benzyl alcohol under a stream of N2 gas at 120 °C in toluene, open flask conditions; 2.4 is
observed as product. The peak at 4.7 ppm corresponds to the CH2 group in the starting benzyl
alcohol. ........................................................................................................................................ 102
Figure 6.2.4.
1
H NMR spectrum of the mixture obtained after flash chromatography in
90:10 hexanes:EtOAc for the reaction of N-benzylidenetryptamine with 4-fluorobenzyl
alcohol after 2 days; 2.5b' and 2.3b' together constitute 38% yield. .......................................... 126
Figure 6.2.5.
1
H NMR of the crude reaction mixture for the reaction of 10 with benzyl
alcohol at 110 °C. ........................................................................................................................ 128
xv
Figure 6.2.6.
1
H NMR of the crude reaction mixture for the reaction of N-benzyltryptamine
and benzyl alcohol at 110 °C without In(OTf)3. ......................................................................... 129
Figure 6.2.7.
1
H NMR of the crude reaction mixture for the reaction of N-benzyltryptamine
and 4-bromobenzyl alcohol with 1 equivalent anhydrous MgSO4. ............................................ 130
Figure 6.2.8.
13
C NMR spectrum of the isolated product for the reaction of N-
benzyltryptamine and 4-fluorobenzyl alcohol; C1, C2, C3 and C4 appear as doublets due to
13
C-
19
F coupling. ......................................................................................................................... 132
Figure 6.2.9. HMBC spectrum of the isolated product for the reaction of N-benzyltryptamine
and 4-fluorobenzyl alcohol; C3, C4, and C6 shows correlation with H5; thus, identity of the
product is confirmed as 2.7b. ...................................................................................................... 133
Figure 6.2.10.
1
H NMR of the crude reaction mixture for the reaction of tryptamine and
benzyl alcohol with 1 equivalent anhydrous MgSO4. Compound 2.6 is formed in 20% NMR
yield............................................................................................................................................. 134
Figure 6.2.11.
13
C spectrum of 2.1-d3; doubly deuterated carbon appears as a quintet in the
spectrum. ..................................................................................................................................... 135
Figure 6.2.12.
1
H spectrum of 2.6-d1. ........................................................................................ 137
Figure 6.2.13.
13
C spectrum of 2.6-d1. ....................................................................................... 137
Figure 6.2.14.
2
H spectrum of 2.6-d1. ........................................................................................ 138
Figure 6.2.15.
1
H NMR spectrum of the crude reaction mixture for the coupling of
tryptamine with 1,4-butanediol; 2.8 and 2.9 are observed as products....................................... 139
Figure 6.2.16.
1
H NMR spectrum of the crude reaction mixture for the coupling of
tryptamine with 1,5-butanediol; Peaks (t) at 2.97 (merges with the tetracyclic alkaloid) and
3.61 belongs to 2.9. ..................................................................................................................... 143
Figure 6.2.17.
1
H NMR (500 MHz) spectrum of N-benzylidenetryptamine at 25 °C in CDCl3. 147
Figure 6.2.18.
13
C NMR (126 Hz) spectrum of N-benzylidenetryptamine at 25 °C in CDCl3. . 147
Figure 6.2.19.
1
H NMR (500 MHz) spectrum of 2.6 at 25 °C in CD2Cl2. ................................. 148
Figure 6.2.20.
13
C NMR (126 MHz) spectrum of 2.6 at 25 °C in CD2Cl2. ................................ 148
Figure 6.2.21.
1
H NMR (600 MHz) spectrum of 2.6b at 25 °C in CDCl3. ................................ 149
Figure 6.2.22.
13
C NMR (151 MHz) spectrum of 2.6b at 25 °C in CDCl3. ............................... 149
Figure 6.2.23.
19
F NMR (564 MHz) spectrum of 2.6b at 25 °C in CDCl3. ............................... 150
Figure 6.2.24.
1
H NMR (500 MHz) spectrum of 2.6c at 25 °C in CDCl3. ................................. 150
Figure 6.2.25.
13
C NMR (126 MHz) spectrum of 2.6c at 25 °C in CDCl3. ............................... 151
Figure 6.2.26.
1
H NMR (500 MHz) spectrum of 2.6d at 25 °C in CDCl3. ................................ 151
Figure 6.2.27.
13
C NMR (126 MHz) spectrum of 2.6d at 25 °C in CDCl3. ............................... 152
Figure 6.2.28.
1
H NMR (600 MHz) spectrum of 2.6e at 25 °C in CDCl3. ................................. 152
Figure 6.2.29.
13
C NMR (151 MHz) spectrum of 2.6e at 25 °C in CDCl3. ............................... 153
Figure 6.2.30.
1
H NMR (600 MHz) spectrum of 2.6f at 25 °C in CDCl3. ................................. 153
Figure 6.2.31.
13
C NMR (151 MHz) spectrum of 2.6f at 25 °C in CDCl3. ................................ 154
Figure 6.2.32.
1
H NMR (400 MHz) spectrum of N-benzyltryptamine (2.3) at 25 °C in CDCl3. 154
Figure 6.2.33.
13
C NMR (101 MHz) spectrum of N-benzyltryptamine (2.3) at 25 °C in CDCl3.
..................................................................................................................................................... 155
Figure 6.2.34.
1
H NMR (500 MHz) spectrum of 2.7b at 25 °C in CDCl3. ................................ 155
Figure 6.2.35.
13
C NMR (126 MHz) spectrum of 2.7b at 25 °C in CDCl3. ............................... 156
xvi
Figure 6.2.36.
1
H NMR (500 MHz) spectrum of 2.7c at 25 °C in CDCl3. ................................. 156
Figure 6.2.37.
13
C NMR (151 MHz) spectrum of 2.7c at 25 °C in CDCl3. ............................... 157
Figure 6.2.38.
1
H NMR (500 MHz) spectrum of 2.7d at 25 °C in CDCl3. ................................ 157
Figure 6.2.39.
13
C NMR (126 MHz) spectrum of 2.7d at 25 °C in CDCl3. ............................... 158
Figure 6.2.40.
1
H NMR (500 MHz) spectrum of 2.7e at 25 °C in CDCl3. ................................. 158
Figure 6.2.41.
13
C NMR (126 MHz) spectrum of 2.7e at 25 °C in CDCl3. ............................... 159
Figure 6.2.42.
1
H NMR (500 MHz) spectrum of 2.7f at 25 °C in CDCl3. ................................. 159
Figure 6.2.43.
13
C NMR (126 MHz) spectrum of 2.7f at 25 °C in CDCl3. ................................ 160
Figure 6.2.44.
1
H NMR (600 MHz) spectrum of 2.7g at 25 °C in CDCl3. ................................ 160
Figure 6.2.45.
13
C NMR (151 MHz) spectrum of 2.7g at 25 °C in CDCl3. ............................... 161
Figure 6.2.46.
1
H NMR (600 MHz) spectrum of 2.7h at 25 °C in CDCl3. ................................ 161
Figure 6.2.47.
13
C NMR (151 MHz) spectrum of 2.7h at 25 °C in CDCl3. ............................... 162
Figure 6.2.48.
1
H NMR (500 MHz) spectrum of 2.7i at 25 °C in CDCl3. .................................. 162
Figure 6.2.49.
13
C NMR (126 MHz) spectrum of 2.7i at 25 °C in CDCl3. ................................ 163
Figure 6.2.50.
1
H NMR (600 MHz) spectrum of 2.7j at 25 °C in CDCl3. ................................. 163
Figure 6.2.51.
13
C NMR (151 MHz) spectrum of 2.7j at 25 °C in CDCl3. ................................ 164
Figure 6.2.52.
1
H NMR (600 MHz) spectrum of 2.7k at 25 °C in CDCl3. ................................ 164
Figure 6.2.53.
13
C NMR (151 MHz) spectrum of 2.7k at 25 °C in CDCl3. ............................... 165
Figure 6.2.54.
1
H NMR (500 MHz) spectrum of 2.7l at 25 °C in CDCl3. .................................. 165
Figure 6.2.55.
1
H NMR (500 MHz) spectrum of 2.5 at 25 °C in CDCl3. ................................... 166
Figure 6.2.56.
13
C NMR (126 MHz) spectrum of 2.5 at 25° C in CD2Cl2. ................................ 166
Figure 6.2.57.
1
H NMR spectrum of 2.8 at 25 °C in CDCl3. ...................................................... 167
Figure 6.2.58.
13
C NMR spectrum of 2.8 at 25° C in CDCl3. .................................................... 167
Figure 6.2.59.
1
H NMR (400 MHz) spectrum of 2.9 at 25 °C in CDCl3. .................................. 168
Figure 6.2.60.
1
H NMR (400 MHz) spectrum of 2.11 at 25 °C in CDCl3. ................................ 168
Figure 6.2.61.
1
H NMR (500 MHz) spectrum of 2.12 at 25 °C in CDCl3. ................................ 169
Figure 6.2.62.
1
H NMR (500 MHz) spectrum of 2.13 at 25 °C in CDCl3. ................................ 169
Figure 6.3.1.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-
dibenzylethylenediamine (1equiv) and 1,3-propanediol (4 equiv) with 1 mol % C4 for 44 h. .. 172
Figure 6.3.2. LC-QTOF spectrum of the crude reaction mixture for the coupling of N,N’-
dibenzylethylenediamine (1equiv) and 1,3-propanediol (4 equiv) with 1 mol % C4 for 44 h. . 173
Figure 6.3.3.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-
dimethylethylenediamine (2 equiv) and 1,3-propanediol (1 equiv) with 1 mol % C4 for 44 h.
The peaks at 2.33 ppm and 2.67 ppm belongs to the excess starting diamine............................ 196
Figure 6.3.4.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-
diisopropyl-1,3-propanediamine (1 equiv) and ethylene glycol (2 equiv) with 1 mol % C4
for 44 h. ....................................................................................................................................... 197
Figure 6.3.5.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-
dibenzyl-ethylenediamine (1 equiv) and 1,4-butanediol (2 equiv) with 1 mol % C4 for 44 h. .. 203
Figure 6.3.6. LC-QTOF spectra of the crude reaction mixture for the coupling of N,N’-
dibenzyl-ethylenediamine (1 equiv) and 1,4-butanediol (2 equiv) with 1 mol % C4 for 44 h. .. 204
xvii
Figure 6.3.7.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-
dibenzyl-ethylenediamine (1 equiv) and 1,2-benzenedimethanol (2 equiv) with 2 mol % C4
for 44 h. ....................................................................................................................................... 205
Figure 6.3.8. LC-QTOF spectrum of the crude reaction mixture for the coupling of N,N’-
dibenzyl-ethylenediamine (1equiv) and 1,2-benzenedimethanol (2 equiv) with 2 mol % C4
for 44 h. Peak at 247.17 belongs to the starting diamine. ........................................................... 206
Figure 6.3.9.
1
H NMR spectrum of reaction of 3.1a and 1,5-pentaneanediol with 3 mol % C4
at 110
o
C in neat condition for 44 h after passing through a silica column in dichloromethane:
methanol. Spectrum shows mixture of 3.27 and 1,5-pentanediol. .............................................. 209
Figure 6.3.10. LC-QTOF spectra of reaction of 3.1d and 1.4-butanediol (top two spectra),
which shows desired product peaks at 309.2327 (M+H)
+
and 327.2432 (M+H2O+H)
+
along
with the starting amine peak at 255.1858 (M+H)
+
, and reaction of 3.1a and 1,5-pentanediol
(bottom spectrum) which shows desired peak at 327.2432 (M+H2O+H)
+
along with starting
amine peak at 241.1700 (M+H)
+
. ............................................................................................... 210
Figure 6.3.11. List of diamines and diols that became unreactive or provide complex
mixture under our catalytic condition. ........................................................................................ 212
Figure 6.3.12. Stacked
1
H NMR spectrum of the crude reaction mixture for reaction
between complex C4 and ethylenediamine. ............................................................................... 214
Figure 6.3.13. Stacked
31
P NMR spectrum of the crude reaction mixture for reaction
between complex C4 and ethylenediamine. ............................................................................... 214
Figure 6.3.14: Mass spectra of reaction of 3.13c with 3.4a at 0.25% C4. ................................. 216
Figure 6.3.15: Mass spectra of reaction of 3.13c with 3.4a at 3.0 mol % C4............................ 216
Figure 6.3.16.
1
H NMR (500 MHz) spectrum of 3.1b at 25 °C in CDCl3. ................................ 230
Figure 6.3.17.
13
C NMR (151 MHz) spectrum of 3.1b at 25 °C in CDCl3. ............................... 230
Figure 6.3.18.
1
H NMR (600 MHz) spectrum of 3.1b' at 25 °C in CDCl3. ............................... 231
Figure 6.3.19.
13
C NMR (151 MHz) spectrum of 3.1b' at 25 °C in CDCl3. .............................. 231
Figure 6.3.20.
1
H NMR (600 MHz) spectrum of 3.1c at 25 °C in CDCl3. ................................ 232
Figure 6.3.21.
13
C NMR (151 MHz) spectrum of 3.1c at 25 °C in CDCl3. ............................... 232
Figure 6.3.22.
1
H NMR (600 MHz) spectrum of 3.1f at 25 °C in CDCl3. ................................. 233
Figure 6.3.23.
13
C NMR (151 MHz) spectrum of 3.1f at 25 °C in CDCl3. ................................ 233
Figure 6.3.24.
1
H NMR (400 MHz) spectrum of 3.1g at 25 °C in CDCl3. ................................ 234
Figure 6.3.25.
1
H NMR (500 MHz) spectrum of 3.1j at 25 °C in CDCl3. ................................. 234
Figure 6.3.26.
13
C NMR (126 MHz) spectrum of 3.1j at 25 °C in CDCl3. ................................ 235
Figure 6.3.27.
1
H NMR (400 MHz) spectrum of 3.1k at 25 °C in CDCl3. ................................ 235
Figure 6.3.28.
13
C NMR (126 MHz) spectrum of 3.1k at 25 °C in CDCl3. ............................... 236
Figure 6.3.29.
1
H NMR (500 MHz) spectrum of 3.1e at 25 °C in CDCl3. ................................ 236
Figure 6.3.30.
13
C NMR (151 MHz) spectrum of 3.1e at 25 °C in CDCl3. ............................... 237
Figure 6.3.31.
1
H NMR (600 MHz) spectrum of 3.1l at 25 °C in CDCl3. ................................. 237
Figure 6.3.32.
13
C NMR (151 MHz) spectrum of 3.1l at 25 °C in CDCl3. ................................ 238
Figure 6.3.33.
1
H NMR (500 MHz) spectrum of 3.1m at 25 °C in CDCl3. ............................... 238
Figure 6.3.34.
13
C NMR (151 MHz) spectrum of 3.1m at 25 °C in CDCl3. .............................. 239
Figure 6.3.35.
1
H NMR (600 MHz) spectrum of 3.1n at 25 °C in CD3OD. .............................. 239
Figure 6.3.36.
13
C NMR (151 MHz) spectrum of 3.1n at 25 °C in CD3OD. ............................. 240
xviii
Figure 6.3.37.
1
H NMR (600 MHz) spectrum of 3.1o at 25 °C in CDCl3. ................................ 240
Figure 6.3.38.
13
C NMR (151 MHz) spectrum of 3.1o at 25 °C in CDCl3. ............................... 241
Figure 6.3.39.
1
H NMR (600 MHz) spectrum of 3.1p at 25 °C in CDCl3. ................................ 241
Figure 6.3.40.
13
C NMR (151 MHz) spectrum of 3.1p at 25 °C in CDCl3. ............................... 242
Figure 6.3.41.
1
H NMR (600 MHz) spectrum of 3.19a at 25 °C in CDCl3. .............................. 242
Figure 6.3.42.
13
C NMR (151 MHz) spectrum of 3.19a at 25 °C in CDCl3. ............................. 243
Figure 6.3.43.
1
H NMR (600 MHz) spectrum of 3.1q at 25 °C in CDCl3. ................................ 243
Figure 6.3.44.
13
C NMR (151 MHz) spectrum of 3.1q at 25 °C in CDCl3. ............................... 244
Figure 6.3.45.
1
H NMR (600 MHz) spectrum of 3.19i at 25 °C in CDCl3. ............................... 244
Figure 6.3.46.
1
H NMR (600 MHz) spectrum of 3.1r at 25 °C in CDCl3. ................................ 245
Figure 6.3.47.
13
C NMR (151 MHz) spectrum of 3.1r at 25 °C in CDCl3. ............................... 245
Figure 6.3.48.
1
H NMR (600 MHz) spectrum of 3.5a at 25 °C in CDCl3. ................................ 246
Figure 6.3.49.
13
C NMR (151 MHz) spectrum of 3.5a at 25 °C in CDCl3. ............................... 246
Figure 6.3.50.
1
H NMR (400 MHz) spectrum of 3.5b at 25 °C in CDCl3. ................................ 247
Figure 6.3.51.
13
C NMR (151 MHz) spectrum of 3.5b at 25 °C in CDCl3. ............................... 247
Figure 6.3.52.
1
H NMR (400 MHz) spectrum of (±)-(4aR,8aR)-1,4-
dibenzyldecahydroquinoxaline at 25 °C in CDCl3. .................................................................... 248
Figure 6.3.53.
13
C NMR (151 MHz) spectrum of (±)-(4aR,8aR)-1,4-
dibenzyldecahydroquinoxaline at 25 °C in CDCl3. .................................................................... 248
Figure 6.3.54.
1
H NMR (500 MHz) spectrum of 3.5c at 25 °C in CDCl3. ................................ 249
Figure 6.3.55.
13
C NMR (126 MHz) spectrum of 3.5c at 25 °C in CDCl3. ............................... 249
Figure 6.3.56.
1
H NMR (400 MHz) spectrum of 3.3a at 25 °C in CDCl3. ................................ 250
Figure 6.3.57.
13
C NMR (151 MHz) spectrum of 3.3a at 25 °C in CDCl3. ............................... 250
Figure 6.3.58.
1
H NMR (600 MHz) spectrum of 3.3b at 25 °C in CDCl3. ................................ 251
Figure 6.3.59.
13
C NMR (151 MHz) spectrum of 3.3b at 25 °C in CDCl3. ............................... 251
Figure 6.3.60.
1
H NMR (600 MHz) spectrum of 3.3c at 25 °C in CDCl3. ................................ 252
Figure 6.3.61.
13
C NMR (151 MHz) spectrum of 3.3c at 25 °C in CDCl3. ............................... 252
Figure 6.3.62.
1
H NMR (600 MHz) spectrum of 3.3d at 25 °C in CDCl3. ................................ 253
Figure 6.3.63.
13
C NMR (151 MHz) spectrum of 3.3d at 25 °C in CDCl3. ............................... 253
Figure 6.3.64.
1
H NMR (600 MHz) spectrum of 3.3e at 25 °C in CDCl3. ................................ 254
Figure 6.3.65.
13
C NMR (151 MHz) spectrum of 3.3e at 25 °C in CDCl3. ............................... 254
Figure 6.3.66.
1
H NMR (600 MHz) spectrum of 3.1f at 25 °C in CDCl3. ................................. 255
Figure 6.3.67.
13
C NMR (151 MHz) spectrum of 3.1f at 25 °C in CDCl3. ................................ 255
Figure 6.3.68.
1
H NMR (600 MHz) spectrum of 3.3i at 25 °C in CDCl3. ................................. 256
Figure 6.3.69.
13
C NMR (151 MHz) spectrum of 3.3i at 25 °C in CDCl3. ................................ 256
Figure 6.3.70.
1
H NMR (600 MHz) spectrum of 3.3j at 25 °C in CDCl3. ................................. 257
Figure 6.3.71.
13
C NMR (151 MHz) spectrum of 3.3j at 25 °C in CDCl3. ................................ 257
Figure 6.3.72.
1
H NMR (600 MHz) spectrum of 3.3k at 25 °C in CDCl3. ................................ 258
Figure 6.3.73.
13
C NMR (151 MHz) spectrum of 3.3k at 25 °C in CDCl3. ............................... 258
Figure 6.3.74.
1
H NMR (500 MHz) spectrum of 3.3l at 25 °C in CDCl3. ................................. 259
Figure 6.3.75.
13
C NMR (126 MHz) spectrum of 3.3l at 25 °C in CDCl3. ................................ 259
Figure 6.3.76.
1
H NMR (500 MHz) spectrum of 3.3m at 25 °C in CDCl3. ............................... 260
Figure 6.3.77.
13
C NMR (126 MHz) spectrum of 3.3m at 25 °C in CDCl3. .............................. 260
xix
Figure 6.3.78.
1
H NMR (600 MHz) spectrum of complex 3.12 at 25 °C in MeOD. ................. 261
Figure 6.3.79.
13
C NMR (151 MHz) spectrum of complex 3.12 at 25 °C in MeOD. ................ 261
Figure 6.3.80.
19
F NMR (564 MHz) spectrum of complex 3.12 at 25 °C in MeOD. ................ 262
Figure 6.3.81.
31
P NMR (243 MHz) spectrum of complex 3.12 at 25 °C in MeOD. ................ 262
Figure 6.3.82.
1
H NMR (600 MHz) spectrum of 3.32 at 25 °C in CDCl3. ................................ 263
Figure 6.3.83.
13
C NMR (151 MHz) spectrum of 3.32 at 25° C in CDCl3. ................................ 263
Figure 6.3.84.
1
H NMR (500 MHz) spectrum of 3.39 at 25 °C in CDCl3. ................................ 264
Figure 6.4.1.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD
(1 equiv) and n-butanol (2 equiv) with 1 mol % C4 for 44 h. .................................................... 272
Figure 6.4.2.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD
(1 equiv) and 1-octanol (2 equiv) with 1 mol % C4 for 63 h. .................................................... 273
Figure 6.4.3. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 1-octanol, which shows desired product peak at 270.252 (M+H2O+H)
+
. ........................... 273
Figure 6.4.4.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD
(1 equiv) and 1-hexadecanol (2 equiv) with 1 mol % C4 for 44 h. ............................................ 274
Figure 6.4.5. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 1-hexadecanol, which shows desired product peak at 382.3782 (M+H2O+H)
+
. ................. 275
Figure 6.4.6.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD
(1 equiv) and cyclobutanemethanol (2 equiv) with 1 mol % C4 for 44 h. ................................. 276
Figure 6.4.7. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and cyclobutanemethaol, which shows desired product peak at 226.1913 (M+H2O+H)
+
. ........ 276
Figure 6.4.8.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and 1-adamantanemethanol (2 equiv) with 1 mol % C4 for 44 h. Peaks of the desired
product 4.2e is merging with starting materials except two CH2 peaks at 2.50 (t, 2H) and
2.14 (s, 2H). ................................................................................................................................ 277
Figure 6.4.9. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 1-adamantanemethanol, which shows desired product peak at 306.2552 (M+H2O+H)
+
. ... 278
Figure 6.4.10.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and furfuryl alcohol (4 equiv) with 1 mol % C4 for 44 h. ............................................... 279
Figure 6.4.11. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 1-furfuryl alcohol, which shows desired product peak at 238.1568 (M+H2O+H)
+
. ............ 279
Figure 6.4.12.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and cyclopentanol (2 equiv) with 1 mol % C4 for 92 h. ................................................. 280
Figure 6.4.13. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and cyclopentanol, which shows desired product peak at 226.1930 (M+H2O+H)
+
. .................. 281
Figure 6.4.14.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and cyclopentanol (2 equiv) with 3 mol % C4 for 44 h. ................................................. 282
Figure 6.4.15. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and cyclohexanol, which shows desired product peak at 240.2090 (M+H2O+H)
+
. ................... 282
Figure 6.4.16.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and 2-butanol (2 equiv) with 1 mol % C4 for 44 h. Peaks of the desired product 4.2i
is merging with starting materials except two CH3 peaks at 0.77 (t, 3H) and 0.91 (d, 3H). ...... 283
xx
Figure 6.4.17. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 2-butanol, which shows desired product peak at 214.1919 (M+H2O+H)
+
. ......................... 284
Figure 6.4.18.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and benzyl alcohol (2 equiv) with 1 mol % C4 for 44 h. ................................................ 285
Figure 6.4.19. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and benzyl alcohol, which shows desired product peak at 248.1795 (M+H2O+H)
+
. ................. 285
Figure 6.4.20.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and 4-chlorobenzyl alcohol (2 equiv) with 1 mol % C4 for 44 h. ................................... 286
Figure 6.4.21. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 4-chlorobenzyl alcohol, which shows desired product peak at 282.1386 (M+H2O+H)
+
. .... 287
Figure 6.4.22.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and 1-phenylethanol (2 equiv) with 1 mol % C4 for 63 h. .............................................. 288
Figure 6.4.23. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 1-phenylethanol, which shows peak of enamine 4.2l at 260.1771 (M+H2O+H)
+
. .............. 288
Figure 6.4.24. Aliphatic region of the HSQC spectrum of the crude reaction mixture for the
coupling of TBD (1 equiv), and 1-phenylethanol (2 equiv) with 1 mol % C4 for 63 h. CH3 or
CH peaks (red dots) belongs to either alcohol substrate or mesitylene. ..................................... 289
Figure 6.4.25.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and 1-(methylphenyl)ethanol (1.4 equiv) with 1 mol % C4 for 44 h. ............................. 290
Figure 6.4.26. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 1-(methylphenyl)ethanol, which shows peak of hemiaminal 4.2m at 274.1910 (M+H)
+
. .. 290
Figure 6.4.27.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and 1-(methoxyphenyl)ethanol (2 equiv) with 1 mol % C4 for 44 h. ............................. 291
Figure 6.4.28. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 1-(methoxyphenyl)ethanol, which shows peak of hemiaminal 4.2n at 290.1867
(M+H)
+
. ....................................................................................................................................... 292
Figure 6.4.29. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 4.3, which shows peak of 4.2o at 229.2041 (M+H2O+H)
+
. ................................................. 293
Figure 6.4.30. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 4.4, which show peaks of 4.2p (261.171), 4.2q (366.230), and 4.2r (471.287). ................. 294
Figure 6.4.31.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1
equiv) and 2,3-butanediol (2 equiv) with 1 mol % C4 for 44 h. Integration for one of the
diastereomer is shown as the peaks of other diastereomer is merging with starting
materials. We identified the diastereomeric ratio from the methyl peak of diastereomers at
0.94 ppm and 0.97 ppm............................................................................................................... 295
Figure 6.4.32. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 4.5, which shows peak of 4.2s at 230.186 (M+H2O+H)
+
. ................................................... 295
Figure 6.4.33. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 4.6, which show peaks of 4.2t at 196.1439 (M) and 4.2u at 214.1543 (M+H)
+
. ................. 296
Figure 6.4.34. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD
and 4.7, which show peaks of 4.2v at 286.2097 (M+H)
+
and 4.2w at 268.2403 (M+H)
+
. ......... 297
xxi
Figure 6.4.35.
1
H NMR spectrum of the crude reaction mixture for the coupling of 2-
aminobenzimidazole (1 equiv) and n-butanol (2 equiv) with 1 mol % C4 for 44 h. Peaks at
0.93 ppm, 1.40 ppm, 1.58 ppm, and 3.68 ppm belong to n-butanol. .......................................... 298
Figure 6.4.36.
1
H NMR spectrum of the crude reaction mixture for the coupling of 2-
aminobenzimidazole (1 equiv) and cyclopentanol (2 equiv) with 1 mol % C4 for 61 h. ........... 299
Figure 6.4.37.
1
H NMR spectrum of the crude reaction mixture for the coupling of 2-
aminobenzimidazole (1 equiv) and cyclohexanol (2 equiv) with 1 mol % C4 for 61 h. ............ 300
Figure 6.4.38.
1
H NMR spectrum of the crude reaction mixture for the coupling of 2-
aminobenzimidazole (1 equiv) and benzyl alcohol (2 equiv) with 1 mol % C4 for 44 h. .......... 301
Figure 6.4.39.
1
H NMR spectrum of the crude reaction mixture for the coupling of 4.15 (1
equiv) and benzaldehyde (2 equiv). ............................................................................................ 302
Figure 6.4.40. LC-QTOF spectrum of the crude reaction mixture for the coupling of 4.15
and benzaldehyde, which shows peak of 4.21 at 202.101 (M). .................................................. 303
Figure 6.4.41. LC-QTOF spectra of the crude reaction mixture for the coupling of 4.19 and
benzyl alcohol, which show peaks of 4.22 (left) at 198.1296 (M+Li)
+
and 4.23 (right) at
288.1758 (M+Li)
+
. ...................................................................................................................... 304
Figure 6.4.42. LC-QTOF spectrum of the crude reaction mixture for the coupling of 4.20
and benzyl alcohol, which shows peak of 4.24 at 302.1685 (M+H)
+
. ........................................ 305
Figure 6.4.43.
1
H NMR spectrum of the crude reaction mixture for the coupling of 4.20 (1
equiv) and ethylene glycol (5 equiv). ......................................................................................... 306
Figure 6.4.44. LC-QTOF spectrum of the crude reaction mixture for the coupling of 4.20
and ethylene glycol, which shows peak of 4.31 at 238.1365 (M+H)
+
. ....................................... 306
Figure 6.4.45.
1
H NMR spectrum of the crude reaction mixture for the coupling of 4.20 (1
equiv) and 1,3-propanediol (5 equiv).......................................................................................... 307
Figure 6.4.46. LC-QTOF spectrum of the crude reaction mixture for the coupling of 4.20
and 1,3-propanediol, which shows peak of 4.34 at 252.1515 (M+H)
+
. ...................................... 308
xxii
Abbreviations
• API Active Pharmaceutical Ingredient
• BINAP 2,2’-bis(diphenylphosphino)-1,1’-binaphthyl)
• Bn Benzyl
• CPME Cyclopentyl Methyl Ether
• DCM Dichloromethane
• DMF Dimethylformamide
• DMT Dimethyltryptamine
• DPEphos Bis[(2-diphenylphosphino)phenyl]ether
• dppe 1,2-Bis(diphenylphosphino)ethane
• dppf 1,1ʹ-Ferrocenediyl-bis(diphenylphosphine)
• dppp 1,3-Bis(diphenylphosphino)propane
• EtOAc Ethyl acetate
• HB Hydrogen-Borrowing
• IR Infrared
• LAH Lithium Aluminium Hydride
• LC-QTOF Liquid Chromatography Quadrupole Time-of-Flight
• NMR Nuclear Magnetic Resonance
• NPS R-568 N-(3-[2-chlorophenyl]propyl)-(R)-α-methyl-3-
methoxybenzylamine
• NSAID Nonsteroidal anti-inflammatory drug
• PSR Pictet-Spengler Reaction
• p-TSA para-toluene sulfonic acid
• rt room temperature
• TBAF Tetra-n-butylammonium fluoride
• TBD Triazabicyclodecene
• TFA Trifluoroacetic acid
• TfOH Triflic acid
• THBC Tetrahydro-β-carboline
• THF Tetrahydrofuran
• THP 2-tetrahydropyranyl
• Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene
• XRD X-ray diffraction
xxiii
Abstract
Formation of C-N bonds is a quintessential transformation in organic synthesis. Most of
the biologically active compounds and natural products contain C-N bond. This thesis focus
hydrogen-borrowing (HB) catalysis, a green, atom economic and cost-effective approach for C-N
bond formation through amine alkylation.
First chapter is devoted to the comparison of HB with different classical and modern C-N
bond forming reactions, its applications, and review of discovery, application, and mechanism of
a HB ruthenium complex from our lab.
Chapter 2 describes development of a tandem Pictet-Spengler reaction condition for the
synthesis of tetrahydro-β-carbolines from alcohols and N-benzyltryptamine. The use of a base free
hydrogen borrowing catalyst for N-alkylation of amines, and a lewis acid catalyst In(OTf)3 for the
cyclization helped to develop a tandem approach for the first time by combining acid catalyzed
and base catalyzed reaction. This method provides the desired products with benzylic alcohols and
heterocycles in good yield under mild conditions. Aliphatic alcohols also can be synthesized with
the aid of styrene as a hydrogen acceptor in moderate to good yield. Mechanistic studies suggest
that In(OTf)3 acts as a dehydrating agent, and can be replaced by MgSO4. This also shows that
the secondary amines to corresponding imines conversions are prohibitively slow; whereas, the
oxidation of alcohols to aldehydes and its reactions with secondary amines are fast.
Although synthesis of piperazines, 6-membered diazacycles, is well explored, catalytic
routes to analogues seven-membered diazepanes are undeveloped. Chapter 3 describes
development of a method to access those 1,4-diazacycles, privileged motifs in drug discovery, by
a ruthenium catalyzed diol-diamine coupling. Our conditions tolerate different amines and alcohol
xxiv
groups that are relevant to key medicinal platforms: we show that our method enables synthesis of
an FDA-approved drug cyclizine, an anti-nausea agent, and seven-membered homochlorcyclizine,
an antihistamine, respectively in 91% and 67% yields. The uniqueness of our catalyst is
demonstrated by screening common hydrogen borrowing scaffolds that fail in this transformation.
We show that a challenge to successful catalysis in this reaction is the chelating reactivity of
diamines that can poison the catalyst, yet we show that while 1 is susceptible to such chelation, it
maintains reactivity in the case of substituted diamines.
Chapter 4 describes a hydrogen-borrowing N-alkylation route to guanidine derivatives.
Guanidines are difficult to functionalize as they possess high basicity and multiple nucleophilic
centers. Broad spectrum of application of guanidine compounds in pharmaceutical industry and
scarcity of methods available to functionalize them attracted us to develop a methodology for its
direct alkylation. We successfully alkylated guanidines such as triazabicyclodecene and 2-
aminobenzimidaole with various alcohols. Moreover, we show cyclization of guanidines with
diols, a one-step method to afford imidazolines.
Chapter 5 comprise some interesting results that we observed during rection optimizations
in the above three chapters along with some miscellaneous experiments we never follow up such
as amine-diol coupling, N-methylation by hydrogen-borrowing, and iron catalyzed N-heterocycle
synthesis.
Chapter 6 discuss experimental procedure and spectra data of the compounds synthesized
in chapter 2 and 3, and 4.
1
Chapter 1. C-N Bond Formation Through Hydrogen-Borrowing
1.1 Introduction
Formation of C-N bond is essential in the bulk synthesis of chemicals and
pharmaceuticals.
1
Undoubtedly, N-alkylation reactions are one of the key synthetic strategies to
achieve C-N bond formation. Among the various methods exist to access N-alkyl compounds
spanning from classical reactions such as amination of halides,
2
reductive amination
3
to modern
methods like coupling of amines with aryl halides
4
and hydroamination,
5
one of the more
promising strategies is the hydrogen-borrowing (HB) coupling of amines with alcohols. The
general mechanism is given in scheme 1.1. It consists of three steps: (1) a hydrogen borrowing
step which include dehydrogenation of alcohol to a carbonyl compound by metal catalysis and
formation of a metal hydride (2) condensation reaction between the carbonyl compound and an
amine to make an imine, and (3) a hydrogen returning step in which metal hydride hydrogenate
the imine to an amine. HB reaction is not only a cost-effective method with widely available
resources such as amine and alcohols, but it is atom economic and a green reaction with water as
the sole by-product. Various homogenous and heterogenous metal catalysts and biocatalysts are
reported in catalyzing these reactions;
6
but ruthenium
7
and iridium
8
based complexes are the most
predominant ones. This chapter comprise the comparison of hydrogen-borrowing reactions to
other N-alkylation methods, its pharmaceutical applications, and reactivity of a novel ruthenium
complex developed in our lab in HB reactions.
2
Scheme 1.1. N-Alkylation by Hydrogen-Borrowing.
1.2. Other Methods for C-N Bond Formation
1.2.1. Amination of Alkyl Halides
An SN2 reaction between amines and alkyl halides is a classical method for producing
substituted amines (Scheme.1.2).
2
Bromides and iodides are the most reactive halides as
electronegativity makes them good leaving groups. This simple method is an efficient way to
generate tertiary and quaternary amines, not primary or secondary amines. When a primary amine
reacts with a halide, the reaction doesn’t stop at secondary amine. This secondary amine is more
nucleophilic than the primary amine and leads to a quaternary ammonium salt. In addition, it
generates toxic halide ions as the side product. With the development of modern organic methods,
the hassle of purification resulting from this selectivity issue make the amination of halides as an
unfavorable reaction in industry application.
Scheme 1.2. Alkylation of Amines with Halides.
3
1.2.2. Reductive Amination
Reductive amination
3
is indeed a powerful reaction in the construction of C-N bonds.
Operational simplicity makes it as the most popular method for producing commercial drug
substances
9
such as imatinib (anticancer), oseltamivir (antibiotic), sitagliptin (antidiabetic), etc.
The main advantage of this method is the selectivity of amines produced compared to the SN2
reaction where mixture of mono, di, tri, and tetra alkylated compounds are formed. Reductive
amination consists of two steps (Scheme 1.3): (1) a condensation reaction between an amine and
a carbonyl compound to form an imine, and (2) reduction of the imine to an amine by a metal
hydride such as NaBH4. Conceptually, this is like hydrogen-borrowing reaction; however, the use
of stoichiometric oxidizing agent for the preparation of aldehyde, and a metal hydride for the imine
reduction make it’s a waste intensive strategy.
Scheme 1.3. Reductive Amination.
1.2.3. Coupling of Amines with Aryl Halides
Aryl Amines can be prepared by coupling amines with aryl halides. Buchwald-Hartwig
amination,
4a-b
copper-catalyzed Ullman type reactions
4c
and Petasis reaction are the common
names reactions in this category.
Buchwald-Hartwig Amination
Buchwald-Hartwig Amination (Scheme 1.4) is a palladium catalyzed cross coupling of
amines with aryl/vinyl/heteroaryl halides or pseudohalides. Due to the ubiquity of C-N bond in
biologically active compounds and natural products, this method has contributed significantly to
the production of small molecule drugs since its discovery.
10
Various generations of Pd catalyst
4
systems have been developed with different phosphine ligands such as Xantphos, dppf, BINAP,
trialkyl phosphines and N-heterocyclic carbenes. The choice of Pd source, ligand system, base and
reaction conditions like solvent and temperature are highly substrate dependent. Compared to the
classical methods like nucleophilic substitution and reductive amination, this Pd catalyzed cross
coupling provide broad substrate scope with variety of amines (primary, secondary, electron
deficient, and heterocyclic).
Scheme 1.4. Buchwald-Hartwig Amination.
Ullmann Condensation
Ullman Condensation is a copper catalyzed cross coupling of nucleophiles (amines,
alcohols, and thiols) with aryl halides (Scheme 1.5). Even though this reaction was applied in the
synthesis of important intermediates in pharmaceutical and polymer industry, it is substituted with
Buchwald-Hartwig reaction since 2000 due to its limited substrate scope and harsh reaction
conditions. Traditional Ullman-type coupling reactions require high temperature, aryl halides with
electron withdrawing groups and activated copper powder as the catalyst. However, scope of the
copper catalyzed coupling reaction is increasing recently with the introduction of soluble copper
catalysts, and simple and inexpensive ligands compared to complex and expensive phosphine
ligands in Buchwald-Hartwig reaction.
4c, 11
5
Scheme 1.5. Ullman Amine Synthesis.
Petasis Reaction
The Petasis boron-Mannich reaction or Petasis reaction is a multi-component reaction of
amine, carbonyl compound and boronic acid to produce substituted amines (Scheme 1.6). As a
mild and selective synthetic strategy, it is employed in the formation of β-amino alcohols, amino
acids, aminophenols etc. A wide variety of carbonyl derivatives (α-hydroxy aldehyde,
salicylaldehyde and derivatives, lactols, glyoxylic acid and derivatives, protected α-amino
aldehydes, α-imino amides, formaldehyde, benzaldehyde, etc.),
12
amine substrates (secondary
amines, tertiary aromatic amines,
13
hydrazine,
14
hydroxyl amine,
15
sulfonamide,
15
indole,
16
etc.),
and boronic acid and esters have been reported. As a powerful reaction to make highly
functionalized amine derivatives with good diastereoselectivity and enantioselectivity, it is utilized
in the total synthesis of natural products like polyhydroxy alkaloids, loline alkaloids and sialic
acids.
12
Scheme 1.6. Multi-Component Petasis Reaction.
6
1.2.4. Hydroamination
Hydroamination is the addition of hydrogen and nitrogen group across the C-C multiple
bonds of an alkene or alkyne (Scheme 1.7).
5
This atom economical and green reaction contribute
to the synthesis of substituted amines via intermolecular addition, and heterocycles and alkaloids
17
in intra molecular fashion. This thermodynamically forbidden [2+2] cycloaddition became feasible
with the development of catalysts that opens new reaction pathways. Another challenge here is the
possibility of both Markovnikov and ani-Markovnikov additions across carbon-carbon multiple
bonds; and product selectivity depends on the catalyst.
18
A broad range of catalysts including acids,
bases, main group elements, non-noble metals, rare-earth metals, and transition metals are
reported,
5,19
yet the research and development in this area remains active because of the scarcity
of enantioselective catalysts.
Scheme 1.7. Hydroamination of Alkene.
1.3. Application of Hydrogen-Borrowing Reaction
C-N bond is ubiquitous in biologically active compounds and natural products. As a cost
effective, atom economical and green reaction to make C-N bonds, hydrogen-borrowing reactions
have significant potential in synthesizing pharmaceutical intermediates and natural products.
1.3.1 ( S)-Rivastigmine
Rivastigmine
20
(brand name: Exelon) is an acetylcholinesterase inhibitor, used to treat
dementia associated with Alzheimer’s or Parkinson disease. Lixin Xia and coworkers applied an
iridium catalyzed diasteroselective amine alkylation to synthesize the intermediate 1.2 in the
7
formation of (S)-rivastigmine (Scheme 1.8).
21
Coupling of racemic alcohol 1.1 and (S)-tert-
butanesulfinamide with an iridium catalyst (C1) yielded the desired alkylated compound 1.2 in
high yield with excellent diastereoselectivity. Next, an acidic cleavage of sulfinyl group in the 1.2
produced an α-chiral amine (S)-1.3 with 99% ee, which was then converted to a N,N-dimethylated
compound 1.4 using excess formic acid and formaldehyde. Then, a deprotection of methyl group
from OMe, followed by carbamoylation with the N-ethyl-N-methylcarbamoylchloride yielded (S)-
rivastigmine in 64% overall yield.
Scheme 1.8. Synthesis of (S)-Rivastigmine.
1.3.2 NPS R-568
N-(3-[2-Chlorophenyl]propyl)-(R)-α-methyl-3-methoxybenzylamine (NPS R-568) is a
type II calcimimetic compound which inhibits the secretion of parathyroid hormone by binding to
the parathyroid Ca
2+
receptor.
22
The intermediate 1.2' was synthesized using the same Iridium (C1)
catalyzed diastereoselective N-alkylation from racemic alcohol and (R)-tert-butanesulfinamide
21
8
(Scheme 1.9). Subsequently, the removal of sulfinyl group followed by reductive amination
afforded NPS R-568 in 63% overall yield with 99% ee.
Scheme 1.9. Synthesis of NPS R-568.
1.3.3. Noranabasamine
Noranabasamine is an amphibian alkaloid which is isolated from a Colombian poison dart
frog Phyllobates terribilis.
23
This compound has gained significant attention due to its resemblance
to the plant derived piperidine alkaloids I and II (Figure 1.1), which shows therapeutic effect on
nicotinic acetylcholine receptor.
24
Trudell and co-workers have reported an enantioselective
synthesis of both (R) and (S) enantiomers of noranabasamine in three steps with more than 30%
overall yield and > 80% ee (Scheme 1.10).
25
Figure 1.1. Noranabasamine and plant derived alkaloids
9
First step was the synthesis of 2-substituted piperidine scaffold by applying an iridium
catalyzed enantioselective N-heterocyclization of primary amine with diols reported by
Yamaguchi and co-workers in 2004.
8s
This reaction proceeded in high yield with both (R) and (S)-
1-phenylethylamine to afford the corresponding diastereomer (1.10a and 1.10b) in excellent
selectivity. Thereafter, the hydrogenolysis of N-phenylethyl auxiliary accompanied by POCl3
treatment yielded 1.11a and 1.11b from 1.10a and 1.10b respectively. Finally, a Suzuki coupling
of 1.11a and 1.11b with 3-pyridineboronic acid produced (S)-noranabasamine and (R)-
noranabasamine respectively in good ee.
26
Scheme 1.10. Synthesis of Noranabasamine.
10
1.3.4. Cinnarizine
Cinnarizine is an antivertigo and antihistamine drug used to treat nausea caused by motion
sickness, vertigo, and tinnitus associated with Ménière's disease and other middle ear diseases.
27
Sundararaju and co-workers synthesized cinnarizine by applying a hydrogen-borrowing method
they developed for the construction of allylic amines from allylic alcohols (Scheme 1.11).
28
They
used Knö lker’s iron complex (C2) to couple commercially available cinnamyl alcohol and 1-
benzydrylpiperazine in the presence of Me3NO to afford cinnarizine in 62% yield.
Scheme 1.11. Synthesis of Cinnarizine.
1.3.5. Nafetifine
Sundararaju and co-workers also synthesized Nafetifine,
29
an antifungal drug by the
Knö lker’s iron complex (C2) catalyzed N-alkylation of allylic alcohols (Scheme 1.12).
28
Here,
cinnamyl alcohol was treated with N-methyl-1-(naphthalen-1-yl)methanamine to yield nafetifine
in 61% yield.
Scheme 1.12. Synthesis of Nafetifine.
11
1.3.6. Piribedil
Piribedil is a dopamine receptor agonist, which is used in the treatment of Parkinson disease
and depression.
30
As a representative example of a larger class of pharmaceutically relevant N-
arylpiperazines,
31
synthesis of piribedil by hydrogen-borrowing has been widely explored with
different catalytic systems (Scheme 1.13).
In 2007, Williams and co-workers utilized [Ru(p-cymene)Cl2]2 to couple commercially
available 1-(2-pyrimidyl)piperazine with piperonyl alcohol to furnish piribedil in 87% yield.
7y
The
yield increased from 87% to 98% when the [Ru(p-cymene)Cl2]2 was replaced with a supported
ruthenium catalyst that was prepared from [Ru(p-cymene)Cl2]2 and a commercially available
polystyrene supported phosphine ligand in 1:6 ratio (Scheme 1.14).
7j
This catalyst also showed
comparable yields (96% and 97%) in the two subsequent runs after its recovery from the initial
mixture. In 2014, Nandan’s group employed an inexpensive Raney Ni catalyst for the same
transformation to yield piribedil in 85% yield.
32
In addition, Ben Feringa and co-workers reported
piribedil synthesis using Knö lker’s iron complex (C2) in 54% yield.
33
Their methodology consists
of a base free one pot synthesis in a green solvent cyclopentyl methyl ether (CPME).
Scheme 1.13. Synthesis of Piribedil.
12
Scheme 1.14. Synthesis of Catalyst C3.
1.3.7. Pyrilamine
Pyrilamine also known as Mepyramine is a first-generation antihistamine which blocks H1
receptor.
34
Nandan and co-workers demonstrated the application of N-alkylation of secondary
amines with W4-Raney Ni by producing pyrilamine (Scheme 1.15).
32
As the first step, N-(2-
(dimethylamino)ethyl)pyridine-2-amine was synthesized by a microwave assisted nucleophilic
substitution reaction, which was then coupled with 4-methoxy benzyl alcohol to yield pyrilamine
in 82% yield.
Scheme 1.15. Synthesis of Pyrilamine.
1.3.8. Saccharide Sensor
A fluorescent saccharide sensor
35
(1.13) is prepared by applying N-alkylation of alcohols
in the presence of a boronic ester group (Scheme 1.16). While Williams and co-workers produced
1.13 in 84% yield by a [Ru(p-cymene)Cl2]2 catalyzed coupling of methyl substituted secondary
amine with a boronic ester , reductive amination yielded the unprotected sensor in 54% yield.
36
13
Scheme 1.16. Synthesis of a Saccharide Sensor 1.13.
1.3.9. Tigan and Itopride
Tigan
37
or trimethobenzamide is an antiemetic drug used to treat nausea and vomiting
related to post surgery or by stomach flu. A structurally similar drug Itopride
38
is an acetylcholine
esterase inhibitor and a dopamine D2 receptor antagonist It is a medication for functional
dyspepsia and other gastrointestinal conditions. In 2018, Banerjee and co-workers extended their
nickel catalyzed phosphine free direct N-alkylation of amides with alcohols to synthesize Tigan
and Itropride.
39
Those reactions proceeded well, and Tigan and Itopride was obtained in 80% and
74% isolated yield respectively (Scheme 1.17)
Scheme 1.17. Synthesis of Tigan and Itopride.
1.3.10. GlyT1 Inhibitor
PF-03463275 (1.15) is a glycine transporter type 1 (GlyT1) inhibitor that has therapeutic
potential against schizophrenia.
40
Process chemists from Pfizer Pharmaceutical Science
demonstrated the first kilogram-scale application of hydrogen-borrowing as a key step in the
synthesis of PF-03463275.
41
It is noteworthy that less than 0.05 mol % of the catalyst loading is
14
required to manufacture the drug intermediate 1.14 in 4.8 kg scale (Scheme 1.18). In addition, this
one pot synthesis replaces a traditional 4 step approach to access 1.14. Their studies on the effect
of solvent and base revealed that water and tertiary amine base are critical in achieving efficient
and robust catalyst performance.
Scheme 1.18. Scale-up Preparation of Pharmaceutical Intermediate 1.14.
1.3.11. Pharmaceutically Relevant Intermediates
In 2015, Newton and co-workers from AstraZeneca conducted a survey of hydrogen-
borrowing strategy to synthesize various pharmaceutically relevant intermediates.
42
They focused
primarily on two catalytic systems: (1) catalytic system developed by Williams group
7u
(2.5 mol
% [Ru(p-cymene)Cl2]2/ 5 mol % DPEphos/ 1 M toluene), and (2) catalytic system from Fujita and
Yamaguchi
8q
(2.5 mol % [Cp*IrCl2]2/ 5 mol % NaHCO3/ 10 M in toluene).
In the first example, they showed an alternate pathway to access a piperazinyl alcohol 1.17,
an important intermediate in the synthesis of a potent SRC kinase inhibitor 1.18 (Scheme 1.19),
by hydrogen-borrowing N-alkylation in 83% yield with a [Ru(Cp)Cl(PPh3)2] catalyst (Scheme
1.20). Although, the previous route to this amino alcohol by reductive amination yielded the
methylated compound in 93% yield, the excess formaldehyde (also a potential carcinogen) has to
be removed by converting it into a volatile diethylmethylamine by treating with diethyl amine.
15
Thus, hydrogen-borrowing established more simpler one pot synthesis of 1.17 with comparable
yield and a trouble-free isolation by distillation.
Scheme 1.19. Role of Amino Alcohol 1.17 in the Synthesis of API 1.18.
Scheme 1.20. N-Methylation Routes to Amino Alcohol 1.17.
One of the entries from Newton and co-workers survey was an aniline derivative (1.22),
an intermediate in the synthesis of an anti-hepatitis API 1.23. Previous synthetic route to 1.22
consists of a sulfonamide (1.19) alkylation with p-nitrobenzyl bromide (1.20), followed by
reduction of the nitro group (Scheme 1.21).
43
The authors employed [Ru(p-cymene)Cl2]2 to
produce compound 1.24 from a piperazine TFA salt (1.19) and Boc protected p-aminobenzyl
alcohol (1.24) (Scheme 1.22). It is noteworthy that the TFA salt of amine was compatible with the
hydrogen-borrowing conditions to afford 1.25 in 92% yield. Then, the acidic cleavage of 1.24
yielded the API intermediate 1.22 in in 89% yield.
16
Scheme 1.21. Previous Route to Intermediate 1.22.
Scheme 1.22. Hydrogen-Borrowing Route to Intermediate 1.22.
Academia has widely explored the breadth of hydrogen-borrowing reactions with different
amine and alcohol substrates with some reports for the API or natural product synthesis. Newton
and co-workers investigated the scope and limitation of hydrogen-borrowing approach to N-
alkylation, the most common transformation required while an API synthesis, in industry context.
Despite the success in the formation of various pharmaceutical intermediates, their study pointed
to several drawbacks with the current systems available to achieve HB transformation, such as
high catalyst loading, poor turn over, catalyst poisoning by the substrate, and catalyst
contamination of API.
17
1.4. Reactivity of a Solvent and Base free Ruthenium Catalyst
This chapter is a review of previous works from our lab by senior graduate students Jeff
Celaje and Valeriy Cherepakhin in ACS Catalysis on the discovery, reaction scope, and mechanism
of a novel (pyridyl)phosphine-ligated ruthenium(II) (C4) amine alkylation catalyst.
44,45
Introduction of a base and solvent free catalyst C4 extended the scope of otherwise well
studied hydrogen-borrowing methodology to substrates with fragile functional groups such as
protic, nucleophilic, and base sensitive groups. Mechanistic studies show that both amine and
alcohol can get oxidized by coordinating to the metal center; but the fast C-H oxidation step
governs product selectivity. Further mechanistic investigation and identification of catalytic
intermediates was conducted by Cherepakhin in 2020.
1.4.1. Design and Synthesis of Catalysts
Biphosphine ligands like dppp, dppe, dppf, DPEphos, and xantphos are generally utilized
in ruthenium catalyzed amine alkylation reactions which usually requires a base for the in situ
generation of the catalyst.
46,7s,u,x
A successful dehydrogenation of formic acid with a pyridyl
phosphine ligand
47
encouraged authors to investigate its application in hydrogen-borrowing
reactions. Besides, this ligand has structural resemblance to the versatile PNP and PNN pincer
ligands from Milstein’s acceptorless dehydrogenation reactions.
48,7c
Two complexes C4 and C5 were synthesized by treating 2-((di-tert-
butylphosphino)methyl)pyridine with precursors [Ru(p-cymene)Cl2]2 and [Cp*IrCl2]2 respectively
with excess NaOTf (Scheme 1.23). While complex C4 was efficient in alkylating primary benzylic
alcohols (at 1 mol % loading), secondary benzylic alcohols (at 5 mol % loading) and aliphatic
alcohol (at 0.2 -0.7 mol% loading), precatalyst C5 didn’t show desired reactivity. An interesting
18
observation from their optimization study was the ability to tune product selectivity between
coupled amine and imine by switching the condition between closed and open flask reactor.
Scheme 1.23. Synthesis of Complex C4 and C5.
1.4.2. Scope of the Reaction
While Celaje and co-workers found conditions for coupling primary and secondary
benzylic alcohols with amines under base and solvent free environment, Cherepakhin extended the
scope to aliphatic alcohols and heterocyclic carbinols with a reduced catalyst loading (Scheme
.1.24). The reaction scope showed excellent functional group tolerance including unprotected
indoles, phenols, and anilines. For example, tryptamine, tyramine, and homoveratrylamine are
alkylated with primary and secondary benzylic alcohols bearing electron rich to poor substituent
on aromatic group in high yield (compounds 1.26-1.36). It is attractive that the indole nitrogen in
tryptamine and phenol group in tyramine are combatable with the reaction condition without
additional protection. This has high significance in alkaloid synthesis and resulted in the
development of a tandem amine-alkylation/Pictet-Spengler reaction to access tetrahydro-β-
carbolines in 2020, which is discussed in the next chapter.
49
19
A remarkable candidate in the reaction scope was alcohols with unprotected amine
functionalities (compounds 1.31, 1.36-1.38). Authors achieved the selectivity in these reactions by
using slightly excess amine partners, the vice versa leads to overalkylation of the amino group in
the product. In addition to primary amines, they showed three examples for the coupling of
secondary amines with benzylic alcohols. Generally, secondary alcohols require 5 mol % catalyst
loading and sometimes showed diminished yield compared to 1 mol % reactions with primary
alcohols. For instance, coupling of homoveratrylamine with benzyl alcohol and 1-phenyl ethanol
yielded the desired products in 79% and 67% respectively. In another example, while reaction of
hexadecyl amine with primary benzyl alcohol gives 90% yield after 20 h, the same with 1-phenyl
ethanol showed 65% product after 24 h stirring. Compounds 1.45-1.50 shows scope with aliphatic
alcohols and heterocyclic carbinols. A similar functional group compatibility such as free indoles,
phenols, and heterocycles like pyridine and thiophen are demonstrated in these cases. Reduced
catalyst loading is essential in achieving selectivity for monoalkylation with aliphatic alcohols,
whereas this is not required for benzylic alcohols.
Cherepakhin demonstrated the uniqueness of complex C4 by comparing it with other
known ruthenium based amine alkylation catalytic systems in the literature such as [Ru(p-
cymene)Cl2]2-dppf, Shvo complex, Ru3(CO)12-PPh3, and CpRuCl(PPh3)2. While C4 and
CpRuCl(PPh3)2 enable the monoalkylated product in 85% and 15% respectively, others showed no
catalytic activity. This may be due to the dependency of other catalysts on base for its activation.
20
Scheme 1.24. Scope of C4 catalyzed Reaction between Amines and Alcohols.
1.4.3. Mechanism
NMR Studies to Probe Redox Reversibility and Origin of [RuH] Species
Celaje and co-workers used a time course
13
C NMR to study redox reversibility and product
selectivity under their reaction condition. They conducted a J-Young tube experiment with hexyl
amine (1 equiv) and deuterated benzyl alcohol (1.1 equiv) in the presence of 1 mol % complex C4
at 110
o
C in neat condition. Analysis of the reaction mixture after 0, 2, 8 and 24 h of heating by
13
C NMR showed incorporation of proton and deuterium into benzyl alcohol and hexylamine
21
respectively (Figure 1.2) due to the equilibration of benzylic α-CH2 group with hexyl amine
through intermediate benzaldehyde and imine species respectively. Thus, both amine and alcohol
can coordinate to the ruthenium and get oxidized; but the fast redox steps compared to the product
formation leads a major product through alcohol oxidation which is governed by thermodynamics
(Scheme 1.25). Besides, they determined the rate of both benzyl alcohol and hexyl amine oxidation
separately through their dimerization reaction and found that alcohol oxidation is 3.5 times faster
than the amine oxidation.
Scheme 1.25. Proposed Mechanism for C4 Catalyzed Amine/Alcohol Coupling.
22
Figure 1.2.
13
C NMR of the coupling of benzyl alcohol-d1 and n-hexylamine at 110 °C (A) after
2 h stirring and (B) after 24 h stirring under neat reaction conditions. The deuterated carbons appear
as 3-line patterns immediately upfield of the corresponding nondeuterated singlets.
In another operando
1
H NMR experiment, Celaje and coworkers observed ratio of
deuterated to non-deuterated starting material remaining and deuterated to non-deuterated product
23
formed as the same (ca 90%). This result along with the absence of deuterium leak into the water
by-product excluded the possibility of a C-H hydride and O-H proton scrambling during catalysis.
Thus, the reactive ruthenium hydride group is derived solely from the alcohol’s C-H bond, not
from the O-H bond.
Mechanism of Precatalyst Activation and Death
Chereapakhin conducted a time course study and isolated series of catalytic intermediates
[(η6-cymene)RuH(PyCH2PtBu2)]OTf (C6), [Ru3H2Cl2(CO)(PyCH2PtBu2)2{μ-
(C5H3N)CH2PtBu2}]OTf (C8), and a diastereomeric pair of [Ru2HCl(CO)2(PyCH2PtBu2)2(μ-
O2CnPr)]X (trans-C9, X = Cl; cis-C10, X = OTf). This unveiled an interesting mechanism for the
precatalyst (C4) activation, evolution and death through dimerization, cluster formation and
multimetallic pathways with substrate decarbonylation (Scheme 1.26). Displacement of a chloride
ligand with hydride, which is formed by β-hydride elimination from a metal alkoxide complex,
(not observed due to its fast formation) produced the first ruthenium intermediate (C6) in the
sequence of precatalyst activation. Further heating leads to the dissociation of cymene ligand, and
formation of a triruthenium complex (C8) with an orthometallated pyridine and a carbonyl ligand.
They proposed a structure for an intermediate diruthenium complex (C7), which links the
formation of a triruthenium cluster from a monometallic species. Finally, complex C8 reacts with
the byproduct water, coupling product secondary amine, and the substrate alcohol to generate two
dead species trans-C9 and cis-C10.
24
Scheme 1.26. Precatalyst Activation and Death.
The mechanism was elucidated with the help of a time course NMR study. In a typical
experiment, C4, hexyl amine, and butanol were taken in 1:6.5:144 molar ratio and was heated to
110
o
C in neat condition for 3 min, 10 min, 1 h and 24 h. After the required time, they removed
the volatile components by hearting, and analyzed the mixture by
1
H and
31
P NMR spectroscopy.
Presence of a new phosphorous peak at 109.75 ppm and a corresponding doublet in the
1
H NMR
at -8.65 ppm after 3 min of stirring were characteristics of a typical hydride complex. Even though
they couldn’t isolate the hydride complex C6, they confirmed its identity by its independent
synthesis from a metal triflate and isopropanol.
Complex C8 formed after 1 h was well characterized by single crystal XRD and NMR
spectroscopy. The multiplicity pattern, ddd and dd, of two distinct hydride peaks in
1
H NMR
helped the authors to assign a µ-H and µ3-H binding modes for bridging hydride ligands. In
addition, presence of six different t-butyl groups in
1
H, and three different phosphorous peaks in
31
P confirmed the existence of three different phosphinopyridine (PN) ligands in complex C8. In
order to account the structure of C7, they attempted to isolate the complexes formed after 10 min
25
of heating, however, they could only confirm the generation of a mixture of dinuclear and
trinuclear complex prior to C8, which they call C8 predecessors. Unlike other intermediates, C9
and C10 forms after 24 h only when a catalytic loading greater than 2.5 mol % is used. Identity of
these complexes were also established by both XRD and NMR. While C10 showed one
31
P peak
with a triplet pattern for bridging hydride indicating two PN ligands of similar nature, C9 showed
two
31
P peaks with a doublet of doublet (dd) hydride indicating two distinct PN ligands.
According to the catalytic comparison study among complexes C4, C6, C8, C9 and C10,
Cherepakhin concluded that none of them represent a catalyst resting state. While C4 gives full
conversion for a representative HexNH2/BuOH coupling, C6 and C8 showed moderate conversion
and C9 and C10 became the dead form with no catalytic activity. Interestingly, observation of full
conversion with C8 predecessors led the authors to assign one of the components from this mixture
as the catalyst resting state.
1.5. Conclusion
Hydrogen-Borrowing is a green alternative for conventional amine alkylation methods
such as nucleophilic substitution of amines with electrophiles, and reductive amination. Currently,
most of the industrial C-N bond formation achieves via the above mentioned SN2 and reductive
amination pathway which introduce handling of toxic reagents and affect atom economy with
byproduct generation. Attempts to replace those conventional reactions with HB to synthesize
pharmaceutical intermediates from researchers of Pfizer and AstraZeneca is a major stepping stone
to the wider application of this methodology in industry context. Even though, several catalytic
systems especially based on ruthenium and iridium are reported for C-N bond formation through
HB, a need for the catalytic system which tolerate fragile functional groups remained open. Thus,
discovery of a base and solvent free ruthenium catalyst by Celaje encouraged author of this
26
manuscript to screen various reactions such as tandem amine alkylation/Pictet Spengler reaction,
diazepanes from diol-diamine coupling, and guanidine N-alkylation which were not possible
before.
27
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32
Chapter 2. Ruthenium Catalyzed Tandem Amine Alkylation/Pictet-
Spengler Reaction to Access Tetrahydro-β-Carbolines
This chapter comprise a manuscript that was published in Organic Letters in 2020
(Nalikezhathu, A.; Cherepakhin, V.; Williams, T. J. Ruthenium Catalyzed Tandem Pictet–
Spengler Reaction. Organic Letters 2020, 22 (13), 4979-4984). Senior graduate student Valeriy
Cherpakin mentored me in planning and executing the experiments and analyzing the data.
2.1. Introduction
The indole alkaloids are one of the largest and most medicinally important classes of the
alkaloid natural products.
1
Many feature a tetrahydro-β-carboline (THBC) core; for example,
approved drugs in this group include the NSAID etodolac,
2
tadalafil,
3
reserpine,
4
and strictosidine,
5
which is a synthetic gateway to ajmalicine,
6
serpentine,
7
and quinine
8
(Figure 2.1B). Among the
many routes to tetrahydro-β-carboline derivatives,
9
the most widely used is the biomimetic Pictet-
Spengler cyclization,
10, 11
originally discovered by Ame Pictet and Theodor Spengler in 1911.
12
This reaction is employed in the synthesis of simple THBCs, and the requisite aldehydes are
usually prepared from alcohols. Thus, development of a tandem reaction
13
for THBC formation
directly from alcohols is a useful way to enable step savings in the construction of these scaffolds
while obviating the isolation of a delicate intermediate aldehyde. Further, the realization of
conditions for direct reactions of alcohols opens the way for a biomimetic cascade sequence in
which additional rings are annulated onto the THBC core.
33
Figure 2.1. A) Proposed synthesis of THBCs. B) Examples of pharmaceutically relevant THBCs.
Hydrogen borrowing catalysis
14
enables a green, waste-free, and cost-efficient approach
for alcohol amination.
15
Several ruthenium
16
and iridium
17
complexes highlight the many
examples of this scheme. We have long considered the development of a tandem hydrogen
borrowing amination followed by Pictet-Spengler reaction (PSR) step (Figure 2.1A), because this
is conceptually the same route through which nature assembles the indole alkaloids.
1
Such a
strategy has an intrinsic problem: Pictet-Spengler cyclization is enabled by the electrophilicity of
an intermediate imine, which necessitates a Bronsted or Lewis
18
acid
catalyst,
19, 11f
whereas most
hydrogen borrowing catalysts rely on a strong base to activate an alcohol for β-hydride
elimination.
17h-k
This adds a challenge to the tandem PSR problem that is not present in the recent
tandem aldol-cyclization work.
20
Resolving this dilemma, our group introduced a base-free
(pyridyl)phosphine ruthenium(II) catalyst, [RuCl(η
6
-cymene){(2-pyridyl)CH2P
t
Bu2}]OTf (1), that
34
enables hydrogen borrowing reactions with excellent functional group tolerance, including
phenols and indoles.
16l-m
2.2. Optimization of Individual Steps in the Tandem Sequence
2.2.1. Coupling of Tryptamine and Benzyl Alcohol
The reaction between benzyl alcohol (2.1) and tryptamine (2.2) catalyzed by complex C4
can produce either N-benzyltryptamine (2.3) or N-benzylidenetryptamine (2.4).
16l
To realize the
tandem sequence, imine 2.4 must be generated selectively as an intermediate. We screened three
conditions to accumulate the intermediate imine by coupling amine and alcohol (Table 2.1). A
closed flask reaction in neat condition produced N-benzyltryptamine selectively (Figure 6.2.1);
whereas, an open flask reaction in neat condition yielded mixture of 2.3 and 2.4 (Figure 6.2.2). We
found that conducting the reaction in refluxing toluene gives a full conversion of 2.2 to 2.4
selectively (Figure 6.2.3).
Table 2.1. Coupling of Benzyl Alcohol with Tryptamine.
Entry Conditions Solvent Temp (
o
C) Conv (%)
a
Product(s)
1 closed flask neat 110 100 2.3
2 open flask neat 110 86 2.3 (67%) 2.4 (33%)
3 open flask toluene 120 100 2.4
a
Conversion was calculated by
1
H NMR integration.
35
2.2.2. Cyclization of N-Benzylidinetryptamine to Tetrahydro-β-Carbolines
We next identified the conditions to cyclize 2.4 by screening Lewis acid catalysts (Table
2.2).
18
Metal chlorides (Entries 1-4) showed some activity, with imine hydrolysis as a competing
reaction. Y(OTf)3 and ZnBr2 showed better activity (Entries 5 and 6), and full conversion was
achieved with In(OTf)3 (Entry 7). Other additives such as p-TsOH•H2O, Al2O3, Al(O-iPr)3, SbCl5,
PCl5, or BF3(OEt)2 didn’t cyclize 2.4.
Table 2.2. Screening of Lewis acid Catalysts.
Entry Catalyst Conversion (%)
a
1 CeCl 3 22
2 ScCl 3 37
3 FeCl 3 41
4 InCl 3 52
5 Y(OTf) 3 88
6 ZnBr 2 92
7 In(OTf) 3 100
a
Conversion was calculated by
1
H NMR integration.
2.3. Optimization of the Tandem Sequence and Substrate Scope for Reactions
from Tryptamine
2.3.1. Optimization
After optimizing the two independent steps of our proposed synthetic sequence, we next
turned to combining these steps in a tandem reaction (Table 2.3). Coupling 2.2 and 2.1 (1.5 equiv)
with 1% C4 and 10% In(OTf)3 in toluene yields a mixture of the expected product 2.5 and its N-
benzylated derivative 2.6 (Entries 1-3). Surprisingly, the combined yield is reduced when we
perform the reaction as a two-step synthesis in a single reactor (compare entries 2 and 3), although
this afforded higher selectivity for 2.5. Selectivity for 2.6 was optimized by increasing the
concentration of benzyl alcohol (2.1): reactions with 5 or 10 equivalents of 2.1 produced 2.6
exclusively (Entries 4-7) with the added benefit of protecting the product amine.
36
Table 2.3. Optimization of the Tandem Sequence.
Entry BnOH
(equiv)
Solvent Temp (
o
C) Yield (%)
a
2.5 2.6
1 1.5 toluene 120 43
b
33
b
2 2.5 toluene 120 39 36
3
c
2.5 toluene 120 44 14
4 5 toluene 120 72
5 10 toluene 120 85
6 5 neat 110 81
7 10 neat 110 60
a
NMR yield with mesitylene as the internal standard.
b
Yield is based on tryptamine.
c
C4, 2.1 and 2.2 were mixed and
refluxed in toluene. After 24 h, 10% In(OTf) 3 was added and refluxed for another 24 h.
2.3.2. Substrate Scope
With high-yielding conditions for the tandem process, we moved on to study its substrate
scope (Table 2.4). A variety of benzylic alcohols participate in the reaction, with the best yields
resulting from catalyst loading of 3 mol % (Entries 4-6). In each of these examples, tryptamine
was completely consumed after 24 hours (
1
H NMR), indicating that side reactions of tryptamine
frustrate material balance. Added catalyst appears to accelerate alcohol oxidation (and thus imine
formation and PSR) relative to tryptamine decomposition.
37
Table 2.4. Substrate Scope for Tandem Pictet-Spengler Reaction of Tryptamine with Benzylic
Alcohols.
Entry X Product Yield (%)
a
1 H 2.6 79
2 F 2.6b 54
3 Cl 2.6c 7
4
b
Br 2.6d 7
5
c
Br 2.6d 29
6
d
Br 2.6d 55
7 SMe 2.6e 29
8 OMe 2.6f 20
a
Isolated yield.
b
with 0.5 mol % catalyst C4.
c
with 1 mol % catalyst C4.
d
with 3 mol % catalyst C4.
2.4. Optimization of the Tandem Sequence and Substrate Scope for Reactions
from N-Benzyltryptamine
2.4.1 Optimization
Different conditions were tried to optimize the tandem oxidation/PSR reaction of N-
benzyltryptamine with benzylic alcohols. Results are summarized in Table 2.5. While formation
of 2.6 from 2.3 proceeds with similar yield to its formation from tryptamine itself (Table 2.4, entry
1), coupling of 2.3 with fluoro- and bromobenzyl alcohol resulted in moderate yield (Entry 2-3).
Increasing the time from 24 h to 96 h did not increase the yield in neat conditions, but these worked
well in refluxing toluene.
38
Table 2.5. Optimization of Tandem Pictet-Spengler Reaction of N-Benzyltryptamine with
Benzylic Alcohols.
Entry X Solvent Temp (
o
C) Time (h) Yield (%)
a
1 H neat 110 24 75
2 Br neat 110 24 62
3 F neat 110 24 55
4 Br neat 110 96 68
5 Br toluene 120 24 34
6 Br toluene 120 96 79
a
NMR yield.
2.4.2. Substrate Scope
Thus, protecting tryptamine as its N-benzylamine (2.3) removes side reactions and enables
a broad substrate scope (Table 2.6). We found good functional group tolerance among benzyl
alcohols bearing fluoro, bromo, t-butyl, and thioether groups at the para position, each affording
the corresponding tetrahydro-β-carboline in a high yield (Entries 2-5). Electron withdrawing ester
(Entry 6) and thiophenyl groups (Entries 8 and 11) are also well tolerated. Oddly, a reaction with
methoxybenzyl alcohol was less successful (Entry 7), even in cases where the respective coupling
components were added slowly.
In addition to aryl and heteroaryl carbinols, various aliphatic alcohols participate in the
tandem reaction under slightly modified conditions (Table 2.6, entries 9-11). This was unexpected,
whereas we’ve recently reported that catalyst loadings well below 1 mol % are needed to enable
alcohol amination with catalyst C4.
16m
As low boiling point of the aliphatic alcohols prevented us
from running their reaction in an open reactor, we identified suitable closed reactor conditions
39
incorporating styrene as a hydrogen acceptor. Besides the entries in the table 2.6, we isolated the
tandem product with 1-naphthalenemethanol in 52% yield (2.7l); but the product was not fully
characterized (see figure 6.2.54 for
1
H NMR)
Table 2.6. Substrate Scope for the Tandem Sequence.
Entry R Product Yield (%)
a
1 R' = H 2.6 73
2 R' = F 2.7b 70
3 R' = Br 2.7c 78
4 R' = t-Bu 2.7d 72
5 R' = SMe 2.7e 70
6 R' = CO 2Me 2.7f 51 (72)
b
7 R' = OMe 2.7g 43
8
2.7h 56
9
c
2.7i 47
10
c
2.7j 70
11
c
2.7k 55
a
Isolated yield.
b
With CF 3COOH as the acid catalyst.
c
A mixture of N-benzyltryptamine (0.2 mmol), alcohol (1 mmol),
styrene (1 mmol), C4 (1 mol %) and In(OTf) 3 (10 mol %) was stirred at 110
o
C for 96 h in a closed reactor. * shows
the carbon in which CH 2OH is attached.
2.4.3. Alcohols that are Bad Coupling Partners
Even though our tandem alcohol oxidation/PSR sequence worked with variety of benzylic
and aliphatic alcohols, we found several alcohols (Figure 2.2) that are not suitable with this tandem
sequence under our optimized condition. We observed either starting materials or polymerized
product, or decomposition of the starting materials in these cases. However, coupling of N-
40
benzyltryptmaine with 1-adamantanemethanol in the presence of 1 equivalent trifluoroacetic acid
yielded 24% of the desired tetrahydro-β-carboline compared to 0% product with 10% In(OTf)3.
But we never optimized this reaction and explored the possibility of TFA as the acid catalyst with
the other alcohol substrates in the figure 2.2.
Figure 2.2. List of alcohols that didn’t show tandem PSR product
a
.
a
General reaction condition: A mixture of N-benzyltryptamine (0.2 mmol), alcohol (0.4 mmol), C4 (1 mol %) and
In(OTf) 3 (10 mol %) was refluxed in toluene at 120
o
C for 96 h.
2.4.4. Tandem PSR with Aliphatic Alcohols
Unlike benzylic alcohols and heterocyclic carbinols, which showed either desired
tetrahydro-β-carbolines or starting material during the reaction, aliphatic alcohols produced both
the desired cyclic product and uncyclized N-alkylation compounds (Table 2.7). Moreover, the low
boiling point of aliphatic alcohols resulted in reduced yield with the open flask condition. Thus,
we screened closed reactor conditions with different hydrogen acceptors such as benzoquinone,
neohexene, and styrene. While styrene and neohexene gave mixture of cyclic and acyclic product
with higher yield compared to the open flask condition without a hydrogen acceptor, benzoquinone
undergoes series of reactions (Scheme 6.2.1) with N-benzyltryptamine that begins with two
Michael addition steps (Entry 4).
41
Table 2.7. Optimization of Tandem PSR with Aliphatic Alcohols.
Entry x y Hydrogen Abstractor Condition Observation
1 5 2 none toluene, reflux, open flask, N 2 I (20%) + II (26%)
2 5 1 styrene neat, 110
o
C, closed flask, N 2 I (10%) + II (70%)
3 2 1 neohexene " I (21%) + II (45%)
4 2 1 benzoquinone "
2.5. Deprotection of 2.6 to Free Amine 2.5
Introduction of the N-benzylamino group of 2.3 is not simply a strategy for improved yield:
it is a versatile protecting group that enables differential substitution of this nitrogen through its
convenient cleavage. While this deprotection has a potential complication of opening the newly
formed piperidine ring, we find chemoselective cleavage of 2.6 with hydrogen and Pd/BaSO4 to
give 2.5 in 80% yield upon screening various heterogeneous hydrogenation catalysts (Table 2.8).
42
Table 2.8. Screening of Catalysts for N-Benzyl Deprotection of 2.6.
Entry Catalyst (mol %) Time (h) 2.6 (%) 2.5 (%) 2.5' (%)
1 Pd/C (7%) 5 0 81 19
2
Pd/C (4%) 5 0 80 20
3
a
Pd/C (7%) 9 ✓ ✓ ✓
4 Pd/BaSO 4 (7%) 5 0 87 13
5 Pd(OH) 2/C (7%) 5 0 79 21
6 Pd/CaCO 3 (7%)
(poisoned with Pb)
5 100 0 0
7
PdCl 2 (1.2 equiv) 5 ✓ ✓ ✓
8 Pt/C (7%) 5 ✓ ✓ ✓
9 Pt/alumina (7%) 5 ✓ ✓ ✓
a
Reaction is done at 5 °C. The symbol ✓ indicates the presence of the corresponding compound in the mixture by
TLC analysis.
Palladium catalysts on different solid support gave full conversion of the starting material
after 5 hours of stirring at 25 °C except in the case of entry 6, where the catalyst is poisoned with
lead. Reducing the temperature to 5 °C (Entry 3) didn’t help to attain chemoselectivity. Even
though, reactions catalyzed by PdCl2 or platinum catalysts on solid supports at 1 atm H2 are slow,
each giving both 2.5 and 2.5'.
2.6. Other Catalyst Screening for Tandem PSR
While our results demonstrate a unique combination of hydrogen borrowing amination
conditions and the PSR, we thought it prudent to check whether the few other known hydrogen
borrowing catalysts might also affect the tandem process. We screened iridium homologues of C4,
complexes C13 and C14,
21
and base-free amination catalysts
17c-d
[Cp*IrCl2]2 and [Cp*IrI2]2
(Figure 2.3). We found that each of these complexes returns starting materials, octanol and 2.3,
under the tandem conditions. Thus, ruthenium complex C4 is the only catalyst we find for the
tandem sequence.
43
Figure 2.3. Other amine-alkylation catalysts.
2.7. Mechanism for the Tandem Sequence
Since 2.3, a secondary amine, is a convenient substrate for our reaction, the intermediate
iminium ion resulting from its condensation with an aldehyde need not be further activated to
enable cyclization. By contrast, imine of the parent tryptamine must be activated by a proton or
Lewis acid. Oddly, reactions of 2.3 retain the need for the In(OTf)3 co-catalyst, so we went about
studying the mechanism
22
of our reaction to identify the role of the Lewis acid. Role of the metal
catalyst in the amination is discussed in Chapter 1,
16m
so we limit this discussion to the sequence
of organic intermediates in the tandem process.
Scheme 2.1. Proposed Mechanisms for the Tandem Sequence.
C13 C14
44
Pathways for the reactions starting from tryptamine (2.2) and N-benzyltryptamine (2.3) are
shown in Scheme 2.1. In the first, tryptamine undergoes condensation with benzaldehyde,
generated in situ, to form 2.4. It can either undergo ring closure in the presence of indium triflate
to afford 2.5 or can be reduced to 2.3. We compared the relative rates of these potentially
competing reactions by analyzing the product distribution in the reaction between 2.4 and 4-
fluorobenzyl alcohol under the catalytic conditions (Scheme 6.2.2). We found that 2.4 converts to
a mixture of 36% of 2.5 and 38% of 2.5b and 2.3b together, where Ph' is a fluorophenyl group.
This indicates that under the tandem conditions both 2.5b and 2.3b are formed and that the
cyclization step (2.4 to 2.5) is faster than the imine reduction (2.4 to 2.3) and the second amination
step (2.5 to 2.5b). This mechanism accounts for the crucial role of the Lewis acid and explains the
distribution of products 2.5 and 2.6 observed in Table 2.3.
When the reaction proceeds from N-benzyltryptamine 2.3, it can take only one pathway
(highlighted on the right of Scheme 2.1). This sequence starts with the formation of iminium ion
2.3a, followed by cyclization to give 2.3b. This formal iminium ion is more electrophilic than the
imine involved in the parent sequence. We perceive that this is one of the advantages of N-
benzyltryptamine as a substrate for the tandem reaction. This sequence proceeds without an acid
catalyst, albeit at lower yield, compare 32% to 73% (Table 2.9), so indium is important but non-
essential. When catalytic indium is replaced with one equivalent of MgSO4 in the reaction of 2.3
with 4-bromobenzyl alcohol, we see similar yields, 78% and 74%. In contrast, the parent
tryptamine cyclization yielded product 2.6 in 20% yield with MgSO4 compared to 79% with
catalytic In(OTf)3. We speculate that the role of indium or magnesium in reactions of 2.3 could be
a dehydrating agent driving iminium formation, rather than Lewis acid promoting iminium
activation.
45
Table 2.9. Substituting MgSO4 for In(OTf)3 in the Tandem Sequence.
Entry X Y Conditions Product and Yield
a
1 H H 1 mol % C4, 1 equiv MgSO 4, neat, 110
o
C, 24 h 2.6 (20%)
2 H H 1 mol % C4, 10 mol % In(OTf) 3, neat, 110
o
C, 24 h 2.6 (79%)
b
3 CH 2Ph H 1 mol % C4, No In(OTf) 3, neat, 110
o
C, 24 h 2.6 (32%)
4 CH 2Ph H 1 mol % C4, 10 mol % In(OTf) 3, toluene, reflux, 96 h 2.6 (73%)
b
5 CH 2Ph Br 1 mol % C4, 10 mol % In(OTf) 3, toluene, reflux, 96 h 2.7c (78%)
b
6 CH 2Ph Br 1 mol % C4, 1 equiv MgSO 4, toluene, reflux, 96 h 2.7c (74%)
a
NMR yield with mesitylene as the internal standard.
b
Isolated yield.
Unlike the parent tryptamine reaction, two products are possible when N-benzyltryptamine
reacts with an alcohol, because either the starting N-benzyl group or the added alcohol could
potentially participate in the cyclization. We observe one product,
23
which has only the added
alcohol participating in cyclization. Isotopic labeling supports this point (Scheme 2.2): reaction of
2.3 and benzyl alcohol-d3, 2.1-d3, gives 2.6-d1 along with its
1
H isotopolog (ca. 25%), but no other
labeled species. A
2
H NMR spectrum (Figure 6.2.14) of the isolated product shows a singlet at
4.67 ppm corresponding to the aliphatic CD position of 2.6-d1. No
2
H is observed at the methylene
positions of 2.6-d1 (3.89 and 3.37 ppm). The absence of
1
H/
2
H scrambling combined with the
reaction’s selectivity for 2.3b indicates that the hydride abstraction from 2.3 is prohibitively slow.
This precludes from our mechanism all C-H oxidation pathways in which 2.3 is the hydride donor.
Scheme 2.2. Deuterium Labeling Experiment.
46
2.8. Reaction of Tryptamine with Diols to Access Tetracyclic Alkaloids
2.8.1. Screening of Acid Catalysts
As a first step towards developing a biomimetic cascade sequence, we tried to develop a
tandem reaction of tryptamine with diols to access one-step total synthesis of tetracyclic alkaloids.
However, In(OTf)3 was inefficient in catalyzing the cyclization step of the tandem sequence; and
we observed only the N-alkylation compounds (Scheme 2.3).
Scheme 2.3. Reaction of Tryptamine with Diols in the Presence of In(OTf)3.
a
NMR yield with mesitylene as the internal standard.
Then, we screened different Bronsted acid catalysts to drive the reactions to tetracyclic
alkaloid (Table 2.10). But the use of Bronsted acids lead to either decomposition or precipitation
of the starting material in most cases. Thus, we screened various solvents to examine the solubility
of starting materials and reaction mixtures. Results are summarized in Table 2.11. Even though,
dioxane, 1,1,2,2,-tetrachloroethane, diglyme, and tetrahydrofuran showed good solubility
properties, we only employed the first two for screening reactions as their boiling points are
appropriate with our reaction conditions. Unfortunately, those reactions gave back starting
materials. Hence, we proceeded with TFA in toluene from Table 2.10 for reaction optimization.
47
Table 2.10. Screening of Bronsted Acid Catalysts.
Entry Bronsted Acid (mol %) Observation
a
1 CF 3COOH (20) A (major) + B (trace)
2 p-TSA (100) tryptamine precipitated out; only A
3 CH 3SO 3H (100) tryptamine precipitated out
4 CH 3SO 3H (40) tryptamine precipitated out; A (16%)
5 H 3PO 4 (65) tryptamine precipitated out
6 TfOH (10) some starting material got decomposed; A (25%) + B (trace)
7 TfOH
b
(50) A (55%)
a
The reaction mixture was quenched with KOH after 96 h, then extracted it in DCM and analyzed by
1
H NMR.
b
Reaction condition: neat, 110
O
C, 24 h
Table 2.11. Screening of Solvents.
Entry Solvent Solubility
Tryptamine 1,4-Butanediol Tryptamine+1,4-butanediol+
CH 3SO 3H
1 toluene insoluble insoluble turbid when mixed; white
precipitate and brown paste
were formed upon heating.
2 dioxane soluble soluble turbid when mixed; but turned
to clear solution when heated.
3 diglyme soluble soluble soluble
4 CH 2Cl-CH 2Cl insoluble soluble insoluble; brown paste was
formed while heating
5 CHCl 2-CHCl 2 soluble insoluble turbid when mixed; but turned
to clear solution when heated.
6 THF soluble soluble turbid when mixed; but turned
to clear solution when heated.
7 EtOAc almost soluble almost soluble turbid when mixed; white
precipitate was formed upon
heating.
8 chlorobenzene insoluble insoluble insoluble
Finally, reaction of tryptamine with 1,4-butanediol in the presence of 1 equivalent
trifluoroacetic acid yielded a one-step total synthesis of harmicine (2.8), a natural product with
antileishmanial
24
and antinociceptive
25
activity. The reaction connects 3 bonds and two rings in
50% yield overall (Scheme 2.4), with tryptamine’s trifluoroacetamide (33%) as the sole side
48
product (Table 6.2.2). Multistep synthesis of (R)-harmicine by enzyme catalysis has been
reported.
26
Our method for the fused ring construction on the THBC core is an important platform
for the alkaloid total synthesis in addition to being a remarkable example of two hydrogen-
borrowing aminations in the presence of an acid. In addition, employment of same condition with
tryptamine and 1,5-pentanediol produced the corresponding tetracyclic alkaloid in 30% yield with
54% tryptamine’s trifluoroacetamide (Figure 6.2.16). Further studies aiming at more complex
heterocycles in high yield are ongoing.
Scheme 2.4. One-Step Synthesis of Harmicine.
2.8.2. Exploring other Strategies to Access Tetracyclic Alkaloids
Proposed Mechanism for the Reaction of Tryptamine with 1,4-Butanediol
We proposed a mechanism for the harmicine synthesis from tryptamine and diol (Scheme
2.5). Tryptamine undergoes condensation with the aldehyde generated in situ from the oxidation
of one of the alcohol groups in diol and generates compound A. This can either undergo cyclization
in the presence of an acid catalyst to produce tetrahydro-β-carboline I or can be reduced to
compound B. Then both compounds I and B will undergo condensation reaction to yield II and C
respectively. When compound II gives harmicine after reduction, C has two fates; it can be
cyclized to harmicine or reduced to pyrrolidine compound D. Reduction of A to B is faster than
cyclization to I as we observed mixture of harmicine (trace) and D (major) while screening acid
catalysts (Table 2.10). Moreover, we never observed the intermediate I in the reaction mixture.
49
Scheme 2.5. Proposed Mechanism for the Reaction of Tryptamine with 1,4-Butanediol.
Reaction of Tryptamine with Monoprotected Diol
As the major pathway involves the formation of compound B, we thought it is prudent to
explore a reaction strategy from a pre-synthesized compound B. Reactions of tryptamine with
monoprotected diols (See chapter 6 for its synthesis) showed either trace of monoprotected B or
starting material or harmicine (Table 6.2.3). Then we synthesized the compound B by opening the
γ-lactone with tryptamine followed by LAH reduction (Scheme 2.6). However, the reactions from
B favored formation of pyrrolidine compound (D) over harmicine (Scheme 2.7). This proves that
reduction of enamine intermediate is faster than iminium ion cyclization. This also explains the
preference of harmicine in a strong acid catalyst TFA compared to In(OTf)3 condition that we
observed in section 2.8.1.
Scheme 2.6. Synthesis of Compound B.
50
Scheme 2.7. Cyclization of Compound B.
Reaction of Tryptamine with Dihydropyran
Next, we explored the possibility of tryptamine protection with a THP group, followed by
a ring opening of the semi cyclic N-O acetal, and then the cyclization of iminium ion to tetracyclic
alkaloid (Scheme 2.8). Even though, we tried different conditions to proceed in the schematic way,
none of them were fruitful (Table 6.2.4). Thus, a tandem synthetic strategy of tetracyclic alkaloid
consisting of an enamine intermediate with a long lifetime and a strong acid catalyst is yet an open
question to explore.
Scheme 2.8. Proposed Synthetic Strategy to Tetracyclic Alkaloid from DHP.
2.9. Exploring Other Amine Substrates in Tandem PSR
Nucleophilicity of tryptamine plays a vital role in Pictet-Spengler reaction. Keeping this in
mind, we also screened some other substrates like L-tryptophan methyl ester hydrochloride,
tyramine and homoveratrylamine to develop a tandem amine oxidation/PSR sequence. We were
unable to discover conditions for tetrahydro-β-carboline synthesis from L-tryptophan methyl ester
hydrochloride because of stability and solubility issues. Its free base is not stable, and the
hydrochloride salt is not suitable with our toluene reflux condition. Even though use of water as
the solvent helped to dissolve the amine salt, those reactions were not successful as water poison
51
our catalyst. Next, we tried a reaction of tyramine with benzyl alcohol in the presence of ScCl 3.
This showed coupled imine as the major species and the PSR product was not observed. We never
optimized this reaction.
Homoveratrylamine is an analogue of human neurotransmitter dopamine with replacing
the two hydroxyl groups by methoxy groups. Those methoxy groups increase the nucleophilicity
of the amine; thus, we were expecting it as a good substrate for our tandem PSR. Regardless of the
various conditions that we screened to produce the desired tetrahydro-β-carboline selectively, all
of them generated mixtures of monoalkylated amine, dialkylated amine, imine, and PSR products
(Table 2.12). Although we coupled N-benzyl homoveratrylamine with benzyl alcohol to generate
more electrophilic iminium ion as the intermediate rather than the imine, a strategy that worked in
the case of tryptamine, those reactions still showed mixtures of compounds (Table 2.13).
52
Table 2.12. Coupling of Homoveratrylamine with Alcohols.
Entry Amine:
Alcohol
R Acid Catalyst
(mol %)
Condition Observation
a
1 1:3 H In(OTf) 3 (10) toluene, reflux, open flask, 96 h B (18%) + C (16%) +
D (20%)
2 1:5 H " neat, 110
o
C, open flask, 24 h A (17%) + B (48%) +
C (20%)
3 1:5 H " neat, 110
o
C, open flask, 96 h found only A and B
(48%)
4 1:3 H CH 3SO 3H
(50)
toluene, reflux, open flask, 24 h found A, C and
homoveratrylamine as
the major peaks along
with trace of D.
5 1:3 CO 2Me In(OTf) 3 (10) toluene, reflux, open flask, 96 h B (12%) + C (16%) +
D (29%)
a
Reaction mixture was analyzed by NMR spectroscopy.
53
Table 2.13. Coupling of N-Benzylhomoveratrylamine with Alcohols.
Entry Catalyst Condition Observation
a
1 C4 (1 mol %), In(OTf) 3 (10
mol %)
toluene, reflux, open flask, 96 h only B (68%)
2 " styrene (2 equiv), neat,
110
o
C, closed Schlenk reactor,
96 h
showed only B and unreacted A
3 C4 (0.5 mol %),
TFA (1 equiv)
toluene, reflux, open flask, 96 h found mainly unreacted A as 1
equiv TFA protonated A.
B (17%) + D (26%)
4 C4 (1 mol %),
TFA (1 equiv)
" A, B and D in 1:1:1 ratio.
a
Reaction mixture was analyzed by NMR spectroscopy.
2.10. Conclusion
In conclusion, we describe the catalytic, tandem synthesis of tetrahydro-β-carbolines from
N-benzyltryptamine and alcohols. This method is applicable to benzylic alcohols, heterocycles,
and aliphatic alcohols when styrene is used as a hydrogen acceptor. Our mechanistic studies
suggest two separate pathways for reactions starting from tryptamine or N-benzyltryptamine. The
latter case involves formation of a free iminium ion intermediate, so the role of the indium co-
catalyst changes. H/D labeling shows that secondary amine/imine equilibrium is prohibitively slow
in our system. This governs the product selectivity for N-benzyltryptamine reactions. The tandem
sequence enables the formation of the ABCD ring of indole alkaloids like harmicine in a single
step.
54
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13
C and HMBC spectra:
13
C NMR shows
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58
Chapter 3. Synthesis of 1,4-Diazacycles from Diamines and Diols
This chapter comprise a manuscript that is prepared for ACS Catalysis submission. Adrian
Tam, an undergraduate student, contributed to this work by synthesizing and purifying substituted
diamine substrates.
3.1. Introduction
Diazacycles are privileged motifs of medicinal chemistry. For example, piperazine is the
third most common nitrogen heterocycle and the fifth most common ring system in small-molecule
drugs, including cyclizine, cetirizine, and sitagliptin (Figure 3.1).
1,2
Similarly, diazepanes, the
corresponding seven-membered diazacycles, are found in numerous drugs including
homochlorcyclizine and homofenazine (Figure 3.1).
3
Several useful piperazines syntheses are
known,
4
but the same is not true diazepanes, where cyclization is kinetically and energetically
more challenging.
Incumbent approaches to diazepanes span from classical methods such as
amination of halides,
5
reaction of primary amines with vinyl cyanides,
6
reductive amination
7
to
intermolecular cyclization,
8
intramolecular cyclization,
9
and Bode’s new SnAP reagents.
10
We are
particularly motivated to introduce hydrogen borrowing conditions to this toolkit
11
to deliver three
key advantages: (1) these enable access to structures that are not easily accessed in other ways; (2)
these generate water as the sole byproduct, making them atom- and cost-efficient and
environmentally friendly; (3) these access products directly from amines and alcohols, which are
inexpensive and readily available.
59
Figure 3.1. Examples of 1,4-diazacycles in drugs.
Our lab has developed a ruthenium catalyst (C4) that enables hydrogen borrowing
amination on substrates such as phenols, anilines, indoles, and halides, that are challenging or
incompatible with other catalysts (Figure 3.2).
12
Complex C4 further facilitates a tandem alcohol
amination/Pictet-Spengler reaction for the synthesis of tetrahydro-ß-carbolines, owing to its
unique ability to operate independently of base, thus enabling an acid-catalyzed Pictet-Spengler
reaction in situ.
13
Hypothesizing that chelation of starting diamines was the principle hurdle to a
hydrogen borrowing route to diazacycles, we suspected that this same ruthenium catalyst might be
tolerant of chelating diamines, thus avoiding this peril and cyclizing simple diamines and diols
where other catalysts struggle. While C4 is not unique in the formation of piperazines,
14
we
perceive a need to address low yield, high catalyst loading, long reaction time, or limited substrate
scope (Figure 3.2) and fill the void for methods for the synthesis of 1,4-diazepanes from diamines
and diols.
7b, 11,15
Ruthenium complex C4 efficiently cyclizes diamines and diols to yield piperazine and 1,4-
diazepane products. Furthermore, we show how our strategy can be applied to drugs such as
60
cyclizine and homochlorcyclizine. While excellent progress has been made by others (Figure 3.2),
we know of no other method to synthesize these drugs from diamines/diols with a hydrogen
borrowing approach. Particularly, we attribute this to the chelating behavior of 1,2- and 1,3-
diamines, which are known to poison many hydride transfer catalysts (vide infra). Therefore, by
overcoming this poisoning problem, our synthetic strategy will enable the synthesis of otherwise
challenging 1,4-diazacycles and related APIs from accessible starting materials that were not
previously viable approaches for these heterocycles.
Figure 3.2. Previous work and proposed hydrogen borrowing strategy to access 1,4-diazacycles.
61
3.2. Optimization of the Homopiperazine Synthesis
Whereas efficient routes to piperazines are known, we began by optimizing our reaction
for seven-membered ring synthesis (Table 3.1), using N,Nʹ-dibenzylethylenediamine (3.1a) and
1,3-propanediol (3.2a). Beginning from our previous N-alkylation conditions with C4 (Table 1,
entry 1), we went about finding conditions for a tandem cycloaddition reaction. The best conditions
supply the diol in gentle excess, with diminishing returns beyond 2 equivalents (compare entries
1/2 with 3, 4 and 5). Even though water is a side product, addition of molecular sieves decreased
the yield (Table 3.1, entry 6), possibly because they impede stirring of the neat reaction. Reducing
the catalyst loading (Table 3.1, entry 7) and reaction time (Table 3.1, entry 8 and 9) decreased
conversion. In the case of entry 5, LC-QTOF studies account for the material balance by showing
imine and an oligomeric material along with the desired product (Figure 6.3.2).
Table 3.1. Optimization of the Homopiperazine Synthesis.
Entry Diamine: Diol C4 (mol %) t (h) Yield (%)
a
1 1:1 1.0 44 71
2 2:1 1.0 44 33
3 1:2 1.0 44 84
4 1:3 1.0 44 80
5 1:4 1.0 44 80
6
b
1:2 1.0 44 66
7 1:2 0.5 44 72
8 1:2 1.0 10 60
9 1:2 1.0 24 78
a
NMR yield with mesitylene as the internal standard.
b
With 4 Å molecular sieves.
62
3.3. Substrate Scope
3.3.1. Synthesis of Piperazines
With high yielding conditions in hand, we proceeded to study the reaction’s scope. While
many useful methods exist for the formation of six-membered piperazine rings, we demonstrate
here some representative examples of how catalyst C4 can contribute to this area (Table 3.2).
These reactions proceed in high yield as expected (Table 3.2, entries 1-3). Compound 3.5a has
special value as a medicinal entity, whereas it has high affinity for sigma receptors and shows
anticocaine activity.
16
Importantly, reaction of chiral diamines retained their configuration through
the reaction, which is consistent with our mechanistic studies showing irreversibility of imine
hydrogenation with catalyst C4.
13
For example, coupling of (1R,2R)-N,N’-dibenzylcyclohexane-
1,2-diamine (3.1b) with ethylene glycol (3.4a) afforded 3.5b with trans configuration and > 99%
ee. Product 3.5b belongs to the decahydroquinoxalines class of compounds, which are potent and
selective κ-opioid receptor agonist with anti-inflammatory activity.
17
In addition to this, compound
3.5c, generated from N-benzyl-Nʹ-hydroxyethyl ethylenediamine (3.1c), is a structural motif found
in APIs like opipramol and cetirizine. This example shows that our process works well in the
presence of free hydroxyl groups, with minimal side reactivity.
63
Table 3.2. Substrate Scope for Piperazine Synthesis.
Entry Diamine x: y C4 (mol %) Product Yield (%)
1
3.1a
1:2 2
3.5a
86
2
3.1b
1:4 5
3.5b
84
3
3.1c
1:3 1
3.5c
78
3.3.2. Synthesis of 1,4-Diazepanes
Unlike the corresponding piperazines, few catalytic syntheses are known for the analogous
diazepanes. Table 3.3 show examples of diazepane synthesis featuring various substitution. While
substituents on either the diamine or diol partner are tolerated, coupling between diamines and
diols having substituent on both partners were less successful (see examples in Scheme 6.3.5). We
further encountered an unanticipated advantage of utilizing glycols (as opposed to propane diols)
as coupling partners: N,Nʹ-dibenzylhomopiperazine (3.3a) is formed more efficiently from a three
carbon diamine and a two carbon diol compared to the complementary reaction involving a three
carbon diol (compare Table 3.3, entries 1 and 2 and other examples in Scheme 6.3.8). We attribute
this to the availability of a tautomerization pathway in the former case, which is sketched in
Scheme 3.1A. Here, the requisite second aldehyde (3.8) is generated from an intermediate iminium
ion (3.6) through tautomerization of enamine 3.7. By contrast, redox steps are needed to generate
the second aldehyde (3.11) from iminium ion 3.9 in the case of reaction with propanediols (Scheme
64
3.1B). We infer that while both routes are accessible, the former is more efficient and leads to
higher yielding reactions.
Scheme 3.1. Synthesis of 1,4-Diazepane A) from Three Carbon Diamine and Two Carbon Diol
B) from Two Carbon Diamine and Three Carbon Diol.
The scope of diazepane synthesis is further developed in Table 3.3. Alkyl groups are
generally well tolerated either on the diamine or diol partner. For example, methyl substituted two-
or three-carbon diols (Table 3.3, entries 3-5), and an ethyl-substituted diamine (Table 3.3, entry 6)
afford the corresponding diazepanes in good yield. In the case of coupling a methyl-substituted
diamine (3.1d) with chiral glycol 3.4c (compare entries 3 and 4), a racemic cycloadduct (3.3b)
results as expected, due to a planar intermediate aldehyde. These alkyl-substituted products are
pharmaceutically valuable compounds, in fact 3.3c has been employed as an intermediate in the
preparation of suvorexant,
18, 19
an FDA approved drug used to treat insomnia.
In addition to the benzyl group, we illustrate other substituents on nitrogen such as
cyclohexyl methyl, methyl, isopropyl, and hydroxyethyl (Table 3.3, entries 7-11). These structures
65
have special value, particularly whereas compounds 3.3f and 3.3g belong to a class of methyl-
substituted diazepanes that are found in the APIs emedastine and homochlorcyclizine, and these
structures are not easily prepared through other catalytic approaches. Further, N,N'-diisopropyl
homopiperazine (3.3h) is used as a ligand for asymmetric deprotonation of N-Boc pyrrolidine.
20
Although, 1,4-diazepanes are observed as the major product in most cases, formation of
materials such as hemiaminal and acyclic products are possible with some substrates. For example,
we observed competition between intermolecular and intramolecular reactions in the case of N-
benzyl-Nʹ-hydroxyethyl ethylenediamine (3.1c) and diols (see Table 6.3.4 and Table 6.3.5). We
successfully optimized the conditions to access our desired 1,4-diazepanes 3.5c (Table 3.2, entry
3) and 3.3i (Table 3.3, entry11). Product 3.3i represent structural motifs common in APIs such as
dilazep and homofenazine.
Bicyclic compounds are attractive targets for our reaction scope (Table 3.2, entry 2; Table
3.3, entries 12-13). A sterically demanding spirocyclic diol (3.2c) produced hemiaminal 3.3j
selectively instead of a simple amine alkylation compound (Table 3.3, entry 12). When we treated
N,Nʹ-dibenzyl-1,3-propanediamine (3.1d) with cis-cyclopentanediol (3.4d), we observed cis-fused
product 3.3k exclusively (Table 3.3, entry 13). Retention of configuration at the amine centers of
3.3k was established in the crystal structure of its PF6 salt (Figure 3.3).
Figure 3.3. Thermal ellipsoid plot of 3.3k. Counter ions and hydrogens are omitted for clarity.
66
Table 3.3. Substrate Scope.
Entry Diamine Diol x: y C4 (mol %) Product Yield (%)
1
3.1a
3.2a
1:2 1
3.3a
78
2
3.1d
3.4a
1:3 2
3.3a
86
3
3.1d
3.4b
1:3 2
3.3b
68
4
a
3.1d
3.4c
1:3 2
3.3b
60
5
3.1a
3.2b
1:3 2
3.3c
71
6
3.1e
3.4a
1:5 5
3.3d
83
7
3.1f
3.2a
1:5 1
3.3e
70
8
3.1g
3.2a
1:2 1
3.3f
71
9
3.1h
3.2a
2:1 1
3.3g
88
b
10
3.1i
3.4a
1:2 1
3.3h
80
b
11
3.1c
3.2a
1:2 1
3.3i
68
67
12
3.1a
3.2c
1:4 1
3.3j
50
c
13
3.1d
3.4d
1:2 2
3.3k
58
a
Diol was (S)-(+)-1,2-propanediol.
b
The yield was determined by
1
H NMR with mesitylene as the internal standard
due to product volatility.
c
The reaction yielded hemiaminal 3.3j exclusively.
3.3.3. Reactions with Chiral Reagents
As expected, reaction of an optically pure two-carbon alcohol yielded a racemic compound
(Table 3.3, entry 3) due to a planar aldehyde intermediate; however, reaction from an optically
pure diamine retained its trans configuration (Table 3.2, entry 2). We tried to prepare a 7-
membered analogue of 3.5b (3.5b') by choosing 1,3-propanediol instead of ethylene glycol as the
diol partner (Table 3.4). While early screening experiments returned starting materials back, the
last two experiments produced mixture of compounds along with the desired product. However,
the best outcome produced 3.5b' in 12% yield after column chromatography separation even with
complete conversion of the starting material. Identity of this novel compound was established by
1
H NMR (Figure 3.4) and LC-QTOF (Figure 3.5) analysis.
68
Table 3.4. Reaction of 3.1b with 1,3-Propanediol.
Entry Diamine: Diol x Result
1 1:2 1
1
H NMR showed starting materials
2 1:2 3
1
H NMR showed starting materials
3 1:2 5 mixture that contains desired product
4 1:4 3 mixture that contains desired product
Figure 3.4.
1
H NMR spectrum of reaction of 3.1b and 1,3-propanediol with 3 mol % C4 at 110
o
C in neat condition for 44 h after passing through a silica column in hexanes: ethyl acetate (80:20).
69
Figure 3.5. LC-QTOF spectrum of reaction of 3.1b and 1,3-propanediol with 3 mol % C4 at 110
o
C in neat condition for 44 h after passing through a silica column in hexanes: ethyl acetate (80:20).
which shows desired product (3.5b') peaks at 335.2526 (M+H)
+
.
Studies of diazepane syntheses involving the electron deficient or bulky groups Boc, CBZ,
TFA, t-butyl, or phenyl on nitrogen did not result in efficient cyclization. Ethylene diamine was
similarly unreactive, likely due to catalytic poisoning by chelation. Details of these studies are
reported in section 6.3.8.
3.4. Screening of Other Catalysts
Whilst numerous catalysts are known to participate in hydrogen borrowing amination and
none has yet been reported for diazepane synthesis, we screened other popular catalysts that we
expected could be effective for this transformation. These include [Cp*IrCl2]2,
21
[Ru(p-
cymene)Cl2]2-xantphos,
11a
(phen)NiBr2,
22
and the Shvo complex
23
(Table 6.3.7). None of these
produced a 1,4-diazepane from either an unsubstituted or substituted diamine (see Table 6.3.7 for
specific conditions). In each case, we observed starting materials in the NMR spectra of the
reaction mixture. We attribute this observation to a unique property of C4 to minimize the impact
70
of catalytic poisoning from diamine chelation in the case of substituted diamines, which we
propose to inhibit the other systems to a greater extent than C4.
3.5. Catalytic Poisoning
To get more insight into a possible mechanism of catalytic poisoning by chelation, we
conducted series of stoichiometric experiments with ethylenediamine and ruthenium catalyst C4:
logically, if ethylene diamine can chelate and deactivate the catalyst, it should be possible to shut
down reactions of C4 with enough of it (as suggested in Table 3.1, entries 1/2), and a structural
view of this poisoning should be observable. In such an experiment (Scheme 3.2A), complex C4
and ethylenediamine were heated in a 1:12 ratio at 110 °C in a Schlenk reactor. Three reactions
were respectively stopped after 15 min, 21 h, and 44 h of stirring, then heated at 75 °C under
vacuum to remove volatiles. Each mixture turned to pale yellow from orange after 15 min of
stirring, indicating formation of a new metal complex. In each, the product was analyzed by
1
H
and
31
P NMR spectroscopy in deuterated methanol. Stacked
1
H NMR spectra (Figure 6.3.12) of
the complex C4 and the respective reaction mixtures show disappearance of C4 within the 15 min
window and formation of the new complex (3.12). The aromatic regions of these spectra confirm
the respective presence of an underivatized phosphinopyridine ligand and absence of cymene in
complex 3.12. Stacked
31
P spectra (Figure 6.3.13) further show one major peak corresponding to
complex 3.12 in each sample. The structure of complex 3.12 was established crystallographically
(Figure 3.6) as a dicationic, pseudo-octahedral bis(ethylene diamine) chelate. We can show that
an excess of ethylene diamine will prevent cyclization with ethylene glycol (Scheme 3.2B): in this
case
1
H and
31
P NMR spectra show formation of 3.12 and no piperazine is observed, even after 44
h. We further show that 3.12 is incompetent in a reaction that is facile with C4: treating N,N’-
dibenzylethylenediamine with 1,3-propanediol using 1 mol % 3.12 yielded no products under
71
conditions in which complex C4 produces diazepane 3.3a in 78% yield (Scheme 3.2C).
Interestingly, catalyst poisoning is not observed in the presence of 1,3-diamines (Scheme 6.3.11):
here we observe a mixture of uncyclized and cyclized products. We attribute the reactivity
difference to the greater stability of the ethylene- versus propane-diamine chelates.
Figure 3.6. Thermal ellipsoid plots of complex 3.12 Counter ions and hydrogens are omitted for
clarity.
Scheme 3.2. Synthesis of Complex 3.12.
72
3.6. Pharmaceutical Applications
Owing to the vital importance of piperazine and diazepane substructures in medicinal
chemistry, we tested our method against two representative pharmaceutical applications (Scheme
3.3): cyclizine,
2
an FDA approved essential drug used as anti-nausea, is produced in 91% yield
from its corresponding diamine and diol. Similarly, a seven membered drug homochlorcyclizine,
3
which is marketed in Japan as an antihistamine, was synthesized in 67% yield. In addition, we
tried to develop a multistep synthesis of APIs dilazep and homofenazine which is discussed in
section 6.3.12. Our synthetic strategy has significant importance in process chemistry department
of drug discovery as it is a green, atom economic and cost-efficient approach.
Scheme 3.3. Pharmaceutical Application: Synthesis of Cyclizine and Homochlorcyclizine.
3.7. Conclusion
In conclusion, we report a catalytic synthesis of 1,4-diazacycles from diols and diamines
that is uniquely enabled by our unusually reactive (pyridyl)phosphine ruthenium(II) complex C4.
The conditions tolerate a broad substrate scope including six- and seven-membered diazacycles
with different substitution. The unique reactivity of our catalyst seems to include some resistance
to diamine chelation: while C4 is susceptible to such chelation at high diamine loading, it maintains
73
reactivity in the case of substituted diamines while other catalysts are not successful. In addition,
we applied the hydrogen-borrowing strategy to the production of pharmaceutical compounds
cyclizine and homochlorcyclizine, thus exhibiting the potential of the method in discovery or
process medicinal chemistry.
24
74
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77
Chapter 4. N-Alkylation of Guanidine Compounds by Hydrogen-
Borrowing Catalysis
This chapter comprise results of an ongoing project in Williams’ lab. Adrian Tam, an
undergraduate student, contributed to this work by screening reactions with guanidine substrates.
All reported yields in this chapter are determined from
1
H NMR spectroscopy with mesitylene as
the internal standard unless otherwise noted.
4.1. Introduction
Guanidine is an important moiety in a plethora of natural products, pharmaceuticals, and
agrochemicals (Figure 4.1).
1
For example, guanidine is found in drugs such as metformin,
epinastine, emedastine and apraclonidine.
Imidacloprid is a nicotine mimicking insecticide with
guanidine moiety and saxitoxin is a neurotoxin with complex structure. Guanidine derivatives such
as simple guanidines, cyclic guanidines, and peptides and peptidomimetics bearing guanidine
moiety have broad range of therapeutic effects such as antivirals, antithrombotic agents,
chemotherapeutic agents, antidiabetic, inhibitors of both NO synthase and Na
+
/H
+
exchanger, anti-
inflammatory etc.
2
Considering the wide spectrum of application, scarcity of methods to develop
guanidine derivatives attracted our attention to this field.
78
Figure 4.1. Representative examples of important compounds with guanidine moiety.
High basicity of guanidines with a pKa of ca. 13 and multiple nucleophilic centers make
them as a challenging group to functionalize.
3
There have been some published methods, such as
using halides with guanidine substrates, but these are usually nonselective or involve protection of
the guanidine group.
3
One of the more promising unrealized strategies is the hydrogen borrowing
reaction. This mechanism would be an efficient way to access these guanidine structures because
water is generated as the sole byproduct, making it atom- and cost-efficient as well as
environmentally friendly. There are a few examples of guanidine alkylation by a hydrogen
borrowing mechanism, but these are extremely limited in scope.
4
To the best of our knowledge,
there has not been a reported reaction on the alkylation of guanidines using a hydrogen borrowing
mechanism that also demonstrates a wide scope of guanidine substrates.
5
79
Our group has developed a ruthenium catalyst (C4) that follows a hydrogen borrowing
mechanism. This catalyst is unique in that it can function under base and solvent-free conditions
(Scheme 4.1). Previously, this ruthenium catalyst has shown success in the N-alkylation of
amines,
6
a tandem alcohol amination/Pictet-Spengler reaction
7
to synthesize tetrahydro-β-
carbolines as well as the synthesis of diazacycles from diamines and diols.
8
Building off these
reactions, we have focused on harnessing this same complex C4 to alkylate guanidines. In this
paper, we will demonstrate that C4 can be used to alkylate guanidine substrates with different
alcohols. Furthermore, we will show how this catalyst can be used to access imidazolines by a
guanidine-diol coupling
Scheme 4.1. Previous Work and Proposed Strategy for N-Alkylation of Guanidines.
80
4.2. Substrate Scope
We screened different guanidine derivatives such as triazabicyclodecene (TBD), 2-
aminobenzimidazole, guanine, creatin, etc. with wide variety of alcohols including primary,
secondary, cyclic, and benzylic alcohols. TBD is a bicyclic guanidine with a pKa of ca 15. This is
utilized as a catalyst in carboxylative cyclization
9
and addition of nitromethane to
cyclopentenone,
10
as a chemiluminescence booster,
11
and a bifunctional organocatalyst for acyl
transfer and ring opening polymerization of cyclic esters.
12
However, functionalization of TBD by
hydrogen-borrowing is not reported yet. Here, we demonstrate efficient coupling of TBD with
primary alcohols, secondary alcohols, and benzylic alcohols in the presence of a ruthenium
catalyst.
4.2.1. N -Alkylation of Triazabicyclodecene with Primary Aliphatic Alcohols
Straight chain alcohols are good coupling partners for TBD and showed excellent yields
with n-butanol and 1-octanol. Reported synthesis of n-butyl TBD (4.2a) utilize nucleophilic
substitution reaction with n-butyl bromide to afford the product in 45% yield.
13
Thus, our reaction
is a better alternative not only in terms of sustainable, atom economic, and cost-effective ways,
but offers a significant improvement in the yield also. It is noteworthy to mention that our
conditions tolerate strained alcohols (4.2d), bulky structures (4.2e), and heterocyclic moieties
(4.2f). All reactions can be further optimized for a better outcome as complete conversion is not
achieved with the condition we screened. While coupling of TBD with methanol, cyclohexyl
methanol, neopentyl alcohol, and 1H-benzimidazole-2-methanol returned starting materials,
reactions with 2-pyridineethanol and 2-thiopheneethanol showed trace of the desired product under
our catalytic conditions.
81
Scheme 4.2. Substrate Scope for the Reaction of TBD with Primary Aliphatic Alcohols.
4.2.2. N -Alkylation of Triazabicyclodecene with Secondary Alcohols
Compared to primary alcohols, guanidine N-alkylation with secondary alcohols via HB is
difficult to achieve as the intermediate ketones are less electrophilic in nature. However, reaction
of TBD with cyclic secondary alcohols produced the desired compounds (4.2g and 4.2h) in good
yield. Coupling of TBD with 2-butanol can be further optimized by increasing the catalyst loading
as in the case of 4.2h. While reactions with L-borneol and hexafluro-2-propanol returned starting
materials, (1R,3R,5R)-3-isopropyl-5-methylcyclohexanol showed trace of iminium ion of the
desired product in LC-QTOF analysis.
Scheme 4.3. Substrate Scope for the Reaction of TBD with Secondary Alcohols.
a
Reaction was stirred for 92 h.
b
3 mol % of catalyst C4 is used.
82
4.2.3. N -Alkylation of Triazabicyclodecene with Benzylic Alcohols
Reaction of TBD with benzylic alcohols gave low to moderate yield compared to the
similar reaction with aliphatic alcohols (Scheme 4.4). Coupling of TBD with benzyl alcohol
showed capricious result with a best yield of 48%. When 4-chlorobenzyl alcohol yielded the
desired product with TBD in 25% yield under our general condition, corresponding reactions with
4-bromobenzyl alcohol and 4-iodobenzyl alcohol showed trace of the product in LC-QTOF
analysis. Besides, reactions with secondary benzylic alcohols produced intermediate imine and
hemiaminal as the major species (4.2l, 4.2m and 4.2n). Use of a sterically bulky alcohol 2,6-
dimethylbenzyl alcohol returned starting materials during the coupling reaction.
Scheme 4.4. Substrate Scope for the Reaction of TBD with Benzyl Alcohols.
4.2.4. Reaction in the Prescence of Multiple Nucleophilic and Electrophilic Centers
Presence of more than one nucleophilic and electrophilic centers in the substrates generally
leads to side reactions. When we employed 3-(methylamino)propan-1-ol (4.3) as the electrophile
for a reaction with TBD, LC-QTOF showed alkylation compound 4.2o as expected (Scheme 4.5A).
However, coupling of TBD with 2-aminobenzyl alcohol (4.4) as the electrophile showed mixture
of compounds generated from intermolecular reaction of alcohols in addition to the desired
alcohol-amine coupling due to the presence of an amino group in 4.4 (Scheme 4.5B).
83
Scheme 4.5. Reaction of TBD with Alcohols Bearing an Amino Group.
a
a
Reaction mixture was analyzed by LC-QTOF and products were tentatively identified based on their mass.
In addition, we conducted three experiments with alcohols bearing multiple electrophilic
centers (Scheme 4.6). While coupling of TBD with a diol (4.5) produced mixture of diastereomers
in excellent yield (Scheme 4.6A) leaving an alcohol open to additional functionalization,
utilization of a diol with a halogen group (4.6) generated trace of tricyclic compounds 4.2t and
4.2u. When one alcohol group and chlorine participated in the reaction with two nitrogens on the
guanidine center to make 4.2t, both alcohol groups coupled with nitrogens on TBD to afford 4.2u.
Likewise, reaction of TBD with 8-chloro-1-octanol (4.7) yielded the desired N-alkylation
compound 4.2v and a tricyclic compound 4.2w through amine-alcohol and amine-halide reaction.
In conclusion, our condition is selective to single N-alkylation with diols; however, presence of a
halogen leads to multiple N-alkylation and mixture of compounds.
84
Scheme 4.6. Reaction of TBD with Alcohols Bearing Multiple Electrophilic Centers.
a
dr was determined from
1
H NMR.
b
Structure was determined tentatively from LC-QTOF spectrum.
4.2.5. N -Alkylation of 2-Aminobenzimidazole
N-Alkylation of 2-aminoimidazoles is well studied by Xie and co-workers
4c
with a
[Cp*IrCl2]2/K2CO3 system. Thus, we screened few reactions with 2-aminobenzimidazole (4.8) as
representative examples (Scheme 4.7). Reaction of 4.8 with n-butanol, cyclic secondary alcohols
and benzyl alcohol yielded the desired alkylated compounds in good yield. Like reactions of 4.1,
coupling of 4.8 with 4-hydroxypiperidine and methanol returned starting materials, and 4-
nitrobenzyl alcohol showed black-brown paste, indicating polymerization. When we replaced 2-
aminobenzimidazole (4.8) with 2-guanidinobenzimidazole (4.10) in its reaction with benzyl
alcohol, it didn’t show any alcohol-amine coupling. This may be due to the presence of bidentate
metal binding sites in the guanidine substrate 4.10. In order to prove this, we added 50 mol % of
4.10 to the reaction of 4.8 with benzyl alcohol and found a drastic decrease in the yield from 94%
85
to 30% (Scheme 4.8). A similar experiment with 4-hydroxypiperidine doesn’t show any effect on
the yield of 4.9d. Thus, one carbon primary diamines appear to chelate to the metal center and
poison the catalyst.
Scheme 4.7. Substrate Scope for the Reaction of 2-Aminobenzimidazole with Alcohols.
a
Reaction condition: toluene (5 equiv), 110
o
C, 61 h, Schlenk reactor; because solid products formation impede
stirring during the reaction under neat condition.
Scheme 4.8. Reaction that Shows the Effect of 2-Guanidinibenzimidazole on Catalyst Poisoning.
4.2.6. Reaction of Other Guanidine Substrates
In addition to guanidines 4.1, 4.8, and 4.10, we screened some other substrates which are
shown in figure 4.2. While reaction mixtures containing guanine (4.11) or substrate 4.12 were
unable to analyze due to its insolubility in organic and aqueous solvents, 2-aminoimidazole (4.13)
and creatin (4.14) decomposed on heating. Regardless of the conditions, all experiments with
guanidine 4.15 and benzyl alcohol returned starting materials in the presence of complex C4 as
well as [Cp*IrCl2]2. Although we attributed earlier this to the less nucleophilicity of 4.15, it
86
successfully formed the iminium ion 4.21 in 63% yield with benzaldehyde (Scheme 4.9). This
indicates possibility of a catalytic poisoning from substrate 4.15, which prevent alcohol oxidation.
Figure 4.2. Guanidine substrates.
Scheme 4.9. Reaction of Guanidine 4.15 with Benzaldehyde.
Boc protected guanidine 4.16 and substrate 4.17 didn’t show any reactivity, possibly due
to chelation in the former case as it is a one carbon primary diamine. While reaction of 2-
aminopyrimidine (4.18) with benzyl alcohol afforded the desired product in 11% yield, coupling
with butanol returned starting materials under our general catalytic condition. These reactions can
be further optimized in future. LC-QTOF analysis of the reaction mixture for the coupling of 4.19
and benzyl alcohol showed mixture of mono and dibenzylated compounds 4.22 and 4.23 with
100% conversion (Scheme 4.10). Likewise, treatment of 4.20 with benzyl alcohol produced
mixture of compounds and we were able to tentatively identify monobenzylated compound 4.24
in 10% yield (Scheme 4.11).
87
Scheme 4.10. Reaction of Guanidine 20 with Benzyl Alcohol.
a
a
Products are tentatively identified as 4.22 and 4.23 based on LC-QTOF spectrum.
Scheme 4.11. Reaction of Guanidine 21 with Benzyl Alcohol.
4.2.7. Cyclization of Guanidines with Diols
Guanidine substrates can be coupled with diols to make cyclic compounds through two
sequential hydrogen-borrowing N-alkylation reactions. Figure 4.3 shows structures of guanidine
substrates screened in the coupling reaction. As expected, guanidine hydrochloride salt 4.25 and
its free base form didn’t apparently show any reactivity due to catalyst poisoning. It is interesting
to note that we observed formation of an imidazoline compound 4.31 by coupling 4.20 with
ethylene glycol (4.30) (Scheme 4.12). Product 4.31 is a structural motif in various APIs such as
apraclonidine, clonidine, and romifidine. Observation of only trace amount of symmetrical
compound 4.32 can be attributed to the steric crowing around guanidine 4.20. This is evident from
the reaction of bulky substrate 4.26 and 4.30 where only trace amount of the product (4.33) is
observed (Scheme 4.13). Likewise, coupling of other guanidine substrates such as 4.27, 4.28, and
4.29 returned starting materials in the presence of complex C4. Moreover, we investigated
formation of a 6-membered cyclic compound from 4.20 and 1,3-propanediol, which showed the
desired product 4.34 in 26% yield (Scheme 4.14).
88
Figure 4.3. Guanidine substrates screened in the coupling with ethylene glycol.
Scheme 4.12. Cyclization of Guanidine 4.20 with Ethylene Glycol.
Scheme 4.13. Cyclization of Guanidine 4.26 with Ethylene Glycol.
Scheme 4.14. Cyclization of Guanidine 4.20 with 1,3-Propanediol.
4.3 Summary
Guanidine derivatives have broad spectrum of applications as pharmaceutical compounds,
agrochemicals, catalysts, and ligands for various organic transformations. However, guanidine
functionalization is difficult as it possesses high basicity and multiple nucleophilic centers. Here,
we demonstrated application of a phosphinopyridine-ligated ruthenium complex (C4) in the
alkylation of various guanidine substrates through hydrogen-borrowing methodology. It is
noteworthy to mention that we achieved a one step synthesis of imidazolines by guanidine-diol
89
coupling. This is an ongoing project in our lab and further optimization studies and isolation of
products are in progress.
90
4.4. References
1. (a) Guanidine. https://en.wikipedia.org/wikiGuanidine (accessed Aug 16, 2021). (b)
Epinastine. http://en.wikipedia.org/wiki/Epinastine (accessed Aug 16, 2021). (c)
Imidacloprid. https://en.wikipedia.org/wiki/Imidacloprid (accessed Aug 16, 2021). (d)
Apraclonidine. https://en.wikipedia.org/wiki/Apraclonidine (accessed Aug 16, 2021). (e)
Emedastine. https://en.wikipedia.org/wiki/Emedastine (accessed Nov 30, 2021). (f)
Metformin. https://en.wikipedia.org/wiki/Metformin (accessed Aug 16, 2021) (g) Saxitoxin.
https://en.wikipedia.org/wiki/Saxitoxin (accessed Aug 16, 2021).
2. Saczewski, F.; Balewski, L. Expert Opin. Ther. Patents 2009, 19 (10), 1417-1448.
3. For select examples, see (a) Hammoud, H.; Schmitt, M.; Bihel, F.; Antheaume, C.;
Bourguignon, J. J. Org. Chem. 2012, 77, 417-423. (b) Cortes-Salva, M.; Nguyen, B.; Cuevas,
J.; Pennypacker, K.; Antilla, J. C. J. Org. Lett. 2010, 12, 1316-1319. (c) Powell, D.; Ramsden,
P.; Batey, R. J. Org. Chem. 2003, 68, 2300-2309.
4. For select examples, see (a) Ramachandran, R.; Prakash, G.; Nirmala, M.;
Viswanathamurthi, P.; Malecki, J. G. J. Organomet. Chem. 2015, 791, 130-140. (b) Martínez-
Asencio, A.; Ramón, D.; Yus, M. Tetrahedron. 2011, 67, 3140-3149. (c) Li, F.; Kang, Q.;
Shan, H.; Chen, L.; Xie, J. Eur. J. Org. Chem. 2012, 5085-5092.
5. Nalikezhathu, A.; Maertens, A.; Navarro, C.; Do, V .; Tam, A.; Zhang, L.; Williams, T. J. C-
N Bond Formation via Hydrogen-Borrowing, Organic Reactions. Chapter in progress.
6. (a) Celaje, J. J. A.; A. Zhang, X.; Zhang, F.; Kam, L.; Herron, J. R.; Williams, T. J ACS Catal.
2017, 7, 1136-1142. (b) Cherepakhin, V .; Williams, T. J. ACS Catal. 2020, 10, 56-65.
7. Nalikezhathu, A.; Cherepakhin, V .; Williams, T. J. Org. Lett. 2020, 22, 4979-4984.
8. Nalikezhathu, A.; Tam. A.; Williams, T. J. Manuscript in progress.
9. Isfeld, K. A., Killeen, C.; Konowalchuk, D. J.; Davis, R. L. Org. Biomol. Chem. 2022, 20,
5730-5734.
10. Batagarawa, S. M.; Mashi, A. L. IOSR Journal of Applied Chemistry. 2020, 13 (3), 20-29.
91
11. Geiselhart, C. M.; Schmitt, C. W.; Jockle, P.; Mutlu, H.; Kowollik, C, B. Sci Rep 9. 2019,
14519.
12. Pratt, R. C.; Lohmeijer, B. G. G.; Long, D. A.; Waymouth, R. M.; Hedrick, J. L. J. Am.
Chem. Soc. 2006, 128 (14), 4556-4557.
13. Bell, J. R.; Luo, H.; Dai, S. Tetrahedron Lett. 2011, 52 (29), 3723-3725.
92
Chapter 5. Miscellaneous Experiments
This chapter comprise some interesting results that we observed during rection
optimizations in the above three chapters along with some miscellaneous experiments we never
follow up.
5.1 Heterocycles from Amine/Diol Coupling
N-Heterocycles can be formed by coupling primary amines with diols through two
consecutive hydrogen-borrowing reaction in the presence of complex C4 (Figure 5.1). While
optimizing harmicine synthesis, we observed formation of heterocycle 5.3 in 74% from tryptamine
(5.1) and 1,4-butanediol (Table 5.1, entry 1). Likewise, reaction of homoveratryl amine (5.4) with
butanediol (5.2) yielded pyrrolidine compound 5.5 in 60%. Here, if single diol and amine
functionalities are participated in the heterocycle formation, a diazacycle can also be formed from
amine-diol coupling. For example, reaction of benzyl amine with ethylene glycol afforded a
piperazine 5.8 from two sequential amine-diol coupling (Table 5.1, entry 3) in neat condition. But
reaction in refluxing toluene showed an imine (5.9) through homo coupling of amines. We attribute
this to the availability of only the benzyl amine in the reaction flask as volatile ethylene glycol and
gaseous H2 escapes during reflux condition. It is interesting to note that our complex C4 is suitable
for not only amine-alcohol coupling, but for amine-amine coupling also.
Figure 5.1. Structure of ruthenium complex C4.
93
Table 5.1. Reaction of Amines with Diols.
Entry Amine Diol Condition Result
a
1
5.1
1 equiv
5.2
1 equiv
C4 (1 mol %),
neat, 110
o
C, 48 h,
sealed flask
5.3 (74%)
2
5.4
1 equiv
5.2
1 equiv
C4 (1 mol %),
neat, 110
o
C, 48 h,
sealed flask
5.5 (60%)
3
5.6
1 equiv
5.7
1 equiv
C4 (1 mol %),
neat, 110
o
C, 44 h,
sealed vial
5.8 (22%)
4 5.6
1 equiv
5.7
1 equiv
C4 (1 mol %),
toluene (3 mL),
reflux, 44 h
5.9 (quant.)
a
Reaction mixture was analyzed by
1
H NMR spectroscopy.
5.2 N-Methylation by Hydrogen-Borrowing
N-methylation by hydrogen-borrowing is challenging as methanol activation is less
feasible compared to higher carbon alcohols. Thus, few homogenous catalysts are reported
1
for
methanol oxidation and some requires forceful conditions. Table 5.2 summarizes our attempts to
methylate various amines in the presence of either complex C4 or [Cp*IrCl2]2. Both catalytic
systems were unable to methylate ethylenediamine in neat condition due to the presence of
bidentate metal binding sites in the substrate. We employed more powerful microwave condition
for rest of the screening experiments. A recreational psychedelic drug,
2
N,N-dimethyl tryptamine
(DMT), can be accessed in more than 50% yield with [Cp*IrCl2]2 (Table 5.2, entry 3). In addition,
DMT is an investigational compound for the treatment of Parkinson disease
3
and depressive
disorders.
4
While reaction of N-phenylethylenediamine (5.12) produced trace of methylated
compound (Table 5.2, entry 4), ethanolamine (5.14) showed 17% conversion (entry 5). This result
is appealing as ethanolamine can poison the catalyst like ethylenediamine. All the reactions can be
94
optimized further to improve the yield as complete conversion was not observed in our single
screening.
Table 5.2. Methylation of Amines.
Entry Amine Catalyst (mol %) Condition Result
b
1
5.10
C4 (1) MeOH (2 equiv),
neat, 110
o
C, 44 h,
sealed vial
observed starting
materials
2 5.10 [Cp*IrCl 2] 2 (1) MeOH (2 equiv),
neat, 110
o
C, 44 h,
sealed vial
observed starting
materials
3
5.1
[Cp*IrCl 2] 2 (1) MeOH (2 mL),
MW, 140
o
C, 1 h,
sealed vial
5.11
53% conversion
4
5.12
[Cp*IrCl 2] 2 (1) MeOH (2 mL),
MW, 140
o
C, 1 h,
sealed vial
5.13 (trace)
5
5.14
[Cp*IrCl 2] 2 (1) MeOH (2 mL),
MW, 140
o
C, 1 h,
sealed vial
5.15
17% conversion
b
Coversion was determined from
1
H NMR.
5.3. Iron Catalyzed Synthesis of N-Heterocycles
Synthesis of N-heterocycles by hydrogen-borrowing method is accomplished mainly by
ruthenium
5
and iridium
6
catalysis. Few methods are reported with cost-effective earth abundant
metals such as iron,
7
nickel,
8
and cobalt
9
for the same which typically require complex expensive
ligands and limited in substrate scope. In 2011, Saito and co-workers achieved the first iron
catalyzed HB alcohol amination with DL-pyroglutamic acid as the bidentate ligand and
pentamethylcyclopentadiene (Cp*H) as an additive.
10
Inspiring from this, Jeff Celaje, a previous
graduate student from our lab, proposed diamine mediated (diamine substrates as the bidentate
ligand) iron catalyzed synthesis of diazacycles which avoid preparation of complex ligands. Table
5.3 summarizes our attempts to develop this proposal. Regardless of the various conditions such
95
as different iron sources, diamines, and solvents, none of the reaction showed any interesting
results. We observed starting material in the crude
1
H NMR after the reaction.
Table 5.3. Screening of Iron Sources and Diamines for Piperazine Synthesis.
Entry Diamine Catalyst Condition Result
1
5.10
FeCl 3 neat, 160
o
C no reaction
2 5.10 Fe(acac) 3 neat, 160
o
C no reaction
3
5.16
FeCl 3 neat, 160
o
C no reaction
4 5.16 FeCl 3 toluene, 100
o
C no reaction
5
5.17
FeCl 3 neat, 160
o
C no reaction
6 5.17 Fe(acac) 3 neat, 160
o
C no reaction
7 5.17 FeCl 3 toluene, 100
o
C no reaction
8 5.17 Fe(acac) 3 toluene, 100
o
C no reaction
9 5.17 FeCl 3 dioxane, 90
o
C no reaction
10 5.17 Fe(acac) 3 dioxane, 90
o
C no reaction
96
5.4. Reference
1. (a) Grigg, R.; Mitchell, T. R. B.; Sutthivaiyakit, S.; Tongpenyai, N. J. Chem. Soc., Chem.
Commun. 1981, 12, 611−612. (b) Arcelli, A.; Khai, B.; Porzi, G. J. Organomet. Chem. 1982,
235, 93−96. (c) Bitsi, G.; Schleiffer, E.; Antoni, F.; Jenner, G. J. Organomet. Chem. 1989,
373, 343−352. (d) Watanabe, Y.; Morisaki, Y.; Kondo, T.; Mitsudo, T. J. Org. Chem. 1996,
61, 4214−4218. (e) Naskar, S.; Bhattacharjee, M. Tetrahedron Lett. 2007, 48, 3367−3370.
(f). Andrushko, N.; Andrushko, V.; Roose, P.; Moonen, K. ChemCatChem 2010, 2, 640−643.
(g) Li, F.; Xie, J.; Shan, H.; Sun, C.; Chen, L. RSC Adv. 2012, 2, 8645−8652. (h) Del Zotto,
A.; Baratta, W.; Sandri, M.; Verardo, G.; Rigo, P. Eur. J. Inorg. Chem. 2004, 2004, 524−529.
2. McKenna, D. J.; Towers, G. H. N.; Abbott, F. Journal of Ethnopharmacology. 1984, 10 (2):
195–223.
3. Pinto, V. New Psychedelic Therapy AKO004 Under Development by Akome. July 30 2021
(accessed December 9, 2022).
4. Small Pharma Ltd An Open-Label Study Investigating the Safety, Tolerability,
Pharmacokinetics, Pharmacodynamics & Exploratory Efficacy of Intravenous SPL026 Drug
Product (DMT Fumarate) Alone or in Combination With SSRIs in Patients With Major
Depressive Disorder https://clinicaltrials.gov/ct2/show/NCT04673383. (accessed December
9, 2022).
5. (a) Hamid, M. H. S. A.; Allen, C. L.; Lamb, G. W.; Maxwell, A. C.; Maytum, H. C.; Watson,
A. J. A.; Williams, J. M. J. Journal of the American Chemical Society 2009, 131 (5), 1766-
1774. (b) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. The Journal of Organic
Chemistry 2011, 76 (7), 2328-2331. (c) Marichev, K. O.; Takacs, J. M. ACS Catalysis 2016,
6 (4), 2205-2210. (d) Shan, S. P.; Xiaoke, X.; Gnanaprakasam, B.; Dang, T. T.; Ramalingam,
B.; Huynh, H. V.; Seayad, A. M. RSC Advances 2015, 5 (6), 4434-4442. (e) Xu, Q.-S.; Li,
C.; Xu, Y.; Xu, D.; Shen, M.-H.; Xu, H.-D. Chinese Chemical Letters 2020, 31 (1), 103-106.
(f) Hamid, M. H. S. A.; Williams, J. M. J. Chemical Communications 2007, (7), 725-727.
(g) Jumde, V. R.; Cini, E.; Porcheddu, A.; Taddei, M. European Journal of Organic
Chemistry 2015, 2015 (5), 1068-1074.
6. (a) Fujita, K.; Fujii, T.; Komatsubara, A. Heterocycles 2007, 74, 673-682. (b) Kawahara, R.;
Fujita, K.-i.; Yamaguchi, R. Advanced synthesis & catalysis. 2011, 353 (7), 1161-1168. (c).
Chamberlain, A. E. R.; Paterson, K. J.; Armstrong, R. J.; Twin, H. C.; Donohoe, T. J.
Chemical Communications 2020, 56 (24), 3563-3566. (d) Saidi, O.; Blacker, A. J.; Lamb, G.
W.; Marsden, S. P.; Taylor, J. E.; Williams, J. M. J. Organic Process Research &
Development 2010, 14 (4), 1046-1049. (e) Cami-Kobeci, G.; Slatford, P. A.; Whittlesey, M.
K.; Williams, J. M. J. Bioorganic & Medicinal Chemistry Letters 2005, 15 (3), 535-537. (f)
Nordstrøm, L. U.; Madsen, R. Chemical Communications 2007, (47), 5034-5036. (g) Fujita,
97
K.-i.; Kida, Y.; Yamaguchi, R. Heterocycles 2009, 77 (2), 1371-1377. (h) Fujita, K.-i.; Fujii,
T.; Yamaguchi, R. Organic letters 2004, 6 (20), 3525-3528. (i) Leonard, J.; Blacker, A. J.;
Marsden, S. P.; Jones, M. F.; Mulholland, K. R.; Newton, R. Organic Process Research &
Development 2015, 19 (10), 1400-1410.
7. Yan, T.; Feringa, B. L.; Barta, K. Nature Communications 2014, 5, 5602.
8. Yang, P.; Zhang, C.; Gao, W.-C.; Ma, Y.; Wang, X.; Zhang, L.; Yue, J.; Tang, B. Chemical
Communications 2019, 55 (54), 7844-7847.
9. (a) Yin, Z.; Zeng, H.; Wu, J.; Zheng, S.; Zhang, G. ACS Catalysis 2016, 6 (10), 6546-6550.
(b) Emayavaramban, B.; Chakraborty, P.; Manoury, E.; Poli, R.; Sundararaju, B. Organic
Chemistry Frontiers 2019, 6 (6), 852-857.
10. Zhao, Y.; Foo, S. W.; Saito, S. Angew. Chem. Int. Ed. 2011, 50, 3006.
98
Chapter 6. Experimental and Spectral Data
6.1. General Procedure
All air and water sensitive procedures were carried out either in a Vacuum Atmospheres
glove box under nitrogen (2-10 ppm O2 for all manipulations) or using standard Schlenk
techniques under nitrogen. Deuterated NMR solvents were purchased from Cambridge Isotopes
Laboratories. Dichloromethane, ethyl acetate, diethyl ether, and hexanes were purchased from
VWR; toluene was dried using sodium benzophenone ketyl; dichloro(p-cymene)ruthenium(II)
dimer was purchased from stream. 2-((Di-tert-butylphosphino)methyl)pyridine
1
and ruthenium
catalyst (C4)
2
were synthesized using the published procedures. All other reagents were purchased
and used as received.
A temperature-controlled oil bath was used a heat source in all reactions where heating is
required. NMR spectra were recorded on a Varian Mercury 400, Varian VNMRS 500, or VNMRS
600 spectrometer. All chemical shifts are reported in units of ppm and referenced to the residual
1
H or
13
C solvent peak. Spectra are line-listed according to (s) singlet, (bs) broad singlet, (d)
doublet, (t) triplet, (dd) double doublet, etc.
13
C spectra are delimited by carbon peaks, not carbon
count. Air sensitive NMR spectra were taken in 8” J-Young tubes (Wilmad or Norell) with Teflon
valve plugs. IR spectra were recorded on Bruker OPUS FTIR spectrometer using type 61
polyethylene IR cards. Enantiomeric excess (ee) was determined by HPLC analysis on Agilent
HPLC units, including the following instruments: pump, 1260 Infinity II G7104C Flexible Pump;
detector, 1260 Infinity II Diode Array Detector WR (G7115A); column Chiralpak IJ-3. X-ray
crystallography data were obtained on a Rigaku XtaLAB Synergy, Dualflex, HyPiX diffractometer
with Mo or Cu as the source as indicated in the CIF files. Optical rotations were recorded on a
99
JASCO temperature-controlled digital polarimeter. High resolution mass spectrometry data were
obtained from Agilent LC-QTOF instrument. Melting points were measured on a MEL-TEMP
apparatus (Laboratory Devices, Cambridge, MA).
6.2. Chapter 2 Experimental and Spectral Data
6.2.1. Reactivity of Ruthenium Complex in the Coupling of Tryptamine and Benzyl Alcohol
Coupling of Tryptamine and Benzyl Alcohol (Closed Flask, Neat)
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with
tryptamine 2.2 (50 mg, 0.31 mmol), benzyl alcohol 2.1 (50.6 mg, 0.47 mmol), and 1 mol %
ruthenium complex C4 (2 mg, 3.1 µmol). The reactor was sealed, taken out of the glovebox, and
was heated to 110 °C for 24 hours. After that, the dark brown reaction mixture was allowed to cool
to room temperature, and an aliquot was obtained for the
1
H NMR analysis in CD2Cl2. Proton
spectrum of the crude mixture showed coupled amine 2.3 and benzyl alcohol. The data are
consistent with a known compound.
3
100
Figure 6.2.1.
1
H NMR spectrum of the crude reaction mixture for the coupling of tryptamine and
benzyl alcohol at 110 °C in neat, closed flask conditions; 2.3 is observed as product. Peaks at 4.63
and 1.55 correspond to benzyl alcohol.
Coupling of Tryptamine and Benzyl Alcohol (Open Flask, Neat)
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with
tryptamine 2.2 (48 mg, 0.30 mmol), benzyl alcohol 2.1 (48.6 mg, 0.45 mmol), and 1 mol %
ruthenium complex C4 (2 mg, 3.0 µmol). The reactor was sealed, taken out of the glovebox, and
connected to a N2 line. This system was heated to 110 °C for 24 hours. After that, the dark brown
reaction mixture was allowed to cool to room temperature, and
1
H NMR was taken in CDCl3.
Proton spectrum of the crude mixture showed 2.3 and 2.4 in 2:1 ratio. The data are consistent with
known compounds.
3, 4
101
Figure 6.2.2.
1
H NMR spectrum of the crude reaction mixture for the coupling of tryptamine and
benzyl alcohol under a stream of N2 gas at 110 °C in neat, open flask conditions; 2.3 and 2.4 are
observed as products.
102
Coupling of Tryptamine and Benzyl Alcohol (Open Flask, Toluene)
In the glovebox, a 10 mL round bottom flask was charged with tryptamine 2.2 (100 mg,
0.62 mmol), 1.5 equiv benzyl alcohol 2.1 (101 mg, 3.10 mmol), and 1 mol % ruthenium complex
C4 (4.10 mg, 6.2 µmol). After adding 3 mL dry toluene to this mixture, the flask was closed with
a condenser and a septum, taken out of the glovebox, and kept it for refluxing under a N2 stream.
After 24 hours, solvent was removed under reduced pressure, and an aliquot was obtained for
1
H
NMR analysis in CDCl3. The spectrum showed neither the starting tryptamine 2.2 nor the coupled
amine 2.3 peaks, but only the N-benzylidenetryptamine 2.4 peaks. The data are consistent with a
known compound.
4
Figure 6.2.3.
1
H NMR of the crude reaction mixture for the coupling of tryptamine and benzyl
alcohol under a stream of N2 gas at 120 °C in toluene, open flask conditions; 2.4 is observed as
product. The peak at 4.7 ppm corresponds to the CH2 group in the starting benzyl alcohol.
a
1
b
1
C
1
103
6.2.2. Catalyst Screening for the Pictet-Spengler Cyclization
Synthesis of N-Benzylidenetryptamine
4
In a 100 mL round-bottom flask, a solution of tryptamine (2 g, 12.48 mmol) and freshly
distilled benzaldehyde (1.35 mL, 1.05 eq.) in methanol (50 mL) was stirred at 25 °C for 16 hours.
Then, methanol was removed under reduced pressure, and the product was crystallized from a
concentrated ethyl acetate solution. Yield: 70% (2.17 g). Data are consistent with the known
compound.
4
1
H NMR (500 MHz, Chloroform-d) δ 8.18 (s, 1H), 7.99 (bs, 1H), 7.76 – 7.65 (m, 3H), 7.41 (dd,
J = 5.3, 1.8 Hz, 3H), 7.36 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 7.5 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H),
7.02 (d, J = 2.3 Hz, 1H), 3.95 (t, J = 7.3 Hz, 2H), 3.18 (t, J = 7.3 Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 161.5, 136.5, 136.4, 130.7, 128.7, 128.2, 127.7, 122.2,
122.1, 119.4, 119.1, 114.3, 111.2, 62.2, 27.0.
General Procedure for Catalyst Screening
In the glovebox, a 10 mL round bottom flask was charged with N-benzylidenetryptamine
2.4 (100 mg, 0.40 mmol), and 10 mol % Lewis acid catalyst as specified in Table 2.2. After adding
3 mL dry toluene to this mixture, the flask was closed with a condenser and a septum, taken out of
the glovebox, and maintained at reflux under a N2 stream. After 24 hours, solvent was removed
under reduced pressure, and an aliquot was obtained for
1
H NMR analysis in CDCl3.
Optimized Procedure for the Imine Cyclization
In the glovebox, a 10 mL round bottom flask was charged with N-benzylidenetryptamine
2.4 (100 mg, 0.40 mmol), and 10 mol % indium triflate (23 mg, 0.04 mmol). After adding 3 mL
dry toluene to this mixture, the flask was closed with a condenser and a septum, taken out of the
glovebox, and maintained at reflux under a N2 stream. After 24 hours, solvent was removed under
reduced pressure, and an aliquot was obtained for
1
H NMR analysis in CDCl3.
104
6.2.3. Substrate Scope for the Tandem Pictet-Spengler Cyclization from Tryptamine
2-Benzyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[ 3,4-b]indole
The product was obtained in 79% yield (166 mg) as a white solid after flash column
chromatography (97:3 hexanes: ethyl acetate).
Data are consistent with the known compound.
5
1
H NMR (500 MHz, Methylene Chloride-d2) δ 7.53 – 7.44 (m, 3H), 7.45 – 7.28 (m, 8H), 7.24 (td,
J = 7.1, 1.7 Hz, 1H), 7.18 (dd, J = 7.6, 1.6 Hz, 1H), 7.06 (tdd, J = 8.2, 7.3, 5.7 Hz, 2H), 4.67 (s,
1H), 3.89 (d, J = 13.6 Hz, 1H), 3.37 (d, J = 13.6 Hz, 1H), 3.20 (dt, J = 9.3, 3.4 Hz, 1H), 2.89 (dddd,
J = 14.6, 9.5, 4.9, 2.4 Hz, 1H), 2.82 – 2.71 (m, 1H), 2.65 (dddd, J = 11.6, 9.7, 4.3, 1.8 Hz, 1H).
13
C NMR (126 MHz, Methylene Chloride-d2) δ 142.1, 140.1, 136.8, 135.4, 129.3, 129.1, 129.1,
128.6, 128.4, 127.6, 127.2, 121.8, 119.6, 118.7, 111.1, 58.7, 48.7, 21.6.
2.6
105
2-(4-Fluorobenzyl)-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 29% (67 mg) yield as a white solid after flash column chromatography
(97:3 hexanes: ethyl acetate).
mp: 173 – 175 °C.
1
H NMR (600 MHz, CDCl3): δ 7.54 (d, J = 7.5 Hz, 1H, ArH), 7.39 (dd, J = 8.7, 5.4 Hz, 2H, ArH),
7.29 (dd, J = 8.4, 5.6 Hz, 2H, ArH), 7.24 (bs, 1H, NH), 7.21 (d, J = 7.4 Hz, 1H, ArH), 7.18 – 6.97
(m, 6H, ArH), 4.64 (s, 1H, NCH), 3.82 (d, J = 13.5 Hz, 1H, NCH2Ar), 3.35 (d, J = 13.5 Hz, 1H,
NCH2Ar), 3.23 – 3.16 (m, 1H, CH2CH2), 2.94 – 2.85 (m, 1H, CH2CH2), 2.85 – 2.77 (m, 1H,
CH2CH2), 2.71 – 2.63 (m, 1H, CH2CH2).
13
C NMR (151 MHz, CDCl3): δ 163.2 (d, JCF = 85.8 Hz), 161.6 (d, JCF = 83.9 Hz), 137.3, 136.4,
135.1, 134.5, 130.7 (d, JCF = 7.9 Hz), 130.2 (d, JCF = 7.9 Hz), 127.2, 121.9, 119.6, 118.5, 115.8 (d,
JCF = 21.4 Hz), 115.2 (d, JCF = 21.2 Hz), 111.0, 109.3, 63.8, 57.5, 48.2, 21.2.
19
F NMR (564 MHz, CDCl3): δ –114.00, –115.94.
FT-IR (KBr) cm
-1
: 3413, 2948, 2903, 2828, 1613, 1514, 1307, 1235, 841.
HRMS (ESI) m/z: [M+H]
+
Calcd for C24H21F2N2 375.1667; Found 375.1677.
2.6b
106
2-(4-Bromobenzyl)-1-(4-bromophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
2.6c
The product was obtained in 7% yield (18 mg) as a yellow solid after flash column chromatography
(97:3 hexanes: ethyl acetate).
1
H NMR (500 MHz, CDCl3): δ 7.54 (d, J = 7.4 Hz, 1H, ArH), 7.46 – 7.05 (m, 12H, ArH, NH),
4.63 (s, 1H, NCH), 3.82 (d, J = 13.6 Hz, 1H, NCH2Ar), 3.36 (d, J = 13.7 Hz, 1H, NCH2Ar), 3.24
– 3.12 (m, 1H, CH2CH2), 2.98 – 2.76 (m, 2H, CH2CH2), 2.74 – 2.60 (m, 1H, CH2CH2).
13
C NMR (126 MHz, CDCl3): δ 140.0, 138.0, 136.5, 134.1, 134.1, 132.8, 130.4, 130.0, 129.1,
128.6, 127.2, 122.0, 119.7, 118.5, 111.0, 109.4, 63.9, 57.7, 48.3, 21.2.
HRMS (ESI) m/z: [M+H]
+
Calcd for C24H21Cl2N2 407.1076; Found 407.1084.
107
2-(4-Bromobenzyl)-1-(4-bromophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
2.6d
The product was obtained in 55% yield (168 mg) as a yellow solid after flash column
chromatography (97:3 hexanes: ethyl acetate).
mp: 170 – 172 °C.
1
H NMR (500 MHz, CDCl3): δ 7.56 – 7.41 (m, 5H, ArH), 7.35 – 7.07 (m, 8H, ArH, NH), 4.61 (s,
1H, NCH), 3.79 (d, J = 13.7 Hz, 1H, NCH2Ar), 3.34 (d, J = 13.7 Hz, 1H, NCH2Ar), 3.16 (dt, J =
11.6, 4.5 Hz, 1H, CH2CH2), 2.97 – 2.75 (m, 2H, CH2CH2), 2.74 – 2.59 (m, 1H, CH2CH2).
13
C NMR (126 MHz, CDCl3): δ 140.5, 138.5, 136.5, 134.0, 132.1, 131.5, 130.8, 130.4, 127.2,
122.2, 122.0, 120.9, 119.7, 118.5, 111.0, 109.4, 64.0, 57.8, 48.3, 21.2.
FT-IR (KBr) cm
-1
: 3453, 2951, 2924, 2825, 1490, 1305, 1072, 1013, 825, 742.
HRMS (ESI) m/z: [M+H]
+
Calcd for C24H21Br2N2 495.0066; Found 495.0071.
108
2-(4-Methylthiobenzyl)-1-(4-methylthiophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
2.6e
The product was obtained in 29% yield (77 mg) as a yellow solid after flash column
chromatography (97:3 hexanes: ethyl acetate).
mp: 179 – 182 °C.
1
H NMR (600 MHz, CDCl3): δ 7.52 (d, J = 7.2 Hz, 1H, ArH), 7.34 (d, J = 8.3 Hz, 2H, ArH), 7.29
– 7.16 (m, 8H, ArH, NH), 7.14 – 7.07 (m, 2H, ArH), 4.59 (s, 1H, NCH), 3.84 (d, J = 13.6 Hz, 1H,
NCH2Ar), 3.32 (d, J = 13.6 Hz, 1H, NCH2Ar), 3.24 – 3.17 (m, 1H, CH2CH2), 2.94 – 2.85 (m, 1H,
CH2CH2), 2.83 – 2.76 (m, 1H, CH2CH2), 2.68 – 2.61 (m, 1H, CH2CH2), 2.49 (s, 6H, 2Me).
13
C NMR (151 MHz, CDCl3): δ 138.4, 138.3, 136.8, 136.7, 136.4, 134.8, 129.6, 129.3, 127.3,
126.9, 126.9, 121.7, 119.5, 118.4, 110.9, 109.1, 64.1, 57.9, 48.4, 21.3, 16.2, 15.9
FT-IR (KBr) cm
-1
: 3353, 2923, 2830, 1602, 1496, 1308, 1094, 820, 729.
HRMS (ESI) m/z: [M+H]
+
Calcd for C26H27N2S2 431.1610; Found 431.1624.
109
2-(4-Methoxybenzyl)-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
Compound was isolated using flash column chromatography in 95:5 hexanes: ethyl acetate.
Isolated yield: 20% (49 mg).
1
H NMR (600 MHz, Chloroform-d) δ 7.51 (d, J = 7.4 Hz, 1H, ArH), 7.38 – 7.02 (m, 8H, ArH,
NH), 6.94 – 6.79 (m, 4H, ArH), 4.58 (s, 1H, NCH), 3.91 – 3.65 (m, 7H, 2Me, NCH2Ar), 3.34 –
3.16 (m, 2H, NCH2Ar, CH2CH2), 2.96 – 2.69 (m, 2H, CH2CH2 ), 2.68 – 2.57 (m, 1H, CH2CH2).
13
C NMR (151 MHz, Chloroform-d) δ 159.5, 158.8, 136.4, 135.4, 133.6, 131.7, 130.2, 130.0,
127.4, 121.6, 119.4, 118.4, 114.2, 113.7, 110.9, 109.0, 63.9, 57.6, 55.4, 48.3, 21.3.
FT-IR (KBr) cm
-1
: 3390, 3013, 2910, 2838, 1614, 1514, 1470, 1306, 1245, 1032, 831.
HRMS (ESI) m/z: [M+H]
+
Calcd for C26H27N2O2 399.2067; Found 399.2075.
2.6f
110
6.2.4. Substrate Scope for the Tandem Pictet-Spengler Cyclization from N -Benzyltryptamine
Synthesis of N-Benzyltryptamine 2.3
3
In a 250 mL round bottom flask, tryptamine (5 g, 32 mmol) and benzaldehyde (3.2 mL, 32
mmol) were dissolved in 120 mL methanol. After cooling the system with ice bath, NaBH4 (1.2 g)
was added slowly as portions. Ice bath was removed, and the solution was stirred at room
temperature. After 15 hours, 60 mL saturated NaHCO3 solution was added, concentrated to 25 mL,
dissolved in dichloromethane, and washed with brine. Organic layer was extracted, dried over
anhydrous sodium sulfate and concentrated in vacuo. The mixture was purified by flash column
chromatography (1:3 hexanes: ethyl acetate) to yield 6.9 g of the pure N-benzyltryptamine (86%)
as pale-yellow oil.
Data are consistent with the known compound.
3
1
H NMR (400 MHz, Chloroform-d) δ 8.17 (bs, 1H), 7.63 (d, J = 8.0, 1H), 7.37 – 7.28 (m, 5H),
7.25 – 7.18 (m, 2H), 7.13 (t, J = 8.0, 1H), 7.01 (d, J = 2.3 Hz, 1H), 3.84 (s, 2H), 3.02 (s, 4H).
13
C NMR (101 MHz, Chloroform-d) δ 140.4, 136.5, 128.5, 128.2, 127.6, 127.0, 122.1, 122.1,
119.4, 119.0, 114.1, 54.0, 49.5, 25.9.
General Procedure
In the drybox, a 10 mL round bottom flask with a teflon stirbar was charged with N-
benzyltryptamine 2.3 (50 mg, 0.20 mmol), alcohol (2 equiv, 0.4 mmol), 1 mol % ruthenium
catalyst C4 (1.3 mg, 2µmol), and 10 mol % indium triflate (11.3 mg, 0.02 mmol). After adding 3
mL dry toluene to this mixture, the flask was closed with a condenser and a septum, taken out of
the glovebox, and maintained at reflux under a N2 stream. After 96 hours, solvent was removed
under reduced pressure, and the corresponding carbolines were isolated by silica flash column
chromatography in 95:5 hexanes: ethyl acetate.
111
2-Benzyl-1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[ 3,4-b]indole
The product was obtained in 73% yield (49 mg) as a white solid after flash column chromatography
(97:3 hexanes: ethyl acetate).
Data are consistent with the known compound.
5
1
H NMR (500 MHz, Methylene Chloride-d2) δ 7.53 – 7.44 (m, 3H), 7.45 – 7.28 (m, 8H), 7.24 (td,
J = 7.1, 1.7 Hz, 1H), 7.18 (dd, J = 7.6, 1.6 Hz, 1H), 7.06 (tdd, J = 8.2, 7.3, 5.7 Hz, 2H), 4.67 (s,
1H), 3.89 (d, J = 13.6 Hz, 1H), 3.37 (d, J = 13.6 Hz, 1H), 3.20 (dt, J = 9.3, 3.4 Hz, 1H), 2.89 (dddd,
J = 14.6, 9.5, 4.9, 2.4 Hz, 1H), 2.82 – 2.71 (m, 1H), 2.65 (dddd, J = 11.6, 9.7, 4.3, 1.8 Hz, 1H).
13
C NMR (126 MHz, Methylene Chloride-d2) δ 142.1, 140.1, 136.8, 135.4, 129.3, 129.1, 129.1,
128.6, 128.4, 127.6, 127.2, 121.8, 119.6, 118.7, 111.1, 58.7, 48.7, 21.6.
2.6
112
2-Benzyl-1-(4-fluorophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 70% yield (50 mg) as a white solid after flash column chromatography
(95:5 hexanes: ethyl acetate).
Data are consistent with the known compound.
5
1
H NMR (500 MHz, Chloroform-d) δ 7.56 – 7.51 (m, 1H), 7.44 – 7.38 (m, 2H), 7.36 – 7.28 (m,
4H), 7.25 – 7.18 (m, 3H), 7.18 – 7.00 (m, 4H), 4.65 (s, 1H), 3.88 (d, J = 13.6 Hz, 1H), 3.39 (d, J
= 13.6, 1H), 3.24 – 3.19 (m, 1H), 3.00 – 2.84 (m, 1H), 2.87 – 2.73 (m, 1H), 2.70 – 2.65 (m, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 163.6, 161.7, 139.5, 137.4, 137.4, 136.4, 134.6, 130.7,
130.6, 128.8, 127.3, 127.1, 121.8, 119.6, 118.5, 115.8, 115.7, 110.9, 109.3, 63.8, 58.3, 48.3, 21.2.
2.7b
113
2-Benzyl-1-(4-bromophenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 78% yield (65 mg) as a white solid after flash column chromatography
(95:5 hexanes: ethyl acetate).
Data are consistent with the known compound.
6
1
H NMR (500 MHz, Chloroform-d) δ 7.56 – 7.46 (m, 3H), 7.40 – 7.28 (m, 7H), 7.28 – 7.17 (m,
2H), 7.13 – 7.01 (m, 2H), 4.65 (s, 1H), 3.85 (d, J = 13.7 Hz, 1H), 3.40 (d, J = 13.5 Hz, 1H), 3.24
– 3.17 (m, 1H), 2.93 – 2.72 (m, 2H), 2.70 – 2.63 (m, 1H).
13
C NMR (151 MHz, Chloroform-d) δ 140.8, 139.4, 136.5, 134.2, 132.0, 130.8, 128.8, 128.4,
127.2, 127.2, 122.1, 121.9, 119.6, 118.5, 111.0, 109.4, 64.0, 58.4, 48.3, 21.2.
2.7c
114
2-Benzyl-1-(4-(tert-butyl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 72% yield (57 mg) as a white solid after flash column chromatography
(95:5 hexanes: ethyl acetate).
mp: 167 – 169 °C.
1
H NMR (500 MHz, Chloroform-d) δ 7.55 – 7.49 (m, 1H), 7.40 – 7.23 (m, 10H), 7.23 – 7.16 (m,
1H), 7.14 – 7.05 (m, 2H), 4.63 (s, 1H), 3.92 (d, J = 13.6 Hz, 1H), 3.37 (d, J = 13.6 Hz, 1H), 3.29
– 3.14 (m, 1H), 3.00 – 2.73 (m, 2H), 2.72 – 2.57 (m, 1H), 1.32 (s, 9H).
13
C NMR (126 MHz, Chloroform-d) δ 151.1, 139.9, 138.3, 136.4, 135.2, 128.8, 128.7, 128.3,
127.4, 127.0, 125.8, 121.5, 119.4, 118.4, 110.9, 109.0, 64.3, 58.4, 48.5, 34.7, 31.5, 21.3.
FT-IR (KBr) cm
-1
: 3412, 2964, 2909, 1457, 1308, 1274, 1117, 835, 749.
HRMS (ESI) m/z: [M+H]
+
Calcd for C28H31N2 395.2482; Found 395.2492.
2.7d
115
2-Benzyl-1-(4-(methylthio)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 70% yield (54 mg) as a yellow solid after flash column
chromatography (95:5 hexanes: ethyl acetate).
mp: 178 – 181 °C.
1
H NMR (500 MHz, Chloroform-d) δ 7.52 (d, J = 7.2, 1H), 7.40 – 7.23 (m, 10H), 7.22 – 7.16 (m,
1H), 7.14 – 7.06 (m, 2H), 4.62 (s, 1H), 3.90 (d, J = 13.6 Hz, 1H), 3.37 (d, J = 13.6 Hz, 1H), 3.26
– 3.18 (m, 1H), 3.00 – 2.73 (m, 2H), 2.71 – 2.60 (m, 1H), 2.49 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 139.6, 138.4, 138.4, 136.4, 134.8, 129.6, 128.8, 128.4,
127.3, 127.1, 126.9, 121.7, 119.5, 118.4, 110.9, 109.2, 64.2, 58.4, 48.5, 21.3, 15.9.
FT-IR (KBr) cm
-1
: 3409, 3031, 2900, 2814, 1601, 1497, 1453, 1307, 1149, 1120, 826, 747.
HRMS (ESI) m/z: [M+H]
+
Calcd for C25H25N2S 385.1733; Found 385.1741.
2.7e
116
Methyl 4-(2-benzyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl]benzoate
The product was obtained in 51% yield (40 mg) as a white solid after flash column chromatography
(95:5 hexanes: ethyl acetate).
mp: 201 – 204 °C.
1
H NMR (500 MHz, Chloroform-d) δ 8.03 (d, J = 7.7 Hz, 2H), 7.60 – 7.49 (m, 3H), 7.46 – 7.01
(m, 9H), 4.73 (s, 1H), 3.92 (s, 3H), 3.86 (d, J = 13.6 Hz, 1H), 3.43 (d, J = 13.6 Hz, 1H), 3.28 –
3.19 (m, 1H), 3.01 – 2.78 (m, 2H), 2.77 – 2.61 (m, 1H).
13
C NMR (126 MHz, Chloroform-d) δ 167.0, 147.1, 139.3, 136.5, 133.9, 130.1, 130.0, 129.1,
128.8, 128.4, 127.2, 127.2, 121.9, 119.6, 118.5, 111.0, 109.4, 64.1, 58.5, 52.3, 48.2, 21.1.
FT-IR (neat) cm
-1
: 3386, 3062, 2952, 2898, 2848, 1712, 1437, 1289, 1118, 743.
HRMS (ESI) m/z: [M+H]
+
Calcd for C26H25N2O2 397.1911; Found 397.1918.
2.7f
117
2-Benzyl-1-(4-methoxyphenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 43% yield (32 mg) as a yellow solid after flash column
chromatography (95:5 hexanes: ethyl acetate).
Data are consistent with the known compound.
7
1
H NMR (600 MHz, Chloroform-d) δ 7.53 (d, J = 8.2 Hz, 1H), 7.43 – 7.23 (m, 8H), 7.22 – 7.18
(m, 1H), 7.15 – 7.08 (m, 2H), 6.91 (d, J = 8.7 Hz, 2H), 4.62 (s, 1H), 3.92 (d, J = 13.5 Hz, 1H),
3.82 (s, 3H), 3.36 (d, J = 13.6 Hz, 1H), 3.27 – 3.19 (m, 1H), 2.96 – 2.87 (m, 1H), 2.83 – 2.76 (m,
1H), 2.71 – 2.62 (m, 1H).
13
C NMR (151 MHz, Chloroform-d) δ 159.6, 139.8, 136.4, 135.3, 133.4, 130.3, 128.8, 128.3,
127.4, 127.0, 121.6, 119.4, 118.4, 114.2, 110.9, 109.0, 64.1, 58.3, 55.4, 48.5, 21.3.
2.7g
118
2-Benzyl-1-(thiophen-2-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 56% yield (39 mg) as a yellow solid after flash column
chromatography (95:5 hexanes: ethyl acetate).
Data are consistent with the known compound.
5
1
H NMR (600 MHz, Chloroform-d) δ 7.52 (d, J = 7.6 Hz, 1H), 7.48 – 7.40 (m, 3H), 7.37 – 7.19
(m, 5H), 7.18 – 7.06 (m, 3H), 7.00 (dd, J = 5.1, 3.5 Hz, 1H), 5.04 (s, 1H), 4.00 (d, J = 13.6 Hz,
1H), 3.49 (d, J = 13.6 Hz, 1H), 3.29 – 3.22 (m, 1H), 2.90 – 2.77 (m, 2H), 2.76 – 2.69 (m, 1H).
13
C NMR (151 MHz, Chloroform-d) δ 146.0, 139.3, 136.4, 134.0, 128.9, 128.4, 127.4, 127.2,
126.4, 126.4, 126.3, 121.9, 119.6, 118.6, 111.0, 108.7, 59.3, 58.3, 48.0, 20.9.
2.7h
119
2-Benzyl-1-(heptyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 47% yield (34 mg) as yellow oil after flash column chromatography
(95:5 hexanes: ethyl acetate).
1
H NMR (500 MHz, Chloroform-d) δ 7.63 (s, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.46 – 7.23 (m, 6H),
7.22 – 7.05 (m, 2H), 3.81 (d, J = 13.4 Hz, 1H), 3.76 (d, J = 13.5 Hz, 1H), 3.67 – 3.60 (m, 1H),
3.35 – 3.21 (m, 1H), 3.07 – 2.75 (m, 2H), 2.70 – 2.52 (m, 1H), 1.89 – 1.63 (m, 2H), 1.60 – 1.11
(m, 10H), 0.91 (t, J = 6.9 Hz, 3H).
13
C NMR (126 MHz, Chloroform-d) δ 140.1, 135.9, 135.8, 129.1, 128.3, 127.5, 127.0, 121.5,
119.4, 118.2, 110.8, 108.0, 57.4, 56.7, 44.9, 34.8, 32.0, 29.9, 29.5, 26.4, 22.8, 18.1, 14.3.
FT-IR (thin film) cm
-1
: 3417, 2922, 2855, 1685, 1477, 1466, 1076, 733.
HRMS (ESI) m/z: [M+H]
+
Calcd for C25H33N2 361.2638; Found 361.2646.
2.7i
120
2-Benzyl-1-(propyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 70% yield (43 mg) as pale-yellow oil after flash column
chromatography (95:5 hexanes: ethyl acetate).
Data are consistent with the known compound.
8
1
H NMR (600 MHz, Chloroform-d) δ 7.50 (bs, 1H), 7.42 (d, J = 7.7 Hz, 1H), 7.31 – 7.12 (m, 6H),
7.08 – 6.99 (m, 2H), 3.70 (d, J = 13.5 Hz, 1H), 3.65 (d, J = 13.5 Hz, 1H), 3.57 – 3.50 (m, 1H),
3.20 – 3.10 (m, 1H), 2.89 – 2.75 (m, 2H), 2.55 – 2.44 (m, 1H), 1.76 – 1.55 (m, 2H), 1.49 – 1.27
(m, 2H), 0.78 (t, J = 7.4 Hz, 3H).
13
C NMR (151 MHz, Chloroform-d) δ 140.0, 135.9, 135.8, 129.0, 128.3, 127.5, 127.0, 121.4,
119.4, 118.2, 110.8, 107.9, 57.4, 56.5, 44.8, 37.0, 19.6, 18.0, 14.3.
2.7j
121
2-Benzyl-1-(thiophen-3-ylmethyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 55% yield (40 mg) as yellow oil after flash column chromatography
(95:5 hexanes: ethyl acetate).
1
H NMR (600 MHz, Chloroform-d) δ 7.53 (d, J = 7.6 Hz, 1H), 7.38 – 7.26 (m, 6H), 7.23 – 7.08
(m, 3H), 7.07 (bs, 1H), 6.96 – 6.91 (m, 1H), 6.87 (dd, J = 4.9, 1.3 Hz, 1H), 3.96 (dd, J = 8.6, 5.8
Hz, 1H), 3.86 (s, 2H), 3.37 – 3.30 (m, 1H), 3.25 (dd, J = 14.0, 5.8 Hz, 1H), 3.14 – 3.02 (m, 2H),
3.00 – 2.92 (m, 1H), 2.67 – 2.61 (m, 1H).
13
C NMR (151 MHz, Chloroform-d) δ 139.7, 139.6, 135.8, 134.9, 129.0, 128.8, 128.4, 127.1,
127.1, 125.8, 122.2, 121.6, 119.4, 118.2, 110.8, 108.1, 57.9, 57.6, 44.9, 35.5, 18.4.
FT-IR (thin film) cm
-1
: 3418, 2927, 2855, 1682, 1456, 1329, 1013, 742.
HRMS (ESI) m/z: [M+H]
+
Calcd for C23H23N2S 359.1576; Found 359.1581.
2.7k
122
2-Benzyl-1-(naphthalen-1-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole
The product was obtained in 52% yield (40 mg) as a white solid after flash column chromatography
(95:5 hexanes: ethyl acetate). This compound is not included in the published work as it is not
fully characterized.
1
H NMR (500 MHz, CDCl3) δ 8.48 (s, 1H), 7.87 (dd, J = 12.0, 8.2 Hz, 2H), 7.61 (d, J = 7.0 Hz,
1H), 7.59 – 7.54 (m, 1H), 7.51 – 7.40 (m, 3H), 7.30 – 7.19 (m, 6H), 7.18 – 7.06 (m, 3H), 5.32 (s,
1H), 3.94 (d, J = 13.4 Hz, 1H), 3.44 – 3.31 (m, 2H), ), 3.09 – 2.98 (m, 1H), 2.95 – 2.88 (m, 1H),
2.80 – 2.60 (m, 1H).
Synthesis of 2.6 on 2 mmol scale
As a representative example, we are giving the synthesis of 2.6 on 2 mmol scale from N-
benzyltryptamine.
In the drybox, a 50 mL round bottom flask with a teflon stirbar was charged with N-
benzyltryptamine 2.3 (500 mg, 2 mmol), alcohol (2 equiv, 4 mmol), 1 mol % ruthenium catalyst
C4 (13 mg, 20µmol), and 10 mol % indium triflate (113 mg, 0.2 mmol). After adding 15 mL dry
toluene to this mixture, the flask was closed with a condenser and a septum, taken out of the
glovebox, and maintained at reflux under a N2 stream. After 96 hours, solvent was removed under
reduced pressure, and the corresponding carboline 2.6 was isolated in 68% yield (460 mg) by silica
flash column chromatography in 95:5 hexanes: ethyl acetate. The small difference in the yield
while scaling up the reaction may be the result of inefficient heat transfer.
2.7l
123
6.2.5. Tandem PSR with CF3COOH as the Acid Catalyst
General Procedure
In the drybox, a 10 mL round bottom flask with a teflon stirbar was charged with N-
benzyltryptamine 2.3 (50 mg, 0.20 mmol), alcohol (2 equiv, 0.4 mmol), 1 mol % ruthenium
catalyst C4 (1.3 mg, 2µmol), and 1 equiv trifluoroactic acid (15 µL, 0.20 mmol). After adding 3
mL dry toluene to this mixture, the flask was closed with a condenser and a septum, taken out of
the glovebox, and maintained at reflux under a N2 stream. After 96 hours, solvent was removed
under reduced pressure, washed the product with 20 mL saturated K2CO3 solution, and extracted
in DCM.
Table 6.2.1. Tandem Pictet Spengler Reaction with CF3COOH as the Acid Catalyst.
Entry Alcohol Yield (%)
1 R = CO 2Me 72
a
(51)
2 R = OMe 44
b
(43)
3
40
b
(47)
a
Isolated yield.
b
NMR yield. Isolated yield of the corresponding reactions with In(OTf) 3 are given in bracket.
6.2.6. Tandem PSR with Aliphatic Alcohols
General Procedure
In the drybox, a 5 mL Schlenk reactor with a teflon stirbar was charged with N-
benzyltryptamine 2.3, alcohol, hydrogen abstractor (styrene, neohexene or benzoquinone),
ruthenium catalyst C4, and 10 mol % indium triflate. The reactor was closed with a teflon cap,
taken out of the glovebox, and stirred at 110
o
C for 96 h. The products were isolated by silica flash
124
column chromatography. The desired tetrahydro-β-carboline came in 95:5 hexanes: ethyl acetate
and the uncyclized N-alkylation compound was eluted in 30:70 hexanes: ethyl acetate.
Benzoquinone as the Hydrogen Acceptor
Benzoquinone was purified by sublimation prior use due to the presence of quinhydrone
(1:1 mixture of benzoquinone and hydroquinone). Crude benzoquinone was taken in a beaker with
a watch glass as the lid. When heated it slowly, yellow crystals were deposited on the watch glass.
When N-benzyltryptamine (0.2 mmol) is treated with 1-butanol (0.4 mmol), complex C4
(1 mol %), and In(OTf)3 (10 mol %) with benzoquinone (0.4 mmol), rather than acting as a
hydrogen acceptor, benzoquinone reacted stoichiometrically with N-benzyltryptamine. We believe
that two Michael addition steps followed by a PSR (Scheme 5.2.1) yielded the observed product
(predicted based on the peak observed in MALDI-TOF mass spectrum).
Scheme 6.2.1. Proposed Mechanism for the Reaction of N-benzyltryptamine with Benzoquinone.
125
6.2.7. Studies to Probe the Mechanism of Reactions Starting from Tryptamine
Scheme 6.2.2. Reaction of 2.4 and 2.5 to Probe the Mechanism of Tandem PSR Sequence Starting
from Tryptamine.
Reaction of N-Benzylidenetryptamine with 4-Fluorobenzyl Alcohol (48 h)
In the drybox, a 10 mL round bottom flask with a teflon stir bar was charged with N-
benzylidenetryptamine (150 mg, 0.60 mmol), 4-fluorobenzyl alcohol (152 mg, 1.2 mmol), 1 mol
% ruthenium catalyst C4 (3.9 mg, 6µmol), and 10 mol % indium triflate (34 mg, 0.06 mmol). After
adding 5 mL dry toluene to this mixture, the flask was closed with a condenser and a septum, taken
out of the glovebox, and maintained at for refluxing under a N2 stream. After 48 hours, solvent
was removed under reduced pressure. 38% of compounds 2.5b' and 2.3 b', and 36% of 2.5 were
obtained after flash column chromatography. The data are consistent with a known compound.
11
126
b
a
a
b
a
a
Figure 6.2.4.
1
H NMR spectrum of the mixture obtained after flash chromatography in 90:10
hexanes:EtOAc for the reaction of N-benzylidenetryptamine with 4-fluorobenzyl alcohol after 2
days; 2.5b' and 2.3b' together constitute 38% yield.
Reaction of N-Benzylidenetryptamine with 4-Fluorobenzyl Alcohol (96 h)
In the drybox, a 10 mL round bottom flask with a teflon stirbar was charged with N-
benzylidenetryptamine (150 mg, 0.60 mmol), 4-fluorobenzyl alcohol (152 mg, 1.2 mmol), 1 mol
% ruthenium catalyst C4 (3.9 mg, 6µmol), and 10 mol % indium triflate (34 mg, 0.06 mmol). After
adding 5 mL dry toluene to this mixture, the flask was closed with a condenser and a septum, taken
out of the glovebox, and kept it for refluxing under a N2 stream. After 96 hours, solvent was
removed under reduced pressure. Compounds 2.5b' and 2.3b' were obtained in 60% yield after
flash column chromatography. Compound 2.5 was not present in the mixture.
127
Synthesis of 2.5
2.5
In the glovebox, a 10 mL round bottom flask was charged with N-benzylidinetryptamine
(100 mg, 0.40 mmol) and 10 mol % indium triflate (23 mg, 0.04 mmol). After adding 3 mL dry
toluene to this mixture, the flask was closed with a condenser and a septum, taken out of the
glovebox, and maintained at for refluxing under a N2 stream. After 24 hours, solvent was removed
under reduced pressure. Then it was dissolved in dichloromethane and water. The organic layer
was collected, and fresh 15 mL portion of dichloromethane was added to the aqueous layer two
more times to extract the product. The combined organic layer was dried over anhydrous Na2SO4.
Product was recrystallized from ethanol. Data are consistent with the known compound.
11
Yield: 52% (52 mg)
1
H NMR (500 MHz, Chloroform-d) δ 7.69 (s, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.40 – 7.26 (m, 5H),
7.24 – 7.09 (m, 3H), 5.15 (s, 1H), 3.43 – 3.32 (m, 1H), 3.19 – 3.08 (m, 1H), 3.01 – 2.78 (m, 2H),
1.79 (s, 1H).
13
C NMR (126 MHz, Methylene Chloride-d2) δ 142.7, 136.3, 135.3, 129.1, 128.8, 128.4, 127.9,
121.9, 119.6, 118.5, 111.1, 110.3, 58.5, 43.3, 22.9.
Reaction of 2.5 with Benzyl Alcohol
Inside the glovebox, a 5 mL Schlenk reactor with conical bottom was charged with 2.5 (25
mg, 0.10 mmol), benzyl alcohol (22 mg, 0.2 mmol), and 1 mol % ruthenium catalyst C4 (0.7 mg,
1 µmol). The reactor was sealed, taken out of the glovebox, and was heated to 110 °C for 24 hours.
After that, the dark brown reaction mixture was allowed to cool to room temperature, and an
128
b
a,b,c (overlapping with
residual 2.5)
c
d
benzylic CH
of 2.5
aliquot was obtained for the
1
H NMR analysis in CDCl3. The proton spectrum of the crude mixture
showed 2.5b in 42% yield.
Figure 6.2.5.
1
H NMR of the crude reaction mixture for the reaction of 10 with benzyl alcohol at
110 °C.
6.2.8. Studies to Probe the Mechanism of Reactions Starting from N -Benzyltryptamine
Reaction of N-Benzyltryptamine and Benzyl Alcohol (without In(OTf)3)
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with N-
benzyltryptamine 2.3 (112 mg, 0.45 mmol), benzyl alcohol (97 mg, 0.9 mmol), and 1 mol %
ruthenium catalyst C4 (2.95 mg, 4.5µmol). The reactor was sealed, taken out of the glovebox, and
was heated to 110 °C for 24 hours. After that, the dark brown reaction mixture was allowed to cool
129
b b
c
d
c
a (overlapping with
residual N-benzyl
tryptamine peak)
to room temperature, and an aliquot was obtained for the
1
H NMR analysis in CDCl3. The proton
spectrum of the crude mixture showed corresponding THBC in 32% yield.
Figure 6.2.6.
1
H NMR of the crude reaction mixture for the reaction of N-benzyltryptamine and
benzyl alcohol at 110 °C without In(OTf)3.
Reaction of N-Benzyltryptamine and 4-Bromobenzyl Alcohol (with MgSO4)
In the glovebox, a 10 mL round bottom flask was charged with N-benzyltryptamine (50
mg, 0.20 mmol), 4-bromobenzyl alcohol (75mg, 0.40 mmol), 1 mol % ruthenium catalyst C4 (1.3
mg, 4 µmol), and 1 equivalent anhydrous magnesium sulfate (24 mg, 0.20 mmol). After adding 3
mL dry toluene to this mixture, the flask was closed with a condenser and a septum, taken out of
benzyl alcohol CH 2
mesitylene CH 3
130
b b
c
c
d (overlapping
with alcohol CH 2)
the glovebox, and kept it for refluxing under a N2 stream. After 94 hours, solvent was removed
under reduced pressure, and dissolved it in dichloromethane and water. The organic layer was
collected, and fresh 15 mL portion of dichloromethane was added to the aqueous layer two more
times to extract the product. The combined organic layer was dried over anhydrous Na2SO4.
Mesitylene was added as an internal standard after removing the solvent under reduced pressure.
An aliquot was obtained for the
1
H NMR analysis in CDCl3. The proton spectrum of the crude
mixture showed corresponding THBC in 74% yield.
Figure 6.2.7.
1
H NMR of the crude reaction mixture for the reaction of N-benzyltryptamine and
4-bromobenzyl alcohol with 1 equivalent anhydrous MgSO4.
a
131
Reaction of N-Benzyltryptamine with 4-Fluorobenzyl Alcohol
In the drybox, a 10 mL round bottom flask with a teflon stirbar was charged with N-
benzyltryptamine (100 mg, 0.40 mmol), 4-fluorobenzyl alcohol (100 mg, 0.8 mmol), 1 mol %
ruthenium catalyst C4 (2.6 mg, 4µmol), and 10 mol % indium triflate (22.6 mg, 0.04 mmol). After
adding 3 mL dry toluene to this mixture, the flask was closed with a condenser and a septum, taken
out of the glovebox, and kept it for refluxing under a N2 stream. After 96 hours, solvent was
removed under reduced pressure, and the corresponding carboline was isolated by flash column
chromatography in 97:5 hexanes: ethyl acetate.
13
C NMR spectrum of the isolated product in
CDCl3 is shown in Figure 6.2.8. C1, C2, C3, and C4 (at 163.63, 161.67; 115.83, 115.66; 130.71,
130.64; 137.39, 137.36 ppm respectively) appear as doublets in the
13
C spectrum due to
13
C-
19
F
coupling, with the coupling constant increasing in the order J4 < J3 < J2 < J1. Also, the quaternary
carbon C6 is observed at 134.61 ppm. HMBC spectrum (Figure 6.2.9) shows correlation of C3, C 4
and C6 with H5; and thus supports our proposed mechanism for N-benzyltryptamine reactions.
132
Figure 6.2.8.
13
C NMR spectrum of the isolated product for the reaction of N-benzyltryptamine
and 4-fluorobenzyl alcohol; C1, C2, C3 and C4 appear as doublets due to
13
C-
19
F coupling.
C
3
C
6
H
5
133
C 3
C 6
C 4
H 5
Figure 6.2.9. HMBC spectrum of the isolated product for the reaction of N-benzyltryptamine and
4-fluorobenzyl alcohol; C3, C4, and C6 shows correlation with H5; thus, identity of the product is
confirmed as 2.7b.
Reaction of Tryptamine and Benzyl Alcohol (with MgSO4)
Inside the glovebox, a 5 mL Schlenk reactor with a conical bottom was charged with
tryptamine 7 (50 mg, 0.31 mmol), benzyl alcohol (169 mg, 1.56 mmol), 1 mol % ruthenium
catalyst C4 (2 mg, 3.1 µmol) and MgSO4 (37.5 mg, 0.31 mmol, 1 equiv). The reactor was sealed,
taken out of the glovebox, and was heated to 110 °C for 24 hours. After that, the dark brown
reaction mixture was allowed to cool to room temperature. Then it was dissolved in
dichloromethane and water. The organic layer was collected, and fresh 15 mL portion of
dichloromethane was added to the aqueous layer two more times to extract the product. The
combined organic layer was dried over anhydrous Na2SO4. Mesitylene was added to this reaction
H 5
134
c
mixture as an internal standard, and an aliquot was taken for
1
H NMR analysis in CDCl3. The
proton spectrum of the crude mixture showed corresponding THBC 2.6 in 20% yield.
Figure 6.2.10.
1
H NMR of the crude reaction mixture for the reaction of tryptamine and benzyl
alcohol with 1 equivalent anhydrous MgSO4. Compound 2.6 is formed in 20% NMR yield.
6.2.9. H/D Scrambling Experiment to Probe the Equilibrium between N-
Benzylidenetryptamine and N-Benzyltryptamine
Synthesis of 2.1-d3
Benzyl alcohol 2.1-d3 was synthesized by the reduction of methyl benzoate using lithium
aluminium deuteride (98% D4, Cambridge Isotope Laboratories), followed by D2O hydrolysis. To
135
a 10 mL ether solution of LiAlD4 (0.2 g, 4.76 mmol) was added a 10 mL ether solution of methyl
benzoate (1.08 g, 7.9 mmol) dropwise. THF (1 mL) was also added to the reaction mixture to
dissolve the product and getting efficient stirring. After 24 hours, few drops of D2O were added
while stirring the solution. The mixture was filtered, and the filtrate extracted with ether (3 x 10
mL). The solution was dried over Na2SO4. Pure compound was isolated by vacuum distillation.
Yield = 54% (ca. 98% D).
Figure 6.2.11.
13
C spectrum of 2.1-d3; doubly deuterated carbon appears as a quintet in the
spectrum.
Reaction of 2.1-d3 with N-Benzyltryptamine
To gain more insight into the mechanism of reaction starting from tryptamine, we studied
about secondary amine/imine equilibrium by checking H/D scrambling in a reaction of N-benzyl
136
tryptamine with 2.1-d3. In the drybox, a 10 mL round bottom flask with a teflon stirbar was charged
with N-benzyltryptamine (50 mg, 0.20 mmol), benzyl alcohol 2.1-d3 (45 mg, 0.40 mmol), 1 mol
% ruthenium catalyst C4 (1.3 mg, 2 µmol), and 10 mol % indium triflate (11.2 mg, 0.02 mmol).
After adding 3 mL dry toluene to this mixture, the flask was closed with a condenser and a septum,
taken out of the glovebox, and kept it for refluxing under a N2 stream. After 96 hours, solvent was
removed under reduced pressure, and the corresponding carboline 2.6-d1 was isolated by flash
column chromatography in 97:5 hexanes: ethyl acetate.
1
H spectrum (Figure 6.2.12) of the isolated
product showed 2.6-d1 along with its isotopomer (ca. 25%). We observed under integration for
peak ‘d’; whereas benzylic CH2 peaks ‘c’ were not underintegrated indicating absence of
equilibrium between N-benzylidenetryptamine and N-benzyltryptamine. In addition to the
1
H
spectrum,
13
C NMR also showed isotopic shift (Figure 6.2.13). Furthermore, we took a
2
H
spectrum (Figure 6.2.14) to examine the H/D scrambling, and we found no deuterium peaks for
‘c’. Peak at 4.68 ppm corresponds to benzylic CD, which was already present in the starting
alcohol.
137
Figure 6.2.12.
1
H spectrum of 2.6-d1.
Figure 6.2.13.
13
C spectrum of 2.6-d1.
138
Figure 6.2.14.
2
H spectrum of 2.6-d1.
6.2.10. Reaction of Tryptamine with 1,4-Butanediol
Coupling of tryptamine and 1,4-butanediol with C4 and trifluoroacetic acid gives
harmicine (2.8) and trifluoroacetamide of tryptamine (2.9). Optimization studies are shown in
Table 6.2.2.
General Procedure (for entries 3-9)
In the drybox, a 10 mL round bottom flask with a teflon stirbar was charged with
tryptamine, alcohol, ruthenium catalyst C4, and trifluoroacetic acid. After adding 3 mL dry toluene
residual CDCl 3
139
a
b
b
b, a
a,c
f
d,e
to this mixture, the flask was closed with a condenser and a septum, taken out of the glovebox, and
maintained at for refluxing under a N2 stream. After required hours, reaction was quenched with
saturated NaHCO3 solution, and extracted the product in DCM. Collected organic layer was dried
over anhydrous sodium sulfate and concentrated in vacuo. Mesitylene was added to this reaction
mixture as an internal standard, and an aliquot was taken for
1
H NMR analysis in CDCl3. Crude
proton spectrum showed harmicine 2.8 and the side product 2.9 (Figure 6.2.15). Data are consistent
with known compounds.
9, 10
Figure 6.2.15.
1
H NMR spectrum of the crude reaction mixture for the coupling of tryptamine
with 1,4-butanediol; 2.8 and 2.9 are observed as products.
e (merging with
mesitylene peak)
140
Table 6.2.2. Optimization Studies for One Step Synthesis of Harmicine.
Entry Tryptamine:
Diol
C4
(mol %)
Time
(h)
Condition Product (%)
2.8 2.9
1 1:1 1 6 1 eq styrene, neat, 110 °C, closed 5 0
2 1:1 1 96 1 eq styrene, toluene, reflux, closed 23 30
3 1:1 1 96 toluene, reflux, open, N 2 39 27
4 1:2 1 96 toluene, reflux, open, N 2 55 37
5 1:5 1 96 toluene, reflux, open, N 2 39 31
6 1:1 3 96 toluene, reflux, open, N 2 13 35
7 1:1 0.3 96 toluene, reflux, open, N 2 9 60
8 1.5:1 1 96 toluene, reflux, open, N 2 15 85
9 1:1 1 5 toluene, reflux, open, N 2 2 11
Reactions using styrene as the hydrogen acceptor (entries 1-2) were not efficient to increase
the yield of 2.8. Interestingly, changing amine/diol ratio from 1:1 to 1:2 increased yields of both
2.8 and 2.9, but no significant change was observed with 5 equivalent diol. Low catalyst loading
favors formation of 2.9, whereas the low yield of 2.8 in entry 6 can be attributed to the deactivation
of our ruthenium catalyst at higher catalyst loadings as reported recently.
12
When we compared
entry 3 with entry 9, we thought that the change in the distribution of both products may be coming
from the conversion of 2.9 to 2.8 during the course of reaction. We neglected this assumption by
running a separate reaction starting from pure 2.9.
Optimized Procedure
In the drybox, a 10 mL round bottom flask with a teflon stirbar was charged with
tryptamine (50 mg, 0.31 mmol), alcohol (56 mg, 0.62 mmol, 2 equiv), 1 mol % ruthenium catalyst
C4 (2.0 mg, 3.1µmol), and trifluoroacetic acid (24 µL, 0.31 mmol, 1 equiv). After adding 3 mL
dry toluene to this mixture, the flask was closed with a condenser and a septum, taken out of the
glovebox, and maintained at for refluxing under a N2 stream. After 96 hours, reaction was
quenched with saturated NaHCO3 solution, and extracted the product in DCM. Collected organic
layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The product 2.8 was
141
obtained in 50 % yield (33 mg) as white solid after silica flash column chromatography in 1:1
DCM:MeOH.
Data are consistent with known a compound.
10
1
H NMR (400 MHz, Chloroform-d) δ 7.94 (bs, 1H), 7.55 – 7.44 (m, 1H), 7.34 – 7.28 (m, 1H), 7.19
– 7.06 (m, 2H), 4.28 – 4.17 (m, 1H), 3.38 – 3.28 (m, 1H), 3.15 – 3.03 (m, 1H), 3.02 – 2.82 (m,
3H), 2.72 – 2.60 (m, 1H), 2.36 – 2.19 (m, 1H), 2.01 – 1.78 (m, 3H)
13
C NMR (126 MHz, Chloroform-d) δ 136.1, 135.5, 127.5, 121.5, 119.5, 118.2, 110.9, 107.9, 57.1,
49.4, 46.1, 29.6, 23.6, 17.9
The side product 2.9 was isolated as a white solid in 30% yield (24 mg) from the crude mixture by
silica flash column chromatography (3:1, hexanes: ethyl acetate).
Data are consistent with a known compound.
9
1
H NMR (400 MHz, Chloroform-d) δ 8.10 (s, 1H), 7.60 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 8.2 Hz,
1H), 7.26 – 7.20 (m, 1H), 7.20 – 7.12 (m, 1H), 7.09 – 6.98 (m, 1H), 6.36 (s, 1H), 3.70 (q, J = 6.5
Hz, 2H), 3.06 (t, J = 6.7 Hz, 2H).
Reaction of 2.9 with 1,4-butanediol
Compound 2.9 was synthesized according to the reported literature procedure.
9
Reaction of 2.9
with 2 equivalent 1,4-butanediol in the presence of 1 mol % C4, and 10% TFA didn’t produce
harmicine.
142
6.2.11. Reaction of Tryptamine with 1,5-Pentanediol
In the drybox, a 10 mL round bottom flask with a teflon stirbar was charged with
tryptamine (50 mg, 0.31 mmol), 1,5-pentanediol (32 mg, 0.31 mmol, 1 equiv), 1 mol % ruthenium
catalyst C4 (2.0 mg, 3.1µmol), and trifluoroacetic acid (24 µL, 0.31 mmol, 1 equiv). After adding
3 mL dry toluene to this mixture, the flask was closed with a condenser and a septum, taken out of
the glovebox, and kept it for refluxing under a N2 stream. After 96 h hours, reaction was quenched
with saturated NaHCO3 solution, and extracted the product in DCM. Collected organic layer was
dried over anhydrous sodium sulfate and concentrated in vacuo. Mesitylene was added to this
reaction mixture as an internal standard, and an aliquot was taken for
1
H NMR analysis in CDCl3.
Crude proton spectrum showed desired tetracyclic alkaloid (2.10) in 30% and the side product 2.9
in 54% yield (Figure 5.2.16). Data are consistent with known compounds.
10, 13
143
Figure 6.2.16.
1
H NMR spectrum of the crude reaction mixture for the coupling of tryptamine
with 1,5-butanediol; Peaks (t) at 2.97 (merges with the tetracyclic alkaloid) and 3.61 belongs to
2.9.
6.2.12. Exploring Other Strategies to Access Tetracyclic Alkaloids
Synthesis of Monoprotected Diols
Into an ice bath cooled solution of 1,4-butanediol (6.59 g, 73.0 mmol, 1 equiv) in THF (70
mL) in a 250 mL round bottom flask, 60% sodium hydride dispersion in mineral oil (2.05 g, 51
mmol, 0.7 equiv) was added slowly while stirring. After 30 min, TBSCl (7.66 g, 51 mmol, 0.7
equiv) was added to the mixture and stirred at rt. After 1 h, the mixture was quenched with
saturated NH4Cl (30 mL) solution, extracted with ethyl acetate 3 times, washed the collected
organic layer with brine and dried over anhydrous Na2SO4. The product was obtained in 98% yield
144
after silica flash column chromatography in hexanes: ethyl acetate (80:20). Data are consistent
with a known compound.
14
1
H NMR (400 MHz, CDCl3) δ 3.69 – 3.57 (m, 4H), 2.79 (bs, 1H), 1.69 – 1.53 (m, 4H), 0.91 –
0.81 (m, 9H), 0.10 – 0.03 (m, 6H).
A 250 mL round bottom flask was charged with 2.11 (2.30 g, 11.25 mmol, 1 equiv),
pyridine (0.97 g, 12.3 mmol, 1.1 equiv) and acetic anhydride (1.53 g, 15 mmol, 1.3 equiv) in ethyl
acetate. After overnight stirring at rt, mixture was diluted with more ethyl acetate, washed with 1
N HCl, sat. NaHCO3 solution (50 mL), followed by brine (50 mL). The organic layer was
collected, dried over anhydrous Na2SO4 and used without further purification (96%) for the next
step. Data are consistent with the reported compound.
15
1
H NMR (500 MHz, CDCl3) δ 4.07 (t, J = 6.7 Hz, 2H), 3.62 (t, J = 6.3 Hz, 2H), 2.03 (s, 3H),
1.74 – 1.63 (m, 2H), 1.61 – 1.52 (m, 2H), 0.88 (s, 9H), 0.04 (s, 6H).
A 100 mL round bottom flask was charged with 2.12 (1.25 g, 5.07 mmol, 1 equiv.) and 1
M TBAF in THF (13 mL, 13 mmol, 2.56 equiv.) in tetrahydrofuran. After 48 h of stirring at rt,
volatiles were removed under reduced pressure. The product was obtained in 40% yield after silica
flash column chromatography in hexanes: ethyl acetate (50:50). Data are consistent with the
known compound.
16
1
H NMR (500 MHz, CDCl3) δ 4.09 (t, J = 6.5 Hz, 2H), 3.67 (t, J = 6.4 Hz, 2H), 2.04 (s, 3H),
1.77 – 1.67 (m, 2H), 1.67 – 1.57 (m, 2H), 1.52 (bs, 1H).
145
Reaction of Monoprotected Diols with Tryptamine
We tried various conditions to couple monoprotected diols with tryptamine. Results are
summarized in table 6.2.3.
Table 6.2.3. Coupling of Monoprotected Diols with Tryptamine.
Entry Amine: Diol P Catalyst Condition Observation
1 1.0:1.0 TBS 1 (0.2%) neat, 110
o
C, closed
flask, 20 h
starting material
2 " Ac " " "
3 1.2:1.0 Ac 1 (1%) neat, 110
o
C, closed
flask, 24 h
observed 1,4-butanediol and
4 1.0:2.0 TBS 1 (1%) neat, 110
o
C, closed
flask, 48 h
MALDI showed peaks at
216.34, 359.50 and 401.30.
We couldn’t identify
compound having those
masses; but it differ either 12
or 13 from ,
and
.
5 1.2:1.0 Ac 1 (1%) toluene (2 mL),
160
o
C, MW, 1 h
starting material
6 1.0:1.0 TBS " " "
7 " " " dichloromethane (2
mL), 110
o
C, MW, 1
h
"
8 " " [Cp*IrCl 2] 2
(1%)
methanol (2 mL),
140
o
C, MW, 1 h
tryptamine coupled with
methanol instead of diol and
showed
146
9 1.2:1.0 Ac 1 (1%) toluene, reflux,
closed Schlenk
reactor, 24 h
starting material
10 1.0:1.1 TBS 1 (1%),
In(OTf) 3
(10%)
toluene, reflux, open
flask, 96 h
we could not identify the
mixture of compounds formed.
Compound B, D, I and III
were not observed.
11 " Ac " " showed trace of
and
harmicine; compound. I was
not observed.
Reaction of Dihydropyran with Tryptamine
We tried various conditions to couple dihydropyran with tryptamine. Results are summarized in
table 6.2.4.
Table 6.2.4. Coupling of Dihydropyran with Tryptamine.
Entry Amine: DHP Catalyst (mol %) Condition Observation
1 1.0:1.0 MgBr 2 (3) dichloromethane, rt, 7h starting material
2 1.0:1.2 " MeOH (20%), dichloromethane,
30
o
C, 7 h
starting material
3 1.0:1.2 " water (1 drop) dichloromethane,
30
o
C, 7 h
starting material
4 3.0:1.0 FeCl 3.6H 20 (10) dioxane, 80
o
C, 20 h starting material
5 1.0:1.0 Conc. HCl (20) dichloromethane, rt, 1 h starting material
6 " TFA (20) " starting material
147
6.2.13. NMR Spectra
Figure 6.2.17.
1
H NMR (500 MHz) spectrum of N-benzylidenetryptamine at 25 °C in CDCl3.
Figure 6.2.18.
13
C NMR (126 Hz) spectrum of N-benzylidenetryptamine at 25 °C in CDCl3.
148
Figure 6.2.19.
1
H NMR (500 MHz) spectrum of 2.6 at 25 °C in CD2Cl2.
Figure 6.2.20.
13
C NMR (126 MHz) spectrum of 2.6 at 25 °C in CD2Cl2.
2.6
149
Figure 6.2.21.
1
H NMR (600 MHz) spectrum of 2.6b at 25 °C in CDCl3.
Figure 6.2.22.
13
C NMR (151 MHz) spectrum of 2.6b at 25 °C in CDCl3.
2.6b
150
Figure 6.2.23.
19
F NMR (564 MHz) spectrum of 2.6b at 25 °C in CDCl3.
Figure 6.2.24.
1
H NMR (500 MHz) spectrum of 2.6c at 25 °C in CDCl3.
2.6c
151
Figure 6.2.25.
13
C NMR (126 MHz) spectrum of 2.6c at 25 °C in CDCl3.
Figure 6.2.26.
1
H NMR (500 MHz) spectrum of 2.6d at 25 °C in CDCl3.
2.6d
152
Figure 6.2.27.
13
C NMR (126 MHz) spectrum of 2.6d at 25 °C in CDCl3.
Figure 6.2.28.
1
H NMR (600 MHz) spectrum of 2.6e at 25 °C in CDCl3.
2.6e
153
Figure 6.2.29.
13
C NMR (151 MHz) spectrum of 2.6e at 25 °C in CDCl3.
Figure 6.2.30.
1
H NMR (600 MHz) spectrum of 2.6f at 25 °C in CDCl3.
2.6f
154
Figure 6.2.31.
13
C NMR (151 MHz) spectrum of 2.6f at 25 °C in CDCl3.
Figure 6.2.32.
1
H NMR (400 MHz) spectrum of N-benzyltryptamine (2.3) at 25 °C in CDCl3.
155
Figure 6.2.33.
13
C NMR (101 MHz) spectrum of N-benzyltryptamine (2.3) at 25 °C in CDCl3.
Figure 6.2.34.
1
H NMR (500 MHz) spectrum of 2.7b at 25 °C in CDCl3.
2.7b
156
Figure 6.2.35.
13
C NMR (126 MHz) spectrum of 2.7b at 25 °C in CDCl3.
Figure 6.2.36.
1
H NMR (500 MHz) spectrum of 2.7c at 25 °C in CDCl3.
2.7c
157
Figure 6.2.37.
13
C NMR (151 MHz) spectrum of 2.7c at 25 °C in CDCl3.
Figure 6.2.38.
1
H NMR (500 MHz) spectrum of 2.7d at 25 °C in CDCl3.
2.7d
158
Figure 6.2.39.
13
C NMR (126 MHz) spectrum of 2.7d at 25 °C in CDCl3.
Figure 6.2.40.
1
H NMR (500 MHz) spectrum of 2.7e at 25 °C in CDCl3.
2.7e
159
Figure 6.2.41.
13
C NMR (126 MHz) spectrum of 2.7e at 25 °C in CDCl3.
Figure 6.2.42.
1
H NMR (500 MHz) spectrum of 2.7f at 25 °C in CDCl3.
2.7f
160
Figure 6.2.43.
13
C NMR (126 MHz) spectrum of 2.7f at 25 °C in CDCl3.
Figure 6.2.44.
1
H NMR (600 MHz) spectrum of 2.7g at 25 °C in CDCl3.
2.7g
161
Figure 6.2.45.
13
C NMR (151 MHz) spectrum of 2.7g at 25 °C in CDCl3.
Figure 6.2.46.
1
H NMR (600 MHz) spectrum of 2.7h at 25 °C in CDCl3.
2.7h
162
Figure 6.2.47.
13
C NMR (151 MHz) spectrum of 2.7h at 25 °C in CDCl3.
Figure 6.2.48.
1
H NMR (500 MHz) spectrum of 2.7i at 25 °C in CDCl3.
2.7i
163
Figure 6.2.49.
13
C NMR (126 MHz) spectrum of 2.7i at 25 °C in CDCl3.
Figure 6.2.50.
1
H NMR (600 MHz) spectrum of 2.7j at 25 °C in CDCl3.
2.7j
164
Figure 6.2.51.
13
C NMR (151 MHz) spectrum of 2.7j at 25 °C in CDCl3.
Figure 6.2.52.
1
H NMR (600 MHz) spectrum of 2.7k at 25 °C in CDCl3.
2.7k
165
Figure 6.2.53.
13
C NMR (151 MHz) spectrum of 2.7k at 25 °C in CDCl3.
Figure 6.2.54.
1
H NMR (500 MHz) spectrum of 2.7l at 25 °C in CDCl3.
166
Figure 6.2.55.
1
H NMR (500 MHz) spectrum of 2.5 at 25 °C in CDCl3.
Figure 6.2.56.
13
C NMR (126 MHz) spectrum of 2.5 at 25° C in CD2Cl2.
2.5
167
Figure 6.2.57.
1
H NMR spectrum of 2.8 at 25 °C in CDCl3.
Figure 6.2.58.
13
C NMR spectrum of 2.8 at 25° C in CDCl3.
168
Figure 6.2.59.
1
H NMR (400 MHz) spectrum of 2.9 at 25 °C in CDCl3.
Figure 6.2.60.
1
H NMR (400 MHz) spectrum of 2.11 at 25 °C in CDCl3.
169
Figure 6.2.61.
1
H NMR (500 MHz) spectrum of 2.12 at 25 °C in CDCl3.
Figure 6.2.62.
1
H NMR (500 MHz) spectrum of 2.13 at 25 °C in CDCl3.
170
6.2.14. References
1. Beddie, C.; Wei, P.; Douglas, S. Can. J. Chem. 2006, 84, 755-761.
2. Celaje, J. J. A.; Zhang, X.; Zhang, F.; Kam, L.; Herron, J. R. ACS Catal. 2017, 7, 1136-1142.
3. Abe, T.; Yamada, K. Org. Lett. 2018, 20, 1469-1472.
4. Dai, K. J.; Dan, W.J.; Li, N.; Du, H. T.; Zhang, J. W.; Wang, J. R. Bioorg. Med. Chem. Lett.
2016, 26, 580-583.
5. Qi, L.; Hou, H.; Ling, F.; Zhong, W. Org. Biomol. Chem. 2018, 16, 566-574.
6. Huang, D.; Xu, F.; Lin, X.; Wang, Y. Chem. Eur. J. 2012, 18, 3148-3152.
7. Sewgobind, N. V.; Wanner, M. J.; Ingemann, S.; Gelder, R.; Maarseveen, J. H.; Hiemstra, K.
J. Org. Chem. 2008, 73, 6405-6408.
8. Ascic, E.; Hansen, C. L.; Quement, S. T. L.; Nielsen, T. E. Chem. Commun. 2012, 48, 3345-
3347.
9. Wesche, F.; Adihou, H.; Kaiser, A.; Wurglics, M.; Schubert-Zsilavecz, M.; Kaiser, M.; Bode,
H. B. J. Med. Chem. 2018, 61, 3930-3938.
10. Pressnitz, D.; Fischereder, E.; Pletz, J.; Kofler, C.; Hammerer, L.; Hiebler, K.; Lechner, H.;
Richter, N.; Eger, E.; Kroutil, W. Angew. Chem. Int. ed. 2018, 57, 10683-10687.
11. Wang, Q.; Chai, H.; Yu, Z. Organometallics 2018. 37, 584-591.
12. Cherepakhin, V.; Williams, T. J. ACS Catal. 2020, 10, 56-65.
13. Byeong-Yun, L.; Bo-Eun, J.; Cheon-Gyu, C. Org.Lett. 2014, 16, 4492-4495.
14. Michael, D.; Manuel, K.; Pengfei, L.; Sven, R.; Daniel, H.; Dirk, M. Angew. Chem. Int. Ed.
2012, 51, 5667-5670.
171
15. Chien- Tien, Chen.; Jen-Huang, K.; Vijay, D. P.; Yogesh, S. M.; Shieu-Shien, W.; Cheng-
Hsiu, K.; Cheng-Yuan, L. J. Org. Chem. 2005, 70, 1188-1197.
16. Andivelu, E.; Karnambaram, A.; Prasad, K. M. Tetrahedron Lett., 2015, 56, 1081-1084.
172
b
c
d
diol
6.3. Chapter 3 Experimental and Spectral Data
6.3.1. Optimization of the Homopiperazine Synthesis
General Procedure
In the drybox, a 1-dram vial was charged with 1,3-propanediol (1–4 equiv), N,N’-
dibenzylethylenediamine, (1–2 equiv), and catalyst 1 (0.5–1.0 mol %). The vial was sealed, taken
out of the glovebox, and heated to 110 °C. The solution turned to dark brown color. After the given
time, the reaction mixture was allowed to cool to room temperature. Mesitylene was added to this
reaction mixture as an internal standard, and an aliquot was taken for
1
H NMR analysis in CDCl3.
Results are summarized in Table 3.1.
Figure 6.3.1.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-
dibenzylethylenediamine (1equiv) and 1,3-propanediol (4 equiv) with 1 mol % C4 for 44 h.
a (merging with diol peak)
173
Even though reactions with excess alcohol and 1 mol % C4 for 44 h achieved full
conversion, crude NMR showed some peaks that do not correlate to the target compound (Figure
6.3.1). An LC-QTOF spectrum of the products of entry 5 (Table 3.1) with positive ionization
method showed three major peaks (Figure 6.3.2), that may be correspond to the desired product I
(m/z calcd for [C19H25N2]
+
281.20122), an iminium ion intermediate II (m/z calcd for
[C19H25N2O]
+
297.19614) and a dimerized side product III (m/z calcd for [C38H49N4O2]
+
593.38500).
Figure 6.3.2. LC-QTOF spectrum of the crude reaction mixture for the coupling of N,N’-
dibenzylethylenediamine (1equiv) and 1,3-propanediol (4 equiv) with 1 mol % C4 for 44 h.
174
6.3.2. Synthesis of Diamine Substrates
(1R,2R)-N
1
,N
2
-dibenzylcyclohexane-1,2-diamine
In a 250 mL round bottom flask, the diamine (1R,2R)-(–)-1,2-diaminocyclohexane (1
equiv, 13.13 mmol) and benzaldehyde (2 equiv, 26.26 mmol) were dissolved in methanol (80 mL)
and stirred at room temperature. After 24 h, sodium borohydride (2.2 equiv, 28.89 mmol) was
slowly added to the mixture at 0 °C and then stirred at room temperature for 24 hours. After this
time, the solvent was removed under reduced pressure and DI water was added. The product was
extracted into dichloromethane, dried over anhydrous Na2SO4; and the solvent was removed under
reduced pressure.
The product 3.1b was obtained in 88% yield (3.4 g) as an orange oil after silica flash
chromatography (95:5 dichloromethane: methanol).
Data are consistent with the known compound.
3
1
H NMR (600 MHz, CDCl3) δ 7.34 – 7.28 (m, 8H), 7.26 – 7.22 (m, 2H), 3.91 (d, J = 13.1 Hz, 2H),
3.67 (d, J = 13.2 Hz, 2H), 2.33 – 2.25 (m, 2H), 2.20 – 2.13 (m, 2H), 1.78 – 1.68 (m, 2H), 1.29 –
1.18 (m, 2H), 1.11 – 1.00 (m, 2H).
13
C NMR (151 MHz, CDCl3) δ 140.9, 128.5, 128.2, 127.0, 61.0, 50.9, 31.6, 25.1.
Optical Rotation: [𝛼 ]
WI
20
= − 55 . 4 (c = 1.0, CH2Cl2).
Racemic compound (3.1b') was synthesized for chiral HPLC from (±)-trans-1,2-
diaminocyclohexane and benzaldehyde using the above procedure. The product was obtained in
87% yield as an orange oil after silica flash chromatography (50:50 hexanes: ethyl acetate).
3.1b
175
1
H NMR (400 MHz, CDCl3) δ 7.40 – 7.17 (m, 10H), 3.91 (d, J = 13.1 Hz, 2H), 3.67 (d, J = 13.2
Hz, 2H), 2.34 – 2.23 (m, 2H), 2.21 – 2.12 (m, 2H), 2.03 (bs, 2H), 1.79 – 1.67 (m, 2H), 1.31 – 1.16
(m, 2H), 1.13– 1.00 (m, 2H).
13
C NMR (151 MHz, CDCl3) δ 141.2, 128.5, 128.2, 126.9, 61.0, 51.0, 31.7, 25.2.
Optical Rotation: [𝛼 ]
WI
20
= 0 . 0 (c = 0.8, CH2Cl2).
General Procedure A
In a 250 mL round bottom flask, diamine 3.13 and aldehyde 3.14 were dissolved in
methanol at 0 °C, then warm to room temperature while stirring. After 1 h, sodium borohydride
was slowly added to the mixture at 0 °C, then stirred at room temperature for 40 hours. After the
reaction, 1 M NaOH solution or saturated NaHCO3 solution was added to the mixture until the pH
is basic and stirred for 10 more minutes. The mixture was then concentrated to ca. half of its
volume, partitioned with dichloromethane, and the organic extract was washed with brine. The
collected organic layer was dried over anhydrous Na2SO4 and the solvent was removed under
reduced pressure.
Table 6.3.1. Synthesis of Simple Diamine Substrates.
Entry Diamine R Aldehyde R
1
Product
1 3.13a CH 2CH 2OH 3.14a Ph 3.1c
2 3.13b Bn 3.14b Cy 3.1f
3 3.13c Me 3.14a Ph 3.1g
4 3.13d Ph 3.14a Ph 3.1j
5 3.13b Bn 3.14c 4-OMePh 3.1k
176
2-((2-(Benzylamino)ethyl)amino)ethan-1-ol
Diamine 3.13a (1 equiv, 39.9 mmol), aldehyde 3.14a (1 equiv, 39.9 mmol) and sodium
borohydride (2 equiv, 79.3 mmol) were subjected to general procedure A.
The product 3.1c was obtained in 81% yield (6.23 g) as a yellow oil. The diamine is used for the
next step without further purification.
Data are consistent with the known compound.
4
1
H NMR (600 MHz, CDCl3) δ 7.34 – 7.22 (m, 5H), 3.79 (s, 2H), 3.63 (t, 2H), 2.76 – 2.72 (m, 6H),
2.41 (bs, 3H).
13
C NMR (151 MHz, CDCl3) δ 140.2, 128.6, 128.3, 127.2, 61.0, 54.0, 51.2, 48.9, 48.8.
177
N
1
-Benzyl-N
2
-(cyclohexylmethyl)ethane-1,2-diamine
Diamine 3.13b (1 equiv, 7.0 mmol), aldehyde 3.14b (1 equiv, 7.0 mmol) and sodium borohydride
(1 equiv, 7.0 mmol) were subjected to general procedure A.
The product 3.1f was obtained in 93% yield (1.60 g) as a yellow oil after silica flash
chromatography (75:25 dichloromethane: methanol).
1
H NMR (600 MHz, CDCl3) δ 7.34 – 7.27 (m, 4H), 7.26 – 7.21 (m, 1H), 3.79 (s, 2H), 2.80 – 2.66
(m, 4H), 2.41 (d, J = 6.7 Hz, 2H), 1.87 – 1.58 (m, 7H), 1.49 – 1.38 (m, 1H), 1.28 – 1.08 (m, 3H),
0.95 – 0.83 (m, 2H).
13
C NMR (151 MHz, CDCl3) δ 140.6, 128.5, 128.2, 127.0, 56.8, 54.1, 49.6, 48.8, 38.0, 31.6, 26.8,
26.2.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C16H27N2 247.2169; Found 247.2179.
FT-IR (thin film) cm
-1
: 3385, 2920, 2850, 1647, 1577, 1452, 1406, 1265, 959, 809, 741, 698.
178
N
1
-Benzyl-N
2
-methylethane-1,2-diamine
Diamine 3.13c (1 equiv, 9.31 mmol), aldehyde 3.14a (1 equiv, 9.31 mmol) and sodium
borohydride (2 equiv, 18.6 mmol) were subjected to general procedure A.
The product 3.1g was obtained in 56% yield (856 mg) as a yellow oil. The diamine is used without
further purification.
Data are consistent with the known compound.
5
1
H NMR (400 MHz, CDCl3) δ 7.35 – 7.21 (m, 5H), 3.80 (s, 2H), 2.80 – 2.67 (m, 4H), 2.42 (s, 3H),
1.87 (bs, 2H).
N
1
-Benzyl-N
2
-phenylethane-1,2-diamine
Diamine 3.13d (1 equiv, 16.0 mmol), aldehyde 3.14a (1 equiv, 16.0 mmol) and sodium
borohydride (1 equiv, 16.0 mmol) were subjected to general procedure A.
The product 3.1j was obtained in 88% yield (3.19 g) as a pale-yellow solid after silica flash
chromatography (90:10 dichloromethane: methanol).
Data are consistent with the known compound.
6
1
H NMR (500 MHz, CDCl3) δ 7.37 – 7.23 (m, 5H), 7.22 – 7.15 (m, 2H), 6.72 (tt, J = 7.3, 1.1 Hz,
1H), 6.65 (dd, J = 8.6, 1.0 Hz, 2H), 3.83 (s, 2H), 3.24 (t, J = 5.7 Hz, 2H), 2.92 (t, 2H).
13
C NMR (126 MHz, CDCl3) δ 148.6, 140.1, 129.4, 128.6, 128.3, 127.2, 117.5, 113.1, 53.7, 48.1,
43.6.
179
N
1
-Benzyl-N
2
-(4-methoxybenzyl)ethane-1,2-diamine
Diamine 3.13b (1 equiv, 6.66 mmol), aldehyde 3.14c (1 equiv, 6.66 mmol) and sodium
borohydride (2 equiv, 13.0 mmol) were subjected to general procedure A.
The product 3.1k was obtained in 85% yield (1.53 g) as a yellow oil after silica flash
chromatography (90:10 dichloromethane: methanol).
1
H NMR (400 MHz, CDCl3) δ 7.32 (d, J = 4.5 Hz, 4H), 7.28 – 7.22 (m, 3H), 6.89 – 6.83 (m, 2H),
3.79 (s, 3H), 3.78 (s, 2H), 3.74 (s, 2H), 2.78 (s, 4H).
13
C NMR (126 MHz, CDCl3) δ 158.9, 140.0, 131.6, 129.7, 128.5, 128.3, 127.2, 113.9, 55.4, 53.8,
53.0, 48.2, 48.2.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C17H23N2O 271.1805; Found 271.1803.
FT-IR (thin film) cm
-1
: 3275, 2918, 2848, 1675, 1610, 1512, 1457, 1252, 1177, 1032, 1839, 759,
697.
Table 6.3.2. Synthesis of Substituted Diamine Substrates.
Entry Diamine n R
1
Product
1 3.13e 2 Et 3.1e
2 3.13f 1 Me 3.1l
3 3.13g 3 H 3.1m
180
N
1
,N
3
-Dibenzylpentane-1,3-diamine
Diamine 3.13e (1 equiv, 20.0 mmol), aldehyde 3.14a (2 equiv, 40.0 mmol) and sodium
borohydride (2 equiv, 40.0 mmol) were subjected to general procedure A.
The product 3.1e was obtained in 73% yield (4.12 g) as a pale orange oil after silica flash
chromatography (70:30 dichloromethane: methanol).
1
H NMR (500 MHz, CDCl3) δ 7.49 – 7.16 (m, 10H), 3.88 – 3.73 (m, 4H), 2.91 – 2.60 (m, 3H),
2.27 (bs, 2H), 1.85 – 1.41 (m, 4H), 0.94 (t, J = 7.4 Hz, 3H).
13
C NMR (126 MHz, CDCl3) δ 140.7, 140.0, 128.3, 128.3, 128.1, 126.9, 126.8, 57.4, 54.0, 50.9,
46.9, 33.1, 26.3, 9.8.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C19H27N2 283.2169; Found 283.2195.
FT-IR (thin film) cm
-1
: 3295, 3030, 2934, 2913, 1494, 1455, 1364, 1121, 1028, 739, 698.
181
N
1
,N
2
-Dibenzylpropane-1,2-diamine
Diamine 3.13f (1 equiv, 33.7 mmol), aldehyde 3.14a (2 equiv, 67.4 mmol) and sodium borohydride
(2 equiv, 67.4 mmol) were subjected to general procedure A.
The product 3.1l was obtained as a yellow oil in 80% yield (6.86 g) after silica flash
chromatography (80:20 dichloromethane: methanol).
Data are consistent with the known compound.
7
1
H NMR (600 MHz, CDCl3) δ 7.33 – 7.24 (m, 8H), 7.24 – 7.18 (m, 2H), 3.85 (d, J = 13.2 Hz, 1H),
3.71 (s, 2H), 3.66 (d, J = 13.1 Hz, 1H), 2.80 – 2.72 (m, 1H), 2.63 (dd, J = 11.8, 4.2 Hz, 1H), 2.49
(dd, J = 11.8, 8.4 Hz, 1H), 1.06 (d, J = 6.3 Hz, 3H).
13
C NMR (151 MHz, CDCl3) δ 140.9, 140.7, 128.5, 128.4, 128.2, 128.1, 127.0, 126.9, 55.2, 54.0,
52.0, 51.4, 18.7.
182
N
1
,N
4
-Dibenzylbutane-1,4-diamine
Diamine 3.13g (1 equiv, 22.7 mmol), aldehyde 3.14a (2 equiv, 45.5mmol) and sodium borohydride
(2 equiv, 45.5mmol) were subjected to general procedure A.
The product 3.1m was obtained in 99% yield (6.0 g) as a pale-yellow oil after silica flash
chromatography (80:20 dichloromethane: methanol).
Data are consistent with the known compound.
8
1
H NMR (500 MHz, CDCl3) δ 7.43 – 7.20 (s, 10H), 3.81 (s, 4H), 2.72 – 2.60 (m, 4H), 1.67 – 1.47
(m, 6H).
13
C NMR (126 MHz, CDCl3) δ 140.4, 128.3, 128.0, 126.8, 53.9, 49.2, 27.8.
183
N,N'-(Ethane-1,2-diyl)bis(2,2,2-trifluoroacetamide)
This compound was synthesized using published procedures.
9
In a 25 mL round-bottom flask, ethylene diamine 3.13h (1.0 equiv, 7.47 mmol) was dissolved in
5 mL diethyl ether at 0 °C. Then, trifluoroacetic anhydride 3.15 (2.2 equiv, 16.5 mmol) in diethyl
ether (5 mL) was slowly added dropwise to the flask. After stirring for 1 hour, the white solid was
concentrated in vacuo and then washed with water, filtered, and dried under reduced pressure.
Scheme 6.3.1. Synthesis of 3.1n.
The product 3.1n was obtained in 90% yield (1.70 g) as a white solid.
Data are consistent with the known compound.
9
1
H NMR (600 MHz, CD3OD) δ 3.46 (s, 4H).
13
C NMR (151 MHz, CD3OD) δ 159.5 (q, J = 37.3 Hz), 117.4 (q, J = 286.7 Hz), 39.7.
184
Dibenzyl ethane-1,2-diyldicarbamate
This compound was synthesized using published procedures.
10
In a 25 mL round-bottom flask, ethylene diamine 3.13h (1 equiv, 4.48 mmol) was dissolved in 1
M NaOH solution (2 equiv, 8.96 mmol). This solution was cooled to 0 °C and benzyl
chloroformate 3.16 (2 equiv, 8.94 mmol) was slowly added dropwise over the course of 45
minutes. The reaction was stirred for another 4 hours. The solid product was filtered, washed with
water and hexane, and then left to airdry overnight.
Scheme 6.3.2. Synthesis of 3.1o.
The product 3.1o was obtained in 75% yield (1.10 g) as a white solid.
Data are consistent with the known compound.
10
1
H NMR (600 MHz, CDCl3) δ 7.39 – 7.28 (m, 10H), 5.19 (bs, 2H), 5.08 (s, 4H), 3.39 – 3.20 (m,
4H).
13
C NMR (151 MHz, CDCl3) δ 157.0, 136.5, 128.8, 128.7, 128.3, 128.2, 67.0, 41.4.
185
Di-tert-butyl ethane-1,2-diyldicarbamate
This compound was synthesized using published procedures.
11
In a 25 mL round-bottom flask, di-tert-butyl dicarbonate 3.17 (2 equiv, 14.94 mmol) and sulfamic
acid (5 mol %, 0.374 mmol) were mixed. Then, ethylene diamine 3.13h (1 equiv, 7.47 mmol) was
added and the mixture was stirred for 3 minutes at room temperature. After the reaction, the white
solid was filtered off and washed with cold water.
Scheme 6.3.3. Synthesis of 3.1p.
The product 3.1p was obtained in 73% yield (1.42 g) as an off-white solid.
Data are consistent with the known compound.
12
1
H NMR (600 MHz, CDCl3) δ 4.86 (bs, 2H), 3.22 (s, 4H), 1.43 (s, 18H).
13
C NMR (151 MHz, CDCl3) δ 156.5, 79.5, 40.9, 28.5.
186
General Procedure B
In a 100 mL round bottom flask, the diamine 3.13 and the aldehyde 3.18 were dissolved in
toluene. p-TsOH •H2O was then added, and the mixture was refluxed for 48 hours using a Dean
Stark trap open to air. After the reaction, 40 mL of 1 M NaOH was added to the mixture until the
pH is basic (according to pH paper). The solution was stirred for an additional10 minutes. The
organic layer was collected, and a fresh portion of toluene (15 mL) was added to the aqueous layer
two more times to extract the product. The combined organic layer was dried over anhydrous
Na2SO4 and the solvent was removed under reduced pressure.
The product from the first step (above) was dissolved in MeOH and sodium borohydride
was added to the mixture at 0 °C. The mixture was brought to room temperature and stirred
overnight. Thereafter, 40 mL of 1 M NaOH was added. The mixture was partitioned between
dichloromethane and brine. The combined organic layers were collected, dried over anhydrous
Na2SO4, and the solvent was removed under reduced pressure.
Table 6.3.3. Synthesis of Substituted Diimines and Diamines.
Entry Diamine n Aldehyde R Product
1 3.13c 1 3.18a H 3.19a / 3.1q
2 3.13i 2 3.18i Cl 3.19i / 3.1r
187
N
1
-Benzhydryl-N
2
-methylethane-1,2-diamine
This was synthesized using General Procedure B. For the first step, the diamine 3.13c (1 equiv,
13.5 mmol) and the aldehyde 3.18a (1 equiv, 13.5 mmol) were dissolved in toluene (25 mL). Then,
p-TsOH •H2O (10 mol %, 1.35 mmol) was added.
1
H NMR (600 MHz, CDCl3) δ 7.83 – 7.14 (m, 10H), 3.49 (t, J = 5.9 Hz, 2H), 2.89 (t, J = 6.3 Hz,
2H), 2.47 (s, 3H).
13
C NMR (151 MHz, CDCl3) δ 169.3, 139.8, 137.7, 137.0, 132.5, 130.2, 130.1, 128.7, 128.5,
128.4, 128.4, 128.2, 127.8, 53.2, 52.8, 36.4.
For the second step, the resulting product from the first step 3.19a was dissolved in 30 mL MeOH.
Sodium borohydride (2 equiv, 27 mmol) was added at 0 °C.
The product 3.1q was obtained in 58% yield (1.89 g) after silica flash chromatography (50:50
dichloromethane: methanol) as a colorless oil.
1
H NMR (600 MHz, CDCl3) δ 7.44 (d, J = 6.7 Hz, 4H), 7.31 (t, J = 7.7 Hz, 4H), 7.22 (t, J = 7.3
Hz, 2H), 4.84 (s, 1H), 2.72 (s, 4H), 2.41 (s, 3H), 2.30 (bs, 2H).
13
C NMR (151 MHz, CDCl3) δ 144.1, 128.3, 127.2, 126.8, 67.5, 51.4, 47.1, 36.0.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C16H21N2 241.1699; Found 241.1705.
FT-IR (thin film) cm
-1
: 3301, 3027, 2918, 2849, 2798, 1600, 1493, 1383, 1262, 1105, 1028, 745,
703.
188
N
1
-((4-Chlorophenyl)(phenyl)methyl)-N
3
-methylpropane-1,3-diamine
This was synthesized using General Procedure B. For the first step, the diamine 3.13i (1 equiv,
11.3 mmol) and the aldehyde 3.18i (1 equiv, 11.3 mmol) were dissolved in toluene (25 mL). Then,
p-TsOH •H2O (10 mol %, 1.13 mmol) was added.
1
H NMR (600 MHz, CDCl3) δ 7.57 – 7.07 (m, 9H), 3.43 – 3.38 (m, 2H), 2.69 – 2.62 (m, 2H), 2.44
– 2.39 (m, 3H), 1.88 – 1.811 (m, 2H), 1.62 (bs, 1H).
For the second step, the resulting product from the first step 3.19i was dissolved in 40 mL MeOH.
Sodium borohydride (2 equiv, 21.9 mmol) was added at 0 °C.
The product 3.1r was obtained in 73% yield as a pale-yellow oil (2.4 g) after silica flash
chromatography (50:50 dichloromethane: methanol).
1
H NMR (600 MHz, CDCl3) δ 7.37 – 7.15 (m, 9H), 4.76 (s, 1H), 2.68 – 2.55 (m, 4H), 2.40 (s, 3H),
1.83 (bs, 2H), 1.69 (p, J = 6.9 Hz, 2H).
13
C NMR (151 MHz, CDCl3) δ 143.9, 142.8, 132.6, 128.6, 128.6, 127.2, 127.2, 67.1, 50.5, 46.6,
36.5, 30.2.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C17H22N2Cl 289.1466; Found 289.1467.
FT-IR (thin film) cm
-1
: 3278, 3026, 2920, 2848, 2800, 1490, 1270, 1089, 1015, 809, 757, 717, 700.
189
6.3.3. Substrate Scope
General Procedure
In the drybox, a 1-dram vial was charged with diamine (x equiv), diol (y equiv), and catalyst
C4. The vial was capped, taken out of the glovebox, and heated to 110 °C. The solution turned to
a dark brown color. After the given time, the reaction mixture was allowed to cool to room
temperature followed by a dichloromethane/water work up. Products were isolated either by a
gravity column or flash column. Substrate concentrations are summarized in Table 3.2 and Table
3.3. Reactions are on 0.2 mmol scale unless otherwise noted.
Scheme 6.3.4. Synthesis of 1,4-Diazacycles.
190
1,4-Dibenzylpiperazine
The product was obtained in 86% yield (46 mg) as a white solid after silica flash column
chromatography (90:10 hexanes: ethyl acetate).
Data are consistent with the known compound.
13
1
H NMR (600 MHz, CDCl3) δ 7.35 – 7.29 (m, 8H), 7.28 – 7.23 (m, 2H), 3.53 (s, 4H), 2.51 (s, 8H).
13
C NMR (151 MHz, CDCl3) δ 138.3, 129.3, 128.3, 127.1, 63.2, 53.2.
(4aR, 8aR)-1,4-Dibenzyldecahydroquinoxaline
The reaction was done on 0.6 mmol scale. The product was obtained in 84% yield (162 mg) as a
colorless oil (which turned to off white solid upon standing) after silica flash column
chromatography (80:20 hexanes: ethyl acetate).
1
H NMR (400 MHz, CDCl3) δ 7.38 – 7.13 (m, 10H), 4.11 (d, J = 13.4 Hz, 2H), 3.17 (d, J = 13.4
Hz, 2H), 2.62 (d, J = 7.9 Hz, 2H), 2.33 – 2.25 (m, 2H), 2.21 (d, J = 7.8 Hz, 2H), 2.14 – 2.07 (m,
2H), 1.82 – 1.73 (m,2H), 1.44 – 1.12 (m, 4H).
13
C NMR (151 MHz, CDCl3) δ 139.0, 129.3, 128.2, 126.8, 66.1, 57.6, 52.4, 29.7, 25.2.
FT-IR (thin film) cm
-1
: 3030, 2969, 2941, 2919, 2855, 2799, 2750, 2713, 1494, 1455, 1378, 1253,
1155, 1087, 1029, 828,737, 696, 482.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C22H29N2 321.2331; Found 321.2344.
Optical Rotation: [ 𝛼 ]
WI
20
= − 118 . 2 (c = 0.74, CH2Cl2). > 99% ee (HPLC condition: Chiralpak IJ-
3 column, n-hexane/i-PrOH = 99:1, flowrate = 3mL/min, wavelength = 230 nm, tR = 2.03 min for
major isomer and tR= 2.96 min for minor isomer).
3.5a
3.5b
191
Racemic compound was synthesized for chiral HPLC from 3.1b' and ethylene glycol using the
same procedure on 0.6 mmol scale. The product was obtained in 80% yield as colorless oil (which
turned to off white solid upon standing) after silica flash chromatography (80:20 hexanes: ethyl
acetate).
1
H NMR (400 MHz, CDCl3) δ 7.42 – 7.13 (m, 10H), 4.11 (d, J = 13.4 Hz, 2H), 3.17 (d, J = 13.4
Hz, 2H), 2.63 (d, J = 7.9 Hz, 2H), 2.33 – 2.25 (m, 2H), 2.21 (d, J = 7.8 Hz, 2H), 2.14 – 2.05 (m,
2H), 1.84 – 1.75 (m, 2H), 1.44 – 1.13 (m, 4H).
13
C NMR (151 MHz, CDCl3) δ 138.9, 129.4, 128.2, 126.9, 66.1, 57.6, 52.3, 29.6, 25.2.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C22H29N2 321.2331; Found 321.2341.
Optical Rotation: [𝛼 ]
WI
20
= 0 . 0 (c = 0.54, CH2Cl2).
192
2-(4-Benzylpiperazin-1-yl)ethan-1-ol
The product was obtained in 78% yield (34.5 mg) as a yellow oil after silica gravity column
chromatography (95:5 dichloromethane: methanol).
Data are consistent with the known compound.
14
1
H NMR (500 MHz, CDCl3) δ 7.32 (d, J = 4.4 Hz, 4H), 7.28 – 7.23 (m, 1H), 3.62 (t, J = 5.4 Hz,
2H), 3.52 (s, 2H), 3.18 (s, 1H), 2.75 – 2.31 (m, 10H).
13
C NMR (126 MHz, CDCl3) δ 138.1, 129.3, 128.3, 127.2, 63.1, 59.4, 59.4, 57.8, 57.8, 53.1, 53.0.
1,4-Dibenzyl-1,4-diazepane
The product was obtained in 78% yield (44 mg) from N,N’-dibenzylethylenediamine (3.1a) and
1,3-propanediol (3.2a); and in 86% yield (48 mg) from N,N’-dibenzylpropanediamine (3.1d) and
ethylene glycol (3.4a) as a pale-yellow oil after silica flash column chromatography (50:50
hexanes: ethyl acetate).
Data are consistent with the known compound.
15
1
H NMR (400 MHz, CDCl3) δ 7.36 – 7.28 (m, 8H), 7.27 – 7.20 (m, 2H), 3.65 (s, 4H), 2.77 – 2.71
(m, 4H), 2.68 (s, 4H), 1.85 – 1.75 (m, 2H).
13
C NMR (151 MHz, CDCl3) δ 139.8, 128.9, 128.2, 126.9, 62.8, 55.2, 54.4, 27.8.
3.3a
3.5c
193
1,4-Dibenzyl-2-methyl-1,4-diazepane
The product was obtained in 68% yield (40 mg) as a colorless oil after silica flash column
chromatography (90:10 hexanes: ethyl acetate).
1
H NMR (600 MHz, CDCl3) δ 7.44 – 7.37 (m, 4H), 7.37– 7.30 (m, 4H), 7.29 – 7.22 (m, 2H), 3.86
(d, J = 13.9 Hz, 1H), 3.78 – 3.66 (m, 3H), 3.02 – 2.94 (m, 1H), 2.93 – 2.86 (m, 1H), 2.77 – 2.67
(m, 3H), 2.64 – 2.58 (m, 1H), 2.58 – 2.52 (m, 1H), 1.83– 1.75 (m, 1H), 1.70 – 1.61 (m, 1H), 1.04
(d, J = 6.5 Hz, 3H).
13
C NMR (151 MHz, CDCl3) δ 141.1, 140.2, 128.9, 128.8, 128.3, 128.2, 126.9, 126.7, 63.1, 61.0,
57.4, 57.2, 55.9, 48.7, 28.0, 17.8.
FT-IR (thin film) cm
-1
:2950, 2810, 1459, 1262, 1155, 1072, 756, 701, 638.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C20H27N2 295.2174; Found 295.2184.
The same compound was synthesized from the coupling of N,Nʹ-dibenzyl-1,3-propanediamine
(3.1d) and (S)-(+)-1,2-propanediol (3.4c). The product was obtained in 60% yield (350 mg) as a
colorless oil after silica flash column chromatography (90:10 hexanes: ethyl acetate). Optical
rotation of the compound was measured, which conformed that it is a racemic mixture.
Optical Rotation: [𝛼 ]
WI
25
= 0 . 0 (c = 1.24, CHCl3).
3.3b
194
1,4-Dibenzyl-5-methyl-1,4-diazepane
The product was obtained in 71% yield (42 mg) as a colorless oil after silica flash column
chromatography (95:5 dichloromethane: methanol with 1% Et3N).
1
H NMR (600 MHz, CDCl3) δ 7.37 – 7.20 (m, 10H), 3.79 (d, J = 13.8 Hz, 1H), 3.70 – 3.65 (m,
3H), 3.06 – 2.98 (m, 1H), 2.96 – 2.89 (m, 1H), 2.88 – 2.82 (m, 1H), 2.75 – 2.56 (m, 4H), 2.05 –
1.96 (m, 1H), 1.82 – 1.73 (m, 1H), 1.12 (d, J = 6.3 Hz, 3H).
13
C NMR (151 MHz, CDCl3) δ 140.2, 129.5, 129.1, 128.9, 128.5, 128.4, 127.5, 127.0, 62.9, 58.1,
56.8, 56.2, 52.2, 48.2, 34.9, 18.6.
FT-IR (thin film) cm
-1
: 2955, 2813, 1457, 1374, 1260, 1155, 1031, 738, 697, 639.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C20H27N2 295.2174; Found 295.2197.
1,4-Dibenzyl-5-ethyl-1,4-diazepane
The product was obtained in 83% yield (51 mg) as a colorless oil after silica flash column
chromatography (80:20 hexanes: ethyl acetate).
1
H NMR (600 MHz, CDCl3) δ 7.38 – 7.20 (m, 10H), 3.84 – 3.73 (m, 2H), 3.66 – 3.58 (m, 2H),
2.94 (dd, J = 16.4, 5.9 Hz, 1H), 2.85 – 2.79 (m, 1H), 2.77 – 2.67 (m, 2H), 2.63 – 2.51 (m, 3H),
1.98 – 1.87 (m, 1H), 1.84 – 1.75 (m, 1H), 1.68 – 1.56 (m, 1H), 1.52 – 1.42 (m, 1H), 0.91 (t, J =
7.4 Hz, 3H).
13
C NMR (151 MHz, CDCl3) δ 140.9, 139.1, 129.2, 128.8, 128.3, 128.3, 127.1, 126.8, 64.2, 63.2,
57.1, 55.0, 53.4, 49.2, 32.4, 27.0, 11.2.
FT-IR (thin film) cm
-1
: 2960, 2814, 1676, 1494, 1455, 1351, 1262, 1105, 1027, 734, 697.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C21H29N2 309.2325; Found 309.2349.
3.3d
3.3c
195
1-Benzyl-4-cyclohexylmethyl-1,4-diazepane
The product was obtained in 70% yield (38 mg) as a colorless oil after silica flash column
chromatography (50:50 hexanes: ethyl acetate).
1
H NMR (600 MHz, CDCl3) δ 7.37 – 7.21 (m, 5H), 3.64 (s, 2H), 2.75 – 2.63 (m, 8H), 2.28 (d, J =
7.0 Hz, 2H), 1.82 – 1.74 (m, 4H), 1.73 – 1.62 (m, 3H), 1.46 – 1.36 (m, 1H), 1.27 – 1.10 (m, 3H),
0.90 – 0.80 (m, 2H).
13
C NMR (151 MHz, CDCl3) δ 139.8, 129.0, 128.3, 126.9, 65.4, 62.7, 55.6, 55.0, 54.9, 54.6, 36.3,
32.0, 27.5, 27.0, 26.3.
FT-IR (thin film) cm
-1
: 3028, 2920, 2848, 2811, 1680, 1449, 1356, 1124, 729, 697.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C19H31N2 287.2482; Found 287.2503.
1-Benzyl-4-methyl-1,4-diazepane
The reaction was done on 0.4 mmol scale. The product was obtained in 71% yield (58 mg) as a
pale-yellow oil after silica flash column chromatography (80:20 dichloromethane with 1% Et3N:
methanol with 1% Et3N).
1
H NMR (600 MHz, CDCl3) δ 7.38 – 7.18 (m, 5H), 3.64 (s, 2H), 2.75 – 2.61 (m, 8H), 2.38 (s, 3H),
1.83 (p, J = 6.3 Hz, 2H).
13
C NMR (151 MHz, CDCl3) δ 139.7, 129.0, 128.3, 127.1, 63.0, 58.3, 56.9, 54.4, 47.1, 27.4.
FT-IR (thin film) cm
-1
: 3030, 2922, 2850, 1654, 1457, 1029, 742, 701.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C13H21N2 205.1699; Found 205.1702.
3.3e
3.3f
196
1,4-Dimethyl-1,4-diazepane
Reaction was performed on 8.0 mmol scale in a Schlenk reactor. Volatility of the compound
precluded its separation from the excess volatile diamine substrate.
1
H NMR spectra of the crude
reaction mixture in CDCl3 showed desired product in 88% NMR yield with mesitylene as the
internal standard.
Data are consistent with the known compound.
16
Figure 6.3.3.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-
dimethylethylenediamine (2 equiv) and 1,3-propanediol (1 equiv) with 1 mol % C4 for 44 h. The
peaks at 2.33 ppm and 2.67 ppm belongs to the excess starting diamine.
3.3g
197
1,4-Diisopropyl-1,4-diazepane
Volatility of the compound precluded its separation from the excess volatile diamine substrate.
1
H
NMR spectra of the crude reaction mixture in CDCl 3 showed desired product in 80% NMR yield
with mesitylene as the internal standard.
Data are consistent with the known compound.
17
Figure 6.3.4.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-
diisopropyl-1,3-propanediamine (1 equiv) and ethylene glycol (2 equiv) with 1 mol % C4 for 44
h.
3.3h
198
2-(4-Benzyl-1,4-diazepan-1-yl)ethan-1-ol
The product was obtained in 68% yield (32 mg) as an orange oil after silica flash column
chromatography (80:20 dichloromethane: methanol with 1% Et3N).
1
H NMR (600 MHz, CDCl3) δ 7.35 – 7.28 (m, 4H), 7.25 – 7.21 (m, 1H), 3.63 (s, 2H), 3.57 – 3.52
(m, 2H), 2.80 – 2.76 (m, 2H), 2.75 – 2.72 (m, 2H), 2.71 – 2.65 (m, 6H), 1.80 (tt, J = 7.1, 5.4 Hz,
2H).
13
C NMR (151 MHz, CDCl3) δ 139.5, 128.9, 128.3, 127.0, 62.9, 59.2, 58.5, 55.5, 55.2, 54.3, 54.2,
28.0.
FT-IR (thin film) cm
-1
: 3398, 2938, 2818, 1454, 1355, 1168, 1073, 1054, 740, 699.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C14H23N2O 235.1810; Found 235.1797.
5,8-Dibenzyl-5,8-diazaspiro[2.6]nonan-4-ol
The product was obtained in 50% yield (32 mg) as a colorless oil after amine modified silica flash
column chromatography (95:5 hexanes: ethyl acetate).
1
H NMR (600 MHz, CDCl3) δ 7.41 – 7.19 (m, 10H), 4.41 (d, J = 12.6 Hz, 2H), 3.75 (s, 2H), 3.22
(d, J = 12.7 Hz, 2H), 3.04 – 2.87 (m, 2H), 2.60 (s, 1H), 2.40 – 2.29 (m, 2H), 0.68 – 0.63 (m, 2H),
0.55 – 0.50 (m, 2H).
13
C NMR (151 MHz, CDCl3) δ 138.9, 128.7, 128.6, 127.3, 91.6, 68.1, 58.4, 50.0, 20.4, 7.7.
FT-IR (thin film) cm
-1
: 3298, 3029, 2834, 1495, 1453, 1028, 870, 742, 700.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C21H27N2O 323.2123; Found 323.2148.
3.3j
3.3i
199
cis-N, N'-Dibenzyl-2,6-diazabiyclo[5.3.0]decane
The reaction was performed on 2.28 mmol scale using N,Nʹ-dibenzyl 1,3-propanediamine (3.1d)
and cis-1,2-cyclopentanediol (3.2c) as the starting materials. The product was obtained in 58%
yield (421 mg) as a pale-orange oil after silica flash column chromatography (95:25
dichloromethane: methanol with 1% Et3N).
1
H NMR (600 MHz, CDCl3) δ 7.48 – 7.40 (m, 4H), 7.36 (t, J = 7.6 Hz, 4H), 7.30 – 7.24 (m, 2H),
4.16 (d, J = 13.7 Hz, 2H), 3.76 (d, J = 13.7 Hz, 2H), 3.27 – 3.20 (m, 2H), 2.92 – 2.83 (m, 2H),
2.55 (ddd, J = 14.3, 9.9, 3.1 Hz, 2H), 2.09 – 2.00 (m, 2H), 1.95 – 1.75 (m, 4H), 1.49 – 1.38 (m,
2H).
13
C NMR (151 MHz, CDCl3) δ 141.0, 128.8, 128.3, 126.7, 68.1, 57.3, 51.7, 31.0, 28.4, 22.7.
FT-IR (thin film) cm
-1
: 3026, 2950, 2868, 2833, 1493, 1451, 1348, 1028, 739, 698.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C22H29N2 321.2331; Found 321.2353.
Crystal structure of the compound with PF6 showed retention of the cis configuration.
3.3k
200
Cyclizine
The product was obtained in 91% yield (48 mg) as a white solid after silica gravity column
chromatography (95:5 dichloromethane: methanol).
Data are consistent with the known compound.
18
1
H NMR (500 MHz, CDCl3) δ 7.45 (d, J = 6.6 Hz, 4H), 7.29 (t, J = 7.6 Hz, 4H), 7.19 (t, J = 7.3
Hz, 2H), 4.24 (s, 1H), 2.47 (bs, 8H), 2.31 (s, 3H).
13
C NMR (126 MHz, CDCl3) δ 142.9, 128.6, 128.0, 127.0, 76.3, 55.4, 51.8, 45.9.
Homochlorcyclizine
The product was obtained in 67% yield (42 mg) as a pale-yellow oil after amine modified silica
flash column chromatography (100% dichloromethane).
1
H NMR (500 MHz, CDCl3) δ 7.41 – 7.16 (m, 9H), 4.57 (s, 1H), 2.80 – 2.57 (m, 8H), 2.40 (s, 3H),
1.81 (p, J = 6.3 Hz, 2H).
13
C NMR (126 MHz, CDCl3) δ 143.1, 142.3, 132.5, 129.3, 128.7, 128.7, 127.9, 127.2, 74.9, 59.2,
56.4, 52.7, 52.7, 47.0, 27.7.
FT-IR (thin film) cm
-1
: 2928, 2801, 1663, 1488, 1453, 1088, 1013, 805, 759, 701.
HRMS (LC-QTOF) m/z: [M+H]
+
Calcd for C19H24ClN2 315.1628; Found 315.1627.
3.3l
3.3m
201
Coupling between Substituted Diamine and Substituted Diol
Scheme 6.3.5. Coupling between Substituted Diamine and Substituted Diol.
After executing the reaction as described in the general procedure, mesitylene was added
to the mixture as an internal standard, and NMR were recorded in CDCl3. While a reaction with 1
mol % catalyst loading gave back both starting materials, one with 5 mol % loading produced a
complex mixture that was difficult to analyze. In another instance, coupling of N
1
,N
2
-
dibenzylpropane-1,2-diamine (3.1l) with propane-1,2-diol and 1-phenylethane-1,2-diol in the
presence of 1 mol % C4 showed starting materials and complex mixture respectively.
202
6.3.4. Other Interesting Substrates through Diamine-Diol Coupling
Reactions to yield eight membered diazacycles produce side products. For example,
coupling of N,Nʹ-dibenzylethylenedimaine (3.1a) with 1,4-butanediol (3.20) showed both 1,4-
diazocane (3.21) and an acyclic product 3.22 (Scheme 6.3.6). Moreover, a reaction between 3.1a
and 1,4-benzenedimethanol (3.23) favored a five membered compound imidazolidine 3.24 rather
than an eight membered 1,4-diazocane (Scheme 6.3.7).
Reaction between N,N’-Dibenzylethylenediamine and 1,4-Butanediol
Scheme 6.3.6. Coupling between N,N’-Dibenzylethylenediamine and 1,4-Butanediol.
In the drybox, a 1-dram vial was charged with N,N’-dibenzylethylenediamine (1 equiv, 0.4
mmol), 1,4-butanediol (2 equiv, 0.8 mmol), and catalyst C4 (1.0 mol %, 0.004 mmol). The vial
was capped, taken out of the glovebox, and heated to 110 °C. The solution turned to a brown color.
After 44 h, the reaction mixture was allowed to cool to room temperature, mesitylene was added
as an internal standard, and an aliquot was taken for
1
H NMR analysis in CDCl3. Structure of the
product was elucidated with the help of NMR spectroscopy and HRMS.
The
1
H NMR spectrum showed 1,4-diazocane in 30%, and LC-QTOF (positive ionization)
showed both 1,4-diazocane and the acyclic product (3.22) from the coupling of diamine with two
diols.
203
a
b
Figure 6.3.5.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-dibenzyl-
ethylenediamine (1 equiv) and 1,4-butanediol (2 equiv) with 1 mol % C4 for 44 h.
c
d
204
Figure 6.3.6. LC-QTOF spectra of the crude reaction mixture for the coupling of N,N’-dibenzyl-
ethylenediamine (1 equiv) and 1,4-butanediol (2 equiv) with 1 mol % C4 for 44 h.
Reaction between N,N’-Dibenzylethylenediamine and 1,2-Benzenedimethanol
Scheme 6.3.7. Coupling between N,N’-Dibenzylethylenediamine and 1,2-Benzenedimethanol.
In the drybox, a 1-dram vial was charged with N,N’-dibenzylethylenediamine (1 equiv, 0.2
mmol), 1,2-benzenedimethanol (2 equiv, 0.4 mmol), and catalyst C4 (1.0 mol %, 0.002 mmol).
The vial was capped, taken out of the glovebox, and heated to 110 °C. The solution turned to a
yellow color. After 44 h, the reaction mixture was allowed to cool to room temperature, mesitylene
was added as an internal standard, and an aliquot was taken for
1
H NMR analysis in CDCl3.
205
a
b
d
Structure of the product was elucidated with the help of 1-D and 2-D NMR spectroscopy and
HRMS.
The
1
H NMR spectrum showed an imidazolidine compound 3.24 in 51%, starting diamine, and
diol peaks.
Figure 6.3.7.
1
H NMR spectrum of the crude reaction mixture for the coupling of N,N’-dibenzyl-
ethylenediamine (1 equiv) and 1,2-benzenedimethanol (2 equiv) with 2 mol % C4 for 44 h.
c
e
f
t
206
Figure 6.3.8. LC-QTOF spectrum of the crude reaction mixture for the coupling of N,N’-dibenzyl-
ethylenediamine (1equiv) and 1,2-benzenedimethanol (2 equiv) with 2 mol % C4 for 44 h. Peak
at 247.17 belongs to the starting diamine.
6.3.5. Three Carbon Diamine/Two Carbon Diol Coupling Vs Two Carbon Diamine/Three
Carbon Diol Coupling
1,4-Diazepanes can be synthesized either from three carbon diamines and two carbon diols
or from two carbon diamines and three carbon diols. Reactions employing glycol adducts are
favored compared to the three carbon diols as the first requires only one redox step to access
diazacycles because of the two tautomerization steps involved (see Scheme 3.1). This effect on
yield of the number of redox is more evident in the synthesis of homochlorcyclizine and its
dechlorinated analogue 1-benzhydryl-4-methyl-1,4-diazepane (Scheme 6.3.8).
207
Scheme 6.3.8. 1,4-Diazepane Synthesis from Two Carbon Diol Vs Three Carbon Diol
a
NMR yield with mesitylene as the internal standard.
6.3.6. Intramolecular vs Intermolecular Cyclization
We observed competition between intermolecular and intramolecular reactions in the case
of N-benzyl-Nʹ-hydroxyethyl ethylenediamine (3.1c) and diols (Table 6.3.4). While the reaction
of 3.1c with ethylene glycol (3.4a) can produce both intramolecular cyclization (3.25) and
intermolecular cycloaddition (3.5c) products (Table 6.3.4); 3.5c can be formed selectively with
excess ethylene glycol. By contrast, treatment of 3.1c with propanediol afforded seven membered
intermolecular product 3.3i selectively (Table 6.3.5).
Table 6.3.4. Coupling between 3.1c and Ethylene Glycol.
Entry Diol (equiv) Yield (%)
a
3.25 3.5c
1 1 25 36
2 2 24 60
3 3 0 86
208
Table 6.3.5. Coupling between 3.1c and 1,3-Propanediol.
Entry Diol (equiv) Yield (%)
a
3.25 3.3i
1 1 4 65
2 2 3 85
a
NMR yield with mesitylene as an internal standard.
6.3.7. Synthesis of 9-Membered Diazacycles
In addition to six, seven-, and eight-membered cyclic compounds, we investigated the
possibility of constructing 9-membered diazacycles from diamine and diols with a hydrogen
borrowing strategy. To our delight, all the four attempts showed promising results in the formation
of 9-membered 1,4-diazo and 1,5-diazo compounds. For example, we achieved the synthesis of
N,N’-dibenzyl-1,5-diazonane (3.26) with 81% conversion from N,N’-dibenzyl-1,3-
propanediamine (3.1d) and 1.4-butanediol (Scheme 6.3.9); yet, we didn’t optimize this reaction.
Even though, construction of N,N’-dibenzyl-1,4-diazonane (3.27) from N,N’-
dibenzylethylenediamine (3.1a) and 1,5-pentaneanediol was optimized to 100% conversion (Table
6.3.6), we couldn’t discover a condition for isolating the product from the mixture. Separation
using both column chromatography in dichloromethane: methanol (70:30), and pH extraction
provided the desired product along with diol substrate (Figure 6.3.9). Identity of the both novel 9-
membered diazacycles are confirmed by LC-QTOF analysis (Figure.6.3.10).
Scheme 6.3.9. Reaction of N,N’-Dibenzyl-1,3-propanediamine and 1,4-Butanediol.
209
Table 6.3.6. Reaction of N,N’-Dibenzylethylenediamine and 1,5-Pentaneanediol.
Entry x Conversion
a
1 1 75
2 3 100
3 5 100
a
Conversion was determined from
1
H NMR integration.
Figure 6.3.9.
1
H NMR spectrum of reaction of 3.1a and 1,5-pentaneanediol with 3 mol % C4 at
110
o
C in neat condition for 44 h after passing through a silica column in dichloromethane:
methanol. Spectrum shows mixture of 3.27 and 1,5-pentanediol.
210
Figure 6.3.10. LC-QTOF spectra of reaction of 3.1d and 1.4-butanediol (top two spectra), which
shows desired product peaks at 309.2327 (M+H)
+
and 327.2432 (M+H2O+H)
+
along with the
starting amine peak at 255.1858 (M+H)
+
, and reaction of 3.1a and 1,5-pentanediol (bottom
spectrum) which shows desired peak at 327.2432 (M+H2O+H)
+
along with starting amine peak at
241.1700 (M+H)
+
.
211
6.3.8. Scope Limitations
Despite having a broad reaction scope, we encountered some substrates (Figure 6.3.11)
that either remain unreactive or provide complex mixture under our catalytic conditions.
Generally, diazepane synthesis with electron deficient or bulky groups on nitrogen such as Boc,
CBZ, TFA, t-butyl, or phenyl showed no hydrogen borrowing coupling in our reaction. In addition
to this, two-carbon unsubstituted primary diamines are not coupling partners in diazacycle
synthesis. Inactivity of the first group can be explained by the effects of electronic and steric factors
on nitrogen nucleophilicity, while the second one is due to catalytic poisoning (Scheme 6.3.10).
Diamines with highly electron withdrawing groups are not sufficiently nucleophilic to undergo
high-yielding addition to intermediate aldehydes at the rate required by the kinetics of the catalysis,
so the reaction of Boc protected ethylenediamine showed no reactivity with benzaldehyde (3.14a,
Scheme 6.3.10B). Similarly, coupling of ethylenediamine (3.13h) with benzyl alcohol (3.28) using
our catalyst did not result in product, whereas reaction of 3.13h with 3.14a produced N,N’-
dibenzylidine ethylenediamine (3.29). This shows the inability of the catalyst C4 to oxidize benzyl
alcohol in the presence of an unsubstituted diamine. We further confirmed this catalytic inactivity
by adding isopropanol to the reaction mixture C to check whether the catalyst could transfer
hydrogen from isopropanol (3.30) to 3.28. As expected, transfer hydrogenation was not observed.
212
Figure 6.3.11. List of diamines and diols that became unreactive or provide complex mixture
under our catalytic condition.
Scheme 6.3.10. Reactions to Probe the Scope Limitation Factor.
213
6.3.9 Reaction of Complex C4 with Ethylenediamine
Experiment 1-3: Complex C4 (20 mg, 1 equiv) and freshly distilled ethylenediamine (22 mg, 12
equiv) were stirred at 110
o
C (oil bath) in a Schlenk reactor for 15 min (Exp. 1) or 21 h (Exp. 2)
or 44 h (Exp. 3). Then, all volatile components were removed by heating at 75
o
C (oil bath) for 10
min, the residue was dissolved in dry deuterated methanol and analyzed by
1
H and
31
P NMR
spectroscopy.
Experiment 4: Complex C4 (20 mg, 1 equiv) and ethylene glycol (19 mg, 10 equiv) were dissolved
in freshly distilled ethylenediamine (0.8 mL), stirred at 110
o
C (oil bath) in a Schlenk reactor for
1h. Then, all volatile components were removed by heating at 90
o
C (oil bath) for 10 min, the
residue was dissolved in dry deuterated methanol and analyzed by
1
H and
31
P NMR spectroscopy.
Stacked
1
H NMR spectra showed disappearance of cymene ligand within 15 min of stirring and
formation of a new complex 3.12 with new phosphinopyridine ligands peak. Besides,
31
P spectrum
showed a new peak corresponding to complex 3.12.
214
Figure 6.3.12. Stacked
1
H NMR spectrum of the crude reaction mixture for reaction between
complex C4 and ethylenediamine.
Figure 6.3.13. Stacked
31
P NMR spectrum of the crude reaction mixture for reaction between
complex C4 and ethylenediamine.
Phosphinopyridine peaks
Complex 1
Exp. 1
Exp. 2
Exp. 3
Exp. 4
Complex C4
Exp. 1
Exp. 2
Exp. 3
Exp. 4
Cymene peaks
215
Complex 3.12 was crystallized by adding dichloromethane and hexanes to the methanol solution
of crude reaction mixture from experiment 4.
1
H NMR (600 MHz, MeOD) δ 8.84 – 8.80 (m, 1H), 7.74 – 7.68 (m, 1H), 7.67 – 7.63 (m, 1H), 7.26
– 7.20 (m, 1H), 4.62 – 4.48 (m, 2H, NH2), 4.42 – 4.32 (m, 1H, NH2), 3.91 – 3.85 (m, 2H, NH2),
3.80 (dd, J = 17.4, 11.3 Hz, 1H), 3.72 – 3.65 (m, 1H, NH2), 3.46 – 3.39 (m, 1H), 3.19 – 3.11 (m,
2H, NH2), 3.09 – 3.00 (m, 1H), 2.95 – 2.88 (m, 1H), 2.78 – 2.69 (m, 1H), 2.66 – 2.50 (m, 4H),
1.89 – 1.80 (m, 1H), 1.42 (d, J = 12.4 Hz, 9H), 1.00 (d, J = 11.2 Hz, 9H).
13
C NMR (151 MHz, MeOD) δ 168.2 (d, J = 4.6 Hz), 154.8, 136.9, 125.5 (d, J = 8.1 Hz), 123.9,
122.9, 120.7, 47.3, 45.6, 43.7, 43.5, 38.1 (d, J = 11.6 Hz), 37.0 (d, J = 16.8 Hz), 36.9 (d, J = 18.5
Hz), 30.8 (d, J = 4.0 Hz), 30.1 (d, J = 3.5 Hz).
19
F NMR (564 MHz, MeOD) δ -76.17.
31
P NMR (243 MHz, MeOD) δ 94.96.
Anal. Calcd for C19H40ClF3N5O3PRuS: C 35.49, H 6.27, N 10.89, S 4.99. Found: C 34.89, H 6.20,
N 11.28, S 4.65
6.3.10. Reaction of Three Carbon Diamine with Diols
In the drybox, a 1-dram vial was charged with N-methylethylenediamine (1 equiv, 0.2
mmol), ethylene glycol (2 equiv, 0.4 mmol), and catalyst 4. The vial was sealed, taken out of the
glovebox, and heated to 110 °C. The solution turned to yellow color. After 44 h, the reaction
mixture was allowed to cool to room temperature and analyzed by LC-QTOF.
Scheme 6.3.11. Coupling between N-Methylethylenediamine (3.13c) and Ethylene Glycol (3.4a).
216
Figure 6.3.14: Mass spectra of reaction of 3.13c with 3.4a at 0.25% C4.
Figure 6.3.15: Mass spectra of reaction of 3.13c with 3.4a at 3.0 mol % C4.
217
6.3.11. Catalyst Screening
Different catalysts were screened under the condition specific to the catalyst that is reported
in the literature for hydrogen-borrowing piperazine
19
or benzodiazepine
20
synthesis, or N-
alkylation.
21
Unfortunately, none of the catalyst that were examined, except complex C4, showed
activity for the 1,4-diazepane synthesis.
Table 6.3.7: Screening of Different Hydrogen-Borrowing Catalysts for 1,4-Diazepane Synthesis.
Entry Diamine Diol Catalyst Condition Result
1
3.13h
3.2a
C4(1 mol %) neat,
110
o
C,
44 h, sealed
vial
no reaction
a
2
3.13b
3.2a C4 (1 mol %) " no reaction
3
3.1p
3.2a C4 (1 mol %) " no reaction
4
3.1a
3.2a C4 (1 mol %) "
78%
5 3.13h 3.2a Shvo catalyst
(1 mol %)
KOH
(5 mol %),
neat,
110
o
C,
44 h, sealed
vial
no reaction
6 3.1a 3.2a Shvo catalyst
(1 mol %)
" no reaction
7 3.13h 3.2a [Cp*IrCl 2] 2
(0.5 mol %)
NaHCO 3
(5 mol %),
toluene
(0.5 mL)/neat,
110
o
C,
24 h, sealed
vial
no reaction
8 3.13b 3.2a [Cp*IrCl 2] 2
(0.5 mol %)
" no reaction
9 3.1p 3.2a [Cp*IrCl 2] 2
(0.5 mol %)
" no reaction
10 3.1a 3.2a [Cp*IrCl 2] 2
(0.5 mol %)
" no reaction
11 3.13b 3a [Ru(p-
cymene)Cl 2] 2
xantphose no desired
product
b
218
(5 mol %) (5 mol %),
toluene
(1 mL)/neat,
160
o
C,
24 h, Schlenk
reactor
12 3.1a 3.2a [Ru(p-
cymene)Cl 2] 2
(5 mol %)
" no desired
product
13 3.13b 3.2a NiBr 2
(10 mol %)
Phen
(20 mol %),
t-BuOK
(1 equiv),
toluene,
130
o
C,
48 h, Schlenk
reactor
no reaction
14 3.1a 3.2a NiBr 2
(10 mol %)
" no reaction
a
No reaction means that we observed only both starting materials in the
1
H NMR spectra.
b
No desired product means
that we observed some other compounds along with starting materials; but we were not able to elucidate the structure
of the compounds present in the mixture.
6.3.12. Exploring Synthesis of Dilazep and Homofenazine
Dilazep
Dilazep
22
, a coronary and cerebral vasodilator, which inhibits platelet adenosine uptake, is
used to treat cardiopathy and renal disorders. The current synthetic strategy (Scheme 6.3.12) to
access dilazep involves formation of a 1,4-diazepane from bis-(3-hydroxypropyl)-ethylene
diamine and 1-bromo-3-chloro-propane via two consecutive SN2 reactions. Esterification of this
diazacycle with 3,4,5-teimethoxybenzoyl chloride gives dilazep in 66-70% yield.
23
We proposed
an alternate route to furnish dilazep by replacing the amination of halides with a green hydrogen-
borrowing method to access the 7-membered diazacycle (Scheme 6.3.13). In this route, complex
C4 catalyzed coupling of N,N’-dibenzylethylenediamine with 1,3-propanediol produce
dibenzylhomopiperazine (3.3a), which is already achieved in our reaction scope. In parallel, an
esterification reaction can lead to the formation of our second regent, 3-hydroxypropyl 3,4,5-
219
trimethoxybenzoate (3.32). Finally, treatment of 3.32 with 3.33, that is formed from 3.3a by benzyl
deprotection, under our catalytic conditions affords dilazep (3.34).
Scheme 6.3.12. Previous Route to Dilazep.
Scheme 6.3.13. Retrosynthesis of Dilazep through Hydrogen-Borrowing Strategy.
We started our multistep synthesis with the esterification reaction, and it yielded the desired
compound in good yield (Scheme 6.3.14). Identity of this novel compound was confirmed by
1
H
220
NMR,
13
C NMR, and 2-D NMR spectroscopy such as COSEY, HSQC, and HMBC. However, the
coupling of homopiperazine with the ester under our catalytic condition didn’t furnish dilazep
(Scheme 6.3.15). Other known amine alkylation catalysts or different conditions can be screened
for a better outcome in future.
Scheme 6.3.14. Synthesis of 3-Hydroxypropyl 3,4,5-trimethoxybenzoate.
Scheme 6.3.15. Reaction of Homopiperazine with 3-Hydroxypropyl 3,4,5-trimethoxybenzoate.
3-Hydroxypropyl 3,4,5-trimethoxybenzoate
To an ice-cold solution of 1,3-propanediol (0.99 g, 13.02 mmol, 3 equiv.) and Et3N (0.88
g, 8.68 mmol, 2 equiv.) in dry dichloromethane in a 100 mL round bottom flask, 3,4,5-
trimethoxybenzoyl chloride (1g, 4.34 mmol, 1 equiv.) was added slowly. Allowed the solution to
warm to room temperature and kept it for stirring. After 9 h, the mixture was diluted with water,
and the product was extracted in dichloromethane 3 times. Collected organic layer was dried over
221
anhydrous magnesium sulfate and concentrated in vacuo. The product was obtained in 80% yield
(0.94 g) as a white solid after flash column chromatography (50:50 hexanes: ethyl acetate).
1
H NMR (600 MHz, CDCl3) δ 7.27 (s, 2H), 4.47 (t, J = 6.2 Hz, 2H), 3.89 (s, 9H), 3.76 – 3.72 (m,
2H), 2.19 (s, 1H), 1.99 (p, J = 6.1 Hz, 2H).
13
C NMR (151 MHz, CDCl3) δ 166.8, 153.0, 142.4, 125.2, 107.0, 62.1, 61.0, 59.2, 56.3, 32.1
Homofenazine
Homofenazine is a psycho sedative drug developed in Germany. Major pharmaceutical
companies like Pfizer, Astrazeneca, and Eli Lily manufacture this expensive drug and its reported
multistep synthesis is given in scheme 6.3.16.
24
First, nucleophilic substitution of phenothiazine
3.31 with 1-(3-bromopropyl)-1,4-diazepane (3.36) produce compound 3.37, which is then treated
with 2-chloroethanol to furnish homofenazine (3.38). This route is not cost effective, because the
7-membered cyclic reagent 3.36 is as expensive as the drug.
Scheme 6.3.16. Reported Synthesis of Homofenazine.
We proposed two retrosynthetic pathways to access homofenazine (Schemes 6.3.17 and
6.3.18). In both cases, first step is the synthesis of an α,β-unsaturated ketone 3.39 from
phenothiazine and acryloyl chloride. Further treatment of 3.39 with either 1,3-propanediamine or
N-(2-hydroxyethyl)ethylenediamine can yield the corresponding 1,4-addition product 3.40 or 3.42
respectively. Subsequent carbonyl group reduction followed by a diamine-diol coupling under our
catalytic condition will lead to the formation of homofenazine.
222
Scheme 6.3.17. Retrosynthetic Strategy 1 to Access Homofenazine.
223
Scheme 6.3.18. Retrosynthetic Strategy 2 to Access Homofenazine.
We begin our multistep synthesis of homofenazine by screening three different conditions
to access the first intermediate, 3.39 (Table 6.3.8). While reaction of phenothiazine and acryloyl
chloride with and without a base gave poor yield in dichloromethane, refluxing reaction in toluene
showed complete conversion with 86% NMR yield. Identity of this compound was established by
NMR spectroscopy and MALDI analysis. Unfortunately, treatment of 3.39 with both 1,3-
propanediamine and N-(2-hydroxyethyl)ethylenediamine at different conditions attacked the
carbonyl group to give back phenothiazine rather than proceeding via the desired 1,4-addition
pathway (Table 6.3.9). With this result, we ceased further experiments in retrosynthetic approach
1 and 2.
224
Table 6.3.8. Reaction of Phenothiazine 3.35 with Acryloyl Chloride.
Entry Additive Solvent Temp Time (h) Yield
a
1 — DCM (dry) 0 °C - rt 24 14
2 Et 3N DCM (dry) 0 °C - rt 24 4
3 — toluene (dry) 0 °C - reflux 6 86
a
The yield was determined by
1
H NMR spectroscopy with mesitylene as the internal standard.
Table 6.3.9. Reaction of 3.39 with Amines.
Entry Amine Temp Result
1
0 °C-rt
2 " 0 °C - reflux "
3
0 °C - rt
4 " 0 °C - reflux "
225
1-(2-(trifluromethyl)-10H-phenothiazin-10-yl)prop-2-en-1-one
To an ice-cold solution of 2-(trifluromethyl)-10H-phenothiazine (4.0 g, 15.0 mmol, 1.0
equiv.) in dry toluene in a 100 mL round bottom flask, acryloyl chloride (2.0 g, 22.5 mmol, 1.5
equiv.) was added slowly. The solution was warmed to room temperature and then maintained at
reflux for 6 h. Then, excess acryloyl chloride was quenched with saturated NaHCO3 solution, and
extracted the product in dichloromethane. Collected organic layer was dried over anhydrous
sodium sulfate and concentrated in vacuo. The product was obtained in 86% yield (4.14 g) and
used without further purification.
1
H NMR (500 MHz, CDCl3) δ 7.96 (s, 1H), 7.58 – 7.43 (m, 3H), 7.40 – 7.34 (m, 1H), 7.34 –
7.24 (m, 1H), 6.64 – 6.56 (m, 1H), 6.46 – 6.36 (m, 1H), 5.84 – 5.77 (m, 1H).
HRMS (MALDI-TOF) m/z: [M+H]
+
Calcd for C16H11F3NOS 322.0513; Found 322.7810.
Next, we proposed a third strategy to afford homofenazine in five steps from commercially
available inexpensive starting materials (Scheme 6.3.19). Formation of 1,4-diazepane 3.3i is
achieved previously in our substrate scope study. This diazacycle can then be hydrogenated to
produce benzyl deprotected compound 3.44. Thereafter, reaction of phenothazine 3.35 with a 1,3-
dihaloalkane to furnish 3.45, and its concomitant treatment with 3.44 will eventually lead to the
formation of homofenazine.
226
Scheme 6.3.19. Proposed Synthetic Route 3 to Access Homofenazine.
As a first step, we screened four conditions to produce 3.45 from phenothiazine 3.35 and
1,3-dihaloalkane (Table 6.3.10). While reactions employing cesium carbonate as the base showed
desired product along with lots of additional peaks, reaction with sodium hydride produced
mixture of 3.45 and 3.35. Unfortunately, all the attempts to purify 3.45 yielded the same mixture,
even after column chromatography (hexanes: ethyl acetate 97:3) and recrystallization. We paused
the multistep synthesis of homofenazine at this stage, and the space for further purification trials
and route to homofenazine remains open.
Table 6.3.10. Reaction of 3.35 with 1,3-Dihalopropane.
Entry X Condition Result
1 Cl Cs 2CO 3 (2 equiv.), DMF, 30
o
C, 48h, 80
o
C, 2 h observed 3.45 with lots
of other peaks
2 Br " observed 3.45 with lots
of other peaks
3 Cl NaH (2 equiv.), THF (dry), 65
o
C, 18 h observed 3.45 and 3.35
in 1:3 ratio
4 Cl 1. dry DMF, rt, 30 min
2. NaH (3 equiv), rt, 4 h
observed 3.45 and 3.35
in 1.1:1.0 ratio
227
6.3.13. Homocoupling of Amino Alcohols to Access Diazacycles
Amino alcohols can be self-coupled via hydrogen-borrowing to produce diazacycles. To
the best of our knowledge, Fujita,
25
and Marichev
26
employed this methodology to access
substituted piperazines; but the need for broad substrate scope and higher diazacycles remains
open. Our attempts to synthesize both 6- and 8-membered 1,4-diazacycles is summarized in Table
6.3.11. While screening for diazocane compounds through homocoupling of N-benzyl-3-
aminopropanol yielded complex mixtures, N-benzylethanolamine showed a promising result with
34% desired piperazine. Further optimization studies may lead to better results in this group. As
expected, reaction of ethanolamine returned starting material. This can be attributed to the catalytic
poisoning which is common with substrates having heteroatoms separated by two carbon atoms.
Table 6.3.11. Homocoupling of Amino Alcohols.
Entry Amino Alcohol Result
a
1
complex mixture
2
(34%)
3
starting material
a
Reaction mixture was analyzed by NMR spectroscopy.
6.3.14. Cross-coupling of Amino Alcohols to Access Diazacycles
Synthesis of 1,4-benzodiazepine is reported through cross coupling of amino alcohols.
20
Here, we screened various amino alcohols to access piperazines, 1,4-diazepanes, 1,4-
benzodizepine and 8-membered diazacycles (Table 6.3.12). Regardless of the conditions, solvents
228
and substrates utilized, most of the entries showed either complex mixture or starting material in
the crude
1
H NMR spectroscopy.
Table 6.3.12. Cross-coupling of Amino Alcohols.
Entry Amino Alcohol 1 Amino Alcohol 2 Condition Result
a
1
neat, 110
o
C, 44 h,
sealed vial
complex mixture which didn’t
show desired product peaks
2 " " neat, 110
o
C, 44 h,
Schlenk flask, open,
N 2
(1 atm)
starting material
3 " " toluene, 111
o
C, 44 h,
sealed Schlenk flask
starting material
4 " " dioxane, 101
o
C, 44 h,
sealed Schlenk flask
starting material
5 " " toluene, 111
o
C, 44 h,
open flask, and
condenser, N 2
(1 atm)
starting material
6
neat, 110
o
C, 44 h,
sealed vial
starting material
7
neat, 110
o
C, 44 h,
sealed vial
starting material
8
neat, 110
o
C, 44 h,
sealed vial
starting material
9
neat, 110
o
C, 44 h,
sealed vial
starting material
10
neat, 110
o
C, 44 h,
sealed vial
mixture with trace of the
desired product
11
neat, 110
o
C, 44 h,
sealed vial
complex mixture
a
Reaction mixture was analyzed by NMR spectroscopy.
229
6.3.15. Reaction of Diamines with Allylic Alcohols, and α,β-Unsaturated Carbonyl
Compounds
We explored the possibility of making 8-membered 1,5-diazacompounds from diamines,
and allylic alcohols or α,β-unsaturated carbonyl compounds under our catalytic conditions
(Scheme 6.3.20). We chose allyl alcohol and methyl vinyl ketone as the model substrate along
with N,N’-dibenzylpropanediamine for the desired reaction. As NMR spectra of both reactions
showed mainly starting material peaks, we were discouraged to proceed further here.
Scheme 6.3.20. Reaction of N,N’-Dibenzylpropanediamine with allyl alcohol, and methyl vinyl
ketone.
230
6.3.16. NMR Spectra
Figure 6.3.16.
1
H NMR (500 MHz) spectrum of 3.1b at 25 °C in CDCl3.
Figure 6.3.17.
13
C NMR (151 MHz) spectrum of 3.1b at 25 °C in CDCl3.
231
Figure 6.3.18.
1
H NMR (600 MHz) spectrum of 3.1b' at 25 °C in CDCl3.
Figure 6.3.19.
13
C NMR (151 MHz) spectrum of 3.1b' at 25 °C in CDCl3.
(±)
(±)
232
Figure 6.3.20.
1
H NMR (600 MHz) spectrum of 3.1c at 25 °C in CDCl3.
Figure 6.3.21.
13
C NMR (151 MHz) spectrum of 3.1c at 25 °C in CDCl3.
233
Figure 6.3.22.
1
H NMR (600 MHz) spectrum of 3.1f at 25 °C in CDCl3.
Figure 6.3.23.
13
C NMR (151 MHz) spectrum of 3.1f at 25 °C in CDCl3.
234
Figure 6.3.24.
1
H NMR (400 MHz) spectrum of 3.1g at 25 °C in CDCl3.
Figure 6.3.25.
1
H NMR (500 MHz) spectrum of 3.1j at 25 °C in CDCl3.
235
Figure 6.3.26.
13
C NMR (126 MHz) spectrum of 3.1j at 25 °C in CDCl3.
Figure 6.3.27.
1
H NMR (400 MHz) spectrum of 3.1k at 25 °C in CDCl3.
236
Figure 6.3.28.
13
C NMR (126 MHz) spectrum of 3.1k at 25 °C in CDCl3.
Figure 6.3.29.
1
H NMR (500 MHz) spectrum of 3.1e at 25 °C in CDCl3.
237
Figure 6.3.30.
13
C NMR (151 MHz) spectrum of 3.1e at 25 °C in CDCl3.
Figure 6.3.31.
1
H NMR (600 MHz) spectrum of 3.1l at 25 °C in CDCl3.
238
Figure 6.3.32.
13
C NMR (151 MHz) spectrum of 3.1l at 25 °C in CDCl3.
Figure 6.3.33.
1
H NMR (500 MHz) spectrum of 3.1m at 25 °C in CDCl3.
239
Figure 6.3.34.
13
C NMR (151 MHz) spectrum of 3.1m at 25 °C in CDCl3.
Figure 6.3.35.
1
H NMR (600 MHz) spectrum of 3.1n at 25 °C in CD3OD.
240
Figure 6.3.36.
13
C NMR (151 MHz) spectrum of 3.1n at 25 °C in CD3OD.
Figure 6.3.37.
1
H NMR (600 MHz) spectrum of 3.1o at 25 °C in CDCl3.
241
Figure 6.3.38.
13
C NMR (151 MHz) spectrum of 3.1o at 25 °C in CDCl3.
Figure 6.3.39.
1
H NMR (600 MHz) spectrum of 3.1p at 25 °C in CDCl3.
242
Figure 6.3.40.
13
C NMR (151 MHz) spectrum of 3.1p at 25 °C in CDCl3.
Figure 6.3.41.
1
H NMR (600 MHz) spectrum of 3.19a at 25 °C in CDCl3.
243
Figure 6.3.42.
13
C NMR (151 MHz) spectrum of 3.19a at 25 °C in CDCl3.
Figure 6.3.43.
1
H NMR (600 MHz) spectrum of 3.1q at 25 °C in CDCl3.
244
Figure 6.3.44.
13
C NMR (151 MHz) spectrum of 3.1q at 25 °C in CDCl3.
Figure 6.3.45.
1
H NMR (600 MHz) spectrum of 3.19i at 25 °C in CDCl3.
245
Figure 6.3.46.
1
H NMR (600 MHz) spectrum of 3.1r at 25 °C in CDCl3.
Figure 6.3.47.
13
C NMR (151 MHz) spectrum of 3.1r at 25 °C in CDCl3.
246
Figure 6.3.48.
1
H NMR (600 MHz) spectrum of 3.5a at 25 °C in CDCl3.
.
Figure 6.3.49.
13
C NMR (151 MHz) spectrum of 3.5a at 25 °C in CDCl3.
247
Figure 6.3.50.
1
H NMR (400 MHz) spectrum of 3.5b at 25 °C in CDCl3.
Figure 6.3.51.
13
C NMR (151 MHz) spectrum of 3.5b at 25 °C in CDCl3.
248
Figure 6.3.52.
1
H NMR (400 MHz) spectrum of (±)-(4aR,8aR)-1,4-dibenzyldecahydroquinoxaline
at 25 °C in CDCl3.
Figure 6.3.53.
13
C NMR (151 MHz) spectrum of (±)-(4aR,8aR)-1,4-
dibenzyldecahydroquinoxaline at 25 °C in CDCl3.
(±)
(±)
249
Figure 6.3.54.
1
H NMR (500 MHz) spectrum of 3.5c at 25 °C in CDCl3.
Figure 6.3.55.
13
C NMR (126 MHz) spectrum of 3.5c at 25 °C in CDCl3.
250
Figure 6.3.56.
1
H NMR (400 MHz) spectrum of 3.3a at 25 °C in CDCl3.
Figure 6.3.57.
13
C NMR (151 MHz) spectrum of 3.3a at 25 °C in CDCl3.
251
Figure 6.3.58.
1
H NMR (600 MHz) spectrum of 3.3b at 25 °C in CDCl3.
Figure 6.3.59.
13
C NMR (151 MHz) spectrum of 3.3b at 25 °C in CDCl3.
252
Figure 6.3.60.
1
H NMR (600 MHz) spectrum of 3.3c at 25 °C in CDCl3.
Figure 6.3.61.
13
C NMR (151 MHz) spectrum of 3.3c at 25 °C in CDCl3.
253
Figure 6.3.62.
1
H NMR (600 MHz) spectrum of 3.3d at 25 °C in CDCl3.
Figure 6.3.63.
13
C NMR (151 MHz) spectrum of 3.3d at 25 °C in CDCl3.
254
Figure 6.3.64.
1
H NMR (600 MHz) spectrum of 3.3e at 25 °C in CDCl3.
Figure 6.3.65.
13
C NMR (151 MHz) spectrum of 3.3e at 25 °C in CDCl3.
255
Figure 6.3.66.
1
H NMR (600 MHz) spectrum of 3.1f at 25 °C in CDCl3.
Figure 6.3.67.
13
C NMR (151 MHz) spectrum of 3.1f at 25 °C in CDCl3.
256
Figure 6.3.68.
1
H NMR (600 MHz) spectrum of 3.3i at 25 °C in CDCl3.
Figure 6.3.69.
13
C NMR (151 MHz) spectrum of 3.3i at 25 °C in CDCl3.
257
Figure 6.3.70.
1
H NMR (600 MHz) spectrum of 3.3j at 25 °C in CDCl3.
Figure 6.3.71.
13
C NMR (151 MHz) spectrum of 3.3j at 25 °C in CDCl3.
258
Figure 6.3.72.
1
H NMR (600 MHz) spectrum of 3.3k at 25 °C in CDCl3.
Figure 6.3.73.
13
C NMR (151 MHz) spectrum of 3.3k at 25 °C in CDCl3.
259
Figure 6.3.74.
1
H NMR (500 MHz) spectrum of 3.3l at 25 °C in CDCl3.
Figure 6.3.75.
13
C NMR (126 MHz) spectrum of 3.3l at 25 °C in CDCl3.
260
Figure 6.3.76.
1
H NMR (500 MHz) spectrum of 3.3m at 25 °C in CDCl3.
Figure 6.3.77.
13
C NMR (126 MHz) spectrum of 3.3m at 25 °C in CDCl3.
261
Figure 6.3.78.
1
H NMR (600 MHz) spectrum of complex 3.12 at 25 °C in MeOD.
Figure 6.3.79.
13
C NMR (151 MHz) spectrum of complex 3.12 at 25 °C in MeOD.
262
Figure 6.3.80.
19
F NMR (564 MHz) spectrum of complex 3.12 at 25 °C in MeOD.
Figure 6.3.81.
31
P NMR (243 MHz) spectrum of complex 3.12 at 25 °C in MeOD.
263
Figure 6.3.82.
1
H NMR (600 MHz) spectrum of 3.32 at 25 °C in CDCl3.
Figure 6.3.83.
13
C NMR (151 MHz) spectrum of 3.32 at 25° C in CDCl3.
264
Figure 6.3.84.
1
H NMR (500 MHz) spectrum of 3.39 at 25 °C in CDCl3.
265
6.3.17. Crystal Description
Compound 3.3k
Identification code AT 367 PF6_auto
Empirical formula C22H28F6N2P
Formula weight 465.445
Temperature/K 100.0(2)
Crystal system monoclinic
Space group Cm
a/Å 10.2912(8)
b/Å 13.4966(12)
c/Å 7.8306(6)
α/° 90
β/° 97.280(8)
γ/° 90
Volume/Å
3
1078.87(15)
Z 2
ρcalcg/cm
3
1.433
266
μ/mm
-1
1.707
F(000) 488.5
Crystal size/mm
3
0.144 × 0.05 × 0.025
Radiation Cu Kα (λ = 1.54184)
2Θ range for data collection/° 10.86 to 153.78
Index ranges -12 ≤ h ≤ 12, -13 ≤ k ≤ 16, -5 ≤ l ≤ 9
Reflections collected 3750
Independent reflections 1351 [Rint = 0.0503, Rsigma = 0.0378]
Data/restraints/parameters 1351/2/151
Goodness-of-fit on F
2
1.048
Final R indexes [I>=2σ (I)] R1 = 0.0527, wR2 = 0.1435
Final R indexes [all data] R1 = 0.0584, wR2 = 0.1487
Largest diff. peak/hole / e Å
-3
0.33/-0.20
Flack parameter 0.04(4)
CCDC# 2217365
267
Complex 3.12
Identification code final
Empirical formula C20H42Cl3F3N5O3PRuS
Formula weight 728.03
Temperature/K 100.0(2)
Crystal system triclinic
Space group P-1
a/Å 8.4163(2)
b/Å 10.8725(2)
c/Å 17.9439(4)
α/° 92.663(2)
β/° 90.426(2)
γ/° 105.701(2)
Volume/Å
3
1578.66(6)
Z 2
ρcalcg/cm
3
1.532
268
μ/mm
-1
0.915
F(000) 748.0
Crystal size/mm
3
0.081 × 0.063 × 0.039
Radiation Mo Kα (λ = 0.71073)
2Θ range for data collection/° 5.028 to 66.778
Index ranges -12 ≤ h ≤ 11, -15 ≤ k ≤ 16, -26 ≤ l ≤ 27
Reflections collected 48619
Independent reflections 10744 [Rint = 0.0735, Rsigma = 0.0728]
Data/restraints/parameters 10744/6/340
Goodness-of-fit on F
2
1.048
Final R indexes [I>=2σ (I)] R1 = 0.0489, wR2 = 0.1153
Final R indexes [all data] R1 = 0.0740, wR2 = 0.1240
Largest diff. peak/hole / e Å
-3
1.79/-1.23
CSD# 2217364
269
6.3.18. References
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2. Celaje, J. J. A.; Zhang, X.; Zhang, F.; Kam, L.; Herron, J. R. ACS Catal. 2017, 7 (2), 1136-
1142.
3. Szewczyk, M.; Stanek, F.; Bezlada, A.; Mlynarski, J. Adv. Synth. Catal. 2015, 357, 3727-
3731.
4. Jiang, X.; Lo, P.; Tsang, Y.; Yeung, S.; Fong, W.; Ng, D. Chem. Eur. J. 2010, 16 (16), 4777-
4783.
5. Cortes, S.; Kohn, H. J. Org. Chem. 1983, 48 (13), 2246-2254.
6. Polat, D.; Brzezinski, D.; Beauchemin, A. Org. Lett. 2019, 21 (12), 4849-4852.
7. Ralambomanana, D.; Razafimahefa-Ramilison, D.; Rakotohova, A.; Maugein, J.; Pélinski,
L. Bioorg. Med. Chem. 2008, 16 (21), 9546-9553.
8. Rais, E.; Flörke, U.; Wilhelm, R. Z. Naturforsch. B. 2016, 71 (6), 667-676.
9. Roush, W.; Grover, P. J. Org. Chem. 1995, 60 (12), 3806-3813.
10. King, D.; Firestone, R.; Dubowchik, G. Preparation of Branched Peptide Linkers. WO
9819705 A1, 1998. Provided by SciFinder, 1998:323158 (accessed 2021-09-06).
11. Upadhyaya, D.; Barge, A.; Stefania, R.; Cravotto, G. Tetrahedron Lett. 2007, 48 (47), 8318-
8322.
12. Shirini, F.; Jolodar, O.; Seddighi, M.; Borujeni, H. RSC Adv. 2015, 5, 19790-19798.
13. Chamberlain, A. E. R.; Paterson, K. J.; Armstrong, R. J.; Twin, H. C.; Donohoe, T. J. A
Chem. Commun., 2020, 56 (24), 3563-3566.
270
14. Reddy, B. P.; Reddy, K. R.; Krupadanam, G. L. D.; Reddy, A. P.; Reddy, K. B. C-3 Novel
Triterpenone with C-28 Urea Derivatives as HIV Inhibitors. WO/2017/064628 A1, April 20,
2017.
15. Mohrle, H.; Azodi, K. Journal of Natural Research B., 2006, 61 (8), 1021-1034.
16. Matsunaga, Y.; Fujisawa, K.; Amir, N.; Miyashita, Y.; Okamoto, K. Appl. Organometal.
Chem., 2005, 19, 778-789.
17. Bilke, J L.; OʹBrien, P. J. Org. Chem. 2008, 73 (16), 6452-6454.
18. Borys, A. M.; Gil-Negrete, J. M.; Hevia, E. Chem. Commun., 2021, 57 (71), 8905-8908.
19. Nordstrøm, L. U.; Madsen, R. Chemical Communications 2007, (47), 5034-5036.
20. Jumde, V. R.; Cini, E.; Porcheddu, A.; Taddei, M. European Journal of Organic Chemistry
2015, 2015 (5), 1068-1074.
21. Vellakkaran, M.; Singh, K.; Banerjee, D. ACS Catal. 2017, 7, 8152-8158
22. Deguchi, H.; Takeya, H.; Wada, H.; Gabazza, E. C.; Hayashi, N.; Urano, H.; Suzuki, K.
Blood. 1997, 90 (6), 2345-2356.
23. Arnold, H.; Pahls, K.; Rebling, R.; Brock, N.; Lenke, H-D. N, N'-alkylene-N-N'-bis((alkoxy
benzoyloxy)alkyl)alkylene diimines. US 3532685 A, December 6, 1965.
24. Schuler, W. A.; Hohe, B. H. v. d.; Beschke, H. et al. 3-trifluoromethyl-10-[3'-(4"-(2"'-
hydroxy ethyl)-homopiperazino)-propyl]-phenothiazine and 3-trifluoromethyl-10-[3'-(4"-
(2"'-acetoxyethyl)-homopiperazino)-propyl]-phenothiazine. US 3040043 A, June 19, 1962.
25. Fujita, K-i.; Kida, Y.; Yamaguchi, R. Heterocycles. 2009, 77 (2), 1371-1377.
26. Marichev, K. O.; Takacs, J. M. ACS Catal. 2016, 6 (4), 2205-2210.
271
6.4. Chapter 4 Experimental and Spectral Data
6.4.1. General Procedure
General Procedure A
In the drybox, a 1-dram vial was charged with guanidine substrate (1 equiv), alcohol (2
equiv), and catalyst C4 (1.0 mol %). The vial was sealed, taken out of the glovebox, and heated to
110 °C. The solution turned to orange/brown color. After 44 h, the reaction mixture was allowed
to cool to room temperature. Mesitylene was added to this reaction mixture as an internal standard,
and an aliquot was taken for
1
H NMR analysis.
General Procedure B
In the drybox, a 5 mL Schlenk reactor was charged with guanidine substrate (1 equiv),
alcohol (5 equiv), catalyst C4 (1.0 mol %), and toluene (5 equiv). The reactor was sealed with a
teflon cap, taken out of the glovebox, and heated to 110 °C. The solution turned to orange/brown
color. After 44 h, the reaction mixture was allowed to cool to room temperature and toluene was
removed under reduced pressure. Mesitylene was added to this reaction mixture as an internal
standard, and an aliquot was taken for
1
H NMR analysis.
6.4.2. Substrate Scope
Reaction of TBD with n-Butanol
Scheme 6.4.1. Reaction of TBD with n-Butanol.
General procedure A was employed. Data are consistent with the reported compound.
1
272
Figure 6.4.1.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and n-butanol (2 equiv) with 1 mol % C4 for 44 h.
Reaction of TBD with 1-Octanol
Scheme 6.4.2. Reaction of TBD with 1-Octanol.
General procedure A was employed. Product identity is confirmed from the mass on LC-QTOF
spectra and similarity of its
1
H NMR spectrum with compound 4.2.a.
a (merges with
butanol peak)
c
d
h
f
g,i e
Mesitylene peak
b (merges with
butanol peak)
273
Figure 6.4.2.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and 1-octanol (2 equiv) with 1 mol % C4 for 63 h.
Figure 6.4.3. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 1-
octanol, which shows desired product peak at 270.252 (M+H2O+H)
+
.
Mesitylene peak
merges with
octanol peak;
only 12H
belongs to
4.2b
merges with
octanol peak;
only 3H
belongs to
4.2b
274
Reaction of TBD with 1-Hexadecanol
Scheme 6.4.3. Reaction of TBD with 1-Hexadecanol.
General procedure A was employed. Product is tentatively identified as 4.2c based on LC-QTOF
analysis and NMR spectra.
Figure 6.4.4.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and 1-hexadecanol (2 equiv) with 1 mol % C4 for 44 h.
merges with
alcohol peak;
only 3H
belongs to
4.2c
merges with
alcohol peak;
26H belongs to
4.2c
275
Figure 6.4.5. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 1-
hexadecanol, which shows desired product peak at 382.3782 (M+H2O+H)
+
.
Reaction of TBD with Cyclobutanemethanol
Scheme 6.4.4. Reaction of TBD with Cyclobutanemethanol.
General procedure A was employed. Product is tentatively identified as 4.2d based on LC-QTOF
analysis and NMR spectra.
276
Figure 6.4.6.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and cyclobutanemethanol (2 equiv) with 1 mol % C4 for 44 h.
Figure 6.4.7. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and
cyclobutanemethaol, which shows desired product peak at 226.1913 (M+H2O+H)
+
.
merges with alcohol peak; 12
hydrogens of the product
belong to this region.
277
Reaction of TBD with 1-Adamantanemethanol
Scheme 6.4.5. Reaction of TBD with 1-Adamantanemethanol.
General procedure A was employed. Product is tentatively identified as 4.2e based on LC-QTOF
analysis and NMR spectra.
Figure 6.4.8.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and 1-adamantanemethanol (2 equiv) with 1 mol % C4 for 44 h. Peaks of the desired product 4.2e
is merging with starting materials except two CH2 peaks at 2.50 (t, 2H) and 2.14 (s, 2H).
278
Figure 6.4.9. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 1-
adamantanemethanol, which shows desired product peak at 306.2552 (M+H2O+H)
+
.
Reaction of TBD with Furfuryl Alcohol
Scheme 6.4.6. Reaction of TBD with Furfuryl Alcohol.
General procedure A was employed. Product is tentatively identified as 4.2f based on LC-QTOF
analysis and NMR spectra.
279
b
Figure 6.4.10.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and furfuryl alcohol (4 equiv) with 1 mol % C4 for 44 h.
Figure 6.4.11. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 1-
furfuryl alcohol, which shows desired product peak at 238.1568 (M+H2O+H)
+
.
a
c
d
merges
with
peaks of
TBD
merges
with
peaks of
TBD
280
Reaction of TBD with Cyclopentanol
Scheme 6.4.7. Reaction of TBD with Cyclopentanol.
General procedure A was employed. Product is tentatively identified as 4.2g based on LC-QTOF
analysis and NMR spectra.
Figure 6.4.12.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and cyclopentanol (2 equiv) with 1 mol % C4 for 92 h.
merges with alcohol peak; only
12H belongs to 4.2g
281
Figure 6.4.13. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and
cyclopentanol, which shows desired product peak at 226.1930 (M+H2O+H)
+
.
Reaction of TBD with Cyclohexanol
Scheme 6.4.8. Reaction of TBD with Cyclohexanol.
General procedure A was employed. Product is tentatively identified as 4.2h based on LC-QTOF
analysis and NMR spectra.
282
Figure 6.4.14.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and cyclopentanol (2 equiv) with 3 mol % C4 for 44 h.
Figure 6.4.15. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and
cyclohexanol, which shows desired product peak at 240.2090 (M+H2O+H)
+
.
merges with
alcohol peaks
merges
with
alcohol
peaks
merges
with
TBD
peaks
merges
with TBD
peaks
283
Reaction of TBD with 2-Butanol
Scheme 6.4.9. Reaction of TBD with 2-Butanol.
General procedure A was employed. Product is tentatively identified as 4.2i based on LC-QTOF
analysis and NMR spectra.
Figure 6.4.16.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and 2-butanol (2 equiv) with 1 mol % C4 for 44 h. Peaks of the desired product 4.2i is merging
with starting materials except two CH3 peaks at 0.77 (t, 3H) and 0.91 (d, 3H).
b a
284
Figure 6.4.17. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 2-
butanol, which shows desired product peak at 214.1919 (M+H2O+H)
+
.
Reaction of TBD with Benzyl Alcohol
Scheme 6.4.10. Reaction of TBD with Benzyl Alcohol.
General procedure A was employed. Product is tentatively identified as 4.2j based on LC-QTOF
analysis and NMR spectra.
285
Figure 6.4.18.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and benzyl alcohol (2 equiv) with 1 mol % C4 for 44 h.
Figure 6.4.19. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and
benzyl alcohol, which shows desired product peak at 248.1795 (M+H2O+H)
+
.
a
b
e,g
f
c
merges with
TBD
d
merges with
TBD
286
Reaction of TBD with 4-Chlorobenzyl Alcohol
Scheme 6.4.11. Reaction of TBD with Benzyl Alcohol.
General procedure A was employed. Product is tentatively identified as 4.2k based on LC-QTOF
analysis and NMR spectra.
Figure 6.4.20.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and 4-chlorobenzyl alcohol (2 equiv) with 1 mol % C4 for 44 h.
a
merges with
TBD
TBD
peaks
alcohol CH 2
peak
mesitylene peak
287
Figure 6.4.21. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 4-
chlorobenzyl alcohol, which shows desired product peak at 282.1386 (M+H2O+H)
+
.
Reaction of TBD with 1-Phenylethanol
Scheme 6.4.12. Reaction of TBD with 1-Phenylethanol.
General procedure A was employed. Product is tentatively identified as 4.2l based on LC-QTOF
analysis and NMR spectra. We excluded the possibility of iminium ion rather than enamine as the
product based on the observation CH2 peaks in the aliphatic region of HSQC spectrum.
288
Figure 6.4.22.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and 1-phenylethanol (2 equiv) with 1 mol % C4 for 63 h.
Figure 6.4.23. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 1-
phenylethanol, which shows peak of enamine 4.2l at 260.1771 (M+H2O+H)
+
.
mesitylene peak
merges
with
TBD
merges
with
TBD
CH 3 peak of
alcohol
CH peak of
alcohol
289
Figure 6.4.24. Aliphatic region of the HSQC spectrum of the crude reaction mixture for the
coupling of TBD (1 equiv), and 1-phenylethanol (2 equiv) with 1 mol % C4 for 63 h. CH3 or CH
peaks (red dots) belongs to either alcohol substrate or mesitylene.
Reaction of TBD with 1-(4-Methylphenyl)ethanol
Scheme 6.4.13. Reaction of TBD with 1-(4-Methylphenyl)ethanol.
General procedure A was employed. Product is tentatively identified as 4.2m based on LC-QTOF
analysis and NMR spectrum.
290
Figure 6.4.25.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and 1-(methylphenyl)ethanol (1.4 equiv) with 1 mol % C4 for 44 h.
Figure 6.4.26. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 1-
(methylphenyl)ethanol, which shows peak of hemiaminal 4.2m at 274.1910 (M+H)
+
.
merges with
TBD; only 4H
belongs to
4.2m.
291
Reaction of TBD with 1-(4-Methoxyphenyl)ethanol
Scheme 6.4.14. Reaction of TBD with 1-(4-Methoxyphenyl)ethanol.
General procedure A was employed. Product is tentatively identified as 4.2n based on LC-QTOF
analysis and NMR spectrum.
Figure 6.4.27.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and 1-(methoxyphenyl)ethanol (2 equiv) with 1 mol % C4 for 44 h.
merges with
TBD; only 4H
belongs to
4.2n.
merges with
TBD; only 2H
belongs to
4.2n.
292
Figure 6.4.28. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 1-
(methoxyphenyl)ethanol, which shows peak of hemiaminal 4.2n at 290.1867 (M+H)
+
.
Reaction of TBD with 3-(Methylamino)propan-1-ol
Scheme 6.4.15. Reaction of TBD with 3-(Methylamino)propan-1-ol.
General procedure A was employed. Product is tentatively identified as 4.2o based on LC-QTOF
spectrum.
293
Figure 6.4.29. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 4.3,
which shows peak of 4.2o at 229.2041 (M+H2O+H)
+
.
Reaction of TBD with 2-Aminobenzyl Alcohol
Scheme 6.4.16. Reaction of TBD with 2-Aminobenzyl Alcohol.
General procedure A was employed. Products are tentatively identified as 4.2p, 4.2q, and 4.2r
based on LC-QTOF spectrum.
294
Figure 6.4.30. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 4.4,
which show peaks of 4.2p (261.171), 4.2q (366.230), and 4.2r (471.287).
Reaction of TBD with 2,3-Butanediol
Scheme 6.4.17. Reaction of TBD with 2,3-Butanediol.
a
dr was determined from
1
H NMR spectroscopy.
General procedure A was employed. Product is tentatively identified as 4.2s based on LC-QTOF
analysis and NMR spectra.
295
Figure 6.4.31.
1
H NMR spectrum of the crude reaction mixture for the coupling of TBD (1 equiv)
and 2,3-butanediol (2 equiv) with 1 mol % C4 for 44 h. Integration for one of the diastereomer is
shown as the peaks of other diastereomer is merging with starting materials. We identified the
diastereomeric ratio from the methyl peak of diastereomers at 0.94 ppm and 0.97 ppm.
Figure 6.4.32. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 4.5,
which shows peak of 4.2s at 230.186 (M+H2O+H)
+
.
a d
c e e b
296
Reaction of TBD with 3-Chloro-1,2-propanediol
Scheme 6.4.18. Reaction of TBD with 3-Chloro-1,2-propanediol.
General procedure A was employed. Products are tentatively identified as 4.2t and 4.2u based on
LC-QTOF spectrum.
Figure 6.4.33. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 4.6,
which show peaks of 4.2t at 196.1439 (M) and 4.2u at 214.1543 (M+H)
+
.
297
Reaction of TBD with 8-Chloro-1-octanol
Scheme 6.4.19. Reaction of TBD with 8-Chloro-1-octanol.
General procedure A was employed. Products are tentatively identified as 4.2v and 4.2w based on
LC-QTOF spectrum.
Figure 6.4.34. LC-QTOF spectrum of the crude reaction mixture for the coupling of TBD and 4.7,
which show peaks of 4.2v at 286.2097 (M+H)
+
and 4.2w at 268.2403 (M+H)
+
.
298
Reaction of 2-Aminobenzimidazole with n-Butanol
Scheme 6.4.20. Reaction of 2-Aminobenzimidazole with n-Butanol.
General procedure A was employed. Data are consistent with the known compound.
2
Figure 6.4.35.
1
H NMR spectrum of the crude reaction mixture for the coupling of 2-
aminobenzimidazole (1 equiv) and n-butanol (2 equiv) with 1 mol % C4 for 44 h. Peaks at 0.93
ppm, 1.40 ppm, 1.58 ppm, and 3.68 ppm belong to n-butanol.
e,f,g,h
a
b
c
d
299
Reaction of 2-Aminobenzimidazole with Cyclopentanol
Scheme 6.4.21. Reaction of 2-Aminobenzimidazole with Cyclopentanol.
General procedure B was employed. Data are consistent with the known compound.
2
Figure 6.4.36.
1
H NMR spectrum of the crude reaction mixture for the coupling of 2-
aminobenzimidazole (1 equiv) and cyclopentanol (2 equiv) with 1 mol % C4 for 61 h.
merges with
alcohol peaks;
only 6H belongs
to 4.9b.
300
Reaction of 2-Aminobenzimidazole with Cyclohexanol
Scheme 6.4.22. Reaction of 2-Aminobenzimidazole with Cyclohexanol.
General procedure B was employed. Data are consistent with the known compound.
2
Figure 6.4.37.
1
H NMR spectrum of the crude reaction mixture for the coupling of 2-
aminobenzimidazole (1 equiv) and cyclohexanol (2 equiv) with 1 mol % C4 for 61 h.
merges with
alcohol peaks;
only 3H belongs
to 4.9c.
301
a
Reaction of 2-Aminobenzimidazole with Benzyl Alcohol
Scheme 6.4.23. Reaction of 2-Aminobenzimidazole with Benzyl Alcohol.
General procedure A was employed. Data are consistent with the known compound.
2
Figure 6.4.38.
1
H NMR spectrum of the crude reaction mixture for the coupling of 2-
aminobenzimidazole (1 equiv) and benzyl alcohol (2 equiv) with 1 mol % C4 for 44 h.
302
Reaction of Guanidine 4.15 with Benzaldehyde
Scheme 6.4.24. Reaction of Guanidine 4.15 with Benzaldehyde.
In the drybox, a 1-dram vial was charged with guanidine substrate 4.15 (1 equiv) and
benzaldehyde (2 equiv). The vial was sealed, taken out of the glovebox, and heated to 110 °C. The
solution turned to orange/brown color. After 44 h, the reaction mixture was allowed to cool to
room temperature. Mesitylene was added to this reaction mixture as an internal standard, and an
aliquot was taken for
1
H NMR and LC-QTOF analysis in deuterated dimethyl sulfoxide.
The product is tentatively identified as 4.21 based on LCQTOF spectrum.
Figure 6.4.39.
1
H NMR spectrum of the crude reaction mixture for the coupling of 4.15 (1 equiv)
and benzaldehyde (2 equiv).
a
b
c
303
Figure 6.4.40. LC-QTOF spectrum of the crude reaction mixture for the coupling of 4.15 and
benzaldehyde, which shows peak of 4.21 at 202.101 (M).
Reaction of Guanidine 4.19 with Benzyl Alcohol
Scheme 6.4.25. Reaction of Guanidine 4.19 with Benzyl Alcohol.
General procedure A was employed. Products are tentatively identified as 4.22 and 4.23 based on
LC-QTOF spectrum.
304
Figure 6.4.41. LC-QTOF spectra of the crude reaction mixture for the coupling of 4.19 and benzyl
alcohol, which show peaks of 4.22 (left) at 198.1296 (M+Li)
+
and 4.23 (right) at 288.1758
(M+Li)
+
.
Reaction of Guanidine 4.20 with Benzyl Alcohol
Scheme 6.4.26. Reaction of Guanidine 4.20 with Benzyl Alcohol.
General procedure A was employed. Product is tentatively identified as 4.24 based on LC-QTOF
spectrum.
305
Figure 6.4.42. LC-QTOF spectrum of the crude reaction mixture for the coupling of 4.20 and
benzyl alcohol, which shows peak of 4.24 at 302.1685 (M+H)
+
.
Reaction of Guanidine 4.20 with Ethylene Glycol
Scheme 6.4.27. Cyclization of Guanidine 4.20 with Ethylene Glycol.
General procedure B was employed. Product is tentatively identified as 4.31 based on LC-QTOF
analysis and NMR spectrum.
306
Figure 6.4.43.
1
H NMR spectrum of the crude reaction mixture for the coupling of 4.20 (1 equiv)
and ethylene glycol (5 equiv).
Figure 6.4.44. LC-QTOF spectrum of the crude reaction mixture for the coupling of 4.20 and
ethylene glycol, which shows peak of 4.31 at 238.1365 (M+H)
+
.
ethylene glycol peak
mesitylene
peak
307
Reaction of Guanidine 4.20 with 1,3-Propanediol
Scheme 6.4.28. Cyclization of Guanidine 4.20 with 1,3-Propanediol.
General procedure B was employed. Product is tentatively identified as 4.34 based on LC-QTOF
analysis and NMR spectrum.
Figure 6.4.45.
1
H NMR spectrum of the crude reaction mixture for the coupling of 4.20 (1 equiv)
and 1,3-propanediol (5 equiv).
merges with
diol peak
308
Figure 6.4.46. LC-QTOF spectrum of the crude reaction mixture for the coupling of 4.20 and 1,3-
propanediol, which shows peak of 4.34 at 252.1515 (M+H)
+
.
309
6.4.3. References
1. Bell, J. R.; Luo, H.; Dai, S. Tetrahedron Lett., 2011, 52 (29), 3723-3725.
2. Li, F.; Kang, Q.; Shan, H.; Chen, L.; Xie, J. Eur. J. Org. Chem. 2012, 2012 (26), 5085-
5092.
Abstract (if available)
Abstract
Formation of C-N bonds is a quintessential transformation in organic synthesis. Most of the biologically active compounds and natural products contain C-N bond. This thesis focus hydrogen-borrowing (HB) catalysis, a green, atom economic and cost-effective approach for C-N bond formation through amine alkylation.
First chapter is devoted to the comparison of HB with different classical and modern C-N bond forming reactions, its applications, and review of discovery, application, and mechanism of a HB ruthenium complex from our lab.
Chapter 2 describes development of a tandem Pictet-Spengler reaction condition for the synthesis of tetrahydro-β-carbolines from alcohols and N-benzyltryptamine. The use of a base free hydrogen borrowing catalyst for N-alkylation of amines, and a lewis acid catalyst In(OTf)3 for the cyclization helped to develop a tandem approach for the first time by combining acid catalyzed and base catalyzed reaction. This method provides the desired products with benzylic alcohols and heterocycles in good yield under mild conditions. Aliphatic alcohols also can be synthesized with the aid of styrene as a hydrogen acceptor in moderate to good yield. Mechanistic studies suggest that In(OTf)3 acts as a dehydrating agent, and can be replaced by MgSO4. This also shows that the secondary amines to corresponding imines conversions are prohibitively slow; whereas, the oxidation of alcohols to aldehydes and its reactions with secondary amines are fast.
Although synthesis of piperazines, 6-membered diazacycles, is well explored, catalytic routes to analogues seven-membered diazepanes are undeveloped. Chapter 3 describes development of a method to access those 1,4-diazacycles, privileged motifs in drug discovery, by a ruthenium catalyzed diol-diamine coupling. Our conditions tolerate different amines and alcohol groups that are relevant to key medicinal platforms: we show that our method enables synthesis of an FDA-approved drug cyclizine, an anti-nausea agent, and seven-membered homochlorcyclizine, an antihistamine, respectively in 91% and 67% yields. The uniqueness of our catalyst is demonstrated by screening common hydrogen borrowing scaffolds that fail in this transformation. We show that a challenge to successful catalysis in this reaction is the chelating reactivity of diamines that can poison the catalyst, yet we show that while 1 is susceptible to such chelation, it maintains reactivity in the case of substituted diamines.
Chapter 4 describes a hydrogen-borrowing N-alkylation route to guanidine derivatives. Guanidines are difficult to functionalize as they possess high basicity and multiple nucleophilic centers. Broad spectrum of application of guanidine compounds in pharmaceutical industry and scarcity of methods available to functionalize them attracted us to develop a methodology for its direct alkylation. We successfully alkylated guanidines such as triazabicyclodecene and 2-aminobenzimidaole with various alcohols. Moreover, we show cyclization of guanidines with diols, a one-step method to afford imidazolines.
Chapter 5 comprise some interesting results that we observed during rection optimizations in the above three chapters along with some miscellaneous experiments we never follow up such as amine-diol coupling, N-methylation by hydrogen-borrowing, and iron catalyzed N-heterocycle synthesis.
Chapter 6 discuss experimental procedure and spectra data of the compounds synthesized in chapter 2 and 3, and 4.
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Ruthenium catalyzed hydrogen-borrowing amine alkylation reactions
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Degree Conferral Date
2023-05
Publication Date
01/20/2023
Defense Date
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