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I. Oxidation of diazo phosphonates and diazo bisphosphonates. II. NMR and crystallographic studies of bioactive semicarbazides and Schiff bases of hydroxyguanidine

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I. Oxidation of diazo phosphonates and diazo bisphosphonates. II. NMR and crystallographic studies of bioactive semicarbazides and Schiff bases of hydroxyguanidine

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Content INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. U M i films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UM I a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by sectioning the original, beginning at the upper left-hand comer and continuing from left to right in equal sections with small overlaps. ProQuest Information and Learning 300 North Zeeb Road, Ann Arbor, M l 48106-1346 USA 800-521-0600 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. I. OXIDATION OF DIAZO PHOSPHONATES AND DIAZO BISPHOSPHONATES. H. NMR AND CRYSTALLOGRAPHIC STUDIES OF BIOACTIVE SEMICARBAZIDES AND SHIFF BASES OF HYDROXYGUANIDINE. by Patricia Isabelle Bonaz A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CHEMISTRY) May 2002 Copyright 2002 Patricia Isabelle Bonaz Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 3073750 Copyright 2002 by Bonaz, Patricia Isabelle All rights reserved. ___ __® UMI UMI Microform 3073750 Copyright 2003 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UNIVERSITY OF SOUTHERN CALIFORNIA The Graduate School University Park LOS ANGELES, CALIFORNIA 90089-1695 This dissertation, w ritten b y PftTRrcrfl 6QNQg: Under the direction o f h&C.. D issertation Committee, and approved b y all its members, has been presen ted to and accepted b y The Graduate School, in partial fulfillm ent o f requirements fo r th e degree o f DOCTOR OF PHILOSOPHY o f Graduate Studies D a te May 10 . 2002______________ DISSER TA H ON COMMITTEE f A J A 'k Chairperson Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DEDICATION To the dearest persons in my life, My mother, Liliane BONAZ My husband, Doctor Stephan KRAUSE My cousins, Monique and Jean-Claude CATALA Thank you for your love, support and care, for giving me the strength and for carrying me through the process. How can I ever repay you? In loving memory of my father, Pierre BONAZ. Special thanks to Julia, Helen, Paul Zimmelman and Ceci for nurturing me during the last two months. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ACKNOWLEDGEMENTS There are no words which can described the immense feeling of gratitude I have towards USC Department of Chemistry for its continuous support over those 6 years, and especially during the last stage of my thesis work. I thank the department for allowing me to grow as a person, and develop my skills, and for giving me the opportunity to teach and forge young minds. Michele Dea, I thank you for always being there for us. Your help and support were invaluable. Your generosity and kindness are uncommon traits, keep them safe and sharp, many students will need them in the future. Jim Merritt, I am your biggest fan! I believe there is nothing you cannot accomplish with two pieces of glass and a torch. Many experiments would not have been possible without your skills. Thank you for your generosity, your understanding and your responsiveness. You have my utmost admiration. Allan Kershaw, my NMR mentor, you taught me so much over those years. Thank you for your patience and your dedication. Debating NMR questions with you was a true pleasure and always an invaluable lesson. Prof. Singer, having you as a friend is an honor. Thank you for your support, your teaching and your respect. They were very much needed and very much appreciated. 1 1 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Bruno Herreros, my compatriot and friend, thank you for bringing an attentive ear and for sharing your knowledge of computers, web-paging and networking. Marie De La Torre, you are like a mother to us, from lending an understanding shoulder to making sure we get enough sugar in our blood! Thank you for your support and kindness. Thank you, Tom and Jose. More than once I had only you to check up on me and make sure I was fine. I feel very privileged to have met and worked with graduate fellows Sandra Tomzcak, Jerainne Johnson and Ulrika Erickson. You are beautiful inside and outside. How could [ have done it without you! Through tears and laughter you carried me through it all. You are the absolute best! To all my graduate fellows, past and present: Kevin Janak, Mas Iimura, Patrick Wagner, Paul Boothe, Jim Carrick, Xuewei Liu, Irina Tsyba...Thank you for your help and friendship. Thanks to USC department of chemistry, EPRI and Biokeys Pharmaceuticals, Inc., and the NIH, for financially supporting this research. I also want to give a special “thank you” to Prof. Bau, Irina Tsyba, and Nam Ho for helping with the X-ray crystallography. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Last but not least, I thank Prof. McKenna, my advisor, and Dr. Boris Kashemirov for their help, guidance, and support throughout the whole Ph.D. experience, and for sharing their immense knowledge of chemistry. All of you, please receive my deepest and heartfelt thanks. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TABLE OF CONTENTS Page Dedication ii Acknowledgements iii List of Figures xvi List of Tables xix List of Schemes xxi List of Suppliers xxii Abstract xxiv Summary of Structures xxvi PART I: OXIDATION OF DIAZO PHOSPHONATES AND 1 DIAZO BISPHOSPHONATES Chapter 1: General Introduction 2 References 7 Chapter 2: Synthesis of a>Keto Phosphonates and ct-Keto 9 Bisphosphonates using terf-Butyl Hypochlorite 2t Introduction 9 22 Results and Discussion 13 Optimization o f the conditions fo r the synthesis o f 13 a -keto TIPMDP (3b) Synthesis o f a-keto TEPA (lb) and a-keto PAmide 20 (2b) using t-BuOCl and the “ Moisture Modification ” vi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. References 29 Chapter 3: Catalytic Oxidation of Diazo Phosphonates and 30 Diazo Bisphosphonates 3, Introduction 30 32 Results and Discussion 33 Synthesis of a-keto phosphonates and a-keto 33 bisphosphonates Catalyst effect 40 Epoxide effect 43 Rhodium (II) perfluorobutyramide-mediated O-H 47 and N-H insertion reactions on compounds Ia-3a. References 52 Chapter 4: Reactivity and Spectrophotochemical Analyses 55 of a-Keto Phosphonates and a-Keto Bisphosphonates 4, Reactivity of a-Keto Phosphonates and a-Keto 55 Bisphosphonates 4, Spectrophotochemical Analyses 59 References 65 Chapter 5: Experimental Methods 66 5, General Methods 66 Chromatography 66 Nuclear magnetic resonance spectroscopy: 67 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Infrared spectroscopy 67 Elemental analysis and mass spectrometry 67 Purification o f solvents 68 52 Synthesis and Analytical Data of the Diazo 69 Derivative Precursors NMR and IR data o f triethyl phosphonoacetate 69 (TEPA, 1) NMR and IR data o f tetraisopropyl 69 methylenediphosphonate (TIPMDP, 3) Synthesis of diethyl N,N- 70 dimethylphosphonoacetamide (PAmide, 2) Synthesis of diethyl 70 [ (ethoxyphenylphosphinyl )methvl Jphosphonate (PPP, 4) 53 Synthesis of 2-Naphthalenesulfonyl Azide, and 72 Diazo Transfer Reactions Synthesis of 2-naphthalenesulfonyl azide 72 Precautions for diazo transfer reaction and diazo 74 derivatives Synthesis o f triethyl diazophosphonoacetate 74 (diazo TEPA, la) Synthesis o f diethyl diazo-N,N- 76 dimethylphosphonoacetamide (diazo PAmide, 2a) Synthesis o f tetraisopropyl 77 diazomethylenebisphosphonate (diazo TIPMDP, 3a) V lil Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Synthesis o f diethyl 79 [ ( ethoxyphenylphosphinyl )diazomethyl Jphosphon ate (diazo PPP, 4a) 54 Synthesis of rm-Butyl Hypochlorite (r-BuOCl) and 80 Study of the Synthesis of a-Keto Phosphonates and a-Keto Bisphosphonates using r-BuOCl. Synthesis o f tert-butyl hypochlorite (t-BuOCl) 80 Preliminary studies o f the reaction o f 81 tetraisopropyl diazomethylenebisphosphonate (Diazo-TIPMDP, 3a) and t-BuOCl Typical procedure for the synthesis o f 82 tetraisopropyl carbonylbisphosphonate (a-keto TIPMDP, 3b) from diazo TIPMDP (3a) using t- BuOCl Synthesis o f dimethylaminooxalyl phosphonic acid 83 diethyl ester (a-keto PAmide, 2b) from diazo PAmide (2a) using t-BuOCl and H2 0 Reaction o f diazo PAmide (2a) with t-BuOCl and 84 HCl Reaction o f diazo PAmide (2a) with t-BuOCl and 84 2 eq. trifluoroacetic acid (CF3 COOH) Reaction o f diazo PAmide (2a) with t-BuOCl and 85 10 eq. CFjCOOH Reaction o f diazo PAmide (2a) with t-BuOCl and 86 in CHjCOOH 55 Unsuccessful Methods of Purification of a-Keto 86 TIPMDP (3b) TLC and prep-TLC on silica gel 86 Silica gel column chromatography 87 ix Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Centrifugal chromatography with silica gel rotors TLC on alumina Distillation of the mixture obtained from the reaction with t-BuOCl 56 Study of the Catalytic Synthesis of a-Keto Phosphonates and a-Keto Bisphosphonates Competition reaction between diazo PAmide (2a) and diazo TEPA (la) catalyzed by rhodium (II) perfluorobutyramide (Rh2 (NHCOC3 F7 )4 ) with 1,2- epoxyhexane. Reaction of diazo TIPMDP (3a) with rhodium (II) acetate (Rh2 (OAc)4 ) Reaction of diazo PAmide (2a) with Rh2 (OAc)4 Reaction of diazo PAmide (2a) with rhodium (II) trifluoroacetamide (Rh2 (NHCOCF3 )4 ) Synthesis and purification o f dimethylaminooxalyl phosphonic acid diethyl ester (a-keto PAmide, 2b) from diazo PAmide (2a) and rhodium (II) perfluorobutyramide (Rh2 (NHCOC3 F7 )4 ) Comparison o f the efficiency o f four oxygen donors (propylene oxide, 1,2-epoxybutane, 1,2- epoxyhexane, and styreneoxide) on diazo PAmide (2d) using Rh2 (NHCOC3 F7 )4 for catalyst. Comparison o f the efficiency o f two oxygen donors (1,2-epoxy hexane, and styrene oxide) on diazo TIPMDP (3a) using Rh2 (NHCOC3 F7 )4for catalyst. Synthesis and purification o f tetraisopropyl carbonylbisphosphonate (a-keto TIPMDP, 3b) from diazo TIPMDP (3a) and Rh2 (NHCOC3 F7 )4 88 88 88 89 90 90 91 93 93 95 95 96 x Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Synthesis and purification o f triethyl 97 phosphonoglyoxylic acid (a-keto TEPA, lb) from diazo TEPA (la) and Rh2 (NHCOCjF7 )4 Synthesis o f diethyl 99 [( ethoxyphenylphosphinyl )carbonyl Jphosphonate (a-keto PPP, 4b) from diazo PPP(4a) and Rh2 (NHCOC3 F7 )4 Synthesis o f diethyl benzoylphosphonate (5b) from 100 (diazophenylmethyl)phosphonic acid diethyl ester (5a) and Rh2 (NHCOC3 F7 )4 57 Other Catalytic Reactions with Diazo Phosphonates 102 and Diazo Bisphosphonates Typical synthesis for a-hydroxy derivatives 102 Synthesis of (dimethylcarbamoylphenylamino- 104 methyl)phosphonic acid diethyl ester (PhAmino- PAmide, 2g) Synthesis o f [(diisopropoxyphosphoryl)- 105 phenylaminomethyljphosphonic acid diisopropyl ester (PhAmino-TIPMDP, 3g) 58 Reactivity of a-Keto Phosphonates and a-Keto 107 Bisphosphonates with Water Typical reaction between a a-keto derivatives and 107 water Typical pairwise competition reaction 107 Typical reaction for the characterization o f 108 hydrate derivatives References 111 X I Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 6: General Conclusion 113 PART II: NMR AND CRYSTALLOGRAPHIC STUDIES OF BIOACTIVE ARYLSEMICARBAZIDES AND SCfflFF BASES OF AMINOHYDROXYGUANIDINE 116 Chapter 7: NMR and Crystallographyc Studies of Bioactive Arylsemicarbazides and Schiff Bases of Aminohydroxyguanidine 117 7, Introduction 117 72 Results and Discussion 121 73 Experimental Procedures 128 References 149 Bibliography 150 Appendix A: NMR Spectra 157 A, NMR Spectra of Novel Compounds 157 Diazo PAmide (2a) 157 Diazo PPP (4a) 160 a -Keto PAmide (2b) 164 a-Keto TIPMDP (3b) 167 OH-TEPA (If) 170 OH-PAmide (2f) 173 OH-TIPMDP (3f) 176 PhAmino-PAmide (2g) 179 PhAmino-TIPMDP (3g) 182 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DiOH-TEPA (Id) 185 DiOH-PAmide (2d) 188 DiOH-TlPMDP (3d) 190 A2 Chemical Shifts Comparison Between Methylene, 193 Diazo and a-Keto Derivatives. TEPA series (I, la, lb) 193 PAmide series (2, 2a, 2b) 196 TIPMDP series (3, 3a, 3b) 199 PPP series (4, 4a, 4b) 202 Aj Comparison Between 3lP NMR Chemical Shift of 203 Diazo Derivatives and Their Corresponding a- Hydroxy Adducts and PhenylAmino adducts. Appendix B: IR Spectra 206 B, IR Spectra of Novel Compounds 206 Diazo PAmide (2a) 206 Diazo PPP (4a) 207 a -Keto PAmide (2b) 208 a -Keto TIPMDP (3a) 209 PhAmino-PAmide (2g) 210 PhAmino TIPMDP (3g) 211 OH-TEPA (If) 212 OH-PAmide (2f) 213 xiii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. OH TIPMDP (3f) 214 B2 Comparative IR Spectra 215 TEPA series (1, la, lb) 215 PAmide series (2, 2a, 2b) 216 TIPMDP series (3, 3a, 3b) 217 PPP series (4, 4a) 218 B3 Comparative IR Spectra of Diazo, and a-Keto 219 Derivatives Diazo derivatives (la, 2a, 3a, 4a) 219 a-Keto derivatives (lb, 2b, 3b) 220 Appendix C: Ab Initio Calculations 221 C, Diazo Derivatives 221 Diazo TEPA methoxy analog 221 Diazo PAmide methoxy analog 224 Diazo TIPMDP methoxy analog 227 Diazo PPP methoxy analog 230 C2 a-Keto Derivatives 233 a -Keto TEPA methoxy analog 233 a -Keto PAmide methoxy analog 236 a -Keto TIPMDP methoxy analog 239 a-Keto PPP methoxy analog 242 xiv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. C3 Other Compounds 245 t-BuOCl 245 Acetone 247 Appendix D: X-Ray Crystallography 249 D, l-(2-Hydroxy-3,5-diiodobenzylidene)-4- 249 hydroxysemicarbazide (8) D, l-(l,4-benzodioxan-6-ylmethylene)semicarbazide 256 ‘(34) D3 l-(l,3-benzodioxole-5-methyleneamino)-3- 261 hydroxyguanidine Tosylate (40) xv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF FIGURES Figure 1.1 HEDP as an analog to pyrophosphate. 1.2. a-Keto bisphosphonates as potential synthons. 2.1. Effect of varying amounts of water relative to diazo TIPMDP (3a). Other conditions: r-BuOCl/3a (1.5:1); H,0/Me3 SiCl (1:5); time of reaction is 30 sec.; 1.4 ml EtOAc; temp.: 0-5 °C; 3a/H2 0 is varied from 1:1 to 1:10. 2.2. Effect of varying amounts of r-BuOCl for two different ratios of diazo TIPMDP (3a) to water. All other conditions are kept constant. 2.3. Effect of reaction time. Other conditions: 3a/water (1:3); 3a!t- BuOCl (1:1.5); Me3 SiCl/water (5:1); 1.4 mL EtOAc; 0-5 °C. 2.4. Variation of the temperature during the synthesis of a-keto TIPMDP (3b). 2.5. 3 > P{ ’H } NMR of the synthesis of 3b on a 1 g scale using the proportion determined from microscale experiments. 2.6. 3lP{ lH) NMR after the reaction of diazo TEPA (la) with 4 eq. H2 0 (relat. to la), 2 eq. /-BuOCl (relat. to la), 30 sec experiment time, 0-5 °C. 2.7. 3 IP{ 'H } NMR after the reaction of diazo PAmide (2a) with 2 eq. of H ,0 and 2 eq. of f-BuOCl (relat. to 2a), 5 min reaction time, o-io‘ °c. 2.8. 3lP{ *H } NMR of the progression of the reaction of diazo PAmide (2a) with r-BuOCl in the presence of CF3 COOH. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.9. 3lP{ ‘H} NMR of the reaction of diazo PAmide (2a) with 27 f-BuOCl in the presence of CF3 COOH and H2 0. 2.10. 3lP{'H) NMR of the reaction of diazo PAmide (2a) with 28 r-BuOCl in CH3 COOH. a) 5 min after the reaction start, b) After the reaction ended. 3.1. 3lP{ lH) NMR of the large-scale synthesis of a-keto PPP (4b). a) 35 9 hours into the reaction, b) 48 hours into the reaction, no diazo derivative is left. 3.2. 3 1 P{ *H } NMR of the large-scale synthesis of a-keto TIPMDP 38 (3b). a) Ih 30min after the reaction started, b) 7h 15min after the reaction started, c) 18h after reaction started. 3.3. Ratio of diazo PAmide (2a) over diazo TEPA (la) in the 39 competition oxidation reaction with 1,2-epoxyhexane catalyzed by Rh2 (NHCOC3 F7 )4 . Followed b y 3 1 P NMR spectroscopy. 3.4. 3 1 P{ lH) NMR of rhodium (Il)-catalyzed reaction with 2a in the 42 absence of the oxygen donor, a) 2a and Rh2 (NHCOC3 F7 )4, and b) 2a and Rh2 (OAc)4. 3.5. Rate of formation of a-keto PAmide (2b) with 4 oxygen donors. 44 3.6. Rate of formation of a-keto TIPMDP (3b) with 1,2-epoxyhexane 45 and styrene oxide. 3.7. O-H and N-H insertion reactions with water and aniline using 47 Rh2 (NHCOC3 F7 )4 . 3.8. 3 1 P{ ‘H } NMR showing the quantitative formation of 48 OH-PAmide (2f) in less than 5 min at RT. 3.9. 3 1 P {1 H ) NMR showing the quantitative transfer from diazo 51 TIPMDP (3a) to PhAmino-TIPMDP (3g). a) Before reaction, b) After reaction is completed. xvii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4.1. Independent reactions of compound lb-3b with water. 58 4.2. 3lP{ lH} 8 of compound from 1-5 series. Spectra were taken in 61 CDClj but for lc-3c, which were taken in the reaction solvent (EtOAc). Assignments for lc-3c are in agreement with lit. 6.1. Summary of the oxidative pathways available for oxidation of 113 diazo phosphonates and diazo bisphosphonates. 7.1. General structure of hydroxyurea analogs 118 7.2. Hydroxysemicarbazide structures (1-31). Numbering is shown. 119 7.3. Semicarbazide structures (32-35) and Schiff bases of 120 aminohydroxyguanidine (36-49). 7.4. X-ray crystallography, a) compound 8. b) compound 34. c) 122 compound 40. 7.5. Expected correlation between azomethine and ureido protons in 123 1D differential NOE experiments. 7.6. Irradiation sequence for compound 1. 126 7.7. Results from ID differential NOE experiments on compound 1. 127 xviii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF TABLES Table Page 3.1. Ab initio calculation results on methoxy analogs. Calculations 34 were conducted using McSpartan Plus at the Hartree-Fock level, using basis set 3-21G(’’. 3.2. Summary of the results obtained with the large-scale oxidation of 36 compounds la-4a. a 1,2-Epoxy butane was used as the oxygen donor. b Styrene oxide was used as the oxygen donor. c 1,2- Epoxyhexane was used as the oxygen donor. Time of experiments is affected by the temperature, the amount of catalyst, and the use of styrene oxide. "Evaluated from 3 1 P NMR spectra. 'Commercial anhydrous benzene was used without further purification. 3.3. Effect of the catalyst ligand in the rhodium (Il)-mediated 41 oxidation of diazo phosphonates and diazo bisphosphonates. 3.4. Stability of la-3a towards catalyst in the absence of oxygen 42 donor. 3.5. Boiling point of the oxygen donors and their reaction 43 byproducts. 3.6. O-H insertion reactions with water and Rh,(NHCOC3 F7 )4 . 47 3.7. N-H insertion reactions with aniline and Rh2 (NHCOC3 F7 )4 . 49 4.1. Electrostatic charges obtained from ab initio calculations on 56 methoxy analogs. Calculations were conducted with McSpartan Plus at the Hartree-Fock level, using basis set 3-2lG’’’. 4.2. Main IR bands (cm 1 ) for compound 1-5 (a-g). 59 4.3. 2 JH P -coupling constants (Hz) for compounds bearing hydrogen on 62 ca . xix Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4.4. Comparison of 2 JP P coupling constants (Hz) in compounds 4 ,4a, 62 4b. 4.5. C-P coupling constants (Hz). 64 7.1. Differential NOE spectroscopy. Enhancements observed at the 124 ureido and azomethine resonance. “ Spectra recorded at room temperature. b Spectra recorded at 330 K. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF SCHEMES Scheme Page 1.1. General pathway for the synthesis of a-keto phosphonates and 4 a-keto bisphosphonates. 2.1. Proposed mechanism for the decomposition of diazo 10 bisphosphonate using Regitz’s conditions. 2.2. Synthesis of carbonylbisphosphonates using r-BuOCl and the 11 “moisture modification”. 2.3. Proposed mechanism for the formation of trimer derivatives. 12 3.1. General reaction for the catalytic oxidation of diazo phosphonate 33 and diazo bisphosphonate derivatives. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LIST OF SUPPLIERS Name of Compound FW CAS number Supplier catalog # quantity 1,2-Epoxyhexane, 97% 100.16 1436-34-6 Aldrich 377171 100 g 1,2-Epoxybutane. 99% 72.11 106-88-7 Aldrich 109975 250 mL 2-Chloro-/V,/V-dimethylacetamide, purum > 98.0 % 121.57 2675-89-0 Fluka 24350 25 mL 2-Naphthalenesulfonyl chloride, 99% 226.68 93-11-8 Lancaster 8071 100 g Acetic acid GR glacial 60.05 64-19-7 EM Science AX0073-6 500 mL Aluminum oxide, activated, neutral. Brockmann I, standard grade, - 1 S O mesh, 58 A 101.96 1344-28-1 Aldrich 19,997-4 I kg Benzene 78.11 71-43-2 EM Science BX0220-6 500 mL Benzene, anhydrous 78.11 71-43-2 Aldrich 40.176-5 1 L Chlorobenzene, 99.8% anhydrous 112.56 108-90-7 Aldrich 284513 1 L Chloromethylphosphonic dichloride, 97% 167.36 1983-26-2 Aldrich C56255 10 g Chlorotrimethylsilane, 99+% redistilled 108.64 75-77-4 Aldrich 386529 100 mL Diethyl (chloromelhyl)phosphonale, 97% 186.57 3167-63-3 Acros AC330650050 5g Diethyl benzoylphosphonate, 97% 242.22 3277-27-8 Aldrich 44,879-6 10 g Diethyl phenylphosphonite, 99% 198.20 1638-86-4 Acros AC 165260050 5g xxii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Ethyl Acetate 88.11 141-78-6 Mallinckrodt 4992 4 L Heptafluorobutyramide, 97% 213.06 662-50-0 Lancaster 0736 50 g Hydrochloric acid, 37 % (ACS reagent) 36.46 7647-01-0 Aldrich 258148 500 mL Potassium rm-butoxide 112.22 865-47-4 Fluka 60098 100 g Propylene oxide 58.08 75-56-9 EM Science EM-12492-30 1 L p-Toluene-sulfonhydrazide, 97% 186.23 1576-35-8 Aldrich 13,200-4 25 g Rhodium (II) acetate dimer, 99% 441.99 15956-28- 2 Strem Chemicals 45-1730 2 g Silica Gel 150. 60-200 mesh (75- 250 micron) 112926- 00-8 Mallinckrodt 6551 250 g Sodium azide, 99% 65.01 26628-22- 8 Lancaster 13716 100 g Styrene oxide, 97% 120.15 96-09-3 Aldrich S5006 100 g Tetraisopropyl methylenediphosphonate 344.33 1660-95-3 Albright & Wilson Americas, Inc. Toluene 92.14 108-88-3 Mallinckrodt 8608 1 L Toluene, 99.8% anhydrous 92.14 108-88-3 Aldrich 24,451-1 1 L Triethyl phosphite, 98% 166.16 122-52-1 Aldrich T6,120-4 100 mL Triethyl phosphonoacetate 224.19 867-13-0 Albright & Wilson Americas, Inc. Trifuloroacetic acid, 99+%, redistilled 114.02 76-05-1 Aldrich 29,953-7 100 g xxiii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ABSTRACT Part I: a-Keto bisphosphonates are of interest due to their actual and potential biological activity, but practical routes to an important class of related synthons, carbonylbisphosphonate esters, have only recently become available. This work compares and extends the scope of two previously reported methods for oxidation of a-diazo phosphonate esters: a) oxidation by /-BuOCl using the “moisture modification”; and b) Rh2 L4 -mediated oxygen transfer from an epoxide. Five types of a-diazo phosphonate ester substrates were evaluated: (RO)2 P(0)C(N2 )R \ R = Et and R’ = Ph (5a), C 0 2 Et (la) or QCDNMe,. (2a); (R0)2 P(0)C(N2 )P(0)(0R)(R’), R = /Pr, R’ = /PrO (3a) and R = Et, R’ = Ph (4a). Method (a) readily afforded lb, but required modification to obtain 2b as the major product. Method (b) provided all five products Nb, including distilled, analytically pure 3b. Diazo reactivity depended on the Rh ligand (L = NHC(0)C3 F7 ~ NHC(0)CF3» OCOCH3 ) and substrate structure (2a > la > 3a). For 2a, conversion to 2b was also significantly accelerated by replacing the standard 1,2-alkane oxide [O] donor with styrene oxide. The relative reactivity of the ketones lb, 2b and 3b towards H2 0 was lb > 3b > 2b. In addition to the C=N2 -> C=0 transformation described above, la-3a underwent Rh,(NHC(0)C3 F7 )4 -mediated N-H and O-H a-C insertion reactions with aniline and H2 0 , respectively. xxiv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. P art II: 'H and 1 3 C NMR studies were conducted on a series of Schiff bases prepared (in the laboratory of Prof. E. J. Lien, USC School of Pharmacy ) via reaction of aromatic or heterocyclic aldehydes with various semicarbazide, hydroxysemicarbazide and aminohydroxyguanidine derivatives. Forty-four of the compounds have been included in QSAR studies (Lien group) for antineoplastic activity. In addition to providing necessary structural characterization data, the NMR work reported here includes ID differential NOE results consistent with an E configuration at the imine C=N bond for every compound. To confirm this assignment, single crystal X-ray crystallographic data were obtained for one representative from each compound class. xxv Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. SUMMARY OF STRUCTURES* Methylene derivatives 0 EtO^II E.O-P' o I ! ~C—OEt C— N Triethyl phosphonoacetate (TEPA) CAS RN: 867-13-0 Diethyl N,N-dimethylphosphonoacetamide (PAmide) CAS RN: 3842-86-2 /-Pr-Ov /-Pr-O' O-z-Pr '0-/-Pr O O EtO. 1 1 ___ I I .OEt EtO 4 Ph Tetraisopropyl methylenediphosphonate (TIPMDP) CAS RN: 1660-95-3 Diazo-derivatives Diethyl [(ethoxyphenylphosphinyl)methyl|- phosphonate (PPP) CAS RN: 81073-28-1 O - EtO' 2 o I I c— OEt 1a Triethyl diazophosphonoacetate (Diazo TEPA) CAS RN: 17507-56-1 O ^2 o EtO. I I U I I Me EtO 2fl Me (Diazodimethylcarbamoylmethyl)- phosphonic acid diethyl ester (Diazo PAmide) O [Jz O /-Pr-O. I I 1 1 I I .O-i-Pr ^ P -'-'^ P C /-Pr-0 3a 0-/-Pr Tetraisopropyl diazomethylenebisphosphonate (Diazo TIPMDP) CAS RN: 150542-76-0 O O Eto- | l X ^ OEt EtO^ 4a Ph [Diazo(ethoxyphenylphosphinoyl)methyl|- phosphonic acid diethyl ester (Diazo PPP) * The current IUPAC nomenclature requires the use of “bisphosphonate” in place of the former “diphosphonate”. In this thesis, the earlier nomenclature remains in use for common compounds. In addition, Autoname-generated names were used for novel compounds. xx vi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Ketone derivatives EtO, EtO' O 9 O II I I I I —^'""C—OEt 1b Triethyl phosphonoelyoxylic acid (a-Keto TEPA) CAS RN: 16540-25-3 o 9 o /-Pr-O^II__JLjl^O-/-Pr /-Pr-O' 3b '0-/-Pr EtO. EtO' ° ? \ ° J 1 J L 1 1 2b .Me Me Dimethylaminooxalylphosphonic acid diethyl ester (a-Keto PAmide) EtO. EtO' o 9 o ii I I ii D-— O'" 4b .OEt Ph Tetraisopropyl carbonylbisphosphonate (a-Keto TIPMDP) CAS RN: 161063-26-9 Dichloro derivatives C l O EtO. I I > EtO O I I C—OEt C l 1c Triethyl EtO. EtO O C l C l 2c (Ethoxyphenylphosphinoanecarbonyl)- phosphonic acid diethyl ester (a-Keto PPP) O II •c— n; .Me ‘Me (DiCl-TEPA) CAS RN: 5823-12-1 Hydrate derivatives ester (DiCl-PAmide) /-Pr-O, /-Pr-O' O I I : p' C l C l 3c „0-/-Pr 'O-Z-Pr (Dichlorodimethylcarbamoyl- dichlorophosphonoacetate methyl)phosphonic acid diethyl [Dichloro(diisopropoxy- phosphory I) methyl) - phosphonic acid diisopropyl ester (DiCl-TIPMDP) CAS N: 10596-22-2 O EtO,, I I OH O I I C —OEt OH Id Triethyl dihydroxy phosphonoacetate (DiOH-TEPA) Beil. RN: 6923855 EtO, EtO' O OH O II c - n ; o h 2d .Me 'Me (Dimethylcarbamoyldihydroxy- methy 1 ) phosphonic acid diethyl ester (DiOH-PAmide) /-Pr-O. /-Pr-O' O : p- OH OH 3d i / O-i-Pr '0-/-Pr Tetraisopropyl dihydroximethylene diphosphonate (DiOH-TlPMDP) CAS RN: 252664-00-9 x x v ii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Dimers and Trimer Derivatives O O O O EtOvJ I II EtO. II II ^Me ^ P —O. X - O E t / P — / C —< EtO EtO Me 0 = P — OEt 0 = P — OEt I I OEt OEt 1e 2e (Dimer-TEPA) (Dimer-P Amide) Hydroxi derivatives /-Pr-O /-Pr-O' \ P—O- K „0-/'-Pr O-z-Pr 0 = P — 0-/-Pr I 0-/-Pr 3e (Trimer-TIPMDP) EtO. EtO' O ? H0 C—OEt Ethyl 2-(diethoxyphosphoryl)- 2-hydroxyacetate (OH-TEPA) Beil. RN: 7024104 EtO. EtO' O I I : p - OH o II C- -N Me 'Me 2f (Dimethylcarbamoylhydroxy methyl) phosphonic acid diethyl ester (OH-PAmide) [(Diisopropoxyphosphoryl) hydroxymethyl) phosphonic acid diisopropyl ester (OH-TIPMDP) xxviii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Phenvlamino derivatives r ^ EtO. EtO' O ^H0 'C -O E t ig Ethyl 2-phenylamino- 2-diethylphosphonoacetate (PhAmino-TEPA) Beil. RN: 6658413 E t o J f l ^ J i ? Me c — n cT EtO Me 2g (Dimethylcarbamoylphenylamino methyl) phosphonic acid diethyl ester (PhAmino-PAmide) o VHo /-Pr-O. 1 1 I H/O-z-Pr P— — P /-Pr-O^ ^O -i-P r 3g [(Diisopropoxyphosphoryl)phenylaminomethyll phosphonic acid diisopropyl ester (PhAmino-TIPMDP) Simple phosphonate derivatives Phosphite derivatives EtO. EtO' fl ff2 / = 5a ^ / / (Diazopheny Imethy 1 ) phosphonic acid diethyl ester CAS RN: 19734-13-5 EtO. EtO' 11 5b ^ 0 Diethyl benzoylphosphonate CAS RN: 3277-27-8 O EtO. 1 1 / P — H EtO 6 Diethyl phosphite (DiEt-Phosphite) CAS RN: 762-04-9 /-Pr-O. /-Pr-O' :1 h Phosphonic acid diisopropyl ester (Di'Pr-Phosphite) CAS RN: 1809-20-7 XXIX Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PARTI OXIDATION OF DIAZO PHOSPHONATES AND DIAZO BISPHOSPHONATES Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter I GENERAL INTRODUCTION Since the discovery of hydroxyethylidenediphosphonic acid (HEDP, Figure 1.1) and the use of its disodium salt (Etidronate) in medicine, the field of diphosphonates (currently referred to as bisphosphonates) chemistry has flourished'. This class of derivatives can be regarded as analogs of pyrophosphates (Figure 1.1), which regulate Ca2 + metabolism at the cellular level" 3 . In bisphosphonates, the P-O-P bonds are replaced by the less labile P-C-P linkage. Currently, bisphosphonates are the most widely used anti-resorptive agent with an increasing number of compounds in this class presenting potential applications in osteoporosis4 , Paget’s disease and other bone-related diseases3 -5 -6 - 7 Bioactive moiety P— OH k Bone Hook HEDP R = Me Pyrophosphate Figure 1.1. HEDP as an analog to pyrophosphate. 2 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Their biological activity is associated with two principal features: 1) the “bone-hook” functionality, which is responsible for the chelation of bone minerals, especially calcium ions8 ,9, and 2) the bioactive moiety (R) which is believed to modulate the anti-resorptive potency of the drug10". Our interest in a-keto bisphosphonates (Figure 1.2) is to provide access to a new class of bisphosphonates that possesses a versatile function on the a-carbon1 2 . Those compounds are potential synthons for a variety of derivatives not only in the class of Etidronate (a-hydroxy-a-alkyl derivatives) but also derivatives such as a-amino bisphosphonates and other nitrogen-containing bisphosphonates'3 . RO RO OR OR Nu: RO \ RO' Potential nucleophiles: N u: = C, N, O, P Figure 1.2. a-Keto bisphosphonates as potential synthons. Nu I C I OH OR OR Our group previously described the synthesis of a-keto bisphosphonates by reaction of terr-butyl hypochlorite (f-BuOCl) and H2 0 with the corresponding diazo precursor1 3 . The method requires additional work to optimize and Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. generalize its application. Another class of compounds of interest possesses a P-C-C linkage. Oxidation of such compounds was previously achieved by a catalytic method that did not prove applicable to bisphosphonates1 4 . In the present study, oxidations using r-BuOCl were developed and extended to phosphonates possessing a carbonyl function in ( 3 (P-C-C linkage). In addition, a new catalytic method was developed to provide access not only to compounds in the phosphonate class but also to bisphosphonates (P-C-P linkage). R ° \ ? R P = 0 I CH2 I Y 1-4 RQ OR \ Diazo transfer P = 0 I C = N 2 I Y la - 4a Oxidation R ° \ l OR p=o I c = o I Y lb-4b 1 R = Et, Y = COOEt 2 R = Et, Y = CONMe2 3 R = iPr, Y = P(0)(0iPr)2 4 R = Et, Y = P(0)(0Et)Ph Scheme 1.1. General pathway for the synthesis of a-keto phosphonates and a-keto bisphosphonates. Two representative compounds from each class were chosen as target for this study (Scheme 1.1). Their different attributes make them unique in their class, triethylphosphonoglyoxylic acid (a-keto TEPA, lb) possesses an ester Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. moiety while dimethylaminooxalyl phosphonic acid diethyl ester (a-keto PAmide, 2b) has a basic amide function. Tetraisopropyl carbonylbisphosphonate (a-keto TIPMDP, 3b) is a classic symmetrical bisphosphonate with bulky isopropyl groups, while (ethoxyphenylphosphinoanecarbonyl)phosphonic acid diethyl ester (a-keto PPP, 4b) is unsymmetrical. All oxidative pathways required preparation of the diazo precursors (Scheme 1.1). Many attempts of oxidizing directly the methylene derivatives have been studied and failed1 - 1 6 . Compounds la-4a were synthesized by diazo group transfer from 2-naphthalenesulfonyl azide1 5 . The choice of 2-naphthalenesulfonyl azide over the commonly employed tosyl azide and other azides was driven by the nature of the diazo products (la-4a) as well as efficiency, and safety considerations. During diazo transfer reaction the resulting 2-naphthalenesulfonamide precipitates and is easily removed by filtration while compounds la-4a remain in the supernatant as the main product. The remaining traces of amide and other byproducts can be easily removed by centrifugal chromatography. 2-Naphthalenesulfonyl azide is easily synthesized from its chlorinated precursor by chloride-azide exchange1 6 . Although more costly to produce than tosyl azide, it is considered to be an effective and safer diazo transfer agent1 7 -1 8 . Triethyl phosphonoacetate (TEPA, 1) and tetraisopropyl Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. methylenediphosphonate (TIPMDP, 3) were commercially available'. Diethyl AfJV-dimethylphosphono-acetamide (PAmide, 2) and diethyl [(ethoxyphenylphosphinyl)methyl] phosphonate (PPP, 4)1 9 were prepared from Arbusov type reaction. * The author wants to thank Albright & Wilson Americas, Inc. for graciously providing those compounds. 6 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. REFERENCES 1 Ebetino, F. H.; Francis, M. D.; Rogers, M. J.; Russell, G. R. G. Rev. Contemp. Pharmacother. 1998, 9(4), 233-243. 2 Theriault, R. L.; Hortobagyi, G. N. Semin. Oncol. 2001, 25(3), 284-290. 3 Russell, G. R. G. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 144-146, 793- 820. 4 a) Harris, S. T. Osteopos. Int. 2001, 72(Suppl. 3), SI 1-S16. b) Miller, P. D. Osteopos. Int. 2001, /2(Suppl. 3), S3-S10. 5 Ebetino, F. H. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 144-146,9-12. 6 Berruti, A.; Dogliotti, L.; Tucci, M.; Tarabuzzi, R.; Fontana, D.; Angeli, A. J. Urol. 2001,166(6), 2023-2031. 7 Dunford, J. E.; Thompson, K.; Coxon, F. P.; Luckman, S. P.; Hahn, F. M.; Poulter, C. D.; Ebetino, F. H.; Rogers, M. J. J. Pharmacol. Exp. Ther. 2001, 296(2), 235-242. 8 Rogers, M. J.; Xiong, X.; Brown, R. J.; Watts, D. J.; Russell R. G.; Bayless, A. V.; Ebetino, F. H. Mol. Phamacol. 1995,47, 398-402. 9 van Beek, E. R.; Lowik, C. W.; Ebetino, F. H.; Papapoulos, S. E. Bone 1998, 23,437-442. 1 0 Geddes, A. D.; D’Souza, S. M.; Ebetino, F. H.; Ibbotson, K. J. Bone and Mineral Reseach, 1994, pp 265-306; Elsevier Publishing Co.: Amsterdam. 1 1 Rogers, M. J.; Gordon, S.; Benford, H. L.; Coxon, F. P.; Luckman, S. P.; Monkkonen, J.; Frith, J. C. Cancer 2000,88, 2961-2978. 1 2 Bonaz-Krause, P. I.; Kashemirov, B. A.; McKenna, C. E. Phosphorus, Sulfur Silicon Relat. Elem. 2002, in press. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 3 a) McKenna, C. E.; Kashemirov, B. A.; Li, Z.-M. Phosphorus, Sulfur Silicon Relat. Elem. 1999,144-146, 313-316. b) McKenna, C. E.; Kashemirov, B. A. Preparation and use o f a-keto bisphosphonates PCT Int. Appl. 2000, 28 pp., WO 0002889 (US Patent: 6,147,245, Nov. 14I h 2000). c) McKenna, C. E.; Kashemirov, B. A. Top. Curr. Chem. 2002, 220, 201-238. 1 4 a) McKenna, C. E.; Levy, J. N. J. Chem. Soc. Chem. Commun. 1989, 246-247. b) Levy, J. N. Ph.D. Dissertation, Univ. South. California, Los Angeles, CA, U.S.A., 1987. 1 5 Regitz, M.; Maas, G. Diazo compounds: properties and synthesis, 1986; Academic Press: Orlando, Florida. 1 6 Khare, A. B.; McKenna, C. E. Synthesis 1991, 5 ,405-406; This synthesis is reported in the experimental section with notes and added comments. 1 7 Hazen, G. G.; Weinstock, L. M.; Connell, R.; Bollinger, F. W. Synth. Commun. 1981, 7/(12), 947-956. 1 8 Tuma, L. D. Thermochim. Acta 1994, 243(2), 161-167. 1 9 McKenna, C. E.; Pham, P.-T. T.; Rassier, M. E.; Dousa, T. P. J. Med. Chem. 1992,35,4885-4892; Details of those methods with modifications can be found in the experimental section. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 2 SYNTHESIS OF a-KETO PHOSPHONATES AND a-KETO BISPHOSPHONATES USING TERT-BUTYL HYPOCHLORITE 2, Introduction The first oxidative pathway uses a modified version of Regitz’s method for the formation of vicinal polycarbonyl compounds'. The original method devised by Regitz yields the desired triketone by a purported “oxygen-halogen insertion” of tert-butyl hypochlorite (r-BuOCl) into the a-diazo precursor in formic acid and other solvents. The intermediate easily decomposes into the desired trioxo product under pyrolytic conditions. When applied to diazo bisphosphonate esters this method produced the corresponding carbonylbisphosphonate in poor yield. Side products were formed including a,a-dichloro derivative2 . The purported a-chloro-a-methanoate intermediate (Scheme 2.1) did not easily decompose to the desired ketone under stronger pyrolytic condition than the one used by Regitz. Scheme 2.1 presents the proposed mechanism for this transformation: as shown by ab initio calculations 9 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (appendix C) the chlorine atom in f-BuOCl carries a positive charge which can interact with the negatively polarized diazo carbon. However, it is believed that the presence of a weak acid such as formic acid will favor this interaction by facilitating the departure of rm-butanol. Scheme 2.1. Proposed mechanism for the decomposition of diazo bisphosphonate using Regitz’s conditions. The need for a nucleophile, which will not lead to the formation of stable intermediates, prompted McKenna et al.3 to modify the previous method by replacing formic acid by water. Because of the reactivity of the a-keto bisphosphonates with water, the latter was quenched at the “appropriate” time by chlorotrimethylsilane (Me3 SiCl) (Scheme 2.2). Remarkably, this “moisture modification” leads to the effective transfer of the diazo bisphosphonate derivative to the corresponding ketone at room temperature. The reaction is believed to proceed via transfer of the chlorine to the diazo carbon from the water-activated /-BuOCl, followed by loss of nitrogen and attack of H ,0 to produce the unstable a-chloro-a-hydroxy intermediate. HCOOH s - o . OOCH f-BuOH Stable —O— CH 10 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. p = o OH/H 2 0 or c ^ ^ n 2 - t-BuOH p=o p=o Cl— C—OH p=o p=o H O -C —OH ;PH x 2 2/ (CH3)3SiCI + 4 > 0 -------- ► (CH3)3SiO-Si(CH 3h + HCI Scheme 2.2. Synthesis of carbonylbisphosphonates using r-BuOCl and the “moisture modification”. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The latter spontaneously decomposes to the desired a-keto bisphosphonate with release of hydrochloric acid (HC1). The process is auto- catalytic because HCl can catalyze the whole process again by activating r-BuOCl. HCl can also compete with the water in the nitrogen-releasing step to produce the unwanted a,a-dichlorinated side product. Enough water must be present for the effective formation of the desired ketone product, however, too much water can be detrimental as the ketone-hydrate equilibrium favors the hydrate formation. Under those conditions the hydrate decomposes by releasing CO, and phosphite, which in turn reacts with the ketone to produce a trimer derivative (Scheme 2.3)3 . p RO ^.. ' C= 0 ^ 1 — - lj w. _ _ nu i w nn_D _ _ n d _ P R O ^ /^ H -^ r~ w / P — OH _ | _ -► RO— P— C— P— O p=o RO RO' P = 0 RQ/+ RO'<iR O H O RO^II I I I .OR ^ P —C—o —P < RO T OR 0 = P —OR OR O OH O RO^II I I I .OR > - C — P < RO | OR 0 = P —OR I OR Scheme 2.3. Proposed mechanism for the formation of trimer derivatives. 12 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Of course, this long-awaited success did not arrive without a few shortcomings. First, the formation of the desired product is still accompanied by the formation of a,a-dichlorinated derivative, which resist separation by distillation. Second, the high reactivity of the ketone with water (see chapter 4) produces the corresponding hydrate and subsequent decomposition products if the water is not quenched on time3 . The following work describes our efforts to optimize the previous reaction on diazo TIPMDP (3a) by trying to suppress the formation of unwanted dichlorinated product and by avoiding the decomposition of 3b by water. Then, a similar approach was used for the synthesis of lb and 2b. 22 Results and Discussion Optimization o f the conditions for the synthesis o f a-keto TIPMDP (3b) Preliminary experiments were devised on 20 mg of tetraisopropyl diazomethylenediphosphonate (3a) until the best conditions for the large-scale synthesis of the title compound were found. Trends were deduced from experiments testing the ratio of diazo derivative to water, diazo derivative to /-BuOCl and the time of reaction. The reactions were followed by 3lP NMR, and the amount of compounds were calculated from the integration of the NMR signals. 13 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 100 90 80 I 7 0 w 3 8 60 c ■ o 50 c 3 0 40 0 u a ? 30 20 10 o ■ 0 Figure 2.1. Effect of varying amounts of water relative to diazo TIPMDP (3a). Other conditions: r-BuOCl/3a (1.5:1); H2 0/Me3 SiCl (1:5); time of reaction is 30 sec.; 1.4 ml EtOAc; temp.: 0-5 °C; 3a/H2 0 is varied from 1:1 to 1:10. Figure 2.1 shows that the production of ketone remains fairly constant between 1 to 5 equivalents of water relative to the diazo derivative (3a). 10 eq. of water decrease sharply the production of the desired product by encouraging the formation of hydrate (not shown due to poor resolution in the 3,P NMR spectra, but followed by the subsequent formation of phosphite). The amount of dichlorinated side product is also increased. With this amount of water, the decomposition of the ketone becomes more predominant. Water seems to be 14 Keto TIPMDP ( 3b) DiCI-TIPMDP f3 c ) D iiP r-P hosphite (7 ) 4 — f ~ 4 - 1 2 3 4 5 6 7 8 9 E q u iv a le n t o f w a t e r r e l a ti v e t o d ia z o TIPMDP ( 3 a ) i 10 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. removed form the competition with HCl, which encourages the formation of dichlorinated product. One equivalent of water is not enough to compete with HCl and prevent the formation of 3c. Four equivalents of water achieved both maximum ketone (3b) production with minimum dichloro (3c) formation.. For the isolation of a-keto TIPMDP (3b), the presence of trimer (3e) resulting from excess water is less inconvenient than the presence of DiCl-TIPMDP (3c) resulting from the lack of water. The properties of 3e are expected to be sufficiently different from 3b to allow its separation by distillation. Keto TIPMDP (3b) (Diazo (3a)/W ater 1:3) ---------- Keto TIPMDP (3b) (Diazo (3a)/W ater 1:4) DiCl-TIPMDP (3c) (Diazo (3 a)/W ater 1 : 3 ) DiCl-TIPMDP ( 3 0 (Diazo (3 a)/W ater 1:4) 100 90.......................I ........................................................... 1 80 '• 3 = 70 O .= < * > ■ o 50 c 2 ^o Q . | 30 o se 2 0 10 o . -------------------------------- ---------------------- 4 = 1 1.5 2 2.5 3 3.5 E q u iv a len ts o f t -BuOCI r e la tiv e t o D iazo TIPMDP (3 a ) Figure 2.2. Effect of varying amounts of r-BuOCl for two different ratios of diazo TIPMDP (3a) to water. All other conditions are kept constant. 15 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Only a few tests have been performed varying the amount of /-BuOCl (Figure 2.2). Although /-BuOCl is synthesized in high purity (> 99 % )4 the main side product is Cl-,, which can interfere with the production of ketone by promoting dichloro derivative. As a general method it did not seem wise to use a large excess of this reactant and its total amount was limited to 3 equivalents. The influence of /-BuOCl on the reaction was studied at two different ratios of diazo TIPMDP (3a) to water: 1:3 and 1:4. Those experiments revealed that the amount of ketone (3b) produced vary only slightly with reasonable amounts of r-BuOCl. Three equivalents of /-BuOCl along with four equivalents of water seem to promote slightly higher amount of ketone (3b) while reducing the amount of dichloro derivative (3c) formed. A plot of the formation of the products versus the experiment time (Figure 2.3), determined by the quenching of the water, shows that the ketone forms very rapidly during the first few seconds (0-20 sec.) of reaction. The reaction is conveniently followed by observing the evolution of gas and the change of color from pale yellow to very bright yellow. The use of a slight vacuum during reaction to help eliminate HCl did not appear to reduce significantly the amount of dichlorinated derivative formed. However it was used during large-scale synthesis as a precaution. 16 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Keto TIPMDP (3b) - DiiPr-Phosphite (7) — DiCl-TIPMDP (3c) Trimer-TIPMDP (3e) 100 c o 3 O ■ o c 3 o a E o o 90 80 70 60 50 40 30 20 10 0 l£fr 0 50 100 150 200 250 300 Time o f R eaction (se c ) Figure 2.3. Effect of reaction time. Other conditions: 3a/water (1:3); 3a//- BuOCl (1:1.5); Me3 SiCl/water (5:1); 1.4 mL EtOAc; 0-5 °C. Because of the exothermicity of this reaction (Figure 2.4) the diazo mixture is always cooled below 5 °C before addition of the /-BuOCl solution. From microscale experiments, it was determined that the best conditions for the production of 3b would use 4 eq. of water and 3 eq. of /-BuOCl relative to 3a. The reaction would be quenched with 5 eq. of Me3 SiCl shortly after start (about 20-30 sec., or as determined by the cessation of evolution of gas and the change of color). 17 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 18 16 Injection o f Me3SiCI • Solution tu rn s b rig h t yellow a o • 0 10 20 30 40 50 60 70 T im e (s e c ) Figure 2.4. Variation of the temperature during the synthesis of a-keto TIPMDP (3b). Using those conditions, excellent yields were achieved on 0.250 g, 0.500 g, 1.000 g (Figure 2.5) and 2.000 g of diazo TIPMDP (3a). The proportion of a,a-dichloro derivative (3c) varies between 5 and 10 % in experiments using 0.5 to 2.00 g of starting material (3a). Albeit, high vacuum distillation of the crude mixture of a-keto TIPMDP (3b), DiCl-TIPMDP (3c), and trimer-TIPMDP (3e) did not completely separate 3b and 3c, a small improvement was observed in the early fraction suggesting that 3c possess a slightly higher boiling point than 3b. Other methods of purification based on silica gel and alumina failed (see chapter 18 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5). The reactivity of a-keto TIPMDP (3b) with water and free hydroxy provokes its decomposition on those media no matter the amount of care taken. a-Keto TIPMDP (3b) 92% Trimor-TIPMDP (3c) 3% DiCI-TIPMDP (3c) 5% A ' i 'o ' ' ' I ' ' ' 4 ' ' ' ’ Figure 2.5. 3 1 P{ ‘H) NMR of the synthesis of 3b on a 1 g scale using the proportion determined from microscale experiments. 19 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Synthesis o f a-keto TEPA (lb) and a-keto PAmide (2b) using t-BuOCl and the “Moisture Modification Although conditions were not optimized for diazo TEPA (la), it reacted in a similar manner than diazo TIPMDP (3a) (Figure 2.6). ^ ^ n n i I ■ r* . ® ( 0 rvj nj i I S £ m ^ < o o o o m oi o o o -• ~ I I I I I I • t Keio TEPA (lb) 7 4 % v DiOH-TEPA(ld) \ 4 % \ Dimer-TEPA(le) DiCl-TEPA (Ic) \ y ii c > % Dimer-TEPA(lc) 8 % \ DiEi Phosphite (6) 10 Figure 2.6. 3IP{ ‘H} NMR after the reaction of diazo TEPA (la) with 4 eq. H2 0 (relat. to la), 2 eq. r-BuOCl (relat. to la), 30 sec experiment time, 0-5 °C. 20 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DiCI-PAmide (2c) ? keto PAmide (2b) Jo T T T 40 ~ r 30 I -30 -10 Figure 2.7. 3IP{ ‘H} NMR after the reaction of diazo PAmide (2a) with 2 eq. of H ,0 and 2 eq. of t-BuOCl (relat. to 2a), 5 min reaction time, 0-10 °C. 2 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. As demonstrated in Chapter 4, a-keto TEPA (lb) is much more reactive to water than a-keto TIPMDP (3b). Not surprisingly, more decomposition product due to the reaction between lb and H2 0 is observed. Yet, the amount of DiCl- TEPA (lc) formed is very small (= 3 %). The synthesis of a-keto PAmide (2b) using the above method did not yield the corresponding ketone (2b) in quantitative yield (Figure 2.7). After the initial activation by water, the production of HC1 most probably stops the desired reaction by protonating the amide moiety. Derivative 2a transferred mostly to a compound which 3IP NMR signal appears at 9.0 ppm. This compound was believed to be either the dichlorinated derivative (2c) or maybe the a-chloro-a- /m-butoxy derivative postulated by Regitz1 . In an effort to investigate the identity of the 9.0 ppm peak, I eq. of diazo PAmide (2a) was reacted with 2 eq. of r-BuOCl and 0.6 eq. HC1 (11.9 N). After 5 min. of reaction, the 3lP NMR spectrum shows 2 main products: the 9 ppm peak (71 %) and the a-keto PAmide (2b) at -1.5 (27 %). When the solvent was evaporated and replaced by CDC13 , the proton spectrum was consistent with the dichlorinated derivative (2c) and did not show any signal for the rm-butoxide group. When diazo PAmide (2a) is dissolved in EtOAc and left in the presence of 1.2 eq. of f-BuOCl for 36 hours only small amounts of the purported 2c derivative (6.8 %, 9.0 ppm) and ketone 2b (1.4 %, -1.7 ppm) are formed initially. Addition 22 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. of another 2 eq. r-BuOCl and subsequent heating to about 50 °C for 2 hours did not yield any change to the mixture (Figure 2.8 a)). When 2 eq. of trifluoroacetic acid (CF3 COOH) are injected inside the mixture at room temperature, diazo PAmide (2a) quickly transfer to a new derivative at 6.5 ppm. After 28 min, there is no more starting material (2a) remaining in the mixture which displays the following composition: 28.1 % purported DiCl-PAmide (2c, 9.0 ppm), 47.7 % purported a-chloro-a-trifluoroacetoxy derivative (6.5 ppm), and 24.1 % a-keto PAmide (2b, -1.7 ppm) (Figure 2.8 b)). The reaction was left at room temperature for 24 h. After this time, the intermediate at 6.5 ppm transferred to the ketone peak (-1.7 ppm) while the purported DiCl-P Amide peak (9.0 ppm) remained stable (Figure 2.8 c)). The new signal at 4.6 ppm is of unknown nature, it does not display any strong P-H coupling (thus not DiEt-phosphite (6)), it increased very slowly with time and seems to come from the ketone derivative (Figure 2.8 d)). In order to increase the yield of the a-keto PAmide (2b) and decrease the amount of side products, other conditions were explored. A larger excess of CF3COOH (10 eq.) yielded the same result with the earlier and increased formation of the derivative at 4.5 ppm. Re-introducing the participation of water along with the acid did not seem to help the yield, instead the ketone engaged in the expected reaction with water to form the hydrate (2d) (Figure 2.9). 23 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Diazo PAmide (2a) / 91.7 % DiCI-PAmide (2c) '! 28.1 % \ Kcto-PAmidc (2b) 24.1 9 r \ DiCI-PAmidc (2c) ? I 6.8 % Ke to-PAmide (2b) / 1.4% T * T to 1 0 I S c) d) Kcto-PAmidc (2b) 66.2 % DiCI-PAmide (2c) ? 28.7 7c / I ' ! a \ Keto-PAmide (2b) J DiCI-PAmidc (2c) ? 29.5 % 10.8 « 59.7% * ; V 8 Figure 2.8. 3 lP{ *H} NMR of the progression of the reaction of diazo PAmide (2a) with f-BuOCl in the presence of CF3 COOH. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The reaction was performed in dry and distilled acetic acid (CH3 COOH) with l.3eq. of r-BuOCl at room temperature. Five minutes after the reaction start, the mixture had the following composition: 28 % DiCI-PAmide (2c), 43 % of the purported a-chloro-a-acetoxy intermediate (which chemical shift is more downfield at 9.1 ppm), and 29 % a-keto PAmide (2b) (Figure 2.10 a)). To activate the transfer from the intermediate to the ketone, the solvent was removed and the remaining mixture was heated at 120 °C for 1 hour (Figure 2.10 b)). Sadly, none of the attempts yielded satisfactory results in decreasing the amount of a,a-dichlorinated derivative. In the case of diazo PAmide (2a), water does not promote the conversion to the ketone derivative (2b). The replacement of water by a weak acid such as trifluoroacetic acid or acetic acid promotes the desired reaction without the production of strong acid (HC1). The acid anion is then expected to add to the diazo carbon with the concurrent release of nitrogen and form the a-chloro-a-acetate (or a-trifluoroacetate) intermediate, which in this case, transfers spontaneously to the desired ketone. Very preliminary tests of diazo PPP (4a) suggest that its reactivity towards r-BuOCl resembles diazo TIPMDP (3a). More studies are necessary to determine the role of water in this reaction. r-Butyl hypochlorite oxidations provide a mild route to a-keto phosphonates and a-keto bisphosphonates. The major inconvenience is the 25 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. concurrent formation of a,a-dichlorinated derivative, especially in the case of diazo PAmide (2a). Separation of this side product by distillation has not been possible and purifications using silica or alumina decompose the ketone derivative. Thus, this method could not be used to obtain a sample suitable for elemental analysis. 2 6 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Keio-PAm ide (2b) / .\U '* ■ DiCI-PAmidc (2c) \ 28.7 <*■ DiOII-PAmide (2d) w * \ Intermediate / .1.8 V • > 2 .2 < S . J ! cn o i m I " • — i— r 10 T ■ r 0 T r io Figure 2.9. 3,P{ ‘H) NMR of the reaction of diazo PAmide (2a) with f-BuOCl in the presence of CF3 COOH and H2 0 . 27 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Intermediate 4 3 % DiCI-PAmide (2c) \ 2 8 % \ K.eto PAmide (2b) \ 2 9 % \ A Keto PAmide F 8) r* |s §1 & (2b) 72 % DiCI-PAmide / ( 2c) / 2 8 % 8 1 I » » I 1 I I I I » I T '» I ■ I I » » I to 0 T * - to Figure 2.10. 3 lP{ 'H) NMR of the reaction of diazo PAmide (2a) with r-BuOCl in CH3 CCX)H. a) 5 min after the reaction start, b) After the reaction ended. 2 8 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. REFERENCES 1 Regitz, M.; Adolph, H. G. Justus Liebigs Ann. Chem. 1969, 723, 47-60. 2 McKenna, C. E.; Khare, A.; Ju, J.-Y.; Li, Z.-M; Duncan, G.; Cheng, Y.-C.; Kilkuskie, R. Phosphorus, Sulfur Silicon Relat. Elem. 1993, 76(1-4), 399- 402.(139-142.) 3 a) McKenna, C. E.; Kashemirov, B. A.; Li, Z.-M. Phosphorus, Sulfur Silicon Relat. Elem. 1999,144-146, 313-316. b) McKenna, C. E.; Kashemirov, B. A. Preparation and use o f a-keto bisphosphonates PCT Int. Appl. (2000), 28 pp., WO 0002889 (US Patent: 6,147,245, Nov. 14th 2000). c) McKenna, C. E.; Kashemirov, B. A. Top. Curr. Chem. 2002, 220,201-238. 4 Mintz, M. J.; Walling, C. Org. Synth., Coll. Vol. V 1973, 184-187. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. electron-rich specie to give the product and regenerate the catalyst. This catalytic cycle was first proposed by Yates6 in 1952 for the copper catalyzed decomposition of diazo compounds. Moody, Haigh and al. extensively studied the rhodium-catalyzed O-H and N-H insertion reaction on a-diazo phosphonate8 '1 0 . Their interest in intramolecular carbenoid mediated O-H insertion reaction as a route to cyclic ethers7 -8 prompted them to study the intermolecular version of this reaction9 -1 0 . They further extended their work to other X-H insertion reaction, especially N-H which provided simple access to aminophosphonate derivatives1 1 -1 2 . For the first time, they introduced the more active dinuclear rhodium catalysts: rhodium (II) trifluoroacetamide (Rh2 (NHCOCF3 )4 ) and rhodium (II) perfluorobutyramide (Rh2 (NHCOC3 F7 )4 )4 g . Previously, Paquet and Sinay1 3 had used such reaction to functionalize a protected glucose derivative by inserting the remaining primary hydroxy group into diazotrimethylphosphonoacetate using the rhodium (II) acetate (Rh2 (OAc)4 ) catalyzed reaction. The added functionality provided by O-H insertion on diazo phosphonates was also exploited by Pawlak1 4 and Woodls who independently developed the reaction using rhodium octanoate dimer. Other significant rhodium mediated reactions involving diazo phosphonates include intermolecular addition of the intermediate carbene to C=C bond1 6 , intramolecular aliphatic1 7 and aromatic1 8 C-H insertion, and oxidation of the diazo carbon1 9 . 31 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Three studies laid the foundations for our own research. In 1994, Cox, Moody et a l9 studied the insertion of 2-propanol and other alcohols in diazo compounds possessing various electron-withdrawing groups attached to the diazo carbon. Diazo TEPA (la) and tetraethyl diazomethylenebisphosphonate (an analog of our own diazo TIPMDP, 3a) were included in this study. They confirmed that the presence of a phosphonate group rendered the Rh2 (OAc)4 - catalysed insertion sluggish (thus, the temperature was raised to 110 °C), and the addition of a second phosphonate group prevented such reaction. This difficulty was overcome by using the more active Rh2 (NHCOCF3 )4 . A few years prior, McKenna and Levy1 9 demonstrated that oxidation of the diazo carbon in diazo TEPA (la) was possible using an oxygen donor such as propylene oxide and Rh2 (OAc)4 (the reaction did not proceed at room temperature but was smooth in refluxing benzene). Similarly to the result of Cox and Moody, oxidation failed with the less active diazo TIPMDP (3a). Also in 1994, the third decisive study4 g compared ligand effects in the rhodium (U)-catalyzed reactions of diazoamide. Dramatic chemoselectivity was induced by using the appropriate ligand. Rh2 (OAc)4 promotes aliphatic C-H insertion, O-H insertion, addition to alkenic and alkynic bonds, and ylide formation. However, when a perfluorocarboxamide ligand was introduced in place of the acetate ligand, aromatic C-H insertion reaction superseded all other reactions. Furthermore, Rh2 (NHCOCF3 )4 and Rh2 (NHCOC3 F7 )4 emerged as superior catalysts reducing experiment time from a 32 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. few days to a few minutes. Synthesis of the long-sought a-keto TIPMDP (3b) seemed within reach2 0 . 0 S 2 [O] (epoxide) Rh2(N HCOC3 F7) 4 o o Y Y 1 a -5 a in benzene or toluene 1 b -5 b RT. or A 1 R = Et, Y = COOEt 2 R = Et, Y = CONMe2 3 R = iPr, Y = P(0)(0iPr)2 4 R = Et, Y = P(0)(0Et)Ph 5 R - Et, Y = Ph Scheme 3.1. General reaction for the catalytic oxidation of diazo phosphonate and diazo bisphosphonate derivatives. 32 Results and discussion Synthesis o f a-keto phosphonates and a-keto hisphosphonates Oxidation of diazo compounds la-4a was achieved using rhodium (II) perfluorobutyramide and an appropriate oxygen donor (Scheme 3.1). Although diazo TEPA (la) and diazo PAmide (2a) were readily converted to the corresponding ketone (lb and 2b respectively) at room temperature, diazo TIPMDP (3a) and diazo PPP (4a) did not undergo oxidation at this temperature. The result was in agreement with Cox and Moody’s observation of decreased 33 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. reactivity of bisphosphonates9 . Thus, when the temperature was raised, the reaction proceeded smoothly towards the desired ketone in the case of 3a giving rise to the first large-scale synthesis of those types of compounds. The reaction with diazo PPP (4a) gave the keto derivative (4b) in a mixture of unknown side products. Isolation of 4b was not possible at this stage. As previously observed9 , the stability of the diazo compounds towards rhodium (Il)-catalyzed decompositions depends on the substituent attached to the diazo carbon. Carbonyl groups (C=0) can delocalize charges in a way which is impossible for phosponate (P=0) making compounds la and 2a better nucleophiles. Ab initio calculations on methoxy-analogs of our diazo derivatives (Table 3.1) shows the negative polarization of the diazo carbon. Compound Electrostatic Charge on C Electrostatic Charge on Na Electrostatic Charge Difference in C=N, la -1.09 0.76 1.85 2a -0.91 0.71 1.62 3a -1.27 0.82 2.08 4a -1.09 0.73 1.82 Table 3.1. Ab initio calculation results on methoxy analogs. Calculations were conducted using McSpartan Plus at the Hartree-Fock level, using basis set 3- 21G(* > . 34 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a) <i S I S : S § V 11 V II keto PPP b) ! ! ! !? !? ! ■ s i . JU. I * R ^ A ' i ' ’ A A' ’ it ' ' 4 ’ ~ ' ’ & Figure 3.1. 3lP{‘H} NMR of the large-scale synthesis of a-keto PPP (4b). a) 9 hours into the reaction, b) 48 hours into the reaction, no diazo derivative is left. 35 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The difficulties encountered during the synthesis of 4b are not well understood at this time. After about 9 hours, 44 % of 4a was converted to the purported ketone adduct. Decomposition products probably derived from the ketone started forming and might have been responsible for the subsequent inactivation of the catalyst. As the reaction came to a stop, more catalyst was added and more decomposition product formed. When all of the starting diazo compound was reacted, the expected product was only an estimated 20-40 % of the mixture (Figure 3.1). The distillation did not provide a clean fraction of the product, which underwent massive decomposition under the distillation conditions. Compound Rhi(NHCOCJ F7 )4 (mol %) 1 Timed Temp. (°C) Yield of conversion' Overall yield after purification Bp r c ) at 0.002 mmHg lb a 0.23 10 h + 12 h 50 + RT 85 %r 53% 58-60 2bb 0.36 5 h RT 93 % 54% 69-71 3bc 1.04 18 h 93 98% 60% 79-81 Table 3.2. Summary of the results obtained with the large-scale oxidation of compounds la-4a. a 1,2-epoxy butane was used as the oxygen donor. b Styrene oxide was used as the oxygen donor. cl,2-epoxyhexane was used as the oxygen donor. Time of experiments is affected by the temperature, the amount of catalyst, and the use of styrene oxide. "Evaluated from3 1 P NMR spectra. f Commercial anhydrous benzene was used without further purification. 36 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. In large-scale reactions, compounds 2b and 3b gave almost quantitative conversion to the corresponding ketone (monitored by 3lP NMR spectroscopy) with minimal amount of side product (Figure 3.2). After evaporation of the solvent and the excess epoxide, the product was purified and separated from the catalyst by high vacuum distillation (Table 3.2). The reactivity of diazo compound la and 2a were compared in a competitive oxidation reaction catalyzed by Rh,(NHCOC3 F7 )4 and using 1,2- epoxyhexane as the oxygen donor. The result (Figure 3.3) shows the following order of reactivity for the diazo phosphonate substituents in rhodium (II)- mediated oxidation: CONMe, > COOEt > P(0)0iPr This result agrees with previous studies on the effect of diazo substituents on the rhodium-catalyzed insertion of propanol9 . In the case of the amide derivative the charge is further dispersed due to the presence of nitrogen. A good indication of the progression of the reaction is the evolution of gas accompanying the production of the ketone, and the change of color of the reaction mixture to bright yellow. A more reddish or brownish color indicates the formation of side products. Oxidation of la and 2a is slightly exothermic. 37 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Diazo TIPMDP OH-TIPMDP Kelo TIPMDP A i" o i -io & > to ' ! -io 0 Trimer TIPMDP J O n io S ' mJ" Figure 3.2. 3 IP{ lH) NMR of the large-scale synthesis of a-keto TIPMDP (3b). a) Ih 30 min after the reaction started, b) 7h 15min after the reaction started, c) 18h after reaction started. 38 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. < C L o N ( 0 5 S 0 ) ■ o E < o. o N 1 0 1 0.8 0.6 0.4 0.2 0 80 0 20 40 100 60 Tim e (m in) Figure 3.3. Ratio of diazo PAmide (2a) over diazo TEPA (la) in the competition oxidation reaction with 1,2-epoxyhexane catalyzed by Rh2 (NHCOC3 F7 )4 . Followed b y 3 1 P NMR spectroscopy. This method proved to be effective for the oxidation of simple diazo phosphonates such as (diazophenylmethyl)phosphonic acid diethyl ester (5a). 0.33 mol% of Rh2 (NHCOC3 F7 )4 successfully converted 5a into the corresponding ketone 5b in the presence of a slight excess of 1,2-epoxybutane. Quantitative transfer was achieved in about 5 min at room temperature. 39 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Catalyst effect A dramatic ligand effect was observed when switching from the acetate to a perfluorocarboxamide ligand denoting the increased activity of the latter. Reactions previously impossible became accessible, and reactions requiring refluxing in benzene or toluene ran smoothly at room temperature. As we became aware of similar properties between Rh2 (NHCOCF3 )4 and Rh2 (NHCOC3 F7 )4 the former was abandoned because of reports of uneasy generation and purification and because of our own study which graded the activity of this catalyst towards oxidation of diazo PAmide (2a) intermediate between Rh2 (OAc)4 and Rh2 (NHCOCF3 )4 (Table 3.3). Diazo TIPMDP (3a) was confirmed inert to Rh2 (OAc)4 in an experience similar to the one ran by Levy2 1 . Compound 3a was left to react with 1,2-epoxyhexane at reflux of the benzene in presence of catalytic amount of Rh2 (OAc)4 . After 20 hours, diazo TIPMDP showed no sign of decomposition. When a small amount of Rh2 (NHCOCF3 )4 was dropped directly inside the mixture the reaction proceeded smoothly towards the desired product, and was completed after 22 hours. Although the increased reactivity due to the replacement of the acetate ligand by a perfluorocarboxamide ligand is still not understood, two arguments might be raised: 1) the presence of a more electronegative ligand might favor the interaction between the metal and the diazo 4 0 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. carbon, 2) the presence of the nitrogen in place of the oxygen in the ligand might improve the coordination with the diazo derivative. Catalyst Compound Temperature (°C) Yield Rh2 (OAc)4 la 80 >95% 2a 80 40-65% 3a 90 NR Rh2 (NHCOCF3 )4 la RT NR 2a RT NR Rh2 (NHCOC3 F7 )4 la RT >95% 2a RT >95% 3a 100 >95% 4a 100 40-60 % Table 3.3. Effect of the catalyst ligand in the rhodium (Il)-mediated oxidation of diazo phosphonates and diazo bisphosphonates. The stability of the diazo compounds (la-3a) toward both Rh2 (OAc)4 and Rh2 (NHCOC3 F7 )4 catalyst was tested in the absence of oxygen donor. Under the same condition than the one used for the oxidation reactions, all compounds showed some amount of decomposition into numerous products as shown by TLC (Table 3.4). Albeit, the rate of formation of those unwanted side products is slower, it is important to provide enough epoxide to avoid their formation. In the case of the Rh2 (OAc)4 catalyzed oxidation of compound 2a, side reactions not involving the oxygen donor compete with the oxidation and are responsible for the poor yield of conversion to the ketone 2b (40-65 %, Table 3.3). Although such side reactions have not been studied in detail and products have not been characterized, it is interesting to note that Rh2 (OAc)4 and Rh2 (NHCOC3 F7 )4 do not catalyze the same side reactions to the same extent (Figure 3.4). 41 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Catalyst Entry Temp. (°C) Time (h) % Decomp. Rh2 (OAc)4 la 85-90 20 -7 0 2a 85-90 2 100 3a 85-90 20 <3 Rh2 (NHCOC3 F7 )4 la RT 24 -5 0 2a RT 3 100 3a 85-90 20 -2 0 Table 3.4. Stability of la-3a towards catalyst in the absence of oxygen donor. b) - u > LI . . . . _JL._ i 1.. 3 ' S ■ 5 T o ------- ■ --------1 -------- r Figure 3.4. 3 1 P{ *H) NMR of rhodium (El)-catalyzed reaction with 2a in the absence of the oxygen donor, a) 2a and Rh2 (NHCOC3 F7 )4 , and b) 2a and Rh2 (OAc)4 . 42 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Epoxide effect The rhodium-catalyzed oxidation displayed some dependence on the oxygen donor. Four epoxides were used during this study: Propylene oxide which was the original oxygen donor used by Levy in the oxidation of diazo TEPA1 9 , 1,2-epoxybutane, 1,2-epoxyhexane both of which were chosen for their higher boiling points (Table 3.5), and finally styrene oxide elected for the properties of its byproduct, styrene. Oxygen donor Bp (°C) Oxygen donor byproduct Bp(“ C) Propylene oxide 34.5 Propene -47.7 1,2-Epoxy butane 63 1-Butene -6.3 1,2-Epoxyhexane 118-120 1-Hexene 64 Styrene oxide 194 Styrene 145-146 Table 3.5. Boiling point of the oxygen donors and their reaction byproducts. The efficiency of the four epoxides in transferring oxygen to a diazo compound was compared in the room temperature experiment of diazo PAmide (2a) catalyzed by Rh2 (NHCOC3 F7 )4 . The dramatic acceleration of the reaction observed when styrene oxide is attributed to the formation of the thermodynamically more stable styrene. The small differences in rates of formation of a-keto PAmide (2b) observed with the non-aromatic oxides are in agreement with increasing steric hindrance (Figure 3.5). The same phenomenon 43 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. was observed with diazo TEPA (la). Those observations suggest that the rate limiting step for la and 2a is the reaction of the Rh-carbenoid intermediate with the oxygen donor and not the formation of the Rh-carbenoid complex itself. Propylene oxide 1.2 -ep o x y b u tan e 1 ,2 -e p o x y h e x a n e ------------ S ty ren e oxide 100 « 8 0 1 2 a o 0 w 0 J £ o 4 0 20 0 200 4 0 0 6 0 0 1000 8 0 0 1200 1 4 0 0 tim e (m in .) Figure 3.5. Rate of formation of a-keto PAmide (2b) with 4 oxygen donors. A similar experiment compared the rate of formation of a-keto T1PMDP (3b) when 1,2-epoxyhexane or styrene oxide is used (Figure 3.6). Since the reaction was run at 100 °C it seemed inappropriate to use propylene oxide or 1,2- epoxybutane. After about 12 hours both reaction achieved over 95 % conversion. At higher temperature the choice of the oxygen donor does not affect the reaction 44 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. kinetics as dramatically as the room temperature experiments suggesting that, in this case, the rate limiting step is the formation of the Rh-carbenoid complex. No competition from the possible rhodium catalyzed cyclopropanation with the alkene byproduct was observed, especially with 1-hexane and styrene, which have higher boiling points. 1 ,2 - e p o x y h e x a n e ------------- S ty re n e o x ide 100 9 0 8 0 & 7 0 1 6 0 » - 50 0 ) ■* 4 0 0 u u- 0 3 0 a ? 20 10 O 100 1 5 0 5 0 200 Time (m in.) Figure 3.6. Rate of formation of a-keto TIPMDP (3b) with 1,2-epoxyhexane and styrene oxide. After those preliminary experiments, styrene oxide appeared to be the better choice for the large-scale conversion of diazo PAmide (2a) and diazo TEPA (la). Indeed, very good results were obtained for the oxidation of 45 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. compound 2a, which readily yield the a-keto adduct (2b) at room temperature. However, after concentration of the solvent, more product then expected remained inside the flask which was attributed to excess styrene oxide. During high vacuum distillation, a light clear fraction hard to control was collected (bp = 30 °C at 0.002 mmHg). When diazo TEPA (la) was converted to the desired ketone with styrene oxide, the reaction proceeded as expected and completed in about 7 hours with 0.2 mol % of Rh2 (NHCOC3 F7 )4 at room temperature. After evaporation of the solvent, again more compound than expected remained in the flask. However, this time, the residue did not distill and the color turned progressively brownish indicating that decomposition was taking place. Despite all our efforts, a-keto TEPA (lb) remained in an undistillable tar. Two factors can account for the unsuccessful purification of lb: first, styrene is a very reactive compound which can undergo spontaneous polymerization at room temperature; second, as shown in chapter 4 compound lb is more reactive than compound 2b. The last attempt to use styrene oxide, which revealed yet another feature of this particular oxygen donor, was during the large-scale synthesis of 4b. Although Figure 3.6 shows similar rate of conversion in the case of diazo TIPMDP (3a), styrene oxide pushed the very tedious diazo PPP (4a) conversion to completion. 46 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Rhodium (II) perfluorobutyramide- mediated O-H and N-H insertion reactions on compounds la-3a. Compounds la-3a underwent classic O-H and N-H insertion reactions9-1 1 2 2 in the presence of water, and aniline (Figure 3.7). All three compounds were converted to the corresponding a-hydroxy product (If - 3f) when reacted with water in the presence of Rh2 (NHCOC3 F7 )4 in EtOAc (Table 3.6). O R<X j| a HzO or Ph-NHZ O OH O NH Rh2(NHCOCjF7 ),| RO || RO. || -Y ----------------------- ► ----- -Y or P- RO _ in benzene or toluene RO _ „ RO „ « 1a-3a A If - 3f 2g-3g RT. or A 1 R = Et, Y = COOEt 2 R = Et, Y = CONMe2 3 R = iPr, Y = P(0)(0iPr)2 Figure 3.7. O-H and N-H insertion reactions with water and aniline using Rh2 (NHCOC3 F7 )4 . Compound Rh,(NHCOC3 F7 )4 (mol%) HjO (eq.) Temp. ("O Time la 1.6 mol% 2 RT < 10 min 2a 1.6 mol% 2 RT < 5 min 3a 1.5 mol% 10 115 4 days Table 3.6. O-H insertion reactions with water and Rh2 (NHCOC3 F7 )4 . 47 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 3.8. 3IP{1 H } NMR showing the quantitative formation of OH-PAmide (2f) in less than 5 min at RT. The reaction with diazo PAmide (2a) was first attempted in benzene but proved to be sluggish probably due to the insolubility of water in this solvent. It took 5 hours for the reaction to complete under those conditions (1.5 mol% 48 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. catalyst, 2 eq. water). The same reaction in EtOAc took less than 5 minutes. Reaction with 3a was more sluggish. Complete transfer was observed only after 4 days, and the use of higher temperatures (equivalent to reflux of the toluene). It is noteworthy that the same reaction at reflux of EtOAc with larger amounts of catalyst and water proceed extremely slowly towards the product (more than 2 weeks). Moreover, after a week, the catalyst is inactivated. All reactions gave quantitative transfer to the expected product (Figure 3.8). Aniline underwent N-H insertion reaction on 2a and 3a, giving the corresponding phenyl amino product (2g, 3g) (Table 3.7). Both reactions gave quantitative transfer to the desired product (Figure 3.9). The synthesis of PhAmino-TEPA (lg) was described using Rh2 (OAc)4 3 g ' l2 b . Compound Rh2 (NHCOC3 F7 )4 (mol%) Ph-NH2 (eq.) Temp. (°C) Time (h.) 2a 3a 1.4 mol% 2.4 mol% 5 eq. 5 eq. 85 115 1 48 Table 3.7. N-H insertion reactions with aniline and Rh2 (NHCOC3 F7 )4. The first rhodium-mediated mild oxidation of diazo phosphonates (la, 2a, 5a) is reported as well as the first rhodium-catalyzed oxidation of diazo bisphosphonate (3a) in a large-scale synthesis permitting isolation of the ketone product (3b). a-Keto bisphosphonates have long been sought in our lab and are 49 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. now accessible from readily available precursors. Also, diazo bisphosphonates undergo classic O-H and N-H insertion reactions. O-H insertion reaction from adventitious water is a side reaction to oxidation, especially with the more reactive diazo compounds. The presence of small amounts of water is a twofold inconvenience, since the ketones are known to produce the corresponding hydrates. The choice of catalyst is critical for the oxidation reaction, which suggests that further research in this area would be of interrest. The oxygen donor plays also an important role as it exercises some degree of control on the reaction. During our study two other accounts of rhodium- mediated oxidation were reported in the literature. The first one is a patent accepted in 19992 3 , which described the oxidation of ot-diazolactam using various epoxides as oxygen donor and a variety of rhodium (II), rhenium (V) and (VI), and copper (I) and (II) catalysts. Amongst the rhodium catalyst used were rhodium acetate dimer, rhodium octanoate dimer and rhodium pivalate dimer. The second study by Moody and a/.2 4 reports the oxidation of allylic and benzylic alcohols by rm-butyl hydroperoxide in the presence of a rhodium (II) carboxylate dimer. 50 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure 3.9. 3IP{ ‘H} NMR showing the quantitative transfer from diazo TIPMDP (3a) to PhAmino-TIPMDP (3g). a) Before reaction, b) After reaction. 51 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. REFERENCES 1 a) Doyle, K. J.; Moody, C. J. Tetrahedron 1994,50(12), 3761-3772. For reviews, see: b) Ye, T.; McKervey, M. A. Chem. Rev. 1994,94, 1091-1160. c) Shapiro, E. A.; Dyatkin, A. B.; Nefedov, O. M. Chem. Rev. 1993,62(5), 447- 472. d) Padwa, A.; Krumpe, K. E. Tetrahedron 1992,48, 5385-5453. e) Maas, G. Top. Curr. Chem. 1987, 137, 75-253. f) Doyle, M.P. Chem. Rev. 1986, 86, 919-939. 2 a) Moody C. J.; Miah, S.; Slawin, A. M. Z.; Mansfield, D. J.; Richards, I. C. Tetrahedron 1998,54,9689-9700. b) Padwa, A.; Weingarten, M. D. Chem. Rev. 1996, 96, 223-269. c) Padwa, A. Acc. Chem. Res. 1991,24, 22-. d) Padwa, A.; Hombuckle, S. F. Chem. Rev. 1991, 91, 263-309. e) Honda, T.; Ishige, H.; Tsubuki, M.; Naito, K.; Suzuki, Y. J. Chem. Soc. Perkin Trans. 1 1991, 4, 954- 955. 3 a) Davies, H. M. L.; Grazini, M. V. A.; Aouad, E. Organic Letters 2001, 3(10), 1475-1477. b) Buck, R. T.; Clarke, P. A.; Coe, D. M.; Drysdale, M. J.; Ferris, L.; Haigh, D.; Moody, C. J.; Pearson, N. D.; Swann, E. Chem. Eur. J. 2000, 6(12), 2160-2167. c) Muller, P.; Matt rejean, E. Collect. Czech. Chem. Commun. 1999,64, 1807-1826. d) Moody, C. J.; Miller, D. J. Tetrahedron 1998,54, 2257-2268. e) Moody C. J.; Miah, S.; Slawin, A. M. Z.; Mansfield, D. J.; Richards, I. C. J. Chem. Soc. Perkin Trans. 1 1998, (24), 4067-4075. f) Ferris, L.; Haigh, D.; Moody, C. J. Synlett, 1995, 921-922. g) Haigh, D. Tetrahedron 1994,50(10), 3177-3194. h) Motallebi, S.; Muller, P. Helv. Chim. Acta 1993, 76(8), 2803-2813. i) Paulissen, R.; Reimlinger, H.; Hayez, E.; Hubert, A. J.; Teyssie, Ph. Tetrahedron Lett. 1973, 24,2233-2236. 4 a) Davies, H. M. L.; Townsend, R. J. J. Org. Chem. 2001, 66,6595-6603. b) Nelson, T. D.; Song, Z. J.; Thompson, A. S.; Zhao, M.; DeMarco, A.; Reamer, R. A.; Huntington, M. F.; Grabowski, E. J. J.; Reider, P. J. Tetrahedron Lett. 2000,41, 1877-1881. c) Savinov, S. N.; Austin, D. J. Chem. Commun. 1999, (18), 1813-1814. d) Prein, M.; Manley, P. J.; Padwa, A. Tetrahedron 1997, 53(23), 7777-7794. e) Prein, M.; Padwa, A. Tetrahedron Lett. 1996,37(39), 6981-6984. f) Aller, E.; Brown, D. S.; Cox, G. G.; Miller, D. J.; Moody, C. J. J. Org. Chem. 1995,60,4449-4460. g) Brown, D. S.; Elliot, M. C.; Moody, C. J.; 52 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Mowletn, T. J.; Marino, J. P. Jr.; Padwa, A. J. Org. Chem. 1994, 59(9), 2447- 2455. 5 a) Pirrung, M. C.; Hao, L.; Morehead, A. T. Jr. J. Am. Chem. Soc. 2002,124(6), 1014-1023. b) Qu, Z.; Shi, W.; Wang, J. J. Org. Chem. 2001,66, 8139-8144. c) Pirrung, M. C.; Morehead, A. T. Jr. J. Am. Chem. Soc. 1996,118, 8162-8163. 6 Yates, P. J. Am. Chem. Soc. 1952, 74, 5376-5381. 7 Davies, M. J.; Moody, C. J.; Taylor, R. J. J. Chem. Soc. Perkin Trans. 1 1991,1, 1-7. 8 Moody, C. J.; Sie, E.-R. H. B.; Kulagowski, J. J. J. Chem. Soc. Perkin Trans. 1 1994,5, 501-506. 9 Cox, G. G.; Miller, D. J.; Moody, C. J.; Sie, E.-R. H. B.; Kulagowski, J. J. Tetrahedron 1994, 50(10), 3195-3212. 1 0 Haigh, D.; Birrell, H. C.; Cantello, B. C. C.; Hindley, R. M.; Ramaswamy, A.; Rami H. K.; Stevens, N. C. Tetrahedron: Asymmetry 1999,10(1), 1335-1352. 1 1 a) Buck, R. T.; Clarke, P. A.; Coe, D. M.; Drysdale, M. J.; Ferris, L.; Haigh, D.; Moody, C. J.; Pearson, N. D.; Swann, E. Chem. Eur. J. 2000,6(12), 2160-2167. b) Aller, E.; Buck, R. T.; Drysdale, M. J.; Ferris, L.; Haigh, D.; Moody, C. J.; Pearson, N. D.; Sanghera, B. J. J. Chem. Soc. Perkin Trans. 1 1996,24,2879- 2884. 1 2 a) Bagley, M. C.; Hind, L. S.; Moody, C. J. Tetrahedron Lett. 2000,41(35), 6897-6900. b) Ferris, L.; Haigh, D.; Moody, C. J. J. Chem. Soc. Perkin Trans. 1 1996,24, 2885-2888. 1 3 Paquet, F.; Sinay, P. Tetrahedron Lett. 1984, 25(29), 3071-3074. 1 4 Pawlak, J. L.; Berchtold, G. A. J. Org. Chem. 1987,52(9), 1765-1771. 1 5 Wood, H. B.; Buser, H.-P.; Ganem, B. J. Org. Chem. 1992,57(1), 178-184. 53 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 6 Dappen, M. S.; Pellicciari, R.; Natalini, B.; Monahan, J. B.; Chiorri, C.; Cordi, A. A. J. Med. Chem. 1991, 34( 1), 161-168. 1 7 a) Mikolajczyk, M.; Zurawinski, R.; Kielbasinski, P. Tetrahedron Lett. 1989, 50(9), 1143-1146. b) Corbel, B.; Hemot, D.; Haelters, J.-P.; Sturtz, G. Tetrahedron Lett. 1987, 28(52); 6605-6608. 1 8 a) Collomb, D.; Deshayes, C.; Doutheau, A. Tetrahedron 1996, 52(19), 6665- 6684. b) Collomb, D.; Chantegrel, B.; Deshayes, C Tetrahedron 1996, 52(31), 10455-10472. 1 9 McKenna, C. E.; Levy, J. N. J. Chem. Soc. Chem. Commun. 1989, 246-247. 2 0 McKenna, C. E.; Kashemirov, B. A. Top. Curr. Chem. 2002, 220, 201-238. 2 1 Levy, J. N. Ph.D. Dissertation, Univ. South. California, Los Angeles, CA, U.S.A., 1987. 2 2 Moody, C. J.; Sie, E.-R. H. B.; Kulagowski, J. J. Tetrahedron Lett. 1991, 52(47), 6947-6948. 2 3 Buynak, J. D.; Rao, A. S. Process for the preparation o f a-oxolactams from a- diazolactams consisting o f reaction with an oxygen donor in the presence o f a transition metal catalyst PCT Int. Appl. 1999, 23 pp., WO 9933837. 2 4 Moody, C. J.; Palmer, F. N. Tetrahedron Lett. 2002, 43, 139-141. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 4 REACTIVITY AND SPECTROPHOTOCHEMICAL ANALYSES OF a-KETO PHOSPHONATES AND a-KETO BISPHOSPHONATES 4, Reactivity of a-Keto Phosphonates and a-Keto Bisphosphonates Since a-keto TIPMDP (3b) was the first compound of its class accessible in pure form, its reactivity towards a nucleophile (H2 0 ) was investigated and compared to a-keto TEPA (lb) and a-keto PAmide (2b). The pattern of decomposition of lb-3b was first investigated independently and then compared in pairwise reactions. Figure 4.1 shows the pattern of decomposition of compounds lb-3b in independent but similar reaction conditions. While compound 2b and 3b require several hours to achieve 50 % transfer to the hydrate (2d, 3d resp.), compound lb transfers to Id in a matter of minutes with only 1 eq. of water. The transfer from lb to Id is almost quantitative, in addition Id decomposes only very slowly to phosphite (6). From the graphs, it is also evident 55 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. groups depolarizes the carbonyl group which achieves stability by reaction with the water. The more depolarized the carbonyl group (lb) the more unstable and reactive the ketone. Besides Id, the hydrate derivatives are very short-lived species, which decompose into the corresponding phosphites (6, 7). The phosphite undergoes nucleophilic addition on the ketone yielding a trimer derivative (3e) in the case of a-keto TIPMDP (3b)', and dimers derivatives for a-keto TEPA and a-keto PAmide (le and 2e respectively). The decomposition of a-keto TIPMDP (3b) is accelerated because 2 molecules of phosphites (7) are released for each molecule of hydrate (3d) (Scheme 2.3, chapter 2). In order to characterize further the hydrate derivatives, transfer in a deuterated solvent was achieved. It allowed for proton and carbon assignments in the case of DiOH-TEPA (Id) and DiOH-TIPMDP (3d). ‘H assignment was not possible for DiOH-P Amide (2d) due to the partial obliteration of the spectra by the water peak and the presence of other species. > 3 C assignment for 2d is tentative. Remarkably, ketones (lb - 3b) have been stored for several months under inert atmosphere without noticeable sign of decomposition. 57 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reaction of Keto-TEPA (1 b) with water 1 0 0 | 90 3 80 ° 70 £ 60 1 50 £ *o | . 30 O 20 a e io o 5 10 15 20 -K e to TEPA (1b) 25 Tim e (h ou rs) Reation o f keto PAmide (2b) with w ater D tO H > T E P A (Id) - - — - DiEt-Phosphite (6) O im er-T E P A (le) 1 0 0 90 § 80 * 5 2 70 I « ^ SO 9 40 O 30 o £ 20 10 O 20 4 Add 5 eq. H f i 80 40 Time (hours) 6 0 Add 1 eq. H jO Keto PAmide (2b) • * - DOH.PAnude (2d) • • — ■ O iE t-p n osp n ite (6) D v n e r - P A m id e ( 2 e ) 100 Reaction o f keto TIPMOP (3b) with w ater 90 | 80 2 70 | 80- g S O i 40 § 30 u £ 20 20 Add 1 eq. o fH f i 40 60 80 Time (hours) Add 1 eq. H jO Koto TIPMOP (3D) DOH-TIPMOP (3d) O P r-P hQ ipm 'e (7) rn m er TIPMOP (3e) 1 0 0 Figure 4.1. independent reactions of compound lb-3b with water. 58 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 42 Spectrophotochemical Analyses The main IR frequency bands for compounds in the series 1-5 (Table 4.2) are consistent with literature values3 3 . Note the frequency of the CN, stretch at about 2100 cm'1 . Cpd. CN, p=o c=o P-O-C OH NH la 2132 1284 1708 1025 - - 2a 2104 1264 1636 1025 - - 3a 2111 1265 - 993 - - 4a 2112 1252 - 1022 - - 5a 2079 1258 - 1018 - - lb - 1271 1739 1026 - - 2b - 1266 1658 1023 - - 3b - 1266 1665 995 - - 5b - 1257 1655 1050, 1022 - - If - 1245 1751 1040, 1027 3283 - 2f - 1263 1656 1033 3388 - 3f - 1253 - 1000 3229 - lg4 - 1240 1745 3300 2g - 1257 1656 1052, 1027 3348 3g - 1252 - 994 - 3425. 3287 Table 4.2. Main IR bands (cm 1 ) for compound 1-5 (a-g). All 3 1 P chemical shifts are comprised within 50 ppm ranging from 40 to - 10 ppm (Figure 4.2). This region is characteristic of R2 POOR’ (64-15 ppm), RPO(OR’), (37-15 ppm), (RO)3 PO (4-(-)18 ppm) and (RO)2 PHO (I l-(-) 1 ppm) groups5 . It is in agreement with the phosphinyl (PhEtOP(0)) signal of compound 4 ,4a, 4b being more downfield than the phosphonyl ((EtO)2 P(0)) signal. Polar 59 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. substituents (N2 , OH, NH, Cl, O) placed on the a carbon provoke the expected upfield shift. The effect is very marked with the ketone series (lb-5b) with an upfield shift of 22-25 ppm compared to the methylene series (1-4). Additional shielding is provided when another polar substituent is placed on the a carbon. Hence, dihydroxy (ld-3d) and dichloro (lc-3c) derivatives are upfield to the monohydroxy (lf-3f) derivatives. Compounds 4, 4a, and 4b present interesting effects: the phosphinyl moiety is slightly more affected by the presence of the diazo group on Ca than the phosphonyl moiety (upfield shift of 7.99 and 5.74 ppm respectively). The situation is reversed with the presence of the carbonyl: the phosphonyl moiety experience an upfield shift of more than twice the value of the one incurred by the phosphinyl group (16.6 and 7.4 respectively). In the proton spectra, three-bond coupling constants between phosphorus and protons in the alkoxy group were not accessible due to the high multiplicity of these protons probably caused by diastereotopic effects. Two-bond coupling constants (2 JH P ) between the phosphorus and the protons on the a-carbon were calculated (Table 4.3). The presence of a geminal hydroxy group has a shielding effect which decreases the value of the coupling constant in compounds If, 2f, and 3f compared to their methylenic counterparts (1,2, and 3). The phenylamino 60 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. group (lg, 2g, 3g) is dishielding compared to the hydroxy group (If, 2f, 3f) but give very similar coupling constants to the methylene derivatives (1, 2, 3). 1 2 3 4 1a 2a 3a 4a 5a 1b 2b 3b 4b 5b 1 f 2 f 3 f 1d 2d 3d 1c 2 c 3c *ig 2g 3g 4 0 3 0 2 0 1 0 0 -1 0 ppm Figure 4.2. 3 I P{ lH) 5 of compound from 1-5 series. Spectra were taken in CDC13 but for lc-3c, which were taken in the reaction solvent (EtOAc). Assignment for lc-3c are in agreement with lit.6 . 61 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Compound * J h p TEPA (1) 21.5 (CHi) OH-TEPA (If) 16.0 (CHOH) PhAmino-TEPA (lg)4 23.1 (CHNHPh) PAmide (2) 22.0 (CH,) OH-PAmide (2f) 9.5 (CHOH) PhAmino-PAmide (2g) 18.1 (CHNHPh) TIPMDP (3) 21.1 (CH-,) OH-TIPMDP (3f) 17.7 (CHOH) PhAmino-TIPMDP (3g) 22.2 (CHNHPh) Table 4.3. :JH P -coupling constants (Hz) for compounds bearing hydrogen on Ca. P-P coupling constants could be observed only for the unsymmetrical compounds 4 ,4a, and 4b (Table 4.4). The enhanced polarity introduced at the central carbon in 4a and 4b, increases the coupling constants in the expected order: CH: < CN-, < C=0. The decreased electron density at the central carbon going from diazo to carbonyl is also observed in the ab initio calculation presented in Table 4.1 herein and Table 3.1 chapter 3. Compound M p p ( H z ) PPP (4) 7.2 Diazo PPP (4a) 32.4 a-Keto PPP (4b) 217.6 Table 4.4. Comparison of 2 JP P coupling constants (Hz) in compounds 4 ,4a, 4b. The C-P coupling constants (Table 4.5) follow the general order1 Jcp» 2 Jcp - 3 JC P as expected. It is not unusual for 3 JC P to be larger than 2 JC P in consecutive 62 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. two- and three-bond coupling. In compound 4 and 4a, this effect is enhanced by resonance factors due to the aromatic ring. The two-bond coupling constant with the ester or amide group increases when a diazo or carbonyl group is present in the middle carbon (la, lb, 2a, 2b) but decreases if an hydroxy and phenylamino is introduced on the same carbon (If, 2g). This result reflects the inductive withdrawal (diazo/carbonyl group) or releasing (hydroxy/phenylamino group) of electron density between P and Cp . Surprisingly, the value of the one-bond C-P coupling is much greater when the carbon bears a diazo group than a carbonyl group. Electronic factors cannot account for this phenomenon, which would give a greater deshielding effect to the carbonyl as observed in the chemical shifts (the carbonyl is much more downfield). 63 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Cpd. If Jcp 2 Jcp 3 | Jcp 4J c p 1 134.0 (CHt ) 5.0 (OCH,CH3 ) 6.0 (C=0) 6.3 (OCH,CH3 ) - la 226.4 (CN2) 4.6 (OCHiCHj) 12.2 (C=0) 6.7 (OCHiCHj) - lb 183.1 (C=0) 6.1 (OCH,CHj) 78.6 (C=0) 5.7 (OCH2CH3 ) - If 154.4 (CHOH) 6 . 6 (OCH1CH3 ) 2.0 (C=0) 5.3 (OCHjCH,) - lg4 148.5 (CHNH) 7.0, 6 . 6 (OCH^CHj) - (C=0) 5.5, 5.4 (OCH2 CH3 ) 11.2 (arom-C,) - 2 133.5 (CH2 ) - (OCH,CH3 ) 5.0 (C=0) 6.0 (OCH2CH3 ) - 2a 220.1 (CN2 ) 5.0 (OCH,CH3 ) 11.3 (C=0) 6.0 (OCH,CH,) - 2b 172.2 (C=0) 6.7 (OCHiCH3 ) 65.9 (C=0) 6.1 (OCH2CHj) - 2f 154.7 (CHOH) 6 .6 , 7.2 (OCH,CH3 ) -(C =0) 6.0 (OCH2CH3 ) - 2g 152.9 (CHNH) 6.7. 7.4 (OCH,CH3 ) 3.1 (C=0) 7.2 (OCHiCHj) 8 . 8 (arom-C,) - 3 138.1 (CH:) 6 . 2 (OCH(CH3 )2 ) 6 3.9, 5.3 (O C ^ C H j)/ - 3a 205.0 (CN:) - (OCH(CH3 ):) - (OCH(CH3 )2 ) - 3b 149.5 (C=0) - (OCH(CH3 )j) - (OCH(CH3)2 ) - 3f 156.3 (CHOH) - (OCH(CH3 )2) - (OCH(CH3 )2 ) - 3g 146.8 (CHNH) - (OCH(CH3 )j) - (OCH(CH3 )2 ) 5.0 (arom-C,) - 4 134.9 (arom-C,) 134.9, 91.2 (CHi) 10.3 ( ortho-O 5.0 (OCH,CH3 ) 13.3 (meta-C) 6.5 (OCH2CH3 ) 3.2 (para-C) 4a 159.7 (arom-C,) 201.47, 133.30 (CN2 ) 10.8 {ortho-C) 6.0 (OCH2CH3 ) 14.6 (meta-C) 6.7 (OCH2CH3 ) 2.7 (para-C) Table 4.5. C-P coupling constants (Hz). 64 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. REFERENCES 1 a) McKenna, C. E.; Kashemirov, B. A.; Li, Z.-M. Phosphorus, Sulfur Silicon Relat. Elem. 1999,144-146, 313-316. b) McKenna, C. E.; Kashemirov, B. A. Preparation and use o f a-keto bisphosphonates PCT Int. Appl. 2000, 28 pp., WO 0002889 (US Patent: 6,147,245, Nov. 14I h 2000). c) McKenna, C. E.; Kashemirov, B. A. Top. Curr. Chem. 2002,220,201-238. 2 Regitz, M.; Maas, G. Diazo compounds: properties and synthesis, 1986; Academic Press: Orlando, Florida. 3 Lambert, J. B.; Shurvell, H. F.; Lightner, D. A.; Cooks, G. R. Organic Structural Spectroscopy, 1998; Prentice-Hall, Inc.: New Jersey. 4 Haigh, D. Tetrahedron 1994,50(10), 3177-3194. 5 Quin, L. D. A Guide to Organophosphorus Chemistry, 2000; Wiley Interscience: New York. 6 Vepsalainen, J.; Nupponen, H.; Pohjala, E.; Ahlgren, M.; Vainiotalo, P. J. Chem. Soc. Perkin Trans. 2 1992, 835-842. 65 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 5 EXPERIMENTAL METHODS 5, General Methods For chemicals please refer to the List of Suppliers, p. xxii. Chromatography TLCs were performed using silica gel 60 WF2 5 4 s precoated aluminum- backed sheets (20 x 20 cm) from EM SCIENCE unless alumina is specified (Aluminum oxide ISO, Neutral ^ 2 5 4 precoated (type T) aluminum-backed sheets (20 x 20 cm) from EM SCIENCE were used). TLCs were revealed under UV (254 nm) and/or in I2 chamber. Results are presented in the following format: TLC (eluent). R f ( C ompoun*i 's abbreviation)* Chromatographic columns were performed using silica gel unless otherwise specified. Centrifugal chromatography was performed on a Cyclograph from Analtech using 2 mm, 4 mm or 8 mm silica gel rotors depending on the amount of compound to be separated (follow manufacturer’s specifications). 66 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Nuclear magnetic resonance spectroscopy: NMR spectra were recorded on a Bruker AMX 500MHz. ‘H and 1 3 C NMR spectra were referenced relative to TMS, 3 1 P NMR spectra were externally referenced using 85% H3 P04 . Chemical shifts (5) are reported in ppm. When the solvent is not specified, the spectrum of the reaction mixture was recorded unlocked. Results are presented in the following format: ‘H NMR (solvent) 8 chemical shift (peak multiplicity, coupling constant, integration, shift assignment). I3 C signal assignments were further confirmed by running the proton-coupled C-13 spectra. Doubtful coupling constants were confirmed by running the same sample in a different field, a Bruker AC-250 MHz was used. Infrared spectroscopy Infrared spectra were recorded on an FT-IR spectrometer Spectrum 2000 from Perkin-Elmer. The sample was recorded neat otherwise specified using KBr crystal windows. Elemental analysis and mass spectrometry Elemental analysis were done by Galbraith Laboratories, Inc. HRMS/MS were done by the University of California at Riverside Mass Spectrometry Facility. 67 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Purification o f solvents1 : After purification, all the solvents were stored in desiccators over molecular sieves, and under inert atmosphere. Acetic Acid glacial (bp 117-118 °C) was dried over P2 0 5 (only for a few minutes since it partly reacts with the drying agent to form the anhydride), filtrated and distilled. Benzene (bp 80.1 °C) was dried over sodium at reflux, followed by two distillations under argon. 1.2-Epoxybutane (bp 63 °C) was dried over CaH, at reflux for 1 hour followed by 2 consecutive distillations under argon. 1.2-Epoxyhexane (bp 118-120 °C) was distilled twice under argon. Ethyl Acetate (bp 76-78 °C) was dried over P2 Os at reflux, followed by two consecutive distillations under argon. Propylene oxide (bp 34.5 °C) was dried over CaH2 at reflux, followed by two consecutive distillations under argon. Styrene oxide (bp 194 °C) was distilled twice under reduced pressure. Toluene (bp 110.6 °C) was dried over sodium at reflux, followed by two consecutive distillations under argon. 68 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 52 Synthesis and Analytical Data of the Diazo Derivative Precursors NMR and IR data o f triethyl phosphonoacetate (TEPA, I ) 'H NMR (CDCI3 ) 6 3.82 (m, 6H, CH3 C//2 0), 2.61 (d, 2H, 2 JH P = 21.5 Hz, P(0)C//2 C(0)), 0.99 (t, 6H, (Ctf 3 CH2 0 )2 P(0)), 0.93 (t, 3H, C //3 CH2 0C(0)). I 3 C{'H) NMR (CDC13 ) 5 164.9 (d, 2 JC P = 6.0 Hz, C=0), 61.80 (d, 2 JC P = 5.0 Hz, (CH3 CH2 0 )2 P(0», 60.61 (s, CH3 CH2 0C(0)), 33.55 (d, 'JC P = 134.0 Hz, P(0)CH2 C(0)), 15.54 (d, 2 JC P = 6.3 Hz, (CH3 CH2 0 )2 P(0)), 13.30 (s, CH3 CH2 0C (0». 3 1 P{'H} NMR (CDCI3 ) 6 20.61 (s). 3IP NMR (CDCI3 ) 5 20.61 (m). IR (cm’1 ) 2985, 2936 (m-s, CH2 , CH3 ), 1739 (vs, C=0), 1269 (broad vs, P=0, C-O-C), 1030, 968 (broad vs, P-O-C). Analytical data are in agreement with literature2,3,4,s. NMR and IR data of tetraisopropyl methylenediphosphonate (TIPMDP, 3) 'H NMR (CDC13 ) 6 4.61 (m, 4H, (CH3 )2 C/ZO), 2.21 (t, 2H, :JH P = 21.1 Hz, P(0)C//2 P(0)), 1.19, 1.18 (2d, 24H, (C//3 )2 CHO). ,3 C NMR (CDC13 ) 6 70.84 (s, (CH3 )2 CHO), 27.48 (t, lJC P = 138.1 Hz, P(0)CH2 P(0)), 23.79,23.61 (2s, (CH3 )2 CHO). 3,P{'H) NMR (CDC13 ) 6 18.08 (s). 3,P NMR (CDC13 ) 6 18.08 (tt, 2 JP H = 21.0 Hz, 3 Jph = 5.4 Hz). IR (cm 1 ) 2981, 2934, 2900 (m-vs, CH, CH2 , CH3 ), 69 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1464 (m, CH3 ), 1381 (s, iPr.), 1256 (broad vs, P=0), 993 (broad vs, P-O-C). Analytical data are in agreement with literature"6 7 8 . Synthesis o f diethyl N,N-dimethylphosphonoacetamide (PAmide, 2) In a 100 mL rb flask equipped with a condenser connected to a drying agent was placed 29.50 g (0.178 mol; 1.00 eq.) of triethyl phosphite with 28.44 g (0.234 mol; 1.31 eq.) of 2-chloro-N,N-dimethylacetamide. The mixture was slowly heated to reflux (about 160 °C) for 4 to 5 h. During the reaction, white fumes were shooting up the condenser, and the color turns from yellow/green to rust. The product (66% by 3 IP NMR) was vacuum distilled to yield 14.6 g (28%) of a colorless, somewhat viscous liquid; bp = 87-89 °C/0.002 mmHg). 'H NMR (CDCI3 ) 8 3.95 (m, 4H, CH3 C //2 0), 2.92,2.76 (2s, 3H each, N ( C 2.84 (d, :JH P = 22.0 Hz, P(0)C//2 C(0)), 1.15 (t, 6H, Ctf3 CH2 0). ,3 C{'H} NMR (CDC13 ) 8 164.14 (d, 2 JC P = 5.0 Hz, C=0), 61.84 (s, CH3 CH2 0), 37.86, 35.06 (2s, N(CH3 )2 ), 32.70 (d, 'JC P = 133.5 Hz, P(0)CH2 C(0)), 15.67 (d, 3 JC P = 6.0 Hz, CH3 CH2 0). 3 ,P{'H} NMR (CDCIj) 8 22.28 (s). 3,P NMR (CDCI3 ) 8 22.28 (m). IR (cm 1 ) 2983,2936 (m, CH3 , CH2 ), 1649 (vs, C=0), 1259 (vs, P=0), 1029 (vs, P-O-C). Analytical data are in agreement with literature9 ’1 0 Synthesis o f diethyl [(ethoxyphenylphosphinyl)methyl]phosphonate“ (PPP, 4) Diethyl phenylphosphonite was purchased from Acros (99%), and was used without further purification. Diethyl (chloromethyl)phosphonate was 70 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. usually synthesized using the method of Park1 2 . In one instance, the 97% pure commercial product from Acros was substituted and used without further purification with similar results. Noteworthy was the change of color of the reaction mixture due to the commercial diethyl (chloromethyl)phosphonate, which turns from yellow (the reactants were both clear when pure) to very dark brown during the synthesis of the title compound. Despite of the color, the 3 IP NMR spectrum of the reaction mixture was identical to the one obtained when using the synthesized and freshly distilled diethyl (chloromethyl)phosphonate. Distillation of the title compound was found to be difficult (bp = 130-132 °C/0.002 mmHg), thus centrifugal chromatography was used as the preferred method of purification. Using an EtOAc/Acetone gradient, the purification yielded a fraction over 99% pure (by 3 1 P and 'H NMR). For diazo transfer reactions we typically used a fraction over 95% pure. The yield after purification was 62%. TLC (acetone): Rf(P P P )= 0.047. 'H NMR (CDCI3 ) & 7.59 (dd, 3 JH P = 12.5 Hz, 3 Jhh = 8.0 Hz, 2H, ortho-H), 7.29 (t, IH, para-H), 7.21 (m, 2H, meta-H), 3.85, 3.71 (m, 6H, CH3 C //2 0), 2.37 (m, 2H, P(0)Ctf2 P(0)), L.04, 1.01,0.89 (t, 6H; t, 3H, C//3 CH2 0). ,3 C{'H} NMR (CDC13 ) 6 132.29 (d, 4 JC P = 3.2 Hz, para- 0 , 131.52 (d,2 JCP= 10.3 Hz, ortho-C), 128.20 (d,3 JC P= 13.3 Hz, meta-C), 130.54 (d, ‘ JC P = 134.9 Hz, arom-C,), 62.14,61.85,60.96 (3d,2 JC T = 5.0 Hz, CH3 CH2 0), 29.1 (dd, ‘ JCP= 134.9 Hz, P(0)CH2 P(0)), 16.11, 15.97, 15.84 (3d, 3 JC P = 6.5 Hz, 71 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CH3 CH2 0). 3,P{'H> NMR (CDCI3) 5 33.83 (d, :JP P = 6.0 Hz, IP, Ph(CH3 CH2 0)/>(0)), 19.73 (d, % P = 7.2 Hz, IP, (CH3 CH2 0 )2 P(0». 3,P NMR (CDCIj) 8 33.83 (large s, IP, Ph(CH3 CH2 0)P(0)), 19.73 (m, 2 JP P = 7.2 Hz, IP, (CH3 CH2 0 )2 P(0)). IR (cm 1 ) 3057, 2984,2934,2904 (m-s, CH3 , CH2 , arom-CH), 1480, 1442, 1393, 1369 (m, arom-C=C), 1249 (broad vs, P=0), 1031 (broad vs, P-O-C). NMR data are in agreement with literature1 1 . 53 Synthesis of 2-Naphthalenesulfonyl Azide, and Diazo Transfer Reactions Synthesis o f 2-naphthalenesulfonyl azide'J 2-Naphthalenesulfonyl chloride 28.30 g (0.125 mol; 1.00 eq.) in 150 mL acetone was placed in a 300 mL 3 neck rb flask equipped with a condenser, a moisture trap, a magnetic rod, and an addition funnel. Upon stirring, the solution turns brownish. In the addition funnel, 8.24 g (0.127 mol, 1.02 eq.) of sodium azide in 25 mL of distilled water was placed. This solution was added dropwise over 15 min. When the addition starts, NaCl precipitates. The mixture was stirred for 2 hours at room temperature. When the reaction was over, 125 mL of distilled water was added to the flask (the solid re-dissolves), and the mixture was transferred into a decanter. Small portions of water (about 25 mL) were added 72 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. which releases 2-naphthalenesulfonyl azide as a brownish oil. After each addition of water the lower brownish organic layer was separated until no more organic layer forms. In turn, the aqueous layer was extracted with several portions of dichloromethane. All organic fractions were pooled together and evaporated. The residue was recrystallized in 95% EtOH until clean (as shown by TLC). Recrystallization in petroleum ether is possible, it yields beautiful white needles but it is unpractical as it is time consuming, and requires large amounts of solvent (especially for dirtier fractions). Yield: 21.87 g (75%), mp 44-45 °C in agreement with literature. TLC (petroleum ether/acetone (5:1)): Rf(2 .n a p h ,h a i e „ e s U if o „ y ,c h .o rid e , = 0.62, Rf(2 - n a P h ,h a ie n e s u i! b n y i a z id e ) = °-52- This procedure can be scaled up 4 times. ‘H NMR (CDCIj) 6 8.52 (d, 4 JH H = L4 Hz, 1H, Hg ), 8.02, 7.99, 7.93,7.87 (3d, dd, 3 Jhh = 8.7 Hz, 4 Jhh = 1.9 Hz, 4H, H2JA 7), 7.70, 7.65 (2t, 3 JH H = 7.3 Hz, 2H, H5 . 6 ). I3 C NMR (CDCIj) 8 135.58, 135.10, 131.81 (O , 130.14, 129.94, 129.54, 129.41, 128.13, 128.03, 121.70 (CH). IR in nujol (cm 1 ) 2950-2850 (broad vs, arom- CH), 2125 (m, N=N=N), 1459, 1376 (vs, 0=S=0). Analytical data are in agreement with literature1 4 73 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Precautions for diazo transfer reaction and diazo derivatives Diazo transfer reactions are moisture sensitive, therefore reactants were dried overnight under dry vacuum*, toluene was dried and distilled, and all glassware was dried overnight in an oven. r-BuOK was kept inside a dry box (N2 atm.) since its purchase and was used “as is”. Diazo products were preferentially stored under inert atm. and protected from the light. Synthesis o f triethyl diazophosphonoacetate (diazo TEPA, la) A 250 mL 3 necks rb flask was equipped with a magnetic rod, a moisture trap/bubbler on the central port, an argon inlet with thermometer on one side port, and an addition funnel on the other side port. A suspension of f-BuOK (2.74 g, 24.4 mmol, l.l eq; measured in a dry box.) in 100 mL dry and dist. toluene was placed inside the flask, stirred, and cooled to ice temperature. The system was kept under argon at all times. TEPA (1) (dried, clear liquid, 4.98 g, 22.2 mmol, 1 eq.) in 15 mL dry and dist. toluene was charged in the addition funnel under flaw of argon, and added dropwise to the r-BuOK suspension (rate « 1 drop/sec.). During addition, the mixture turns milky in color and jelly-like. Due to the gel, the magnetic rod was unable to stir the mixture efficiently'. The mixture was left * Rotary evaporator connected to an oil pump and a liq. N2 trap. + Another mode of stirring is strongly recommended. 74 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. to warm up to room temperature for 30 min, after which dropwise addition (rate = 1 drop/sec.) of 2-naphthalenesulfonyl azide (5.69 g, 24.4 mmol, l.l eq., brownish liquid) in 15 mL toluene was started through the addition funnel. To help the stirring, the condenser was momentarily disconnected under flow of argon, and a stirring rod was used until the mixture liquidizes. Upon addition of 2- naphthalenesulfonyl azide, the mixture turns cloudy yellow, and the temperature rises from 20 °C to 29 °C. After the addition ended, the reaction was stirred for another hour (the reaction was followed by 3 1 P NMR), then filtered and concentrated under dry vacuum (yield: 83%). The resulting product was a straw- colored liquid. The residue was purified (99+%) by centrifugal chromatography using a hexane/EtOAc gradient. Yield 3.16 g (57%). TLC (hexane/EtOAc (1:1)): ^f(N aphlhalene-2-sulfonyl azide) — 0.81, R f(d iaz0tepai = 0.51, Rf( T E P A ) = 0.40. This procedure was successfully adapted for 20.0 g of TEPA (1). 'H NMR (CDCI3 ) 5 3.99 (q, 2H, CH3 C//2 OC), 3.92 (m, 4H, (CH3 C//2 0 )2 P), 1.09 (t, 6H, (C//3 CH2 0 )2 P), 1.03 (t, 3H, C//3 CH2 OC). ,3 C{'H} NMR (CDCI3 ) & 162.65 (d, 2 JC P = 12.2 Hz, C=0), 63.04 (d, 2 JC P = 4.6 Hz, (CH3 CH2 0 )2 P), 61.05 (s, CH3 CH2 OC), 53.01 (d, ‘JC P = 226.4 Hz, P(0)C(N2 )C(0)), 15.46 (d, 3 JC P = 6.7 Hz, (CH3 CH2 0 )2 P), 13.67 (s, CH3 CH2 OC). 3IP{'H} NMR (CDCI3 ) 6 10.78. 3IP NMR (CDCI3 ) 8 10.78 (p, 3 JP H = 8.3 Hz). IR (cm 1 ) 2987,2938 (m, CH3 , CH.J, 2132 (vs, C=N=N), 1708 (vs, 75 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. C=0), 1284 (vs, P=0, C-O-C), 1025 (vs, P-O-C). Analytical data are in agreement with literature1 3 - lS -1 6 . Synthesis o f diethyl diazo-N,N-dimethylphosphonoacetamide (diazo PAmide, 2a) r-BuOK (5.74 g, 51.2 mmol, 1.1 eq., measured in a dry box) in 200 mL dry and dist. toluene was placed in a 500 mL 3 necks rb flask equipped with a condenser and a moisture trap. The suspension was stirred, and cooled to 0 °C. PAmide (2, 10.4 g, 46.6 mmol, 1 eq.) in 30 mL dry and dist. toluene was added to the suspension, dropwise over I hour. Upon addition the mixture becomes first cloudy, then clears up. Once the addition was completed, the solution was stirred vigorously for 15 min. To the mixture was added dropwise over 30 min a solution of 2-naphthalenesulfonyl azide (brownish, 12.0 g, 51.2 mmol, 1.1 eq.) in 35 mL dry and dist. toluene. Precipitation of 2-naphthalenesulfonyl amide was observed a few minute after the start of the addition, the mixture turns yellow. After the addition ended, the reaction was stirred 30 min at 0 °C and another 30 min at room temperature. The reaction was followed by 3 IP NMR. Apparition of a reddish color is a sign of decomposition, the reaction should be stopped, filtered, and evaporated. The resulting product was an orange oil (yield 95%). The residue was purified (99+%) by centrifugal chromatography using a chloroform/acetone gradient. Excess of 2-naphthalenesulfonyl azide and other 76 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. low-polarity impurities can be selectively separated from the desired product by washing the silica gel with benzene. Yield 7.78 g (67%). TLC (chloroform/acetone (1:4)): Rfo( f t, h lta ien«.iron,i«iae) = °*87’ Rf< d ia ,o P A m id o = 0*64. Rf < P A m id e > = 0.37. This procedure was successfully adapted for 20.0 g of PAmide (2). 'H NMR (CDC13 ) 6 3.98 (m, 4H, CH3 C//2 0), 2.81 (s, 6H, N(C//3 ),), 1.15 (t, 6H, C//3 CH2 0). I 3 C{'H) NMR (CDCI3 ) 6 162.27 (d, 2 JC P = 11.3 Hz, C=0), 63.03 (d, 2 JC P = 5.0 Hz, CHjCTLO), 52.30 (d, ‘JC P = 220.1 Hz, C=N2 ), 37.08 (s, N(CH3 )2 ), 15.67 (d, 3 JC P = 6.0 Hz CH3 CH2 0). 3,P{'H} NMR (CDCI3 ) 5 13.66 (s). 3 IP NMR (CDC13 ) 8 13.66 (p, 3 JP H = 8.4 Hz). IR (cm'1 ) 2985, 2936 (s, CH3 , CHj), 2104 (vs, C=N=N), 1636 (vs, C=0), 1264 (vs, P=0), 1025 (vs, P-O-C). MS: calcd = 249 m/e; found = 249 m/e. Synthesis o f tetraisopropyl diazomethylenebisphosphonate (diazo TIPMDP, 3a) f-BuOK (7.18 g, 63.9 mmol, 1.1 eq., measured in a dry box) in 300 mL of dry and dist. toluene was placed in a 500 mL 3 necks rb flask equipped with a condenser and a moisture trap. The suspension was stirred and cooled to 0 °C. TIPMDP (3) (dried, 20.0 g, 58.0 mmol, 1 eq.) in 40 mL of dry and dist. toluene was added to the suspension, dropwise over 1 hour. Upon addition the mixture becomes first cloudy, then clears up. Once the addition was completed, the solution was stirred vigorously for 15 min. To the mixture was added 2- 77 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. naphthalenesulfonyl azide (14.9 g, 63.9 mmol, 1.1 eq., brownish) in 40 mL dry and dist. toluene, dropwise over 30 min. The solution turns yellow. Precipitation of the amide co-product was observed halfway through the addition. After addition, the reaction was stirred 30 min at 0 °C and another hour at room temperature. The reaction was followed by 3lP NMR, when completed the mixture was filtered, and concentrated under dry vacuum. The resulting crude product was 80-85% pure by ‘H/3 IP NMR. The residue was purified by column chromatography or centrifugal chromatography. Up to 10 g of product were separated at once on silica gel column using first benzene to remove 2- naphthalenesulfonyl azide, then a gradient of heptane/EtOAc (1:1 to 3:7) until elution of the desired compound (Yield = 45%, the fraction is 99% pure by lH/3,P NMR). For centrifugal chromatography a gradient heptane/acetone was used. The resolution and separation time were improved but the limiting factor was the maximum amount of compound that can be separated at once (3 to 4 g on a 8 mm rotor). The product, a yellow liquid, was obtained in a fraction over 99% pure by ‘H/3 1 P NMR (61%). TLC (heptane/acetone (7:3)): R fo sa p h ih a ic n e su ifo n y ia z id e ) = °-4> Rfidiazotipmdp) ~ 0.3, R ffnpM D P)= 0.1. *H NMR (CDClj) 6 4.72 (m, 4H, (CH3 )2 CHO), 1.33 (d, 24H, (C//3 )2 CHO). ,3C NMR (CDC13 ) 6 72.28 (broad s, (CH3 )2 CHO), 40.08 (t, lJC P = 205.0 Hz, P(0)C(N2 )P(0)), 23.85, 23.67 (2s, (CH3 )2 CHO). 3 ,P{'H) NMR (CDC13 ) 5 11.59 (s). 3 IP NMR (CDC13 ) b 11.59 (t, 78 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3 JP H = 3.7 Hz). IR (cm 1 ) 2982, 2936 (s, CHS , CH), 2111 (vs, C=N=N), 1265 (vs, P=0), 993 (vs, P-O-C). Analytical data are in agreement with literature1 5 . Synthesis o f diethyl [(ethoxyphenylphosphinyl)diazomethyljphosphonate (diazo PPP, 4a) r-BuOK (2.36 g, 21.0 mmol, l.l eq., measured in a dry box) in 86 mL dry and dist. toluene was placed in a 150 mL 3 necks rb flask equipped with a condenser, and a moisture trap. The suspension was stirred and cooled to 0 °C. PPP (4) (6.12 g, 19.1 mmol, 1.0 eq., dry) in 15 mL dry and dist. toluene was added to dropwise the suspension. Upon addition, the mixture turns yellow cloudy, then clears up and becomes bright yellow. Once the addition was completed, the solution was stirred vigorously for 15 min. To the mixture was added dropwise a solution of 2-naphthalenesulfonyl azide (4.66 g, 20.0 mmol, 1.1 eq., brownish) in 21 mL dry and dist. toluene. Precipitation of the amide co product was observed 2 to 5 min after the start of the addition, the mixture was discolored and the temperature raised 5 °C. After the addition ended, the reaction was stirred 30 min at 0 °C and another 30 min at room temperature. The reaction was followed b y 3 1 P NMR. Once completed, the reaction was filtered and evaporated. The brownish residue was purified by centrifugal chromatography using EtOAc for elution. Yield (84%, 92% pure by ‘H/3 1 P NMR). Further purification was required to obtain a fraction over 98% pure. TLC (EtOAc): 79 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. R ftdiazoppp)= 0.42. 'H NMR (CDCIj) 8 7.78 (m, 2H, ortho-H), 7.44 (tm, 1H, para- H), 7.36 (m, 2H, meta-H), 4.16-3.77 (m, 6H, CH3 C//2 0), 1.29, 1.10, 1.09 (3t, 9H, C//3 CH2 0). I3 C{'H} NMR (CDC13 ) 8 132.48 (d, 4 JC P = 2.7 Hz, para-C), 131.21 (d, 2 JC P = 10.8 Hz, ortho-C), 128.23 (d,3 JC P = 14.6 Hz, meta-C), 130.93 (d, lJC P = 159.71 Hz, arorn-C,), 62.85,62.78, 61.80 (3d,2 JC P = 6.0 Hz, CH3 CH2 0), 40.86 (dd, 'JC P = 201.47 Hz, 'JC P = 133.30 Hz, CN2 ), 15.98, 15.70 (d & broad d, 3 JC P = 6.7 Hz, CH3 CH2 0). 3 IP{'H} NMR (CDCl,) 8 25.84 (d, 2 JP P = 32.4 Hz, IP, Ph(CH3 CH2 0)P(0)), 13.99 (d, 2 JP P = 32.4 Hz, IP, (CH3 CH2 0 )2 P(0)). 3,P NMR (CDCI3 ) 8 25.84 (dm, 2 JP P = 32.4 Hz, IP, Ph(CH3 CH2 0)P(0)), 13.99 (dp, 2 JP P = 32.4 Hz, 3 Jp h = 8.0 Hz, IP, (CH3 CH2 0 )2 P(0)). IR (cm 1 ) 3061, 2986, 2938, 2909 (m, CH3 , CH2 , arom-CH), 2112 (vs, C=N=N) 1479, 1443, 1393, 1369 ( m, arom. C=C), 1252 (broad vs, P=0), 1022 (broad vs, P-O-C). 54 Synthesis of terf-Butyl Hypochlorite (1-BuOCl) and Study of the Synthesis of a-Keto Phosphonates and a-Keto Bisphosphonates using f-BuOCl. Synthesis o f tert-butyl hypochlorite (t-BuOCl) As described by Mintz and Walling1 7 . Please note that “to avoid vigorous decomposition, the product should be handled only in dim light and should not be 80 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. heated above its boiling point” (77-78 °C / 760 mm1 8 ) “or be exposed to rubber”1 7 . r-BuOCl synthesized following this procedure was 99-100 % pure. r-BuOCl was never stored for more than 1 month. Preliminary studies o f the reaction of tetraisopropyl diazomethylenebisphosphonate (diazo-TIPMDP, 3a) and t-BuOCl Experiments were conducted on about 20.0 mg of diazo TIPMDP (3a), and the ratio diazo TIPMDP/r-Bu0Cl/H2 0/Me3 SiCl was known. In a 1 ml assay vial equipped with a seal and a magnetic stirrer, 20.0 mg of dried diazo TIPMDP (3a) was measured with a 25.0 pL Hamilton syringe. 0.500 mL of an EtOAc solution containing a known amount of H2 0 was added to the vial (pale yellow). The vial was flushed with UHP argon for a few minutes, and stirred over ice 5 to 10 min. In a 0.5 mL vial equipped with a Teflon septum screw cap, a solution of r-BuOCl in 0.200 mL EtOAc containing a known amount of water was freshly prepared (pale yellow). The f-BuOCl solution was injected to the diazo TIPMDP solution. After about 2 seconds, the mixture turns bright yellow and vigorous evolution of gas was observed. After a pre-defined time, a large excess (typically 5 eq. to water) of Me3 SiCl was injected inside the solution to neutralize the water. 3IP NMR of the final mixture was recorded. 3 IP{'H} NMR 5 of typical products: 14.85 (s, DiOH-TIPMDP, 3d), 13.1 (d, trimer-TIPMDP, 3e), 7.33 (s, DiCl- 81 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TIPMDP, 3c)1 9 , 4.7 (s, DfPr-Phosphite, 7), -1.2 (t, trimer-TIPMDP, 3e), -5.91 (s, a-keto TIPMDP, 3b). Typical procedure for the synthesis o f tetraisopropyl carbonylbisphosphonate (a-keto TIPMDP, 3b) from diazo TIPMDP (3a) using t-BuOCl Diazo TIPMDP (3a) was dried overnight under dry vacuum at 30 °C. A solution of 60.00 mL dry and dist. EtOAc and 0.195 mL dist. H2 0 was prepared under dry conditions. A 100 mL 3 necks rb flask was equipped with a magnetic stirrer, Ar. inlet/outlet, vacuum outlet, and a septum on its side port. In this flask, previously cooled to ice temperature and flushed with Ar, was dissolved 1.00 g (2.71 mmol, 1.0 eq.) of diazo derivative in 40.00 mL of the mixture EtOAc/H2 0. 6.85 mL (54.0 mmol, 5.0 eq. relative to H2 0 ) of Me3 SiCl was set aside in a gas- tight Hamilton syringe equipped with a sample lock system. In a round bottom flask with a bent ground joint was placed 0.8794 g (8.1 mmol, 3.0 eq.) of r-BuOCl in 20.00 mL of EtOAc/H2 0 . This flask was connected to the 3 necks rb flask containing the diazo TIPMDP solution by the free side port and allows for fast addition when swiveled. The total amount of dist. H2 0 was 10.8 mmol (4 eq.). A slight vacuum was established, and the r-BuOCl solution was added at once. Almost immediately, the solution turned bright yellow and vigorous evolution of gas was observed. After 10 sec of reaction, Me3 SiCl was injected directly inside the solution through the septum, and the ice bath was removed. After the reaction 82 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. has ended, flow of Ar was re-established, the addition flask was replaced by a glass cap, and the serum cap was replaced by a vacuum outlet. A warm water bath was placed under the 3 necks rb flask. Concentration of the reaction mixture was controlled by a slight Ar flow. The mixture was washed with 3 portions of 5 mL dry EtOAc. The residue was stored in a dry box (N2 atm). This procedure has been successfully adapted for 0.5 g to 2.0 g of diazo TIPMDP (3a). The yield of a-keto TIPMDP (3b) is typically between 90 and 95 % as observed by 3lP and ‘H NMR. For common 3lP NMR signals see above. Synthesis o f dimethylaminooxalyl phosphonic acid diethyl ester (a-keto PAmide, 2b) from diazo PAmide (2a) using t-BuOCl and HfO In a 5 mL rb flask equipped with a magnetic rod and a serum cap, 4 mL of dry and distilled EtOAc containing 11.7 pL (0.65 mmol, 2.0 eq.) of H2 0 was cooled down to about 10 °C. The flask was flushed with Ar for a few minutes. 1 mL of this solution was withdrawn and placed in a vial equipped with a Teflon septum screw cap. To the solution in the rb flask was added 81.1 mg (0.32 mmol, 1.0 eq.) of diazo PAmide (2a). The solution takes a pale yellow color. In dimmed light, 70.3 mg of f-BuOCl (0.65 mmol, 2.0 eq.) was added to the vial containing the mixture EtOAc/BLO. A Hamilton syringe equipped with a sample lock and containing 0.500 mL of MejSiCl was set aside. The solution contained in the vial (r-BuOCl/EtOAc/TLO) was injected under flow of Ar directly inside 83 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. the rb flask containing diazo PAmide (2a). Since no massive evolution of gas and significant change of color were observed, the reaction was left to run for 5 min before injecting Me3 SiCl. The solution was sampled in an NMR tube and 3lP NMR spectra were recorded. 3,P{'H} NMR 6 15.0-14.0 (3s, unknown), 9.0 (s, 85%, DiCl-PAmide, 2c), -1.7 (s, 15%, a-keto PAmide, 2b). 3lP NMR: None of those peaks displayed 'JP H coupling. Reaction o f diazo PAmide (2a) with t-BuOCl and HCl In a 5 mL rb flask equipped with a septum and a magnetic rod, 10.0 mg (0.040 mmol, 1.0 eq.) of diazo PAmide (2a), and 8.0 mg (0.070 mmol, 1.8 eq.) of r-BuOCl in 0.500 mL of dry and dist. EtOAc were placed. The solution was stirred for 10 min. HCl (2.0 pL, 11.9 N; 0.024 mmol, 0.6 eq.) was injected inside the solution. After a few seconds, evolution of gas was observed and the color changed for a more intense yellow. The solvent was evaporated and replaced by CDClj. 'H NMR (CDClj) 6 4.34 (m, 4H, (CH3 C//2 0 )2 P), 3.36, 3.01 (2s, 3H each, (C//3 )2 N), 1.37 (broad s, 6H, (C//3 CH2 0 )2 P). 3,P{'H) NMR (CDC13 ) 6 9.2 (71.1 %, DiCl-PAmide, 2c), -1.5 (26.8 %, a-keto PAmide, 2b). Reaction of diazo PAmide (2a) with t-BuOCl and 2 eq. trifluoroacetic acid (CFjCOOH) In an NMR tube equipped with a Teflon septum screw cap and flushed with Ar., I mL of dried and dist. EtOAc was placed with 10.0 mg (0.040 mmol, 84 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1.0 eq.) of diazo PAmide (2a) and 5.2 mg (0.048 mmol, 1.2 eq.) of r-BuOCl. The reaction was followed by 3 1 P NMR. This mixture was first left for 36 hours in the dark. 3 IP{'H} NMR 8 13.57 (93 %, diazo PAmide, 2a), 9.05 (7 %, DiCl-PAmide, 2c). Then, another 10.0 mg (0.092 mmol, 2.1 eq.) of r-BuOCl was added. The NMR tube was warmed over I h 20 min to 47 °C. 3 IP{'H} NMR 8 13.57 (92 %, diazo PAmide, 2a), 9.05 (8 %, DiCl-PAmide, 2c). The mixture was left to return to room temperature, and 6.0 pL (0.08 mmol, 2 eq.) of CF3 COOH was injected into the solution. After 8 min., 3,P{'H} NMR 8 14.1 (13.4 %, diazo PAmide, 2a), 8.9 (23.9 %, DiCl-PAmide, 2c), 6.5 (46.7 %, purported a-Cl-a-OCOCF3 PAmide intermediate), -1.7 (16.0 % a-keto PAmide, 2b). The reaction continued to be observed by 3 1 P NMR over 2 days. 3,P{'H} NMR 8 9.1 (29.5 %, DiCl-PAmide, 2c), 4.7 (10.8 %, ?), -1.6 (59.7% a-keto PAmide, 2b). Reaction o f diazo PAmide (2a) with t-BuOCl and 10 eq. CFjCOOH In a 5 mL rb flask equipped with a Teflon septum side port and Ar. intake/outtake, was placed 9.0 mg (0.036 mmol, 1 eq.) of diazo PAmide (2a) and 28.0 pL (0.36 mmol, 10 eq.) of CF3 COOH in 1.0 mL of dried and dist. EtOAc. The solution was stirred for 5-10 min. Then, 5.2 mg (0.05 mmol, I eq.) of t- BuOCl was injected directly inside the solution. After 30 min., 3 ,P{'H} NMR 8 8.9 (25.4 %, DiCl-PAmide, 2c), 6.5 (33.4 %, purported a-Cl-a-OCOCF3 PAmide intermediate), -1.8 (39.9 % a-keto PAmide, 2b). The reaction continued to be 85 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. observed by 3IP NMR over 2 days. 3 IP{'H} NMR 6 9.1 (25.4 %, DiCl-PAmide, 2c), 4.7 (3.2 %, ?), -1.8 (62.0 % a-keto PAmide, 2b). Reaction o f diazo PAmide (2a) with t-BuOCl and in CHjCOOH In a 5 mL RB flask equipped with a septum cap and flushed with Ar., 11.7 mg (0.047 mmol, 1.0 eq.) of diazo PAmide (2a) was placed in 400 pL of dried and distilled CH3 COOH. In a separate vial, 6.6 mg (0.061 mmol, 1.3 eq.) of t- BuOCl was placed in 100 pL of CH3 COOH. The r-BuOCl solution was injected inside the diazo PAmide (2a) solution and the reaction was followed b y 3 1 P NMR. After 5 min., 3,P{'H} NMR 6 9.2 (28 %, DiCl-PAmide, 2c), 9.1 (43 %, purported a-Cl-a-OCOCH3 PAmide intermediate), -1.9 (29 % a-keto PAmide, 2b). The solvent was removed and the mixture heated to 120 °C for 1 h.. After replacing the reaction mixture in EtOAc, phosphorus-31 spectrum was recorded. J IP{'H} NMR 5 9.1 (28 %, DiCl-PAmide, 2c), -1.8 (72 % a-keto PAmide, 2b). 5S Unsuccessful Methods of Purification of a-Keto TIPMDP (3b) TLC and prep-TLC on silica gel Silica gel TLCs were dried for about 1 hour on a hot plate at about 100 °C, in the glove box. All solvents were dried and distilled by conventional methods before use. Compounds were extracted from the TLC plate by dry EtOAc and 86 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. analyzed by 3lP NMR. Pure DiCl-TIPMDP (3c) was used as a reference. The band containing the ketone was visible to the naked eye due to its bright yellow color. The other compounds were revealed by UV (254 nm) and/or I2 after cutting a small band of TLC along the eluent path. The following solvents combinations gave poor separation and/or yield of recovery: 100% EtOAc, EtOAc/heptane (7:3), EtOAc/CHCl3 (3:2). The combination which gave the best results was EtOAc/CHCl3 (3:7) containing 0.75% Me3 SiCl. Using the latter solvents combination, a fraction containing 17.7% a-keto TIPMDP (3b), 24.1% DiCl-TIPMDP (3c), and 58.1% trimer-TIPMDP (3c) was purified by 2 successive TLCs. After the first separation the yellow band was collected and showed the following composition by 3 IP NMR: 57.8% a-keto TIPMDP (3b), 14.0% DiCl- TIPMDP (3c), and 24.3% trimer-TIPMDP (3e). The second separation yield a fraction containing 84.0% a-keto TIPMDP (3b), 7.8% DiCl-TIPMDP (3c), and 8.2% Di'Pr Phosphite (7). Silica gel column chromatography A 5 cm long silica gel column was packed inside a Pasteur pipette in dry EtOAc. The silica gel was dried for several hours at 200 °C. A small sample containing 18% DiCl-TIPMDP (3c), 31% trimer-TIPMDP (3e), and 51% a-keto TIPMDP (3b) was eluted using dry EtOAc. The yellow fraction was collected in 4 aliquots. While most of the trimer-TIPMDP (3e) was removed, all fractions 87 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. were showing the presence of both a-keto TIPMDP (3b) and DiCl-TIPMDP (3c), ranging from 25 to 45%, along with some other minor impurities. A similar experiment using EtOAc / heptane (7:3) yielded comparable results. Centrifugal chromatography with silica gel rotors Centrifugal chromatography was attempted, inside a glove box (N; atm.), using a I mm rotor previously vacuumed dried in an oven at 30 °C for 24 hours. EtOAc/CHCl3 (3:2) was used for eluent. 0.200 mL of a reaction mixture containing 67% a-keto TIPMDP (3b), 12% DiCl-TIPMDP (3c), 11% diazo TIPMDP (3a), and 11% trimer-TIPMDP (3e) was introduced on the rotor in 2.0 mL CHC13 . All fractions collected showed poor separation and massive decomposition. TLC on alumina The separation was unsatisfactory on this media. Distillation o f the mixture obtained from the reaction with t-BuOCl A micro-distillation apparatus connected to a high vacuum line, and equipped with a Teflon 50 mm spin band was used to distilled a 0.5 mL crude reaction mixture containing 76.1% a-keto TIPMDP (3b), 6.5% DiCl-TIPMDP (3c) and 17.4% trimer-TIPMDP (3e) (by 3lP NMR). The apparatus was assembled inside a glove box (N2 atm.) to protect the ketone derivative from 88 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. decomposing. Then, the apparatus was safely connected to the high vacuum line outside the glove box for distillation. The first fraction was collected between 55 and 80 °C [3,P{1H} NMR: 7.8 % (DiCl-TIPMDP, 3c), 86.2 % (a-keto TIPMDP, 3b), 5.9 % (trimer-TIPMDP, 3e)], the second was collected between 80 and 86 °C [3 IP{1HJ NMR: 8.3 % (DiCl-TIPMDP, 3c), 85.9 % (a-keto TIPMDP, 3b), 5.8 % (trimer-TIPMDP, 3e)], and the third one between 87 and 85 °C [3IP{1H> NMR: 9.1 % (DiCl-TIPMDP, 3c), 73.2 % (a-keto TIPMDP, 3b), 17.6 % (trimer- TIPMDP, 3e)]. 56 Study of the Catalytic Synthesis of a-Keto Phosphonates and a-Keto Bisphosphonates The following reactions were performed under Ar. Reactants and glassware were dried overnight. Solvents were freshly dried and distilled. All additions to the reaction mixture were performed under flow of Ar. unless the reaction was performed inside the glove box (N, atm.). 89 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Competition reaction between diazo PAmide (2a) and diazo TEPA (la) catalyzed by rhodium (II) perfluorobutyramide (Rh2 (NHCOC3 F7 )4 ) with 1,2- epoxyhexane. In an NMR tube equipped with a Teflon septum screw cap, 23.3 mg (93.5 x I O '3 mmol, 1.0 eq.) of diazo PAmide (2a) and 24.2 mg (96.7 x 10'3 mmol, 1.0 eq.) of diazo TEPA (la) were dissolved in 0.450 mL toluene. 3 IP NMR of the mixture was recorded. In a vial, a solution containing 3.8 mg (3.6 x 10'3 mmol, 0.037 eq.) of Rh2 (NHCOC3 F7 )4 and 17.5 pL (0.145 mmol, 1.5 eq) of 1,2- epoxyhexane in 0.200 mL toluene was prepared. The solution in the vial was injected directly into the NMR tube and the reaction was monitored b y 3 1 P NMR spectroscopy. After 36 min another 1.5 eq. of 1,2-epoxyhexane was added to the mixture. 3 IP{'H} NMR (toluene) 6 16.94,16.01 (consistent with OH-PAmide (2f) and DiOH-PAmide (2d) respectively), 13.66 (s, diazo PAmide, 2a), 10.53 (s, diazo TEPA, la), -1.35 (s, a-keto PAmide, 2b), -1.68 (s, a-keto TEPA, lb). Reaction o f diazo TIPMDP (3a) with rhodium (II) acetate (Rh2 (OAc)4 ) In a vial equipped with a Teflon septum screw cap, 48.8 mg (0.130 mmol, 1.0 eq.) diazo TIPMDP (3a) was dissolved in 0.100 mL benzene. In a 5 mL rb flask equipped with a condenser, and Ar. inlet/outlet, was placed 0.100 mL (0.830 mmol, 6.0 eq.) of 1,2-epoxyhexane, and 5 mg (0.01 mmol; 0.1 eq.) Rh2 (OAc)4 in 4.0 mL benzene. The catalyst solution was heated to reflux. The diazo TIPMDP 90 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (3a) was introduced through the condenser to the refluxing solution. The mixture adopts an emerald green color. After 20 h, the reaction was checked by 3 1 P NMR. No changes were recorded. A solution containing about 5 mg (0.005 mmol, 0.04 eq.) Rh2 (NHCOC3 F7 )4 , 0.100 mL (0.830 mmol, 6.0 eq.) of 1,2-epoxyhexane in 1.00 mL benzene was added to the reaction mixture. The reaction was followed b y 3 1 P NMR and progressive conversion to a-keto TIPMDP (3b) was observed. After 22 hours, the conversion was completed. 3,P{'H} NMR 5 11.43 (s, diazo TIPMDP), -4.65 (s, a-keto TIPMDP). Reaction o f diazo PAmide (2a) with Rh2 (OAc)4 With propylene oxide: In a 100 mL rb flask equipped with a condenser, and Ar. inlet/outlet, and an addition funnel at the very top, was placed 10.5 mL (0.150 mol, 11.0 eq.) of propylene oxide, and 47.4 mg (0.11 mmol; 0.0079 eq.) Rh2 (OAc)4 in 64.0 mL benzene. In the addition funnel, diazo PAmide (2a, 3.50 g, 0.014 mol, 1.0 eq.) was dissolved in 20.0 mL benzene. The catalyst solution was heated to reflux. The diazo PAmide (2a) was introduced through the condenser to the refluxing solution. The mixture adopts a bright apple-green color after 20 min, turns progressively yellow-green, yellow-brown, then reddish (indication of side products). After 4 h 30 min, no more diazo PAmide remains in the solution by 3lP 91 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. NMR. 3IP{'H} NMR 6 17.65, 17.40 (8 %, ?), 13.70, 13.57 (9 %, ?), 9.50, 9.49 (26 %, ?), 5.16, 5.15 (27 %, ?), -1.86 (s, 30 %, a-keto PAmide, 2b). With 1.2-epoxvhexane: In a vial equipped with a Teflon septum screw cap, 208.5 mg (0.802 mmol, 1.0 eq.) diazo PAmide (2a) was dissolved in 1.5 mL benzene. In a 10 mL rb flask equipped with a condenser, and Ar. inlet/outlet, was placed 0.494 mL (4.01 mmol, 5.0 eq.) of 1,2-epoxyhexane, and 1.8 mg (0.004 mmol; 0.005 eq.) Rh2 (OAc)4 in 2.5 mL benzene. The catalyst solution was heated to reflux. The diazo PAmide (2a) was introduced through the condenser to the refluxing solution. The mixture turns quickly form apple-green to yellow-brown color, and evolution of gas was observed. During the reaction, another 0.900 mL (7.46 mmol, 9.3 eq.) of 1,2-epoxyhexane was introduced. The reaction was followed by M P NMR for 24 h. Similar side products than with propylene oxide, and only about 7% conversion to a-keto PAmide (2b). The procedure was repeated with 30 to 40 eq. of 1,2-epoxyhexane in benzene, and substituting the benzene by 1,2- epoxy hexane. Similar results were obtained. 92 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Reaction o f diazo PAmide (2a) with rhodium (II) trifluoroacetamide (Rh2 (NHCOCF3 )4 ) In an NMR tube equipped with a Teflon septa screw cap, was placed 0.8 mg (1.2 x 10'3 mmol, 0.03 eq.) of Rh2 (NHCOCF3 )4 and 0.100 mL (1.40 mmol, 35.0 eq.) of propylene oxide in 0.500 mL of toluene. Diazo PAmide (2a, 10 mg, 0.04 mmol, 1.0 eq.) was added to the mixture. The reaction was left at room temperature for 24 h. 3 IP{'H} NMR 8 16.71 (s, 47 %, OH-PAmide, 2f), 12.94 (s, 53 %, diazo PAmide, 2a), -1.86 (s, traces, a-keto PAmide, 2b). No changes were observed when the mixture was heated to 40 °C for several hours. Synthesis and purification o f dimethylaminooxalyl phosphonic acid diethyl ester (a-keto PAmide, 2b) from diazo PAmide (2a) and rhodium (II) perfluorobutyramide (Rh2 (NHCOC3 F7 )4 ) In a 500 mL 3 necks rb flask equipped with a magnetic rod, a condenser with Ar. inlet/outlet at its top, thermometer, and addition funnel, was placed 150.4 mg (0.143 mmol, 2.74 x 10'3 eq.) Rh2 (NHCOC3 F7 )4, and 23.0 mL (0.202 mol, 5.05 eq.) styrene oxide in 150.0 mL of benzene. The navy-blue solution was left to stir for 30 min to allow for complete dissolution of the catalyst. Diazo PAmide (2a, 10.0 g, 0.040 mol, 1.0 eq., yellow solution) was dissolved in the addition funnel with 50.0 mL benzene. The dropwise addition of the diazo derivative was started, the reaction mixture adopts a bright, clear red color. Evolution of gas was 93 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. observed. After completion of the reaction (about 2 h 30 min, indicated b y 3 1 P NMR), the mixture was concentrated under dry vacuum. When no more boil off was observed, 30.2 g of residue was remaining inside the flask, more than twice the expected amount. The residue was transferred inside the glove box, where the high vacuum distillation apparatus was assembled. Outside the glove box, the distillation column was connected to the high vacuum system and distillation was started. In about 1 h, 3 fractions were collected. The distillation yielded 6.64 g (54%, fraction 2 and 3) of a bright yellow liquid, a-keto PAmide (> 97%): bp 69- 71 °C (0.002 mmHg). 'H NMR (CDC13 ) 5 4.04 (m, 4H, CH3 Ctf2 0), 2.78, 2.76 (2s, 6H, N(C//3 )2 ), 1.11 (t, 6H, C//3 CH2 0). ,3 C{'H} NMR (CDCI3 ) 6 198.05 (d, 'JC P = 172.2 Hz, P(0)C(0)C(0)), 164.25 (d, 2 JC P = 65.9 Hz, P(0)C(0)C(0)), 64.03 (d, 2 JC P = 6.7 Hz, CH3 CH2 0), 35.92, 34.02 (2s, N(CH3 )2 ), 15.71 (d, 3 JC P = 6.1 Hz CH3 CH2 0). 3,P{'H} NMR (CDCI3 ) 5 -2.31 (s). 3,P NMR (CDCI3 ) 6 - 2.31 (p, 3 JP H = 8.0 Hz) IR (cm'1 ) 2986,2938 (m, CH3 , CH2 ), 1658 (broad vs, C=0), 1266 (vs, P=0), 1023 (vs, P-O-C). Elemental analysis: Ceiled: C 40.51%, H 6.80%, N 5.91%; Found: C 40.65%, H 7.05%,N 6.09%. 94 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Comparaison o f the efficiency offour oxygen donors (propylene oxide, 1,2- epoxybutane, 1,2-epoxyhexane, and styrene oxide) on diazo PAmide (2a) using Rh2 (NHCOC2 F7 )4 for catalyst A solution containing 4.7 x I O '3 mg of Rh,(NHCOC3 F7 )4 in 1.200 mL benzene was divided into 4 equivalent aliquots. Each aliquot were placed in an NMR tube (numbered from 1 to 4) equipped with a Teflon septum screw cap, and flushed with argon. 7 eq. of each oxygen donor were respectively added to the NMR tubes: 0.100 mL of propylene oxide in tube #1,0.121 mL of 1,2- epoxybutane in tube #2,0.169 mL of 1,2-epoxyhexane in tube #3, and 0.160 mL of styrene oxide in tube #4. The volume in the tube was adjusted to 0.500 mL with benzene. In 4 vials (numbered from 1 to 4) each equipped with a Teflon septum screw cap, was prepared diazo PAmide (2a, 50.0 mg, 0.201 mmol, 1.0 eq.) in 0.100 mL benzene. At 10 min intervals, the content of the vials were added to the corresponding NMR tube. 3 IP NMR spectra of the 4 reactions were recorded at regular intervals. 3,P{,H} NMR 8 16.9 (s, OH-PAmide. 2f), 13.2 (s, diazo PAmide, 2a), -1.8 (s, a-keto PAmide, 2b). Comparaison of the efficiency o f two oxygen donors (1,2-epoxyhexane, and styrene oxide) on diazo TIPMDP (3a) using Rh2 (NHCOCiF7 )4for catalyst In 2 NMR tubes (#1 and #2) each equipped with Teflon septum screw cap, was placed 2.2 mg (2.1 x 10'3 mmol, 0.015 eq.) Rh2 (NHCOC3 F7 )4 in 0.400 mL 95 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. toluene. To tube #1 was added 81.1 mg (0.675 mmol, 5 eq.) styrene oxide. To tube #2 was added 67.6 mg (0.675 mmol, 5 eq.) 1,2-epoxyhexane. At 15 min intervals, diazo TIPMDP (3a, 50.0 mg, 0.135 mmol, 1 eq.) in 0.200 mL toluene was added to each tube. After 2 h 30 min, another 3.0 mg (2.8 x 10'3 mmol, 0.021 eq.) Rh2 (NHCOC3 F7 )4 in 0.200 mL toluene was added to each tube. The reactions were followed by 3,P NMR for about 4 h. 3,P{'H} NMR 5 17.14 (s, OH- T1PMDP, 3f ?) 13.25 (d, 2P, 3 JP P = 13.97 Hz, trimer-TIPMDP, 3e), 11.18 (s, diazo TIPMDP, 3a), -1.02 (t, IP, 3 JP P = 13.97 Hz, trimer-TIPMDP, 3e), -4.90 (s, a-keto TIPMDP, 3b). Synthesis and purification o f tetraisopropyl carbonylbisphosphonate (a-keto TIPMDP, 3b) from diazo TIPMDP (3a) and Rh2 (NHCOC3 F7 )4 Inside the glove box (N2 atm.), a 250 mL 3 necks rb flask equipped with a magnetic rod was loaded with 250.0 mg (0.24 mmol, 0.010 eq.) Rh2 (NHCOC3 F7 )4 , and 14.5 mL (0.120 mol, 5.2 eq.) 1,2-epoxyhexane in 90.0 mL toluene. Also inside the glove box, an addition funnel was loaded with 8.67 g ( 0.023 mol, 1 eq.) diazo TIPMDP (3a) in 30 mL toluene. Outside the glove box, and under flow of UHP Ar., the 250 mL rb flask was equipped with a condenser with Ar. inlet/outlet at its top, a thermometer, and the addition funnel containing the diazo solution. The catalyst solution was heated to 93 °C, the solution turns navy-blue. Dropwise addition of the diazo solution was started. After about 18 h, 96 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. the reaction was completed (determined by 3 1 P NMR). The solvent and the epoxide were easily removed under vacuum, inside the glove box. The distillation apparatus was also assembled inside the glove box, then transferred outside to be connected to the high vacuum line. High vacuum distillation yielded 4.96 g (60 %, fraction 2 & 3) of a bright yellow liquid, a-keto TIPMDP (3b > 95%): bp 79-81 °C (0.002 mmHg). 'H NMR (CDCI3 ) 6 4.75 (m, 4H, (CH3 )2 C //0), 1.28, 1.27 (2d, 24H, (C//3 )2 CHO). ,3 C NMR (CDCI3 ) 6 216.38 (t, 'JC P = 149.5 Hz, C=0), 73.66 (large s, (CH3 )2 CHO), 24.02, 23.51 (2s, (CH3 )2 CHO). 3 iP{'H} NMR (CDC13 ) 6 -5.9L (s). 3,P NMR (CDC13 ) 6 -5.91 (t, 3 JP H = 3.5 Hz). IR (cm'1 ) 2984, 2937 (s, CH3 , CH), 1665 (m, C=0), 1266 (vs, P=0), 995 (broad vs, P-O-C). Elemental analysis: Calcd: C 43.58%, H 7.88%; Found: C 43.75%, H 8.04%. Synthesis and purification o f triethyl phosphonoglyoxylic acid (a-keto TEPA, lb) from diazo TEPA (la) and Rh2 (NHCOCsF7 )4 The following reaction was performed inside a globe box (N2 atm.). In a 100 mL rb flask equipped with a condenser with a moisture trap at its top, was placed 49.4 mg (46.9 x 103 mmol, 1.7 x 10* 3 eq.) Rh2 (NHCOC3 F7 )4 with 12.07 mL (0.140 mol, 5.0 eq.) 1,2-epoxy butane in 63 mL benzene. The purple catalyst solution was heated to 50 °C. Dropwise addition of diazo TEPA (la, 7.01 g, 0.028 mol, 1.0 eq.) in 20 mL benzene was started using and addition funnel 97 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. connected to the top of the condenser. The solution turns first pinkish, then bright yellow, and evolution of gas was observed. After 10 h, 50% of diazo TEPA (la) remained in the solution, thus 17.3 mg (16.4 x 10'3 mmol, 2.3 x I O '3 eq.) Rh2 (NHCOC3 F7 )4 in 1.0 mL 1,2-epoxybutane was added to the mixture, heating was stopped, and the reaction was left overnight. At the end of the reaction, the color was yellow-orange. The solvent, and excess epoxide were evaporated under vacuum inside the glove box. The distillation apparatus was assemble inside the glove box and transferred outside to be connected to the high vacuum line. High vacuum distillation yielded 3.52 g (53 %, fraction 1 & 2) of a bright yellow liquid, a-keto TEPA (lb > 99%): bp 58-60 °C (0.002 mmHg). ‘H NMR (CDCI3 ) 8 4.29 (q, 2H, CHjCZ/jOC), 4.22 (m, 4H, (CH3 C //2 0 )2 P), 1.28 (t, 9H, C//3 CH2 0). ,3 C{‘H} NMR (CDCIj) 8 193.54 (d, 'JC P = 183.1 Hz, P(0)C(0)C(0)), 159.19 (d, 2 JC P = 78.6 Hz, C(0)0CH2 CH3 ), 64.60 (d, 2 JC P = 6.1 Hz, (CH3 CH2 0 )2 P), 63.07 (s, CH3 CH2 OC), 16.12 (d, 3 JC P = 5.7 Hz, (CH3 CH2 0 )2 P), 13.67 (s, CH3 CH2 OC). 3IP{'H} NMR (CDCIj) 8 -2.57 (s). 3IP NMR (CDCI3 ) 8 -2.57 (p, 3 JP H = 8.2 Hz). IR (cm'1 ) 2987,2939 (m, CH3 , CH2 ), 1739 (broad vs, C=0), 1271 (broad vs, C-O- C, P=0), 1026 (vs, P-O-C). Analytical data are in agreement with literature1 5 ’2 0 . 98 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Synthesis diethyl [(ethoxyphenylphosphinyl)carbonyljphosphonate (a-keto PPP, 4b) from diazo PPP(4a) and Rh2 (NHCOC3 F7 )4 The following reaction was performed inside a globe box (N2 atm.). In a 10 mL rb flask equipped with a condenser with a moisture trap at its top, were placed 11.0 mg (10.4 x 10'3 mmol, 8.8 x 10'3 eq.) Rh2 (NHCOC3 F7 )4 with 0.640 mL (7.43 mmol, 6.2 eq.) 1,2-epoxybutane in 3 mL benzene. The purple catalyst solution was heated to reflux. Dropwise addition of diazo PPP (4a, 0.412 g, 1.19 mmol, 1.0 eq.) in 2 mL benzene was started using a Pasteur pipette. The solution goes from pinkish, to orange, to red and finally brownish. Evolution of gas was observed right when the addition started. The reaction was followed b y 3 1 P NMR, after 5 h 40 min only 23% conversion is observed. After almost 7 h, more catalyst (30.0 mg, 28.4 x 10'3 mmol, 23.5 x 103 eq.) was added to the mixture along with more epoxide (1.0 mL, 11.6 mmol, 9.7 eq.). One hour after the last addition, 44% conversion was observed. Before the end of the reaction more catalyst and epoxide were added bringing the proportions to: 66.4 mg (63.0 x 10* 3 mmol, 52.6 x 10‘ 3 eq.) of Rh2 (NHCOC3 F7 )4 and 2.64 mL (30.6 mmol, 26.0 eq.) 1,2-epoxybutane in 7 mL of benzene. After about 24 h of reaction, a-keto PPP (4b) seemed to be the major product, but diazo PPP (4a) was still present in the mixture along with some decomposition products. 2.5 mL (21.9 mmol, 4.6 eq.) of styrene oxide is added to the mixture to drive the reaction. 48 h after the reaction 99 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. started, no more diazo compound is left inside the mixture. The reaction was stopped and high vacuum distillation was attempted. The product underwent massive decomposition during distillation, a-keto PPP (4b, 20-40%): 3 ,P{,H} NMR (benzene) 6 18.42 (d, 2 JP P = 217.6 Hz, IP, Ph(CH3 CH2 0)/>(0)), -2.61 (d, 2 JP P = 217.6 Hz, IP, (CH3 CH2 0 )2 />(0)). Synthesis o f diethyl benzoylphosphonate (5b) from (diazophenylmehtyl)phosphonic acid diethyl ester1 (5a) and Rh2 (NHCOCJ F7 )4 Et02 P(0)C(N2 )Ph(5a, 304.0 mg, 1.19 mmol, 1.00 eq., bright red) was dissolved in 0.500 mL commercial anh. benzene in a vial with a Teflon septum screw cap. In a 5 mL rb flask equipped with a condenser, Ar. inlet/outlet, and a side port with a Teflon septum screw cap, was prepared a solution containing 4.20 mg (3.98 x 10‘ 3 mmol, 3.3 x 10‘3 eq.) of Rh2 (NHCOC3 F7 )4 and 0.128 g (1.77 mmol, 1.5 eq.) of 1,2-epoxybutane in 1.00 mL commercial anh. benzene. The diazo derivative solution was added to the catalyst solution. First, the color was very dark, but quickly changed to clear reddish. Evolution of gas was observed. The conversion was quantitative (> 99% by 3 1 P NMR), and was completed in less than 5 min. 261.0 mg (91%) of crude compound was recovered after concentration of the solvent. Centrifugal chromatography was attempted but did not yield satisfactory results due to the sensitivity of the product to moisture. EtCLPfQ)CfQ)Ph (5b): 'H NMR(CDC13 ) 6 8.06 (d, 2H, ortho-H), 7.42 (t, 1H, 100 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. para-H), 7.29 (t, 2H, meta-H), 4.07 (m, 4H, OC//2 CH3 ), 1.17 (td, 6H, OCH2 C //3 ). ,3 C{'H} NMR(CDC13 ) 6 198.46 (d, 'JCP= 174.8 Hz, C=0), 135.08 (d, 2 JC P = 64.14 Hz, arom-C,), 134.28 (s, para-C), 129.27 (s, meta-C), 128.37 (s, ortho-C), 63.47 (d, 2 JC P = 6.5 Hz, CH3 CH2 0), 15.86 (d, 3 JC T = 5.5 Hz, CH3 CH2 0). 3,P{'H} NMR (CDCI3 ) 6 -0.57 (s). 3 IP NMR (CDCI3 ) 6 -0.57 (p, > ] m = 8.1 Hz). IR (cm * ) 3066-2900 (m-w, CH3 , CH2 , arom-CH), 1655 (vs, C=0), 1257 (vs, P=0), 1050, 1022 (vs, P-O-C). EtO.PfOlCflSMPh (5a): 'H NMR(CDC13 ) 6 7.28 (t, 2H, aromatic meta-H), 7.11 (d, 2H, aromatic ortho-H), 7.06 (t, 1H, aromatic para-H), 4.15,4.06 (q, 2H; q, 2H; OCH,CH3 ), 1.26 (t, 6H, OCH2 C//3 ). 1 3 C{'H} NMR (CDCI3 ) b 128.70 (s, meta-C), 126.14 (d, 2 JC P = 9.8 Hz, arom-C/), 124.61 (s, para- 0 , 122.14 (d, 3 Jc, = 4.3 Hz, ortho-C), 63.33 (d, 2 JC T = 4.5 Hz, CH3 CH2 0), 50.04 (d, “ JC P = 226.1 Hz, C=N2 ), 15.59,15.58 (2d, 3 JC P = 4.3 Hz, CH3 CH2 0). 3,P{'H) NMR (CDC13 ) 6 17.92 (s). 3,P NMR (CDC13 ) 6 17.92 (p, 3 Jp„ = 8.2 Hz). IR (cm' ') 3066-2900 (m-w, CH3 , CH2 , arom-CH), 2079 (vs, C=N=N), 1258 (s, P=0), 1018 (s, P-O-C). Analytical data are in agreement with literature2 1 . Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 57 Other Catalytic Reactions with Diazo Phosphonates and Diazo Bisphosphonates and Rh2 (NHCOC3 F7 )4 All reactants and glassware were died before use unless otherwise specified. All solvents were used dry and distilled. Reactions were followed by 3 1 P NMR spectroscopy. Typical synthesis for a-hydroxy derivatives Synthesis of (dimethylcarbamovlhydroxvmethvOphosphonic acid diethvl ester (OH-PAmide. 2f). In an NMR tube equipped with a Teflon septum screw cap, diazo PAmide (2a, 49.1 mg, 0.197 mmol, I eq.) was dissolved in 0.400 mL of EtOAc, the solution was yellow. In a vial, 3.4 mg (3.22 x I O '3 mmol, 0.016 eq.) of Rh2 (NHCOC3 F7 )4, and 7.0 pL (0.388 mmol, 1.97 eq.) dist. H2 0 were dissolved in 0.200 mL EtOAc, the solution was purple. The catalyst solution was injected inside the NMR tube, the color turned briefly red and returned to purple. Vigorous evolution of gas was observed, thus a vent needle was placed on the NMR tube. After reaction has ended, the solvent was evaporated under vacuum and the residue (99 % by weight) was re-dissolved in CDC13 for ‘H and l3 C NMR spectroscopy. 'H NMR (CDC13 ) 6 4.74 (d, 1H, 2 JH P = 9.49, CH), 4.19,4.08 (m, 2H; m, 2H; OC//2 CH3 ), 3.07,3.00 (s, 3H; s, 3H; N(CHJJ, 1.32, 1.25 (t, 3H; t, 102 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3H; OCH2 CA/3 ). ,3 C{'H} NMR (CDC13 ) 6 167.88 (s, C=0), 66.43 (d, ‘ JC P = 154.68 Hz, CHOH), 63.75, 63.47 (d, 2 JC P = 6.6 Hz; d, 2 JC P = 7.2 Hz, CH3 CH2 0), 37.08 (s, N(CH3 )2 ), 15.67 (d, 3 JC P = 6.0 Hz CH3 CH2 0). 3,P{'H} NMR (CDCI3 ) 6 16.97 (s). 3,P NMR (CDCIj) 5 16.97 (sextuplet). IR in CCI4 (cm*1 ) 3388 (broad w, C-OH), 2983, 2933, 2910 (m-w, CH3 , CH2 , CH), 1656 (s, C=0), 1263 (broad m, P=0). 1033 (m, P-O-C). Ethyl 2-(diethoxyphosphoryl)-2-hydroxvacetate (OH-TEPA. If). *H NMR (CDCIj) 6 4.50 (d, 2 JH P = 16.0 Hz, IH, CH), 4.27,4.16 (2m, 6H, CH3 C //2 0), 1.25 (m, 9H, C//3 CH2 0). ,3 C{'H} NMR (CDC13 ) 6 169.20 (d, 2 JC P = 2.0 Hz, C=0), 68.72 (d, ‘ JC P = 154.43 Hz, CH), 63.72, 63.57 (2d, 2 JC P = 6.6 Hz, (CH3 CH2 0 )2 P), 62.36 (s, CH3 CH2 OC), 16.22 (d, 3 JC P = 5.3 Hz, (CH3 CH2 0 )2 P), 13.92 (s, CH3 CH2 OC). 3 ,P{'H} NMR (CDCI3 ) 6 16.80 (s). 3,P NMR (CDC13 ) 5 16.80 (septuplet). IR in CCI4 (cm'1 ) 3283 (broad m, C-OH), 2985, 2934, 2911 (m-w, CH3 , CH2 , CH), 1751 (s, C=0), 1245 (broad s, P=0, C-O-C), 1040, 1027 (vs, P-O-C). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. lYDiisopropoxyphosphoryDhydroxymethyllphosphonic acid diisopropvl ester (QH-TIPMDP- 3n. The reaction was conducted at 115 °C with 1.5 mol% Rh2 (NHCOC3 F7 )4 and 10 eq. H2 0 . After 4 days complete transfer was observed. TLC (CH2 Cl2 /EtOAc (1:1.5) 4% MeOH): Rf( O H .-n p M D P ) = 0.60. 'H NMR (CDCI3 ) 5 4.77 (m, 4H, (CH3 )2 C/ZO), 4.13 (t, 2 JH P = 17.7 Hz, IH, C//OH), 1.31 (m, 24H, (C//3 )2 CHO). ,3 C{'H} NMR (CDCIj) 5 72.79 (broad s, (CH3 )2 CHO), 65.35 (t, 'JC P = 156.3 Hz, CHOH), 23.98, 23.68 (2 broad s, (CH3 )2 CHO). 3 ,P{‘H} NMR (CDCI3 ) 6 16.77 (s). 3,P NMR (CDCI3 ) 5 16.77 (broad d, 2 JP H = 17.6 Hz). IR in CCI4 (cm’1 ) 3229 (broad w, OH), 2981, 2937, 2868 (m-w, CH, CH,), 1386, 1375 (m, iPr.), 1253 (broad m, P=0), 1000 (broad s, P-O-C). Synthesis o f (dimethylcarbamoylphenylaminomethyl)phosphonic acid diethyl ester (PhAmino-PAmide, 2g) In a vial, diazo PAmide (2a, 240.1 mg, 0.963 mmol, 1.00 eq.) was dissolved in 0.500 mL benzene. In a 5 ml rb flask equipped with a condenser and Ar. inlet/outlet, were placed 449.68 mg (4.83 mmol, 5.01 eq.) of aniline 99.5 % used without further purification and 14.64 mg (0.014 mmol, 0.014 eq.) of Rh2 (NHCOC3 F7 )4 in 1.0 mL benzene. The reaction was heated at reflux of the benzene. The diazo compound was added to the catalyst solution through the condenser; under flow of Ar.. The reaction change from pink to orange, and 104 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. evolution of gas was observed. After lh, the reaction was completed and the mixture was concentrated under vacuum. The residue was purified by centrifugal chromatography using EtOAc and EtOAc/10% MeOH for eluent. 242.0 mg of PhAmino-PAmide (2g, 80%) was collected. TLC (EtOAc/10% MeOH): Rf( a n iljn e ) = 0.73, Rf(PhAmino-PAmide) = 0-57, Rf<Rh;(N H C 0C 3 F7> 4) = 0.92. 'H NMR (CDCIj) 8 7.02 (t, 2H, meta-H), 6.61 (t, 1H, para-H), 6.56 (d, 2H, ortho-H), 4.76 (broad d, 3 J h.nh = 6.5 Hz, 1H, N//), 4.67 (dd, 2 JH P = 18.1 Hz, 3J h.nh = 6.5 Hz, IH, CH), 4.03 (m, 4H, OC//2 CH3 ), 3.03, 2.84 (s, 3H; d, 3H; N(CHJJ, 1.16, 1.14 (t, 3H; t, 3H; OCH2 C //3 ). ,3 C{'H> NMR (CDCIj) 8 166.49 (d, 2 JC P = 3.1 Hz, C=0), 146.28 (d, 3 JC P = 8.8 Hz, arom-C,) 128.75 (s, ortho-C), 118.49 (s, para-C), 113.82 (s, meta- C), 63.28, 63.08 (d, 2 JC P = 6.7 Hz; d, 2 JC P = 7.4 Hz, CH3 CH2 0), 53.47 (d, 'JC P = 152.86 Hz, CH), 37.16, 35.84 (2s, N(CH3 )2 ), 15.96, 15.90 (2d, 3 JC P = 7.2 Hz, CH3 CH2 0). 3 IP{'H) NMR (CDCIj) 8 18.58 (s). 3,P NMR (CDCIj) 8 18.58 (sextuplet). IR in CCI4 (cm*1 ) 3348 (broad w, N-H), 3054-2900 (w-m, CH3 , CH2 , arom-CH), 1656 (s, C=0), 1257 (s, P=O),1052, 1027 (s, P-O-C). Synthesis o f [(diisopropoxy-phosphoryl)phenylaminomethyl]phosphonic acid diisopropyl ester (PhAmino-TIPMDP, 3g) In a 5 mL rb flask, were placed 55.0 pL (0.603 mmol, 5.0 eq.) of aniline, 3.1 mg (2.9 x 10'3 mmol, 0.024 eq.) of Rh2 (NHCOC3 F7 )4 , and 45.0 mg (0.121 mmol, 1.00 eq.) of diazo TIPMDP (3a) in 0.600 mL toluene. The mixture was 105 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. heated to reflux, and left to run for 48 hours. The color of the reaction starts to change after a couple of hours from pink to orange. After completion of the reaction the residue was concentrated under vacuum and chromatographed using centrifugal chromatography (gradient of CHCl3 /EtOAc followed by a fraction of EtOAc/10% MeOH to sharpen the band). TLC (EtOAc(lO% MeOH)) R f , aniiine, = 0.73, R ftP h A m in o -T iP M D P )= 0-59, R f(R h;(N H c o c3 F 7 ) 4 )= 0.92. 'H NMR (CDCIj) 5 7.13 (t, 2H, meta-H), 6.71 (t, IH, para-H), 6.64 (d, 2H, ortho-H), 4.75 (m, 4H, (CH3 )2 C //0), 4.04 (m, 2 JH P = 22.2 Hz, 1H, CHNH becomes a triplet with D2 0 ; broad s, IH, CHNf / disappear with D2 0), 1.29 (pseudo t, 12H, (C7/3 )2 CHO), 1.25 (d, 6H, (C//3 )2 CHO), 1.16 (d, 6H, (Ctf3 )2 CHO). I 3 C{'H} NMR (CDCI3 ) 6 146.56 (t, 3 JC P = 5.0 Hz, arom-C,), 129.08 (s, ortho-C), 118.66 (s, para-C), 113.81 (s, meta-C), 72.69, 72.07 (broad s, (CH3 )2 CHO), 51.19 (t, ‘JC P = 146.8 Hz, CHNH), 24.37, 24.11, 23.77, 23.57 (4 broad s, (CH3 )2 CHO). 3,P{'H} NMR (CDCI3 ) 8 16.68 (s). 3,P NMR (CDCI3 ) 8 16.68 (broad d, :JP H = 22.0 Hz). IR in CCI4 (cm ') 3425, 3287 (vw, NH), 3057, 2981, 2936, 2868 (m-w, CH, CH2 , arom-CH), 1386, 1375 (m, iPr.), 1252 (broad m, P=0), 994 (broad s, P-O-C). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5g Reactivity of a-Keto Phosphonates and a-Keto Bisphosphonates with water The a-keto phosphonates and bisphosphonates were handled inside a glove box (N2 atm.)* EtOAc was dried and distilled before use. Reactions were followed by 3 1 P NMR spectroscopy. Typical reaction between a a-keto derivative and water a-Keto TIPMDP (3b, 17.9 mg, 0.050 mmol, 1.00 eq.) in 0.400 mL EtOAc was placed in an NMR tube equipped with a Teflon septum screw cap. 1.0 pL (0.05 mmol, 1 eq.) of water in 0.100 mL EtOAc was injected into the NMR tube. The reaction, originally bright yellow, was progressively discolored. Typical pairwise competition reation a-Keto TEPA (lb, 19.0 mg, 0.080 mmol, 1.0 eq.) in 0.400 mL EtOAc was placed in an NMR tube equipped with a Teflon septum screw cap. 3 1 P NMR spectrum was recorded to provide a reference of the chemical shift relative to the second a-keto derivative. a-Keto PAmide (2b, 18.9 mg, 0.080 mmol, 1.0 eq.) in 0.100 mL EtOAc was added to the NMR tube. Another 3lP NMR spectrum was recorded. 1.4 pL (0.080 mmol, 1.0 eq.) of dist. water in 0.100 mL EtOAc was added to the NMR tube. If necessary, another equivalent of dist. water was added 107 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. to the NMR tube, in the same manner than the first one, to activate the reaction. Dicoloration was observed. Typical reaction for the charaterization o f hydrate derivatives DiOH-TEPA fid): 84.0 mmol (20.0 mg, I eq.) of a-keto TEPA (lb) was placed in an NMR tube containing 0.500 mL of CDC13 and 0.84 mol (15 pL, 10 eq.) H ,0. When most of the ketone (lb) transferred to the hydrate (Id, about 10 min.) proton and carbon NMR spectra were recorded. Composition of the mixture as shown by 3lP NMR spectrum at the time of ‘H and 1 3 C spectra: 95 % DiOH-TEPA (Id), 5 % a- keto PAmide (2b), < 1% other impurities. 'H NMR (CDC13 ) 6 4.29 (q, 2H, CH3 C //2 OC), 4.24 (m, 4H, (CH3 C//2 0 )2 P), 1.30 (td, 9H, C//3 CH2 0). ,3 C{'H} NMR (CDCIj) 6 168.77 (d, 2 JC P = 13.8 Hz, C(0)0CH2 CH3 ), 92.43 (d, 'JC P = 198.7 Hz, C(OH)2 ), 64.62 (d, 2 JC P = 6.3 Hz, (CH3 CH2 0 )2 P), 63.19 (s, CH3 CH2 OC), 16.29 (d, 3 JC P = 5.0 Hz, (CH3 CH2 0 )2 P), 13.86 (s, CH3 CH2 OC). 3IP{'H) NMR (CDCIj) 5 13.49 (s). 3 IP NMR (CDCIj) 6 13.49 (p, 3 JP H = 7.5 Hz). DiOH-PAmide (2d): The same procedure was repeated but CDC13 was replaced by acetone for solubility reasons. Decomposition of the hydrate (2d) to the phosphite (6) started before the transfer from ketone (2b) to hydrate (2d) was completed so another 75 108 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. pL (5 eq.) of H2 0 was added. After 1 hour, proton and carbon NMR spectra were recorded. The proton spectrum is partially obliterated by the water peak. Composition of the mixture as shown by 3lP NMR spectrum at the time of lH and 1 3 C spectra: 49 % DiOH-PAmide (2d), 6 % Dimer-PAmide (2e), 2 % Dimer PAmide (2e’), 22 % DiEt Phosphite (6), 21 % a-keto PAmide (2b). ,3 C{'H} NMR (acetone) 8 169.20 (d, 2 JC P = 17.6 Hz, C=0)\ 94.62 (d, lJC P = 207.5 Hz, C(OH)2 ), 64.69 (d, 2 JC P = 7.4 Hz, CH3 CH2 0)*, 39.32, 38.20 (2s, N(CH3 )2 )*, 16.60 (d, 3 JC P = 5.3 Hz CH3 CH2 0)*. 3,P{'H} NMR (acetone) 8 15.89 (s). 3 IP NMR (acetone) 8 15.89 (p, 3 JP H = 7.5 Hz). DiOH-TIPMDP (3dl: The above procedure was repeated in acetone. Since the transfer is slower than in the case of a-keto TEPA (lb) (although faster than a-keto PAmide (2b)) another 2 eq. of H2 0 were added after a few minutes. After about 30 min, proton and carbon NMR spectra were recorded. Composition of the mixture as shown by 3 IP NMR spectra at the time of ‘H and 1 3 C spectrum: 83 % DiOH-TIPMDP (3d), 10 % a-keto-TIPMDP (3b), and 8 % trimer-TIPMDP (3e). 'H NMR (acetone) 8 4.79 (m, 4H, (CH3 )2 C/ZO), 1.31, 1.29 (2d, 24H, (C//3 )2 CHO). I 3 C{'H} NMR (acetone) 8 94.22 (t, lJC P = 193.9 Hz, C(OH)i), 73.06 (pseudo t, 2 JC P = 3.4 Hz, * Tentative assignment. 109 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (CH3 )2 CHO), 24.39, 23.97 (2s, (CH3 )2 CHO). 3,P{'H} NMR (acetone) 5 14.85 (s). 3 IP NMR (acetone) 8 14.85 (broad t, 3 JP H = 1.9 Hz). 110 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. REFERENCES 1 Perrin, D. D., Purification o f Laboratory Chemicals, 2n d Ed., 1980; Pergamon Press: Oxford, New York. 2 Hutchinson, D. W.; Semple, G. J. Organomet. Chem. 1986, 309, C7-C10. 3 Levy, J. N.; McKenna, C. E Phosphorus, Sulfur, Silicon Relat. Elem. 1993, 55(1-4), 1-8. 4 Kiddle, J. J.; Gurley, A. F. Phosphorus, Sulfur, Silicon Relat. Elem. 2000, 160, 195-206. 5 a) Olivato, P. R.; Filho, R. R.; Zukerman-Schpector, J.; Colle, M. D.; Distefano, G. JCSPGI2001,1 ,97-102. b) Lomakina, V. I. Et al J. Gen. Chem. USSR (Engl. Transl.) 1965, 35, 1752-1757. 6 Vepsalainen, J.; Nupponen, H.; Pohjala, E.; Ahlgren, M.; Vainiotalo, P. J. Chem. Soc. Perkin Trans. 2 1992, 835-842. 7 Prishchenko, A. A.; Livantsov, M. V.; Shagi-Mukhametova, N. M.; Petrosyan, V. S. J. Gen. Chem. USSR (Engl. Transl.) 1991, 61, 924. 8 Blackburn, M. G.; England, D. A.; Kolkmann, F. J. Chem. Soc. Chem. Commun. 1981,17,930-932. 9 Aboujaoude, E. E; Collignon, N.; Teulade, M.-P.; Savignac, P. Phosphorus Sulfur 1985, 25, 57-62. 1 0 Strzalko, T.; Seyden-Penne, J.; Froment, F.; Corset, J.; Simonnin, M.-P. Can. J. Chem. 1988, 66, 391-396. 1 1 McKenna, C. E.; Pham, P.-T. T.; Rassier, M. E.; Dousa, T. P. J. Med. Chem. 1992,35,4885-4892. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 2 Park, J. S. Ph.D. Dissertation, University of Mississippi, University, MS, U.S.A., 1984. 1 3 Khare, A. B.; McKenna, C. E. Synthesis 1991,5 , 405-406. 1 4 Reagan, M. T.; Nickon, A. J. Amer. Chem. Soc. 1968, 90(15), 4096-4105. 1 5 Levy, J. N. Ph.D. Dissertation, Univ. South. California, Los Angeles, CA, U.S.A., 1987. 1 6 Khokhlov, P. S.; Kashemirov, B. A.; Mikityuk, A. D.; Strepikheev, Y. A.; Chimishkyan, A. L. J. Gen. Chem. USSR (Engl. Transl.) 1984,54(12), 2495- 2497. 1 7 Mintz, M. J.; Walling, C. Org. Synth., Coll. Vol. V 1973, 184-187. 1 8 Teeter, H. M.; Bell, E. W. Org. Synth. Coll. Vol. I V 1963, 125-127. 1 9 In agreement with data in ref. 6. 2 0 McKenna, C. E.; Levy, J. N. J. Chem. Soc. Chem. Commun. 1989, 246-247. 2 1 Regitz, M.; Anschutz, W.; Liedhegener, A. Chem. Ber. 1968,101, 3734-3743. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 6 GENERAL CONCLUSION Oxidation of diazo phosphonates and diazo bisphosphonates was achieved. Three pathways are available for this purpose depending on the nature of the diazo compound (Figure 6.1). Pathway A: 1a, 3a 1. t-BuOCI / EtOAc H20 , 0 - 5 °C ► 1b, 3b 2. (CH3)3SiCI Pathway B: 2a FBuOCI / EtOAc CF3COOH or CBjCOOH ► RT 2b Pathway C: 1a, 2a R h 2(OAc)4 A 1b, 2b Pathway D: la-5a Rh2(NHCOC3F7)4 1b-5b Figure 6.1. Summary of the oxidative pathways available for oxidation of diazo phosphonates and diazo bisphosphonates. 113 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Pathway C provided the first route to large-scale synthesis and isolation of carbonylbisphosphonates. Pathways A was proven to be a mild route to the desired products, however it still presents some drawbacks: I) the concurrent formation of a,a-dichlorinated products which can not be separated by distillation, 2) the susceptibility of the yield associated with the nature of the diazo compound or the ketone product, 3) the difficulty in controlling the conditions (amount of water, time of reaction), and 4) the exothermicity and acceleration of the reaction rate which could cause a problem for very large scale syntheses. On the other hand, the advantage of the method is the fast production (a few minutes) of the a-keto derivative, which can be used in situ. Pathway B was adapted from patway A and generates the desired product. The yield was not as good but the conditions are more easily controlled since water is not present. Pathways C and D use the same approach but the efficiency of Rh2 (NHCOC3 F7 )4 overshadows the older Rh2 (OAc)4 catalyst. The only advantage of pathway C is the commercial availability of the catalyst. Pathway D is the method of choice for the large-scale synthesis of a-keto phosphonates and a-keto bisphosphonates. Albeit higher temperatures are required for the bisphosphonates derivatives, the synthesis is usually very clean and the product can be easily separated and purified by distillation. The difficulties encountered during the synthesis of a-keto PPP (4b) remain to be understood but are probably associated with the 114 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. particular nature of this diazo derivative. This approach promises to improve with the increasing number of rhodium catalysts available and the fine-tuning of their activity through their ligands. This method not only provided access to the long- sought ketones from readily available precursors but also to a-amino derivatives by N-H insertion reaction directly on the diazo compound. The exceptional reactivity of those novel ketones needs to be investigated further but is already exemplified by the displacement of the equilibrium towards the hydrate derivatives in the presence of water. Very importantly, the novel ketones were stored under inert atmosphere for several months without appreciable decomposition. 115 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PART II NMR AND CRYSTALLOGRAPHIC STUDIES OF BIOACTIVE ARYLSEMICARBAZIDES AND SCHIFF BASES OF AMINOHYDROXYGUANIDINE Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 7 NMR AND CRYSTALLOGRAPHIC STUDIES OF BIOACTIVE ARYLSEMICARBAZIDES AND SCHIFF BASES OF AMINOHYDROXYGUANIDINE 7t Introduction Semicarbazides, hydroxysemicarbazides and Schiff bases of aminohydroxyguanidine are analogs of hydroxyurea (H2 NC(0)NH0H). Hydroxyurea is a known inhibitor of ribonucleotide reductase, which catalyzes the reduction of ribonucleotides to deoxyribonucleotides during the synthesis of DNA in dividing cells. Ribonucleotide reductase is a target for the development of new drugs design to treat cancer and other malignant tumors. Although, hydroxyurea is used for the treatment of melanoma, certain types of leukemia and ovarian cancer, and was shown to be useful in combination therapy in cancer and AIDS treatment', it presents several disadvantages such as short half-life associated with its small molecular size and its very polar nature, and the rapid development of resistance2 . A need exists for drugs which would possess the efficiency of hydroxyurea without its shortcomings. In this spirit, Schiff bases of 117 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. hydroxysemicarbazide, semicarbazide, and aminohydroxyguanidine (Figure 7.2, Figure 7.3) have been prepared and tested in vitro against L1210 murine leukemia cells. Results of those tests and QSAR analysis are published elsewhere3 -4 -5 . This paper describes the NMR characterization and stereoisomeric assignment (E/Z) of compounds 1-49. Those compounds were characterized by NMR spectroscopy (proton, carbon-13, 2D, and ID differential NOE). Compound 8,34 and 40 were also characterized by X-ray crystallography (see details in appendix D). Proton assignments are based on chemical shift, multiplicity, and differential NOE experiments. Since the azomethine proton (Figure 7.1) is not exchangeable, the chemical shift of this proton could be assign with certainty when spectra were recorded in methanol-d4 . Because the proton chemical shifts did not significantly change whether the spectra were recorded in DMSO-d6 or methanol-d4 , only chemical shifts recorded in DMSO-d6 are reported. Carbon assignments are based on chemical shifts, multiplicity in t3 C - 'H coupled experiments, and literature data6 . Some compounds were further characterized by 'H,‘H-COSY NMR (2,12, 32) and l3 C, 'H correlated NMR spectroscopy (1, 2, 7, 8,12,13,32, 33,45). Azomethine proton I I / P=N— —C—1 ^ H * Ureido proton X Y H X = 0 , NH Y = H, OH Figure 7.1. General structure of hydroxyurea analogs. 118 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. o u 1 2 II Hydroxysemicarbazides c —n —n - c - nhoh ~ H 3 4 N G “ C ^ WV»— I I OH O^N OH 7 8 9 10 11 H a« ) < p > - ( p ? — h°-< Q > — h> c°“0 ” C ^ - (H jCJj HC. Figure 7.2. Hydroxysemicarbazide structures (1-31). Numbering is shown. I Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Semicarbazides o H 1 2 II C—N—N— C -N H , ^ ~ H 3 4 .OCHg 0- cxr < g h > - Gl On 32 HaGO 33 34 35 Schiff B ases of Aminohydroxyguanidine NH /■ ■ v C —N—N -C -N H O H H3C—( k \ — S03H ^ ~ H 2 3 V V HCOCHN - Q - 0 j N ^ k ^ 36 37 38 39 CO, CCC OcV x & 40 41 42 43 44 C l C l 45 46 o 6 r ” “ ) 6 r ° NH2 Br H3C - N 47 48 ch3 49 Figure 7.3. Semicarbazide structures (32-35) and Schiff bases of aminohydroxyguanidine (36-49). 120 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 7 2 R esu lts an d D iscu ssion NMR spectra of compounds 1-49 do not show any evidence for the presence of both stereoisomers in the sample (no duplicate signals were observed). This could also mean that exchange between Z and E is very fast under the conditions of the study. However, several arguments are in favor of the presence of only one stereoisomeric form: 1) after recrystallization compounds 1- 49 display sharp melting points, and a single spot in TLC3 '4 '7 , 2) spectra recorded at lower temperatures (about 0 °C) do not display any splitting of signals or other significant changes, 3) NMR studies on semicarbazones indicate that both stereoisomers are observed and distinguished at room temperature and higher temperatures when present in the spectra8 9 , 4) synthesis of benzaldehyde semicarbazone (analog to compound 1) from a similar procedure yields the E isomer in 80% yield; the E isomer is then photolyzed to produce the Z isomer in a 1.3:1 ratio. The ureido proton of benzaldehyde semicarbazone displays a significant difference in chemical shift whether it is syn or anti to the aromatic ring (9.09 ppm, and 10.33 ppm respectively)1 0 1 1 (the chemical shift of the ureido proton in 1 is 10.42 ppm), 5) crystallographic data on compounds 8,34 and 40 show only isomer E (Figure 7.4). X-Ray crystallography is probably the best method to establish the configuration and spatial arrangement of atoms in a molecule. 121 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a) Ureido H Azomethine H 03 C7 C5 C8 C4 N2 N3 C6 Cl Double bond 02 C2 O I b) Azomethine H M 2 C2 C10 C3 03 C7 C12 N3 C6 Double bond C4 C S C8 0 2 01 c) Azomethine H N3 CS C9 C4 C7 C8 03 N4 C3 l C 6 Double bond N2 C2 02 O I Figure 7.4. X-ray crystallography, a) compound 8. b) compound 34. c) compound 40. 122 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. However, obtaining crystals suitable for crystallography can be arduous. All the compounds studied were very insoluble in most common solvents, thus only two crystals of suitable quality were obtained. Therefore, the use of NMR spectroscopy was explored as a rapid method for the determination of £/Z configuration of compounds 1-49. All the chemical shifts assigned to ureido protons are comprised between 9.97 and 11.01 ppm, with an average of 10.46 ppm. This assignment correlates with the chemical shift observed in the case of the E isomer of benzaldehyde semicarbazone (see above). 1D differential NOE experiments are expected to show correlations between the azomethine and ureido protons for compounds in the E configuration, but not for compounds in the Z configuration (Figure 7.5). Figure 7.5. Expected correlation between azomethine and ureido protons in ID differential NOE experiments. Azomethine proton Ureido proton E Z X = O, NH ; Y = H, OH 123 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 7.1 shows the results obtained for several compounds in the three classes studied. Cpd. Azomethine proton 5 % enhancement . . of the ureido Ureido , . signal when proton ... r ^ azomethine frequency is irradiated % enhancement of the azomethine signal when ureido frequency is irradiated 1“ 7.96 10.42 10 12 2* 8.05 10.46 1.0 1.7 3“ 8.33 10.96 2.5 2.5 8 8.24 11.01 6.6 10 10“ 7.86 9.97 3.5 2.6 13“ 7.94 10.25 5.0 9.9 15 7.95 10.18 7.4 10 18“ 8.65 10.61 1.9 3.9 19 7.93 10.15 4.2 6.2 24 7.97 10.55 4.5 16 25 8.23 10.80 5.1 19 28 8.07 10.42 5.0 13 29b 7.84 10.14 3.7 4.0 31“ 9.25 10.72 4.7 4.1 32“ 8.11 10.38 7.7 20 33 8.18 10.21 1.9 5.0 34“ 7.76 10.06 4.1 5.7 35* 7.91 10.18 1.9 2.2 41 8.64 10.15 NA 21.76 Table 7.1. Differential NOE spectroscopy. Enhancements observed at the ureido and azomethine resonance. “ Spectra recorded at room temperature. b Spectra recorded at 330 K. While correlation for semicarbazides (32-35) and hydroxysemicarbazides (1-31) were easily accessible, aminohydroxyguanidines derivatives (36-49) did 124 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. not give conclusive results. This was due to the aggregate signals of the azomethine proton with two other exchangeable protons, which rendered selective irradiation difficult. On the other hand, the purported ureido resonance signal around 10.S ppm was broad and weak (probably due to the presence of the tosylate moiety), thus irradiation at this site could not provide any information. Various conditions of irradiation power, irradiation time, and temperature were explored unsuccessfully. Only compound 41 displayed enhancement of the azomethine signal when the ureido proton was irradiated. Figure 7.6 shows a typical irradiation sequence (compound 1). Figure 7.7 shows the results obtained after processing the information. When the azomethine proton (7.96 ppm) is irradiated, 10% enhancement is observed at 10.42 ppm (ureido proton), and 10% enhancement is observed at 7.69 ppm, (ortho protons), as expected. Irradiation at 9.33 ppm and 8.57 ppm displayed significant correlation to each other and only smaller correlations with the 10.42 resonance signal, which is consistent with the assignment of those signals to the protons of C(0)NH0H moiety. Finally, irradiation at the 10.42 frequency gives a strong enhancement of the azomethine resonance signal and smaller ones at 9.33 and 8.57 ppm, again as expected for the molecule in the £ configuration. Based on ID differential NOE experiments, proton assignments, and crystallographic data, compound 1-49 were found to be £. 1D differential NOE 125 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. experiments provide a fast and convenient method for the determination of the (£7Z) configuration of semicarbazide and hydroxysemicarbazides (less than 10 min for samples of good concentration). Irradiated frequency Irradiated frequency Irradiated frequency V A / L _ Irradiated frequency Arom-H Ureido H Azomethine H NH. OH 7.5 10.0 9.5 8.5 8.0 9.0 Figure 7.6. Irradiation sequence for compound 1. 126 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Irradiated frequency (ureido) Signal enhanced (azomethine) Irradiated frequency (NH, OH) 1 Signal enhanced (ureido) Signal enhanced (NH, OH) Signal enhanced (ureido) Signal enhanced (NH, OH) Irradiated frequency (NH, OH) Irradiated frequency (azomethine) — i— 8.S \ Signal enhanced (ortho- H) — i— 7.5 10.0 — I -- '—1 —1 —1 —I — 9.5 9.0 r 0.0 Figure 7.7. Results from ID differential NOE experiments on compound 1. 127 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 73 Experimental Procedures NMR spectra were recorded on a Bruker AMX-500 MHz FT-NMR spectrometer, at 320 K unless otherwise indicated. 10 to 20 % samples were prepared in DMSO-d6 in 5 mm tubes under argon and left to equilibrate. lH NMR spectra were also recorded in methanol-d4 to confirm assignments of the exchangeable protons. Before differential NOE experiments, the samples were freshly degassed with dry and oxygen free argon. The frequencies of interest were typically irradiated for 5 sec at 20.00 Db. The enhancements are given in percentage relative to the irradiated frequency. Lower temperature spectra were obtained from sample in CDCl3 /DMSO-d6 mixture, the temperature was lowered as much as possible before freezing of the sample (usually around 0 °C). Diffraction data for 8,34 and 40 were collected at room temperature (T = 23 °C) on SMART APEX CCD diffractometer with graphite monochromated Mo-Ka radiation (X = 0.71073 A). The cell parameters for the compound were obtained from the least-squares refinement of the spots (from 60 collected frames) using SMART program. A hemisphere of the crystal data was collected up to a resolution of 0.75 A, the intensity data were processed using the Saint Plus program. All calculations for structure determination were carried out using the SHELXTL package (version 5.1)1 2 . Initial atomic positions were located by direct methods using XS, and structure was refined by least-squares methods using 128 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. SHELX within the range of theta 1.38 - 24.71°. Absorption corrections were applied by using SADABS1 3 for compound 8. Calculated hydrogen positions were input and refined in a riding manner along with the attached carbons. A summary of the refinement details and the resulting factors are given in Table 1 for each compounds (appendix D). l-benzylidene-4-hydroxysemicarbazide (1) ‘H NMR 5 7.35 (m, 3H, meta-//, para-H), 7.69 (d, 3 JH H = 7.0 Hz, 2H, ortho-//), 7.96 (s, 1H, -C//=), 8.57, 9.33 (2s, 2H, N//OZ/), 10.42 (s, 1H, NH, ureido). 1 3 C NMR 5 128.20, 129.70 (CD , Cm ), 130.82 (Cp ), 135.94 (C,), 145.55 (-CH=), 160.54 (C=0). l-(3-Trit1uoromethylbenzylidene)-4-hydroxysemicarbazide (2) 'H NMR 8 7.59 (t, 3 JH H = 7.3 Hz, 1H, 5-ArH), 7.64 (d, 3 JH H = 7.1 Hz, 1H, 4-Ar//), 7.92 (d, 3 Jhh = 7.5 Hz, IH, 6-AtH), 8.05 (s, 1H, -C//=), 8.10 (s, 1H, 2-ArH), 8.53, 9.48 (2s, 2H, NHOH), 10.46 (s, 1H, NH, ureido). l3 C NMR 8 122.65 (2-ArC), 124.07 (-CF3 ), 125.17 (4-ArC), 129.47 (5-ArC), 129.69 (3-ArC), 130.68 (6-ArQ, 135.90 (1-ArC), 139.96 (-CH=), 156.96 (C=0). l-(2-Hydroxy-3,5-dichlorobenzylidene)-4-hydroxyseinicarbazide (3) lH NMR 8 7.45,7.52 (d, 4 JH H = 2.5 Hz, 1H; d, 4 JH H = 2.5 Hz, 1H; ArH), 8.33 (s, Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. IH, -C//=), 8.78,9.33 (2s, 2H, NHOH), 10.96 (s, 1H, NH ureido) 11.98 (broad s, ArO//). I 3 C NMR 5 121.47, 121.85 (1,3-ArC), 122.93 (5-ArC), 127.21 (6-ArC), 129.16 (4-ArC), 142.06 (-CH=), 151.46 (2-ArC), 156.70 (C=0). l-(2-Hydroxy-5-bromobenzylidene)-4-hydroxysemicarbazide (4) 'H NMR S 6.82 (d, 3 JH H = 8.7 Hz, 1H, 3-ArH), 7.31 (dd, 3 JH H = 8.7 Hz, 4 JH H = 2.5 Hz, 1H, 4-ArH), 7.81 (d, 4 JH H = 2.5 Hz, 1H, 6-ArH), 8.25 (s, IH, -C//=), 8.58,9.32 (2s, 2H, NHOH), 10.58 (s, IH, NH, ureido), 10.75 (broad s, 2-ArO//). 1 3 C NMR 8 110.50, 122.19 (1,5-ArC), 118.30 (3-ArC), 129.66 (6-ArC), 132.47 (4-ArO, 139.50 (-CH=), 155.55 (2-ArC), 156.86 (C=0). l-(2-Hydroxy-3,5-dibromobenzylidene)-4-hydroxysemicarbazide (5) lH NMR 5 7.63, 7.68 (d, 4 JH H = 2.4 Hz, IH; d, 4 JH H = 2.4 Hz, IH, 4,6-ArH), 8.31 (s, IH, -CH=), 8.81 (broad s, IH, NHOtf), 9.31 (s, IH, N//OH), 11.01 (s, IH, NH, ureido), 12.24 (broad s, IH, 2-ArO//). ,3 C NMR 8 110.30 (5-ArC), 111.18, 121.93(1,3-ArC), 130.98 (6-ArC), 134.52 (4-ArC), 142.45 (-CH=), 152.94(2- ArC), 156.65 (C=0). M2-Hydroxy-3-methoxy-5-bromobenzylidene)-4- hydroxysemicarbazide (6) ‘H NMR 8 3.81 (s, 3H, -OCH3 ), 7.05 (d, 4 JH H = 2.2 130 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Hz, IH, 4-Artf), 7.43 (d, 4 JH H = 2.2 Hz, IH, 6-ArH), 8.27 (s, IH, -CH=), 8.65 (very broad s, NHO//), 9.43 (s, IH, N//OH), 10.25 (very broad s, 2-AiOH), 10.66 (s, IH, NH, ureido). 1 3 C NMR 8 56.21 (-OCH3 ), 109.93 (5-ArC), 115.33 (4-ArC), 121.22 (6-ArC), 121.66 (1-ArC), 139.86 (-CH=), 145.32 (2-ArC), 148.87 (3- ArC), 156.66 (C=0). l-(3-Iodobenzylidene)-4-hydro\ysemicarbazide (7) 'H NMR 5 7.17 (t, 3 Jhh = 7.8 Hz, IH, 5-ArH), 7.62 (dt, 3 JH H = 7.8 Hz, 4 JH H = 1.3 Hz, IH, 6-ArH), 7.68 (ddd, 3 Jhh = 7.9 Hz, 4 JH H = 1.7 Hz, 4 JH H = 1.0 Hz, IH, 4-Ar//), 8.16 (t, 4 JH H = 1.6 Hz, IH, 2-ArH), 7.88 (s, IH, -C//=), 8.48, 9.40 (2s, 2H, NHOH), 10.38 (s, IH, NH ureido). 1 3 C NMR 8 94.97 (3-ArC), 126.44 (6-ArC), 130.56 (5-ArC), 134.33 (2-ArO, 137.06 (1-ArC), 137.45 (4-ArC), 139.62 (-CH=), 156.76 (C=0). l-(2-Hydroxy-3,5-diiodobenzylidene)-4-hydroxyseinicarbazide (8) 'H NMR 8 7.68 (d, 4 JH H = 2.4 Hz, IH, 6-ArH), 7.95 (d, 4 JH H = 2.1 Hz, IH, 4-ArH), 8.24 (s, IH, -CH=), 8.82, 9.27 (2s, 2H, NHOH), 11.0l(s, IH, NH ureido), 12.55 (broad s, IH, 2-ArOtf). 1 3 C NMR 8 81.65, 87.43 (3,5-ArC), 121.11 (1-ArC), 137.84 (6-ArC), 143.01 (-CH=), 145.55 (4-ArC), 156.01 (2-ArC), 156.68 (C=0). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. l-(4-Cyanobenzylidene)-4-hydroxysemicarbazide (9) lH NMR 8 7.79, 7.88 (d, 3 Jhh = 8.3 Hz, 2H, Ar-tf; d, 3 JH H = 8.4 Hz, 2H, AiH), 8.00 (s, IH, -CH=), 8.65,9.60 (2s, 2H, NHOH), 10.70 (s, IH, NH, ureido). 1 3 C NMR 8 110.82 (4- ArC), 118.47 (-CN), 127.00 (2,6-ArC), 132.17 (3,5-ArC), 139.11 (1-ArC), 139.29 (-CH=), 156.36 (C=0). l-(4-Dimethylaminobenzylidene)-4-hydroxysemicarbazide (10) 'H NMR 8 2.93 [s, 6H, -N(C//3 )J, 6.69 (d, 3 JH H = 9.0 Hz, 2H, 3,5-ArH), 7.48 (d, 3 JH H = 8.9 Hz, 2H, 2,6-ArH), 7.86 (s, IH, -CH=), 8.41, 8.96 (2s, 2H, NHOH), 9.97 (s, IH, NH, ureido). l3 C NMR 8 39.76 [-N(CH3 ),J, 111.77 (3,5-ArC), 122.34 (1- ArQ, 127.85 (2,6-ArC), 142.74 (-CH=), 151.04 (4-ArC), 157.33 (C=0). l-(2-Hydroxy-3,5-dinitrobenzylidene)-4-hydroxysemicarbazide (11) ‘H NMR 8 8.50 (s, IH, -C//=), 8.68, 8.71 (d, 4 JH H = 2.8 Hz, IH; d, 4 JH H = 2.5 Hz, IH, AtH), 8.50, 8.71,9.46, 11.19 (NH, NH, OH, AiOH). 1 3 C NMR 8 121.22 (4- ArO, 123.65 (1-ArC), 127.44 (6-ArO, 137.12, 137.59 (3,5-ArC), 140.50 (-CH=), 156.43 (C=0), 156.92 (2-ArC). l-(3-Nitrobenzy!idene)-4-hydroxysemicarbazide (12) 'H NMR 8 7.66 (t, 3 Jhh = 8.0 Hz, IH, 5-ArH), 8.08 (s, IH, -C//=), 8.10 (dt, 3 JH H = 7.8 Hz, 4 J = 1.1 132 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Hz, IH, 6-ArH), 8.15 (ddd, 3 JH h = 8.5 Hz, 4 JH H = 2.3 Hz,4 Jhh = 1.1 Hz, IH, 4- ArH), 8.54 (t, 4 JH H = 2.0 Hz IH, 2-ArH), 8.53,9.51 (2s, 2H, NHOH), 10.55 (s, IH, NH, ureido). l3 C NMR 5 120.56 (2-ArC), 123.21 (4-ArC), 130.01 (5-ArC), 132.87 (6-ArC), 136.72 (1-ArC), 139.09 (-CH=), 148.38 (3-ArQ , 156.65 (C=0). l-(3-Metho\ybenzylidene)-4-hydroxysemicarbazide (13) 'H NMR 8 3.79 (s, 3H, -OC//3 ), 6.91 (ddd, 3 JH H = 8.2 Hz, 4 J„H = 2.6 Hz, 4 JH H = 1.0 Hz, IH, 4- ArH), 7.19 (dt, 3 JH H = 7.6 Hz, 4 J = l.l Hz, IH, 6-ArH), 7.28 (t, 3 J„H = 7.8 Hz, IH, 5-ArH), 7.31 (t, 4 JH H = 1.5 Hz, IH, 2-ArH), 7.94 (s, IH, -CH=), 8.44,9.24 (2s, 2H, NHOH), 10.25 (s, IH, NH, ureido). 1 3 C NMR 8 55.03 (-OCH3 ), 110.71 (2-ArC), 115.31 (4-ArC), 119.54(6-ArC), 129.34 (5-ArC), 136.00(I-ArC), 141.36 (- CH=), 156.74 (C=0), 159.41 (3-ArC). l-(2,4-dihydroxybenzylidene)-4-hydroxysemicarbazide (14) 'H NMR 5 6.28 (d, 3 Jhh = 2.4 Hz, IH, 3-ArH), 6.31 (dd, 3 JH H = 8.4 Hz, 4 JH H = 2.4 Hz, IH, 5- ArH), 7.19 (d, 3 JH H = 8.4 Hz, IH, 6-ArH), 8.25 (s, IH, -C//=), 8.99 (s, IH, NHOH), 8.66, 9.75, 11.02 (3 broad s, 3H, NHOH, 2,4-ArOH), 10.37 (s, IH, NH, ureido). 1 3 C N M R 8 102.66, 107.40 (3,5-ArC), 111.06 ( 1-ArC), 130.49 (6-ArC), 145.23 (-CH=), 157.28 (C=0), 158.66, 159.86 (2,4-ArC). 133 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. l-(4-MethoxybenzyIidene)-4-hydroxyseinicarbazide (15) ‘H NMR 8 3.76 (s, 3H, -OCH3 ), 6.92 (d, 3 JH H = 8.8 Hz, 2H, 3,5-ArH), 7.62 (d, 3 JH H = 8.8 Hz, 2H, 2,6-ArH), 7.95 (s, IH, -C//=), 8.51,9.16 (2s, 2H, NHOH), 10.18 (s, IH, NH, ureido). 1 3 C NMR 8 55.18 (-OCH3 ), 114.07 (3,5-ArC), 127.34 (1-ArC), 128.17 (2,6-ArC), 141.86 (-CH=), 157.27 (C=0), 160.22 (4-ArC). l-(2,5-Dimelhoxybenzylidene)-4-hydroxysemicarbazide (16) H NMR 8 3.74 (s, 3H, -OCH3 ), 3.76 (s, 3H, -OCH3 ), 6.89 (dd, 3 JH H = 9.0 Hz, 4 JH H = 3.0 Hz, IH, 4-ArH), 6.95 (d, 3 J„H = 9.0 Hz, IH, 3-Ar//), 7.52 (d, 4 JH H = 2.9 Hz, IH, 6- ArH), 8.26 (s, IH, -C//=), 8.41, 9.30 (2s, 2H, NHOH), 10.29 (s, IH, NH, ureido). 1 3 C NMR 8 55.50, 56.20 (-OCH3 ), 109.93, 113.00, 116.67 (3,4,6-ArQ, 123.51 (l- ArO, 151.72, 153.38 (2,5-ArC), 136.88 (-CH=), 156.89 (C=0). l-(2-Hydroxy-4-methoxybenzylidene)-4-hydroxysemicarbazide (17) 'H NMR 8 3.74 (s, 3H, -OCH3 ), 6.43 (d, 4 JH H = 2.5 Hz, IH, 3-ArH), 6.45 (dd, 3 JH H = 8.5 Hz, 4 Jhh = 2.5 Hz, IH, 5-ArH), 7.31 (d, 3 JH H = 8.6 Hz, IH, 6-ArH), 8.29 (s, IH, -C//=), 8.66,9.03 (2s, 2H, NHOH), 10.46 (s, IH, NH, ureido), 11.28 (broad s, IH, 2-ArO//). 1 3 C NMR 8 55.16 (-OCH3 ), 101.21 (3-ArC), 106.02 (5-ArC), 112.38 (1-ArC), 130.30 (6-ArC), 144.63 (-CH=), 157.17 (C=0), 158.59 (2-ArQ, 161.37 (4-ArQ- 134 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. l-(2-Hydroxy-4,6-dimethoxybenzylidene)-4-hydroxysemicarbazide (18) ‘H NMR 8 3.75 (s, 3H, -OCH3 ), 3.79 (s, 3H, -OCH3 ), 6.07,6.09 (d, 4 JH H = 2.3 Hz, IH; d, 4 JH H = 2.2 Hz, IH; 3,5-Ar//), 8.65 (s, IH, -CH=), 8.67, 8.93 (2s, 2H, NHOH), 10.61 (s, IH, NH, ureido), 12.17 (s, IH, 2-ArOH). l3 C NMR 5 55.27, 55.84 (-OCHj), 90.27,93.90 (3,5-ArC), 101.06 (1-ArC), 159.09, 160.20, 162.30 (2,4,6-ArC), 142.62 (-CH=), 157.17 (C=0). l-(4-benzyloxybenzylidene)-4-hydroxysemicarbazide (19) 'H NMR 5 5.13 (s, 2H, -CH2 0-), 7.02 (d, 3 JH H = 8.8 Hz, 2H, 3,5-Artf), 7.32 (tt, 3 JH H = 7.3 Hz, 4 Jhh = 1.4 Hz, IH, 4’-ArH), 7.38 (td, 3 JH H = 7.4 Hz, 4 JH H = 14 Hz, 2H, 3’,5’-Ar//), 7.44 (dd, 3 Jhh = 7.5 Hz, 4 JH H = 1.4 Hz, 2H, 2’,6’-Ar//), 7.62 (d, 3 JH H = 8.7, 2H, 2,6- ArH), 7.93 (s, IH, -CH=), 8.44,9.12 (2s, 2H, NHOH), 10.15 (s, IH, NH ureido). l3 C NMR 8 69.39 (-CH,0-), 114.99 (3,5-ArC), 127.55, 127.67, 127.82, 128.13, 128.38 ( l,2 ,6 ,2 ’-6’-ArC), 136.89 ( l’-ArC), 141.58 (-CH=), 157.14 (C=0), 159.28 (4-ArC). l-(4-phenylbenzylidene)-4-hydroxysemicarbazide (20) 'H NMR 8 7.35 (tt, 3 Jhh = 7.3 Hz, 4 Jhh = 11 Hz, IH, 4’-ArH), 7.45 (td, 3 JH H = 7.4 Hz, 4 JH H = 1.8 Hz, 2H, 3 \5 ’-ArH), 7.67, 7.78 (d, 3 JH H = 8.4 Hz, 4H; d, 3 JH H = 8.3 Hz, 2H, 135 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2,3,5,6,2\ 6’-Ar//), 8.06 (s, IH, -C//=), 8.51, 9.24 (2s, 2H, NHOH), 10.33 (s, IH, NH, ureido). l3 C NMR 8 126.34 (3’,5’-ArH), 126.55, 127.05, 128.69 (2,6,3,5,2’,6’-ArC), 127.40 (4’-ArC), 133.71, 139.33, 140.58 (1,1’,4-ArC), 141.27 (-CH=), 156.86 (C=0). l-(2,3,4-trihydroxybenzylidene)-4-hydroxysemicarbazide (21) 'H NMR 8 6.32,6.65 (d, 3 JH H = 8.4 Hz, IH; d, 3 J„H = 8.6 Hz, IH, 5,6-Artf), 8.24 (s, IH, -CH=), 8.76, 9.06 (2s, 2H, NHOH), 10.58 (s, IH, NH ureido), 8.35,9.29, II.21 (3 broad s, 3H, 2,3,4-ArO//). l3 C NMR 8 107.35 (5-ArC), 111.45 (1-ArC), 120.17 (6-ArC), 132.68 (3-ArQ , 146.25 (-CH=), 146.83, 147.85 (2,4-ArC), 157.22 (C=0). l-(4-acetamidobenzylidene)-4-hydroxysemicarbazide (22) ‘H NMR 8 2.04 (-NHCOC//3 ), 7.59, 7.60 (d, 3 JH H = 8.7 Hz, 2H; d, 3 JH H = 8.7 Hz, 2H, ArH), 7.92 (s, IH, -CH=), 8.47, 9.14, 9.94, 10.21 (NH, NH, OH, -N//CO-). I3 C NMR 8 23.94 (-NHCOCH3 ), 118.86, 127.17 (2,3,5,6-ArC), 129.38 (1-ArC), 140.17(4- ArO, 141.55 (-CH=), 157.11 (C=0), 168.33 (-NHCOCH3 ). l-(3-pyridylmethylene)-4-hydroxysemicarbazide (23) H NMR 8 7.38 (dd, 3 Jhh = 8.0 Hz, 4 Jhh = 4.9 Hz, IH, 5-ArH), 8.00 (s, IH, -CH=), 8.12 (dt, 3 JH H = 136 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 8.0 Hz, 4 Jhh = 1.9 Hz, IH, 4-Ar//), 8.51 (dd, 3 JH H = 4.9 Hz, 4 JH H = 1.9 Hz, IH, 6- ArH), 8.82 (d, 4 JH H = 1.8 Hz, IH, 2-ArH), 8.54,9.40 (2s, 2H, NHOH), 10.48 (s, IH, NH, ureido). 1 3 C NMR 8 123.60 (5-ArC), 130.57 (3-ArC), 133.18 (4-ArC), 138.60 (-CH=), 148.17, 149.70 (2,6-ArC), 156.78 (C=0). l-[2-(6-methylpyridyl)methylene]-4-hydroxysemicarbazide (24) ‘H NMR 8 2.48 (s, 3H, -CH3 ), 7.16 (d, 3 JH H = 7.6 Hz, IH, 5-AtH), 7.86 (d, 3 JH H = 7.7 Hz, IH, 3-ArH), 7.66 (t, 3 JH H = 7.6 Hz, IH, 4-ArH), 7.97 (s, IH, -C//=), 8.55, 9.35 (2s, 2H, NHOH), 10.55 (s, IH, NH ureido). 1 3 C NMR 8 23.76 (-CH3 ), 116.78, 122.74 (3,5-ArC), 136.57 (4-ArC), 142.31 (-CH=), 153.10, 156.68, 157.36(2,6- ArC, C=0). l-[2-(5-nitrothienyl)methylene]-4-hydroxysemicarbazide (25) ‘H NMR 8 7.37 (d, 3 JH H = 4.3 Hz, IH, 3-ArH), 8.02 (d, 3 JH H = 4.3 Hz, IH, 4-ArH), 8.23 (s, IH, -C//=), 8.64, 9.35 (2s, 2H, NHOH), 10.80 (s, IH, NH ureido). l3 C NMR 8 127.57, 130.26 (3,4-ArC), 135.31 (-CH=), 147.51, 150.07 (2,5-ArQ, 156.17 (C=0). l-(3-indolylmethylene)-4-hydroxysemicarbazide (26) ‘H NMR 8 7.10, 7.16 (td, 3 Jhh = 7.8 Hz, 3 JH H = 1.3 Hz, IH; td, 3 JH H = 7.1 Hz, 4 JH H = 1.3 Hz, IH, 5,6- 137 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Ar//), 7.40, 8.22 (d, 3 JH H = 8.1 Hz, IH; d, 3 JH H = 7.9 Hz, IH, 4,7-Ar//), 7.64 (s, IH, 2-Ar//), 8.24 (s, IH, -C//=), 8.45, 8.75, 9.92, 11.31 (NH, NH, OH, indole- NH). I 3 C NMR 8 111.39 (7-ArC), 111.58 (3-ArQ, 119.89, 121.63, 122.13 (4,5,6- ArO, 124.15 (9-ArC), 128.53 (2-ArC), 136.78 (8-ArC), 139.84 (-CH=), 157.50 (C=0). H3-(6,8-dichloro-4-oxo-4H-l-benzopyran)methylene]-4- hydroxysemicarbazide (27) ‘H NMR 8 7.94, 8.11 (large peak, 4 JH H = 2.3 Hz, IH; large peak, 4 J„H = 2.4 Hz, IH, 5,7-Ar//), 7.99 (s, IH, -CH=), 8.50 (s, IH, 2- ArH), 9.04,9.39 (2s, 2H, NHOH), 10.51 (s, IH, NH ureido). l3 C NMR 8 119.18 (3-ArC), 123.28 (5-ArC), 123.96 (8-ArC), 125.41 (10-ArC), 130.01 (6-ArC), 131.81 (-CH=), 133.68 (7-ArO, 150.24 (9-ArC), 154.20 (2-ArC), 156.53 (C=0), 173.24 (4-ArC)- l-[3-(6-isopropyl-4-oxo-4H-l-benzopyran)methylene]-4- hydroxysemicarbazide (28) ‘H NMR 8 1.24, 1.26 [s, 6H, -CH(C//3 )2 j, 3.04 [sep, 3 JH „ =7.0 Hz, IH, -C//(CH3 )J, 7.61 (d, 3 JH H = 8.7 Hz, IH, 8-ArH), 7.72 (dd, 3 JH H = 8.7 Hz, 4 Jhh = 2.0 Hz, IH, 7-ArH), 7.92 (d, 4 JH H = 2.3 Hz, IH, 5-ArH), 8.07 (s, IH, -C//=), 8.46 (d, 4 Jhh = 1.0 Hz, IH, 2-ArH), 8.93,9.35 (2s, 2H, NHOH), 10.42 (s, IH, NH ureido). ,3 C NMR 8 23.60 [-CH(CH3 )J, 32.87 [-CH(CH3 )J, 118.51 138 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (3-ArC), 118.55 (8-ArC), 121.54, 121.58 (5,7-ArC), 123.12 (10-ArC), 133.05 (- CH=), 146.17 (6-ArC), 154.05 (2-ArC), 154.23 (9-ArC), 156.70 (C=0), 174.83 (4-ArC). l-(l,4-benzodioxin-6-methylene)-4-hydroxysemicarbazide (29) ‘H NMR 8 4.24 [s, 4H, 2,3-CH2 -], 6.83 (d, 3 JH H = 8.5 Hz, IH, 8-ArH), 7.11 (d, 3 JH H = 8.5 Hz, IH, 1-AxH), 7.24 (s, IH, 5-Ar//), 7.84 (s, IH, -C//=), 8.42,9.17 (2s, 2H, NHOH), 10.14 (s, IH, NH ureido). l3 C NMR 5 63.99,64.22 (2,3-C), 114.77, 117.04, 120.34 (5,7,8-ArC), 128.21 (6-ArC), 141.34 (-CH=), 143.54, 144.53 (9,10-ArC), 157.06 (C=0). l-[9-(10-methylanthryl)methylene]-4-hydroxysemicarbazide (30) ‘H NMR 5 3.10 (s, 3H, -C//3 ), 7.58, 8.40, 8.59 (m, 8H, Ar//), 8.63 (s, IH, -C//=), 8.97,9.25 (2s, 2H, NHOH), 10.62 (s, IH, NH, ureido). l3 C NMR 8 13.99 (-CH3 ), 124.95, 125.17, 125.45, 125.86 (ArCH), 124.63, 129.07, 129.19, 132.15 (Ar-C), 142.17 (-CH=), 157.13 (C=0). l-[9-(10-chloroanthryl)methylene]-4-hydroxysemicarbazide (31) ‘H NMR 8 7.67 (td, 3 JH H = 7.5 Hz, 4 JH H = 1.2 Hz, 2H, 2,7-ArH), 7.73 (td, 3 JH H = 7.5 Hz, 4 Jhh = 1.2 Hz, 2H, 3,6- AiH), 8.48 (d, 3 JH H = 8.7 Hz, 2H, 4,5-Ar-H), 8.64 (d, 139 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3 JH H = 8.7, 2H, 1,8-ArH), 8.67, 9.25 (2s, 2H, NHOH), 9.06 (s, IH, -CH=), 10.72 (s, IH, NH, ureido). 1 3 C NMR 5 124.43, 125.76, 127.02, 127.47 (Ar-CH), 126.60, 127.79, 128.88, 129.70 (Ar-C), 141.29 (-CH=), 157.23 (C=0). l-(2-Hydroxy-3,5-dichlorobenzylidene)seinicarbazide (32) ‘H NMR 8 6.45 (s, 2H, NH2 ), 7.38 (d, 4 JH H = 2.6 Hz, IH, 4-Ar//), 7.70 (d, 4 JH H = 2.5 Hz, IH, 6-Ar//), 8.11 (s, IH, -C//=), 10.38 (s, IH, NH, ureido), 10.56 (broad s, IH, 1- ArO//). l3 C NMR 8 122.00, 123.75 (1,3-ArC), 123.55 (5-ArC), 125.65 (4-ArC), 128.78 (6-ArC), 137.22 (-CH=), 150.35 (C=0), 155.94 (2-ArC). l-(2,5-dimethoxybenzylidene)semicarbazide (33) 'H NMR 8 3.74, 3.75 (2s, 6H, -OC//3 ), 6.44 (s, 2H, N//,), 6.88 (dd, 3 JH H = 9.0 Hz, 4 JH H = 3.1 Hz, IH, 4- ArH), 6.93 (d, 3 JH H = 9.1 Hz, IH, 3-ArH), 7.51 (d, 4 JH H = 3.1 Hz, IH, 6-ArH), 8.18 (s, IH, -C//=), 10.21 (s, IH, NH, ureido). l3 C NMR 8 55.49, 56.12 (-OCH3 ), 109.98 (6-ArC), 113.06 (3-ArC), 116.21 (4-ArO, 123.55 (1-ArC), 135.01(-CH=), 151.65, 153.40, 156.86 (2,5-ArC, C=0). l-(l,4-benzodioxan-6-ylmethylene)semicarbazide (34) ‘H NMR 8 4.25 [s, 4H, 2,3-C//,-], 6.37 (s, 2H, NH2 ), 6.85 (d, 3 JH H = 8.3 Hz, IH, 8-ArH), 7.14 (dd, 3 Jhh = 8.4 Hz, 4 Jhh = 2.0 Hz, IH, 7-ArH), 7.26 (d, 4 JH H = 2.0 Hz, IH, 5-Ar//), 7.76 140 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (s, IH, -CH=), 10.06 (s, IH, NH, ureido). I3 C NMR 8 63.88, 64.11 (2,3-0, 114.57, 120.04 (7,8-ArQ, 116.94 (5-ArC), 128.16 (6-ArC), 139.16 (-CH=), 143.44, 144.32 (9,10-ArQ, 156.78 (C=0). l-(4-phenylbenzylidene)semicarbazide (35) lH NMR 5 6.40 (s, 2H, N//,), 7.35 (tt, 3 Jh h = 7.4 Hz, 4 JH H = 1.1 Hz, IH, 4’-Ar//), 7.45 (t, 3 JH H = 7.9 Hz, 2H, 3’,5’-Ar//), 7.67 (m, 4H, 3,5,2’,6’-Ar//), 7.78 (d, 3 JH H = 8.5 Hz, 2H, 2,6- ArH), 7.91 (s, IH, -CH=), 10.18 (s, IH, NH, ureido). 1 3 C NMR 8 126.39, 126.60, 126.93, 128.74(2,3, 5 ,6 ,2 \3 \5 \6 ’-ArC), 127.43 (4’-ArQ, 133.79 (1-ArC), 138.90 (-CH=), 139.38, 140.43 (4,1’-ArQ, 156.56 (C=0). l-(4-Acetamidobenzylidene)amino-3-hydroxyguanidine Tosyiate (36) ‘H NMR d 2.05 (s, 3H, CH3 -C=O), 2.27 (s, 3H, -CH3 , tosyiate), 7.12, 7.49 (d, 2H, 3 Jhh = 8.1 Hz; d, 2H, 3 JH H = 8.2 Hz, ArH, tosyiate), 7.64,1.11 (d, 2H, 3 JH H = 9.0 Hz; d, 2H, 3 JH H = 9.0 Hz, 2,3,5,6-ArH), 8.15 (s, IH, H-C=N-), 8.12 (broad s, 2H), 10.05 (broad s, IH), 10.50 (broad s, IH), 11.00 (very broad s), 12.00 (very broad s) (NH, OH). l3 C NMR d 20.67 (-CH3 , tosyiate), 24.10 (CH3 -C=0), 118.70, 128.42 (2,3,5,6-ArC), 127.96 (1-ArC), 125.43, 128.24 (ArCH, tosyiate), 138.44 (CH3 -ArC, tosyiate), 141.45 (4-ArC), 144.32 (HS03 -ArC, tosyiate), 147.57 (broad s, -CH=N-), 155.96 (-C=NH), 168.69 (C=0). 141 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. l-[2-(5-Nitrofurfurylidene)]amino-3-hydroxyguanidine Tosyiate (37) 'H NMR 8 2.27 (s, 3H, -C//3 , tosyiate), 7.15, 7.53 (d, 2H, 3 J„H = 8.1 Hz; d, 2H, 3 JH H = 8.2 Hz, Ar//, tosyiate), 7.43 (d, IH, 3 JH H = 3.9 Hz, 3-Ar//), 7.82 (d, IH, 3 JH H = 3.9 Hz, 4-Ar//), 8.35 (s, IH, H-C=N-), 8.20 (broad s, 2H), 10.28 (broad s, IH), 11.10 (very broad s), 11.90 (very broad s) (NH, OH). I3 C 8 20.69 (-CH3 , tosyiate), 114.90, 114.93 (3,4-ArC), 125.40, 128.16 (ArCH, tosyiate), 135.60 (broad s, -CH=N-), 138.10 (CH3 -ArC tosyiate), 144.80 (HSOr ArC, tosyiate), 151.20, 151.80 (2,5-ArC), 155.41 (-C=NH). l-[2-(4-Bromothienyl)methylene]amino-3-hydroxyguanidine Tosyiate (38) ‘H NMR 8 2.27 (s, 3H, -C//3 , tosyiate), 7.12, 7.48 (d, 2H, 3 JH H = 8.1 Hz; d, 2H, 3 Jhh = 8.2 Hz, Ar//, tosyiate), 7.64, 7.85 (d, IH; s, IH, 3, 5-Ar//), 8.38 (s, IH, H-O N -), 8.14 (broad s, 2H), 10.10 (broad s, IH), 11.10 (very broad s), 11.90 (very broad s) (NH, OH). 1 3 C 8 20.81 (-CH3 , tosyiate) 109.39, 127.24, 132.76 (ArC), 125.50, 128.27 (ArCH, tosyiate), 138.20, 139.00 (ArC, CH3 -ArC tosyiate), 141.44 (broad s, -CH=N-), 144.87 (HS03 -ArC, tosyiate), 155.61 (-C=NH). l-[(5-Nitro-2-thienyl)methylene]amino-3-hydroxyguanidine Tosyiate (39) lH NMR 8 2.27 (s, 3H, -C//3 , tosyiate), 7.12,7.48 (d, 2H, 3 JH H = 8.1 Hz; d, 142 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2H, 3 Jhh = 8.2 Hz, ArH, tosyiate), 7.62 (d, IH, 3 JH H = 4.3 Hz, 3-Ar//), 8.13 (d, IH, 3 Jhh = 4.2 Hz, 4-Ar//), 8.41 (s, IH, H-O N -), 8.31 (broad s, 2H), 10.20 (broad s, IH), 11.50 (very broad s), 12.00 (very broad s) (N//, OH). ,3 C 8 20.69 (-CH3 , tosyiate), 125.39, 128.09 (ArCH, tosyiate), 130.23, 130.09 (3,4-ArC), 137.91 (CH3 -ArC tosyiate), 140.99(broad s, -CH=N-), 144.87 (HS03 -ArC, tosyiate), 145.05 (2-ArC), 151.64 (5-ArC), 155.34 (-C=NH). l-(l,3-benzodioxole-5-methyleneamino)-3-hydroxygtianidine Tosyiate (40) lH NMR 5 2.27 (s, 3H, -C//3 , tosyiate), 6.09 (s, 2H, 2-C//2 ), 6.98 (d, IH, 3 JH H = 8.0 Hz, 4-Ar//), 7.12, 7.48 (d, 2H, 3 JH H = 8.1 Hz; d, 2H, 3 JH H = 8.2 Hz, ArH, tosyiate), 7.17 (dd, IH, 3 JH H = 8.0 Hz, 4 JH H = 1.4 Hz, 5-Ar//), 7.64 (d, IH, 4 JH H = I.4 Hz, 7-Ar//), 8.12 (s, IH, H-C=N-), 8.07 (broad s, 2H), 10.03 (broad s, IH), II.00 (very broad s), 12.00 (very broad s) (N//, OH). 1 3 C NMR 8 20.88 (-CH3 , tosyiate), 101.71 (2-CH,), 105.70 (4-ArQ, 108.24 (7-ArQ, 124.59 (5-ArQ, 127.92 (6-ArQ, 125.61, 128.51 (ArCH, tosyiate), 138.72 (CH3 -ArC, tosyiate), 144.44 (HS03 -ArC, tosyiate), 147.45 (broad s, -CH=N-), 148.17, 149.56 (8,9- ArQ, 156.02 (-C=NH). l-(6-nitro-l^-benzodioxole-5-methyleneamino)-3-hydroxyguanidine Tosyiate (41) 'H NMR 8 2.27 (s, 3H, -C//3 , tosyiate), 6.28 (s, 2H, 2-C/Q, 7.11, 143 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. l-[3-(6-Chloro-4-oxo-4H-l-benzopyran)methyleneamino]-3- hydroxyguanidine Tosyiate (43) 'H NMR 8 2.27 (s, 3H, -C//3 , tosyiate), 7.13, 7.55 (d, 2H, 3 Jhh = 8.1 Hz; d, 2H, 3 JH H = 8.2 Hz, ArH, tosyiate), 7.73 (d, 3 JH H = 8.9 Hz, IH, 8-Ar//), 7.82 (dd, 3 JH H = 8.9 Hz, 4 JH H = 2.6 Hz, IH, 7-ArH), 7.98 (d, 4 JH H = 2.6 Hz, IH, 5-Ar//), 8.30 (broad s, IH, H-C=N-), 9.11 (s, IH, 2-Ar//), 8.40 (broad s, 2H), 10.20 (broad s, IH), 11.30 (very broad s), 11.70 (very broad s) (NH, OH). 1 3 C 8 20.85 (-CH3 , tosyiate), 117.95 (3-ArC), 121.36 (5-ArC), 124.11 (8-ArC), 124.63 (10-ArC), 125.63, 128.35 (ArCH, tosyiate), 130.79 (6-ArC), 134.60 (7-ArC), 138.37 (CH3 -ArC tosyiate), 139.66 (broad s, -CH=N-), 144.64 (HS03 -ArC, tosyiate), 154.44 (9-ArC), 156.07 (-C=NH), 156.30 (2-ArC), 173.59 (4-C=0). l-[3-(6-Methyl-4-oxo-4H-l-benzopyran)methyleneamino]-3- hydroxyguanidinc Tosyiate (44) 'H NMR 8 2.25 (s, 3H, -C//3 , tosyiate), 2.45 (s, 3H, -C//3 ), 7.15, 7.50 (d, 2H, 3 JH H = 8.1 Hz; d, 2H, 3 JH H = 8.2 Hz, ArH, tosyiate), 7.64 (d, 3 Jhh = 8.6 Hz, IH, 8-Ar//), 7.69 (dd, 3 JH H = 8.7 Hz, 4 JH H = 2.2 Hz, IH, 7- ArH), 7.92 (d, 4 JH H = 2.3 Hz, IH, 5-ArH), 8.40 (s, IH, H-O N -), 9.20 (d, 4 JH H = 0.4 Hz, IH, 2-Ar//), 8.25 (broad s, 2H), 10.20 (broad s, IH), 11.20 (very broad s), 11.80 (very broad s) (NH, OH). l3 C 8 20.54 (CH3 -), 20.85 (-CH3 , tosyiate), 117.61 (3-ArC), 118.53 (5-ArC), 123.15 (10-ArC), 124.45 (8-ArC), 125.64, 145 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 128.42 (ArCH, tosylate), 135.72 (7-ArC), 135.92 (6-ArC), 138.58 (CH3 -ArC tosylate), 138.58 (broad s, -CH=N-), 144.64 (HS03 -ArC, tosylate), 154.11 (9- ArC), 155.86 (2-ArC), 156.06 (-C=NH), 174.49 (4-C=0). l-[3-(6,8-Dichloro-4-oxo-4H-l-benzopyran)methyleneamino]-3- hydroxyguanidine Tosylate (45) ‘H NMR 8 2.27 (s, 3H, -C//3 , tosylate), 7.20, 7.50 (d, 2H, 3 JH H = 8.1 Hz; d, 2H, 3 JH H = 8.2 Hz, ArH, tosylate), 8.00, 8.25 (d, 1H, 4 Jhh = 2.5 Hz; d, IH, 4 JH H = 2.5 Hz, 5,7-Artf), 8.35 (s, 3H, H-C=N-), 9.26 (s, 1H, 2-ArH), 8.30 (broad s, 2H), 10.20 (broad s, IH), 11.20 (very broad s), 11.90 (very broad s) (NH, OH). I 3 C 8 20.81 (-CH3 , tosylate), 118.19 (3-ArC), 123.32 (5- ArO, 124.18, 125.32 (8,10-ArC), 125.60, 128.47 (ArCH, tosylate), 130.50(6- ArC), 134.03 (7-ArC), 138.50 (broad s, -CH=N-), 138.67 (CH3 -ArC tosylate), 144.39 (HS03 -ArC, tosylate), 150.15 (9-ArC), 155.92 (-C=NH), 155.94 (2-ArC), 172.87 (4-C=0). l-[3-(6-Isopropyl-4-oxo-4H-l-benzopyran)methyleneamino]-3- hydroxyguanidine Tosylate (46) ‘H NMR 8 1.20, 1.22 [s, 3H; s, 3H, (CH3 )2 CH- ], 2.26 (s, 3H, -CH}, tosylate), 3.01 [sep, 3 JH H = 6.9 Hz, IH, -C//(CH3 ),J, 7.13, 7.58 (d, 2H, 3 Jhh = 8.1 Hz; d, 2H, 3 JH H = 8.2 Hz, AiH, tosylate), 7.57 (d, 3 JH H = 8.6 Hz, IH, 8-ArH), 7.68 (dd, 3 JH H = 8.7 Hz, 4 JH H = 2.2 Hz, IH, 7-Ar//), 7.89 (d, 4 JH H 146 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. = 2.2 Hz, IH, 5-ArH), 8.35 (s, LH, H-C=N-), 9.20 (s, IH, 2-ArH), 8.17 (broad s, 2H), 10.20 (broad s, IH), 11.20 (very broad s), 11.80 (very broad s) (NH, OH). I3 C 8 20.84 (-CH3 , tosylate), 23.70 [(CH3 )2 CH-], 32.90 [(CH3 )2 CH-|, 117.52, 118.78 (3,8-ArC), 118.78, 121.70 (5,8-ArQ, 125.55, 128.37 (ArCH, tosylate), 133.44 (7-ArC), 138.46 (CH3 -ArC tosylate), 140.26 (broad s,-CH=N-), 144.59 (HS03 -ArC, tosylate), 146.62 (6-ArC), 154.34 (2-ArC), 155.94 (2-ArC), 156.08 (- C=NH), 174.65 (4-C=0). l-[2-Amino-3-(4-oxo-4H-l-benzopyran)methyleneamino]-3- hydroxyguanidine Tosylate (47) 'H NMR 8 2.27 (s, 3H, -C//3 , tosylate), 7.11, 7.48 (d, 2H, 3 JH H = 8.1 Hz; d, 2H, 3 JH H = 8.2 Hz, AiH, tosylate), 7.40, 7.70 (td, IH; td, IH; 3 Jhh = 7.8 Hz, 4 JH H = 1.6 Hz, 6,7-Ar//), 7.40, 7.99 (dd, IH; dd, IH; 3 JH H = 8.0 Hz, 4 Jhh = 1.4 Hz, 5,8-ArH), 8.12 (broad s, 2H, N//2 ), 8.74 (s, IH, H-C=N-), 8.41 (broad s, IH), 9.18 (broad s, IH), 10.20 (broad s, IH), 10.80 (very broad s), 11.50 (very broad s) (NH, OH). 1 3 C 8 20.81 (-CH3 , tosylate), 91.52 (3-ArC), 116.65 (8-ArC), 121.31 (10-ArC), 125.04, 125.22 (5,6-ArQ, 125.52, 128.30 (ArCH, tosylate), 133.43 (7-ArQ, 137.81 (CH3 -ArC tosylate), 144.86 (HSOr ArC, tosylate), 146.76 (broad s, -CH=N-), 152.69 (9-ArQ, 155.43 (-C=NH), 162.03 (2-ArQ, 173.52 (4-C=0). 147 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. REFERENCES 1 Navarra, P.; Preziosi, P. Crit. Rev. Oncol. Hematol. 1999, 29, 249-255. 2 Ren, S.; Wang, R.; Komatsu, K.; Bonaz-Krause, P.; Zyrianov, Y.; McKenna, C. E.; Csipke, C.; Tokes, Z. A.; Lien, E. J. J. Med. Chem. 2002,45(2), 410-419. And references within. 3 For compounds 2 -3 1 : see ref. 2. 4 For compounds 36 - 49: Huang, S. S. C.; Ren, S.; Tokes, Z. A.; Csipke, C.; Guan, Y.; Chou, T.-C.; Bonaz-Krause, P.; Zyrianov, Y.; McKenna, C. E.; Lien, E. J. Med. Chem. Res., submitted. 3 Compound 1 was not tested, compounds 32 - 35 are unpublished results. 6 Breitmaier, E.; Voelter, W. Carbon-13 NMR Spectroscopy, 3r d Ed., 1987; Weinheim, New York. 7 Compound 1, 32 - 35 unpublished. 8 Karabatsos, G. J.; Graham, J. D.; Vane, F. M. J. Am. Chem. Soc. 1962, 84, 753- 755. 9 Karabatsos, G. J.; Vane, F. M.; Taller, R. A.; Hsi, N. J. Am. Chem. Soc. 1964, 56(16), 3351-3357. 1 0 Conlon, P. R.; Sayer, J. M. J. Org. 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Acta 1994, 243(2), 161-167. van Beek, E. R.; Lowik, C. W.; Ebetino, F. H.; Papapoulos, S. E. Bone 1998, 23, 437-442. Vepsalainen, J.; Nupponen, H.; Pohjala, E.; Ahlgren, M.; Vainiotalo, P. J. Chem. Soc. Perkin Trans. 2 1992, 835-842. Wood, H. B.; Buser, H.-P.; Ganem, B. J. Org. Chem. 1992,57(1), 178-184. Yates, P. J. Am. Chem. Soc. 1952, 74,5376-5381. Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091-1160. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Appendix A NMR SPECTRA A, NMR Spectra of Novel Compounds Diazo PAmide (2a) t-8 9S9CI- -s -a Figure A.I. 3 lP {‘HJ NMR (CDC13 ) 8 13.66 (s). In insert: 3 IP NMR showing pentuplet (3 JP H = 8.4 Hz). 157 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. •Kl'l- « n - lotri- Mll- .81 itoo'r ifito-r «0*0 O B O 'O 0000 9 ZE90‘9 g n t Figure A.2. ‘H NMR (CDC13 ) 5 3.98 (m, 4H, CH3 C//2 0), 2.81 (s, 6H, N(CH3 )2 ), 1.15 (t, 6H, C //3 CH2 0). In insert: expansion of various signals. 158 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. I0C 9 90E9 > IM 'S I---- ■ d d -« -S -3 -8 ■ J 8 s Figure A.3. l3 C{‘HJ NMR (CDC13 ) 5 162.27 (d, 2 JC P = 1 L.3 Hz, C=0), 63.03 (d, 2 JC P = 5.0 Hz, CH3 CH2 0), 52.30 (d, ‘ JC f = 220.1 Hz, C=N2 ), 37.08 (s, N(CH3 )2 ), 15.67 (d, Jcp = 6.0 Hz CH3 CH2 0). In insert: expansion of various signals. 159 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Diazo PPP (4a) 2I6T 0 0000'1 -c -R -R Figure A .4.3lP{lH} NMR (CDCl3 ) 8 25.84 (d, 2 JP P = 32.4 Hz, IP, Ph(CH3 CH2 0)P(0)), 13.99 (d, 2 JP P = 32.4 Hz, IP, (CH3 CH,0),P(0)). In insert: expansion of signals. 160 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. mei- 818'EI- •SB'EI- 866'EI- O M H - 820’» l- 1 I IM - 992*62- 128*52- to T B 0 1 ■ 8 ■ R Figure A .5.3 1 P NMR (CDC13 ) 5 25.84 (dm, 2 JP P = 32.4 Hz, IP, Ph(CH3 CH2 0)P(0)), 13.99 (dp, 2 JP P = 32.4 Hz, 3 JP H = 8.0 Hz, IP, (CH3 CH2 0 )2 P(0)). In insert: expansion of signals. 161 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 5 1 2 2 0 * 1 E9B0I 2 0 0 1 I OOII I 0622*1- * 8 2 1- 220EI- 8622 E I062'E ■ 0 1 0 C c h o c mac 20E6E m e 2E29E 0260*0 EIOI 1 2 1 1 osiro 620E 2 OIK 2 S2K*2 0E2£*2 E IK '2 22EO 2 1000*2 2200*2 1292 2 0222*2 Figure A.6. 'H NMR (CDC13 ) 8 7.78 (m, 2H, ortho-H), 7.44 (tm, IH, para-H), 7.36 (m, 2H, meta-H), 4.16-3.77 (m, 6H, CH3 C//2 0), 1.29, 1.10, 1.09 (3t, 9H, C//3 CH2 0). In insert: expansion of signals. 162 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 199*61- £ C £ * 6 » - 619*61- 199*61- *66*61- £00*91- C C 6 ‘6 C - £86 0* - 661*1*- 6 6 1 * e * - -8 • 8 ■ 9 u m - 129*19- 96£*29-v 629*29 9 I - 9 2 I - / 9 2 *921-' *2*061- £ I* IC I— ^ 5 2 IE I----- KKI--- £**261— v 6**261— -8 '3 m '3 I r8 a S -8 -8 -S 5 Figure A .7.1 3 C{ ‘HJ NMR (CDC13 ) 8 132.48 (d, 4 JC P = 2.7 Hz, para-C), 131.21 (d, "JC P = 10.8 Hz, ortho-C), 128.23 (d, J JC P = 14.6 Hz, meta-C), 130.93 (d, 'JC P = 159.71 Hz, arom-C,), 62.85, 62.78, 61.80 (3d, :JC P = 6.0 Hz, CH3 CHX>), 40.86 (dd, ‘ JC P = 201.47 Hz, 'JC P = 133.30 Hz, CN,), 15.98, 15.70 (d & broad d, 3 JC P = 6.7 Hz, CH3 CH2 0 ). In insert: expansion of various signals. 163 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a -Keto PAmide (2b) 60E«- W'!- B O C Z - WZ- K 2 2 - -s -1 Figure A .8.3 1 P{ 'HJ NMR (CDC13 ) 5 -2.31 (s). In insert: 3IP NMR (CDC13 ) showing pentuplet (3 JP H = 8.0 Hz). 164 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1C60I- 2 Z 0 I' I - fieri- 0C9Z2- 0 0 8 * 2 - 8010‘9-v r ti° » - s \ ■aior S K O 'r «zor C K or l « 0 » 9 IW » icra'r i S S O 'P - s*sor aaao’r 9 I* 0 > Figure A.9. ‘H NMR (CDC13 ) 5 4.04 (m, 4H, CH3 C //2 0), 2.78,2.76 (2s, 6H, NCCA/j)^, 1.11 (t, 6H, C//3 CH2 0). In insert: expansion of various signals. 165 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ; -8 0 6 9 fit------ o 2 Figure A.10. l3 C{'H) NMR (CDC13 ) 5 198.05 (d, lJC P = 172.2 Hz, P(0)C(0)C(0)), 164.25 (d, 2 JC P = 65.9 Hz, P(0)C(0)C(0)), 64.03 (d, 2 JC P = 6.7 Hz, CHjCHP), 35.92, 34.02 (2s, N(CH3 ),), 15.71 (d, 3 JC P = 6.1 Hz CH3 CH2 0). In insert: expansion of signals. 166 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a-Keto TIPMDP (3b) Figure A.11. 3 1 P{ lH) NMR (CDC13 ) 5 -5.91 (s). In insert: 3 IP NMR (CDC13 ) showing triplet (3 JP H = 3.5 Hz). 167 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. w v rg aiz\- Z llZ i- nrt 9 IW » - ■U> oczrt- nu»- zau-f- eirr* - sarir- NK> U 9 i» - 2U lt- HK»- CSU'»- L R : V .1 xum n Figure A.12. ‘H NMR (CDC13 ) 5 4.75 (m, 4H, (CH3 ),CM)), 1.28, 1.27 (2d, 24H, (CH3 ),C//0). In insert: expansion of signals. 168 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. M OW -------- 2 9 9 ‘ U- OC'912- LVUZ- R v ■ 8 l-I Figure A.13. 1 3 C NMR (CDC13 ) 5 216.38 (t, ‘ JC P = 149.5 Hz, C=0), 73.66 (broad s, (CH3 ),CHO), 24.02, 23.51 (2s, (CH3 )2 CHO). In insert: expansion of various signals. 169 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. OH-TEPA (If) M T 9 I- 19991- 022*91- (9 T 9 I- 209*91- ►*9*91- ►90*91- ►20*91- "io -s Figure A.14. 3IP{lH) NMR (CDC13 ) 8 16.80 (s). In insert: 3 1 P NMR (CDC13 ) showing septuples 170 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 0000 6 mao Figure A.15. ‘H NMR (CDC13 ) 5 4.50 (d, 2 JH P = 16.0 Hz, IH, CH), 4.27,4.16 (2m, 6H, CHjC//2 0), 1.25 (m, 9H, Ctf3 CH2 0). In insert: expansion of signals. 171 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure A.16. l3 C NMR (CDC13 ) 8 169.20 (d, -JC P = 2.0 Hz, C=0), 68.72 (d ,1 JC P = 154.43 Hz, CH), 63.72, 63.57 (2d, 2 JC P = 6.6 Hz, (CH3 CH,0),P), 62.36 (s, CH3 CH2 OC), 16.22 (d, 3 JC P = 5.3 Hz, (CH3 CH2 0 )2 P), 13.92 (s, CH3 CH2 OC). In inserts: expansion of various signals. 172 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. OH-PAmide (2f) 016*91- 096*91- 066*91- 620*il- t£6*91- -i Figure A.17. 3 1 P( lH} NMR (CDC13 ) 8 16.97 (s). In insert: 3,P NMR (CDC13 ) showing sextuplet. 173 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9 * 2 -9 ! 60E'9I £►£•9! S1S-9E- H 2 * E - ar*9i- -fi ■ « I 2 W E 9 - \ eosE9-^_ 2 2 * '£ 9 S**E9 ► 2 8 5 9 8 » 0 * 9 1 -s -8 rS Figure A.19. ,3 C{‘H} NMR (CDC13 ) 5 167.88 (s, C=0), 66.43 (d, 'JC P = 154.68 Hz, CHOH), 63.75,63.47 (d, 2 JC P = 6.6 Hz; d, 2 JC P = 7.2 Hz, CH3 CH,0), 37.08 (s, N(CH3 )2 ), 15.67 (d, 3 JC P = 6.0 Hz CH3 CH,0). In insert: signal offset. 175 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. OH-TIPMDP (3f) ■ M Figure A.20.3lP{ H} NMR (CDC13 ) 8 16.77 (s). In insert, 3lP NMR (CDC13 16.77 (broad d, 2 JP H = 17.6 Hz). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure A.21. ‘H NMR (CDC13 ) 5 4.77 (m, 4H, (CH3 )2 CtfO), 4.13 (t, 2 JH P = 1 Hz, 1H, C//OH), 1.31 (m, 24H, (C//3 )2 CHO). In insert: expansion of signal. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. O il M Figure A.22.1 3 C{'H) NMR (CDC13 ) 5 72.79 (broad s, (CH3 ),CHO), 65.35 (t, 'JC P = 156.3 Hz, CHOH), 23.98,23.68 (2 broad s, (CH3 ),CHO). 178 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PhAmino-PAmide (2g) res'ss- E 0 9 B I- zra'81- S K 'B I- 429‘0 I- 999 01- Figure A.23. 3,P{ 'HJ NMR (CDC13 ) 8 18.58 (s). In insert: 3IP NMR (CDC13 ) showing septuplet. 179 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. p p a 19.0 19.6 19.4 19.2 19.0 1 B .B IB .6 IB .4 16.2 0000 9 5850*1 Figure A.24. 'H NMR (CDCl3 ) 5 7.02 (t, 2H, meta-H), 6.61 (t, IH, para-H), 6.56 (d, 2H, ortho-H), 4.76 (broad d, 3 JH .N H = 6.5 Hz, 1H, N//), 4.67 (dd, 1 JH P = 18.1 Hz, 3J h .n h = 6.5 Hz, 1H, C/7), 4.03 ( m , 4H, OC//2 CH3 ), 3.03,2.84 (s, 3H; d, 3H; N(C//3 )2 ), 1.16, 1.14 (t, 3H; t, 3H; OCH2 C //3 ). In insert: expansion of signals. 180 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. E 69I > Figure A.25. 1 3 C{lH} NMR (CDC13 ) 8 166.49 (d, 2 JC P = 3.1 Hz, C=0), 146.28 (d, 3 JC P = 8.8 Hz, arom-C,) 128.75 (s, ortho-C), 118.49 (s, para-C), 113.82 (s, meta- C), 63.28,63.08 (d, 2 JC P = 6.7 Hz; d, 2 JC P = 7.4 Hz, CH3 CH,0), 53.47 (d, ‘ JC P = 152.86 Hz, CH), 37.16, 35.84 (2s, N(CH3 ),), 15.96, 15.90 (2d, 3 JC P = 7.2 Hz, CH3 CH,0). 181 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PhAmino-TlPMDP (3g) 1 0 ’ < 0 add in 'to Figure A.26.3 1 P{ ‘H } NMR (CDC13 ) 8 16.68 (s). In insert: 3 1 P NMR (CDC13 ) 16.68 (broad d, 2 JP H = 22.0 Hz). 182 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure A.27. ‘H NMR (CDC13 ) 8 7.13 (t, 2H, meta-H), 6.71 (t, 1H, para-H), 6.64 (d, 2H, ortho-H), 4.75 (m, 4H, (CH3 )2 C //0), 4.04 (m, 2 JH P = 22.2 Hz, IH, C//NH becomes a triplet with D,0; broad s, 1H, CHN// disappear with D,0), 1.29 (pseudo t, 12H, (C//3 )2 CHO), 1.25 (d, 6H, (C7/3 )2 CHO), 1.16 (d, 6H, (C//3 )2 CHO). Insert at 4 ppm shows CHNH signal after treatment with D,0. Insert at 1 ppm is an expansion of the doublet signals. 183 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. is* ea U E 2 II w — ^ * £ * ► 2 U S E 2 - 9 9 4 C 2 - 2ii*»z- 99E‘»2- -S * 0 * 2 * 69*21 U '9£ 00 S 2 * U ■ u -f~ 'L L S I 8 E I I - 99*811- 90*621- C D C I3 690*2£- 999* 2 i- .9 Figure A.28. l3 C{ ‘H| NMR (CDC13 ) 5 146.56 (t, 3 JC P = 5.0 Hz, arom-C,), 129.08 (s, ortho-C), 118.66 (s, para-C), 113.81 (s, meta-C), 72.69, 72.07 (broad s, (CH3 )2 CHO), 51.19 (t, ‘ JC P = 146.8 Hz, CHNH), 24.37, 24.11, 23.77, 23.57 (4 broad s, (CH3 )2 CHO). Inserts are expansions of signals. 184 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DiOH-TEPA (Id) “ n Figure A.29.3,P{ ‘HJ NMR (CDC13 ) 8 13.49 (s). In insert: 3 1 P NMR (CDC13 ) 5 13.49 (p,3 JP H = 7.5 Hz). 185 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Il6e*f « R I esoci 660C I E6IE'I IKC'I 22EEI 6KEI reozr Ltnr 10E2> *2K> 0 ^ 9 2 'r ooK'r 0682'r 2IK> S80E> 0 2 E > »EE'r Figure A.30. lH NMR (CDC13 ) 8 4.29 (q, 2H, CH3 C//,OC), 4.24 (m, 4H, (CH3 C//2 0),P), 1.30 (td, 9H, C //3 CH2 0). 186 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. CDCI3 Figure A.31. 1 3 C{ 'H) NMR (CDC13 ) 8 168.77 (d, 2 JC P = 13.8 Hz, C(0)OCHoCH3 ), 92.43 (d, lJC P = 198.7 Hz, C(OH),), 64.62 (d, 2 JC P = 6.3 Hz, (CH3 CH,6),P), 63.19 (s, CH3 CH,OC), 16.29 (d, 3 JC P = 5.0 Hz, (CH3 CH,0),P), 13.86 (s, CH3 CH,OC). 187 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. pp« DiOH-PAmide (2d) 058*51 5 2 6 * 5 1 Figure A.32. 3lP{ *H } NMR (acetone) 8 15.89 (s). In insert: 3lP NMR (acetone) 5 15.89 (p, 3 JP H = 7.5 Hz). 188 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 9E'9I e»9i 9»*9I 16*91 95*91 E9*9I 1 6 * 6 2 99*62 19*62 £6*62 2 P 0 C 82 0E tr*oe B9 9C 02*9C 2E6C 89*29 2£*29 £9*»9 Ei*»9 ES'59 66*59 06*E6 6 > * 6 6 £169! £2*691 a c e to n e in— r -8 -8 . 9 .8 I Figure A .33.1 3 C{ lH} NMR (acetone) 8 169.20 (d, 2 JC P = 17.6 Hz, C =0)\ 94.62 (d, ‘ JC P = 207.5 Hz, C(OH)2 ), 64.69 (d, 2 JC P = 7.4 Hz, CH3 CH2 0 ) ’, 39.32, 38.20 (2s, N(CH3 )2 )', 16.60 (d, 3 JC P = 5.3 Hz CH3 CH2 0 )‘. In inserts: expansion of signals. * Tentative assignment. 189 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. DiOH-TlPMDP (3d) lE B 'tl- I S 8 H - 9 9 8 'H - IWH- Figure A.34. 3 IP{‘HJ NMR (acetone) 8 14.85 (s). In insert: 3lP NMR (acetone) 8 14.85 (broad t, 3 JP H = 1.9 Hz). 190 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Figure A.35. 'H NMR (acetone) 8 4.79 (m, 4H, (CH3 )2 C //0), 1.31, 1.29 (2d, 24H, (C//3 ),CHO). In insert: expansion of signals. 191 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a c e to n e Figure A.36. l3 C{‘H} NMR (acetone) 8 94.22 (t, 'JC P = 193.9 Hz, C(OH),), 73.06 (pseudo t, 2 JC P = 3.4 Hz, (CH3 )2 CHO), 24.39,23.97 (2s, (CH3 )2 CHO). 192 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. A2 Chemical Schifts Comparison Between Methylene, Diazo and a-Keto derivatives. TEPA series (I, la, lb) a) 2 0 .6 1 (s) 10.78 (s) C) •2.57 (s) in & J ' A " A 4 4 Figure A.37. Comparison of 3lP chemical shifts between: a) TEPA, b) Diazo TEPA, and c) a-keto TEPA. 193 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a) C//3 C H 2 O C (CA/3CH20)2P c h 3 c « 2 o JL P(0)C«2 C(0) c h 3 c h 2c b) (C/y3CH20 ) 2p CH3 CW2OC A (CH30 7 20 ) 2P c) ca/3 c h 2o c h 3 c « 2o c I k (C H tC W -iO h P Figure A.38. Comparison of lH chemical shifts between: a) TEPA 8 3.82 (m, 6H, CH3 C//2 0), 2.61 (d, 2H, 2 JH P = 21.5 Hz, P(0)C//,C(0)), 0.99 (t, 6H, (C//3 CH,0),P), 0.93 (t, 3H, C //3 CH2 OC), b) Diazo TEPA 8 3.99 (q, 2H, CH3 C//2 OC), 3.92 (m, 4H, (CH3 C//,0),P), 1.09 (t, 6H, (C//3 CH,0),P), 1.03 (t, 3H, C//3 CH2 OC), and c) a-keto TEPA 8 4.29 (q, 2H, CH3 Ctf,OC),~4.22 (m, 4H, (CH3 C//,0),P), 1.28 (t, 9H, C //3 CH,0). 194 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. P(0)CH2 C(0) a) C(0)0Et / C H 3C H 2 C (0 ) (CH3c h :0):P(0) CDCI3 / T (CHjCHiO)P(O) CH3CH:C(0) b) (CHjCH:0):P(0) C'(0)0El CDCh ,C=Ni C) P(0)C(0)C(0) C(0)0Ei -J J ____________ L— (CHiCHiOJjPIO) CDClj i (CHiCHiO)P{0) CHjCH:C(0) w m ' lio 1ST I jo IT 'IT T io Figure A.39. Comparison of l3 C chemical shifts between: a) TEPA 5 164.9 (d, 2 JC P = 6.0 Hz, C=0), 61.80 (d, 2 JC P = 5.0 Hz, (CH3 CH,0),P(0)), 60.61 (s, CH3 CH,0C(0», 33.55 (d, ‘ JC P = 134.0 Hz, P(0)CH,C(O)), 15.54 (d, 3 JC P =6.3 Hz, (CH3 CH,0),P(0)), 13.30 (s, CH3 CH,OC(0)), b) Diazo TEPA 5 162.65 (d, 2 JC P = 12.2 Hz, C=0), 63.04 (d, 2 JC P = 4.6 Hz, (CH3 CH2 0 )2 P), 61.05 (s, CH3 CH,OC), 53.01 (d, 'JC P = 226.4 Hz, P(0)C(N,)C(0)), 15.46 (d, 3 JC P = 6.7 Hz, (CH3 CH2 0 )2 P), 13.67 (s, CH3 CH2 o’ C), and c) a-keto TEPA 8 193.54 (d, 'JC P = 183.1 Hz, P(0)C(0)C(0)), 159.19 (d, 2 JC P = 78.6 Hz, C(0)OCH,CH3 ), 64.60 (d, 2 JC P = 6.1 Hz, (CH3 CH,0),P), 63.07 (s, CH3 CH,OC), 16.12 (d, 3 JC P = 5.7 Hz, (CH3 CH,0)2 P), 13.67 (s, CH3 CH,OC). 195 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PAmide series (2, 2a, 2b) a) 22.28 (s) . 13.66 (s) -2.31 (s) T To 12.3 10.0 To I ppi Figure A.40. Comparison o f 3 1 P chemical shifts between: a) PAmide, b) Diazo PAmide, and c) a-keto PAmide. 196 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. IA/' b) c) C H 3 C H 2 O N (C «3 ) 2 CW3C H 2O L N i 4.0 3 .3 3.0 2 .3 2.0 1.3 1.0 Figure A.41. Comparison of ‘H chemical shifts between: a) PAmide 8 3.95 (m, 4H, CH3 C //,0), 2.92,2.76 (2s, 3H each, N(C//3 ),), 2.84 (d, 2 JH P = 22.0 Hz, P(0)CH2 C(6)), 1.15 (t, 6H, C //3 CH,0), b) Diazo PAmide 8 3.98 (m, 4H, CH3 CHnO), 2.81 (s, 6H, N(C//3 )2 ), 1.15 (t, 6H, C//3 CH2 0), and c) a-keto PAmide 5 4.04 (m, 4H, CH3 C//,0), 2.78,2.76 (2s, 6H, N(C//3 )2 ), l.l 1 (t, 6H, C//3 CH2 0). 197 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a ) C tO JN M e ^ CH3CH2O CDCh L P(0)CH2C(0) \ N(CHih V z b) \ CH3CH2O N(CH3) ' C{0)NMe2 CDCh c=n2 \ 1 1 c) P(0)C(0)C(0) y '' C(0)NMe> *-------m lo CH3CH2O 1 125 CDCI3 CH3CH2O X N(CH3) - > 1 1 0 0 75 90 = T = 25 Figure A.42. Comparison of l3 C chemical shifts between: a) PAmide 5 164.14 (d, 2 JC P = 5.0 Hz, C=0), 61.84 (s, CH3 CH,0), 37.86, 35.06 (2s, N(CH3 )2 ), 32.70 (d, lJC P = 133.5 Hz, P(0)CH,C(0)), 15.67“(d, 3 JC P = 6.0 Hz, CH3 CH,0), b) Diazo PAmide 6 162.27 (d, :JC P = 11.3 Hz, C=0), 63.03 (d, 2 JC P = 5.0 Hz, CH3 CH2 0), 52.30 (d, 'JC p = 220.1 Hz, C=N,), 37.08 (s, NtCH^J, 15.67 (d, 2 JC P = 6.0 Hz CH3 CH2 0), and c) a-keto PAmide 8 198.05 (d, ‘JC P = 172.2 Hz, P(0)C(0)C(0)), 164.25 (d, 2 JC P = 65.9 Hz, P(0)C(0)C(0)), 64.03 (d, 2 JC P = 6.7 Hz, CH3 CH,0), 35.92, 34.02 (2s, ^ C H ,)^ , 15.71 (d, 2 JC P = 6.1 Hz CH3 CH,Q). 198 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TIPMDP series (3, 3a, 3b) ^ 18.08 (s) 11.59 (s) c) -5.91 (s) "5" 1 0 T Figure A.43. Comparison o f3 1 P chemical shifts between: a) TIPMDP, b) Diazo TIPMDP, and c) a-keto TIPMDP. 199 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a) b) (CHihCWO ______ A. (CH3)2CMO P(0)C tf2P(0) ill (CW3)2 CHO A (C //3)2CHO Figure A.44. Comparison of ‘H chemical shifts between: a) TIPMDP 8 4.61 (m, 4H, (CH3 ),CtfO), 2.21 (t, 2H, 2 JH P = 21.1 Hz, P(0)C//2 P(0)), 1.19, 1.18 (2d, 24H, (C//3 )2 CHO), b) Diazo TIPMDP 8 4.72 (m, 4H, (CH3 )2 C/ZO), 1.33 (d, 24H, (CH3 ),C//0), and c) a-keto TIPMDP 8 4.75 (m, 4H, (CH3 )2 C //0), 1.28, 1.27 (2d, 24H, (CH3 )2 C //0). 200 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a) (CH3)->CHO (CH3)->CHO \ CDC13 P(0)CH2P(0) X CDCI3 c) 200 190 too Figure A.45. Comparison of l3 C chemical shifts between: a) TIPMDP 8 70.84 (broad s, (CH3 ),CHO), 27.48 (t, ‘JC P = 138.1 Hz, P(0)CH,P(0)), 23.79, 23.61 (2s, (CH3 )2 CHO), b) Diazo TIPMDP 8 72.28 (broad s, (CH3 )2 CHO), 40.08 ( t,1 JC P = 205.0 Hz. P(0)C(N,)P(0)). 23.85, 23.67 (2s, (CH3 )2 CHO), and c) a-keto TIPMDP 8 216.38 "(t, 'JC P = 149.5 Hz, C=0), 73.66 (broad s, (CH3 )2 CHO), 24.02, 23.51 (2s, (CH3 )2 CHO). 201 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PPP series (4, 4a, 4b) a) Ph(CH3CH20 )P (0 ) 33.S3 (d, -JPp = 6.0 Hz) (CH3 CH2 0)2/> (0) 19.73 (d.2JP P = 7.2 Hz) b) c) Ph(CH3CH20)/>(C» 25.84 (dm, 2JP P = 32.4 Hz) / (CH3CH20 ) 2P(0) 13.99 (dp. -Jpp = 32.4 Hz, 3JPH = 8.0 Hz) Ph(CH3 CH2C»/'(C» 18.42 (d,2JPp=: 217.6 Hz) Diazo PPP Jk jl. (CH3 CH20)2/> (0) -2.61 (d,2jpP = 217.6 Hz) Diazo PPP s T T T IT "5” "IS" Figure A.46. Comparison of 3lP chemical shifts between: a) PPP, b) Diazo PPP, and c) a-keto PPP taken in reaction mixture (benzene). 202 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. A3 Comparison Between 3 1 P NMR Chemical Shift of Diazo Derivatives and Their Corresponding a-Hydroxy Adducts and PhenylAmino adducts. a) b) 1T X Figure A.47. a) Diazo TEPA (la), b) OH-TEPA (If). 203 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 13.66 b) 16.97 18.58 T S 77 T1 tl I t It T1 14 PM 16 Figure A.48. a) Diazo PAmide (2a), b) OH-PAmide (2f), and c) PhAmino- PAmide (2g). 2 04 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. LL.59 b) 16.77 16.68 Figure A.49. a) Diazo TIPMDP (3a), b) OH-TIPMDP (3f), and c) PhAmino- TIPMDP (3g). Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Appendix B IR Spectra Bt IR Spectra of Novel Compounds Diazo PAmide (2a) ~ is * s * 2 8 s i 3 s = i S S = X z a = i ~ £ 1 = S Figure B.l. Bands (cm*1 ) 2985, 2936 (s, CH3 , CH,), 2104 (vs, C=N=N), 1636 (vs, C=0), 1264 (vs, P=0), 1025 (broad vs, P-O-C). 206 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Diazo PPP (4a) * Figure B.2. Bands (cm 1 ) 3061, 2986, 2938, 2909 (m, CH3 , CH,, arom.-CH), 2112 (vs, C=N=N) 1479, 1443, 1393, 1369 ( m, arom. C=C), 1252 (broad vs, P=0), 1022 (broad vs, P-O-C). 207 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1 0 9 .4 , a-Keto PAmide (2b) Figure B.3. Bands (cm'1 ) 2986, 2938 (m, CH3 , CH-,), 1658 (broad vs, C=0), 1266 (vs, P=0), 1023 (broad vs, P-O-C). 208 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a-Keto TIPMDP (3a) g 8 S S ~S 8 S 8 s 8 R * 5 S S sT S 8 2 2 " 5 Figure B.4. Bands (cm 1 ) 2984, 2937 (s, CH3 , CH), 1665 (m, C=0), 1266 (vs, P=Q), 995 (broad vs, P-O-C). 209 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PhAmino-PAmide (2g) -8 r t -8 ■ t i i 1 r i -- - - - - - -r — 1 - - - - - - -p- a§S = S§s *s*P i83a-R Sts8 asis 322 •> S Figure B.5. Bands in CC14 (cm*1 ) 3348 (broad w, N-H), 3054-2900 (w-m, CH3 CH,, arom-CH), 1656 (s, C=Q), 1257 (s, P=O),1052, 1027 (s, P-O-C). 210 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PhAmino TIPMDP (3g) S t Figure B.6. Bands in CC14 (cm 1 ) 3425, 3287 (vw, NH), 3057,2981, 2936, 2868 (m-w, CH, CH2 , arom-CH), 1386, 1375 (m, iPr.), 1252 (broad m, P=0), 994 (broad s, P-O-C). 211 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. OH-PAmide (2f) % ■ 8 ( T " * S 8 S S S 8 R S S 8 K 5 S M Q t A O > A O < A O Figure B.8. Bands in CC14 (cm 1 ) 3388 (broad w, C-OH), 2983, 2933,2910 (m-w, CH3 , CH2 , CH), 1656 (s, C=Q), 1263 (broad m, P=0), 1033 (m, P-O-C). 213 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. OH-TIPMDP (3f) Figure B.9. Bands in CC14 (cm 1 ) 3229 (broad w, OH), 2981,2937,2868 (m-w, CH, CH2 ), 1386, 1375 (m, iPr.), 1253 (broad m, P=0), 1000 (broad s, P-O-C). 214 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. B, Comparative IR Spectra TEPA series (1, la, lb) a) 7 1 J. I 1 1 6 3 .0 i 6 3 1 .2 , c=o 1 1 1 7 .1 b) %T c) / I372.ji vm. 1 3 0 0 1000 Figure B.10. a) TEPA (1), b) Diazo TEPA (la), and c) a-Keto TEPA (lb). 215 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. PAmide series (2, 2a, 2b) a) 1 6 3 .! 1096.4 l c= o b) 1 3 0 1 .4 9 7 3 .1 %T c=o I 1636.3 1 C=N=N 3104.3 c) ■<.4 1164.3 3966.1 977.9 1000 3000 3000 1300 I Figure B .ll. a) PAmide (2), b) Diazo PAmide (2a), and c) a-Keto PAmide (2b). 216 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. TIPMDP series (3, 3a, 3b) 117.0 p = o P-O-C % T C=N=N 2 1 1 1 .0 p = o 992.6 'P-O-C M O O 1900 1000 Figure B.12. a) TIPMDP (3), b) Diazo TIPMDP (3a), and c) a-Keto TIPMDP (3b). 217 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission PPP series (4, 4a) a) 1 6 9 1 1475.3 159^.0 1 4 7 ^ .6 1 4 4 1 .1 934.2 • 1 9 .3 S T b ) 1 1 6 2 .3 1 0 9 7 .4 1124.6 7li.6 1 2 9 1 .1 1 9 0 0 4000.0 3000 1000 600.0 Figure B.13. a) PPP (4), and b) Diazo PPP (4a). 218 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. B3 Comparative IR Spectra of Diazo, and a-Keto Derivatives Diazo derivatives (la, 2a, 3a, 4a) a) 1 3 1 6 . 1 P-O-C b) 100.4 %T c) p=o' mo P-O-C d) 1 3 9 1441.3 arom-CH P-O-C 3 000 2000 1 5 0 0 1 0 0 0 • I Figure B.14. a) Diazo TEPA (la), b) Diazo PAmide (2a), c) Diazo TIPMDP (3a), and d) Diazo PPP (4a). 21 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a -Keto derivatives (lb, 2b, 3b) a) 1 3 7 2 .2 1 0 2 6 .3 b) %T 1447.91 1143.3 C) c=o 1171.2 1303.4 1 1 0 4 . 1 1300 1000 3000 2000 » l Figure B.15. a) a-Keto TEPA (lb), b) a-Keto PAmide (2b), and c) a-Keto TIPMDP (3b). 220 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Appendix C AB INITIO CALCULATIONS Ct Diazo Derivatives Diazo TEPA methoxy analog H18 * H19 C15 H17 H22 05 • A^Cc i 6 #H2° H 21 09 04 H13 ^ H14 C7 C11 03 010 H12 N6 N8 Geom etry O p tim iz a tio n 3 -21G (*) Number o f b a s i s f u n c t i o n s : 145 Number o f e l e c t r o n s : 108 T o t a l m o le c u la r c h a r g e : 0 M u l t i p l i c i t y : 1 P o i n t g r o u p : Cl Number o f in d e p e n d e n t d e g r e e s o f freedom : 60 No u s e a b l e symmetry o r sym m etry i n t e n t i o n a l l y d i s a b l e d 221 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. C a r t e s i a n C o o r d in a te s (Angstroms) Atom X Y Z C 1 0.2663568 0.4129347 -0 .5 7 2 8 9 7 2 P 2 1.1947437 0 .5075710 0.9259947 0 3 2 .5563489 0.9418384 0.6386776 0 4 0.3533982 1.3762129 1.9080406 0 5 1.0769991 -0 .9 1 4 4 5 7 7 1.6037453 N 6 0.8718239 0.7388036 -1 .7 0 0 0 2 7 6 C 7 -1 .1 2 8 7 7 4 4 0 .0607537 -0 .6302845 N 8 1.3923212 1.0120005 -2 .6 3 0 8 2 9 3 0 9 -1 .8136750 -0 .2281583 0 .3263317 0 10 -1 .6 0 8 7 2 0 4 0 .0823913 -1 .8 9 3 4 3 0 5 C 11 -3 .0 1 2 5 5 0 6 -0 .2 3 6 1 2 6 6 -2 .0 9 6 0 1 9 4 H 12 -3 .2 2 2 3 6 1 8 -1 .2 3 6 3 1 8 7 -1 .7 5 0 0 2 8 1 H 13 -3 .1 6 8 1 8 4 4 -0 .1 5 5 1 9 5 3 -3 .1 5 7 8 0 0 7 H 14 -3 .6 3 5 0 0 8 2 0.4637939 -1 .5 6 0 5 1 4 5 C 15 -0 .5 0 0 7 3 0 1 0.9273266 3.0105401 C 16 1.8617948 -2 .0660760 1.1826496 H 17 -1.3210263 0 .3655683 2 .6 0 1 6 1 2 1 H 18 -0 .8 4 2 9 4 1 4 1.8254098 3 .4938657 H 19 0.0745595 0.3210810 3 .6898961 H 20 1.7608506 -2 .8 0 4 5 3 8 5 1.9587642 H 21 2.8952005 -1 .7 7 9 2 6 9 1 1.0613297 H 22 1.4723198 -2 .4 5 2 1 9 5 9 0.2513358 E nergy -1 0 1 3 .1 7 6 2 8 1 h a r t r e e s M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s (e l e c t r o n s ) atom M u llik e n e l e c t r o f i t C 1 -0 .2 3 3 2 0 3 -1 .0 8 7 0 8 7 P 2 1.758469 1.754080 O 3 -0 .6 4 7 3 3 3 -0 .822086 0 4 -0 .7 2 4 4 1 9 -0 .700274 O 5 -0 .7 3 3 8 2 6 -0 .5 5 1 9 4 3 N 6 -0 .2 3 1 8 7 2 0.762045 C 7 0.948875 1 .167651 222 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. N 8 0.053369 -0 .2 1 8 3 2 7 0 9 -0 .6 4 9 0 7 5 -0 .6 4 9 1 7 2 0 10 -0 .732824 -0 .5 5 0 8 3 6 C 11 -0 .2 7 9 2 0 8 0.002959 H 12 0.225081 0.081409 H 13 0.226763 0.106502 H 14 0.226691 0.087767 C 15 -0 .2 8 5 5 6 3 0.210166 C 16 -0 .288849 0.004435 H 17 0.256403 0.047336 H 18 0.219472 0.070113 H 19 0.216863 0.021369 H 20 0 .233467 0.106520 H 21 0.233086 0.091141 H 22 0.207633 0.066232 D ip o le moments from M u llik e n and e l e c t r o s t a t i c f i t c h a rg e s and from w a v e f u n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X -2 .1 2 4 8 -3 .0 1 2 1 -2 .9 7 6 7 Y -4 .4 9 6 8 -3 .0 6 7 4 -3 .0 7 8 6 Z 2.5 5 4 9 -1 .6 3 4 0 -1 .6 1 7 8 T o t a l 5.5914 4 .5 9 9 1 4.5778 223 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Diazo PAmide methoxy analog H19 N26 * H21 H20 H16 N9 C 15 0 3 • P2 H17 04 012 H6 H23 H22 H25 H24 Geom etry O p t i m i z a t i o n 3-2 1 G (*) Number o f b a s i s f u n c t i o n s : 160 Number o f e l e c t r o n s : 116 T o t a l m o l e c u l a r c h a r g e : 0 M u l t i p l i c i t y : 1 P o i n t g r o u p : Cl Number o f in d e p e n d e n t d e g r e e s o f freedom : 72 No u s e a b l e sym m etry o r symm etry i n t e n t i o n a l l y d i s a b l e d C a r t e s i a n C o o r d in a te s (Angstroms) Atom X Y Z C 1 0.2515406 0 .0029942 -0 .3 9 1 9 4 5 5 P 2 1.0715956 0.4834763 1.1069368 0 3 2.5051429 0.5792588 0.8523200 0 4 0 .3836001 1.7676730 1.6546863 0 5 0 .6543222 -0 .5 9 1 1 9 2 2 2.1857282 224 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. H 6 2.3451463 -1 .8 1 1 1 3 6 5 2.1748612 C 7 -1 .1 9 3 0 4 9 4 -0 .2392439 -0 .4 4 2 2 5 8 5 H 8 0.8813565 -2 .5 5 0 3 6 4 4 1 .5092001 N 9 0.9830026 0 .0623590 -1 .4 7 9 6 4 5 9 C 10 -0 .6 2 7 8 5 6 1 1.8857136 2 .7073701 C 11 1.2751527 -1 .9 0 4 2 2 2 6 2.2808507 0 12 -1 .8 7 8 4 6 2 7 0.1074832 0.5170714 N 13 -1 .7 4 5 6 3 5 2 -0 .8 2 8 5 3 2 6 -1 .5 3 7 8 9 0 1 C 14 -3 .2079053 -0 .8 2 5 8 9 5 1 -1 .6 5 9 6 2 6 3 C 15 -1 .0 2 9 9 2 5 3 -1 .6 7 1 7 1 6 0 -2 .4967247 H 16 -3 .4 8 6 6 8 0 4 -0 .5 2 4 7 9 3 6 -2 .6 6 2 3 5 1 0 H 17 -3 .6151539 -0 .1 3 5 0 4 8 4 -0 .9 4 1 9 4 5 8 H 18 -3 .6105520 -1 .8 1 4 0 2 8 9 -1 .4 6 2 9 9 5 7 H 19 -0 .7 6 1 1 5 0 3 -1 .1 3 3 3 8 7 8 -3 .3986236 H 20 -1 .6 7 5 8 0 9 9 -2 .4942078 -2 .7757862 H 21 -0 .1 4 0 6 8 3 1 -2 .0957016 -2 .0530224 H 22 -1 .5 2 3 0 4 8 1 1.3954189 2.3742621 H 23 -0 .7 8 0 6 0 5 9 2.9422655 2.8423638 H 24 -0 .2 5 7 5 7 9 2 1.4340910 3.6129203 H 25 1.0209268 -2.29 2 9 1 0 2 3 .2516094 N 26 1.6376374 0.1353065 -2 .3 6 9 7 8 7 2 E nergy -1 0 3 2 .2 5 9 4 6 0 h a r t r e e s M u llik e n an d e l e c t r o s t a t i c f i t c h a r g e s ( e l e c t r o n s ) atom M u llik e n e l e c t r o f i t C 1 -0 .2 2 4 7 6 5 -0 .9 0 9 2 7 2 P 2 1.753318 1.631958 O 3 -0 .6 5 6 1 1 0 -0 .800877 O 4 -0 .720095 -0 .6 8 0 5 3 6 O 5 -0 .7 3 2 0 5 4 -0 .5 2 1 5 5 6 H 6 0.232749 0.089013 C 7 0.951820 0.860187 H 8 0.203764 0.070500 N 9 -0 .2 7 0 6 5 4 0.711069 C 10 -0 .2 8 7 3 2 8 0 .276021 C 11 -0 .2 8 6 3 6 3 0.006282 225 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 0 12 -0 .6 6 0 7 0 3 -0 .5 9 6 5 3 9 N 13 -0 .9 0 5 3 4 1 -0 .3 3 1 2 0 3 C 14 -0 .3 4 5 3 4 4 -0 .2 6 8 5 3 6 c 15 -0 .3 4 8 6 4 4 -0 .1 1 0 1 5 1 H 16 0.205444 0.117615 H 17 0.263774 0.146929 H 18 0.204511 0.118968 H 19 0.213804 0 .082496 H 20 0.229274 0.105595 H 21 0.219328 0.076942 H 22 0.266547 0.022581 H 23 0.214970 0.044448 H 24 0.212183 0.007943 H 25 0.232158 0.099600 N 26 0.033758 -0.249478 D ip o le moments from M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s and from w a v e fu n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X Y Z T o t a l -2 .2 6 3 6 -4 .8 7 7 4 1.4982 5.5819 -3 .0 5 4 2 -4 .1 0 0 9 -2 .2498 5.5863 -3 .0 4 3 7 -4 .0 8 7 3 -2 .2053 5.5528 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Diazo TIPMDP methoxy analog H26 H25 # H19 010 0 5 _ C15 / . 2 . 5 ^ ' A A t * H 2 7 * ° ! i * P 7 « • ^ H2° • J e « . \ / ° 1 leu H 2 3 T-H22 4°9 0 3 • - f * H21 H24 H17 # H18 H16 G eom etry O p t i m i z a t i o n 3 -21G (*) Number o f b a s i s f u n c t i o n s : 179 Number o f e l e c t r o n s : 134 T o t a l m o l e c u l a r c h a r g e : 0 M u l t i p l i c i t y : 1 P o i n t g ro u p : Cl Number o f in d e p e n d e n t d e g r e e s o f freed o m : 75 No u s e a b l e symm etry o r symmetry i n t e n t i o n a l l y d i s a b l e d Atom 0 1 P 2 0 3 C 4 C a r t e s i a n C o o r d in a te s (Angstrom s) X Y Z 1.9369652 1.7270154 2.1215517 0.0639662 -1 .3 5 7 9 4 4 6 -0 .2 5 9 9 3 3 6 1.0778312 -0 .2 9 8 0 3 5 4 -1 .1 8 9 8 6 4 6 -0 .0 8 1 0 4 1 4 -0 .5 2 7 0 1 9 9 0.4959315 227 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 0 5 2 .4828189 -0 .8 9 3 1 9 4 4 1.1431920 N 6 -0 .2 4 9 9 9 7 5 -1 .0 1 4 7 5 4 1 1.5465202 P 7 -1 .1 7 6 2 1 4 5 0.6295717 -0 .3 4 1 6 9 4 7 N 8 -0 .5 1 5 0 7 0 4 -1 .6 1 9 5 8 9 9 2.4331107 0 9 -1 .0 0 2 9 4 2 7 0.5883239 -1 .7 9 5 1 1 3 7 0 10 -2 .4 8 1 9 2 4 1 0.0072248 0 .2737851 0 11 -1 .2 2 3 7 8 0 4 2.0980807 0 .2243889 C 12 -0 .3 3 6 8 6 5 3 3.1693282 -0 .2613855 C 13 -3 .8087557 0.6077387 0.1665163 c 14 1.6196181 -1 .1 2 8 4 8 8 0 -2 .6 1 0 0 0 7 0 c 15 3.8562588 -1 .3 8 7 1 9 2 9 1.0955086 H 16 2.3282575 -0 .4 2 4 3 0 0 3 -3 .0 1 6 1 0 8 5 H 17 0.6194486 -0 .7 3 7 4 8 4 8 -2 .6 9 4 0 8 8 0 H 18 1.7133717 -2 .0 8 8 0 8 7 2 -3 .0878416 H 19 4.0482516 -1 .8 3 3 2 2 7 7 2.0555978 H 20 4.5325690 -0 .5 6 3 7 6 0 1 0.9222624 H 21 3.9463686 -2 .1 1 7 2 6 0 7 0.3072660 H 22 0.6832405 2 .8237353 -0 .2 4 4 9 3 2 9 H 23 -0 .4 8 7 2 7 1 0 3.9978806 0 .4085877 H 24 -0 .6238377 3.4297863 -1 .2 6 7 7 3 7 3 H 25 -3 .7 7 6 8 4 0 2 1.6156002 0.5480508 H 26 -4 .4 6 4 8 0 8 3 -0 .0 0 6 1 3 7 1 0 .7583918 H 27 -4 .1 2 4 8 8 5 0 0.6080329 -0 .8 6 5 7 1 4 0 E nergy -1 4 2 8 .5 8 6 6 2 8 h a r t r e e s M u llik e n an d e l e c t r o s t a t i c f i t c h a r g e s (e l e c t r o n s ) atom M u llik e n e l e c t r o f i t O 1 -0 .7 2 5 8 6 3 -0 .6 0 3 7 4 8 P 2 1.702322 1.824715 0 3 -0 .6 5 0 0 9 9 -0 .8 3 8 4 8 0 C 4 -0 .5 6 8 5 5 1 -1 .2 6 6 3 5 4 O 5 -0 .7 3 6 4 4 2 -0 .6 2 0 4 5 8 N 6 -0 .2 1 4 0 1 9 0.816528 P 7 1.702339 1.825375 N 8 0 .024386 -0 .2 6 9 5 1 0 O 9 -0 .6 5 0 0 9 9 -0 .8 3 7 9 6 7 228 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 0 10 -0 .736458 -0 .6 1 6 1 1 4 0 11 -0 .7 2 5 8 7 4 -0 .593802 C 12 -0 .3 3 0 2 4 6 -0 .021551 C 13 -0 .286563 0 .008768 C 14 -0 .3 3 0 2 1 2 0.009526 C 15 -0 .2 8 6 5 8 4 0 .040857 H 16 0 .224542 0.084475 H 17 0 .277900 0 .115591 H 18 0.216243 0.090173 H 19 0.230440 0.109682 H 20 0.225067 0.072784 H 21 0.231789 0.072745 H 22 0.277927 0 .128121 H 23 0.216235 0.094314 H 24 0.224531 0.092723 H 25 0.231801 0.079867 H 26 0.230436 0.118795 H 27 0.225053 0.082945 D ip o le moments from M u llik e n an d e l e c t r o s t a t i c f i t c h a r g e s and from w a v e f u n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X Y Z T o t a l 1.4620 3 .3388 - 4 .8 9 0 9 6.0997 -0 .4 5 3 3 -1 .0 2 3 2 1.4871 1.8611 - 0 .4 3 3 9 -0 .9 9 0 2 1.4520 1.8102 229 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Diazo PPP methoxy analog H20 • H30 H12 G eom etry O p tim iz a tio n 3-2 1 G (*) Number o f b a s i s f u n c t i o n s : 219 Number o f e l e c t r o n s : 158 T o t a l m o le c u la r c h a r g e : 0 M u l t i p l i c i t y : 1 P o i n t g ro u p : Cl Number o f in d e p e n d e n t d e g r e e s o f freedom : 93 No u s e a b l e symmetry o r symmetry i n t e n t i o n a l l y d i s a b l e d C a r t e s i a n C o o r d in a te s (Angstroms) Atom X Y Z 0 1 2.6150997 0.0961258 -1 .1 2 6 7 5 0 4 P 2 2.7288384 -0 .1 5 1 8 6 4 6 0.4102622 230 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 0 3 3 .8260442 0.4750875 1.1387865 c 4 1.1592602 0.3650849 1.0414876 0 5 2.7518820 -1 .7 3 2 5 3 3 3 0.4514258 c 6 2 .5929501 -0 .9 0 9 9 3 9 2 -2 .1 9 3 7 8 9 1 c 7 2 .9528031 -2 .4 9 5 4 7 8 4 1.6729621 H 8 2.0627084 -2 .4453325 2.2843739 H 9 3 .7990040 -2 .1 0 2 3 3 5 2 2.2160976 H 10 3 .1352739 -3 .5 1 2 5 2 0 4 1.3721923 H 11 3 .4123811 -1 .5 9 7 4 0 7 8 -2 .0 6 8 1 8 9 8 H 12 2 .6963067 -0 .3575897 -3 .1 1 1 6 7 1 7 H 13 1.6496224 -1 .4 2 3 1 4 8 5 -2 .1 4 6 5 8 8 2 N 14 1.1572217 1.0448082 2.1658956 P 15 -0 .3591898 0.0814248 0.1952482 O 16 -0 .2600620 -0 .9 8 7 5 0 2 6 -0 .8 0 7 7 0 6 0 O 17 -1 .3 4 5 1 1 4 9 -0 .1 6 0 6 1 9 8 1.4155512 c 18 -0 .9 3 2 5 8 4 7 1.6200160 -0 .5 1 0 3 0 6 2 c 19 -2 .7 2 4 8 1 4 0 -0 .6 2 1 8 7 5 4 1.2653636 H 20 -3 .0 6 8 4 5 1 5 -0 .8660175 2 .2555136 H 21 -2 .7498560 -1 .4 9 3 4 3 9 5 0 .6294205 H 22 -3 .3299864 0 .1646261 0 .8394449 C 23 -1 .7 6 0 8 6 4 4 4.0028557 -1 .6 6 4 9 7 1 1 C 24 -1 .4 3 0 7 9 9 5 2 .6495633 0.2833628 C 25 -0 .8 6 6 1 9 0 5 1.7915739 -1 .8 8 6 7 4 9 0 C 26 -1 .2 7 7 2 2 5 5 2.9806740 -2 .4616771 C 27 -1 .8 4 0 9 0 1 7 3 .8366338 -0 .2916677 H 28 -1 .5 0 6 2 0 0 8 2.5189509 1.3452576 H 29 -0 .5 0 0 0 4 6 7 0 .9886742 -2 .4 9 3 0 9 4 6 H 30 -1 .2 2 1 7 2 3 7 3 .1 077891 -3 .5242891 H 31 -2 .2225283 4.6267677 0 .3237379 H 32 -2 .0 7 8 2 4 1 8 4.9247803 -2 .1 1 0 4 9 0 0 N 33 1.1587196 1.6145287 3.1141968 E nergy -15 4 3 .5 5 0 6 3 5 h a r t r e e s M u llik e n an d e l e c t r o s t a t i c f i t c h a r g e s ( e l e c t r o n s ) atom M u llik e n e l e c t r o f i t O 1 -0 .7 3 5 0 8 2 P 2 1.722054 -0 .6 8 9 6 3 2 1.744303 231 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 0 3 -0 .6 3 9 4 0 6 -0 .8 2 2 6 0 6 c 4 -0 .5 8 9 7 1 9 -1 .0 9 4 7 6 4 0 5 -0 .7 3 2 8 2 9 -0 .5 4 2 8 3 3 c 6 -0 .2 8 7 9 6 4 0.130070 c 7 -0 .288693 0.007059 H 8 0.209406 0.069622 H 9 0 .229261 0 .090056 H 10 0 .231340 0.099344 H 11 0 .214218 0.043840 H 12 0.212838 0.084191 H 13 0.265511 0.079716 N 14 -0 .2 1 9 2 9 0 0.726716 P 15 1.763696 1.582824 O 16 -0 .644387 -0 .7 8 6 3 1 9 0 17 -0 .740063 -0 .5 8 4 0 7 5 c 18 -0 .4 7 5 5 9 2 -0 .281678 c 19 -0 .2 9 9 6 3 1 -0 .020980 H 20 0.233196 0.119825 H 21 0.235533 0 .096722 H 22 0.220367 0 .076841 C 23 -0 .2 2 6 2 8 7 -0 .1 0 2 4 5 3 c 24 -0 .2 4 6 6 4 5 -0 .0 7 9 6 9 6 c 25 -0 .2 2 7 6 8 5 -0 .1 0 0 8 4 7 c 26 -0 .2 4 1 1 9 2 -0 .1 4 9 2 3 4 c 27 -0 .2 4 1 7 3 9 -0 .1 9 9 5 7 3 H 28 0.245705 0.147378 H 29 0.278469 0.153315 H 30 0.249277 0.147064 H 31 0.247371 0.156580 H 32 0.250048 0.149087 N 33 0.027912 -0 .249864 D ip o le moments from M u llik e n an d e l e c t r o s t a t i c f i t c h a r g e s and from w a v e f u n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X Y Z T o t a l -4 .3 6 2 9 -5 .5 5 8 6 -2 .3 9 2 8 7 .4604 -5 .2 0 2 8 -0 .6 5 7 8 0.4418 5.2628 -5 .1 7 4 8 -0 .6 5 6 1 0.4662 5.2370 232 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. C2 a-Keto Derivatives a -Keto TEPA methoxy analog H10 H11 0 8 C7 H12 01 0 1 6 C5 0 3 C9 P2 0 1 7 0 4 H20 C18 C6 H19 H13 \ H14 H15 H21 G eom etry O p tim iz a tio n 3 -2 1 G (*) Number o f b a s i s f u n c t i o n s : 136 Number o f e l e c t r o n s : 102 T o t a l m o l e c u l a r c h a rg e : 0 M u l t i p l i c i t y : 1 P o i n t g ro u p : C l Number o f in d e p e n d e n t d e g r e e s o f freedom : 57 No u s e a b l e symmetry o r symmetry i n t e n t i o n a l l y d i s a b l e d C a r t e s i a n C o o r d in a te s (Angstroms) Atom X Y Z 0 1 -0 .0 9 8 4 2 7 6 0.9511167 -1 .6 7 4 5 5 4 1 P 2 -0 .1 4 9 2 7 5 0 0.8929724 -0 .1 1 3 4 6 3 9 0 3 0.2721409 2.0960693 0.5934108 233 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. o 4 -1.5905230 0 .3727444 0.1697907 c 5 0.8999948 -0 .5 4 4 9 0 5 7 0.2434219 c 6 -2 .5 0 0 4 0 1 1 0 .8839993 1.1946417 c 7 1.0198194 1.4679893 -2 .4682770 0 8 1.6276686 -1 .0 4 0 9 2 5 0 -0.5856804 c 9 0.9096015 -1 .1 0 4 5 2 3 6 1.6504359 H 10 1.7782697 0.7060590 -2.5273957 H 11 1.4092932 2.3635647 -2 .0080271 H 12 0.6183024 1.6871325 -3.4415523 H 13 -2.6461520 0 .1020901 1.9188914 H 14 -3 .4258606 1.1289432 0.7023132 H 15 -2.0699625 1.7559942 1.6600177 O 16 1.5966263 -2 .0 0 3 2 4 0 9 2.0409676 0 17 0.0351571 -0 .4312886 2.4147433 C 18 -0 .0372945 -0 .7488659 3.8359038 H 19 0.9389833 -0 .6 4 9 1 1 3 9 4.2837051 H 20 -0.3947740 -1 .7 5 8 2 3 2 3 3.9679472 H 21 -0.7258208 -0 .0345289 4.2502962 E n e rg y -979.368210 h a r t r e e s M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s ( e l e c t r o n s ) atom M u llik e n e l e c t r o f i t O 1 -0 .7 1 4 0 9 9 -0 .6 2 1 0 6 1 P 2 1.676987 1.633465 O 3 -0.627912 -0 .8 1 9 8 6 2 O 4 -0 .7 2 2 1 6 1 -0 .6 6 6 4 2 4 C 5 0.075581 -0 .0 3 3 8 8 0 C 6 -0.270492 0.133573 C 7 -0.301352 0 .1 4 5 2 3 1 O 8 -0.4 8 4 9 5 5 -0 .3 2 5 8 7 7 C 9 0.840749 1.004596 H 10 0.243624 0.049297 H 11 0.227515 0.061035 H 12 0.236611 0.077862 H 13 0.223485 0.069193 H 14 0.227211 0 .074535 234 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. H 15 0.235263 0 .075231 0 16 -0 .5 6 9 6 3 7 -0 .5 9 6 2 7 6 0 17 -0 .7 1 3 7 5 5 -0 .5 8 5 1 0 1 C 18 -0 .285359 0 .070851 H 19 0 .237223 0.084883 H 20 0.231051 0.087367 H 21 0 .234421 0.081363 D ip o le moments from M u llik e n an d e l e c t r o s t a t i c f i t c h a r g e s an d from w a v e f u n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X Y Z T o t a l -3 .4 0 5 1 4.7170 3.1775 6.6288 -2 .5 9 4 7 0.9432 1.8712 3 .3352 -2 .5829 0 .9756 1.8473 3 .3220 235 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a-Keto PAmide methoxy analog H25 H23 H10 H12 H24 • '^ C 1 8 H21 y N17 H22 C19 0 3 # P 2 i. 0 1 6 H20 C6 0 4 m T * * H 15 H14 H13 G eom etry O p tim iz a tio n 3 -2 1 G (*) Number o f b a s i s f u n c t i o n s : 151 Number o f e l e c t r o n s : 110 T o t a l m o le c u la r c h a r g e : 0 M u l t i p l i c i t y : 1 P o i n t g ro u p : Cl Number o f in d e p e n d e n t d e g r e e s o f freedom : 69 No u s e a b l e symmetry o r symmetry i n t e n t i o n a l l y d i s a b l e d C a r t e s i a n C o o r d in a te s (Angstroms) Atom X Y Z 0 1 -0.35 8 3 2 5 8 1.2950679 -1 .7 2 2 8 8 6 3 P 2 -0 .1 1 2 9 9 3 1 1.5150869 -0 .1 9 0 0 5 9 9 0 3 1.1252650 2.2030979 0.1522888 0 4 -1.45 7 9 1 7 9 2.1496569 0.2652264 C 5 -0.15 9 4 6 1 8 -0 .2 1 7 6 1 3 4 0.4039505 236 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. c 6 -1 .6 2 2 0 9 7 4 3.1514128 1.3258306 c 7 0.6811232 0.9469201 -2 .6 9 0 6 8 3 4 0 8 -0 .0 1 9 2 5 5 2 -1 .1 3 8 1 4 1 6 -0 .3 7 0 3 2 6 8 c 9 -0 .3178263 -0 .3 4 0 1 6 0 4 1.9209755 H 10 0.8194121 -0 .1 2 1 2 6 5 7 -2 .6 7 6 5 1 9 3 H 11 1.5996648 1.4537578 -2 .4 3 6 2 8 7 5 H 12 0.3219754 1.2735754 -3 .6 5 0 8 1 2 4 H 13 -0 .6 8 6 0 2 1 7 3.6616805 1.4853388 H 14 -1 .9 1 9 6 4 9 9 2.6401419 2.2215746 H 15 -2.38 0 8 6 7 8 3.8312622 0.9797283 0 16 -0.40 1 9 1 1 7 0.7473126 2 .4893762 N 17 -0 .3 5 4 1 9 3 0 -1 .5 1 4 3 5 9 3 2.5519653 C 18 -0 .2616468 -2 .8 4 7 9 3 3 5 1.9436681 C 19 -0 .4970316 -1 .5 1 7 0 2 0 3 4.0146082 H 20 -0.54 2 0 1 4 8 -0 .5 0 0 4 2 4 4 4.3643159 H 21 0.3521050 -2 .0 2 1 3 6 6 5 4.4604842 H 22 -1 .4 0 3 8 6 9 8 -2 .0 4 2 4 2 0 5 4.2905733 H 23 -0 .1 5 6 9 4 0 8 -2 .7 7 2 3 8 0 0 0.8805773 H 24 -1 .1 5 5 4 4 6 1 -3 .4120980 2.1844026 H 25 0.5938623 -3 .3 6 9 5 6 2 9 2.3573068 E n e rg y -998.4 7 2 4 8 0 h a r t r e e s M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s ( e l e c t r o n s ) atom M u llik e n e l e c t r o f i t O 1 -0 .7 1 8 2 6 1 -0 .6 5 9 1 2 8 P 2 1.661993 1.615889 O 3 -0 .626513 -0 .8 0 3 1 7 2 O 4 -0 .7 1 8 3 2 7 -0 .6 3 3 1 1 4 C 5 0.106169 0.113489 C 6 -0 .2 7 6 7 8 7 0.107240 C 7 -0 .2 9 6 4 4 2 0.175747 O 8 -0 .5 3 0 1 8 5 -0 .3 4 6 4 2 4 C 9 0.870536 0.563684 H 10 0.233481 0.023128 H 11 0.228033 0.054568 H 12 0.230523 0.076769 237 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. H 13 0.234322 0.077934 H 14 0.245439 0.081947 H 15 0.217937 0.073940 O 16 -0 .6 3 9 5 2 7 -0 .6 1 2 9 2 8 N 17 -0 .9 0 2 0 3 5 -0 .1 6 9 5 3 9 C 18 -0 .3 7 9 2 1 9 -0 .1 2 0 5 4 3 C 19 -0 .3 5 9 0 3 9 -0 .2 1 1 9 7 4 H 20 0.268566 0.149081 H 21 0.216391 0.095280 H 22 0.214244 0.098956 H 23 0.284506 0.092767 H 24 0.216578 0.077303 H 25 0.217619 0.079099 D ip o le moments from M u llik e n and e l e c t r o s t a t i c f i t c h a rg e s an d from w a v e f u n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X Y Z T o t a l 0.8329 - 0.1212 1.3605 1.5998 -1 .0 9 3 2 -3 .3 0 1 9 1.2156 3.6845 -1 .0 8 3 1 -3 .3 0 6 4 1.2059 3.6823 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a -Keto TIPMDP methoxy analog H21 H16 0 3 H22 C14 H23 0 6 0 8 H17 A1 2 H15 0 9 H25 • P4 0 7 010 C13 C11 05 H24 H20 H26 H19 G eom etry O p tim iz a tio n 3 -2 1 G (*) Number o f b a s i s f u n c t i o n s : 170 Number o f e l e c t r o n s : 128 T o t a l m o le c u la r c h a r g e : 0 M u l t i p l i c i t y : 1 P o i n t g ro u p : Cl Number o f in d e p e n d e n t d e g r e e s o f freedom : 72 No u s e a b l e symmetry o r symm etry i n t e n t i o n a l l y d i s a b l e d C a r t e s i a n C o o r d in a te s (Angstroms) Atom X Y Z P 1 1.0359476 -0 .3 4 0 3 5 8 4 -1 .6 6 6 3 4 3 9 C 2 -0.5259853 -0 .2 1 3 1 7 7 6 -0 .7 4 4 8 9 0 8 0 3 -1 .5 8 2 4 5 3 8 -0 .1 8 4 6 1 2 4 -1 .3 5 8 1 3 5 2 P 4 -0 .5 0 3 7 2 9 6 -0 .1 5 5 8 6 8 5 1.0729674 O 5 0.1636678 1.0196181 1.6182077 0 6 -1 .9955063 -0 .3 2 8 9 5 4 5 1.4876551 0 7 0.1715335 -1 .5 3 3 3 0 6 7 1.3962753 239 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 0 8 1.2246932 -1 .6 2 2 4 5 7 9 -2 .3238166 0 9 0.9828330 0 .9224297 -2 .6 0 1 5 3 7 3 0 10 2.0961662 0.0511300 -0 .5 8 9 5 3 9 3 c 11 2.6402587 1.3802051 -0 .2 4 9 0 1 0 6 c 12 0.2160346 0.9747459 -3 .8523128 c 13 1.4820907 -1 .7 2 9 3 4 9 1 2 .0303607 c 14 -2 .8 6 9 8 5 9 7 -1 .4 7 6 3 3 9 2 1.2353241 H 15 0.5005321 1.8900208 -4 .3 3 9 7 9 1 1 H 16 -0 .8 3 5 8 6 7 0 0.9712890 -3 .6 1 6 1 5 4 7 H 17 0.4667344 0.1194898 -4 .4 5 9 7 2 9 4 H 18 2.5984960 2.0131793 -1 .1 1 8 7 2 8 4 H 19 3.6578310 1.2119066 0.0571950 H 20 2.0413068 1.7657826 0.5556535 H 21 -3 .1 5 5 1 5 6 8 -1 .4 6 9 1 6 0 1 0.1973222 H 22 -3 .7 2 6 6 8 1 6 -1 .3 3 9 9 6 4 9 1.8705212 H 23 -2 .3 5 0 1 9 3 1 -2 .3 8 8 3 7 1 3 1.4848870 H 24 2.2394270 -1 .6 4 8 6 8 3 2 1.2710589 H 25 1.4608850 -2 .7 1 4 7 6 1 0 2.4605672 H 26 1.6306615 -0 .9 7 7 0 9 4 7 2.7882206 E nergy -1 3 9 4.773127 h a r t r e e s M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s ( e l e c t r o n s ) atom M u llik e n e l e c t r o f i t P 1 1.646159 1.407576 C 2 -0 .2 7 6 4 9 4 -0 .0 0 5 7 6 8 O 3 -0 .5 2 1 3 4 7 -0 .3 6 7 9 2 3 P 4 1.673684 1.545209 O 5 -0 .6 3 5 2 3 8 -0 .7 9 7 2 6 7 O 6 -0 .7 1 1 4 4 6 -0 .6 3 2 8 8 9 O 7 -0 .7 4 9 7 8 4 -0 .5 7 6 5 7 9 0 8 -0 .5 9 9 0 1 0 -0 .7 5 8 1 2 3 O 9 -0 .7 3 4 5 5 5 -0 .4 7 6 5 5 3 O 10 -0 .741760 -0 .5 6 8 4 3 0 C 11 -0 .3 2 1 5 5 9 0.022768 C 12 -0 .3 0 5 8 3 3 -0 .0 3 9 5 1 0 C 13 -0 .2 9 3 3 2 8 0.041631 240 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. c 14 -0 .3 0 4 0 8 4 0.158536 H 15 0.233813 0.108488 H 16 0.240805 0.095544 H 17 0 .239966 0.116386 H 18 0.232483 0.061859 H 19 0.226154 0.110333 H 20 0.279426 0.107662 H 21 0.244845 0.053291 H 22 0.238002 0.083202 H 23 0.225764 0.049445 H 24 0.254403 0.061680 H 25 0.228956 0.097472 H 26 0.229978 0.101960 D ip o le moments from M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s an d from w a v e f u n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X Y Z T o t a l 3.1259 0.0139 0 .8 1 6 1 3.2307 0.1622 0 .3031 0 .2252 0.4110 0 .1 8 6 1 0 .3020 0 .2226 0.4188 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. a-Keto PPP methoxy analog H20 C 1 9 > - # H22 / • » ' ft H31 H32 H12 H30 210 G eom etry O p ti m i z a t i o n 3 -2 1 G (*) Number o f b a s i s f u n c t i o n s : Number o f e l e c t r o n s : 152 T o t a l m o le c u la r c h a r g e : 0 M u l t i p l i c i t y : 1 P o i n t g ro u p : Cl Number o f in d e p e n d e n t d e g r e e s o f freedom : 90 No u s e a b l e symmetry o r symmetry i n t e n t i o n a l l y d i s a b l e d C a r t e s i a n C o o r d in a te s (Angstroms) Atom X Y Z 0 1 2.7582865 0 .2157161 -0 .8 2 9 1 4 1 6 P 2 2.5896244 -0 .2017346 0.6598878 0 3 3.5281131 0.3420823 1.6282891 C 4 0.8485759 0 .2275106 0 .9677056 0 5 2.5299478 -1 .7 7 2 7 9 4 2 0.6114886 C 6 2 .9859413 -0 .6 4 4 3 6 1 5 -2 .0 0 1 1 6 9 9 242 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. c 7 3.1037005 -2 .6 7 8 2 1 8 2 1.6077600 H 8 2.2949777 -3 .1 2 6 0 2 7 1 2.1624854 H 9 3 .7567358 -2 .1 2 6 0 8 0 6 2.2645866 H 10 3.6501490 -3 .4 3 4 8 1 1 9 1.0704827 H 11 3 .7704305 -1 .3 5 1 5 1 3 2 -1 .7 8 6 3 2 7 1 H 12 3 .2823742 0.0222741 -2 .7 9 1 3 2 6 5 H 13 2 .0599172 -1 .1 3 9 5 4 3 3 -2 .2 2 4 3 2 4 8 0 14 0 .5060200 0 .7295540 2.0280319 P 15 -0 .4 5 1 2 6 5 9 -0 .1 1 3 3 4 7 7 -0 .2 7 5 3 4 9 1 0 16 0.0008645 -0.95 1 5 2 1 3 -1 .3 8 8 4 9 2 4 0 17 -1 .5 7 7 8 7 7 0 -0 .7 8 1 3 7 3 2 0.5962384 C 18 -1 .0 1 5 6 9 1 8 1.4990568 -0 .7 9 1 1 1 1 5 C 19 -2 .4700895 -0 .2 4 9 2 2 8 4 1.6206974 H 20 -1 .8 8 9 7 0 8 9 0.0672501 2.4709972 H 21 -3 .1281387 -1 .0 5 8 4 1 3 4 1.8841950 H 22 -3 .0356049 0 .5789257 1.2214214 C 23 -1 .9 3 9 3 8 2 6 3.9315907 -1 .7 5 1 9 0 3 1 C 24 -1 .1 7 7 9 4 8 8 2.5786833 0.0736933 C 25 -1 .3 0 3 3 5 5 8 1.6569339 -2 .1 4 3 3 7 6 1 C 26 -1 .7 6 8 3 1 0 4 2 .8678840 -2 .6 2 0 2 0 0 0 C 27 -1 .6 4 0 2 9 3 3 3.7886693 -0 .4 0 7 2 8 8 0 H 28 -0 .9 2 2 8 7 8 1 2 .4799907 1.1092421 H 29 -1 .1 4 7 7 4 7 3 0.8301020 -2 .8 0 6 0 4 9 8 H 30 -1 .9 8 8 1 3 2 0 2.9827265 -3 .6 6 2 6 0 7 4 H 31 -1 .7 5 8 0 9 7 4 4.6178011 0.2611442 H 32 -2 .2954021 4.8724726 -2 .1 2 2 1 5 2 5 E nergy -1 5 0 9 .7 3 9 6 9 0 h a r t r e e s M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s (e l e c t r o n s ) atom M u llik e n e l e c t r o f i t O 1 -0 .734997 -0 .7 2 6 7 7 0 P 2 1.654989 1.668771 O 3 -0 .6 1 0 5 8 8 -0 .8 2 0 4 4 8 C 4 -0 .2 6 4 2 9 7 0.027357 O 5 -0 .744887 -0 .5 5 5 5 1 8 C 6 -0 .2 9 7 5 1 8 0.183597 243 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. C 7 -0 .2 8 6 0 8 3 0.013394 H 8 0 .224547 0.084474 H 9 0 .242128 0.106596 H 10 0.229103 0.089625 H 11 0 .205858 0.051133 H 12 0.222733 0.072416 H 13 0.284958 0.056822 O 14 -0 .5 1 9 2 5 6 -0 .4 1 1 0 3 2 P 15 1.719520 1.066333 O 16 -0 .6 3 1 6 6 4 -0 .7 3 8 5 4 2 O 17 -0 .7 2 4 3 5 2 -0 .4 8 7 0 9 7 C 18 -0 .5 1 2 3 9 7 -0 .0 1 5 7 7 2 C 19 -0 .2 9 9 3 3 2 0.081032 H 20 0.239285 0.092284 H 21 0.237303 0.079616 H 22 0.223311 0.052890 C 23 -0 .2 2 1 5 6 6 -0 .1 0 3 0 9 7 C 24 -0 .2 4 6 8 7 7 -0 .1 4 7 4 3 1 C 25 -0 .2 2 4 9 1 6 -0 .2 1 9 9 8 4 C 26 -0 .242594 -0 .1 4 8 4 8 6 C 27 -0 .242247 -0 .1 9 2 8 1 7 H 28 0.274753 0.156999 H 29 0.286933 0.208192 H 30 0.252061 0.156802 H 31 0.252639 0.168068 H 32 0.253448 0.150595 D ip o le moments from M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s an d from w a v e f u n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X Y Z T o t a l -0 .9 8 0 8 -3 .4 1 7 3 -1 .7 8 5 2 3.9783 •3 .3049 •0.3040 -0 .7107 3 .3940 -3 .2 7 4 8 -0 .2 8 8 1 -0 .7 1 0 0 3.3633 244 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. C3 Other Compounds t-BuOCl H7 - H8 • • H6 • H13 H12 • H7 H14 G eom etry O p tim iz a tio n 3 -2 1 G (*) Number o f b a s i s f u n c t i o n s : 82 Number o f e l e c t r o n s : 58 T o t a l m o le c u la r c h a r g e : 0 M u l t i p l i c i t y : 1 P o i n t g r o u p : CS Number o f in d e p e n d e n t d e g r e e s o f freedom : 22 C a r t e s i a n C o o r d in a te s (Angstrom s) Atom X Y Z C 1 -1 .0 1 0 9 7 6 1 0.0000000 -1 .8 7 1 5 3 7 7 C 2 0.0392188 0.0000000 -0 .7582243 C 3 0.8869376 1.2694714 -0 .7 9 0 2 2 8 3 C 4 0.8869376 -1 .2 6 9 4 7 1 4 -0.79 0 2 2 8 3 0 5 -0 .8 4 1 3 7 0 2 0.0000000 0.4382633 H 6 -0.52 1 3 1 0 3 0.0000000 -2 .8 3 8 0 0 7 0 H 7 -1 .6 3 5 9 0 3 5 0.8790457 -1 .7 8 7 8 5 6 4 H 8 -1 .6 3 5 9 0 3 5 -0 .8 7 9 0 4 5 7 -1 .7 8 7 8 5 6 4 H 9 1.4185242 -1 .3 2 4 3 3 6 8 -1 .7 3 2 5 8 9 5 H 10 0 .2500880 -2 .1 3 9 6 3 2 7 -0 .6 9 4 0 7 1 2 2 4 5 C4 CI15 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. H 11 1.6116562 -1 .2 7 9 0 3 1 6 0.0134773 H 12 1.4185242 1.3243368 -1 .7 3 2 5 8 9 5 H 13 1.6116562 1.2790316 0.0134773 H 14 0.2500880 2.1396327 -0 .6 9 4 0 7 1 2 Cl 15 -0 .0 4 9 9 5 0 9 0.0000000 1.9408995 srgy -687.644962 h a r t r e e s M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s ( e l e c t r o n s ) atom M u llik e n e l e c t r o f i t C 1 -0 .5 3 6 6 6 9 -0 .5 0 3 1 5 4 C 2 0.113924 0 .827244 C 3 -0 .5 7 0 3 3 9 -0 .4 0 4 0 6 8 C 4 -0 .5 7 0 3 3 9 -0 .4 0 4 0 6 8 0 5 -0 .5 3 6 6 3 7 -0 .458501 H 6 0.202873 0.102869 H 7 0.227796 0 .135255 H 8 0 .227796 0.135255 H 9 0.205562 0.087991 H 10 0.226224 0.101051 H 11 0.225337 0.087576 H 12 0.205562 0.087991 H 13 0.225337 0.087576 H 14 0.226224 0.101051 C115 0.127349 0.015933 D ip o le moments from M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s and from w a v e fu n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X Y Z T o t a l 2.6513 0.0000 -2 .7 8 1 4 3 .8426 1.4198 0.0000 -2 .0 9 0 8 2.5273 1.5139 0.0000 -2 .1 0 7 1 2.5946 2 4 6 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Acetone .0 3 H5 C4 C2 * H7 H6 C1 H8 & H9 c H10 G eom etry O p tim iz a tio n 3 - 2 1 G (*) Number o f b a s i s f u n c t i o n s : 48 Number o f e l e c t r o n s : 32 T o t a l m o le c u la r c h a r g e : 0 M u l t i p l i c i t y : 1 P o i n t g ro u p : C2V Number o f in d e p e n d e n t d e g r e e s o f freedom : 8 Atom C a r t e s i a n X C o o r d in a te s Y (Angstroms) Z C 1 1.2780107 0.0000000 -0 .6201908 C 2 0.0000000 0.0000000 0 .1933335 0 3 0.0000000 0.0000000 1.4043269 C 4 -1 .2 7 8 0 1 0 7 0.0000000 -0 .6 2 0 1 9 0 8 H 5 -2 .1 3 1 7 3 3 2 0.0000000 0.0415683 H 6 -1 .3 1 4 0 3 7 9 -0 .8 7 6 5 0 6 7 -1 .2 5 8 8 6 5 8 H 7 -1 .3 1 4 0 3 7 9 0.8765067 -1 .2 5 8 8 6 5 8 H 8 2.1317332 0.0000000 0.0415683 H 9 1.3140379 0.8765067 -1 .2 5 8 8 6 5 8 H 10 1.3140379 -0 .8 7 6 5 0 6 7 -1 .2 5 8 8 6 5 8 E n erg y -1 9 0 .8 8 7 2 2 1 h a r t r e e s 247 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. M u llik e n and e l e c t r o s t a t i c f i t c h a r g e s (e l e c t r o n s ) atom M u llik e n e l e c t r o f i t c 1 -0 .6 8 5 5 1 7 -0 .4 9 2 8 3 4 c 2 0.506901 0.794402 0 3 -0 .5 4 3 4 8 5 -0 .5 7 6 0 4 8 c 4 -0 .6 8 5 5 1 7 -0 .4 9 2 8 3 4 H 5 0 .249507 0 .137363 H 6 0.227151 0.123147 H 7 0.227151 0.123147 H 8 0.249507 0.137363 H 9 0.227151 0.123147 H 10 0.227151 0.123147 D ip o le moments from M u llik e n and e l e c t r o s t a t i c f i t c h a rg e s an d from w a v e f u n c tio n (debyes) comp M u llik e n e l e c t r o f i t a c t u a l X Y Z T o t a l 0 .0000 0.0000 -4 .5 0 4 7 4.5047 0.0000 0.0000 -3 .1 3 4 8 3.1348 0 .0000 0.0000 -3 .1386 3 .1386 248 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Appendix D X-RAY CRYSTALLOGRAPHY D, l-(2-Hydroxy-3,5-diiodobenzylidene)-4-hydroxysemicarbazide (8) Q CIO 0 4 r C9 0 3 C l cs C8 C4 N2 N3 C6 C l 02 C2 O l II 24 9 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 1. Crystal data and structure refinement for C 8H 7N 303I2S*D M S0. Empirical formula Form ula weight Temperature W avelength Crystal system Space group Unit cell dimensions V olum e Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Refinement m ethod Data / restraints / parameters Goodness-of-fit on F A 2 Final R indices [I>2sigma(I)] R indices (all data) Largest diff. peak and hole 2 5 0 C 10 H 1 3 12 N 3 04 S 525.09 293(2) K 0.71073 A monoclinic P2(1)/c [#14] a = 18.031(2) A alpha = 90 deg. b = 11.0595(13) A beta = 102.130(2) deg. c = 8.4905(10) A g a m m a = 90 deg. 1655.3(3) A A 3 4 2.107 M g /m A 3 3.940 m m A -1 992 0.15 x 0.16 x 0.20 m m A 3 2.17 to 27.67 deg. -22<=h<=22, 0<=k<=13, 0<=l<=4 2058 2058 tR(int) = 0.0705] Full-matrix least-squares on F A 2 2058 / 0 / 181 0.707 R 1 = 0.0552, w R 2 = 0.1597 R 1 = 0.0640, w R 2 = 0.1705 0.718 and -1.205 e.AA -3 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 2. Atomic coordinates ( x 10A 4) and equivalent isotropic displacement parameters (AA 2 x 10A 3) for C 8H 7N303I2S*DM S0. U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. X y z U(eq) 1(1) 1062(1) 6454(1) 1652(1) 69(1) 1(2) 691(1) 3290(1) -4211(1) 101(1) S<1) 6990(1) 6628(2) -1489(4) 90(1) 0(1) 2571(2) 7009(4) 480(7) 63(2) 0(2) 4364(2) 8781(3) 348(6) 47(2) 0(3) 5267(3) 8497(4) -2841(8) 57(2) 0(4) 6688(3) 7842(5) -2121(9) 98(2) N<1) 3556(2) 6977(4) -1290(7) 44(2) N C 2) 4205(3) 7414(4) -1731(7) 46(2) N(3) 5167(3) 8794(4) -1328(9) 45(2) C(1) 2182(3) 6192(4) -545(9) 45(2) C C 2) 1481(3) 5800(5) -29000) 57(3) C(3) 1063(3) 4955(6) -1351(10) 59(3) C(4) 1343(4) 4527(6) -2607(10) 58(3) C C S) 2036(3} 4897(5) -2879(10) 54(2) C(6) 2464(3) 5747(4) -1832(9) 42(2) C(7> 3174(3) 6153(5) -2197(10) 51(2) C(8) 4560(3) 8350(4) -834(10) 42(2) C(9) 6190(6) 5761(7) -1390(15) 105(4) COO) 7228(7) 591400) -3138(15) 122(5) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3. Bond lengths [A] and angles [deg] for C8H7N303I2S*DMS0. I(1)-C(2) 2.083(8) I(2)-C<4) 2.106(7) S(1)-0(4) 1.506(6) SC1)-C(10) 1.738(13) S(1)-C(9) 1.750(10) 0(1)-C(1) 1.344(7) 0(2>-C(8) 1.229(9) 0(3)-N(3) 1.374(9) M(1)-C<7) 1.294(8) M C1)-M <2) 1.389(7) N(2)-C(8) 1.362(7) N(3)-C(8) 1.346(8) C(1)-CC6) 1.389(10) CC1)-C(2) 1.396(9) C(2)-C(3) 1.402(9) C(3)*C(4) 1.357(11) C(4)-C(5) 1.380(9) C(5)*C(6) 1.408(8) C(6)-C(7) 1.451(9) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3(continued) Bond lengths [A] and angles [deg] for C8H7N303I2S*DMS0. 0 (4 )-S (1 )-C (1 0 ) 104.5(5) 0 (4 )-S (1 )-C (9 ) 105.4(4) C(10)-S(1)-C<9> 9 7 .8 (6 ) C (7)-N (1)-N (2) 117.2(6) C (8)-N (2)-N (1) 115.9(6) C (8)-N (3)-0(3) 118.6(5) 0 (1 )-C (1)-C (6) 121.3(6) 0(1)-C (1)-C <2) 118.3(7) C (6)-C (1)-C (2) 120.3(6) C (1)-C (2)-C (3) 119.3(7) C (1 )-C (2 )-I(1 ) 120.4(5) C (3 )-C (2 )-I(1 ) 120.3(5) C (4)-C (3)-C (2) 119.9(6) C (3)-C (4)-C (5) 121.8(6) C (3 )-C (4 )-I(2 ) 119.1(5) C (5 )-C (4 )-I(2 ) 119.1(6) C (4)-C (5)-C (6) 119.2(7) C (1)-C (6)-C (5) 119.4(6) C(1)-C(6)-C(7> 123.0(5) C (5)-C (6)-C (7) 117.6(7) M (1)-C(7)-C(6) 118.2(7) 0(2)-C (8)-N (3) 120.4(5) 0(2)-C (8)-M (2) 124.7(6) M (3)-C(8)-N(2) 114.9(7) Symmetry transform ations used to generate equivalent atoms: 253 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. T able 4 . A n iso tro p ic d isp lacem en t p aram eters (AA 2 x 10*3) fo r C8H7N303I2S*DMS0. The a n is o tro p ic d isp lacem en t f a c to r exponent ta k e s th e fo rm :*2 p iA 2 [ hA 2 a*A 2 U11 ♦ . . . ♦ 2 h k a* b* U12 ] U 11 U22 U33 U23 U13 U12 1(1) 61(1) 80(1) 6 9 (1 ) *16(1) 21(1) -3 (1 ) 1(2) 104(1) 97(1) 104(1) -4 8 (1 ) 26(1) -46(1) S(1) 74(1) 92(1) 100(3) -1 4 (1 ) 11(1) 4 (1 ) 0 (1 ) 64(2) 60 (2) 61(5) -2 1 (2 ) 6 (2 ) -1 8 (2 ) 0 (2 ) 70(2) 32(2) 42(4) 2(2) 19(2) -2 (2 ) 0 (3 ) 83(3) 61(2) 35(5) -10(2) 32(3) -16(2) 0 (4 ) 83(3) 63(3) 158(7) -5 (3 ) 49(3) -8 (2 ) N(1) 54(2) 39(2) 40(5) -1 (2 ) 14(2) -6 (2 ) N(2) 60(2) 42 (2 ) 41(4) -7 (3 ) 21(2) -7 (2 ) N(3) 62(2) 43(2) 33(6) -7 (3 ) 20(3) -1 0(2) C(1) 58(3) 31(2) 42(7) -6 (3 ) 2(3) -3 (2 ) C(2) 53(3) 46(3) 71(7) -5 (3 ) 12(3) -1 0(2) C(3) 56(3) 53(3) 69(8) -1 (4 ) 15(3) -1 6 (2 ) C(4) 67(3) 58(3) 51(8) -16(4) 19(4) -1 6 (3 ) C(5) 64(3) 47(3) 51(7) -1 7 (3 ) 11(3) -1 0 (2 ) C(6) 60(3) 30(2) 37(7) -3 (3 ) 10(3) -2 (2 ) C{7) 57(3) 35(2) 6 4 (7 ) 0(3 ) 20(3) -1 (2 ) C(8) 4 8 (2 ) 29(2) 48 (7 ) 2 (3 ) 10(3) -1 (2 ) C(9) 114(6) 65(5) 132(11) 9 (5 ) 13(7) -6 (4 ) C(10) 157(8) 126(8) 92(12) -3 (7 ) 45(8) 55(7) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 5. Hydrogen coordinates ( x 10*4) and isotropic displacement parameters <A*2 x 10*3) for C8H7N303I2S*DMS0. x y z U(eq) H(1) 2849 7596 1194 61 H(2) 577 4688 -1116 62 H(3) 2226 4571 -3782 57 H(4) 3360 5820 -3117 53 H<5) 4384 7080 -2635 47 H(6) 5517 9319 -590 57 H(7) 5333 8269 -3888 67 H(8) 5902 6100 -677 111 H(9) 5857 5668 -2433 111 H(10) 6332 4943 -1006 111 H<11) 6783 5821 -3963 143 H(12) 7593 6364 -3519 53 H(13) 7424 5123 -2818 143 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. D2 l-(l,4-benzodioxan-6-ylmethylene)semicarbazide (34) N2 C2 C10 C3 0 3 C7 C12 N3 C1 C6 C4 C5 C8 02 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 1. Crystal data and structure refinement for CIO H ll N3 03. Empirical fonmila Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta ■ 24.71° Refinement method Data / restraints / parameters Goodness-of-fit cm F2 Final R indices [I>2sigma(I)] R indices (all data) Absolute structure parameter Extinction coefficient Largest diff. peak and hole CIO H ll N3 03 221.23 293(2)K 0.71073 A Orthorombic Pna2(l) a = 13.759(6) A a - 90°. b - 5.267(2) A p-90°. C* 28.202(13) A y = 90°. 2043.9(15) A3 8 1.451 Mg/m3 0.109 m m *1 944 1.44 to 24.71°. -10<=h<*16, -6<=k<=6, -33<*1<=32 9439 3478 (R(int) = 0.0839] 1 0 0.0 % Full-matrix least-squares on F2 3478/1/132 0.927 R1 - 0.1020, wR2 « 0.2665 R1 = 0.1744, wR2 « 0.3073 -3(4) 0.0017(10) 0.596 and -0.544 e.A * 3 257 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Tabi c 2. At omi c coordi nates (x 10*) and equival ent isotropic displace ment parameters (A ^ 1 0 * ) for CI O H ll N3 0 3 . U( eq) it defi ned as one third a t the t race of the otthogonalized I!*' t ensor. X y z U (eq) 0(1) 2284(3) 14332(8) 3063(2) 60(1) 0(2) 6499(3) 3658(8) 5101(1) 62(1) 0(3) 7494(3) 7945(9) 4750(2) 69(1) 0(4) 4990(3) -4311(8) 3053(2) 56(1) 0(3) 929(3) 6576(9) 1011(2) 71(1) 0(6) *173(3) 2338(10) 1388(2) 76(1) N (l) 1980(4) 10611(9) 3428(2) 53(1) N(2) 3482(3) 12418(9) 3459(2) 53(1) N(3) 3789(3) 10409(9) 3748(2) 48(1) N(4) 5311(4) -620(9) 2676(2) 58(2) N(5) 3801(3) -2359(9) 2643(2) 50(1) N(6) 3490(3) •410(9) 2366(2) 44(1) C (l) 2335(4) 12512(10) 3314(2) 38(1) C(2) 4709(4) 10461(12) 3847(2) 49(2) C(3) 5166(4) 8519(12) 4163(2) 51(2) C(4) 4657(4) 6582(11) 4344(2) 47(2) C(5) 5119(5) 4941(12) 4654(2) 57(2) C(6) 6073(4) 5331(11) 4780(2) 41(1) C(7) 6564(4) 7343(11) 4606(2) 44(2) C(») 6118(4) 9031(11) 4295(2) 52(2) C(9) 7839(6) 6459(16) 5114(3) 99(3) COO) 7533(6) 3868(15) 5064(3) 88(2) C (ll) 4708(4) •2514(12) 2809(2) 50(2) C(12) 2612(4) -500(12) 2257(2) 51(2) C(13) 2164(4) 1439(11) 1949(2) 40(1) C(14) 2679(5) 3529(11) 1776(2) 48(2) C(13) 2268(4) 5120(13) 1454(2) 55(2) C(16) 1308(4) 4771(11) 1315(2) 47(2) COT) 794(5) 2799(12) 1489(2) 51(2) C (l«) 1200(4) 1108(12) 1805(2) 49(2) C(I9) -79(6) 6239(18) 938(4) 115(3) C(20) -535(8) 4180(20) 1013(4) 145(4) 258 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3. Boixi lengths [A ] and angles [°] for C IO Hll N 3 03. o d M x n 1.249(7) 0(2)-C(6) 1.393(7) O(2)-C(10) 1.431(9) 0(3)-C(7) 1.380(7) 0(3)-C(9) 1.385(9) 0 (4)-C (ll) 1.233(7) 0(5>C(16) 1.382(7) 0(5HX19) 1.414(10) CK6K(17) 1.382(7) O(6)-C(20) 1.519(12) N(1HX1) 1.316(7) N (2K (1) 1.342(7) N(2>N(3) 1.400(6) N(3)-C(2) 1.296(7) N(4)-C(l 1) 1.350(8) N(5>C(11) 1.335(7) N(5)-N(6) 1.359(6) N (6K (12) 1.248(7) C(2>N(3)-N(2) 113.8(5) C(11).N(5)-N(6) 122.8(5) C(12)-N(6)-N(5) 114.7(5) 0(1)-C(1)*N(1) 122.9(5) 0(1)-C(1)-N(2) 119.1(5) N(l)-C(l)-N(2) 117.9(5) N(3)-C(2)-C(3) 121.7(6) C(4)-C(3)-C(8) 122.6(6) C(4HX3>C(2) 121.9(6) C(8)-C(3)-C(2) 115.1(5) C(3)-C(4)-C(5) 118.5(6) C(6)-C(5)-C(4) 120.6(6) C(7)-C(6)-C(5) 120.0(6) C(7)-C(6>0(2) 121.5(5) C (5K (6> 0(2) 118.4(5) C(6)-C(7)-0(3) 122.5(5) C(6)-C(7)-C(8) 120.7(6) 0(3)-C(7VC(8) 116.6(5) 2 5 9 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3 (continued)*. Boml lengths [A] and angles [°] for CIO HI IN 3 03. C(2K(3) 1.496(8) C(3)-C(4) 1.339(8) C(3)-C(8) 1.387(8) C(4)-C(5) 1.383(8) C(5K(6) 1.375(9) C isy c m 1.350(8) C(7)-C(8) 1.391(8) C(9)-C(10) 1.444(11) C(12>C(13) 1.475(8) C(13)-C(18) 1.399(8) C(13)-C(14) 1.397(8) C(14)-C(15) 1.359(8) C(15)-C(16) 1.390(8) C(16>C(17) 1.349(8) C(17)-C(18) 1.377(8) C(19>C(20) 1.272(13) C(6)-O(2)-C(10) 108.8(5) C(7)-0(3)-C(9) 115.2(5) C(16)-0(5K(19) 112.0(6) C(17)-O(6)-C(20) 110.3(6) C(1>N(2>N(3) 119.5(5) C(3)C(8)-C(7) 117.5(6) O(3)-C(9)-C(10) 110.3(7) 0(2K(10)-C(9) 112.0(7) 0(4)-C(ll)-N(5) 122.5(6) 0(4)-C(ll)-N(4) 122.0(6) N(5>C(11)-N(4) 115.5(5) N(6>-C(12)-C(13) 121.5(6) C(18)-C(13)-C(14) 118.5(5) C(18)-C(13)*C(12) 118.8(5) C(14>C(13>C(12) 122.7(5) C(15)-C(14)-C(13) 120.6(6) C(14HX15)-C(16) 120.1(6) C(17)-C(16)-0(5) 123.9(6) C(17)-C(16K(15) 119.9(6) 0(5)-C(16>C(15) 116.2(5) C(16)-C(17>C(18) 121.3(6) C(16)-C(17)-0(6) 124.4(6) C(18)-C(17>0(6) 114.2(6) C(17>C(18K(13) 119.5(6) C(20)-C(19)-O(5) 124.5(10) C(19)-C(20)O(6) 119.9(10) Symmetry transfonnstions used to generate equivalent atoms: 260 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. D3 l-(1^3-benzodioxole-5-methyIeneamino)-3-hydroxyguanidine Tosylate (40) C14 C12A C15A C16A 261 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 1. Crystal data and stroctnie Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F (O O O ) Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta - 22.50° Refinement wiaiyiJ Data / restraints / parameters Goodness of-fitonF2 Finsl R indices P>2sigma(I)] R indices (sll data) Extinction coefficient Largest diff. peak and hole refinement for [C9N4Q3Hio]*S03C7Hs. [C9N4Q}HlO]*SQ3C7HS 394.41 296(2)K 0.71073 A m onodinic • P2(1)/c, #14 a -6.0369(6) A b - 21.745(2) A c - 14.1239(15) A 1822.0(3) A1 4 1.405 Mg/m3 0.218 nun'1 788 1.74 to 22.50°. -6 < = lK = 6 , -23<=k<=23, -12<=l<*15 7517 2386 [R(im) = 0.0872J 99.9% Full-matrix least-squares on F2 2 3 8 6 /0 /2 9 3 1.000 R1 = 0.0586, wR2 = 0.1686 R1 * 0.0706, wR2 * 0.1769 0.0008(9) 0.449 and -0.226 e.A3 a * 90°. P= 106.669(2)°. y « 9 0 “. 262 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 2. Atomic coordinates ( x 10*4) and equivalent iso tro p ic displacement parameters (A*2 x 10*3) for C9 H10 N 4 03 * C7 H 8 03 S. U(eq) is defined as one th ird of the trace of the orthogonalized Uij tensor. X y z U(eq) s i n 1683(1) 6671(1) 6141(1) 55(1) 0(5) 2662(4) 6926(1) 7080(2) 73(1) 0(6) -728(3) 6770(1) 5920(2) 67(1) 0(4) 2816(4) 6891(1) 5392(2) 73(1) COO) 2232(5) 5877(1) 6236(2) 57(1) C(13) 3252(7) 4620(2) 6430(3) 86(1) C(14) 3787(10) 3947(2) 6520(4) 130(2) C(16A) 904(11) 5502(3) 6601(5) 65(2) CC15A) 1492(15) 4876(3) 6737(6) 90(3) C(12A) 4726(13) 5043(3) 5979(6) 84(3) C(11A) 4170(14} 5688(4) 5858(6) 90(3) C(15B) 1001(15) 4804(3) 6142(7) 90(3) C(11B) 4350(12) 5662(3) 6543(7) 88(3) C(12B) 4799(13) 5026(4) 6660(7) 88(3) C(168) 366(15) 5440(4) 6043(7) 97(3) M(3) 2587(4) 2651(1) 640(2) 50(1) M(4) 4469(4) 3028(1) 719(2) 51(1) M(2) 2743(4) 2801(1) 2278(2) 61(1) N(1) -272(4) 2291(1) 1338(2) 58(1) C(9) 1696(5) 2581(1) 1432(2) 51(1) C(7) 7212(5) 3489(1) -70(2) 51(1) 0(1) 11602(4) 4458(1) 1362(2) 80(1) 0(2) 12836(4) 4546(1) -85(2) 86(1) 0(7) 2091(18) 2566(6) 2994(8) 64(4) 0(3) -999(4) 2103(1) 2154(2) 67(1) C(8) 5241(5) 3112(1) -49(2) 50(1) C(2) 10205(5) 4127(1) 662(2) 57(1) C(6) 8378(5) 3786(1) 762(2) 54(1) C(5) 7987(5) 3546(1) -937(2) 65(1) C(4) 9895(5) 3899(2) -1005(3) 74(1) C(3) 10964(5) 4181(1) -187(3) 64(1) C(1) 13356(6) 4689(2) 905(3) 84(1) Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3. Bond lengths [A] and angles [deg] for C9 H10 N4 03 * C7 H8 03 S. S(1)*0(4) 1.443(2) C(16B)-C(16A)-C(15A) 91.1(9) S(1)-0(6) 1.447(2) C(10)-C(16A)-C(15A) 119.8(6) S(1)*0(5) 1.458(2) C(16B)-C(16A)-C(15B) 60.1(8) SOJ-COO) 1.758(3) C(10)*C(16A)*C(15B) 110.3(6) C(10)-C(16A) 1.315(7) C(15A)*C(16A)*C(15B) 31.0(4) COO)-C(HB) 1.355(8) C(15B)*C(15A)-C(13) 75.9(9) C(10)-C(11A) 1.432(9) C(15B)-C(15A)-C(16A) 90.5(9) C(10)-C(16B) 1.461(9) C(13)*C(15A)*C(16A) 123.4(7) C03)*C(12B) 1.282(8) C(1SB)-C(15A)-C(16B) 61.0(8) C(13)-C(15A) 1.340(10) C(13)*C(15A)*C(16B) 112.5(7) C(13)-C(15B) 1.402(9) C(16A)*C(15A)-C(16B) 29.5(4) C(13)-C(14) 1.501(5) C(12B)-C(12A)-C(11A) 97.0(8) C(13)-C(12A) 1.501(9) C(12B)-C(12A)-C(13) 57.9(7) C(16A)*C(16B) 0.807(10) C(11A)-C(12A)-C(13) 120.1(7) C(16A)-C(15A) 1.410(10) C(12B)-C(12A)-C(11B) 61.0(7) C(16A)*C(15B) 1.655(10) C(11A)*C(12A)-C(11B) 36.1(5) C(15A)-C(15B) 0.853(10) C(13)-C(12A)-C(11B) 98.8(6) C(15A)*C(16B) 1.638(11) C(11B)-C(11A)-C(10) 65.7(7) C(12A)-C(12B) 0.955(11) C(11B)-C(11A)-C(12A) 80.9(8) C(12A)-C(11A) 1.445(11) C(10)-C(11A)-C(12A) 115.0(7) C(12A)-C(11B) 1.600(11) C(11B)*C(11A)~C(12B) 49.7(7) C(11A)-C(11B) 0.954(12) C(10)*C(11A)*C(12B) 94.9(5) C(11A)-C(12B) 1.827(12) C(12A)-C(11A)-C(12B) 31.2(4) C(15B)*C(16B) 1.434(11) C(15A)-C(15B)-C(13) 67.9(9) C(11B)-C(12B) 1.412(10) C(15A)-C(15B)-C(16B) 87.6(9) N(3)-C(9) 1.337(4) C(13)-C(15B)-C(16B) 122.0(7) M(3)-M(4) 1.389(3) C(15A)-C(15B)-C(16A) 58.5(8) N(4)~C(8) 1.270(4) C(13)*C(15B)-C(16A) 104.5(5) N(2)~0(7) 1.258(13) C(16B)-C(15B)-C(16A) 29.2(4) N(2)-C(9) 1.332(4) C(11A)-C(11B)-C(10) 74.4(7) N(1)-C(9) 1.330(4) C(11A)-C(11B)*C(12B) 99.3(10) N(1)*0(3) 1.370(3) C(10)-C(11B)*C(12B) 121.7(6) C(7)*C(5) 1.395(4) C(11A)*C(11B)-C(12A> 63.1(8) C(7)-C(6) 1.410(4) C(10)-C(11B)*C(12A) 110.1(6) C<7)-CC8) 1.450(4) C(12B)-C(11B)-C(12A) 36.3(5) 0(1)*C(2) 1.377(4) C(12A)-C(12B)-C(13) 82.9(8) o(i>-cci) 1.429(4} C(12A)-C(12B)-C(11B) 82.7(9) 2 6 4 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3 (continued). Bond lengths C A ] and angles [deg] for C9 H10 N4 03 * C7 H8 03 S. 0(2)-C(3) 1.366(4) C(13)*C(12B)*C(11B) 0(2)-C(1) 1.410(5) C(12A)-C(12B)*C(11A) C(2)-C(6) 1.358(4) C(13)-C(12B)-C(11A) C(2)-C(3) 1.366(5) C(11B)-C(12B)'C(11A) C(5)-C(4) 1.402(4) C(16A)*C(16B)-C(15B) C(4)-C(3) 1.361(5) C(16A)-C(16B)-C(10) C(15B)-C(16B)*C(10) 0(4)-S(1)-0(6) 112.75(13) C(16A)*C(16B)*C(15A) 0(4)-S(1)-0(5) 111.92(14) C(15B)-C(16B)*C(15A) 0(6)*S(1)*0(5) 111.26(14) C(10)-C(16B)*C(15A) 0(4)-S(1)-C(10) 105.79(14) C(9)-N(3)-N(4) O(6)-S(1)-C(10) 109.28(14) C(8)-H(4)-M(3) 0(5)-S(1)-C(10) 105.40(13) 0(7)-N(2)*C(9) C(16A)*C(10)-C(11B) 105.5(5) C(9)-M(1)-0(3) C(16A)-C(10)*C(11A) 124.6(5) N(1)*C(9)*N(2) C(11B)*C(10)*C(11A) 39.9(5) H(1)-C(9)-M(3) C(16A)*C(10)*C(16B) 33.3(4) M(2)-C(9)-M(3) C(11B)-C(10)*C(16B) 118.9(5) C(5)-C(7)-C(6) C(11A)*C(10)*C(16B) 113.5(6) C(5)-C(7)-C(8) C(16A)-C(10)-S(1) 121.3(4) C(6)-C(7)-C(8) C(11B)-C(10)-S(1) 121.2(3) C(2)-0(1)-C(1) C(11A)-C(10)-S(1) 114.1(4) C(3)-0(2)-C(1) C(16B)-C(10)*S(1) 119.8(4) N(4)-C(8)-C(7) C(12B)*C(13)-C(15A) 102.5(6) C(6)-C(2)-C(3) C(12B)-C(13)-C(15B) 119.9(5) C(6)-C(2)-0(1) C(15A)*C(13)-C(15B) 36.2(5) C(3)-C(2)-0(1) C(12B)*C(13)-C(14) 121.0(5) C(2)-C(6)*C(7) C(15A)-C(13)-C(14) 123.3(5) C(7)-C(5)*C(4) C(15B)-C(13)-C(14) 119.0(5) C(3)*C(4)-C(5) C(12B)-C(13)-C(12A) 39.2(5) C(4)-C(3)-0(2) C(15A)*C(13)-C(12A) 116.9(5) C(4)-C(3)-C(2) C(15B)-C(13)-C(12A) 108.7(5) 0(2)*C(3)-C(2) C(14)-C(13)-C(12A) 119.9(5) 0(2)*C(1)*0(1) C(16B)-C(16A)-C(10) 83.4(9) 121.9(7) 51.7(7) 109.1(6) 31.0(5) 90.7(10) 63.4(7) 115.2(7) 59.4(8) 31.4(4) 98.9(6) 116.8(2) 116.1(2) 114.0(6) 118.5(2) 121.8(3) 117.4(2) 120.8(3) 119.6(3) 118.5(3) 121.8(3) 105.5(3) 105.1(3) 122.0(3) 123.3(3) 127.8(3) 109.0(3) 117.0(3) 121.5(3) 117.0(3) 127.2(3) 121.6(3) 111.2(3) 108.8(3) Symnetry transform ations used to generate equivalent atoms: 2 65 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 4. A nisotropic displacement parameters (AA 2 x 10A 3) for C9 H10 N 4 03 * C 7 H8 03 S. The anisotropic displacement facto r exponent takes the form: -2 p iA 2 I hA 2 a*A 2 U11 ♦ . . . ♦ 2 h k a* b* U12 ] U 11 U22 U33 U23 U13 U12 SCI) 52(1) 58(1) 53(1) 3(1) 3(1) -3(1) 0(5) 74(1) 72(1) 66(1) -14(1) -9(1) 5(1) 0(6) 51(1) 75(1) 71(1) 12(1) 1(1) 3(1) 0(4) 70(1) 77(1) 76(1) 19(1) 23(1) 3(1) C(10) 58(2) 54(2) 57(2) 3(1) 3(2) -4(2) C(13) 101(3) 61(2) 86(3) 4(2) -6(2) -4(2) C(14) 173(4) 55(2) 151(4) 10(3) -3(4) 9(3) C(16A) 65(4) 57(4) 72(4) 10(3) 11(3) -17(3) C(15A) 124(6) 63(4) 79(5) 6(4) 13(5) -29(4) C(12A) 86(5) 58(4) 100(6) -9(4) -3(4) 3(4) cd iA ) 88(5) 92(5) 93(5) 12(5) 23(4) 7(4) C(15B) 104(6) 52(4) 107(6) -3(4) 2(5) -24(4) c d iB ) 51(4) 50(4) 157(8) 2(5) -1(5) -13(3) C(12B) 70(5) 66(4) 121(7) -16(5) -4(5) -7(4) C(168) 82(5) 83(5) 108(7) 4(5) -30(5) -27(4) N(3) 47(1) 48(1) 57(1) -1(1) 14(1) -7(1) N(4) 51(1) 52(1) 53(1) 1(1) 14(1) 4(1) N(2) 67(2) 71(2) 44(1) -5(1) 6(1) -7(1) N(1) 53(1) 60(1) 64(2) 2(1) 17(1) -12(1) C(9) 54(2) 47(2) 52(2) 6(1) 12(1) 6(1) C(7) 50(2) 47(2) 58(2) 7(1) 14(1) 9(1) 0(1) 71(1) 76(1) 95(2) -7(1) 19(1) -19(1) 0(2) 74(1) 68(1) 123(2) 10(1) 40(1) -10(1) 0(7) 41(6) 106(10) 42(7) -19(7) 0(5) -2(6) 0(3) 78(2) 61(2) 67(2) 6(1) 28(1) -9(1) C(8) 51(2) 46(2) 52(2) -3(1) 6(1) 10(1) C(2) 53(2) 43(2) 75(2) 3(1) 15(2) 0(1) C(6) 55(2) 47(2) 60(2) 6(1) 14(1) 6(1) C(S) 73(2) 65(2) 60(2) 6(2) 24(2) 11(2) C(4) 80(2) 71(2) 80(2) 20(2) 41(2) 6(2) C(3) 58(2) 48(2) 92(2) 13(2) 27(2) 5(2) C(1) 57(2) 66(2) 133(3) 0(2) 27(2) -4(2) 266 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 5. Hydrogen coordinates ( x 10A 4) and isotropic displacement parameters (AA 2 x 10A 3) for C 9 H 10 N 4 03 * C 7 H 8 03 S. x y z U(eq) H(8) 4520(5) 2925(1) -615(2) 60 H(6) 7917(5) 3750(1) 1353(2) 65 H(5) 7221(5) 3345(1) -1481(2) 78 H <4) 10407(5) 3938(2) -1584(3) 88 H C 1 A) 13485(6) 5131(2) 991(3) 101 HUB) 14785(6) 4504(2) 1192(3) 101 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

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Creator Bonaz, Patricia Isabelle (author)

Core Title I. Oxidation of diazo phosphonates and diazo bisphosphonates. II. NMR and crystallographic studies of bioactive semicarbazides and Schiff bases of hydroxyguanidine

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