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Novel methods for functional group interconversions in organic synthesis and structural characterization of new transition metal heterogeneous catalysts for potential carbon neutral hydrogen storage
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Novel methods for functional group interconversions in organic synthesis and structural characterization of new transition metal heterogeneous catalysts for potential carbon neutral hydrogen storage
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Content
NOVEL METHODS FOR FUNCTIONAL GROUP INTERCONVERSIONS IN
ORGANIC SYNTHESIS AND STRUCTURAL CHARACTERIZATION OF NEW
TRANSITION METAL HETEROGENEOUS CATALYSTS FOR POTENTIAL
CARBON NEUTRAL HYDROGEN STORAGE
by
Fang Fu
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree of
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
August 2021
Copyright 2021 Fang Fu
ii
DEDICATION
This dissertation is dedicated to my family, mentors and friends.
For their endless love, support and encouragement.
iii
ACKNOWLEDGEMENTS
This thesis becomes a reality with the help and kind support from many individuals. I would
like to extend my deep gratitude to all of them.
First and foremost, I would like to express my sincere thanks to my dissertation advisor
Professor G. K. Surya Prakash for his excellent mentorship, guidance, constant support and
encouragement during my graduate education and research. His enthusiasm, innovative ideas, and
comprehensive insights into chemistry have not only helped me obtain knowledge and skills, but
also inspired me to think in a broader and deeper perspective. It is truly joyful to learn and work
under his supervision, and I am extremely grateful that Professor Prakash provided the opportunity
for me to freely explore scientific areas where I am interested in.
My sincere gratitude also goes to late Professor George A. Olah for the honor and privilege to
enjoy his passion, insightful thoughts and profound vision on science. I will always treasure the
invaluable lessons he shared during our group meeting, which have had a significant impact on
my pursuit in the future scientific career.
My appreciation also extends to my committee members, Professor Susumu Takahashi,
Professor Chao Zhang, late Professor Golam Rasul, and Professor Shaama Mallikarjun Sharada. I
am very grateful for their dedication and commitment to take time in helping me, especially during
my screening, qualifying exams and thesis defense. Professor Susumu Takahashi is acknowledged
for his help with my quantum chemistry studies and introducing me to the computational chemistry
techniques with programming.
I would like to also thank the past and present senior scientists of Olah-Prakash group, Dr.
Thomas Mathew, Dr. Miklos Czuan, Dr. Alain Geoppert, and Dr. Patrice Batamack as well as
iv
post-doctoral scientists, Dr. Laxman Gurung, Dr. Sankarganesh Krishnamoorthy and Dr. Socrates
Munoz for training me with various laboratory instruments and advising me on my research
projects. It has been a great pleasure to learn from and work with you all.
At the same time, I would like to thank all my labmates who have maintained a highly
professional, collaborative and friendly work atmosphere. Special thanks to Hang, Gigi, Archith,
Sahar, Xanath, Vinayak, Sayan, Raktim, Colby, Vicente, Huong, Sankar, Jothi, Cj, Bo and Ziyue
for all their kindness and help, making my Ph.D. life cheerful.
I also want to acknowledge the staff members of both Loker Hydrocarbon Institute and the
Chemistry Department, Dr. Robert Aniszfeld, Jessy May, Ralph Pan, Carole Phillips, David
Hunter, Allan Kershaw, Michele Dea, and Magnolia Benitez, for their support and assistance.
Special thanks to Dr. Shuting Sun, who provided me with the great opportunities to work as
an Intern at BioVinc LLC and take LC-MS training at Waters Corporation from July 2019 to
December 2019. I also would like to thank Dr. Philip Cherian, as my intern mentor who trained
me in new analytical techniques and skills, and guided me in my projects for bone-related drug
discovery.
This thesis would have not been possible without the love and support from my friends and
family. I want to especially thank all my best friends Zhijing Li, Wei Jiang, Linqiu Li, and Shuming
Hao. My life in USC could not be so joyful without our friendship, which I will cherish forever.
Last but not the least, I would like to express my whole-hearted gratefulness to my parents Mr.
Bangjian Fu and Ms. Xuelian Liu, for their endless love, support and encouragement. Finally, I
would like to thank my husband, Dr. Hao Li, who has accompanied me and brought the brightest
sunshine to my long and winding road towards a Ph.D.
v
TABLE OF CONTENTS
DEDICATION .............................................................................................................................. ii
ACKNOWLEDGEMENTS ........................................................................................................ iii
LIST OF FIGURES ................................................................................................................... viii
LIST OF TABLES ......................................................................................................................... x
LIST OF SCHEMES .................................................................................................................. xii
ABSTRACT ................................................................................................................................. xv
Chapter 1. ipso-Bromination/Iodination of Arylboronic Acid: Poly(4-vinylpyridine)-
Br2/I2 Complexes as Safe and Efficient Reagents ................................................................... 1
1.1 Introduction ......................................................................................................................... 1
1.2 Results and discussion ......................................................................................................... 4
1.3 Conclusion ......................................................................................................................... 18
1.4 Experimental details .......................................................................................................... 18
1.4.1 General information .................................................................................................. 18
1.4.2 Preparation of PVP-Br2 (1.5:1) and PVP-I2 (1.2:1) complexes ................................ 19
1.4.3 Preparation of PVP-Br2/I2 (1:1) complexes .............................................................. 19
1.4.4 General procedure for the ipso-bromination of arylboronic acids ........................... 20
1.4.5 General procedure for the ipso-iodination of arylboronic acids ............................... 20
1.4.6 Spectral data of the ipso-bromination products, aryl bromides ................................ 20
1.4.7 Spectral data of the iodination products, aryl iodides .............................................. 23
1.4.8 NMR Spectra ............................................................................................................ 26
1.5 References ......................................................................................................................... 47
vi
Chapter 2. Palladium-Catalyzed Selective Reduction of Carboxylic Acids to Aldehydes
Using a Phosphine-based Reagent System ............................................................................ 51
2.1 Introduction ....................................................................................................................... 51
2.2 Results and discussion ....................................................................................................... 57
2.3 Conclusion ......................................................................................................................... 74
2.4 Experimental details .......................................................................................................... 75
2.4.1 General information .................................................................................................. 75
2.4.2 Reaction optimization studies ................................................................................... 76
2.4.3 General procedure for reduction of carboxylic acids to aldehydes .......................... 85
2.4.4 Experimental details and characterization data of aldehydes ................................... 86
2.4.5 Scale up procedure for the preparation of 2u ......................................................... 100
2.4.6 Additional carboxylic acids tested .......................................................................... 101
2.4.7 Experimental details and characterization data of deuterated aromatic aldehydes 102
2.4.8 Mechanistic investigation ....................................................................................... 104
2.4.9 Synthesis of starting materials ................................................................................ 110
2.4.10 Copies of NMR spectra ........................................................................................ 111
2.5 References ....................................................................................................................... 126
Chapter 3. ipso-Nitration of Arylsilanes .............................................................................. 133
3.1 Introduction ..................................................................................................................... 133
3.2 Results and discussion ..................................................................................................... 159
3.3 Conclusion ....................................................................................................................... 168
3.4 Experimental details ........................................................................................................ 168
3.4.1 General information ................................................................................................ 168
vii
3.4.2 General procedure for optimization of reaction conditions for ipso-nitration of
arylsilanes ........................................................................................................................ 170
3.4.3 Synthesis of arylsilanes .......................................................................................... 171
3.4.4 General procedure for the synthesis of aromatic nitro compounds through ipso-
nitration of arylsilanes ..................................................................................................... 175
3.4.5 Experimental details and characterization data of nitroarenes ............................... 176
3.4.6
1
H and
13
C NMR spectra of nitroarenes ................................................................. 180
3.5 References ....................................................................................................................... 187
Chapter 4. New Molybdenum, Ruthenium and Tungsten Complexes of Tetradentate
Pyridyl Phthalazine Ligand: Synthesis, Structural Characterization and Their
Exploration in Catalytic Applications for Carbon Neutral Chemical Energy Storage .. 199
4.1 Introduction ..................................................................................................................... 199
4.2 Results and discussion ..................................................................................................... 212
4.3 Conclusion ....................................................................................................................... 229
4.4 Experimental details ........................................................................................................ 230
4.4.1 General information ................................................................................................ 230
4.4.2 Synthesis of ligand PAPH2 (1)
2
............................................................................. 231
4.4.3 Preparation of [Mo(PAPH2)(CO)4] complex (2) .................................................... 231
4.4.4 Preparation of [W(PAPH2)(CO)4] complex (3) ...................................................... 232
4.4.5 Preparation of [Ru4(PAP)2(CO)8]•CH3C6H5 complex (4) ..................................... 232
4.4.6 X-ray Crystallography ............................................................................................ 233
4.4.7 HRMS spectra ......................................................................................................... 234
4.5 References ....................................................................................................................... 238
viii
LIST OF FIGURES
Chapter 1
Figure 1.1 (a) SEM image of PVP, (b) PVP:Br2 (1:1) and (c) PVP:I2 (1:1) ................................. 5
Chapter 3
Figure 3.1 Selected biologically active nitro compounds. ......................................................... 133
Figure 3.2 Aromatic nitro compounds used as an essential building block in synthetic organic
chemistry via denitrative reaction of nitroarens. ...................................................... 134
Figure 3.3 Difference between ipso-nitration and classical ordinary nitration. ........................ 136
Figure 3.4 Silicon-containing molecules of medicinal applications. ......................................... 156
Figure 3.5 Organosilicon compounds for cross-coupling reactions .......................................... 157
Chapter 4
Figure 4.1Potential energy sources and primary processes for hydrogen production.
Thermochemical processes include a series of chemical reactions resulting in the
hydrogen and oxygen generation from the decomposition of water with heat provided
by an external source. Some most common cycles are sulfur/iodine, calcium/bromine,
copper/chlorine, and metal/oxide. PV, photovoltaic; NG, natural gas; LT, low
temperature; HT, high temperature. ......................................................................... 202
Figure 4.2 The commercial manufacture of formic acid from non-renewable fossil feedstock (top)
and the production of formic acid from the renewable sources biomass and CO2
(bottom). ................................................................................................................... 204
Figure 4.3 Decomposition pathways of FA: (a) decarboxylation or dehydrogenation; (b)
decarbonylation or dehydration (Adapted with permission from ref 2. Copyright 2016
American Chemistry Society) .................................................................................. 206
Figure 4.4 Structure of metal pincer catalysts active in CO2 hydrogenation in basic media. ... 208
ix
Figure 4.5 Molecular structure of complex [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH. The solvent
molecules have been omitted for clarity. Thermal ellipsoids are drawn at the 50%
probability level. ...................................................................................................... 214
Figure 4.6 Molecular structure of complex [W(PAPH2)(CO)4]•0.5PhMe•MeOH. The solvent
molecules have been omitted for clarity. Thermal ellipsoids are drawn at the 50%
probability level. ...................................................................................................... 219
Figure 4.7 Molecular structure of complex [Ru4(PAP)2(CO)8]•C6H5CH3. The hydrogen atoms
and solvent molecules have been omitted for clarity. Two ligands use different but
similar colors of its nitrogen and carbon atoms for clarity. Thermal ellipsoids are
drawn at the 20% probability level. ......................................................................... 224
x
LIST OF TABLES
Chapter 1
Table 1.1 Optimization of the reaction conditions for ipso-bromination of arylboronic acids using
PVP-Br2 (1.5:1) complex
a
............................................................................................. 7
Table 1.2 Effect of different sodium salts on the ipso-bromination of arylboronic acids using PVP-
Br2 complex (1.5:1)
a
...................................................................................................... 8
Table 1.3 Optimization of reaction conditions for ipso-bromination of p-tolylboronic acid with
PVP-Br2 (1:1) complex
a
................................................................................................. 9
Table 1.4 Activity of the reagents: PVP-Br2(1.5:1), PVP-Br2(1:1) and Br2 for ipso-bromination
of p-tolylboronic acid .................................................................................................. 10
Table 1.5 ipso-Bromination of arylboronic acids with PVP-Br2 (1:1) complex
a
........................ 12
Table 1.6 Screening the optimal conditions for ipso-iodination of p-tolylboronic acid using PVP-
I2 (1:1)
a
......................................................................................................................... 13
Table 1.7 ipso-Iodination of arylboronic acids with PVP-I2 (1:1) complex
a
............................... 15
Chapter 2
Table 2.1 Catalyst and ligand screening for the reduction of benzoic acid to benzaldehyde
a
..... 59
Table 2.2 Pd-Catalyzed reduction of benzoic acid to benzaldehyde: reaction optimization and
side products
a
.............................................................................................................. 63
Table 2.3 Catalyst and ligand screen using THF as solvent ........................................................ 79
Table 2.4 Catalyst and ligand screen using MeCN as solvent ..................................................... 81
Table 2.5 Reaction time screening ............................................................................................... 82
Table 2.6 Solvent screening ......................................................................................................... 83
Table 2.7 Silane screening ........................................................................................................... 83
Table 2.8 The amounts of PPh3 and NBS screening .................................................................... 84
Table 2.9 Catalyst/ligand amount and reaction concentration screening .................................... 84
xi
Chapter 3
Table 3.1 Nitrating agents screening for ipso-nitration of triethoxy-p-tolylsilane
a
................... 161
Table 3.2 Optimization of reaction conditions for ipso-nitration of triethoxy-p-tolylsilane using
silver nitrate and TMSCl
a
.......................................................................................... 163
Chapter 4
Table 4.1 Analytic data of [Mo(CO)4(PAPH2)] by CHNS analysis ........................................ 213
Table 4.2 Crystallographic parameters for [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH ................. 215
Table 4.3 Selected bond lengths (Å) and angles (°) for [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH
.................................................................................................................................. 215
Table 4.4 Analytic data of [W(CO)4(PAPH2)] by CHNS analysis .......................................... 217
Table 4.5 Crystallographic parameters for [W(PAPH2)(CO)4]•0.5PhMe•MeOH ................... 219
Table 4.6 Selected bond lengths (Å) and angles (°) for [W(PAPH2)(CO)4]•0.5PhMe•MeOH
.................................................................................................................................. 220
Table 4.7 Analytic data of [Ru4(PAP)2(CO)8]• C6H5CH3 by CHNS analysis ......................... 222
Table 4.8 Crystallographic parameters for [Ru4(PAP)2(CO)8]•C6H5CH3 ............................... 225
Table 4.9 Selected bond lengths (Å) and angles (°) for [Ru4(PAP)2(CO)8]•C6H5CH3 ............ 226
Table 4.10 Chemical composition of gaseous products from FA decomposition in the presence
of complex 2, 3, or 4 as a catalyst ............................................................................ 227
Table 4.11 Hydrogenation of CO2 in the presence of complex 2, 3, or 4 as a catalyst ............. 228
Table 4.12 Hydrogenation of methyl trans-cinnamate in the presence of complex 2, 3, or 4 as a
catalyst ..................................................................................................................... 228
xii
LIST OF SCHEMES
Chapter 1
Scheme 1.1 Preparation of PVP:Br2 (1:1) and PVP:I2 (1:1) .......................................................... 4
Scheme 1.2 ipso-Halogenation of arylboronic acid using PVP-X2 complexes ............................. 6
Scheme 1.3 Plausible mechanism for the ipso-halogenation of arylboronic acid using PVP-X2
complexes and NO2
-
salt as catalyst ......................................................................... 16
Scheme 1.4 Recycling of poly(4-vinylpyridine) in ipso-bromination/iodination reactions using
PVP-Br2/I2 (1:1). ....................................................................................................... 17
Chapter 2
Scheme 2.1 Prior work for reduction of carboxylic acids to aldehydes. ...................................... 54
Scheme 2.2 Hydrogenation of arenecarboxylic acids to aryl aldehydes. ..................................... 55
Scheme 2.3 Transformation of carboxylic acid to aldehydes via ruthenium-catalyzed
hydrosilane reduction with 1,2-bis(dimethylsilyl)benzene. ..................................... 56
Scheme 2.4 Working Hypothesis ................................................................................................. 57
Scheme 2.5 Substrate scope for the reduction of arenecarboxylic acids and aliphatic carboxylic
acids
a
......................................................................................................................... 66
Scheme 2.6 Strategies for synthesizing deuterated aldehydes; (A) through FG transformation;
(B) through hydrogen isotope exchange (HIE). ....................................................... 70
Scheme 2.7 Synthesis of deuterated aryl aldehydes by deoxygenative deuteration of aromatic
carboxylic acids
a
....................................................................................................... 71
Scheme 2.8 Proposed mechanistic pathway of the Pd-catalyzed reduction of carboxylic acids to
aldehydes. ................................................................................................................. 73
Chapter 3
Scheme 3.1 Recent advances of nitration protocols for the synthesis of aromatic nitro
compounds. ........................................................................................................... 135
xiii
Scheme 3.2 Formation of nitroarenium ion intermediates at low temperature during aromatic
nitration with NO2
+
BF4
-
in superacidic medium. .................................................. 137
Scheme 3.3 ipso-Nitration for the synthesis of nitroarenes and nitroolefins using a nitro radical
through homolytic reactions. ................................................................................. 138
Scheme 3.4 Previous work of synthetic methods to access nitroarenes through ipso-nitration of
aryl halides. ........................................................................................................... 140
Scheme 3.5 Previous work of synthetic methods to access nitro compounds through ipso-
nitration of carboxylic acid and cinnamic acid derivatives. .................................. 142
Scheme 3.6 Previous work of synthetic methods to access nitro aromatics through ipso-
nitration of arylboronic acids during 2000-2011. ................................................. 145
Scheme 3.7 Previous work and proposed mechanisms of synthetic methods to access nitro
aromatics through ipso-nitration of arylboronic acids during 2012-2013. ........... 148
Scheme 3.8 Most recent advances in the synthesis of nitro aromatics through ipso-nitration of
arylboronic acids. .................................................................................................. 151
Scheme 3.9 This work hypothesis: a tandem C–H silylation and ipso-nitration of arylsilanes.
............................................................................................................................... 157
Scheme 3.10 Divergent nitration pathways. A) ipso-nitration of arylsilanes. B) Arene
electrophilic aromatic substitution ........................................................................ 158
Scheme 3.11 Substrate scope for ispo-nitration of arylsilanesthe
a
............................................. 165
Scheme 3.12 Plausible mechanism for ipso-nitration of arylsilanes ........................................... 167
Chapter 4
Scheme 4.1 Decomposition pathways of FA: (a) decarboxylation or dehydrogenation; (b)
decarbonylation or dehydration ............................................................................ 205
Scheme 4.2 Hydrogen generation from FA decomposition in the presence of IrCl3 and selective
N-donor ligands ..................................................................................................... 210
Scheme 4.3 Structure of the ligand PAPH2 ............................................................................... 211
Scheme 4.4 Preparation of [Mo(PAPH2)(CO)4] ....................................................................... 212
xiv
Scheme 4.5 Preparation of [W(PAPH2)(CO)4] ......................................................................... 217
Scheme 4.6 Preparation of [Ru4(PAP)2(CO)8]• C6H5CH3 ........................................................ 221
xv
ABSTRACT
This dissertation mainly explored two areas of research. The first three chapters focus on the
development of novel, practical and efficient organic synthetic methodologies for functional group
transformations. The last chapter of this thesis describes my effort towards designing and
synthesizing new transition metal based heterogeneous catalysts for potential applications in
energy storage.
Chapter one reports the preparation of poly(4-vinylpyridine) supported solid bromine/iodine
complexes. These complexes with a catalytic amount of additive are found to be safe, convenient
and efficient reagent systems for the ipso-bromination/iodination of arylboronic acids. The
reactions occur under mild conditions and tolerate various functional groups resulting in products
with high selectivity and yields. The use of the PVP-Br2/I2 complexes as thermally stable halide
sources and potential recycled reagents, and a simple isolation procedure of the method result in
an overall efficient and green protocol for synthesis of aryl halides.
Chapter two demonstrates the investigation of a fast and practical method for the palladium-
catalyzed selective reduction of carboxylic acids to aldehydes using a phosphine-based reagent
system with commodity chemicals (PPh3, NBS, Et3SiH). This protocol presents high functional
group compatibility, chemoselectivity and scalability under mild reaction conditions, affording
products in good yields with no overreduction to alcohols. The key reaction intermediate,
acyloxyphosphonium ion, has been studied by NMR spectroscopic analysis. Direct reduction of
bio-active pharmaceutical compounds has been demonstrated. This methodology allows access to
deuterated aryl aldehydes using a Et3SiD reagent.
xvi
Chapter three delivers the first efficient method for the ipso-nitration of arylsilanes under
mild reaction conditions employing readily available starting materials. The transformation
employs nitrate salts in combination with TMSCl as an activator, affording nitroarenes in good
yields and a regioselective manner. The scope and limitations of the protocol have also been
presented.
Chapter four conveys the synthesis and structural characterization of three new transition metal
based catalysts, [Mo(PAPH2)(CO)4], [W(PAPH2)(CO)4], and [Ru4(PAP)2(CO)8]•C6H5CH3. These
catalysts have also been investigated on the hydrogenation of carbon dioxide and methyl trans-
cinnamate, and hydrogen production from formic acid decomposition toward a carbon neutral
hydrogen storage.
1
Chapter 1. ipso-Bromination/Iodination of Arylboronic Acid: Poly(4-vinylpyridine)-Br2/I2
Complexes as Safe and Efficient Reagents
1.1 Introduction
Aryl halides, in particular, aryl bromide and aryl iodides are valuable synthetic intermediates
widely applied in carbon-carbon and carbon-heteroatom bond formation.
1-5
Another important
synthetic application of aryl iodides is to prepare various hypervalent iodine reagents.
6-9
Moreover,
the radiolabeled haloarenes are used as target compounds in biological research and as components
of synthetic schemes for diagnostic and therapeutic agents.
10-12
Traditionally, aryl halides are formed via electrophilic aromatic substitution. While
electrophilic aromatic chlorination and bromination work well, due to the low reactivity of iodine
and related iodinating agents compared to the corresponding chloro and bromo analogues, the
direct iodination of arenes is generally not achievable.
13-14
A number of general methods for the
synthesis of iodoarenes have been developed including: (a) oxidative iodination of arenes by using
strong oxidizing agents,
15-29
(b) classic Sandmeyer reaction involving regioselective halogenation
of arenes via aryl diazonium salts under acidic condition
30
and organocatalytic variants of
Sandmeyer reactions,
31-32
and (c) various methods using highly reactive aromatic mercury
33
and
thallium
34
compounds. However, these methods have obvious limitations as they involve
hazardous oxidizing agents, harsh reaction conditions, complex and dangerous work up, low
regioselectivity and yields. Therefore, most of them do not meet the requirements of safe and
environmentally benign methodology.
Organoboron derivatives have drawn considerable attention in ipso substitution reactions, in
particular arylboronic acids, by the ipso substitution of boronic acid group can lead to convenient
2
access to arenes bearing important functional groups with good regioselectivity. Arylboronic
acids
35
are usually crystalline solids, generally nontoxic and stable to air and moisture. A large
number of substituted arylboronic acids are readily prepared via transition metal catalyzed
approach and directed borylation of active C-H bonds without using haloarenes.
36-38
1982, Kabalka and his co-workers developed halogenation of organoboranes with halide salts
in the presence of chloramine-T.
39
Later, in 1998, ipso-halogenation of arylboronic acid was
achieved in good yields using N-halosuccinimides by Prakash et al.
40-44
despite some limitations.
More related works of ipso-halogenation of boronic acid with N-halosuccinimides have been
reported in the following years.
45
In 2004, Szumigala, Jr. described the synthesis of haloarenes
from arylboronic acids using 1,3-dihalo-5,5-dimethylhydantoin (DBDMH) as an effective
halogenating agent.
46
In 2011, Chen et al. developed a copper-catalyzed halodeboronation protocol
using oxygen as the oxidant.
47
Recently, more methods of boron-iodine exchange have emerged
to generate iodoarenes, including copper-catalyzed approaches with iodide salts
48
or iodine,
49
metal-free methods using iodine,
50
using cetyltrimethyl ammonium bromide (CTAB)/I2
51
or
another novel ipso-iodination way via N-iodomorpholinium iodide (NIMI).
52
As compared to ipso-
substitutions of iodine, the reports on the ipso-bromination of arylboronic acids are relatively
scarce. In addition, many reported methods above either require high temperatures, long reaction
times, or large excess of additives/special ligands and some of them are limited to substrate scope
or yields. Therefore, it is very desirable to develop milder, more efficient, less expensive and
environmentally benign alternatives for preparation of haloarenes.
The recent developments of polymer supported reagents have been growing fast in synthetic
organic chemistry.
53-55
Polymeric reagents are generally macromolecules to which chemical
functional groups are connected. They possess the similar potential abilities of the low molecular
3
weight analogues. On the other hand, the main advantages of these polymer-supported species
over their monomeric reagents are (a) easier work-up by simple filtration and subsequent washing
with the solvent because of their insolubility in the reaction medium, (b) using excess of the
reagents to drive the reaction to completion without any concern regarding the separation of the
desired products from the unused reagents, (c) recyclability of these polymer supports, (d) lower
toxicity which makes them environmentally safe, (e) and fine-tuning the stability and selectivity
of the reagents towards different synthetic transformations compared to those carried out on same
functional groups by unsupported reagents.
56
Poly(4-vinylpyridine) (PVP) is one of the most
frequently used polymer as a solid support for various reagents and catalysts because of its
commercial availability, its stability, facile complexation with high loading capacity, fine swelling
properties, and good physicochemical characteristics.
56
During the course of our studies, we
developed environmentally benign methods via polymer-supported reagents such as PVP-HF,
PVP-SO2
,
PVP-H2O2, PVP-NM (nitrating mixture), and PVP-CF3SO3H in recent decades.
57-61
In
continuation of our efforts using these polymeric complexes for various organic transformations,
we decided to explore the application of poly(4-vinylpyridine)- bromine/iodine complexes (PVP-
Br2/I2) as effective reagents for halogenation of arylboronic acids. PVP-Br2 as a polymer-supported
solid complex have been previously studied for bromination of aromatic rings, alkenes, alkynes,
ketones etc.
62-68
However, the application of PVP-Br2/I2 as polymer supported reagents for ipso-
halogenation reactions has very rarely been explored in recent years. Herein, we report the
preparation and the use of PVP-Br2/I2 complexes as green and efficient reagents for ipso-
bromination/iodination of arylboronic acids with catalytic amount of NaNO2 for the synthesis of
the corresponding haloarenes.
4
1.2 Results and discussion
We initiated our investigation by preparing poly(4-vinylpryridine) bromine/iodine complexes
or PVP-Br2/I2. Several methods of making PVP-Br2 had been reported by Zabicky and
Mhasalkar.
68
Accordingly, commercially available poly(4-vinylpyridine), 2% cross linked with
divinylbenzene, was stirred with excess hexane as solvent for 24 hours so that the polymer was
swollen well. Liquid bromine or solid iodine was then carefully added to the swollen polymer
support in hexane with efficient cooling and thorough mixing. As complex formation of PVP-Br2
or PVP-I2 proceeds, the color of the solution became lighter and lighter and stirring continued till
no further significant change in color was observed (about 24 hours). After filtering, washing and
drying under the vacuum, a fluffy, free-flowing, fresh orange (PVP-Br2) or purple black solid
(PVP-I2) was obtained (Scheme 1.1). The complexes are almost odorless which is ready for use as
reagents for bromination and iodination, which are much safer than the molecular bromine or
iodine.
Scheme 1.1 Preparation of PVP:Br2 (1:1) and PVP:I2 (1:1)
The complex can be stored in well-closed containers for many months. From the weight
increment, PVP-Br2 and PVP-I2 complexes are found to have a 1:1 molar ratio, achieved by the
addition of equimolar amounts of bromine or iodine with respect to the monomer unit of the
polymer. During our initial trials, with direct treatment of the polymer and Br2/I2 without swelling
for a day, we got PVP-Br2 and PVP-I2 complexes with 1.5:1 molar ratio and 1.2:1 molar ratio
5
respectively. By prior swelling and proper stirring as mentioned, we were able to get the complexes
with 1:1 molar ratio. The changes in morphology of the polymer samples because of the formation
of the complexes were further studied through scanning electron microscopy (SEM) (Figure 1.1).
The surface morphology of the complexes changed significantly compared to that of the precursor
PVP polymer. The particle sizes of both PVP-Br2 and PVP-I2 were found to be much smaller,
indicating activities of the complexes with increased reaction surfaces (Figure 1.1b, 1.1c).
PVP-Br2 PVP-I2 (a)
(b) (c)
Figure 1.1 (a) SEM image of PVP, (b) PVP:Br2 (1:1) and (c) PVP:I2 (1:1)
To screen their capabilities as reagents for halogenation, the complexes were subsequently
used for ipso-bromination or iodination of various arylboronic acids. Preliminary studies showed
that the complex is a very effective and convenient halogenating reagent (for both bromination
and iodination) under mild conditions (Scheme 1.2).
6
Scheme 1.2 ipso-Halogenation of arylboronic acid using PVP-X2 complexes
We began with the screening of reaction conditions such as amount of the reagents, solvent,
temperature and time for bromination of p-tolylboronic acid with PVP-Br2 complex with molar
ratio 1.5:1 (Table 1.1). Fortunately, 42% product was formed when 1 equiv. alryboronic acid
reacted with 1.5 equiv. PVP-Br2 (1.5:1) in acetonitrile at room temperature for 17 hours (Table
1.1, entry 1). When increasing the temperature to 80
o
C and reducing the reaction time to 3 h, the
result showed significant improvement in yield to 67% though not high as expected (Table 1.1,
entry 2). Next, we added NaNO2 as a nucleophilic additive in different amounts to see whether it
has any impact on the reaction. In order to improve the yield of the product, varying amounts of
the complex and the additive with respect to starting materials were further examined (Table 1.1,
entries 3-7). Reaction using 1.5 equivalents of PVP-Br2 (1.5:1) with 0.25 equiv. sodium nitrite at
80
o
C for 3 hours yielded the ipso-brominated product in 93% yield (Table 1.1, entry 6). The small
amount of sodium nitrite, 0.25 equiv. used in this high yield reaction and much lower yield in its
absence reveal its role as a catalyst (Table 1.1, entry 6).
For the ipso-halogenation reaction, acetonitrile (CH3CN) was found to be the solvent of choice
in terms of the yield and selectivity of the reaction (Table 1.1, entries 3-7, 9). Reaction at a lower
temperature led to lower conversion of 4-tolylboronic acid and lower yield of the desired product,
4-bromotoluene (Table 1.1, entry 8).
7
Table 1.1 Optimization of the reaction conditions for ipso-bromination of arylboronic acids
using PVP-Br2 (1.5:1) complex
a
Entry PVP-Br2
(equiv)
NaNO2
(equiv)
Solvent Temp
(°C)
Time (h) Yield
(%)
b
1 1.5 None CH3CN rt 17 42
2 1.5 None CH3CN 80 3 67
3 1.35 1.2 CH3CN 80 10 100
4 1.8 1.6 CH3CN 80 3 97
5 1.5 1.2 CH3CN 80 3 94
6 1.5 0.25 CH3CN 80 3 93
7 1.5 0.25 CH2Cl2 80 3 63
8 1.5 0.25 CH3CN 60 3 73
9 1.5 0.25 H2O 80 3 0
a
Reaction conditions: 0.25 mmol of 4-tolylboronic acid with 1 equiv. each of PVP-Br 2 (1.5:1) and NaNO 2
in 2 mL of the solvent at the temperature and time indicated in the table.
b
Yield by
1
H NMR.
Next, four different sodium salts were screened in the presence of 1.5 equiv. of PVP-Br2 (1.5:1)
in acetonitrile at 80 °C for 3 hours (Table 1.2). Analytically, catalytic amounts of both sodium
nitrite and sodium nitrate provided the products in similar high yields (Table 1.2, entries 1 and 3).
While conducting the reactions under similar conditions, results from sodium nitrite and sodium
nitrate did not differ significantly though a slightly better yield was obtained with sodium nitrite
(Table 1.2, entries 2 and 4).
8
Table 1.2 Effect of different sodium salts on the ipso-bromination of arylboronic acids using PVP-
Br2 complex (1.5:1)
a
Entry Sodium Salt Yield (%)
b
1 NaNO2 93
2 NaNO2
c
73
3 NaNO3 92
4 NaNO3
c
70
5 Na2CO3 41
6 NaOH
d
74
7 None 67
a
Reaction conditions: 0.25 mmol of 4-tolylboronic acid (1 equiv), 0.38 mmol of PVP-Br 2 (1.5 equiv) in the
presence of 0.063 mmol sodium salt (0.25 equiv) in 2 mL of acetonitrile at 80 °C (15 mL pressure tube) for
3 h.
b
Yield by NMR.
c
Reaction temperature is 60 °C.
d
1.2 equiv of NaOH was used.
The optimal reaction conditions for ipso-bromination reaction using PVP-Br2 (1.5:1) were
found to be: 1.5 equiv. PVP-Br2 (1.5:1) and 0.25 equiv. NaNO2 in acetonitrile at 80 °C for 3 hours.
Accordingly, the optimization of reaction conditions for bromination of p-tolylboronic acid with
PVP-Br2 (1:1) complex was also studied (Table 1.3).
As PVP-Br2 (1.5:1) and PVP-Br2 (1:1) differ in the amount of bromine in the complexes and
the particle size of each polymer complex which are contributing factors toward the variance of
their reaction activity, greater reactivity was anticipated for PVP-Br2 (1:1). Therefore, reactions
were conducted using PVP-Br2 (1:1) with the optimized reaction conditions, acetonitrile as solvent
and NaNO2 as additive. As shown in Table 1.3, ratios of PVP-Br2 (1:1) and NaNO2 display a
significant role on the reaction (Table 1.3, entries 1-4 and 7). The optimum amounts of PVP-Br2
9
(1:1) and NaNO2 which provided the best results are 1.35 and 0.25 equivalents respectively.
Further screening of the reaction conditions showed that yields dropped with decrease in
temperature and time (Table 1.3, entries 4-6, 7 and 8). In general, the best reaction conditions for
ipso-bromination using PVP-Br2 (1:1) are as follows: sodium nitrite (0.25 equiv) as catalyst, PVP-
Br2 (1:1) (1.35 equiv) as the halide source, and acetonitrile as solvent, with the reaction being
carried out at 80 °C for one hour.
Table 1.3 Optimization of reaction conditions for ipso-bromination of p-tolylboronic acid with
PVP-Br2 (1:1) complex
a
Entry
PVP-Br2
(equiv)
NaNO2
(equiv)
Temp
(°C)
Time (h) Yield (%)
b
1 1 1 80 1 86
2 1.5 1.2 80 1 100
3 1.35 1.2 80 1 100
4 1.35 0.25 80 1 97
5 1.35 0.25 60 1 84
6 1.35 0.25 rt 17 91
7 1.35 None 80 1 44
8 1.35 None 80 2 63
a
Reaction conditions: 0.25mmol of 4-tolylboronic acid (1 equiv) with PVP-Br 2, NaNO 2, 2 mL
CH 3CN, temperature and time indicated in table.
b
Yield by NMR.
10
Furthermore, we also compared the potentials of the two PVP-Br2 complexes for ipso-
bromination of arylboronic acids with liquid bromine (Table 1.4). The results revealed that both
PVP-Br2 complexes are excellent in their ability for ipso-bromination of p-tolylboronic acid
(chosen as the model substrate) in comparison with liquid bromine. As expected, PVP-Br2 (1:1)
with higher bromine loading was more active than PVP-Br2 (1.5:1) (Table 1.4, entries 1-3, and 4-
6). In addition, results also show that NaNO2 has more significant effect on reactions with PVP-
Br2 than reactions with bromine liquid. The bromination of p-toylboronic acid with PVP-Br2
complex could reasonably be catalyzed by NaNO2 to reduce the activation energy during the
reaction, therefore a catalytic component plays an important role in the reactions to afford the
products in high yields.
Table 1.4 Activity of the reagents: PVP-Br2(1.5:1), PVP-Br2(1:1) and Br2 for ipso-bromination
of p-tolylboronic acid
a
Reaction condition: 0.25 mmol of 4-tolylboronic acid (1 equiv), 0.38 mmol PVP-Br 2
(1.5:1) (1.5 equiv), 0.34 mmol of PVP-Br 2 (1:1) (1.35 equiv) or 0.38 mmol Br 2 (1.5
equiv) in the presence of 0.063 mmol sodium salt (0.25 equiv) or no salt in 2 mL of
acetonitrile at 80 °C (15 mL pressure tube) for the time indicated.
b
Yield by NMR.
Entry Bromine source Additive Time (h) Yield (%)
b
1 Br2 NaNO2 3 89
2 PVP-Br2 (1.5:1) NaNO2 3 93
3 PVP-Br2 (1:1) NaNO2 1 97
4 Br2 None 3 81
5 PVP-Br2 (1.5:1) None 3 67
6 PVP-Br2 (1:1) None 3 78
11
With optimized reaction conditions of PVP-Br2 complexes as halide sources for ipso-
bromination of arlyboronic acid in hand, the scope and functional-group tolerance of this
transformation were tested with a variety of representative arylboronic acids, as summarized in
Table 1.5. A series of substrates were smoothly converted into the brominated products with good
to excellent yields. Both complexes PVP-Br2 (1.5:1) and PVP-Br2 (1:1) exhibited similar trends of
reactivity for different functional groups. As the reactions with 1:1 complex resulted in higher
yields in a shorter time, reactions with 1:1 complex were more focused and the results are displayed
in Table 1.5.
Arylboronic acids containing both electron-donating groups as well as electron-withdrawing
groups underwent the reaction as expected with precise regioselectivity (at the ipso position)
though the latter required longer reaction time for satisfactory yields. Various substituents
including methyl, halide, acetyl, cyano, nitro and phenyl were safe and tolerant (Table 1.5, entries
1-9). The bromination of 2-naphthylboronic acid also produces the product in impressive yield.
Notably, reactions with all the three isomeric electron deficient boronic acids, o-, m-, and p-nitro
phenylboronic acids resulted in the corresponding ipso-brominatied products in good yields (Table
1.5, entries 6-8). The o-nitro phenylboronic acid took the longest time due to the electron
withdrawing effect of the nitro group as well as anchimeric resistance (steric hindrance) from its
proximity.
12
Table 1.5 ipso-Bromination of arylboronic acids with PVP-Br2 (1:1) complex
a
a
Reaction conditions: 0.25 mmol of boronic acid (1 equiv), 0.34 mmol of PVP-Br2 (1:1) (1.35
equiv) in the presence of 0.063 mmol NaNO2 (0.25 equiv) in 2 mL acetonitrile at 80 °C for the
time indicated in the table.
b
Isolated yields.
13
Table 1.6 Screening the optimal conditions for ipso-iodination of p-tolylboronic acid using PVP-
I2 (1:1)
a
a
Reaction conditions: 0.25mmol of 4-tolylboronic acid (1 equiv) with PVP-I 2 (1:1),
NaNO 2, 2 mL acetonitrile, temperature and time indicated in table.
b
Yield by NMR.
c
NaNO 3 used as sodium salt.
Entry PVP-I2 (equiv) NaNO2 (equiv) Temp (°C) Time (h) Yield
b
(%)
1 1 1 80 0.5 90
2 1.35 1.2 80 0.5 100
3 1.2 1.1 80 0.5 98
4 1.2 0.25 80 0.5 92
5 1.2 0.25 60 0.5 79
6 1.2 0.25 60 1 85
7 1.2 0.25
c
80 0.5 90
8 1.2 0.25
c
60 0.5 73
9 1.2 0.25
c
60 1 79
10 1.2 None 80 0.5 39
14
To enhance the synthetic utility of this protocol, the iodination reactions of arylboronic acids
with PVP-I2 (1:1) were evaluated in the same way. The results of screening of the reaction
conditions for the ipso-iodination of p-tolylboronic acid with PVP-I2 (1:1) are shown in Table 1.6.
When compared to bromination reaction with PVP-Br2 (1:1), iodination with PVP-I2 (1:1) was
faster (Tables 1.3 & 1.6). As in the case of the bromination reactions, a catalytic amount of NaNO2
or NaNO3 (0.25 equiv) and CH3CN as the solvent of choice are key components in the iodination
reactions also. Results in Table 1.6 show that reaction with conditions 1.2 equiv. of PVP-I2 (1:1)
in the presence of 0.25 equiv. NaNO2 in acetonitrile at 80 °C is the most efficient one giving the
best yields and therefore, further reactions were conducted under similar conditions. The reaction
was also conducted with I2, in the absence and presence of NaNO2. It is worth mentioning that in
the absence of NaNO2 no product was obtained, emphasizing the role of NaNO2 as catalyst.
However, reaction of p-tolylboronic acid with PVP-I2 complexes even in the absence of NaNO2
resulted in p-iodotoluene in significant amounts (39%) showing that complexation improves the
reactivity considerably.
After screening various reaction conditions for ipso-iodination reaction with PVP-I2 complexes
and finding the optimal conditions, the scope and generality of the reaction were explored using a
series of arylboronic acids. The results are summarized in Table 1.7. As in the case of bromination
using PVP-Br2 complexes, electron rich phenylboronic acids showed much higher reactivity for
iodination also (Table 1.7, entries 1, 2, 3, 4 and 10), although electron deficient arylboronic acids
required longer reaction time to obtain the products in good yields (Table 1.7, entries 5-9).
15
Table 1.7 ipso-Iodination of arylboronic acids with PVP-I2 (1:1) complex
a
a
Reaction conditions: 0.25 mmol of boronic acid, 0.3 mmol of PVP-I2 (1.2:1) (1.35 equiv) or 0.3
mmol of PVP-I2 (1:1) (1.2 equiv) in the presence of 0.063 mmol NaNO2 (0.25 equiv) in 2 mL
acetonitrile at 80 °C for the time indicated.
b
Isolated yields.
16
A plausible mechanism for the ipso-halogenation of arylboronic acid explaining the role of
NO2
-
salt as catalyst is shown in Scheme 1.3. Addition of nitrite to electron deficient boron in
boronic acid increases electron density at the ipso-carbon and promotes the ipso-substitution by
electrophilic X (Br or I) from the PVP-X2 complex resulting in the formation of the expected ipso-
halogenated product and the elimination of (ONO)B(OH)2. Subsequent substitution of NO2
-
in
(ONO)B(OH)2 with X
-
helps the recycling of NO2
-
to continue the catalytic cycle.
Scheme 1.3 Plausible mechanism for the ipso-halogenation of arylboronic acid using PVP-X2
complexes and NO2
-
salt as catalyst
Finally, we investigated the recovery and recycling of the polymer from solid bromine and
iodine complexes after the initial course of reactions. At the end of the halogenation reaction of
arylboronic acid, the solution containing the product was pipetted out of the pressure tube and the
solid polymer residue was rinsed with CH2Cl2 to remove the product adhered to the polymer
followed by washing the extract with Na2S2O4 solution to remove the excess Br2/I2 left with the
polymer. The solution in CH2Cl2 was then washed with water, dried over MgSO4 and product was
recovered by evaporating the solvent in a rotary evaporator.
B
OH HO
X
ONO
(ONO)B(OH)
2
B
OH HO
X
-XB(OH)
2
NO
2
N
n
N
n
X
X
+
X
2
X = Br, I
Recycle
17
The solid polymer was subsequently washed with water, acetone and dried under vacuum. The
recovered dry PVP solid was used again to prepare the PVP-Br2/I2 (1:1) complexes. The
recyclability of this PVP-Br2/I2 sample made of recycled PVP was examined by repeating the ipso-
bromination and ipso-iodination of 4-biphenylboronic acid with the sample. The brominated and
iodinated products were obtained in 97% and 98% yields respectively (Scheme 1.4), almost similar
to the yields obtained with the PVP-Br2/I2 complexes prepared using fresh PVP (Table 1.5, entry
9; Table 1.7, entry 10).
Scheme 1.4 Recycling of poly(4-vinylpyridine) in ipso-bromination/iodination reactions using
PVP-Br2/I2 (1:1).
B(OH)
2
MeCN, 80 °C, 1h
MeCN, 80 °C,1h
Br
99%
97%
B(OH)
2
MeCN, 80 °C, 0.5 h
MeCN, 80 °C,0.5h
I
99%
98%
PVP-Br
2
(1:1) (1.35 equiv)
NaNO
2
(0.25 equiv)
Rec. PVP-Br
2
(1:1)
(1.35 equiv)
NaNO
2
(0.25 equiv)
Rec. PVP-I
2
(1:1)
(1.2 equiv)
NaNO
2
(0.25 equiv)
PVP-I
2
(1:1) (1.2 equiv)
NaNO
2
(0.25 equiv)
Rec. PVP = Recycled PVP
18
1.3 Conclusion
In summary, we have developed a safe and environmentally friendly protocol for the ipso-
bromination/iodination of arylboronic acids using poly(4-vinylpyridine) supported bromine/iodine
complexes. The complexes are free-flowing stable solids and very convenient to handle. Presence
of NaNO2 as catalyst promotes the conversion of arylboronic acids bearing various both activated
and deactivated functional groups to the corresponding ipso-bromo/iodo derivatives with high
selectivity and isolated yield. Mild reaction conditions including short reaction times, high yields,
easy product-separation as well as purification, and high recyclability of the polymer are the salient
features of this methodology. Further studies on the scope of these PVP complexes as safe and
efficient "green" reagent systems for halogenation in various other synthetic transformations are
currently underway.
This chapter is reprinted with permission from Tetrahedron Letters, 2019, 60, 151020, wherein, I
am the first author, who carried out the reported work.
Copyright 2019 Elsevier Ltd.
69
1.4 Experimental details
1.4.1 General information
Unless otherwise mentioned, all chemicals were purchased from commercial sources and used
without further purification. Analytical grade acetonitrile was used as the solvent.
1
H and
13
C
NMR spectra were recorded on a Varian 400 MHz NMR spectrometer.
1
H NMR chemical shifts
were determined relative to internal tetramethylsilane at 0.0 ppm and
13
C NMR chemical shifts
19
were determined relative to the
13
C signal of either CDCl3 at 77.16 ppm. Scanning Electron
Microscope images were obtained from a JEOL JSM6610 instrument at the Center for Electron
Microscopy and Microanalysis, University of Southern California.
1.4.2 Preparation of PVP-Br2 (1.5:1) and PVP-I2 (1.2:1) complexes
Cross-linked (with 2% divinylbenzene) poly(4-vinylpyridine) (3.2 g, 0.03 mol, based on the
monomer) in 50 mL hexane was cooled to 0 °C in a 500 mL Nalgene bottle. Liquid Br2 (4.8g, 0.03
mol) was then carefully added with constant stirring and cooling to ensure a controlled reaction.
After adding Br2, the mixture in the bottle was allowed to come to room temperature and stirred
for 24 hours followed by filtration, washing and vacuum drying. A fluffy, free-flowing, fresh
orange PVP-Br2 complex (1.5:1) was obtained. PVP-I2 (1.2:1) was also prepared in a similar
fashion to yield a fluffy, cream colored solid.
1.4.3 Preparation of PVP-Br2/I2 (1:1) complexes
Cross-linked (with 2% divinylbenzene) poly(4-vinylpyridine) (1.05 g, 0.01 mol, based on the
monomer) was stirred with 15 mL hexane at room temperature for 24 hours in a 500 mL Nalgene
bottle. Then the swollen polymer support in hexane was cooled to 0 °C. Liquid Br2 (2g, 0.0125
mol) or solid iodine (3 g, 0.012 mol) was carefully added with efficient mixing and cooling. As
complex formation of PVP-Br2 or PVP-I2 proceeds, the stirring was continued for 24 hours
followed by filtering, washing and drying under the vacuum. A fluffy, free-flowing, fresh orange
PVP-Br2 (1:1) or purple black solid PPVP-I2 (1:1) was obtained and stored in well-closed
containers.
20
1.4.4 General procedure for the ipso-bromination of arylboronic acids
In a pressure tube, to a solution of a selected arylboronic acid (0.25 mmol) and sodium nitrate
(4.3 mg, 0.063 mmol) in dry acetonitrile (2 mL), PVP-Br2 (1:1) (89 mg, 0.34 mmol) was added.
The reaction mixture was stirred vigorously at 80 °C for the required time. Upon completion, the
reaction mixture was diluted with dichloromethane and filtered through celite, washing with more
dichloromethane. The filtrate was washed with Na2S2O4 solution, saturated NaCl solution and
dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure afforded the product
in pure form, as verified by
1
H NMR and
13
C NMR.
1.4.5 General procedure for the ipso-iodination of arylboronic acids
In a pressure tube, to a solution of a selected arylboronic acid (0.25 mmol) and sodium nitrate
(4.3 g, 0.063 mmol) in dry acetonitrile (2 mL), PVP-I2 (1:1) (108 mg, 0.3 mmol) was added. The
reaction mixture was stirred vigorously at 80 °C for the required time. Upon completion, the
reaction mixture was diluted with dichloromethane and filtered through celite, washing with more
dichloromethane. The filtrate was washed with saturated Na2S2O4 solution, saturated NaCl
solution and dried over anhydrous Na2SO4. Removal of the solvent under reduced pressure
afforded the product in pure form, as verified by
1
H NMR and
13
C NMR.
1.4.6 Spectral data of the ipso-bromination products, aryl bromides
1-Bromo-4-methylbenzene:
1
H NMR (400 MHz, CDCl3): d 7.38 (d, J = 8.4 Hz, 2H), 7.06 (d, J
= 8.4 Hz, 2H), 2.32 (s, 3H).
13
C NMR (100 MHz, CDCl3): d 136.9, 131.4, 130.9, 119.2, 21.0.
Br
21
1-Bromo-4-chlorobenzene:
1
H NMR (400 MHz, CDCl3): d 7.42 (d, J = 8.8 Hz, 2H), 7.21 (d, J
= 8.8 Hz, 2H).
13
C NMR (100 MHz, CDCl3): d 133.4, 132.9, 130.4, 120.4.
1, 4-Dibromobenzene:
1
H NMR (400 MHz, CDCl3): d 7.36 (s, 4H).
13
C NMR (100 MHz, CDCl3):
d 133.3, 121.2.
1-(4-Bromophenyl)ethanone:
1
H NMR (400 MHz, CDCl3): d 7.81 (d, J = 8.4 Hz, 2H), 7.59 (d,
J = 8.4 Hz, 2H), 2.57 (s, 3H).
13
C NMR (100 MHz, CDCl3): d 197.1, 136.0, 132.0, 130.0, 128.4,
26.7.
4-Bromobenzonitrile:
1
H NMR (400 MHz, CDCl3): d 7.64 (d, J = 8.8 Hz, 2H), 7.53 (d, J = 8.8
Hz, 2H).
13
C NMR (100 MHz, CDCl3): d 133.5, 132.8, 128.2, 118.2, 111.4.
Br
Cl
Br
Br
Br
NC
Br
O
2
N
Br
O
22
1-Bromo-4-nitrobenzene:
1
H NMR (400 MHz, CDCl3): d 8.11 (d, J = 9.1 Hz, 2H), 7.69 (d, J =
9.1 Hz, 2H).
13
C NMR (100 MHz, CDCl3): d 147.2, 132.8, 130.1, 125.2.
1-Bromo-2-nitrobenzene:
1
H NMR (400 MHz, CDCl3): d 7.85 (d, J = 7.5 Hz, 1H), 7.75 (d, J =
8.0 Hz, 1H), 7.49-7.41 (m, 2H).
13
C NMR (100 MHz, CDCl3): d 150.1, 135.2, 133.3, 128.4, 125.7,
114.6.
1-Bromo-3-nitrobenzene:
1
H NMR (400 MHz, CDCl3): d 8.39 (dt, J = 2.0, 2.0, 2.0 Hz, 1H), 8.18
(ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.84 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.44 (dt, J = 8.1, 8.1, 0.3 Hz,
1H).
13
C NMR (100 MHz, CDCl3): d 149.0, 137.8, 130.7, 126.9, 123.0, 122.3.
4-Bromobiphenyl:
1
H NMR (400MHz, CDCl3): d 7.58-7.54 (m, 4H), 7.48-7.34 (m, 5H).
13
C
NMR (100 MHz, CDCl3): d 140.3, 140.2, 132.0, 129.0, 128.9, 127.8, 127.1, 121.7.
Br
NO
2
Br
NO
2
Br
Br
23
2-Bromonaphthalene:
1
H NMR (400 MHz, CDCl3): d 8.01 (d, J = 2.0 Hz, 1H), 7.82-7.80 (m,
1H), 7.77-7.70 (m, 2H), 7.56-7.47 (m, 3H);
13
C NMR (100 MHz, CDCl3): d 134.6, 132.0, 130.1,
129.7, 129.4, 128.0, 127.1, 127.0, 126.4, 119.9.
1.4.7 Spectral data of the iodination products, aryl iodides
1-Iodo-4-methylbenzene:
1
H NMR (400 MHz, CDCl3): d 7.56 (d, J = 8.2 Hz, 2H), 6.92 (d, J =
8.4 Hz, 2H), 2.29 (s, 3H).
13
C NMR (100 MHz, CDCl3): d 137.6, 137.4, 131.3, 90.3, 21.2.
1-Iodo-4-chlorobenzene:
1
H NMR (400 MHz, CDCl3): d 7.61 (d, J = 8.7 Hz, 2H), 7.09 (d, J =
8.7 Hz, 2H).
13
C NMR (100 MHz, CDCl3): d 138.9, 134.4, 130.7, 91.3.
1-Bromo-4-iodobenzene:
1
H NMR (400 MHz, CDCl3): d 7.54 (d, J = 8.4 Hz, 2H), 7.23 (d, J =
8.4 Hz, 2H).
13
C NMR (100 MHz, CDCl3): d 139.2, 133.6, 122.3, 92.2.
I
I
Cl
I
Br
I
O
24
1-Iodo-4-methoxybenzene:
1
H NMR (400 MHz, CDCl3): d 7.55 (d, J = 9.0 Hz, 2H), 6.68 (d, J =
9.0 Hz, 2H), 3.78 (s, 3H).
13
C NMR (100 MHz, CDCl3): d 159.6, 138.3, 116.5, 82.8, 55.5.
1-(4-Iodophenyl)ethanone:
1
H NMR (400 MHz, CDCl3): d 7.83 (d, J = 8.6 Hz, 2H), 7.66 (d, J =
8.6 Hz, 2H), 2.57 (s, 3H).
13
C NMR (100 MHz, CDCl3): d 197.5, 138.1, 136.5, 129.9, 101.2, 26.6.
4-Iodobenzonitrile
1
H NMR (400 MHz, CDCl3): d 7.85 (d, J = 8.6 Hz, 2H), 7.37 (d, J = 8.6 Hz,
2H).
13
C NMR (100 MHz, CDCl3): d 138.7, 133.3, 118.4, 111.9, 100.4.
1-Iodo-4-nitrobenzene:
1
H NMR (400 MHz, CDCl3): d 7.96-7.90 (m, 4H).
13
C NMR (100
MHz, CDCl3): d 147.9, 138.8, 125.0, 102.8.
1-Iodo-2-nitrobenzene:
1
H NMR (400 MHz, CDCl3): d 8.05 (d, J = 7.9 Hz, 1H), 7.86 (d, J = 8.1
Hz, 1H), 7.51-7.47 (m, 1H), 7.29-7.25 (m, 1H).
13
C NMR (100 MHz, CDCl3): d 153.2, 142.0,
133.5, 129.2, 125.6, 86.3.
I
O
I
NC
I
O
2
N
I
NO
2
25
1-Bromo-3-nitrobenzene:
1
H NMR (400 MHz, CDCl3): d 8.57 (s, 1H), 8.21 (ddd, J = 8.3, 2.2,
1.0 Hz, 1H), 8.03 (ddd, J = 7.9, 1.6, 1.0 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H).
13
C NMR (100 MHz,
CDCl3): d 148.7, 143.6, 132.6, 130.8, 122.9, 93.6.
4-Iodobiphenyl:
1
H NMR (400MHz, CDCl3): d 7.77 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.1 Hz,
2H), 7.44 (t, J = 7.6 Hz, 2H), 7.38-7.31 (m, 3H).
13
C NMR (100 MHz, CDCl3): d 140.9, 140.2,
138.0, 129.2, 129.1, 127.8, 127.0, 93.2.
2-Iodonaphthalene:
1
H NMR (400 MHz, CDCl3): d 8.24 (s, 1H), 7.82-7.78 (m, 1H), 7.73-7.70
(m, 2H), 7.59-7.47 (m, 3H).
13
C NMR (100 MHz, CDCl3): d 136.8, 135.1, 134.5, 132.2, 129.6,
128.0, 126.9, 126.8, 126.6, 91.6.
I
NO
2
I
I
26
1.4.8 NMR Spectra
1
H NMR and
13
C NMR of 1-Bromo-4-methylbenzene:
27
1
H NMR and
13
C NMR of 1-Bromo-4-chlorobenzene:
28
1
H NMR and
13
C NMR of 1, 4-Dibromobenzene:
29
1
H NMR and
13
C NMR of 1-(4-Bromophenyl)ethanone:
30
1
H NMR and
13
C NMR of 4-Bromobenzonitrile:
31
1
H NMR and
13
C NMR of 1-Bromo-4-nitrobenzene:
32
1
H NMR and
13
C NMR of 1-Bromo-2-nitrobenzene:
33
1
H NMR and
13
C NMR of 1-Bromo-3-nitrobenzene:
34
1
H NMR and
13
C NMR of 4-Bromobiphenyl:
35
1
H NMR and
13
C NMR of 2-Bromonaphthalene:
36
1
H NMR and
13
C NMR of 1-Iodo-4-methylbenzene:
37
1
H NMR and
13
C NMR of 1-Iodo-4-chlorobenzene:
38
1
H NMR and
13
C NMR of 1-Bromo-4-iodobenzene:
39
1
H NMR and
13
C NMR of 1-Iodo-4-methoxybenzene:
40
1
H NMR and
13
C NMR of 1-(4-Iodophenyl)ethenone:
41
1
H NMR and
13
C NMR of 4-Iodobenzonitrile:
42
1
H NMR and
13
C NMR of 1-Iodo-4-nitrobenzene:
43
1
H NMR and
13
C NMR of 1-Iodo-2-nitrobenzene:
44
1
H NMR and
13
C NMR of 1-iodo-3-nitrobenzene
45
1
H NMR and
13
C NMR of 4-Iodobiphenyl:
46
1
H NMR and
13
C NMR of 2-Iodonaphthalene:
47
1.5 References
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60, 1-6.
51
Chapter 2. Palladium-Catalyzed Selective Reduction of Carboxylic Acids to Aldehydes Using
a Phosphine-based Reagent System
2.1 Introduction
Aldehydes of the general structure RCHO are highly reactive and are widely applied as
important synthetic intermediates in many industries and pharmaceutical studies. With their
electrophilic property, aldehydes can undergo nucleophilic addition reactions with thiols, primary
and secondary amines, hydroxyls and amides to form a variety of functional groups existing in
biologically active compounds for example in cellular proteins.
1,2
For aldehyde preparation, one of the most common methods is the redox reaction of readily
stable, available and economical alcohols via oxidations and carboxylic acids or their derivatives
via selective reductions. The conversion of alcohols into aldehydes is a frequently used
transformation in organic synthesis. Currently, chemists have already investigated plethora of
effective, reliable and scalable approaches for oxidation of alcohols to access aldehydes.
3
However,
the reduction of carboxylic acids is difficult to achieve selectively due to overreduction to alcohols
because aldehydes are more reactive when compared to carboxylic acids.
4–6
Thus, the reduction of
carboxylic acid or derivatives to aldehydes has always been a challenging research topic over the
past decades.
The traditional method is the Rosenmund reduction of carboxylic acid chloride into aldehydes
catalyzed by palladium complexes with atmospheric pressure of hydrogen.
7–9
This reaction is
relatively atom-economical providing products in high yields. However, the byproducts from
overreduction can only be prevented by elaborating flow-through reaction layouts which is
impractical for small-scale laboratory syntheses. Additionally, it requires preparation of acyl
52
chlorides in the first place and also a stoichiometric amount of bases to neutralize the hydrogen
chloride. Extensive efforts have been made to improve the Rosenmund reduction over the years.
10
Improvements in reduction of carboxylic acids and derivatives to aldehydes have employed
alternative hydrogen sources. The utility of hydrosilanes like HSiEt3 or HSnBu3 as reductive source
is also effective for acid chlorides reduction to aldehydes.
11,12
The specialized hydride reagents as
other replacements of H2 to prepare aldehydes from carboxylic acids, esters, amides and other
derivatives also have been invented, such as tris-tert-butoxyaluminium hydride,
13,14
aminoaluminum hydride,
15,16
thexylchloroborane-dimethyl sulfide,
17
tert-butyllithium,
18
lithium
triethyl-borohydride (super-hydride),
19
DIBAL-H,
20,21
NaAlH4,
22
and NaBH4.
23
However,
handling of these metal hydrides requires extreme caution and are rigorous exclusion of air and
moisture.
Moreover, modifications of acid derivatives by replacing chloride with other leaving groups
have been explored, as it is not practical to handle acid chlorides. At the same time, acid chlorides
are susceptible to racemization because of the acidity of the α C-H bond adjacent to the carbonyl
group. Fukuyama and co-workers developed an elegant route of aldehydes synthesis through the
reduction of thioesters with triethylsilanes performed by palladium on carbon catalyst to avoid the
racemization problem.
24–28
Then, Seki et al. improved the Fukuyama reaction, making it more
practical in the industrial process.
29
Nakanishi et al. reported a new synthesis of aldehydes by the
palladium-catalyzed reduction of 2-pyridinyl ester with HSiEt3.
30
Most recently, Ogiwara et al.
implemented a novel palladium-catalyzed reductive conversion of acyl fluorides to aldehydes
using a hydrosilane.
31
In all these methods, however, acid derivatives must be generated first in an
additional reaction step.
53
Consequently, organic chemists usually prefer to utilize the two-step protocols to synthesize
aldehydes from carboxylic acids (Scheme 2.1, top and bottom pathways) in spite of that these
methods have low redox-economy: either via reducing carboxylic acid all the way to alcohols
followed by selectively partial re-oxidation to aldehydes such as Swern oxidation, the Dess-Martin
oxidation, and oxidation by PCC or MnO2;
32
or via the transformation of carboxylic acids to more
reactive derivatives such as acyl halides, acid anhydrides, esters, and amides followed by
hydrogenation or hydride reduction with suitable catalysts. Despite numerous reports, most of the
procedures still exhibit poor chemoselectivities and are incompatible with various sensitive
functional groups. Meanwhile, practical application of many of the reported reagents remains
limited due to toxicity, environmental pollution, thermal instability and drastic reaction conditions.
Therefore, advanced efficient methods for conversion of carboxylic acids to aldehydes remain a
major synthetic challenge.
In order to overcome this challenge, the direct reduction of carboxylic acids to aldehydes have
received considerable attention as a fundamental transformation in organic synthesis. Previously,
Yokoyama et al. indicated a novel direct hydrogenation process of aromatic carboxylic acid to
aldehydes with zirconia catalyst under H2 pressure.
33
Later, a pioneering study by Yamamoto et
al. reported that in situ carboxylic acids were activated by treatment with pivalic anhydride (Piv2O)
resulting in mixed acid anhydrides which subsequently were hydrogenated in the presence of high
hydrogen pressures (30 bar) and a Pd catalyst.
34–37
The reaction mechanism in Scheme 2.2 displays
that the corresponding anhydride undergoes oxidative addition to a Pd(0) center. The steric
hindrance of the bulky tert-butyl group specifies the selective regiochemistry of this step leading
to exclusive formation of the acylpalladium(II) pivalate. This intermediate finally reacts with
hydrogen to produce the aldehyde along with liberating pivalic acid.
38
To solve the impractical
54
problem of high H2 pressure application and waste intensive issue of hypophosphite salts as
reducing agents, Gooßen subsequently reported that sodium hypophosphite (NaH2PO2) functions
as a is more practical reductant in the hydrogenation of acid anhydrides and refined the reaction
by reducing the pressure to 5 bar for hydrogenation of arenecarboxylic acids to aryl aldehydes.
39,40
Fujihara et al. also investigated an analogous reducing reagent with a Pd catalyst and MePhSiH2
together.
41
Very recently, Iosub et al. discovered that dimethyl dicarbonate (DMDC) serving as an
activator combined with a Ni catalyst and silane reductant also can achieve selective reduction of
carboxylic acids to aldehydes.
42
Scheme 2.1 Prior work for reduction of carboxylic acids to aldehydes.
OH
O
H
O
X
O
OH
complete
reduction
partial
oxidation
replacement selective
reduction
novel method desired
challenging
multiple steps
poor redox-economy
drastic reaction conditions
X = Cl, OC(O)R,
NRR’, OR
Previous work:
This work:
OH
O
H
O
PPh
3
/ [O]
cat., H source
broad substrate scope
55
Scheme 2.2 Hydrogenation of arenecarboxylic acids to aryl aldehydes.
In addition to forming reactive mixed anhydrides as intermediates, researchers also have
designed other innovative routes to achieve the direct reduction of carboxylic acids to aldehydes.
One of the most attractive methodologies is hydrosilylation of carboxylic acids leading to
formation of disilyl acetals which can be further hydrolyzed to aldehydes in acids. Nagashima and
colleagues reported that hydrosilane reduction of carboxylic acids can be facilely accomplished by
Ru carbonyl cluster catalysts in one-pot reaction through dehydrogenative silylation,
43
providing
a new synthetic protocol for aldehydes from carboxylic acids directly with a bifunctional
organosilane, 1,2-bis(dimethylsilyl)-benzene as a suitable reducing reagent (Scheme 2.3).
44
Soon,
a one-pot procedure for iron-catalyzed hydrosilylation of carboxylic acids to aldehydes or alcohols
selectively was published by Darcel et al., in which the choices of catalysts and silanes played a
significant role in chemoselectivity of the products.
45
Brookhart originally performed the direct
reduction with a catalytic system utilizing triethylsilane and a strong Lewis acid B(C6F5)3.
46
Sortais
et al. employed a manganese catalyzed hydrosilylation reaction to achieve the selective reduction
of carboxylic acids to aldehydes.
45
Besides hydrosilylation catalysis methodology, visible light-
induced photoredox catalysis is another convenient approach for direct reduction of carboxylic
Pd
O
Ar
O
t-Bu
O
Ar O t-Bu
O O
Ar OH
O
Piv
2
O
L
2
Pd
H
2
Ar H
O
+ PivOH
56
acids to aldehydes. Zhu et al. successfully designed a simple catalytic system for aldehyde
synthesis from carboxylic acid transformation based on the combination of single electron transfer
and hydrogen atom transfer through visible light photoredox catalysis with DMDC as activator
and a hydrosilane as a redunctant.
47
Doyle offered a photoredox process to synthetically access
acyl radicals enabling the direct reduction of carboxylic acids to corresponding aldehydes.
48
Scheme 2.3 Transformation of carboxylic acid to aldehydes via ruthenium-catalyzed
hydrosilane reduction with 1,2-bis(dimethylsilyl)benzene.
Despite of these impressive developments, most of the methods still suffer from insufficient
scope of substrates and poor practicality of reaction conditions. Therefore, more practical and
operationally simple methods with access to a wide variety of aldehydes are still sought-after. In
this context, we sought out to develop a novel convenient and less costly protocol for direct
reduction of carboxylic acids to aldehydes with exceptional chemoselectivity. Recognizing the
abundant chemistry of phosphorus reagents
49,50
and acyloxyphosphonium species (I in Scheme
2.4) as an acylating agent for acyl transfer process in peptide coupling,
51–62
as well as in classic
Appel
63
and Mitsunobu reactions,
64,65
we surmised that this kind intermediates could be selectively
reduced into corresponding aldehydes with proper H source reductant and catalysts. Unexpectedly,
a seemingly straightforward transformation has not been reported so far. Herein, we conceive a
direct and selective conversion of carboxylic acids to aldehydes, via in situ generated
acyloxyphosphonium salts as a novel intermediate from the phosphorus reagents, in combination
R
O
OH
SiH
SiH
Si
Si
Me
Me
Me
Me
O
O
H R R
H
O
+
Ru cat.
hydrolysis
57
with catalysts and additives as activators, and using silane as a weak reductant, with the aim to
establish a practical, selective, mild and cost-effective reduction system (Scheme 2.4). This
method is expected to enjoy practical utility and operational simplicity, employing widely
available commodity chemicals, and enabling an efficient preparation procedure for the desired
aldehydes.
Scheme 2.4 Working Hypothesis
2.2 Results and discussion
Reaction optimization
With the envisioned method in mind, we started our investigation by employing benzoic acid
1a as a model substrate and reaction conditions which are similar to other reported approaches for
acyloxyphosphonium ion formation
54,62
and following reduction to the corresponding
aldehydes.
30,31,34
To interrogate the working hypothesis, catalyst and ligand screening were
initially conducted for a direct reduction of benzoic acid 1a to benzaldehyde 2a, using a catalytic
amount of various palladium catalysts and ligands in combination with PPh3/NBS and
triethylsilane (Table 2.1).
R
O
OH R
O
O
P
R’
R’
R’
R H
O
X
H
-
source
(-OPR’
3
)
cat.
1 2
acyloxyphosphonium ion
I
58
The desired benzaldehyde 2a was obtained in good yield after activation of 1a by 1.3 equiv of
PPh3 and 1.4 equiv of NBS in MeCN from 0 ºC to room temperature for 15 min, followed by
reaction with the specific 5 mol % Pd catalyst and 10 mol % ligand as well as an excess of Et3SiH
(2 equiv) in acetonitrile at room temperature for 12 h. When the reaction was performed using
Pd(OAc)2 as a catalyst without ligand, the yield of the desired product 2a reached 62% measured
by
1
H NMR analysis (entry 1). However, the utilization of PPh3 with Pd(OAc)2 afforded 2a in only
45% yield, while generating a considerable amount of benzoic anhydride 3d as a byproduct (entry
2). Although P(o-tolyl)3 as a replacement of PPh3 with Pd(OAc)2 as a catalyst led only to marginal
improvements and a large amount of 3d as well, the uses of P(4-CF3C6H4)3 and P(C6F5)3 with
electron withdrawing groups substituting the benzene ring increased the yield of 2a to 81% and
82%, respectively (entries 3, 5, and 6). The best protocol for the selective formation of
benzaldehyde 2a reduced from 1a was obtained utilizing the mixture of Pd(OAc)2 as a catalyst and
P(4-FC6H4)3 as a ligand, giving 88% yield of 2a (entry 4). We also studied dialkylbiarylphosphines
as ligands for instance BrettPhos and RuPhos, and a trialkylphosphine, PCy3, combined with
catalyst Pd(OAc)2. The results indicated that they were less efficient for the reaction in terms of
reactivity, and the ligand BrettPhos induced over reduction of the benzoic acid, which provided
benzyl alcohol 3a (entries 7, 9, and 10). In addition, reaction using a bidentate phosphine ligand,
Xantphos performed together with Pd(OAc)2 ended with 74% yield of 2a (entry 8). Instead of
using Pd(OAc)2, Pd(OCOCF3)2 and PdCl2 as alternatives of common palladium catalysts were also
screened with various phosphine ligands. Both Pd(OCOCF3)2 and PdCl2 as catalysts with the
employment of the ligand P(4-FC6H4)3 generated less desired products compared to catalyst
Pd(OAc)2 with P(4-FC6H4)3 as a ligand (entries 4, 12, and 13), while Pd(OCOCF3)2 in combination
with ligand P(o-tolyl)3 achieved a much higher reactivity compared to Pd(OAc)2 with the same
59
P(o-tolyl)3 ligand (entry 11). The combination of catalyst PdCl2 and ligand P(4-CF3C6H4)3 was
also tested and gave yield of 2a around 80% that was similar with the results of reaction conducted
by Pd(OAc)2 as a catalyst and P(4-CF3C6H4)3 as a ligand (entry 14). Meanwhile, the
dialkylphosphine ligand P
t
Bu2Ph combined with PdCl2 and the available commodity catalytic
complex (IMes)Pd(allyl)Cl were also tested for this reduction both resulting around 50% yield of
the expected aldehyde (entries 15 and 16). With the palladium(0) catalysts such as Pd(t-Bu3P)2 and
Pd/C (10 wt %), the direct reduction proceed to form 2a in 43% and 65% yields which is not as
good as the palladium(II) catalyst Pd(OAc)2 with P(4-FC6H4)3 as a ligand. Furthermore, additional
catalytic systems were also investigated and summarized in the section of Experiment Details of
this chapter.
Table 2.1 Catalyst and ligand screening for the reduction of benzoic acid to benzaldehyde
a
Entry Catalyst Ligand Yield (%)
b
1 Pd(OAc)2
62%
2 Pd(OAc)2 PPh3 45%
3 Pd(OAc)2 P(o-tolyl)3
49%
4 Pd(OAc)2 P(4-FC6H4)3
88%
5 Pd(OAc)2 P(4-CF3C6H4)3
81%
6 Pd(OAc)2 P(C6F5)3
82%
7 Pd(OAc)2 P(Cy)3 39%
8 Pd(OAc)2 Xantphos
74%
O
OH H
O
1a 2a
PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
MeCN (0.125 M), 0℃ - rt, 15 min
then
cat. (5 mol %) / Ligand (10 mol %)
Et
3
SiH (2 equiv.), MeCN (0.0714 M), rt, 12 h
60
9 Pd(OAc)2 BrettPhos 67%
10 Pd(OAc)2 RuPhos 31%
11 Pd(OCOCF3)2 P(o-tolyl)3
80%
12 Pd(OCOCF3)2 P(4-FC6H4)3
85%
13 PdCl2 P(4-FC6H4)3
75%
14 PdCl2 P(4-CF3C6H4)3 83%
15 PdCl2 P
t
Bu2Ph
54%
16 (IMes)Pd(allyl)Cl
53%
17 Pd(t-Bu3P)2
43%
18
c
Pd/C 65%
a
Reaction conditions: to a suspension of benzoic acid 1a (0.25 mmol, 1 equiv) and PPh3 (0.325
mmol, 1.3 equiv) in MeCN (2 ml, 0.125 M), solid N-Bromosuccinimide (NBS) (0.35 mmol, 1.4
equiv) was added at 0 ºC. After stirring for 15 min at room temperature, catalyst (5 mol %) and
ligand (10 mol %) in MeCN (1.5 ml) and Et3SiH (0.5 mmol, 2 equiv) were added followed by
stirring at room temperature for 12 hours.
b
Yields were determined by
1
H NMR spectroscopy vs a
standard.
c
The 10 wt % Pd/C catalyst was employed.
To further evaluate the reaction platform, we continued our studies by examining the reduction
of 1a to form 2a under varied reaction conditions and arrived at the optimized protocol reported
in Table 2.2 with employment of the selected catalytic system of Pd(OAc)2 as catalyst and P(4-
FC6H4)3 as ligand. In order to achieve the selective conversion of carboxylic acids 1 to the
corresponding aldehyde 2, a modified method for preparation of acyloxyphosphonium bromide
was initially performed by mixing the benzoic acid 1a and triphenylphosphine with N-
bromosuccinimide (NBS) at 0 ºC until room temperature which had been demonstrated to be an
productive approach for accessing the reactive acyloxyphosphonium intermediate I in recent
decades.
53,54,58,62
Then, we used Pd(OAc)2/ P(4-FC6H4)3 as a catalytic system, triethylsilane as a
reductant, and acetonitrile as a solvent to transfer the acyloxyphosphonium intermediate into the
61
derived product 2a. The additional variations of these optimized conditions were also screened
and displayed in Table 2.2.
65
The absence of a palladium catalyst and ligand resulted in no
formation of the expected product, whereas diminishing the Pd loading and the phosphine ligand
loading to 2.5/5 mol % or 3.5/7 mol % still led to moderate or good yields (entries 2-4). Entry 2
resulted in a high yield of the byproduct benzyl anhydride 3d in Table 2.2. Ogiwara and Sakai
31
reported that the non-decarbonylative and decarbonylative conversions of acyl fluoride can be
controlled by not only the structure of the ligand but also the phosphine molar ratio of ligand versus
the palladium catalyst. We examined, herein, different molar ratios of [Pd] from catalyst versus [P]
from phosphine ligand in the reductive transformation of carboxylic acids. The molar ratio of
Pd(OAc)2 to phosphine ligand P(4-FC6H4)3 with the best performance is 1:2 while the molar ratio
of 1:1 and 1:3 also achieved efficient reactivity (entries 1, 5, and 6). In fact, a variety of silane
derivatives particularly the hydrosilanes have been proven to be feasible and effective reductants
as hydride sources and hydrogen atom transfer agents owing to the lower electronegativity of
silicon (1.7) than that of the hydrogen (2.1). Examples include triethylsilane, phenylsilane,
diphenylsilane, trichlorosilane, tris(trimethylsilyl)silane (TMSH), poly(methylhydrosiloxane)
(PMHS) and many others.
66–71
Utilization of (MeO)3SiH and Cl3SiH afforded 2a in almost 0%
yield since they are too reactive and the reaction formed methyl benzoate and benzyl chloride
instead of benzaldehyde (entries 7-8). Other hydrosilanes commonly used as reducing agents such
as Ph2SiH2, TMSH and PMHS had inefficient reactivity potentially due to their steric effects
compared to Et3SiH (entries 9-11). Interestingly, during our optimization investigation, it was
observed that MeCN as a solvent was superior to DCM, which probably could be explained by the
solubility issue of palladium catalyst in DCM (entry 12). Utilizing THF as a solvent, the reactions
also proceeded in high yields of product while the tetrahydrofuran ring can be opened with the
62
acyloxyphosphonium intermediate I in our catalytic system to afford 4-bromobutyl ester in around
10% yield (entry 13). Related ring opening reactions and results were also discussed by Zhang et
al. using a samarium catalyst.
56
Other solvents such as dioxane and DME led to less yield of the
product as well (entries 14 and 15). Furthermore, it was discovered that a molar ratio of PPh3:NBS
of 1.3:1.4 afforded 2a in excellent yield, while the use of smaller amounts proved less efficient
(entry 16). The use of larger amounts of PPh3/NBS did not result in any yield improvement (entry
17), but it was found to promote the formation of some aryl aldehydes with electron withdrawing
substituent on the benzene ring (products 2c, 2h, 2i, 2aa, and 2cc in Scheme 2.5). Similarly,
increasing reaction time did not provide higher yield for 2a (entries 20-22). Overall, this
transformation can be accomplished at room temperature in 4 h with 79% yield of 2a or in 2 h with
66% yield of 2a.
In the optimized protocol, NBS (1.4 equiv) is added to a suspension of carboxylic acid 1 and
PPh3 (1.3 equiv) in MeCN at 0 ºC under air. After the activation step (15 min), a catalytic solution
of Pd(OAc)2 (5 mol %) and P(4-FC6H4)3 (10 mol %) mixed in MeCN and Et3SiH (2 equiv) are
added and briskly stirred at room temperature. In this fashion, the corresponding aldehydes are
formed in high yields within a few hours under extremely mild reaction conditions. Additionally,
the decarbonylative transformation of benzoic acid to benzene 3b and the byproduct benzyl
bromide 3c from bromination were not observed during our reaction optimization process.
Although the common competitive byproducts such as benzyl alcohol 3a and benzoic anhydride
3d were observed under the optimized conditions, they were generated in low yields (2% for 3a
and 4% for 3d).
63
Table 2.2 Pd-Catalyzed reduction of benzoic acid to benzaldehyde: reaction optimization and side
products
a
Entry Deviation from optimized conditions
a
Yield (%)
b
1 none 88%
2 no Pd(OAc)2 / P(4-FC6H4)3 0%
3
Pd(OAc)2 (2.5 mol %) / P(4-FC6H4)3 (5 mol %) 66%
4
Pd(OAc)2 (3.5 mol %) / P(4-FC6H4)3 (7 mol %) 82%
5
Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (5 mol %) 75%
6
Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (15 mol %) 74%
7 (MeO)3SiH instead of Et3SiH 2%
8 Cl3SiH instead of Et3SiH 0%
9 PMHS instead of Et3SiH 25%
10
c
Ph2SiH2 instead of Et3SiH 41%
11 TMSH instead of Et3SiH 50%
12 DCM instead of MeCN 0%
13 THF instead of MeCN 80%
14 Dioxane instead of MeCN 74%
15 DME instead of MeCN 5%
16
PPh
3
(1.1 equiv.), NBS (1.2 equiv.)
50%
17
PPh
3
(1.5 equiv.), NBS (1.6 equiv.)
88%
18 MeCN (0.1 M) 86%
19 MeCN(0.13 M) 88%
O
OH H
O
1a 2a
PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
MeCN (0.125 M), 0℃ - rt, 15 min
then
Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (10 mol %)
Et
3
SiH (2 equiv.), MeCN (0.0714 M), rt, 6 h
64
20 12 h instead of 6 h 88%
21 4 h instead of 6 h 79%
22 2 h instead of 6 h 66%
a
Reaction optimized procedure and conditions: to a suspension of benzoic acid 1a (0.25 mmol, 1
equiv) and PPh3 (0.325 mmol, 1.3 equiv) in MeCN (2 ml, 0.125 M), solid N-Bromosuccinimide
(NBS) (0.35 mmol, 1.4 equiv) was added at 0 ºC. After stirring for 15 min at room temperature,
Pd(OAc)2 (5 mol %) and P(4-FC6H4)3 (10 mol %) in MeCN (1.5 ml) and Et3SiH (0.5 mmol, 2
equiv) were added followed by stirring at room temperature for 6 hours.
b
Yields were determined
by
1
H NMR spectroscopy vs a standard.
c
Used 1.5 equiv of Ph2SiH2.
Substrate scope
With the newly developed catalytic system and the optimized conditions, we sought to evaluate
the synthetic scope by applying this strategy to the selective reduction of a great variety of aromatic
carboxylic acids as well as several aliphatic substrates (Scheme 2.5). Benzoic acid and its
derivatives, bearing a broad range of electron-neutral, electron-donating (-Me, -OMe, -
t
Bu, -Ph, -
NHAc), and electron-withdrawing functional groups (-F, -Br, -CHO, -Ac, -COOMe, -CN, -CF3)
at the para position of the benzene ring, were successfully converted to the corresponding aryl
aldehydes in moderate to good yields with excellent selectivity (2a-m). Surprisingly, a variety of
sensitive yet versatile functional groups including phenyl ether (2c), aryl bromide (2f), aldehyde
(2g), ketone (2h), ester (2i), nitrile (2j) and amide (2l) in these substrates were tolerated the
reduction conditions well, which illustrates promising wide-ranging applications in organic
OH
H
Br
O
O O
3a 3b 3c 3d
not observed not observed
65
synthesis and medicinal chemistry. Some of the substituents at the meta, othro or multiple
positions of an aryl ring attached to the carboxylic acid group were also thoroughly compatible
with the present protocol, providing the corresponding products in high yields with good
selectivity (2n-t). Reactions of methyl substituted arenecarboxylic acids at ortho, meta, para-
positions and 2,5-dimethyl benzoic acid afforded the corresponding aldehydes in high yields (88%
2b, 87% 2o, 85% 2q and 89% 2t). When 2,5-difluoro benzoic acid was used as the starting
substrate, however, the yield was dramatically decreased (2s).
In a previous study of Ni-catalyzed reduction, Iosub et al.
42
suggested that 4-
trifluoromethylbenzoic acid and other electron-deficient aromatic carboxylic acids were reduced
in low yields with only a trace amount of the corresponding aldehyde products. Intriguingly, our
protocol for catalytic reduction was amenable to not only p-CF3 and o-CF3 benzoic acids but also
3,5-di(trifluoromethyl)benzoic acid with two electron withdrawing functionalities in more than 70%
yields (2k, 2r and 2n). Arenecarboxylic acids containing heterocycles were also explored, such as
thiophene and 2-naphthyl, affording desired aldehyde products in yields of 77% and 86% ,
respectively (2u and 2v).
Furthermore, this strategy exhibits another appealing feature of its scalability: product 2u was
obtained in 77% yield after working up the reaction mixture and silica column chromatography
when the reaction was carried out on a 10 mmol scale (> 1 g), more information is provided in the
experimental section. Thus, these results prove that Pd(OAc)2 and P(4-FC6H4)3 could be utilized
as an efficient catalyst system for the synthesis of aromatic aldehydes.
66
Scheme 2.5 Substrate scope for the reduction of arenecarboxylic acids and aliphatic carboxylic
acids
a
R
O
OH R H
O
1 2
2. Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (10 mol %)
Et
3
SiH (2 equiv.), MeCN (0.0714 M), rt, 6 h
Aromatic and allphatic carboxylic acids
Me MeO
t
Bu
2a
81% (88%)
2b
83% (88%)
2c
71% (74%)
b
2d
78% (82%)
F Br
OHC
2e
70% (78%)
2f
61% (65%)
b
O
2g
65% (69%)
b
2h
62% (73%)
b
N
H
MeO
O
NC F
3
C
O
2i
70% (72%)
c
2j
74% (77%)
2k
72% (81%)
2l
51% (58%)
b
F
3
C
CF
3
Me OMe
2m
72% (79%)
2n
74% (80%)
2o
87% (91%)
2p
89% (94%)
Me
CF
3
F
F Me
Me
2q
85% (89%)
2r
74% (88%)
2s
(17%)
2t
89% (94%)
S
O
H
2u
85% (86%)
77% (1.20 g)
2v
86% (93%)
n=1 2w (37%)
b
n=2 2x 50% (56%)
b
n=3 2y 55% (60%)
b
2z
59% (68%)
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
H
O
O
H
n
1. PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
MeCN (0.125 M), 0℃ - rt, 15 min
67
a
Reaction conditions: 1 (0.25 mmol, 1 equiv), PPh3 (0.325 mmol, 1.3 equiv), MeCN (2 ml, 0.125
M), N-Bromosuccinimide (NBS) (0.35 mmol, 1.4 equiv), 0 ºC to rt, 15 min. Next, Pd(OAc)2
(0.0125 mmol, 5 mol %), P(4-FC6H4)3 (0.025 mmol, 10 mol %), Et3SiH (0.5 mmol, 2 equiv),
MeCN (1.5 ml, 0.071 M), rt, 6 h. Isolated yield, average of two runs. Yields in parentheseswere
determined by
1
H NMR spectroscopy vs an internal standard. See the supporting information for
full experimental details.
b
Reaction used 1.5 equiv of PPh3 and 1.6 equiv of NBS.
c
Reaction time
is 18 min for the first step.
Next, our attention was turned toward the reduction to aliphatic aldehyde structures. Under the
present reaction conditions, phenylacetic acid failed to yield a considerable amount of the
corresponding product 2w. However, the reduction of the starting aliphatic acid derivatives with
longer linear alkyl chains, such as 1x and 1y, proceeded more reactively to form the desired
aldehydes 2x and 2y in moderate yields. Besides, tertiary carboxylic acids were also good
Pharmaceutically relevent substrates
S
N
Me
O O
O
Me
Me
N
S
Me
O
H
NC
H
N
H
O
O
Me Me
Me Me
(antineoplastic drugs) (xantine oxidase inhibitors) (uricosuric drugs)
O
H
2aa
70% (76%)
b
2bb
(32%)
2cc
(46%)
b
Me
O
O
Me
H
H
H
Me
H
O
O
H
From Probenecid From Febuxostat From Tamibarotene
From Adapalene From Hiestrone
2dd
74% (82%)
(antiacne drugs)
2ee
81% (91%)
(hormone drugs)
68
substrates and tolerated with our reduction system, as demonstrated by the preparation of product
2z in 59% isolated yield. Notably, this Pd-catalyzed reduction using a phosphine-based reagent
system exhibited remarkable chemoselectivity not only toward selective reduction to aldehydes.
This property was proved by the reduction of substrates with reducible functionalities including
phenyl ether (2c), aryl bromide (2f), aldehyde (2g), ketone (2h), ester (2i), nitrile (2j) and amide
(2l), providing corresponding aldehydes in high yields without reducing the sensitive substituents
(2c, 2f, 2g, 2h, 2i, 2j and 2l). Additionally, we also tested the optimized reaction conditions with
trans-cinnamic acid and several of its derivatives. The desired products were obtained in low yield,
possibly due to the high reactivity of the double bond with palladium catalysts (more experimental
details in the supplementary information).
This exceptional functional group tolerance suggests the potential application of this approach
in medicinal synthesis of larger and more complex aldehydes, which could be accomplished by
the functionalization of biologically active pharmaceutical ingredients (APIs). In this case, a series
of pharmaceutically relevant carboxylic acids was also subjected to our reaction conditions to
further investigate the synthetic scope of this method (Scheme 2.5). Using present protocol,
aldehyde 2aa (from Probenecid, uricosuric drugs) was prepared in isolated yields of 70%, also
indicating the tolerance of sulfonamide functional group. The reduction of pharmaceuticals such
as febuxostat (xanthine oxidase inhibitors, product 2bb) and tamibarotene (antineoplastic drugs,
product 2cc), however, was achieved in 32-46% proton NMR yield with an internal standard,
potentially due to the inefficient reactivities of substrates bearing thiazole and amide
functionalities as well as the low solubility of the formed corresponding acyloxyphosphonium salts.
Aldehydes 3dd and 3ee were accessed directly from adapalene (1dd, antiacne drugs) and hiestrone
(1ee, hormone drugs) in the yields of 74% and 81%, respectively. This collection of results
69
demonstrates that this protocol enables practical and synthetic modification in a pharmaceutical
setting.
Synthesis of deuterated aromatic aldehydes
To gain further insight into our method, the deoxygenative deuteration of carboxylic acids was
also investigated with our present protocol by just replacing Et3SiH with the commercially
available Et3SiD to construct the deuterated aromatic aldehydes (Scheme 2.7). Deuteration as a
labeling technique has a diverse range of applications in the studies of mass spectrometry
72,73
and
nuclear magnetic resonance spectroscopy
74
, as well as in the investigation of reaction
mechanisms
75
and the analysis of drug metabolism.
76–78
Moreover, the first deuterium-labled drug,
deutetrabenazine (Austedo) was approved by the US Food and Drug Administration (FDA) to the
market recently.
79
In such case, the demand for more deuterated drugs has certainly motivated and
accelerated the development of synthetic approaches for deuteration.
80–86
Regarding the importance of deuteration, the method to synthesize aryl aldehydes deuterated
at the formyl position could raise the accessibility of deuterated bioactive compounds. Thus far,
scientists have reported several methodologies for the synthesis of deuterium-containing aryl
aldehydes which could be divided into two major pathways (Scheme 2.6). As for the first
representative way (Scheme 2.6A), aromatic aldehydes deuterated at the formyl position are
produced from the corresponding aryl halides and carboxylic acid derivatives through functional
group transformation including: (a). reductive carbonylation of aromatic halides using Pd and Rh
catalysts under CO pressure;
87
(b). careful reduction of aryl esters with highly reactive deuterated
reductants LiAlD4 followed by oxidation;
88–90
(c). reductive reaction of aryl amides with
deuterated Schwartz’s reagent;
91
(d). Ir-catalyzed deoxygenative deuteration of carboxylic acids
70
with D2O via synergistic photoredox.
92
The other main pathway (Scheme 2.6B) is the direct
hydrogen isotope exchange (HIE) at the formyl C-H bond of aromatic aldehydes such as the
reported Ir- and Ru-catalyzed HIE at the formyl moiety, albeit alternative deuteration on reactive
aryl ring moiety.
93,94
Besides, a W-catalyzed formyl-selective deuterium labeling of aldehydes
with D2O by synergistic organic and photoredox catalysis was reported very recently.
95
However,
method with mild conditions to selectively introduce the deuterium into aromatic aldehydes still
remains a challenge in synthetic chemistry.
Scheme 2.6 Strategies for synthesizing deuterated aldehydes; (A) through FG
transformation; (B) through hydrogen isotope exchange (HIE).
With all these considerations, our protocol was applied with Et3SiD instead of Et3SiH as an
inexpensive deuterium source and successfully converted the aromatic carboxylic acids 1a, 1k, 1p,
1g and 1u directly into the desired deuterium labelled aryl aldehydes 4 at formyl position with
good incorporation as well as moderate to high isolated yields in 60-85% (Scheme 2.7). This
D
O
FG
Br/I
FG
OR
O
FG
NR
2
O
FG
OH
O
FG
[Pd]/[Rh], D
2
O
CO (15-25 bar)
1. LiAlD
4
2. Oxidation
Cp
2
ZrDCl
[Ir], thiol, Ph
3
P
KH
2
PO
4
, DCM/D
2
O
H
O
FG
[Ir]/acetone-d6(or D
2
)
or
[Ru]/D
2
O
D
O
FG
D
H
O
FG
photoredox catalysis
[W], thiol, DCM/D
2
O
A. Previous work of formyl deuterated aldehyde synthesis by FG transformation
B. Previous work of formyl deuterated aldehyde synthesis by hydrogen isotope exchange (HIE)
photoredox catalysis
71
strategy also supplements the recently reported Ni-catalyzed system
42
that cannot produce
deuterated aldehydes from aromatic carboxylic acids, although efficient for the transformation of
aliphatic carboxylic acids. It is clearly evident that our protocol could serve as a general and
promising step-economical method for the deoxygenative deuteration of aromatic carboxylic acids
to formyl-selective deuterated aldehydes under mild reaction conditions with short reaction time
and functional group compatibility.
Scheme 2.7 Synthesis of deuterated aryl aldehydes by deoxygenative deuteration of aromatic
carboxylic acids
a
a
Reaction conditions: 1 (0.25 mmol, 1 equiv), PPh 3 (0.325 mmol, 1.3 equiv), MeCN (2 ml, 0.125 M), N-
Bromosuccinimide (NBS) (0.35 mmol, 1.4 equiv), 0 ºC to rt, 15 min. Next, Pd(OAc) 2 (0.0125 mmol, 5
mol %), P(4-FC 6H 4) 3 (0.025 mmol, 10 mol %), Et 3SiD (0.5 mmol, 2 equiv), MeCN (1.5 ml, 0.071 M), rt, 6
h. Isolated yield, average of two runs. See the supporting information for full experimental details.
b
Reaction used 1.5 equiv of PPh 3 and 1.6 equiv of NBS.
4a
80%
D
O
R
O
OH R D
O
1 4
1. PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
MeCN (0.125 M), 0℃ - rt, 15 min
2. Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (10 mol %)
Et
3
SiD (2 equiv.), MeCN (0.0714 M), rt, 6 h
Synthesis of Deuterated Aldehydes
OMe
4p
85%
D
O
F
3
C
4k
73%
D
O
4u
82%
D
O
OHC
4g
60%
b
D
O
72
Proposed mechanism
For a mechanistic understanding of this transformation, we conducted a series of the
1
H and
31
P NMR as well as gas chromatography with respect to the former studies in our group on
deoxyfluorination of carboxylic acids through the similar acyloxyphosphonium intermediate (see
more details in supplementary information). Addition of NBS to a solution of PPh3 with no 1a in
MeCN at 0 ºC, afforded the formation of a
31
P signal which corresponds to bromophosphonium
salt and appearing at 𝛿 31.43. Meanwhile, a new signal appeared at 𝛿 43.53 when NBS was added
into a solution with both PPh3 and benzoic acid 1a in MeCN at 0 ºC resulting from the formation
of acyloxyphosphonium ion I as the new species. These compounds disappeared upon the addition
of the mixture of palladium catalysts and ligands with triethylsilane. After the reaction, the
appearance of 2a (𝛿 31.5, -CHO group in
1
H NMR) along with quantitative amount of O=PPh3
was indicated in both
1
H NMR spectrum and GC analysis. These observations of the formation
and reduction of acyloxyphosphonium ion are in full agreement with previous reported studies.
Based on these observations and former literature reports of Pd-catalyzed reductions of carboxylic
acids with silanes as reductants,
30,31,38,39
the following plausible mechanistic pathway is proposed
in Scheme 2.8.
The mechanism possibly begins with the oxidative addition of PPh3 by NBS to generate a
bromophosphonium salt A, which is followed by reaction with starting carboxylic acid derivatives
1, forming acyloxyphosphonium intermediate I as redox-active electrophiles for Pd-catalyzed
acylative cross-coupling reaction. These acyloxyphosponium ions can undergo oxidative addition
of an acyl C-O bond to a palladium active species [LnPd
0
], which would afford an acylpalladium
bromide species (RCO-[Pd
II
]-Br) 5. The [LnPd
0
] species can be formed by the reduction of Pd(II)
catalysts with triethylsilanes. The observation of a series of bubbles at the very beginning of the
73
reaction reveals an induction time needed before the oxidative addition of the intermediate I. After
the formation of complex 5, transmetalation with a hydrosilane then occurs between the Pd-Br
bond and the Si-H bond to produce a palladium-acyl hydride species 6, releasing Et3SiBr at the
same time. Subsequently, a reductive elimination of the acyl C-[Pd
II
]-H from the
Scheme 2.8 Proposed mechanistic pathway of the Pd-catalyzed reduction of carboxylic acids to
aldehydes.
species 6 could provide the final desired aldehyde and restore the active Pd(0) species for catalysts
recycling. While previous reports of Pd-catalyzed decarbonylative cross-coupling reactions to
continue reducing aldehydes with hydrosilanes exist,
31
the decarbonylation process can be
controlled by the ligand selection according to their properties such as sigma donor abilities and
PPh
3
NBS
PPh
3
Br X
R
O
OH
A 1
+
(-succinimide)
[L
n
Pd
0
]
O=PPh
3
Palladium Cycle:
Acylative Cross-Coupling
R
O
Pd
II
L
L
Br
R
O
Pd
II
L
L
H
R
O
H
R
O
OPPh
3
Br
I
Oxidative
Addition
Reductive
Elimination
Transmetallation
Et
3
Si-H
Et
3
SiBr
2
5
6
Pd(OAc)
2
P(4-FC
6
H
4
)
3
Et
3
SiH
N
O O
X =
Acyloxyphosphorium
Intermediate Formation
74
structures, and/or elevated reaction temperature of the reaction. Meanwhile, our reaction most
probably yields Pd-H species in the acylative cross-coupling cycle with increased availability for
reductive elimination rather than intermolecular hydride addition to an aldehyde. On the basis of
these arguments, we could explain: (a). the absence of the formation of the hydrocarbons by
decarbonylative conversions from the carboxylic acids; (b). and the lack of further reduction to
alcohols under our reaction conditions.
2.3 Conclusion
In conclusion, a novel and efficient protocol for the direct and selective reduction of carboxylic
acids to aldehydes, involving the palladium-catalyzed acylative cross-coupling of an
acyloxyphosphonium intermediate in conjunction with hydrosilanes, has been developed. We
successfully deliver a safe, simple and practical synthetic method employing inexpensive
commercially available chemicals. A broad range of aldehydes were obtained in moderate to good
yields with high selectivity, illustrating that the reaction is compatible with various functional
groups. Mild reaction conditions including short reaction times are also the salient features of this
methodology. The scalability as evidenced by the gram-scale example 2u further emphasizes the
significance of this protocol. Further application of this method in the highly precise reduction of
several complex bio-active pharmaceutical compounds bearing -COOH was also successfully
demonstrated. This reaction also provides a promising and convenient approach for the
transformation of carboxylic acids to deturated aryl aldehydes by deoxygenative deuteration using
a Et3SiD reagent system.
75
2.4 Experimental details
2.4.1 General information
Materials. All the chemicals were purchased from commercial sources such as Sigma-Aldrich,
Alfa Aesar, Combi-Blocks, Fisher Scientific, Frontier Scientific, TCI and Oakwood, and used
without further purification excluding the following exceptions. N-bromosuccinimide (NBS) was
recrystallized from water and dried over P2O5 under high vacuum before use. Acetonitrile (MeCN)
was purchased from EMD (drysolv) and distilled/degassed over P2O5 and stored over molecular
sieves in a N2-filled Straus flask prior to use unless otherwise noted. Tetrahydrofuran (THF) was
distilled over CaH2 using sodium and benzophenone as a colorimetric indicator and stored over
molecular sieves in a N2-filled Straus flask. Dichloromethane (DCM), 1,2-dimethoxyethane
(DME), and dioxane were purchased from EMD or Sigma-Aldrich in anhydrous form and used as
received.
General Procedure. Unless otherwise noted, reactions were performed under a nitrogen
atmosphere with the exclusion of moisture. N2-flushed stainless steel needles and plastic syringes
were used to transfer air and moisture sensitive solvents or solutions. Reaction solutions were
worked up and concentrated using a rotary evaporator under different reduced pressures based on
the boiling points of products. Flash column chromatograph was performed to isolate products
with proper eluent as monitored by thin-layer chromatography (TLC) on Silica Gel 60 F254 plates
from EMD, visualizing with UV light (254 nm) or KMnO4 stain.
Instrumentation.
1
H,
13
C,
19
F and
31
P nuclear magnetic resonance (NMR) spectra were recorded
on 400 MHz, 500 MHz or 600 MHz Varian NMR spectometers. NMR data are represented as
follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
76
multiplet), coupling constant in Hertz (Hz), and integration.
1
H NMR chemical shifts were
determined relative to CDCl3 as the internal standard at 7.26 ppm.
13
C NMR shifts were determined
relative to CDCl3 at 77.16 ppm.
19
F NMR chemical shifts were determined relative to CFCl3 as the
internal standard at 0.00 ppm. Gas chromatography (GC) was performed on Bruker 450-GC
instrument equipped with flame ionization detectors. Mass spectra were recorded on a high-
resolution mass spectrometer Bruker 300-MS in the ESI mode.
2.4.2 Reaction optimization studies
Experimental operating process optimization
Operating process A: On the bench-top, benzoic acid 1a (1 equiv, 0.25 mmol, 30.5 mg),
triphenylphosphine, PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), and N-bromosuccinimide, NBS (1.4
equiv, 0.35 mmol, 62.3 mg) were charged into an oven-dried 5 mL crimp top vial equipped with
magnetic stir bar. The vial was then sealed with a crimp top septum cap and purged with N2 under
Schlenk line three times. At 0 ºC cold MeCN (2 ml) was added and stirred for 15 min from 0 ºC
to room temperature. During this time, another oven-dried 5 mL crimp vial equipped with
magnetic stir bar was charged with palladium acetate, Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8
mg), and tris(o-tolyl)phosphine, P(o-tolyl)3 (0.1 equiv, 0.025 mmol, 7.6 mg). This vial was also
sealed with a crimp top septum cap and purged with N2 using Schlenk line three times. At r.t.
MeCN (1 mL) was added with stirring. After 15 min of reaction in the first vial, the [Pd] solution
in the second vial was transferred into the first vial and rinsed with MeCN (0.5 mL), followed by
quickly adding triethylsilane, Et3SiH (2 equiv, 0.5 mmol, 80 µL). The mixture was stirred at r.t.
for 12 h. After that, the vial was opened, and the reaction mix was diluted with EtOAc (~10 mL)
77
and sat. aq. NaHCO3 (~10 mL), stirring for 2 min. Then, the internal standard, 1,3,5-
trimethoxybenzene (14 mg, 0.083 mmol, 100% of theoretical yield for 3 protons on the aromatic
ring) dissolved in EtOAc (1 mL) was added and stirred. The aqueous layer was washed with ethyl
acetate (2 x 10 mL). The combined organic layers were washed with brine (~ 30 mL), dried over
MgSO4, filtered and then analyzed by GC. Finally, the reaction mixture was concentrated and
analyzed by
1
H NMR. The yield was determined by comparing the relative integration of internal
standard (1,3,5-trimethoxybenzene,
1
H NMR 6.08 ppm) with the -CHO from the aldehyde product.
The final
1
H NMR yield was 37%.
Operating process B: On the bench-top, benzoic acid 1a (1 equiv, 0.25 mmol, 30.5 mg) and
triphenylphosphine, PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg) were charged into an oven-dried
screw-cap vial equipped with a magnetic stir bar. After this, dry acetonitrile, MeCN (2 mL) was
added, the vial was capped, and this mixture was then cooled to 0 ºC using an ice-bath.
Subsequently, N-bromosuccinimide, NBS (1.4 equiv, 0.35 mmol, 62.3 mg) was added as a solid
in one portion, the vial was re-capped, and the mixture was kept in the ice-bath for two minutes.
After this time, the ice-bath was removed, and this solution was further stirred for 15 min. During
this time, an oven-dried 5 mL crimp vial equipped with magnetic stir bar was charged with
palladium acetate, Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), and tris(o-tolyl)phosphine, P(o-
tolyl)3 (0.1 equiv, 0.025 mmol, 7.6 mg). This vial was then sealed with a crimp top septum cap
and purged with N2 using Schlenk line three times. At r.t. MeCN (1 mL) was added and stirred.
After the first 15 min, the reaction mixture in the screw-cap vial was transferred into the crimp vial
with [Pd] catalyst solution and rinsed with MeCN (0.5 mL) under steam of N2 using Schlenk line,
followed quickly by adding triethylsilane, Et3SiH (2 equiv, 0.5 mmol, 80 µL). The mixture was
stirred at r.t. for 12 h. Upon reaction completion, the work up procedure was exactly the same as
78
operating process A. The final
1
H NMR yield was 49%. In conclusion, the experimental operating
process B improved the reaction yield compared to operating process A. Hence, the operating
process B was selected to apply in the further screening of other reaction conditions.
General procedure for optimization of reaction conditions and additional details
Preparation of palladium catalyst solution: An oven-dried 5 mL crimp vial equipped with
magnetic stir bar was charged with palladium acetate, Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8
mg) and ligand tris(4-fluorophenyl)phosphine, P(4-FC6H4)3 (0.1 equiv, 0.025 mmol, 7.9 mg), and
then sealed with a crimp top septum cap in the N2 glovebox, followed by adding anhydrous
acetonitrile, (1 mL). The mixture was stirred vigorously at room temperature for 10 min. For some
of the catalysts and ligands, the solution is not fully clear and dispensed as a suspension.
Screening reaction set-up: On the bench-top, benzoic acid 1a (1 equiv, 0.25 mmol, 30.5 mg) and
triphenylphosphine, PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg) were charged into an oven-dried
screw-cap vial equipped with a magnetic stir bar. After this, anhydrous, acetonitrile, MeCN (2 mL)
was added, the vial was capped, and this mixture was then cooled to 0 ºC using an ice-bath.
Subsequently, N-bromosuccinimide, NBS (1.4 equiv, 0.35 mmol, 62.3 mg) was added as a solid
in one portion, the vial was re-capped, and the mixture was kept in the ice-bath for two minutes.
Then, the ice-bath was removed, and this solution was further stirred for 15 min. Once the 15 min
completed, the reaction mixture in the screw-cap vial was transferred into the crimp vial with [Pd]
catalyst solution and rinsed with MeCN (0.5 mL), followed quickly by adding triethylsilane,
Et3SiH (2 equiv, 0.5 mmol, 80 µL) via Hamilton syringe under a stream of N2 using Schlenk line.
The reaction mixture was stirred at r.t. for 6 h. Upon reaction completion, the vial was then opened,
and the reaction mix was diluted with EtOAc (~10 mL) and sat. aq. NaHCO3 (~10 mL), stirred for
79
1 min. Next, the internal standard, 1,3,5-trimethoxybenzene (14 mg, 0.083 mmol, 100% of
theoretical yield for 3 protons on the aromatic ring) dissolved in EtOAc (1 mL) was added and
stirred. The aqueous layer was washed with ethyl acetate (2 x 10 mL). The combined organic
layers were washed with brine (~ 30 mL), dried over MgSO4, filtered and analyzed by GC. Finally,
the reaction mixture is concentrated and then analyzed by
1
H NMR. The yield was determined by
comparing the relative integration of internal standard (1,3,5-trimethoxybenzene,
1
H NMR d 6.08
ppm) with the -CHO from the aldehyde product.
The representative procedure above for the synthesis of 2a was used for reaction condition
optimization and the yields are determined by the NMR yield described in the general optimization
procedure. Reaction conditions were screened by control experiments as shown in the following
tables (Table 2.3-2.9).
Table 2.3 Catalyst and ligand screen using THF as solvent
Entry Catalyst Ligand Yield (%)
1 Pd(OAc)2
54%
2 Pd(OAc)2 PPh3
33%
3 Pd(OAc)2 P(o-tolyl)3
56%
4 Pd(OAc)2 P(4-FC6H4)3
80%
5 Pd(OAc)2 P(4-CF3C6H4)3
83%
6 Pd(OAc)2 P(C6F5)3
75%
7 Pd(OAc)2 P(Cy)3
18%
8 Pd(OAc)2 Xantphos
39%
1. PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
THF (0.125 M), 0℃ - rt, 15 min
2. Cat (5 mol %) / Ligand (10 mol %)
Et
3
SiH (2 equiv.), THF (0.0714 M), rt, 12 h
O
OH
1a
H
O
2a
80
9 Pd(OAc)2 BrettPhos
71%
10 Pd(OAc)2 RuPhos
18%
11 Pd(OCOCF3)2
45%
12 Pd(OCOCF3)2 PPh3
53%
13 Pd(OCOCF3)2 P(o-tolyl)3
59%
14 Pd(OCOCF3)2 P(4-FC6H4)3
70%
15 Pd(OCOCF3)2 P(4-CF3C6H4)3
70%
16 Pd(OCOCF3)2 P(C6F5)3
69%
17 Pd(OCOCF3)2 P(Cy)3
43%
18 Pd(OCOCF3)2 Xantphos
38%
19 Pd(OCOCF3)2 BrettPhos
59%
20 Pd(OCOCF3)2 RuPhos
47%
21 PdCl2
33%
22 PdCl2 PPh3
40%
23 PdCl2 P(o-tolyl)3
24%
24 PdCl2 P(4-FC6H4)3
41%
25 PdCl2 P(4-CF3C6H4)3
78%
26 PdCl2 P(C6F5)3
42%
27 PdCl2 P(Cy)3
63%
28 PdCl2 Xantphos
0%
29 PdCl2 BrettPhos
40%
30 PdCl2 RuPhos
46%
31 PdCl2 P
t
Bu2Ph
2%
32 (IMes)Pd(allyl)Cl
34%
33 Pd(t-Bu3P)2
88%
34 10 wt % Pd/C
69%
81
Table 2.4 Catalyst and ligand screen using MeCN as solvent
Entry Catalyst Ligand Yield (%)
1 Pd(OAc)2 62%
2 Pd(OAc)2 PPh3 45%
3 Pd(OAc)2 P(o-tolyl)3 49%
4 Pd(OAc)2 P(4-FC6H4)3 88%
5 Pd(OAc)2 P(4-CF3C6H4)3 81%
6 Pd(OAc)2 P(C6F5)3 82%
7 Pd(OAc)2 P(Cy)3 39%
8 Pd(OAc)2 Xantphos 74%
9 Pd(OAc)2 BrettPhos 67%
10 Pd(OAc)2 RuPhos 31%
11 Pd(OCOCF3)2 49%
12 Pd(OCOCF3)2 PPh3 72%
13 Pd(OCOCF3)2 P(o-tolyl)3 80%
14 Pd(OCOCF3)2 P(4-FC6H4)3 85%
15 Pd(OCOCF3)2 P(4-CF3C6H4)3 78%
16 Pd(OCOCF3)2 P(C6F5)3 65%
17 Pd(OCOCF3)2 P(Cy)3 2%
18 Pd(OCOCF3)2 Xantphos 31%
19 Pd(OCOCF3)2 BrettPhos 65%
20 Pd(OCOCF3)2 RuPhos 34%
21 PdCl2 61%
22 PdCl2 PPh3 40%
23 PdCl2 P(o-tolyl)3 30%
24 PdCl2 P(4-FC6H4)3 75%
25 PdCl2 P(4-CF3C6H4)3 83%
26 PdCl2 P(C6F5)3 90%
1. PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
MeCN (0.125 M), 0℃ - rt, 15 min
2. Cat (5 mol %) / Ligand (10 mol %)
Et
3
SiH (2 equiv.), MeCN (0.0714 M), rt, 12 h
O
OH
1a
H
O
2a
82
27 PdCl2 P(Cy)3 72%
28 PdCl2 Xantphos 25%
29 PdCl2 BrettPhos 74%
30 PdCl2 RuPhos 58%
31 PdCl2 P
t
Bu2Ph 54%
32 (IMes)Pd(allyl)Cl 53%
33 Pd(t-Bu3P)2 43%
34 10 wt % Pd/C 65%
Using the catalysts and ligands of the selected entries with higher yields, we continued to test their
reaction time (Table 2.5).
Table 2.5 Reaction time screening
Entry Catalyst Ligand Time (h) Yield (%)
1 PdCl2 P(C6F5)3 12 90%
2 PdCl2 P(C6F5)3 6 85%
3 Pd(OAc)2 P(4-FC6H4)3 12 88%
4 Pd(OAc)2 P(4-FC6H4)3 6 88%
5 Pd(OAc)2 P(4-FC6H4)3 4 79%
6 Pd(OAc)2 P(4-FC6H4)3 2 66%
7 Pd(OCOCF3)2 P(o-tolyl)3 12 80%
8 Pd(OCOCF3)2 P(o-tolyl)3 6 77%
9 Pd(OCOCF3)2 P(4-FC6H4)3 12 85%
10 Pd(OCOCF3)2 P(4-FC6H4)3 6 82%
11
a
Pd(t-Bu3P)2 12 88%
12
a
Pd(t-Bu3P)2 6 57%
a
The reaction solvent is THF.
1. PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
MeCN (0.125 M), 0℃ - rt, 15 min
2. Cat (5 mol %) / Ligand (10 mol %)
Et
3
SiH (2 equiv.), MeCN (0.0714 M), rt, time
O
OH
1a
H
O
2a
83
Using the optimized catalyst system and reaction time, we then tested the other solvents and silanes
under this condition (Table 2.6-2.7).
Table 2.6 Solvent screening
Entry Solvent Yield (%)
1 DCM 0%
2 THF 80%
3 DME 5%
4 MeCN 88%
5 Dioxane 74%
Table 2.7 Silane screening
Entry Silane Yield (%)
1 (MeO)3SiH 2%
2 Cl3SiH 0%
3 PMHS 25%
4
a
Ph2SiH2 41%
5 TMSH 50%
6 Et3SiH 88%
7
b
Et3SiH 57%
a
Ph 2SiH 2 is 1.5 equiv.
b
Et 3SiH is 1.5 equiv.
1. PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
Solvent (0.125 M), 0℃ - rt, 15 min
2. Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (10 mol %)
Et
3
SiH (2 equiv.), Solvent (0.0714 M), rt, 6 h
O
OH
1a
H
O
2a
1. PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
MeCN (0.125 M), 0℃ - rt, 15 min
2. Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (10 mol %)
Silane (2 equiv.), MeCN (0.0714 M), rt, 6 h
O
OH
1a
H
O
2a
84
Finally, the amounts of reagents and the reaction concentration were screened in Table 2.8-2.9.
Table 2.8 The amounts of PPh3 and NBS screening
Entry
Ratio of
1a/PPh3/NBS
Yield (%)
1 1/1.1/1.2 50%
2 1/1.3/1.4 88%
3 1/1.5/1.6 88%
Table 2.9 Catalyst/ligand amount and reaction concentration screening
Entry
MeCN concentration
(step1/step2, M)
Pd(OAc)2
(mol %)
P(4-FC6H4)3
(mol %)
Yield (%)
1 0.125/0.071 2.5 5 66%
2 0.167/0.100 2.5 5 71%
3 0.250/0.125 2.5 5 74%
4 0.250/0.125 2.5 2.5 63
5 0.250/0.125 2.5 7.5 72%
6 0.125/0.071 3.5 7 82%
7 0.167/0.100 3.5 7 81%
8 0.250/0.125 3.5 7 83%
9 0.125/0.071 5 5 75%
10 0.125/0.071 5 15 74%
11 0.125/0.071 5 10 88%
12 0.167/0.100 5 10 86%
13 0.250/0.125 5 10 88%
1. PPh
3
, NBS
MeCN (0.125 M), 0℃ - rt, 15 min
2. Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (10 mol %)
Et
3
SiH (2 equiv.), MeCN (0.0714 M), rt, 6 h
O
OH
1a
H
O
2a
1. PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
MeCN, 0℃ - rt, 15 min
2. Pd(OAc)2 (mol %) / P(4-FC6H4)3 (mol %)
Et
3
SiH (2 equiv.), MeCN, rt, 6 h
O
OH
1a
H
O
2a
85
2.4.3 General procedure for reduction of carboxylic acids to aldehydes
Unless otherwise stated, the following representative procedure was used for the synthesis and
purification of aldehyde products 2. On the bench-top, carboxylic acid derivative 1 (1 equiv, 0.25
mmol) and triphenylphosphine, PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg) were charged into an oven-
dried screw-cap vial equipped with a magnetic stir bar. After this, anhydrous, acetonitrile, MeCN
(2 mL) was added, the vial was capped, and this mixture was then cooled to 0 ºC using an ice-bath.
Subsequently, N-bromosuccinimide, NBS (1.4 equiv, 0.35 mmol, 62.3 mg) was added as a solid
in one portion, the vial was re-capped, and the mixture was kept in the ice-bath for two minutes.
Then, the ice-bath was removed, and this solution was further stirred for 15 min. Once the 15 min
completed, the reaction mixture in the screw-cap vial was transferred into the crimp vial with [Pd]
catalyst solution and rinsed with MeCN (0.5 mL), followed quickly by adding triethylsilane,
Et3SiH (2 equiv, 0.5 mmol, 80 µL) via Hamilton syringe under a stream of N2 using Schlenk line.
The reaction mixture was stirred at r.t. for 6 h. After completion, the vial was then opened, and the
reaction mixture was quenched with sat. aq. NaHCO3 (~5 mL) and extracted with EtOAc (3 x 10
mL). The combined organic layers were dried over MgSO4, then the solvent was removed under
vacuo. The residue was purified with column chromatography on silica gel (gradient eluent of
hexane and ethyl acetate) to give the corresponding aldehyde products.
R
O
OH
1
PPh
3
(1.3 equiv.)
NBS (1.4 equiv.)
MeCN (0.125 M)
0℃ - rt, 15 min
R
O
O PPh
3
Br
Et
3
SiH (2 equiv.), MeCN (0.0714 M), rt, 6 h
Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (10 mol %)
R H
O
2
86
2.4.4 Experimental details and characterization data of aldehydes
Benzaldehyde
102
(2a)
The reaction was carried out according to the general procedure, using benzoic acid 1a (1 equiv,
0.25 mmol, 30.5 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol, 62.3
mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025 mmol,
7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2a as a colorless oil in 81% yield (21.6 mg).
1
H NMR (600 MHz,
Chloroform-d) d 10.00 (s, 1H), 7.86 (d, J = 7.0 Hz, 2H), 7.60 (t, J = 7.3 Hz, 1H), 7.51 (t, J = 7.6
Hz, 2H).
13
C NMR (151 MHz, Chloroform-d) δ 192.45, 136.41, 134.52, 129.78, 129.04.
4-Methylbenzaldehyde
102
(2b)
The reaction was carried out according to the general procedure, using 4-methylbenzoic acid 1b
(1 equiv, 0.25 mmol, 34 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2b as a colorless oil in 83% yield (24.9 mg).
1
H NMR (600 MHz,
Chloroform-d) δ 9.95 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.32 (d, J = 7.8 Hz, 2H), 2.43 (s, 3H).
13
C
NMR (151 MHz, Chloroform-d) δ 192.13, 145.65, 134.24, 129.94, 129.80, 21.98.
H
O
Me
H
O
87
4-Methoxybenzaldehyde
103
(2c)
The reaction was carried out according to the general procedure, using 4-methoxybenzoic acid 1c
(1 equiv, 0.25 mmol, 38 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4 mmol,
71.2 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2c as a colorless oil in 71% yield (24.1 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 9.84 (s, 1H), 7.79 (d, J = 8.9 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 3.84 (s, 3H).
13
C
NMR (101 MHz, Chloroform-d) δ 190.80, 164.64, 131.99, 129.98, 114.34, 55.60.
4-tert-Butylbenzaldehyde
103
(2d)
The reaction was carried out according to the general procedure, using 4-tert-butylbenzoic acid
1d (1 equiv, 0.25 mmol, 44.6 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35
mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash
column chromatography to afford 2d as a colorless oil in 78% yield (31.7 mg).
1
H NMR (400
MHz, Chloroform-d) δ 10.01(s, 1 H), 7.85 (d, J =8.5 Hz, 2 H), 7.59 (d, J = 8.5 Hz, 2 H), 1.41 (s,
9 H).
13
C NMR (101 MHz, Chloroform-d) δ 191.19, 158.55, 134.21, 129.91, 126.20, 35.46, 31.15.
HRMS-EI
+
m/z (% relative intensity) 162 (M+, 25), 148 (11), 147 (100), 119 (30), 91 (43), 77
(10).
MeO
H
O
t
Bu
H
O
88
4-Fluorobenzaldehyde
102
(2e)
The reaction was carried out according to the general procedure, using 4-fluorobenzoic acid 1e (1
equiv, 0.25 mmol, 35 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2e as a colorless oil in 70% yield (21.8 mg).
1
H NMR (600 MHz,
Chloroform-d) δ 9.97 (s, 1H), 7.95 – 7.87 (m, 2H), 7.24 – 7.18 (m, 2H).
13
C NMR (151 MHz,
Chloroform-d) δ 190.61, 166.68 (d,
1
JC-F = 256.9 Hz), 133.14 (d,
4
JC-F = 2.7 Hz), 132.38 (d,
3
JC-F
= 9.7 Hz), 116.51 (d,
2
JC-F = 22.3 Hz).
19
F NMR (564 MHz, Chloroform-d) δ -102.91 (m, 1F).
4-Bromobenzaldehyde
102
(2f)
The reaction was carried out according to the general procedure, using 4-bromobenzoic acid 1f (1
equiv, 0.25 mmol, 50.3 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4 mmol,
71.2 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2f as a white solid in 61% yield (28.3 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 9.98 (s, 1H), 7.75 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H).
13
C NMR (101
MHz, Chloroform-d) δ 191.19, 135.24, 132.61, 131.12, 129.94.
F
H
O
Br
H
O
89
Benzene-1,4-dicarboxaldehyde
104
(2g)
The reaction was carried out according to the general procedure, using 4-formylbenzoic acid 1g (1
equiv, 0.25 mmol, 37.5 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4 mmol,
71.2 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2g as a white solid in 65% yield (21.7 mg).
1
H NMR (500 MHz,
Chloroform-d) δ 10.13 (s, 0H), 8.05 (s, 1H).
13
C NMR (151 MHz, Chloroform-d) δ 191.62, 140.17,
130.27.
4-Acetylbenzaldehyde
105
(2h)
The reaction was carried out according to the general procedure, using 4-acetylbenzoic acid 1h (1
equiv, 0.25 mmol, 41 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4 mmol,
71.2 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2h as a white solid in 62% yield (23.1 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 10.10 (s, 1H), 8.09 (d, J = 8.2 Hz, 2H), 7.97 (d, J = 8.3 Hz, 2H), 2.65 (s, 3H).
13
C
NMR (101 MHz, Chloroform-d) δ 197.50, 191.71, 141.36, 139.19, 128.95, 27.10.
OHC
H
O
O
H
O
90
Methyl 4-formylbenzoate
106
(2i)
The reaction was carried out according to the general procedure, using mono-methyl terephthalate
1i (1 equiv, 0.25 mmol, 45 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35
mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The reaction time of the first step
was 18 min to form the acyloxyphosphonium ions. The residue was purified by flash column
chromatography to afford 2i as a white solid in 70% yield (28.8 mg).
1
H NMR (500 MHz,
Chloroform-d) δ 10.10 (s, 1H), 8.20 (d, J = 7.1 Hz, 2H), 7.95 (d, J = 7.0 Hz, 2H), 3.96 (s, 5H).
13
C
NMR (151 MHz, Chloroform-d) δ 191.77, 166.21, 139.31, 135.26, 130.35, 129.67, 52.72.
4-Formylbenzonitrile
107
(2j)
The reaction was carried out according to the general procedure, using 4-cyanobenzoic acid 1j (1
equiv, 0.25 mmol, 36.8 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2j as a white solid in 74% yield (24.4 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 10.08 (s, 1H), 7.99 (d, J = 8.6 Hz, 2H), 7.84 (d, J = 8.1 Hz, 2H).
13
C NMR (101
MHz, Chloroform-d) δ 190.72, 138.83, 132.99, 129.98, 117.81, 117.68.
MeO
O
H
O
NC
H
O
91
4-(Trifluoromethyl)benzaldehyde
107
(2h)
The reaction was carried out according to the general procedure, using 4-(trifluoromethyl)benzoic
acid 1h (1 equiv, 0.25 mmol, 47.5 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv,
0.35 mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash
column chromatography to afford 2h as a colorless oil in 72% yield (31.5 mg).
1
H NMR (400 MHz,
Chloroform-d): δ 10.14 (s, 1H), 8.14 (d, J = 8.2 Hz, 2H), 7.89 (d, J = 8.2 Hz, 2H).
13
C NMR (101
MHz, Chloroform-d): δ 191.17 (s), 138.89 (s), 135.76 (q, J = 32.9 Hz), 130.03 (s), 126.32 (q, J =
3.7 Hz), 123.62 (q, J = 273.9 Hz).
19
F NMR (376 MHz, Chloroform-d) δ -63.1 (s, 3F).
4-Acetamidobenzaldehyde
40
(2h)
The reaction was carried out according to the general procedure, using 4-acetamidobenzoic acid
1h (1 equiv, 0.25 mmol, 44.8 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4
mmol, 71.2 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash
column chromatography to afford 2h as a white solid in 51% yield (21 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 9.93 (s, 1H), 7.86 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 8.5 Hz, 2H), 2.24 (s, 3H).
13
C
NMR (101 MHz, Chloroform-d) δ 191.21, 168.90, 143.78, 132.84, 131.50, 119.87, 25.10.
F
3
C
H
O
N
H
O H
O
92
Biphenyl-4-carboxaldehyde
102
(2m)
The reaction was carried out according to the general procedure, using 4-phenylbenzoic acid 1m
(1 equiv, 0.25 mmol, 49.6 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35
mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash
column chromatography to afford 2m as a white solid in 72% yield (33 mg).
1
H NMR (500 MHz,
Chloroform-d) δ 10.07 (s, 1H), 7.96 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 7.0 Hz, 2H), 7.65 (d, J = 7.3
Hz, 2H), 7.52-7.47 (m, J = 7.2 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H).
13
C NMR (151 MHz, Chloroform-
d) δ 192.05, 147.36, 139.88, 135.37, 130.42, 129.16, 128.62, 127.84, 127.52.
3,5-Bis(trifluoromethyl) benzaldehyde
108
(2n)
The reaction was carried out according to the general procedure, using 3,5-
bis(trifluoromethyl)benzoic acid 1n (1 equiv, 0.25 mmol, 64.5 mg), PPh3 (1.3 equiv, 0.325 mmol,
85.2 mg), NBS (1.4 equiv, 0.35 mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg),
ligand P(4-FC6H4)3 (0.1 equiv, 0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The
residue was purified by flash column chromatography to afford 2n as a colorless oil in 74% yield
(44.7 mg).
1
H NMR (500 MHz, Chloroform-d) δ 10.01 (s, 1H), 8.21 (s, 2H), 8.01 (s, 1H).
13
C
NMR (151 MHz, Chloroform-d) δ 188.86, 137.34, 132.88 (q, J = 34.4 Hz, 2C), 129.28 (q, J = 3.2
H
O
F
3
C
CF
3
H
O
93
Hz, 2C), 127.34 (q, J = 3.4 Hz), 122.55 (q, J = 271.3 Hz, 2C).
19
F NMR (376 MHz, Chloroform-
d) δ -63.44 (s, 6F).
3-Methylbenzaldehyde
102
(2o)
The reaction was carried out according to the general procedure, using 3-methylbenzoic acid 1o
(1 equiv, 0.25 mmol, 34 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2o as a colorless oil in 87% yield (26.1 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 9.97 (s, 1H), 7.67-7.65 (m, 2H), 7.44-7.38 (m, 2H), 2.41 (s, 3H).
13
C NMR (101
MHz, Chloroform-d) δ 192.65, 138.97, 136.56, 135.35, 130.08, 128.94, 127.28, 21.23.
3-Methoxybenzaldehyde
102
(2p)
The reaction was carried out according to the general procedure, using 3-methoxybenzoic acid 1p
(1 equiv, 0.25 mmol, 38 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
Me
H
O
OMe
H
O
94
chromatography to afford 2p as a colorless oil in 89% yield (30.4 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 9.97 (s, 1H), 7.46-7.41 (m, 2H), 7.39 (d, J = 2.0 Hz, 1H), 7.25-7.15 (m, 1H), 3.86
(s, 3H).
13
C NMR (101 MHz, Chloroform-d) δ 192.53, 160.49, 138.18, 130.42, 123.91, 121.90,
112.38, 55.82.
2-Methylbenzaldehyde
109
(2q)
The reaction was carried out according to the general procedure, using 2-methylbenzoic acid 1q
(1 equiv, 0.25 mmol, 34 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2q as a colorless oil in 85% yield (25.6 mg).
1
H NMR (600 MHz,
Chloroform-d) δ 10.27 (s, 1H), 7.80 (d, J = 7.7 Hz, 1H), 7.48 (td, J = 7.5, 1.5 Hz, 1H), 7.36 (t, J =
7.5 Hz, 1H), 7.26 (d, J = 7.5 Hz, 1H), 2.67 (s, 3H).
13
C NMR (151 MHz, Chloroform-d) δ 190.67,
138.37, 132.05, 131.66, 130.04, 129.68, 124.26, 17.53.
2-(Trifluoromethyl)benzaldehyde
110
(2r)
The reaction was carried out according to the general procedure, using 2-(trifluoromethyl)benzoic
acid 1r (1 equiv, 0.25 mmol, 47.5 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv,
0.35 mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
Me
H
O
CF
3
H
O
95
0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The reaction time of the first step
was 15 min to form the acyloxyphosphonium ions. The residue was purified by flash column
chromatography to afford 2r as a pale yellow oil in 74% yield (32.4 mg).
1
H NMR (400 MHz,
Chloroform-d): δ 10.41 (s, 1H), 8.17 – 8.12 (m, 1H), 7.83 – 7.77 (m, 1H), 7.75 – 7.70 (m, 2H).
13
C
NMR (101 MHz, Chloroform-d): δ 189.14, 133.76, 132.43, 129.19, 126.21 (q, JC–F = 5.8 Hz),
125.16, 122.43.
2,5-Dimethylbenzaldehyde
111
(2t)
The reaction was carried out according to the general procedure, using 2,5-dimethylbenzoic acid
1t (1 equiv, 0.25 mmol, 37.5 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35
mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The reaction time of the first step
was 15 min to form the acyloxyphosphonium ions. The residue was purified by flash column
chromatography to afford 2t as a colorless oil in 89% yield (29.9 mg).
1
H NMR (400 MHz,
Chloroform-d): δ 10.26 (s, 1H, CHO), 7.62 (s, 1H, Ar-H), 7.30 (d, J = 7.7 Hz, 1H, Ar-H), 7.16 (d,
J = 7.7 Hz, 1H, Ar-H), 2.63 (s, 3H, CH3), 2.39 (s, 3H, CH3).
13
C NMR (101 MHz, Chloroform-d):
δ δ 192.93, 137.57, 136.03, 134.34, 134.12, 132.17, 131.73, 20.70, 18.96.
2-Naphthaldehyde
102
(2u)
Me
Me
H
O
H
O
96
The reaction was carried out according to the general procedure, using 2-naphthoic acid 1u (1
equiv, 0.25 mmol, 43 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The reaction time of the first step was 15
min to form the acyloxyphosphonium ions. The residue was purified by flash column
chromatography to afford 2u as a white solid in 86% yield (33.7 mg). For a 10 mmol (1.721 g)
scale reaction, the product was purified by flash column chromatography; obtained isolated 2u in
77% yield (1.20 g).
1
H NMR (600 MHz, Chloroform-d) δ 10.17 (s, 1H), 8.35 (s, 1H), 8.01 (d, J =
8.1 Hz, 1H), 7.99 – 7.89 (m, 3H), 7.66 – 7.58 (m, 2H).
13
C NMR (151 MHz, Chloroform-d) δ
192.37, 136.61, 134.67, 134.28, 132.80, 129.67, 129.25, 128.23, 127.24, 122.93.
3-Thiophenecarboxaldehyde
40
(2v)
The reaction was carried out according to the general procedure, using 3-thiophenecarboxylic acid
1v (1 equiv, 0.25 mmol, 32.1 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35
mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The reaction time of the first step
was 15 min to form the acyloxyphosphonium ions. The residue was purified by flash column
chromatography to afford 2v as a colorless oil in 86% yield (24.2 mg).
1
H NMR (400 MHz,
Chloroform-d): δ 9.94 (s, 1H), 8.14 (s, 1H), 7.55 (d, J = 5.1Hz, 1H), 7.39 (d, J = 5.1Hz, 1H).
13
C
NMR (101 MHz, Chloroform-d): δ 185.02, 143.02, 136.83, 127.44, 125.34.
S
H
O
97
3-Phenylpropanal
31
(2x)
The reaction was carried out according to the general procedure, using 3-phenylpropionic acid 1x
(1 equiv, 0.25 mmol, 37.6 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4 mmol,
71.2 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2x as a colorless oil in 50% yield (17.5 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 9.82 (s, 1 H, CHO), 7.31-7.28 (m, 2 H), 7.23-7.13 (m, 3 H), 2.96 (t, J = 7.5 Hz,
2 H), 2.78 (t, J = 7.5 Hz, 2 H).
13
C NMR (101 MHz, Chloroform-d) δ 201.67, 140.48, 128.76,
128.32, 126.39, 45.34, 28.21.
4-Phenylbutanal
112
(2x)
The reaction was carried out according to the general procedure, using 4-phenylbutyric acid 1y (1
equiv, 0.25 mmol, 41.1 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4 mmol,
71.2 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2y as a colorless oil in 55% yield (20.3 mg).
1
H NMR (400 MHz,
Chloroform-d) δ 9.72 (s, 1 H), 7.27-7.15 (m, 5 H), 2.63 (t, J = 7.5 Hz, 2 H), 2.41 (t, J = 7.5 Hz, 2
H), 1.93 (p, J = 7.4 Hz, 2 H).
13
C NMR (101 MHz, Chloroform-d) δ 202.25, 141.23, 128.64,
126.21, 43.23, 35.02, 23.61.
H
O
H
O
98
2,3-Dihydro-1H-indene-2-carbaldehyde
113
(2z)
The reaction was carried out according to the general procedure, using indan-2-carboxylic acid 1z
(1 equiv, 0.25 mmol, 40.5 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35
mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The reaction time of the first step
was 15 min to form the acyloxyphosphonium ions. The residue was purified by flash column
chromatography to afford 2z as a colorless oil in 59% yield (21.7 mg).
1
H NMR (400 MHz,
Chloroform-d): δ 9.80 (s, 1H), 7.27 – 7.23 (m, 2H), 7.22 – 7.15 (m, 2H), 3.36 – 3.25 (m, 3H), 3.26
– 3.16 (m, 2H).
13
C NMR (101 MHz, Chloroform-d): δ 202.79, 141.01, 126.79, 124.66, 50.68,
33.03.
4-formyl-N,N-dipropylbenzenesulfonamide
48
(2aa)
The reaction was carried out according to the general procedure, using probenecid 1aa (1 equiv,
0.25 mmol, 71.3 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4 mmol, 71.2
mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025 mmol,
7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2aa as a white solid in 70% yield (46.9 mg).
1
H NMR (600 MHz,
Chloroform-d) δ 10.09 (s, 1H), 8.02 – 7.95 (m, 4H), 3.14 – 3.10 (m, 4H), 1.55 (dq, J = 14.9, 7.4
O
H
S
N
Me
O O
O
H
Me
99
Hz, 4H), 0.87 (t, J = 7.4 Hz, 6H).
13
C NMR (151 MHz, Chloroform-d) δ 191.04, 145.68, 138.66,
130.27, 127.77, 50.05, 22.07, 11.27.
6-(4-Methoxy-3-tricyclo[3.3.1.1
3,7
]dec-1-ylphenyl)-2-naphthalenecarboxaldehyde
114
(2dd)
The reaction was carried out according to the general procedure, using adapalene 1dd (1 equiv,
0.25 mmol, 103.1 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4 mmol, 71.2
mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025 mmol,
7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified by flash column
chromatography to afford 2dd as a white solid in 74% yield (72.9 mg).
1
H NMR (500 MHz,
Chloroform-d) δ 10.12 (s, 1H), 8.31 (s, 1H), 8.00 (t, J = 3.2 Hz, 2H), 7.93 (s, 2H), 7.82 (dd, J =
7.6 & 3.2 Hz, 1H), 7.58 (d, J = 3.2 Hz, 1H), 7.51 (dd, J = 7.7 & 3.1 Hz, 1H), 6.96 (d, J = 7.6 Hz,
1H), 3.88 (s, 3H), 2.16 (br, 6H), 2.07 (br, 3H), 1.77 (br, 6H).
13
C NMR (151 MHz, Chloroform-d)
δ 192.1, 159.1, 142.3, 139.1, 136.9, 134.3, 133.7, 132.3, 131.3, 129.9, 129.1, 126.8, 126.0, 125.8,
125.0, 123.2, 112.1, 55.2, 40.6, 37.1, 29.1.
O
O
Me
H
100
(8R,9S,13S,14S)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-
cyclopenta[a]phenanthrene-3-carbaldehyde
47
(2ee)
The reaction was carried out according to the general procedure, using 3-deoxyestrone-3-
carboxylic acid 1ee (1 equiv, 0.25 mmol, 74.6 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS
(1.6 equiv, 0.4 mmol, 71.2 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3
(0.1 equiv, 0.025 mmol, 7.9 mg), and Et3SiH (2 equiv, 0.5 mmol, 80 µL). The residue was purified
by flash column chromatography to afford 2ee as a white solid in 81% yield (57.2 mg).
1
H NMR
(600 MHz, Chloroform-d) δ 9.95 (s, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.61 (s, 1H), 7.47 (d, J = 8.0
Hz, 1H), 3.07 – 2.94 (m, 2H), 2.56 – 2.42 (m, 2H), 2.37 - 2.32 (m, 1H), 2.21 – 2.12 (m, 1H), 2.11
– 2.02 (m, 2H), 1.99-1.96 (m, 1H), 1.68 – 1.43 (m, 6H), 0.92 (s, 3H).
13
C NMR (151 MHz,
Chloroform-d) δ 220.41, 192.26, 147.10, 137.52, 134.29, 130.23, 127.25, 126.07, 50.55, 47.87,
44.89, 37.76, 35.81, 31.55, 29.19, 26.19, 25.59, 21.61, 13.82.
2.4.5 Scale up procedure for the preparation of 2u
2-Naphthaldehyde
102
(2u)
For a 10 mmol gram scale reaction, the reaction was carried out according to the general procedure,
using 2-naphthoic acid 1u (1 equiv, 10 mmol, 1.721 g), PPh3 (1.3 equiv, 13 mmol, 3.410 g), NBS
H
H
Me
H
O
O
H
H
O
101
(1.4 equiv, 14 mmol, 2.492 g), Pd(OAc)2 (0.05 equiv, 0.5 mmol, 112 mg), ligand P(4-FC6H4)3 (0.1
equiv, 1 mmol, 316 mg), and Et3SiH (2 equiv, 20 mmol, 3.2 mL). The residue was purified by
flash column chromatography to afford 2u as a white solid in 77% yield (1.20 g).
1
H NMR (600
MHz, Chloroform-d) δ 10.17 (s, 1H), 8.35 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.99 – 7.89 (m, 3H),
7.66 – 7.58 (m, 2H).
13
C NMR (151 MHz, Chloroform-d) δ 192.37, 136.61, 134.67, 134.28, 132.80,
129.67, 129.25, 128.23, 127.24, 122.93.
2.4.6 Additional carboxylic acids tested
Additional substrates were tested under the reaction condition according to the general procedure,
including more heteroaromatic carboxylic acid derivatives and trans-cinnamic acid dervatives.
Yield was determined by GC analysis using acetophenone as internal standard.
H
O
HO
H
O
H
O
H
O
N
H
O
N
H
O
N
H
O
H
O
H
O
N
H
H
O
N
Me
H
O
N
Me
H
O
N
Me
H
O
Cl
O
2
N
O
2
N
NO
2
16% 14% 0% 30%
0% 0% 13% 8%
0% 0% 5% 32% 18%
R
O
OH R H
O
2. Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (10 mol %)
Et
3
SiH (2 equiv.), MeCN (0.0714 M), rt, 6 h
1. PPh
3
(1.3 equiv.), NBS (1.4 equiv.)
MeCN (0.125 M), 0℃ - rt, 15 min
102
2.4.7 Experimental details and characterization data of deuterated aromatic aldehydes
Benzaldehyde-1-d1 (4a)
The reaction was carried out according to the general procedure, using 3,5- benzoic acid 1a (1
equiv, 0.25 mmol, 30.5 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiD (2 equiv, 0.5 mmol, 80 µL). The residue was worked up following the
general procedure for optimization of reaction conditions to afford 4a in GC yield of 80%.
4-(Trifluoromethyl)benzaldehyde-formyl-d1 (4k)
The reaction was carried out according to the general procedure, using 4-(trifluoromethyl)benzoic
acid 1k (1 equiv, 0.25 mmol, 47.5 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv,
0.35 mmol, 62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv,
0.025 mmol, 7.9 mg), and Et3SiD (2 equiv, 0.5 mmol, 80 µL). The residue was worked up
following the general procedure for optimization of reaction conditions to afford 4k in GC yield
of 73%.
R
O
OH
1
PPh
3
(1.3 equiv.)
NBS (1.4 equiv.)
MeCN (0.125 M)
0℃ - rt, 15 min
R
O
O PPh
3
Br
Et
3
SiD (2 equiv.), MeCN (0.0714 M), rt, 6 h
Pd(OAc)2 (5 mol %) / P(4-FC6H4)3 (10 mol %)
R D
O
4
D
O
F
3
C
D
O
103
3-Methoxybenzaldehyde-formyl-d1 (4p)
The reaction was carried out according to the general procedure, using 3-methoxybenzoic acid 1p
(1 equiv, 0.25 mmol, 38 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiD (2 equiv, 0.5 mmol, 80 µL). The residue was worked up following the
general procedure for optimization of reaction conditions to afford 4p in GC yield of 85%.
Benzene-1,4-dicarboxaldehyde-d1 (4g)
The reaction was carried out according to the general procedure, using 4-formylbenzoic acid 1g (1
equiv, 0.25 mmol, 43 mg), PPh3 (1.5 equiv, 0.375 mmol, 98.4 mg), NBS (1.6 equiv, 0.4 mmol,
71.2 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiD (2 equiv, 0.5 mmol, 80 µL). The residue was worked up following the
general procedure for optimization of reaction conditions to afford 4g in GC yield of 60%.
2-Naphthaldehyde-formyl-d1 (4u)
OMe
D
O
OHC
D
O
D
O
104
The reaction was carried out according to the general procedure, using 2-naphthoic acid 1u (1
equiv, 0.25 mmol, 43 mg), PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg), NBS (1.4 equiv, 0.35 mmol,
62.3 mg), Pd(OAc)2 (0.05 equiv, 0.0125 mmol, 2.8 mg), ligand P(4-FC6H4)3 (0.1 equiv, 0.025
mmol, 7.9 mg), and Et3SiD (2 equiv, 0.5 mmol, 80 µL). The residue was worked up following the
general procedure for optimization of reaction conditions to afford 4u in GC yield of 85%.
2.4.8 Mechanistic investigation
The reaction active intermediate species were identified by NMR spectroscopic studies and GC-
MS analysis. Two control experiments were investigated to obtain insight into the mechanistic
pathway of the transformation for our methodology. At the same time, the GC-MS results of the
completed reaction mixture were also discussed and shown as below.
Control experiment 1
On the bench-top, a solution of triphenylphosphine, PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg) and
dry acetonitrile, MeCN (2.5 mL) was charged into an oven-dried screw-cap vial equipped with a
magnetic stir bar. Then, This solution was cooled to 0 ºC using an brine ice-bath. Subsequently,
N-bromosuccinimide, NBS (1.4 equiv, 0.35 mmol, 62.3 mg) was quickly added 0 ºC. After stirring
for 2-3 min, an vigorous color change was observed followed by fast taking an aliquot (1 mL) of
the reaction mixture for unlock NMR analysis. The following
31
P NMR spectrum displayed one
P
Ph
Ph
Ph + N
O
O
Br
MeCN (0.1 M)
Br P
Ph
Ph
Ph
N
O
O
A
bromophosphonium ion
105
signal at δ 31.43. This peak has been assigned to bromophosphonium ion A in the scheme above.
Compared to former reported results from our group
62
, we didn’t see the formation of OPPh3 since
our solution was pretty dry and fresh.
Control experiment 2
-40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 110
f1 (ppm)
0
10
20
30
40
50
60
70
80
90
100
3 1 . 4 3
3 1
P N M R ( 162 M H z , u nl o c k)
P
Ph
Ph
Ph + N
O
O
Br
MeCN (0.1 M) O P
Ph
Ph
Ph
PhCOOH
+
Ph
O
Br
I
acyloxyphosphonium ion
106
In a separate experiment, a solution of benzoic acid 1a (0.25 mmol, 30.5 mg), triphenylphosphine,
PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg) and dry acetonitrile, MeCN (2.5 mL) was charged into an
oven-dried screw-cap vial equipped with a magnetic stir bar. Then, This solution was cooled to 0
ºC using an brine ice-bath. Subsequently, N-bromosuccinimide, NBS (1.4 equiv, 0.35 mmol, 62.3
mg) was quickly added 0 ºC. After stirring for 5-10 min, an vigorous color change was observed
followed by fast taking an aliquot (1 mL) of the reaction mixture for unlock NMR analysis. . The
following
31
P NMR spectrum displayed two signal at δ 31.43 and δ 43.53. Since the peak at δ
31.43 has been assigned to bromophosphonium ion A, the new peak at δ 43.53 can be demonstrated
as the acyloxyphosphonium ion I which were newly formed in the scheme above. Those two
peaks are both close to the former reported results by our group
62
where anhydrous DCM was used
as the solvent instead of MeCN.
-40 -30 -20 -10 0 10 20 30 40 50 60 70 80 90 100 110
f1 (ppm)
5
10
15
20
25
30
35
40
45
50
55
60
65
70
3 1 . 4 3
4 3 . 5 3
20 30 40 50
f1 (ppm)
20
40
60
80
3 1 . 4 3
4 3 . 5 3
31P N M R ( 162 M H z , un l oc k )
107
GC-MS analysis
In a separate experiment, a solution of benzoic acid 1a (0.25 mmol, 30.5 mg), triphenylphosphine,
PPh3 (1.3 equiv, 0.325 mmol, 85.2 mg) and dry acetonitrile, MeCN (2 mL) was charged into an
oven-dried screw-cap vial equipped with a magnetic stir bar. Then, This solution was cooled to 0
ºC using an brine ice-bath. Subsequently, N-bromosuccinimide, NBS (1.4 equiv, 0.35 mmol, 62.3
mg) was quickly added 0 ºC. Then, the ice-bath was removed, and this solution was further stirred
for 15 min. Once the 15 min completed, the reaction mixture in the screw-cap vial was transferred
into the crimp vial with [Pd] catalyst solution and rinsed with MeCN (0.5 mL), followed quickly
by adding triethylsilane, Et3SiH (2 equiv, 0.5 mmol, 80 µL) via Hamilton syringe under a stream
of N2 using Schlenk line. The reaction mixture was stirred at r.t. for 6 h. After completion, the vial
was then opened, and the reaction mix was quenched with sat. aq. NaHCO3 (~5 mL) and extracted
with EtOAc (3 x 10 mL). The combined organic layers were dried over MgSO4, then the organic
layer was analyzed by GC-MS. The following GC-MS results indicated the formation of the
benzaldehyde at 5.3 min as the desired product as well as the formation of triphenylphosphine
oxide (O=PPh3) at 17.2 min.
Ph
O
OH
1a
PPh
3
(1.3 equiv.)
NBS (1.4 equiv.)
MeCN (0.125 M)
0℃ - rt, 15 min
Ph
O
O PPh
3
Br
Et
3
SiH (2 equiv.)
MeCN (0.0714 M), rt, 6 h
Pd(OAc)2 (5 mol %)
P(4-FC6H4)3 (10 mol %)
Ph H
O
2a
+
O=PPh
3
108
109
110
2.4.9 Synthesis of starting materials
Following a reported procedure
47
, Step 1. Pyridine (10.0 mmol, 2.0 equiv) was added to a stirred
solution of estrone (5.0 mmol, 1.0 equiv) in DCM (25 mL) under Ar. Following that, triflic
anhydride (6.0 mmol, 1.2 equiv) was added dropwise to the mixture in ice bath. The mixture was
slowly warmed to r.t. and stirred for another 5 h. Water was used to quench the reaction. After
organic layer separation, the aqueous phase was extracted with DCM (30 mL x 3). The combined
organic phase was washed with brine, dried over sodium sulfate, filtered, and evaporated under
reduced pressure to afford the corresponding crude product.
Step 2: Pd(OAc)2 (0.25 mmol, 5 mol %), 1,1′-bis(diphenylphosphino) ferrocene (1 mmol, 20
mol %), and potassium acetate (20 mmol, 4 equiv) were mixed with the crude compound in DMSO
(50 mL). The reaction mixture was stirred at 60 °C under a balloon filler with CO overnight. The
reaction mixture was then cooled to room temperature, then quenched with 1 M HCl, and extracted
with EtOAc (50 mL x 3). The combined organic phase was washed with brine, dried over sodium
sulfate, filtered, and evaporated under reduced pressure to afford the crude carboxylic acid. The
carboxylic acid was purified by column chromatography on silica gel.
H
H
Me
H
O
HO
H
H
Me
H
O
O
HO
1. Py (2.0 equiv), Tf
2
O (1.2 equiv)
DCM (0.2 M), 0℃ - rt, 5 h
2. CO, Pd(OAc)2 (5 mol %) / dppf (20 mol %)
KOAc (4 equiv.), DMSO (0.1 M), 60℃, 16 h
111
2.4.10 Copies of NMR spectra
1
H NMR and
13
C NMR of Benzaldehyde (2a)
-2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
2 . 0 6
1 . 0 3
2 . 0 3
1 . 0 0
7 . 5 0
7 . 5 1
7 . 5 2
7 . 6 0
7 . 6 1
7 . 6 2
7 . 8 5
7 . 8 7
1 0 . 0 0
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
0
1000
2000
3000
4000
5000
6000
7000
8000
1 2 9 . 0 4
1 2 9 . 7 8
1 3 4 . 5 2
1 3 6 . 4 1
1 9 2 . 4 5
112
1
H NMR and
13
C NMR of 4-Methylbenzaldehyde (2b)
-2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0
f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
3 . 1 9
2 . 0 3
2 . 0 3
1 . 0 0
2 . 4 3
7 . 3 1
7 . 3 3
7 . 7 6
7 . 7 7
9 . 9 5
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
0
500
1000
1500
2000
2500
3000
3500
4000
2 1 . 9 8
1 2 9 . 8 0
1 2 9 . 9 4
1 3 4 . 2 4
1 4 5 . 6 5
1 9 2 . 1 3
113
1
H NMR and
13
C NMR of 4-Methoxybenzaldehyde (2c)
-1.5 -0.5 0.5 1.5 2.5 3.5 4.5 5.5 6.5 7.5 8.5 9.5 10.5 11.5 12.5 13.5
f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
3 . 2 5
2 . 0 0
2 . 0 0
1 . 0 0
3 . 8 4
6 . 9 5
6 . 9 7
7 . 7 8
7 . 8 1
9 . 8 4
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-100000
0
100000
200000
300000
400000
500000
600000
700000
800000
900000
1000000
1100000
1200000
1300000
1400000
1500000
1600000
1700000
1800000
1900000
2000000
5 5 . 6 0
1 1 4 . 3 4
1 2 9 . 9 8
1 3 1 . 9 9
1 6 4 . 6 4
1 9 0 . 8 0
114
1
H NMR,
13
C NMR and
19
F NMR of 4-Fluorobenzaldehyde (2e)
-2.0 -1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
2 . 0 0
2 . 0 1
1 . 0 0
7 . 2 0
7 . 2 0
7 . 2 2
7 . 2 3
7 . 2 3
7 . 9 0
7 . 9 0
7 . 9 0
7 . 9 1
7 . 9 1
7 . 9 1
7 . 9 2
7 . 9 2
7 . 9 2
7 . 9 3
9 . 9 7
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-40
-20
0
20
40
60
80
100
120
140
160
180
200
220
240
260
280
300
320
340
360
380
400
420
440
460
480
500
520
1 1 6 . 4 4
1 1 6 . 5 8
1 3 2 . 3 4
1 3 2 . 4 1
1 3 3 . 1 3
1 3 3 . 1 4
1 6 5 . 8 3
1 6 7 . 5 4
1 9 0 . 6 1
115
19
F NMR of 3,5-Bis(trifluoromethyl) benzaldehyde (2n)
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
-2000
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
15000
16000
17000
18000
19000
20000
- 1 0 2 . 9 1
-200 -190 -180 -170 -160 -150 -140 -130 -120 -110 -100 -90 -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 30
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
6500
7000
7500
- 6 3 . 4 4
116
1
H NMR and
13
C NMR of 4-Bromobenzaldehyde
102
(2f)
-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0
f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
15000
16000
17000
18000
2 . 0 1
2 . 0 1
1 . 0 0
7 . 6 8
7 . 7 0
7 . 7 4
7 . 7 6
9 . 9 8
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-10000
0
10000
20000
30000
40000
50000
60000
70000
80000
90000
100000
110000
120000
130000
1 2 9 . 9 4
1 3 1 . 1 2
1 3 2 . 6 1
1 3 5 . 2 4
1 9 1 . 1 9
117
1
H NMR and
13
C NMR of Benzene-1,4-dicarboxaldehyde (2g)
-2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
4 . 1 8
2 . 0 0
8 . 0 5
1 0 . 1 3
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
1 3 0 . 2 7
1 4 0 . 1 7
1 9 1 . 6 2
118
1
H NMR and
13
C NMR of 4-Acetylbenzaldehyde (2h)
-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5
f1 (ppm)
0
500
1000
1500
2000
2500
3000
3500
4000
4500
3 . 2 0
2 . 0 1
2 . 0 2
1 . 0 0
2 . 6 5
7 . 9 6
7 . 9 8
8 . 0 8
8 . 1 0
1 0 . 1 0
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
0
50000
100000
150000
200000
250000
300000
350000
400000
2 7 . 1 0
1 2 8 . 9 5
1 2 9 . 9 5
1 3 9 . 1 9
1 4 1 . 3 6
1 9 1 . 7 1
1 9 7 . 5 0
119
1
H NMR and
13
C NMR of Methyl 4-formylbenzoate (2i)
-2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
6500
7000
7500
8000
3 . 5 5
2 . 3 4
2 . 0 0
1 . 0 0
3 . 9 6
7 . 9 5
7 . 9 6
8 . 1 9
8 . 2 0
1 0 . 1 0
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-200
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2100
5 2 . 7 2
1 2 9 . 6 7
1 3 0 . 3 5
1 3 5 . 2 6
1 3 9 . 3 1
1 6 6 . 2 1
1 9 1 . 7 7
120
1
H NMR and
13
C NMR of 4-Formylbenzonitrile (2j)
-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0
f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
2 . 0 0
2 . 1 0
1 . 0 0
7 . 8 3
7 . 8 5
7 . 9 8
8 . 0 0
1 0 . 0 8
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
0
50000
100000
150000
200000
250000
300000
350000
400000
450000
1 1 7 . 6 8
1 1 7 . 8 1
1 2 9 . 9 8
1 3 2 . 9 9
1 3 8 . 8 3
1 9 0 . 7 2
121
1
H NMR and
13
C NMR of Biphenyl-4-carboxaldehyde (2m)
-2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0
f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
1 . 0 0
2 . 1 2
2 . 1 1
2 . 1 2
2 . 0 7
1 . 0 0
7 . 4 1
7 . 4 2
7 . 4 4
7 . 4 8
7 . 4 9
7 . 5 0
7 . 6 4
7 . 6 5
7 . 7 6
7 . 7 7
7 . 9 5
7 . 9 7
1 0 . 0 7
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-300
-200
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
2000
2100
2200
2300
1 2 7 . 5 2
1 2 7 . 8 4
1 2 8 . 6 2
1 2 9 . 1 6
1 3 0 . 4 2
1 3 5 . 3 7
1 3 9 . 8 8
1 4 7 . 3 6
1 9 2 . 0 5
122
1
H NMR and
13
C NMR of 3-Methylbenzaldehyde (2o)
-1.5 -1.0 -0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0 12.5 13.0 13.5 14.0
f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
15000
16000
17000
18000
19000
3 . 3 1
2 . 0 2
1 . 9 7
1 . 0 0
2 . 4 1
7 . 3 8
7 . 3 8
7 . 4 0
7 . 4 0
7 . 4 1
7 . 4 2
7 . 4 2
7 . 4 3
7 . 4 4
7 . 6 5
7 . 6 5
7 . 6 6
7 . 6 7
7 . 6 7
9 . 9 7
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-100000
0
100000
200000
300000
400000
500000
600000
700000
800000
900000
1000000
1100000
2 1 . 2 3
1 2 7 . 2 8
1 2 8 . 9 4
1 3 0 . 0 8
1 3 5 . 3 5
1 3 6 . 5 6
1 3 8 . 9 7
1 9 2 . 6 5
123
1
H NMR and
13
C NMR of 2-Methylbenzaldehyde (2q)
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
6500
7000
7500
4 . 0 7
2 . 0 3
0 . 9 8
1 . 1 7
1 . 0 2
1 . 0 0
2 . 6 7
7 . 2 6
7 . 2 7
7 . 3 5
7 . 3 6
7 . 3 7
7 . 4 6
7 . 4 6
7 . 4 7
7 . 4 8
7 . 4 9
7 . 4 9
7 . 7 9
7 . 8 0
1 0 . 2 7
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-400000
-200000
0
200000
400000
600000
800000
1000000
1200000
1400000
1600000
1800000
2000000
2200000
2400000
2600000
2800000
2 0 . 7 5
1 2 6 . 8 0
1 2 8 . 4 6
1 2 9 . 6 0
1 3 4 . 8 7
1 3 6 . 0 8
1 3 8 . 5 0
1 9 2 . 1 7
124
1
H NMR and
13
C NMR of 2-Naphthaldehyde (2u)
-2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0
f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
13000
14000
15000
1 . 0 2
0 . 9 9
3 . 0 6
1 . 0 1
1 . 0 4
1 . 0 0
7 . 5 8
7 . 5 8
7 . 5 9
7 . 6 0
7 . 6 0
7 . 6 1
7 . 6 1
7 . 6 4
7 . 6 4
7 . 6 5
7 . 6 5
7 . 6 6
7 . 6 6
7 . 9 0
7 . 9 2
7 . 9 3
7 . 9 5
7 . 9 6
7 . 9 6
7 . 9 7
7 . 9 7
8 . 0 1
8 . 0 2
8 . 3 5
1 0 . 1 7
121.0 122.0 123.0 124.0 125.0 126.0 127.0 128.0 129.0 130.0 131.0 132.0 133.0 134.0 135.0 136.0 137.0 138.0
f1 (ppm)
-200
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1900
1 2 2 . 9 3
1 2 7 . 2 4
1 2 8 . 2 3
1 2 9 . 2 5
1 2 9 . 2 5
1 2 9 . 6 7
1 3 2 . 8 0
1 3 4 . 2 8
1 3 4 . 6 7
1 3 6 . 6 1
125
1
H NMR and
13
C NMR of 4-Formyl-N,N-dipropylbenzenesulfonamide (2aa)
-2.0 -1.0 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 11.0 12.0 13.0 14.0
f1 (ppm)
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
A (s)
10.09
C (m)
3.11
D (dq)
1.55
E (t)
0.87
B (m)
7.99
6.05
3.70
3.92
4.14
1.00
0 . 8 5
0 . 8 7
0 . 8 8
1 . 5 2
1 . 5 3
1 . 5 4
1 . 5 6
1 . 5 7
1 . 5 8
3 . 1 0
3 . 1 1
3 . 1 3
7 . 9 6
7 . 9 6
7 . 9 7
7 . 9 7
8 . 0 0
8 . 0 0
8 . 0 0
8 . 0 1
8 . 0 1
8 . 0 1
8 . 0 1
1 0 . 0 9
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000
3200
1 1 . 2 7
2 2 . 0 7
5 0 . 0 5
1 2 7 . 7 7
1 3 0 . 2 7
1 3 8 . 6 6
1 4 5 . 6 8
1 9 1 . 0 4
126
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133
Chapter 3. ipso-Nitration of Arylsilanes
3.1 Introduction
At the beginning of the 19
th
century, the chemistry of nitro compounds began and has
vigorously blossomed together with organic and synthetic chemistry over the last century.
Meanwhile, a variety of properties and applications of nitro groups has been elucidated.
1
Figure 3.1 Selected biologically active nitro compounds.
Nitro-containing compounds particularly nitroarenes have been considered as versatile
constituents because of their broad range of applications in the synthesis of plastics, dyes, perfumes,
pesticides, polymers, agrochemicals, energetic materials, industrial chemicals, and
O
2
N
OH
OH
HN
O
Cl
Cl
N
H
NO
2
N
N
O
O
Me
Me
R
OH
O
2
N
O
O
Me
Me
OMe
O
O
O
NH
O
2
N
Cl Cl
Cl
Cl
H
N
H
N
NO
2
Me
O
O
Me
O
Me
O
2
N
Me Me Me
O
Chloramphenicol
(antibiotic for treating
bacterial infections)
Thaxtomin A: R = OH
Thaxtomin B: R = H
(natural products)
Orinocin
(natural product)
Dioxapyrrolomycin
(natural product)
Azomycin
(macrolide-type antibiotic for
treating bacterial infections)
Neoaureothin
(antibiotic for treating
bacterial infections)
O F
3
C NO
2
NO
2
O O
O
2
N
N
NO
2
H
3
C
Fluorodifen
(pesticide)
6-Nitro coumarin
(antifungal activity)
7-Methyl-8-nitroquinoline
(anticancer, antiallergic agents
for treating Alzheimer’s disease)
134
pharmaceuticals (Figure 3.1).
2–8
Nitroaromatic compounds are also key materials for the
development of mechanistic concepts.
9
Moreover, these nitro compounds have played a vital role
in various organic transformations since the synthetic versatility of the nitro group makes them
valuable building blocks, lead compounds, and important intermediates.
10–19
For instance, the
transition-metal-catalyzed reductive coupling reactions of nitro compounds with alcohols or
alkenes afford concise approaches to prepare amines. Besides, the direct utilization of nitroarenes
with transition-metal-catalyzed denitrative cross coupling reactions has attracted lot of attention in
recent years, and has been extensively studied because of their potential to atom- and step-
economy processes in synthetic and medicinal chemistry (Figure 3.2).
20
In this context, the
nitration of organic compounds (aliphatic, aromatic, and heterocyclic) to prepare nitro compounds
has been extensively explored as one of the most attractive reactions in the organic chemistry
community.
21–25
Figure 3.2 Aromatic nitro compounds used as an essential building block in
synthetic organic chemistry via denitrative reaction of nitroarens.
Traditional preparation of aromatic nitro compounds
Traditionally, the method for the synthesis of nitroarenes is the direct electrophilic aromatic
substitution of the arenes. For the electrophilic nitration process, the nitronium ion (NO2
+
) is
NO
2
H
N
R
R
R
R
OR
SR
S
O
O
Ar
135
generated usually from the strongly oxidizing mixed acids (HNO3/H2SO4) or a mixture of
concentrated HNO3 and dinitrogen pentoxide as the nitrating agents. Apart from mixed acid
systems, different nitronium salts has been studied and tested as effective nitration agents, as well
as the nitration methods employing metalation (mercuration, palladation, thallation, and others).
22
Besides, a wide variety of electrophilic nitration reagents are available to date.
26
These approaches,
however, often lead to further nitration and the mixture of isomers due to the use of excess strong
nitrating agents. Oxidation of other functional groups also occurs resulting in the formation of
various undesired by-products since most of these nitrating agents are reactive oxidants. Because
of these disadvantages, the traditional strategy of electrophilic aromatic nitration suffers from poor
regioselectivity and limited functional group compatibility. Therefore, the development of
efficient and novel methods for the regioselective syntheses of nitroarenes under mild reaction
conditions is of substantial practical interest (Scheme 3.1), albeit efforts have been made to
improve the traditional nitration protocol by modifying nitrating agents.
Scheme 3.1 Recent advances of nitration protocols for the synthesis of aromatic nitro compounds.
NO
2
N
3
NH
2
H
H
B(OH)
2
Li/Sn
COOH
X
DG
X = I, Br, Cl, OTf, ONf
Metal nitrates
or Metal-free
Nitrating agents
C(NO
2
)
4
/N
2
O
4
HNO
3
/AlBN
/[DSim]NO
3
Pd/Cu Cat.
MNO
2
(M = Na, K, nBu
4
N)
Oxidation
HNO
3
/H
2
SO
4
Electrophilic
nitration
Pd/Cu Cat.
AgNO
2
/AgNO
3
R
R
R
R
R
R
R
R
HOF•MeCN
DG = directing group
136
Recent syntheses of aromatic nitro compounds
To overcome these drawbacks, the direct oxidation of aromatic primary amines to nitroarene
products has significant potential for fundamental synthesis and industrial applications.
27–34
The
regiospecific problems can also be circumvented by the widely explored regioselective syntheses
of nitroarenes employing ipso-nitration of organometallic compounds through nitro-
demetallation,
35,36
aryl halides (including pseudohalides) using palladium or copper catalysts,
37–41
aryl carboxylic acids through nitro-decarboxylation, and most commonly ipso-nitration of
arylboronic acids with diverse nitrating agents.
25
Moreover, transitional-metal-catalyzed direct
C(sp
2
)-H nitration reactions of aromatic hydrocarbons for nitroarenes preparation and for gaining
mechanistic insights have also been widely investigated.
12,42
Nitro compounds can also be
synthesized in moderate yields upon oxidation of aromatic azides in the presence of a HOF·MeCN
system with extraordinary regioselectivity.
43
Figure 3.3 Difference between ipso-nitration and classical ordinary nitration.
ipso-Nitration of arenes
Over the past decade, the ipso-nitration reaction has emerged as an efficient and practical
alternative to the classical electrophilic nitration reaction for the synthesis of aromatic nitro
compounds.
38
Reaction of a nitro group replacing the leaving functional groups such as alkyls,
acyls, hydroxyl, esters, carboxylic acids, sulfonic acids, boronic acids, halogens and so on that are
H
FG
NO
2
FG
H
NO
2
Traditional Nitration
ipso-Nitration
FG = functional group
137
attached to aliphatic chains or aromatic rings using a nitrating system is called ipso-nitration.
Figure 3.3 clearly displays the main differences between ipso-nitration and traditional nitration.
25
Perrin and Skinner
44
initially reported this kind of aromatic nitration reaction as ipso-
substitution in 1971. The mechanistic studies on nitronium salts as well as the nitration of aromatic
compounds reported by Olah et al.
45
and Ingold et al.
46
demonstrated the significance of ipso-
nitration, revealing the subsequent intramolecular migration pathway. It was also reported that
nitration using the mixture of nitric acid and sulfuric acid provided substantial amounts of ipso-
nitration products for both ortho-cymene and para-diisopropylbenzene.
47–49
Additionally,
dealkylative ipso-nitration products were discovered by Olah
50
and Myhre
51
in varying yields
along with the common ortho- and para- nitro products from the nitration of alkylbenzene utilizing
nitronium tetrafluoroborate (NO2
+
BF4
-
) with sulfolane. Significantly, Olah’s group reported the
first direct observation of stable and long-lived nitroarenium ion intermediates formed during the
nitration of hexamethylbenzene and trifluoromesitylene at low temperature using NO2
+
BF4
-
with
superacid, experimentally demonstrating the electrophilic ipso-substitution reactions (Scheme
3.2).
52
Scheme 3.2 Formation of nitroarenium ion intermediates at low temperature during
aromatic nitration with NO2
+
BF4
-
in superacidic medium.
H
3
C
R
CH
3
R R
CH
3
H
3
C
R
CH
3
R R
H
3
C NO
2
+ NO
2
+
BF
4
-
FSO
3
H-SO
2
-70 °C
R = CH
3
, F
R = CH
3
, F
138
Furthermore, evidence of ipso attack in electrophilic aromatic nitration by protonated methyl
nitrate (CH3OH-NO2
+
) has also been investigated in the gas phase by Fourier transform ion
cyclotron resonance (FT-ICR), collisional activated dissociation (CAD) mass spectrometry and
radiolytic technique.
53
When it comes to electron-deficient arenes such as haloarenes, ipso attack
of nucleophilic aromatic substitution involving Meisenheimer intermediates occurs upon nitration
reaction using nitrite salts to provide nitro aromatic derivatives.
54
Correspondingly, the mechanism
of nucleophilic ipso-nitration was established by the formation of diaryl halonium ions using
sodium nitrite by McEwen, and Olah et al. respectively.
55,56
In addition to the mechanism involving
nitronium cation (NO2
+
) or nitronium anion (NO2
-
), ipso-nitration reaction can also be carried out
through homolytic nitration by employing nitrogen dioxide radical (·NO2), affording a powerful
strategy to access nitro aromatic compounds (Scheme 3.3).
24,57
For instance, Hodgson et al.
prepared nitroarenes by conducting Cu(I)-catalyzed dediazoniation of arenediazonium salts
followed by replacement with a nitro group under neutral or alkaline solution.
38
Scheme 3.3 ipso-Nitration for the synthesis of nitroarenes and nitroolefins using a nitro
radical through homolytic reactions.
With energetic development and insightful apprehension in mechanistic concept studies, the
traditional acidic nitrating mixtures has been refined by tuning the amount of nitric acid in the
Ar H
Ar B(OH)
2
Ar COOH
R
COOH
Ar
Ar B
Ar COO
R
COO
O
OH
NO
2
sources
NO
2
Ar NO
2
Ar NO
2
Ar NO
2
R
NO
2
139
mixture, using acid anhydride, and employing various metal salts together with the mixed acids.
The evolution of ipso-nitration of calixarenes is a representative example. The regioselective ipso-
nitration reactions have been achieved to various calixarenes with selected acid mixtures of nitric
acid, glacial acetic acid (HOAc) or acetic anhydride in combination with or without copper nitrate,
cerium (IV) ammonium nitrate or other metal salts under different optimized reaction conditions,
providing nitro calixarene derivatives in moderate to excellent yields with remarkable
regioselectivity.
58–65
ipso-Nitration of aryl halides
Since organohalides have been extensively used as key precursors in transition-metal-
catalyzed cross-coupling reactions, copper and palladium-catalyzed reactions of C(sp
2
)-N bond
formation with aryl halides have been explosively developed in recent years.
66–76
These
investigations promoted novel methods for the synthesis of aromatic nitro compounds using
haloarenes (Scheme 3.4). In 2005, Saito et al.
39
disclosed a new protocol for ipso-nitration of
iodoarenes to form the corresponding nitro products employing nitrite salts in the presence of a
copper powder/DMEDA catalytic system under neutral conditions. A plausible mechanistic
hypothesis similar to Ullmann-type reactions was also proposed (Scheme 3.4A). After that, Jones
and colleagues
77
developed this ipso-nitration reaction with indole iodides by the application of
microwave to give corresponding nitroarenes in very good yields, albeit at high catalyst and ligand
loading (Scheme 3.4B). Subsequently, Buchwarld and Fors
41
reported an elegant and practical
strategy for Pd-catalyzed regioselective transformation of aryl chlorides, triflates and nonaflates
into aromatic nitro compounds with excellent functional group compatibility for a broad scope of
heteroaromatic containing substrates. They also further explored this method with chloro-, bromo-,
140
iodoarenes and found that the transmetalation reaction rate follows the order Cl > Br > I based on
the rate of oxidative addition with the catalyst (Scheme 3.4C).
Scheme 3.4 Previous work of synthetic methods to access
nitroarenes through ipso-nitration of aryl halides.
X
R
N
H
H
N
Cu bronze
(5 mol%)
n-Bu
4
NNO
2
(1.2 equiv), dry DMF
100 °C, 21 - 27 h
X = I
NO
2
R
A: Satio et al., in 2005
X
R
N
H
H
N
Cu bronze
(5 mol%)
n-Bu
4
NNO
2
(1.2 equiv), dry DMF
MW 110 °C, < 20 min
X = I
NO
2
R
B: Jones et al., in 2010
X
R
Pd
2
(dba)
3
(0.5 mol%)
L (1.2 mol%), TDA (5 mol%)
NaNO
2
(2 equiv), tBuOH
130 °C, 24 h
X = Cl, OTf,
ONf
NO
2
R
C: Buchwald et al., in 2009
MeO P(t-Bu)
2
OMe
i-Pr i-Pr
i-Pr
L: t-BuBrettPhos
N
O
O
O
O
O
O
TDA = tris(3,6-dioxaheptyl)amine
X
R
Cu(OSO
2
CF
3
)
2
(25 mol%)
KNO
2
(3 equiv), dry DMSO
120 - 130 °C, N
2
, 48 h
X = I, Br
NO
2
R
D: Kantam et al., in 2012
141
With all these developments, it is of great interest to explore the ipso-nitration of aryl bromides.
Besides, a more practical and inexpensive protocol is also desirable owing to the use of
air/moisture sensitive nitrogen/phosphine ligands and costly palladium catalysts in former studies.
In order to circumvent the employment of a phase transfer catalyst, Kantam and co-workers
37
presented an handy and effective procedure for copper-catalyzed conversion of various structurally
divergent aryl halides into corresponding nitroaromatics including bromoarenes, iodoarenes, and
heterocyclic haloarenes using potassium nitrite as a nucleophile. This protocol also tolerates
diverse functional groups with high regioselectivity requiring harsh reaction conditions and long
reaction times (Scheme 3.4D).
ipso-Nitration of aromatic carboxylic acids
Carboxylic acids have served as versatile synthons for a wide array of organic synthesis since
they are low-cost, simple to handle, easy to store, and commercially available in a great structural
variety.
12,78,79
In particular, a huge number of straightforward methods have been well established
to conveniently synthesize carboxylic acids, which makes them promising building blocks for
chemical transformations.
80–83
Therefore, cross-coupling reactions using carboxyl substituents as
leaving group have attracted considerable attention for various carbon-carbon and carbon-
heteroatom bonds formation in recent decades.
84–86
142
Scheme 3.5 Previous work of synthetic methods to access nitro compounds through
ipso-nitration of carboxylic acid and cinnamic acid derivatives.
COOH
R
1
AIBN (2 mol%)
HNO
2
(3 equiv), MeCN
50 °C, 4 - 24 h
NO
2
R
1
A: Roy et al., in 2002
R
2
COOH
R
2
NO
2
COOH
R
1
Cellulose supported
Cu-nano (10 mol%)
Bi(NO
3
)
3
5H
2
O (2 equiv)
MeCN, 60-80 °C
15-160 min
NO
2
R
1
B: Baruah et al., in 2015
R
2
COOH
R
2
NO
2
COOH
R
1
Ag
2
CO
3
(0.5 equiv)
NO
2
BF
4
(1.5 equiv), DMA
90 °C, 12 h, N
2
NO
2
R
1
C: Natarajan et al., in 2015
R
2
COOH
R
2
NO
2
COOH
R
1
[Dsim]NO
3
Solvent-free
50 °C, 8-35 min, N
2
NO
2
R
1
D: Zolfigol et al., in 2018
R
2
COOH
R
2
NO
2
[Dsim]NO
3
COOH
R
1
NO
2
BF
4
(2.5 equiv)
190 °C, 26 h, N
2
NO
2
R
1
E: Natarajan et al., in 2019
R
2
COOH R
2
NO
2
Me Me Me Me
R
3
R
3
MIM3
4-chloropyridine (1 equiv)
NH N
CH
3
n-C
6
H
13
H
3
C CH
3
BF
4
MIM3
N N
SO
3
H HO
3
S
NO3
143
Because of the explosive growth of decarboxylative reactions, the ipso-nitration of carboxylic
acids is also of substantial interest and stands as a desirable strategy (Scheme 3.5).
87
The first
decarboxylative nitration of aromatic carboxylic acids was reported by Roy and colleagues
88
using
catalytic AIBN and nitric acid in 2002, even though only two examples were tested (Scheme 3.5A).
With the objective of developing a ipso-nitration protocol for synthesis of a wide range of
nitroaryls from aromatic carboxylic acids, Baruah and co-workers
89
in 2015 disclosed the
cellulose-supported copper nanoparticles catalyzed nitro-decarboxylation of several aromatic
carboxylic acids using bismuth(III) nitrate in good stereoselectivity and yields (Scheme 3.5B).
Although this protocol efficiently obtained nitroaryl products with electron-rich substrates,
electron-withdrawing functional groups were not tolerated under this reaction condition. Based on
the well-known studies of silver salts as efficient catalysts for decarboxylation,
90,90,91
Natarajan et
al.
92
described a novel one-pot method for the decarboxylative nitration of various aromatic and a
few heteroaromatic carboxylic acids to prepare corresponding nitroarenes using silver carbonate
and nitronium tetrafluoroborate (Scheme 3.5C). The optimized reaction conditions tolerated
common functional groups and could be applied in the synthesis of two bioactive nitro compounds,
fexinidazole and nitazoxanide. In 2018, Zolfigol and co-workers
93
investigated the ipso-nitration
of benzoic acid derivatives by in situ generation of NO2 to afford nitroarenes utilizing a designed
ionic liquid {[Dsim]NO3} as a novel nitrating agent without using any cocatalysts (Scheme 3.5D).
This method was under solvent free condition with high yields and very short reaction time which
makes it complementary to previous protocols, evading issues of harsh reaction conditions, albeit
with the need of ionic liquid preparation and limited substrate scope. Furthermore, it is worthy to
elucidate that this reaction protocol was also successfully employed in ipso-nitration of various
arylboronic acids and nitro-Hunsdiecker reaction of respective α,β-unsaturated carboxylic acids.
144
Recently, Natarajan
94
and colleagues developed an analogous volatile organic solvent-free access
to aromatic nitro products through decarboxylative nitration using ionic liquid MIM3 and
nitronium tetrafluoroborate (Scheme 3.5E). Unfortunately, however, this protocol requires
extremely high reaction temperature and relatively long time for completion.
ipso-Nitration of arylboronic acids
In recent years, arylboronic acids have been extensively used as synthetic intermediate in
organic chemistry for functional group conversions because of their relative low toxicity and
higher stability to air and moisture, as well as commercial availability with a diverse range of
substrates and well-developed synthesis methods.
95–97
As important synthons, arylboronic acids
have been mainly implemented in Suzuki couplings and Petasis reactions.
98–103
In addition, they
have also been widely applied in ipso-substitution type reactions, where the functional group
boronic acid could be displaced by a series of other useful substituents including azides, sulfones,
aminic, hydroxylic, halo and many other functional groups,
104–118
particularly the nitro
groups.
8,113,119–129
In 2000, ipso-nitration of arylboronic acids was initially carried out by Prakash, Olah and co-
coworks
122
using ammonium nitrate and trifluoroacetic anhydride as the nitrating agent which is
also known as Crivello’s reagent (Scheme 3.6a). Moreover, they observed a competition existing
between the ipso-type nitration and classic nitration of C-H bond on other positions of the aromatic
ring, giving ipso-mononitro products and multi-nitro byproducts. The regioselective nitration of
arylboronic acids was dependent on the concentration of the nitrating mixture used in the reaction.
The results also indicated that at lower concentration the ipso-nitration took place, affording the
145
mononitro products. While at higher concentration, the substitution can also occur on Ar-H bond
resulting in aromatic dinitro compounds.
Scheme 3.6 Previous work of synthetic methods to access nitro aromatics
through ipso-nitration of arylboronic acids during 2000-2011.
Later on, a modified protocol for ipso-nitration of arylboronic acid was reported in 2004 by
the same research group
124
using chlorotrmethylsilane and nitrate salts as a milder nitrating mixture
B(OH)
2
R
NH
4
NO
3
/(CF
3
CO)
2
O
MeCN
-35 °C, 2-6 h
NO
2
R
a) Prakash, Olah et al., in 2000
NO
2
R
NO
2
+
B(OH)
2
R
MNO
3
(2.2 equiv)
M = Ag, NH
4
TMS-Cl (2.2 equiv)
DCM, rt, 30-72 h
NO
2
R
b) Prakash, Olah et al., in 2004
Proposed mechanism
(CH
3
)
3
Si-Cl + AgNO
3
(CH
3
)
3
Si-O-NO
2
+ AgCl
B
OH HO
O
NO
2
Si(CH
3
)
3
B
HO
OH
O
Si(CH
3
)
3
NO
2
+
NO
2
B(OH)
2
R
Cu
2
O (0.1 equiv)
NH
3
●H
2
O (1.8 equiv)
NaNO
2
(7 equiv), H
2
O
rt, 36-48 h, air
NO
2
R
c) Fu et al., in 2011
B(OH)
2
R
t-BuONO (10 equiv)
Dioxane
80 °C, 16 h, air
NO
2
R
d) Wu et al., in 2011
146
with higher regioselectivity to produce the corresponding nitroarene products in moderate to
excellent yields (Scheme 3.6b). This simple and convenient method also works well with a variety
of functionalized boronic substrates. Besides, possible explanations for reaction mechanism were
also elucidated. The intermediate TMS-O-ON2 species were first in situ generated as an active
nitrating agent from TMS-Cl reacting with nitrate salts. Therefore, the boronic acid group and
TMS-O-ON2 species react with each other through a prominent electronic interaction of boron and
the siloxy group because of the powerful oxophilicity of boron atom. Then, the phenyl group from
tetracoordinated complex migrated to the nitrogen atom resulting in N-O bond cleavage and
produced the nitroarene.
Inspired by the idea of preparing nitroaromatics from arylboronic acids, attention has been
devoted to the investigation of the efficient and practical protocols for the ipso-nitration of
arylboronic acids.
In 2011, Fu and co-workers
113
reported a general copper-catalyzed protocol for transformations
of various functional groups including -NO2 on aromatic rings from arylboronic acids using
sodium nitrite (NaNO2) and aqueous ammonia as nitro sources in water under air and room
temperature (Scheme 3.6c). One of the major features of this method is the employment of
environmentally friendly water as the solvent, oxygen in the air as the oxidant, and the readily
available and inexpensive reagents including nitro sources and the mixture of Cu2O/NH3 for the
catalyst system. Surprisingly, this reaction could be recycled for several times by reusing the
remaining catalyst system recovered from the aqueous phase. Nevertheless, the protocol
synthesized nitroarenes in moderate yields with relatively long reaction times. Subsequently, Yan
and his colleagues
121
developed a very similar protocol to Fu’s for ipso-nitration of arylboronic
acids using the copper catalyst system Cu2O/Pyridine and n-Bu4NNO2 or NaNO2 as nitrating
147
agents under air at room temperature but in organic solvent. This protocol shows excellent
functional group tolerance, albeit the nitration of heteroaromatic boronic acids remained
problematic under this reaction condition. However, the competitive side reaction of the biphenyl
derivatives formation as byproducts was also observed in this protocol. In the same year, another
novel and catalyst-free strategy for the ipso-nitration of arylboronic acids was developed by Wu
and Beller’s research group
126
via the use of the inexpensive tert-butyl nitrite. Various aromatic
nitro compounds were produced using this process in moderate to good yields (45% - 87%).
Notably, the advantages of this protocol are the simple and convenient operation, and no demands
for high-cost transitional metal catalyst systems. This procedure works well for arylboronic acid
derivatives with electron-donating groups, but not for substrates with electron-withdrawing
functional groups (Scheme 3.6d). Later, Yan and co-workers
128
reported a similar green metal-free
methodology for direct ipso-nitration of aromatic boronic acids using the same nitrating agent
under further optimized reaction conditions, such as lower reaction temperature and shorter
reaction time. The process contributed an alternative to the traditional nitration protocols with a
plausible mechanistic rationale.
In 2012, the ipso-nitrosation of a broad variety of aryl and hetroaryltrifluoroborates followed
by addition of the oxidant was conducted by Molander and Cavalcanti
119
to afford nitro aromatic
compounds using nitrosonium tetrafluoroborate (NOBF4) under mild conditions with excellent
regioselectivity (Scheme 3.7a). This protocol first prepared corresponding nitroso aromatic
products with high yields in around one hour, which is very efficient. However, it required a
minimal workup for the nitrosation reaction mixture before oxidation of nitroso compounds using
oxone. In order to circumvent the problematic synthesis of heterocyclic nitro compounds,
nitroaromatics were also synthesized by Maiti and colleagues
8
in 2012 from ipso-nitration of
148
Scheme 3.7 Previous work and proposed mechanisms of synthetic
methods to access nitro aromatics through ipso-nitration of arylboronic
acids during 2012-2013.
BF
3
K
R
NOBF
4
(1.03 equiv)
MeCN, rt, 1 min
Open flask
NO
R
a) Molander et al., in 2012
NO
2
R
Oxone (1.5 equiv)
Acetone/H
2
O
60 °C, 2 h,
B(OH)
2
R
Bi(NO
3
)
3
●5H
2
O(2 equiv)
K
2
S
2
O
8
(1 equiv)
Toluene, 70-80 °C, 12 h, N
2
NO
2
R
b) Maiti et al., in 2012
B(OH)
2
R
Bi(NO
3
)
3
●5H
2
O(2 equiv)
Toluene, 80 °C, 2 h, N
2
NO
2
R
c) Bharate et al., in 2012
Proposed mechanism
B
OH HO
O
NO
2
Bi(NO
3
)
2
B
HO
OH
O
Bi(NO
3
)
2
NO
2
+
NO
2
B(OH)
2
R
Fe(NO
3
)
3
●9H
2
O(0.5 equiv)
Toluene, 80 °C, 18 h, N
2
NO
2
R
d) Fu et al., in 2013
Proposed mechanism
S
2
O
8
2-
SO
4
-
B(OH)
3
+ HSO
4
-
Bi(NO
3
)
3 Bi
(3+n)+
SO
4
2-
ArB(OH)
2
+ H
2
O
+ NO
2
Ar
Ar NO
2
Proposed mechanism
Fe(NO
3
)
3
Fe(NO
3
)
2 NO
3 +
NO
3
O
2
N O O NO
2
NO
2
+ O
2
H
3
C B(OH)
2
+ NO
2
H
3
C
B(OH)
2
NO
2
H
3
C
B(OH)
2
NO
2
H
3
C NO
2
+ B(OH)
2 H
3
C N
O
OB(OH)
2
149
arylboronic acids with the use of bismuth nitrate and perdisulfate as a new nitrating agent.
Nitroarenes possessing a wide range of electron-donating and electron-withdrawing functional
groups were obtained following this protocol (Scheme 3.7b). Moreover, it showed that some
heterocyclic nitro compounds were also prepared using this method in good yield with great
substrate compatibility. They also proposed a radical-based mechanistic insight for this protocol,
which was verified by the common employment of radical scavenger such as TEMPO,
hydroquinone and thiourea. Based on Baran and co-works’
130,131
investigation into the formation
of aryl radical species from arylboronic acid in the presence of metal salts and perdisulfate, the
addition of TEMPO in this protocol resulted in dramatically decreased yield of desired nitroarenes
which demonstrated the existance of sulfate radical anion, NO2 radical or aryl radical during
reaction process. After that, in an effort to develop an efficient catalyst-free protocol for ipso-
nitration, Bharate and coworkers
120
carried out this reaction with aryl and heteroaryl boronic acids
similarly using bismuth nitrate as nitro source without adding any catalyst (Scheme 3.7c). Notably,
this is a practical and economical protocol because of simple experimental operations and excellent
substrates tolerance. Besides, the catalyst-free feature of this procedure makes it more ecofriendly
and feasible for large scale synthesis of nitroarenes, and have further application in both academic
and industrial fields. They also sought to provide a plausible mechanistic pathway according to
studies of Olah and co-workers after ruling out the possibility of free radical involvement through
addition of radical scavengers TEMPO to this protocol. They presumed that Bi-O-NO2 species as
active nitrating intermediate were generated from bismuth nitrate and electronically interacted with
boronic acid group to afford a ArB(OH)2-O-NO2 tetracoordinated complex which undergo
intramolecular migration of the phenyl group to NO2 group resulting in desired nitro products.
Subsequently, Fu and co-workers
123
in 2013 developed a practical and efficient method for ipso-
150
nitration of arylboronic acids with ion nitrate as the nitrating agent instead of bismuth nitrate
(Scheme 3.7d). This protocol was performed without addition of catalyst and additives affording
corresponding nitro compounds in good to excellent yields with high tolerance of various
functional groups in the substrates. The reaction mechanism was also explored by TEMPO under
the standard reaction protocol. It was found that the ipso-nitration of arylboronic acids involves a
radical process using this method. Most importantly, further experimental studies were explored
to ascertain the existence of a radical during this reaction by EPR spectroscopy. On the basis of
EPR signal analysis, iron nitrates produce NO3 radicals which could dimerize followed by
decomposition to form NO2 radicals and oxygen. The NO2 radical continues to react with
arylboronic acid generating cyclohexdienyl radical that loses B(OH)2 radical to give the final
aromatic nitro compound (scheme 3.7d).
In 2015, Goswami and co-works
127
developed an easy, mild and transition metal free
methodology for oxidative ipso-nitration of diversely functionalized organoboronic acid
derivatives using a combination of [bis-(trifluoroacetoxy)-iodo]benzene (PIFA), N-
bromosuccinimide (NBS) and soudium nitrite as a novel nitrating agent. A wide range of aryl-,
heteroaryl- boronic acids as well as alkyboronic acids can be transformed into the expected
corresponding nitro aromatics at ambient temperature with good to excellent yields in a
significantly shorter reaction time (Scheme 3.8a). This protocol also exhibits high regioselectivity
and a broad range of functional group tolerance as well as supreme substrate compatibility.
Additionally, they proposed that the reaction proceeds through in situ generation of NO2 and O-
centred organoboronic acid radicals followed by the formation of an O-N bond through interactive
reaction of the mentioned radicals, finally providing the desired products by transfer of the NO2
group to the aryl moiety via 1,3-aryl migration. In 2017, Shen and co-workers
125
investigated a
151
Scheme 3.8 Most recent advances in the synthesis of nitro aromatics through
ipso-nitration of arylboronic acids.
B(OH)
2
R
PhI(OCOCF
3
)
2
(3 equiv)
NBS (2.1 equiv), NaNO
2
(3 equiv)
MeCN, rt, 3 h, air
NO
2
R
a) Goswami et al., in 2015
B(OH)
2
R
68% HNO
3
(aq), CF
3
COOH
80 °C, 18 h, air
NO
2
R
b) Shen et al., in 2017
B(OH)
2
R
NO
2
R
c) Zolfigol et al., in 2018
[Dsim]NO
3
Solvent-free
50 °C, 8-35 min, N
2
[Dsim]NO
3
NH N
SO
3
H HO
3
S
NO3
B(OH)
2
R
NO
2
R
d) Zhang et al., in 2020
[Ru(bpy
3
)](PF
6
)
2
(2.5 mol%)
I (2.0 equiv)
MeCN, Blue LEDs
rt, 19 h, argon
B(OH)
2
R
NO
2
R
HFIP, II (1.3 equiv)
60 °C, 19 h, argon
I:
II: N N
S
O
O
NO
2
O
O
O
NO
2
152
convenient and metal-free protocol to access various aromatic nitro compounds through ipso-
nitration of commercially available boronic acid derivatives using nitric acid and trifluoroacetic
acid as the reactive nitrating mixture (Scheme 3.8b). This novel reaction method is efficient,
economical, operationally simple, and delivered the corresponding nitro products in moderate to
excellent yields without employing of any metals. Most recently, Zhang and colleagues
129
disclosed two general photocatalytic and metal-free protocols to address the remaining challenges
in the ipso-nitration of various aryl- and heteroarylboronic acids using bench-stable and recyclable
nitrating reagents (Scheme 3.8d). One photocatalytic protocol used Ru catalyst system and N-
nitroheterocycle as nitro-transfer reagent under Blue LEDs light, resulting in the corresponding
nitro aromatic compounds in moderate to excellent yields. Another metal-free protocol was
conducted using HFIP and N-nitroheterocycle as active nitro-transfer reagent. Due to development
of the different two reaction procedures, the substrate scope could be broadly raised tolerating a
various set of aryl functionalized derivatives and the synthesis of nitroheterocyclic compounds
could be enabled. Notably, this protocol could be carried out in a gram scale with no significant
decrease in the yield. Furthermore, they also gained insight into the reaction mechanistic studies
through both computational DFT calculation of the two reaction processes and the employment of
radical scavengers. In this context, a plausible catalytic cycle for the ipso-nitration reaction of aryl-
and heteroarylboronic acids enabled by photoredox catalysis was proposed and discussed. This
work could also provide valuable perception into the evolution of new alternative ipso-nitration
methods upon their investigation of mechanistic pathway of the two protocols and the identified
factors governing the regioselectivity.
Advanced strategies for the synthesis of aromatic nitro compounds have been noticeably
developed in recent years. Numerous new nitrating reagents and efficient methodologies, for
153
instance using nitrate salts, nitrite salts, N-nitroheterocycle, nitrate ionic liquid and many others as
the nitro source, have been vigorously investigated and found to improve the ipso-nitration
reaction of aromatic rings. Of all the reported studies above, most methods worked well for the
nitration of aromatic derivatives with electron donating functional groups. However, they still
display some problems of poor functional group tolerance and regioselectivity as well as
possessing the limited scope of substrates. Besides, most of the protocols require either the costly
chemical reagents, or harsh reaction conditions and long reaction times. Thus, more practical and
operationally simple methods with efficient access to a wide variety of aromatic nitro compounds
are still sought-after as one of the research challenges with strong interest. With the aim of
exploring new methodologies to address these issues, one strategy is to develop and implement
novel economical, experimentally easy handling, efficient and green nitrating agents. Furthermore,
new coupling reactions by the selective conversions of other functional groups into a nitro group
except for transformations of alkyl, halo, carboxyl, and boronic acid derivatives, are also
anticipated for the ipso-nitration reaction in organic chemistry and synthetic community.
Arylsilanes as valuable organosilicon reagents in functional group transformations
While the boronic acid derivatives as coupling partners have monopolized the interest and
attention of chemists for functional group transformations, the advantages and superiority of
organosilicon compounds should not be disregarded since they provide multiple significant
alternative sources of carbon nucleophiles in organic syntheses.
132,133
The main reasons that
boronic acid derivatives are very appealing are their stability and versatility. All these features
justify their utility as key building blocks in synthetic organic chemistry. However, several boronic
acids and esters were discovered with toxic and mutagenic properties in 2011 and were reported
to represent a novel class of bacterial mutagen.
134
This report was further evidenced by a recent
154
study that discloses the mutagenicity of a large number of boronic acids, esters, MIDA boronates,
and potassium trifluoroborates, as well as their precursors, such as bis-boronic acids and
bis(pinacolato)diboron.
132,132,135
These unveiled genotoxicity of boronic acid derivatives could
cause problematic limitations and serious issues to their applications in medicinal chemistry and
industrial processes, due to worker exposure hazards and stringent purification policy to
circumvent the persistence of genotoxic impurities. In this context, it is highly necessary to
investigate and appreciate the potentials of other classes of nucleophiles as a paradigm shift in the
organic synthetic chemistry.
132
Therefore, it is foreseeable that arylsilanes as valuable
organosilicon reagents could be utilized in functional group conversions, because they enjoy the
benefits of good chemical stablility toward oxygen and moisture, low toxicity, low cost, versatility,
easy accessibility with diversity of synthetic methods for preparation, and high functional group
tolerance when compared to other organometallic reagents such as organoboron,
organomagnesium or organolithium derivatives.
Organosilicon compounds, particularly arylsilanes, have been widely developed as an
increasingly attractive moiety in modern chemistry community in the last decade. Furthermore,
they constitute an important organometallic class of intermediates in a diverse range of functional
group transformations in the synthesis of natural products, pharmaceutical molecules, and
functional materials.
132,136–142
The silyl functional group provide organosilicon compounds with
both unique chemical and physical properties:
143,144
(1) Silicon has larger covalent radius, leading to longer bond lengths, different bond angles,
and various ring conformations compared to organometallic intermediates or similar
carbon molecules, and causing differences in reactivity.
155
(2) Silicon-containing drugs are more lipophilic compared to their carbon analogues,
providing improved cell and tissue penetration and changes in drug selectivity.
(3) On the basis of accessibility of 3d orbitals and low-lying Si-C antibonding orbitals for
hyper-conjugation, organosilicon molecules possess different bonding preferences to
targets compared to corresponding carbon analogues, which influences the metabolic
pathways.
(4) Based on the steric environment around the silicon atom, the Si-OC and Si-N bonds are
thermodynamically stable but kinetically labile in aqueous and acidic conditions. As a
result, they can be applied as synthetic protecting groups and prodrug segments.
(5) Organosilicon molecules have low toxicity relative to other organometallic compounds, as
they are not associated with intrinsic element.
The distinctive chemical and physical properties of organosilanes contribute to enhanced
biopotency and improved pharmacological attributes in medicinal applications. Thus, it is of strong
interest for the biological development of organosilicon molecules. Numerous methodologies have
been reported for the synthesis of new silicon-containing compounds and organosilicon derivatives
of well-known drugs with medicinal applications (Figure 3.4).
143,145–148
Besides, the applications
of organosilanes also have extended to inhibitor design, drug release technology, imaging, and
mapping inhibitor binding.
143
The traditional synthesis of organosilicon compounds is the addition
reaction of grinard or organolithium reagents to chlorosilanes or cyclosiloxanes.
149–152
Additionally, transition-metal-catalyzed cross-coupling reactions of organohalides with
hydrosilanes, siloxanes or disilanes were also reported to prepare arylsilanes.
153–160
In recent years,
catalytic silylation of C-H bonds in inactivated arenes and heteroarenes with excellent
regioselectivity as well as substrate compatibility have been greatly explored, significantly
156
improving the availability of arylsilanes.
161–170
On the basis of greatly expended easy accessibility
of arylsilanes, metal-catalyzed coupling reaction of organosilanes have emerged as a powerful tool
for the regioselective functionalization of aromatics to form a variety of C-C, C-N, C-O, C-P, C-S
and C-F bonds in organic transformations (Figure 3.5).
171–184
For instance, a broad range of
arylsilanes have been untilized as cross-coupling carbon donors in the Hiyama cross-coupling
reactions to achieve the formation of new C-C bonds.
185–187
Figure 3.4 Silicon-containing molecules of medicinal applications.
157
Figure 3.5 Organosilicon compounds for cross-coupling reactions
Unfortunately, despite these energetically developed strategies of cross-coupling reactions of
organosilicon compounds, the direct ipso-nitration of organosilanes remains elusive and is
expected for further investigation. Moreover, a novel and efficient method for ipso-nitration of
arylsilanes with practical, economical, and simple experimental procedure, as well as high reaction
yields, excellent regioselectivity, exceptional functional group tolerance and mild reaction
conditions still remains as a major challenge. Organosilanes are fascinating alternatives to
arylboronic acids for ipso-nitration reactions. Because the catalytic silylation of aromatic C-H or
C-X (X = Cl, Br, I) bonds results in arylsilanes with higher regioselectivities compared to
borylation of C-H bonds forming boronic acid derivatives in some cases.
162,188
Furthermore,
arylsilanes are less costly, less toxic, and more stable relative to the corresponding arylboronate
analogues.
132,135,143,184
The superior selectivity of aromatic C-H silylation compared to C-H
borylation and better stability of arylsilanes than arylboronic acids afford the ability to
functionalize, such as ipso-nitration, aryl- or heteroarenes that could not be functionalized via C-
H borylation reactions.
179
Scheme 3.9 This work hypothesis: a tandem C–H silylation and ipso-nitration of arylsilanes.
[Si]
R
Si(OTMS)
2
Me [Si] =
TMSCl / NO
3
-
conditions
NO
2
R
H
R
X
R
or
X = I, Br
Ir, Rh, Pd, Pt
multiple methods
Silylation
Si(OEt)
3
158
Based on the potential of arylsilanes prepared from C-H bond functionalization to serve as
important building blocks for the synthesis of aromatic nitro coumpounds via ipso-nitration, we
sought a new efficient approach for the ipso-nitration of arylsilanes which are readily accessible
by C-H or C-X silylation. Taking this lead, we herein disclose a one-pot protocol for the ipso-
nitration of arylsilanes employing readily available reagents, under mild conditions. The scope and
limitations of the present method is presented, and this is also the first reported ipso-nitration of
arylsilanes using nitrating agents. In addition, efforts towards a tandem C–H silylation/nitration
protocol are also expected to synthesize nitro-aromatics through the direct regioselective ipso-
nitration of aromatic C-H bonds (Scheme 3.9), with the aim to exploit silyl substituent as a
temporary functional group to conduct aromatic C-H ipso-nitration. With this protocol, we can
also prepare the nitroarenes that are difficult to obtain via arene nitration such as m-xylene (Scheme
3.10). Furthermore, this method is expected to enjoy practical utility and operational simplicity
and enable an efficient preparation procedure for the desired aromatic nitro products.
Scheme 3.10 Divergent nitration pathways. A) ipso-nitration of arylsilanes.
B) Arene electrophilic aromatic substitution
H
NO
2
NO
2
NO
2
vs
mixtures
+
NO
2
+
ipso-nitration
[Si]
silylation
159
3.2 Results and discussion
Reaction optimization
With the envisioned method in mind, we started our investigation by employing triethoxy-p-
tolylsilane 1a as a model substrate to explore different nitrate sources. The use of
chlorotrimethylsilane (TMS-Cl) in combination with silver nitrate (AgNO3) and chromium
trioxide (CrO3) as a reagent system for the synthesis of 2-nitroketones from olefins has been
reported in the early days.
189
Our group previously reported a mixture of ammonium nitrate and
chlorotrimethylsilane with a catalytic amount of AlCl3 which can be used as a great nitrating agent
for the electrophilic nitration of aromatics.
190
Our group subsequently reported that the aromatic
nitro compounds can be accessed by the ipso-nitro substitution of arylboronic acids using a mixture
of TMS-Cl and nitrate salts (AgNO3/NH4NO3) without the use of Lewis acidic AlCl3, and the
nitration took place at the ipso-position of the aromatic ring in the absence of ring nitration or
sequential nitration.
124
Motivated by our previous studies on nitrating agents, similar nitrating
agents were initially examined for ipso-nitration of triethoxy-p-tolylsilane 1a to p-nitrotoluene 2a,
using various commercially available nitrate salts (3.0 equiv) in conjunction with different
activators (2.1 equiv) in 1,2-dichloroethane (DCE) at 100 °C under nitrogen atmosphere for 24 h
(Table 3.1).
As the results shown in Table 3.1, eleven nitrate salts in conjunction with chlorotrmethylsilane
were first tested (entries 1-11). Nitrate sources such as NH4NO3 and NaNO3 failed to give the nitro
product 2a. However, instead of ipso-nitration, 60% ipso-chlorination was observed (entries 1-2).
This is reasonable because the combination of TMS-Cl and nitrate salt could form nitryl chloride
species (Cl-NO2) that can also act as a chlorinating agent. We also found that the yield of 4-
160
nitrotoluene was enhanced when NH4NO3 and NaNO3 were replaced by KNO3 or CsNO3, while
the extent of chlorination significantly decreased (entries 3-4). This was possibly caused by the
fact that the increased atom radius of potassium ion or caesium ion decreases the solubility of KCl
or CsCl compared to NH4Cl or NaCl, promoting the ipso-nitration by potentially sequestering
chlorination during the reaction. When using Fe(NO3)3×9H2O, Bi(NO3)3×5H2O, and
Cu(NO3)2×3H2O as nitrate salts, nitro product was generated in 51%, 63%, and 49% yield after 24
h respectively, albeit relatively lower yields were obtained with Mg(NO3)2, Zn(NO3)2×6H2O and
Ni(NO3)2×6H2O under the same reaction conditions (entries 5-10). Among all these nitrate salts,
AgNO3 was found to be the best for ipso-nitration of the arlysilane 1a, affording the nitroarene
product 2a in 76% yield (entry 11). This is probably due to the fact that the silver ion can most
efficiently avoid chlorination effect from the reaction system because of the formation of AgCl
precipitate.
Furthermore, we also performed the reaction with a diversity of activators. It was found that
using TMS-Br instead of TMS-Cl with AgNO3 provided the product in lower yield along with the
formation of the bromination byproduct (entry 12), indicating that TMS-Cl is more effective than
TMS-Br for the ipso-nitration of triethoxy-p-tolylsilane. Although the successful studies in the
syntheses of aromatic nitro compounds by using Bi(NO3)3×5H2O/ K2S2O8, Fe(NO3)3×9H2O, and
Bi(NO3)3×5H2O for ipso-nitration of aryl boronic acids as well as using NO2BF4/Ag2CO3 for ipso-
nitration of aromatic carboxylic acids were reported, the similar reaction conditions failed for
selective ipso-nitro substitution of the aryl silane 1a (entries 13, 15-17). It is possibly because of
the higher stability of arylsilanes compared to the corresponding arylboronic acids or aryl
carboxylic acids. In addition, we also conducted the control experiment using only AgNO3 as the
nitrating agent without TMSCl, resulting in no formation of the nitro product 2a (entry 14). This
161
Table 3.1 Nitrating agents screening for ipso-nitration of triethoxy-p-tolylsilane
a
Entry M(NO3)n×mH2O Activator Yield (%)
b
1 NH4NO3 TMSCl
6
2 NaNO3 TMSCl 5
3 KNO3 TMSCl 46
4 CsNO3 TMSCl 42
5 Fe(NO3)3×9H2O TMSCl
51
6 Bi(NO3)3×5H2O TMSCl 63
7 Mg(NO3)2 TMSCl 10
8 Cu(NO3)2×3H2O
TMSCl 49
9 Zn(NO3)2×6H2O TMSCl
27
10 Ni(NO3)2×6H2O
TMSCl
31
11 AgNO3 TMSCl
76
12 AgNO3 TMSBr 45
13 Bi(NO3)3×5H2O K2S2O8
8
14 AgNO3 0
15
c
Fe(NO3)3×9H2O
20
16
c,d
Bi(NO3)3×5H2O 6
17 NO2BF4 Ag2CO3 0
18
e
AgNO3 TMSCl 54
a
Reaction conditions: triethoxy-p-tolylsilane 1a (0.5 mmol, 1 equiv), M(NO 3) n×mH 2O (1.5 mmol, 3 equiv),
and activator (1.05 mmol, 2.1 equiv) in DCE (1 ml, 0.5 M) at 100 °C for 24 hours under nitrogen atmosphere.
b
Yields were determined by
1
H NMR spectroscopy vs a standard.
c
Used toluene as solvent, trimethoxy-p-
tolylsilane as the starting arylsilane reagent
d
Reaction was stirred at 100 °C for 3 hours.
e
Under air
atmosphere. More information is in the experimental details of this chapter.
Si(OEt)
3
Me
M(NO
3
)
n
•mH
2
O (3.0 equiv)
Activator (2.1 equiv.)
NO
2
Me
DCE (0.5 M), 100 ℃, 24h, N
2
1a 2a
162
result demonstrate the necessity and advantage of the addition of TMSCl in the formation of the
active nitrating species. Besides, this reaction protocol was also performed under air atmosphere
in the presence of oxygen and moisture (entry 18), providing lower yield of 2a in 54%. The result
of this control experiment suggested the sensitivity of the reaction conditions for the ipso-nitration
of arylsilanes.
After selecting the most efficient nitrating agent, we began to optimize the reaction conditions
under nitrogen atmosphere for the protocol of ipso-nitartion of arylsilane 1a, including the
amounts of silver nitrate and chlorotrimethylsilane, solvent, reaction temperature and time (Table
3.2). Utilization of a 2.2:2.1 molar ratio of AgNO3/TMSCl at room temperature afforded the
desired product 2a in only 10% yield after 24 hours (entries 1-2). When the reaction temperature
was increased, the yields were also promoted but not by a significant degree (entires 3-4).
Subsequent attempt has shown that employing a 3:2.1 molar ratio of AgNO3/TMSCl, the nitro
product could be formed in 76% yield with DCE at 100 °C after 24 h (entry 4). The yields of 2a
were not improved by increasing the amount of TMSCl to 2.1 equiv or raising the reaction
temperature up to 120 °C, affording the desired nitro product in 71% and 75% yields, respectively
(entries 5-6).
The effect of various solvents was also investigated (compare entries 4, and 7-12), and 1,2-
dichloroethane (DCE) was found to be the most suitable solvent giving the best performance (entry
4). Nonpolar solvents such as benzene, toluene, and CCl4 led to no improvements, affording low
yields or no desired nitro products (entry 7, 9, and 12). Other polar solvents such as DCM and
acetonitrile produced little nitro product in 51% and 2% yields, respectively (entries 8 and 10).
Besides, oxygenated aprotic solvents including ether, THF and dioxane (entry 11) are either
unsuitable since TMSCl can be consumed and wasted due to interacting with these oxygenated
163
solvents. Alcohols could not be utilized in this protocol, as they undergo silylation of the hydroxy
functional group with TMSCl. Moreover, increasing the reaction time to 36 h led to only marginal
improvements (entry 14) while lower conversion of ipso-nitration was observed by reducing the
reaction time to 12 h (entry 13). In the final optimal protocol, AgNO3 (3.0 equiv) and TMSCl (2.1
equiv) are added to arylsilanes 1 (1 equiv) in DCE at 100 °C under nitrogen atmosphere reacting
for 24 hours.
Table 3.2 Optimization of reaction conditions for ipso-nitration of triethoxy-p-tolylsilane using
silver nitrate and TMSCl
a
Entry
AgNO3
(equiv)
TMSCl
(equiv)
Solvent
Temp
(°C)
Time
(hr)
Yield (%)
1 2.2 2.1 DCE rt 24 10
2 2.2 2.1 DCE 80 24 25
3 2.2 2.1 DCE 100 24 37
4 3.0 2.1 DCE 100 24 76
5 3.0 2.5 DCE 100 24 71
6 3.0 2.1 DCE 120 24 75
7 3.0 2.1 CCl4 100 24 30
8 3.0 2.1 DCM 100 24 53
9 3.0 2.1 Benzene 100 24 0
Si(OEt)
3
Me
AgNO
3
, TMSCl
NO
2
Me
solvent, temperature
reaction time, N
2
1a
2a
164
10 3.0 2.1 MeCN 100 24 2
11 3.0 2.1 Dioxane 100 24 7
12 3.0 2.1 Toluene 100 24 3
13 3.0 2.1 DCE 100 12 64
14 3.0 2.1 DCE 100 36 77
a
Reaction conditions: triethoxy-p-tolylsilane 1a (0.5 mmol, 1 equiv), Ag(NO3) and
TMSCl in solvent (1 mL, 0.5 M), under nitrogen atmosphere.
b
Yields were determined
by
1
H NMR spectroscopy vs a standard. More information is in the experimental details
of this chapter.
Substrate scope
Having fully identified the optimal protocol for the ipso-nitration reaction of arylsilanes in our
hand, we next set out to investigate the substrate scope of the transformation of a wide range of
arylsilanes to the corresponding aromatic nitro products (Scheme 3.11). The results shown in
Scheme 3.11 indicated that our reaction protocol worked well for arylsilanes with different
functionalities, albeit the yields vary. Substrates bearing alkyl, ether, or bromide functional group
gave the corresponding aromatic nitro products in good yields (2a-2g). Arylsilanes with electron
donating groups participated well in this reaction. Triethoxyphenylsilane and triethoxy-1-
naphthylsilane (2j) also undergoes ipso-nitration with the same reagent system and reaction
conditions, resulting in good yields. Thus, the organosilane group orients the nitro group very
easily toward the ipso position to obtain the desired aromatic nitro compounds in good yields. This
protocol is very practical when the availability and preparation of the nitro aromatics or the
corresponding boronic acid derivatives are rather difficult or need drastic reaction conditions. On
165
Scheme 3.11 Substrate scope for ipso-nitration of arylsilanes
a
a
Reaction conditions: 1 (0.5 mmol, 1 equiv), AgNO 3 (1.5 mmol, 3 equiv), and
TMSCl (1.05 mmol, 2.1 equiv) in DCE (1 mL, 0.5 M), reaction mixture was
stirred at 100 °C for 24 hours under nitrogen atmosphere.. Isolated yield, average
of two runs. Yields in parentheses were determined by
1
H NMR spectroscopy vs
an internal standard. Some of the starting silane reagents were freshly synthesized
rather than being purchased. See the supporting information for full experimental
details.
NO
2
NO
2
NO
2
NO
2 NO
2
Me MeO
Me
Me Me
Cl
NO
2
Br
2a
64% (76%)
2b
71% (82%)
2c
63% (68%)
2d
72% (80%)
2e
66% (72%)
2f
41% (53%)
NO
2
H
2g
62% (71%)
NO
2
2h
(39%)
O
H
3
C
NO
2
HN
2I
(0%)
O
H
3
C
NO
2
2j
75% (80%)
NO
2
2k
(0%)
N NO
2
2g
(7%)
Si(OEt)
3
AgNO
3
(3.0 equiv)
TMSCl (2.1 equiv.)
NO
2
DCE (0.5 M), 100 ℃
24h, N
2 1 2
R
R
N
166
the other hand, arylsilanes substituted with electron withdrawing group such as acetyl produced
the expected 4-nitroacetophenone in 39% yield which was lower than that of the electron rich
arylsilanes (2h). In addition, N-[4-(triethoxysilyl)phenyl]acetamide did not undergo ipso-nitration
using this reaction conditions (2i). The reaction of heterocyclic arylsilanes containing nitrogen
atom such as 5-(triethoxysilyl)indole (2k) and 4-(triethoxysilyl)pyridine (2g) had been found to be
very sluggish using our protocol either. The inefficiency of the reaction protocol with both
electron-poor arylsilanes and hetero-arylsilanes illustrated the necessity of additional optimization
and investigation to extend the scope of the synthetic methodology that we developed.
Proposed mechanism
With the aim to explore the plausible reaction mechanistic pathway, we attempted to discuss
and explain the regioselective nitration of arylsilanes in several different ways (Scheme 3.12) on
the basis of the formerly reported ipso-nitration mechanism from our group.
124
First, it is well-
known that the reaction of TMS-Cl and nitrate salts provide the active nitrating species TMS-O-
NO2. In the reaction mixture, the dinitro products has not been observed using our method.
Moreover, silicon is commonly known as a highly oxophilic atom in nature. On the basis of these
two facts, it is most likely that an electronic interaction between the silyl group from arylsilanes
and the intermediate active nitrating agent TMS-O-NO2 species takes place, resulting in the
formation of ionic species that promotes the nitration to occur at the ipso-position as represented
in Scheme 3.12. With the fact that aliphatic silanes did not undergo nitration with our reaction
conditions, it is possible that the aromatic ring plays a significant electronic role in the ipso-
nitration.
167
Scheme 3.12 Plausible mechanism for ipso-nitration of arylsilanes
Additionaly, other plausible mechanistic routes are based on the generation of nitryl chloride
(NO2Cl) species which can be produced through the further reaction of TMS-O-NO2 with TMS-
Cl affording hexamethyldisiloxane as well. The nitryl chloride species are able to act as both active
nitrating and chlorinating agent. For the generation of the nitryl chloride, excess TMSCl is requied,
but we found that arylsilanes can undergo both ipso-nitration and ipso-chlorination with very
similar equivalents of AgNO3 and TMSCl while excess AgNO3 compared to TMSCl condition
gave nitroaromatics as substitution products completely. This demonstrates that the TMS-O-NO2
species serves as a major active nitrating intermediate, and also explains the formation of minor
(CH
3
)
3
Si Cl
+ AgNO
3
(CH
3
)
3
Si O NO
2
+ AgCl
Si
R
EtO OEt
+
O
Si(CH
3
)
3
NO
2
EtO
Si
R
EtO
EtO
OEt
O
Si(CH
3
)
3
NO
2
NO
2
R
(CH
3
)
3
Si O NO
2
Active Nitrating Species
(CH
3
)
3
Si Cl
Cl NO
2
+ (H
3
C)
3
Si O Si(CH
3
)
3
168
number of chlorinated byproducts in some cases depending on the ratio of nitrate salts versus
TMSCl.
3.3 Conclusion
In conclusion, we have developed the simple, practical and efficient strategy for the synthesis
of aromatic nitro compounds via ipso-nitration of arylsilanes for the first time. This method merits
complete regioselectivity, good functional group tolerance and substrate scope with moderate to
high yields under mild reaction conditions. The other salient features of this method are the ease
of workup and allowing orientation reaction for the preparation of nitroarenes that are difficult to
obtain via arene nitration. Furthermore, this process, in combination with a tandem C-H silylation,
provides prospect to the synthesis of nitro-derivatives in bio-active pharmaceutical compounds
directly from inactivated arenes and heteroarenes. However, this procedure works much better for
arylsilanes with electron-donating functional groups than the ones with electron-withdrawing
groups. Further studies on optimization and application of this approach for a broader range of
substrate scope including heterocyclic arylsilanes are needed.
3.4 Experimental details
3.4.1 General information
Reagent Information. Unless otherwise stated, all the chemicals were purchased from
commercial sources such as Sigma-Aldrich, Alfa Aesar, Combi-Blocks, Fisher Scientific, Frontier
Scientific, TCI, Gelest and Oakwood, and used without further purification excluding the
following exceptions. Some of the arylsilanes were synthesized according to the literature
preocedures.
152, 155, 193, 195, 196
Moleculer sieves (4Å; particle size 2–3 μ) were bought from Sigma-
169
Aldrich. Moleculer sieves were always kept in oven in small amount before use. TMSCl and
TMSBr were procured from Sigma-Aldrich in sure/seal bottom and were used under nitrogen
atmosphere through Schlenk lines. Acetonitrile (MeCN) was purchased from EMD (drysolv) and
distilled/degassed over P2O5 and stored over molecular sieves in a N2-filled Straus flask prior to
use unless otherwise noted. 1,2-Dichloroethane (DCE), benzene, toluene, and N-methyl-2-
pyrrolidinone (NMP) was purchased from EMD (drysolv), and distilled over CaH2 using sodium
and benzophenone as a colorimetric indicator and stored over molecular sieves in a N2-filled Straus
flask. Dichloromethane (DCM), 1,2-dimethoxyethane (DME), and dioxane were purchased from
EMD or Sigma-Aldrich in anhydrous form and used as received.
General Procedure. Unless otherwise noted, all reactions and air-sensitive steps were performed
under a nitrogen atmosphere with the exclusion of moisture. Glassware used in the reactions was
dried overnight in the oven. N2-flushed stainless steel needles and plastic syringes were used to
transfer air and moisture sensitive solvents or solutions. Reaction solutions were worked up and
concentrated using a rotary evaporator under different reduced pressures based on the boiling
points of products. Flash column chromatography was performed to isolate products with proper
eluent as monitored by thin-layer chromatography (TLC) on Silica Gel 60 F254 plates from EMD,
visualizing with UV light (254 nm) or KMnO4 stain.
Analytical Information.
1
H and
13
C nuclear magnetic resonance (NMR) spectra were recorded
on 400 MHz, 500 MHz or 600 MHz Varian NMR spectrometers. NMR data are represented as
follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet), coupling constant in Hertz (Hz), and integration.
1
H NMR chemical shifts were
determined relative to CDCl3 as the internal standard at 7.26 ppm.
13
C NMR shifts were determined
170
relative to CDCl3 at 77.16 ppm.
19
F NMR chemical shifts were determined relative to CFCl3 as the
internal standard at 0.00 ppm. Coupling constants were reported in Hz. Gas chromatography (GC)
was performed on Bruker 450-GC instrument which was equipped with flame ionization detectors.
Mass spectra were recorded on a high-resolution mass spectrometer Bruker 300-MS in the ESI
mode.
3.4.2 General procedure for optimization of reaction conditions for ipso-nitration of
arylsilanes
In an over-dried pressure tube equipped with magnetic stir bar, to a solution of arylsilane (0.5
mmol, 1 equiv) and nitrate salt in dry solvent (1-5 mL), an additive was added. The reaction
mixture was stirred vigorously at a specific temperature for several hours. Upon reaction
completion, the reaction mixture was diluted with dichloromethane (DCM), then quenched with
saturated sodium bicarbonate solution for 2 min. After that, the internal standard 1,3,5-
trimethoxybenzene (84 mg, 0.5 mmol, 1 equiv, 100% of theoretical yield for 3 protons on the
aromatic ring) dissolved in DCM (1 mL) was added and stirred. The organics were extracted using
dichloromethane. Next, the organic layers were combined and washed with brine followed by
being dried over MgSO4, filtered and analyzed by GC. Finally, the reaction mixture is concentrated
and analyzed by
1
H NMR. The yield was determined by comparing the relative integration of
internal standard (1,3,5-trimethoxybenzene, aromatic
1
H NMR 6.08 ppm) with the integration of
the protons at the aromatic ring from the nitroarene products.
171
3.4.3 Synthesis of arylsilanes
(4-Bromophenyl)triethoxysilane
193
(1c)
Pd(dba)2 (34 mg, 0.06 mmol, 0.03 equiv) and (t-Bu)2P(o-biphenyl) (36 mg, 0.12 mmol, 0.06 equiv)
were mixed in 8 mL of NMP under nitrogen in pressure tube. To this solution, 1-Bromo-4-
iodobenzene (566 mg, 2.00 mmol, 1 equiv) and i-Pr2NEt (1046 µL, 6.00 mmol, 3 equiv) were
added. Following that Triethoxysilane (554 µL, 3.0 mmol, 1.5 equiv) was added, leading to the
darkening of the solution and formation of yellow foam. The reaction mixture was stirred for 2
hours at room temperature. After the reaction, the black mixture was extracted with 5x25 mL
pentane. NMP was removed by washing the combined organic phase with 3x25 mL water. Finally
the organic phase was dried over MgSO4 and filtered. Pentane was removed under reduced
pressure and the residue was purified with chromatography column on silica gel by gradient elution
of pentane and ethyl acetate, giving 416 mg (65% yield) of (4-bromophenyl)triethoxysilane as a
colorless oil. The
1
H and
13
C NMR data were identical to published spectral data.
193
NMR Spectroscopy:
1
H NMR (400 MHz, Chloroform-d) δ 7.55 – 7.52 (m, 4H), 3.86 (q, J = 7.2
Hz, 6H), 1.24 (t, J = 7.2, 9H).
13
C NMR (101 MHz, Chloroform-d) δ136.36, 131.37, 129.82,
125.30, 58.86, 18.20.
I
Si(OEt)
3
Pd(dba)2 (3 mol%)
P(t-Bu)
2
(biphenyl) (6 mol%)
HSi(OEt)
3
(1.5 equiv)
i-Pr
2
NEt (3.0 equiv)
NMP, 2 h, rt
Br Br
172
4-(Triethoxysilyl)acetophenone
159
(1h)
4-Iodoacetonphenone (492 mg, 2.00 mmol, 1 equiv) and [Rh(cod)(MeCN)2]BF4 (22 mg, 0.06
mmol, 0.03 equiv) were mixed in 8 mL of DMF under nitrogen in pressure tube. To this solution,
triethylamine (820 µL, 6.00 mmol, 3 equiv) and triethoxysilane (720 µL, 4.00 mmol, 2 equiv) were
added. The reaction mixture was stirred for 2 hours at 80 °C. After the reaction, the mixture was
cooled down to room temperature and diluted with 50 mL ether before washed with 3x20 mL
water. Finally the organic phase was dried over Na2SO4 and filtered. Solvents were removed under
reduced pressure and the residue was purified with chromatography column on silica gel by
gradient elution of pentane and ethyl acetate, giving 385 mg (68% yield) of 4-
(triethoxysilyl)acetophenone as a colorless oil. The
1
H and
13
C NMR data were identical to
published spectral data.
159
NMR Spectroscopy:
1
H NMR (400 MHz, Chloroform-d) δ 7.93 (dd, J = 6.4 Hz, J = 1.4 Hz, 2H),
7. (dd, J = 6.4 Hz, J = 1.4 Hz, 2H), 3.88 (q, J = 7.2, 6H), 2.60 (s, 3H), 1.24 (t, J = 7.2, 9H) .
13
C
NMR (101 MHz, Chloroform-d) δ 198.57, 138.55, 137.50, 135.16, 127.22, 58.86, 26.88, 18.20.
I
Si(OEt)
3
[Rh(cod)(MeCN)
2
]BF
4
(3 mol%)
HSi(OEt)
3
(2.0 equiv)
NEt
3
(3.0 equiv)
DMF, 2 h, 80 ℃
O
Me
O
Me
173
4-(Triethoxysilyl)acetanilide
193
(1i)
Pd(dba)2 (34 mg, 0.06 mmol, 0.03 equiv) and (t-Bu)2P(o-biphenyl) (36 mg, 0.12 mmol, 0.06 equiv)
were mixed in 8 mL of NMP under nitrogen in pressure tube. To this solution, 6-iodoacetanilide
(520 mg, 2.00 mmol, 1 equiv) and i-Pr2NEt (1046 µL, 6.00 mmol, 3 equiv) were added. Following
that Triethoxysilane (554 µL, 3.0 mmol, 1.5 equiv) was added, leading to the darkening of the
solution and formation of yellow foam. The reaction mixture was stirred for 2 hours at room
temperature. After the reaction, the black mixture was extracted with 5x25 mL pentane. NMP was
removed by washing the combined organic phase with 3x25 mL water. Finally the organic phase
was dried over MgSO4 and filtered. Pentane was removed under reduced pressure and the residue
was purified with chromatography column on silica gel by gradient elution of pentane and ethyl
acetate, giving 382 mg (64% yield) of 4-(triethoxysilyl)acetanilide as a colorless oil. The
1
H and
13
C NMR data were identical to published spectral data.
193
NMR Spectroscopy:
1
H NMR (400 MHz, Chloroform-d) δ 7.70 (d, J = 7.8 Hz, 2H), 7.58 (d, J =
7.8 Hz, 2H), 7.40 (broad, s, 1H), 3.86 (q, J = 7.0 Hz, 6H), 2.15 (s, 3H), 1.24 (t, J = 7.0, 9H).
13
C
NMR (101 MHz, Chloroform-d) δ168.22, 139.60, 135.55, 126.30, 119.02, 58.56, 24.40, 18.20.
I
Si(OEt)
3
Pd(dba)2 (3 mol%)
P(t-Bu)
2
(biphenyl) (6 mol%)
HSi(OEt)
3
(1.5 equiv)
i-Pr
2
NEt (3.0 equiv)
NMP, 12 h, rt
HN HN
H
3
C
O
H
3
C
O
174
6-(Quinolinyl)triethoxysilane
196
(1k)
6-(Quinolinyl)trifluoromethanesulfonate (614 mg, 2.00 mmol, 1 equiv), [Rh(cod)Cl]2 (30 mg, 0.06
mmol, 0.03 equiv) and tetra-n-butylammonium idodide (738 mg, 2.00 mmol, 1 equiv) were mixed
in 8 mL of DMF under nitrogen in pressure tube. To this solution, triethylamine (820 µL, 6.00
mmol, 3 equiv) and triethoxysilane (720 µL, 4.00 mmol, 2 equiv) were added. The reaction mixture
was stirred for 2 hours at 80 °C. After the reaction, the mixture was cooled down to room
temperature and diluted with 50 mL ether before washed with 3x20 mL water. Finally the organic
phase was dried over MgSO4 and filtered. Solvents were removed under reduced pressure and the
residue was purified with chromatography column on silica gel by gradient elution of pentane and
ethyl acetate, giving 422 mg (73% yield) of 6-(Quinolinyl)triethoxysilane as a colorless oil. The
1
H and
13
C NMR data were identical to published spectral data.
196
NMR Spectroscopy:
1
H NMR (400 MHz, Chloroform-d) δ 8.93 (dd, J = 4.0 Hz, J = 1.4 Hz, 1H),
8.19-8.15 (m, 2H), 8.09 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 8.5 Hz, 1H), 7.40 (dd, J = 8.4 Hz, J = 4.2
Hz, 1H), 3.90 (q, J = 7.2, 6H), 2.60 (s, 3H), 1.26 (t, J = 7.2 Hz, 9H) .
13
C NMR (101 MHz,
Chloroform-d) δ 151.20, 149.02, 136.42, 136.05, 134.40, 129.72, 128.55, 127.58, 58.80, 18.19.
[Rh(cod)Cl]
2
(3 mol%)
HSi(OEt)
3
(2.0 equiv)
TBAI (1.0 equiv)
NEt
3
(2.0 equiv)
DMF, 2 h, 80 ℃
OTf
N
Si(OEt)
3
N
175
3.4.4 General procedure for the synthesis of aromatic nitro compounds through ipso-
nitration of arylsilanes
Unless otherwise stated, the following representative procedure was used for the synthesis and
purification of aromatic nitroarene products 2. In an over-dried pressure tube equipped with
magnetic stir bar, to a solution of arylsilane (0.5 mmol, 1 equiv) and silver(I) nitrate (254.8 mg,
1.5 mmol, 3 equiv) in anhydrous 1,2-dichloroethane (DCE) (1 mL, 0.5 M), chlorotrimethylsilane
(TMSCl) (133 µL, 1.05 mmol, 2.1 equiv) was added under nitrogen atmosphere. The reaction
mixture was stirred vigorously at 100 °C for 24 h. Upon reaction completion, the pressure tube
was cooled to room temperature and then opened. Next, the reaction mixture was diluted with
dichloromethane (DCM), and then quenched with saturated sodium bicarbonate solution for 2 min.
The organics were extracted using dichloromethane and the organic layers were combined. Then,
the organic layer was washed with brine and dried over MgSO4. The solvent was removed under
reduced pressure. The residue was purified with column chromatography on silica gel (gradient
eluent of hexane and ethyl acetate) to give the corresponding aromatic nitro products in good
yields.
Si(OEt)
3
AgNO
3
(3.0 equiv)
TMSCl (2.1 equiv.)
NO
2
DCE (0.5 M), 100 ℃
24h, N
2 1
2
R
R
176
3.4.5 Experimental details and characterization data of nitroarenes
4-Nitrotoluene
92
(2a)
The reaction was carried out according to the general procedure, using triethoxy-p-tolylsilane 1a
(129 µL, 0.5 mmol, 1 equiv), silver(I) nitrate (254.8 mg, 1.5 mmol, 3 equiv) in anhydrous 1,2-
dichloroethane (DCE) (1 mL, 0.5 M), and chlorotrimethylsilane (TMSCl) (133 µL, 1.05 mmol,
2.1 equiv) at 100 °C for 24 h under nitrogen atmosphere. The residue was purified by flash column
chromatography through a silica gel column to afford 2a as a light yellow solid in 64% yield (44.1
mg).
1
H NMR (400 MHz, Chloroform-d) δ 8.11 (d, J = 8.3 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 2.46
(s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ146.28, 146.07, 129.92, 123.63, 21.72.
4-Nitroanisole
129
(2b)
The reaction was carried out according to the general procedure, using triethoxy(4-
methoxyphenyl)silane 1b (133 µL, 0.5 mmol, 1 equiv), silver(I) nitrate (254.8 mg, 1.5 mmol, 3
equiv) in anhydrous 1,2-dichloroethane (DCE) (1 mL, 0.5 M), and chlorotrimethylsilane (TMSCl)
(133 µL, 1.05 mmol, 2.1 equiv) at 100 °C for 24 h under nitrogen atmosphere. The residue was
purified by flash column chromatography through a silica gel column to afford 2b as a light yellow
solid in 71% yield (54.0 mg).
1
H NMR (500 MHz, Chloroform-d) d 8.20 (d, J = 9.2 Hz, 2H), 6.96
(d, J = 9.2 Hz, 2H), 3.91 (s, 3H).
13
C NMR (101 MHz, Chloroform-d) δ 165.2, 142.2, 126.5, 114.6,
56.51.
NO
2
Me
NO
2
MeO
177
1-Bromo-4-nitrobenzene
129
(2c)
The reaction was carried out according to the general procedure, using (4-bromophenyl)
triethoxysilane 1c (129 µL, 0.5 mmol, 1 equiv), silver(I) nitrate (254.8 mg, 1.5 mmol, 3 equiv) in
anhydrous 1,2-dichloroethane (DCE) (1 mL, 0.5 M), and chlorotrimethylsilane (TMSCl) (133 µL,
1.05 mmol, 2.1 equiv) at 100 °C for 24 h under nitrogen atmosphere. The residue was purified by
flash column chromatography through a silica gel column to afford 2c as a light yellow solid in
63% yield (63.1 mg).
1
H NMR (400 MHz, Chloroform-d) d 8.10 (d, J = 8.5 Hz, 2H), 7.69 (d, J =
8.5 Hz, 2H).
13
C NMR (101 MHz, Chloroform-d) δ 147.16, 132.75, 130.11, 125.13.
1,3-Dimethyl-5-nitrobenzene
129
(2d)
The reaction was carried out according to the general procedure, using 1,3-Dimethyl-5-
(triethoxysilyl)benzene 1d (138 µL, 0.5 mmol, 1 equiv), silver(I) nitrate (254.8 mg, 1.5 mmol, 3
equiv) in anhydrous 1,2-dichloroethane (DCE) (1 mL, 0.5 M), and chlorotrimethylsilane (TMSCl)
(133 µL, 1.05 mmol, 2.1 equiv) at 100 °C for 24 h under nitrogen atmosphere. The residue was
purified by flash column chromatography through a silica gel column to afford 2d as a light yellow
solid in 72% yield (53.9 mg).
1
H NMR (400 MHz, Chloroform-d) d 7.82 (s, 2H), 7.30 (s, 1H), 2.41
(s, 6H).
13
C NMR (101 MHz, Chloroform-d) δ 148.41, 139.55, 136.28, 121.20, 21.24.
NO
2
Br
NO
2
Me
Me
178
3-Nitrotoluene
123
(2e)
The reaction was carried out according to the general procedure, using triethoxy(3-
methoxyphenyl)silane 1e (133 µL, 0.5 mmol, 1 equiv), silver(I) nitrate (254.8 mg, 1.5 mmol, 3
equiv) in anhydrous 1,2-dichloroethane (DCE) (1 mL, 0.5 M), and chlorotrimethylsilane (TMSCl)
(133 µL, 1.05 mmol, 2.1 equiv) at 100 °C for 24 h under nitrogen atmosphere. The residue was
purified by flash column chromatography through a silica gel column to afford 2e as a light yellow
oil in 66% yield (45.4 mg).
1
H NMR (400 MHz, Chloroform-d) d 7.94 (d, J = 8.0 Hz, 2H), 7.45
(d, J = 7.6 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 2.41 (s, 3H).
13
C NMR (126 MHz, Chloroform-d) δ
148.13, 139.77, 135.32, 129.01, 123.68, 120.51, 21.08.
1-Chloro-4-nitrobenzene
129
(2f)
The reaction was carried out according to the general procedure, using (4-chlorophenyl) triethoxy
silane 1f (129 µL, 0.5 mmol, 1 equiv), silver(I) nitrate (254.8 mg, 1.5 mmol, 3 equiv) in anhydrous
1,2-dichloroethane (DCE) (1 mL, 0.5 M), and chlorotrimethylsilane (TMSCl) (133 µL, 1.05 mmol,
2.1 equiv) at 100 °C for 24 h under nitrogen atmosphere. The residue was purified by flash column
chromatography through a silica gel column to afford 2f as a light yellow oil in 41% yield (32.1
mg).
1
H NMR (500 MHz, Chloroform-d) δ 8.21 – 8.14 (m, 2H), 7.55 – 7.47 (m, 2H).
13
C NMR
(126 MHz, Chloroform-d) δ 146.65, 141.50, 129.70, 125.06.
NO
2
Me
NO
2
Cl
179
Nitrobenzene
129
(2g)
The reaction was carried out according to the general procedure, using triethoxyphenylsilane 1g
(121 µL, 0.5 mmol, 1 equiv), silver(I) nitrate (254.8 mg, 1.5 mmol, 3 equiv) in anhydrous 1,2-
dichloroethane (DCE) (1 mL, 0.5 M), and chlorotrimethylsilane (TMSCl) (133 µL, 1.05 mmol,
2.1 equiv) at 100 °C for 24 h under nitrogen atmosphere. The residue was purified by flash column
chromatography through a silica gel column to afford 2g as a light yellow oil in 62% yield (38.0
mg).
1
H NMR (500 MHz, Chloroform-d) δ 8.22 (d, J = 7.8 Hz, 2H), 7.70 (t, J = 7.4 Hz, 1H), 7.54
(t, J = 8.1 Hz, 2H).
13
C NMR (126 MHz, Chloroform-d) δ 148.33, 134.71, 129.43, 123.59.
1-Nitronaphthalene
129
(2j)
The reaction was carried out according to the general procedure, using (1-naphthyl)triethoxysilane
1j (145.2 mg, 0.5 mmol, 1 equiv), silver(I) nitrate (254.8 mg, 1.5 mmol, 3 equiv) in anhydrous
1,2-dichloroethane (DCE) (1 mL, 0.5 M), and chlorotrimethylsilane (TMSCl) (133 µL, 1.05 mmol,
2.1 equiv) at 100 °C for 24 h under nitrogen atmosphere. The residue was purified by flash column
chromatography through a silica gel column to afford 2j as a light yellow solid in 75% yield (64.9
mg).
1
H NMR (500 MHz, Chloroform-d) d 8.56 (d, J = 8.7 Hz, 1H), 8.22 (d, J = 7.6 Hz, 1H), 8.11
(d, J = 8.2 Hz, 1H), 7.95 (d, J = 8.2 Hz, 1H), 7.71 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.53
(t, J = 7.9 Hz, 1H).
13
C NMR (101 MHz, Chloroform-d) δ 146.69, 134.77, 134.44, 129.55, 128.71,
127.45, 125.22, 124.23, 124.11, 123.21.
NO
2
NO
2
180
3.4.6
1
H and
13
C NMR spectra of nitroarenes
1
H NMR and
13
C NMR of 4-Nitrotoluene (2a)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0
f1 (ppm)
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
3 . 2 1
2 . 0 2
2 . 0 0
2 . 4 6
7 . 3 0
7 . 3 2
8 . 1 0
8 . 1 2
1
H N M R ( 400 M H z , c d c l 3 )
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
0
100
200
300
400
500
600
700
800
900
2 1 . 7 2
1 2 3 . 6 3
1 2 9 . 9 2
1 4 6 . 0 7
1 4 6 . 2 8
13
C N M R ( 126 M H z , c dc l 3 )
181
1
H NMR and
13
C NMR of 1-Bromo-4-nitrobenzene (2c)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
6500
7000
7500
8000
8500
9000
2 . 0 0
2 . 0 0
7 . 6 8
7 . 7 0
8 . 0 9
8 . 1 1
1
H N M R ( 400 M H z , c dc l 3 )
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-20000
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
220000
240000
260000
280000
300000
1 2 5 . 1 3
1 3 0 . 1 1
1 3 2 . 7 5
1 4 7 . 1 6
13
C N M R ( 101 M H z , c dc l 3 )
182
1
H NMR and
13
C NMR of 1,3-Dimethyl-5-nitrobenzene (2d)
-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5
f1 (ppm)
-1000
0
1000
2000
3000
4000
5000
6000
7000
8000
9000
10000
11000
12000
6 . 5 8
1 . 0 0
1 . 9 6
2 . 4 1
7 . 3 0
7 . 8 2
1
H N M R ( 400 M H z , c d c l 3 )
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-20000
0
20000
40000
60000
80000
100000
120000
140000
160000
180000
200000
220000
240000
260000
280000
2 1 . 2 4
1 2 1 . 2 0
1 3 6 . 2 8
1 3 9 . 5 5
1 4 8 . 4 1
13
C N M R ( 101 M H z , c dc l 3 )
183
1
H NMR and
13
C NMR of 3-Nitrotoluene (2e)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
6500
7000
7500
3 . 1 8
1 . 0 0
1 . 0 0
1 . 9 5
2 . 4 1
7 . 3 4
7 . 3 6
7 . 3 8
7 . 4 4
7 . 4 6
7 . 9 3
7 . 9 5
1
H N M R ( 400 M H z , c dc l 3 )
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-200
0
200
400
600
800
1000
1200
1400
1600
1800
2000
2200
2400
2600
2800
3000
3200
3400
2 1 . 0 8
1 2 0 . 5 1
1 2 3 . 6 8
1 2 9 . 0 1
1 3 5 . 3 2
1 3 9 . 7 7
1 4 8 . 1 3
13
C N M R ( 126 M H z , c d c l 3 )
184
1
H NMR and
13
C NMR of 1-Chloro-4-nitrobenzene (2f)
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
2 . 0 1
2 . 0 0
7 . 5 1
7 . 5 1
7 . 5 2
7 . 5 3
8 . 1 7
8 . 1 8
8 . 1 9
1
H N M R ( 5 00 M H z , c d c l 3 )
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-100
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
1500
1600
1700
1800
1 2 5 . 0 6
1 2 9 . 7 0
1 4 1 . 5 0
1 4 6 . 6 5
1 3
C N M R ( 12 6 M H z , c d c l 3 )
185
1
H NMR and
13
C NMR of Nitrobenzene (2g)
-0.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0 8.5 9.0 9.5 10.0 10.5 11.0 11.5 12.0
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
6000
6500
2 . 0 0
1 . 0 0
1 . 9 4
7 . 5 3
7 . 5 5
7 . 5 6
7 . 6 8
7 . 7 0
7 . 7 1
8 . 2 2
8 . 2 3
1
H N M R ( 50 0 M H z , c d c l 3 )
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
0
100
200
300
400
500
600
700
800
900
1 2 3 . 5 9
1 2 9 . 4 3
1 3 4 . 7 1
1 4 8 . 3 3
13
C N M R ( 1 26 M H z , c dc l 3 )
186
1
H NMR and
13
C NMR of 1-Nitronaphthalene (2j)
-2 -1 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
f1 (ppm)
-500
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5500
1 . 0 3
1 . 0 4
1 . 0 7
1 . 0 6
1 . 0 4
1 . 0 2
1 . 0 0
7 . 5 1
7 . 5 3
7 . 5 4
7 . 6 0
7 . 6 1
7 . 6 3
7 . 6 9
7 . 7 1
7 . 7 2
7 . 9 4
7 . 9 5
8 . 1 0
8 . 1 1
8 . 2 1
8 . 2 3
8 . 5 5
8 . 5 6
1
H N M R ( 500 M H z ,
c dc l 3 )
-10 0 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190 200 210 220 230
f1 (ppm)
-50000
0
50000
100000
150000
200000
250000
300000
350000
400000
450000
500000
1 2 3 . 2 1
1 2 4 . 1 1
1 2 4 . 2 3
1 2 5 . 2 2
1 2 7 . 4 5
1 2 8 . 7 1
1 2 9 . 5 5
1 3 4 . 4 4
1 3 4 . 7 7
1 4 6 . 6 9
13
C N M R ( 10 1 M H z , c dc l 3 )
187
3.5 References
1. Nishiwaki, N. Molecules 2020, 25, 3680.
2. Ono, N. The Nitro Group in Organic Synthesis; Wiley Series in Organic Nitro Chemistry;
John Wiley & Sons, Inc.: New York, USA, 2001.
3. Ju, K.-S.; Parales, R. E. MMBR 2010, 74, 250.
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Chapter 4. New Molybdenum, Ruthenium and Tungsten Complexes of Tetradentate Pyridyl
Phthalazine Ligand: Synthesis, Structural Characterization and Their Exploration in
Catalytic Applications for Carbon Neutral Chemical Energy Storage
4.1 Introduction
According to a United Nations report, the world population had reached 7.8 billion at the end
of 2020, growing at a rate of around 1.05% per year. The report also indicated a growth of one
billion over the last decade. Furthermore, the world population is expected to reach 8 billion within
the next 10 years and to further increase by more than three billion by the end of the 21
st
century
according to the medium-variant projects of the United Nations Population Division.
1
Therefore,
the impressive increase of the global population accompanied by a rapid technological
development in industry has resulted in an ever growing energy demand by humankind.
2
According to a report of the International Energy Agency, over 80% of the total world energy
came from fossil fuels, mainly oil, natural gas and coal. Burning of these fossil fuels to fulfill the
increasing energy demand and consumption has led to a new record of the annual global carbon
dioxide emissions which reached to 33.1 billion metric tons. In fact, the high carbon dioxide levels
in the atmosphere produced from fossil fuel combustion and industrial processes caused a series
of increasingly severe consequences such as global warming, climate change and seawater
acidification, desiring for a sustainable energy cycle to replace the existing one.
3
Additionally, the
Intergovernmental Panel on Climate Change (IPCC) indicates a prediction of an increase in global
temperature of up to 4.8 °C over the next century unless necessary measures are adopted to use
alternative clean energy sources particularly regarding solar, geothermal, and wind as well as
nuclear energy.
4,5
200
In recent years, a promising paradigm shift has been seen in the development of the utilization
and effectiveness of carbon dioxide as a valuable industrial C1 feedstock.
6–11
The finite nature of
fossil fuels and the global environmental challenges in combination with the development of novel
technologies are paving the way for carbon dioxide to be increasingly used as an abundant, non-
toxic, and inexpensive C1 raw material in chemical reactions instead of being seen as a harmful
greenhouse gas.
2,12–14
In general, carbon dioxide can be readily captured from a variety of sources
such as flue gases of coal or natural gas burning power plants and ultimately from ambient
air.
10,12,15–21
However, the pressing anthropogenic carbon dioxide emission problem implies that
the chemical carbon cycle to meet the increasing energy demand for a sustainable future is still
enormously challenging.
Despite the much emphasized and addressed energy deficiency in the future, most of our
energy comes from fossil fuels, which are formed over long geological times by anaerobic
conversion of plant and animal life, as well as from the energy of the Sun.
9
It also should be noted
that the Sun provides us a sufficient amount of renewable energy in the form of sunlight. Moreover,
the amount of energy that the Earth receives from sunlight striking its surface in 1 h exceeds all
the energy required by humankind for an entire year.
22
Although the Sun is estimated to last for at
least another 4.5 billion years, the efficient and feasible ways to properly harness this energy, such
as capturing it, storing it, and transporting it to the points of utilization are highly desired.
5
Besides,
extensive exploitation of other renewable energy sources including solar, such as hydro, wind and
geothermal in addition to the utilization of nuclear power provides environmentally benign
approaches to generate electricity. Solar and wind, as the most common and scalable renewable
sources, are intermittent and highly fluctuating in nature, implying the necessity of storing the
obtained electrical power. It is also a main challenge for the storage of large amounts of electrical
201
energy because of several impediments associated with large-scale conventional battery storage,
such as utilization of toxic and expensive metals, large battery size and limitations on the number
of discharge/charge cycles.
2,11
Thus, a practical and large-scale technology for the storage of
energy is still a major research challenge that needs to be solved.
A myriad of theoretical and experimental studies have been reported on the approaches for the
storage of energy, such as thermal-, mechanical-, electrical-, chemical-, and superconducting
magnetic energy storage, which have attracted great attention in the last decades.
2
Among the
variety of substances that can be utilized as potential carriers of alternative clean energy for
chemical energy storage, hydrogen is considered to be a promising candidate as a chemical “energy
vector” for a sustainable energy technology of the future.
23–28
Furthermore, annually more than 60
million tons of hydrogen has been widely consumed around the world, primarily for fixation of
nitrogen from the air in the Haber-Bosch ammonia process, fertilizer and methanol production as
well as for petroleum refining. Other smaller usage of hydrogen involves reduction of metallic
ores, hydrogen welding and cutting, hydrogenation of fats and oils as well as industrial processes,
such as cooling in power plant generators, food processing, glass purification, heat treatment,
semiconductor manufacturing, chemical production, biological processes and pharmaceuticals.
29,30
Hydrogen, as the simplest molecule which only consists of two protons with two electrons, can be
generally produced by water electrolysis using electricity from renewable sources
31
followed by
storage, distribution, and then utilization of hydrogen to generate electricity on demand, which
would be a “clean” approach to store energy since the only product of the hydrogen combustion is
water, an environmentally benign compound.
2,3,32
However, only a tiny percentage of the total
production of hydrogen (around 1%) is used as an energy carrier. Concurrently, more hydrogen is
increasingly produced through water splitting technologies integrated with the improved quantity
202
of electricity generated from fossil fuel or renewable energy sources. Nevertheless, the route of
water electrolysis as well as biomass gasification may only produce hydrogen in significantly
minor scales, while the majority of hydrogen (around 95%) is prepared from fossil fuels employing
steam reforming or partial oxidation of methane and coal gasification (Figure 4.1).
33,34
Figure 4.1 Potential energy sources and primary processes for hydrogen production.
Thermochemical processes include a series of chemical reactions resulting in the
generation of hydrogen and oxygen from the decomposition of water in the presence
of heat provided by an external source. Some most common cycles are sulfur/iodine,
calcium/bromine, copper/chlorine, and metal/oxide. PV, photovoltaic; NG, natural
gas; LT, low temperature; HT, high temperature.
In recent years, hydrogen has attracted considerable attention as an advantageous energy
storage medium and sustainable fuel due to the fact that the only product generated by burning
hydrogen is water, and it has an energy density of approximately 120 MJ/kg on a mass basis,
almost three times more than diesel or gasoline.
2,35,36
In this context, the hydrogen economy is
established on the sustainable generation of hydrogen without liberating the stoichiometric
amounts of carbon dioxide.
37,38
For the accomplishment of hydrogen economy, safe and practical
203
strategies for hydrogen storage, transportation and utilization are also required.
39
Despite
enormous progress achieved in the fields of hydrogen storage technologies,
40,41
hydrogen
adsorption,
42
metal hydride technologies,
43–45
using hydrogen as a practical fuel still constitutes a
yet insufficiently solved issue particularly due to several technical problems related to its storage
and distribution. The volumetric energy density of hydrogen is pretty low. To circumvent the
difficulties associated with the transportation and storage of this highly volatile, flammable and
explosive gas, general solution for continuous production, controlled storage and efficient
distribution of hydrogen in large quantities has become a quite challenging and expanding field of
research. Hence, the development of the safe and effective approach is desired to meet the
industrial demands (ambient conditions, high power-to-volume ratios).
24,25
A variety of substances, for instance, ammonia borane,
46
alkali borohydrides,
47
hydrous
hydrazine,
47
methane,
48
methanol,
8,49
etc., have been promoted as convenient hydrogen carriers
for chemical energy storage because of their high energy density as well as the simplicity of storage,
transportation and dispensing. However, some of these materials may suffer from their relatively
high cost, toxicity and safety concerns, hampering the practical applicability and feasibility of
these substances as potential energy carriers. In addition to these chemical compounds, formic acid
(FA) and formates also have been suggested and studied as attractive candidates for hydrogen
generation since they are stable, nonflammable and nontoxic organic chemical reagents with high
hydrogen contents.
2,3,25,47,50–53
Formic acid and HCOONa/H2O can generate 4.4 wt % and 2.3 wt %
hydrogen, respectively. As formates are also noncorrosive and nonirritating, it is convenient to
handle them as safe hydrogen storage media.
24
Besides, formic acid has recently gained significant
interest for fuel cell applications on the basis of its facile oxidation kinetics, high theoretical cell
potentials, and low fuel crossover.
54
204
Figure 4.2 The commercial manufacture of formic acid from non-renewable fossil
feedstock (top) and the production of formic acid from the renewable sources biomass
and CO2 (bottom).
As the simplest yet strongest organic acid with notable values, formic acid is eco-friendly,
noncorrosive, and easily biodegradable with widespread applications. Formic acid is not only a
prominent chemical commodity in chemical-related industries, such as agriculture, animal feeds,
leather, rubbery, pharmaceuticals, and textiles,
54
but also a substantial energy carrier in renewable
energy-related fields.
55–57
Additionally, it is particularly regarded as one of the most promising
hydrogen storage materials with a significant volumetric capacity of ~53.4 g/L with the potential
to furnish the solutions to the storage and transportation issues of the gaseous fuels.
58
While the
industrial manufacture of formic acid still involves non-renewable fossil feedstock using methanol
under high pressure of carbon monoxide (CO) to form methyl formate followed by hydrolysis to
205
give FA (Figure 4.2, top),
58
the alternative strategies for large-scale production of formic acid from
renewable sources are highly desirable to reduce carbon emission and fight against climate change
for a more sustainable humankind society.
59
Recently, the most vigorously developed renewable
resources from which formic acid can be primarily synthesized are biomass
60–65
and carbon dioxide
feedstock
66–74
(Figure 4.2, bottom). Biomass representing the largest carbon resource around the
world with naturally rich functionalities
75–78
can be transformed into FA utilizing a variety of
methods including acid hydrolysis,
79–81
wet oxidation,
82–87
and catalytic oxidation
61,63,88–92
with
good yield and selectivity. As biomass is generally produced from CO2 and water through
photosynthesis using solar energy, the biobased FA obtained by economically appealing
production is an eco-friendly and safe agent for energy storage and chemical processes, which
would emit the carbon back into the atmosphere to close the carbon cycle without releasing extra
carbon upon decomposition.
58,93
Meanwhile, carbon dioxide as another crucial resource can be
directly converted to formic acid via hydrogenation/reduction with various strategies, for instance
chemical, photochemical and electrochemical catalysis, and the commonly used reducing agents
are hydrogen, water, etc.
Scheme 4.1 Decomposition pathways of FA: (a) decarboxylation or dehydrogenation; (b)
decarbonylation or dehydration
206
Figure 4.3 Decomposition pathways of FA: (a) decarboxylation or dehydrogenation;
(b) decarbonylation or dehydration (Adapted with permission from ref 2. Copyright
2016 American Chemistry Society)
Furthermore, many theoretical and experimental studies have reported that the decomposition
of formic acid may take place through two main pathways: (a) decarboxylation resulting in a 1:1
mixture of carbon dioxide and hydrogen; and (b) decarbonylation giving carbon monoxide and
water in a 1:1 ratio (Scheme 4.1).
3,25,94
Subsequently, the former hydrogen and carbon dioxide
mixture can be utilized directly as a feedgas in a hydrogen/air proton exchange membrane (PEM)
fuel cell, which is a remarkable and well-built technology providing high fuel cell efficiencies.
95–
97
In the presence of an appropriate and efficient catalyst, formic acid can be decomposed into
CO2 and hydrogen selectively and a “carbon neutral” energy/hydrogen storage system will be
established and envisioned (Figure 4.3), where carbon dioxide formed via decomposition reaction
can be recycled and converted back to formic acid.
2,3,25,98–104
Since carbon monoxide from the
decomposition reaction of FA through pathway (b) has deteriorative effect on the catalyst of fuel
cells where the gaseous products can be fed into, the development of novel catalysts for the
selective decarboxylation of FA are highly desirable to minimize the decarbonylation pathway (b)
as much as possible.
101
Moreover, achieving high activity and robustness of the catalysts, as well
207
as suppressing CO formation in the course of formic acid decomposition are challenging in both
HCO2H to H2 + CO2 and HCO2Na + H2O to H2 + NaHCO3 systems for renewable hydrogen
storage.
2,14,105–107
Over several decades of research, homogeneous hydrogenation of carbon dioxide to formic
acid or formate salts has been widely studied with a number of ruthenium-,
14,70,105,108–127
iridium-,
101,128–134
rhodium-,
135–141
iron-,
142–147
nickel-,
148–151
copper-,
152,153
and molybdenum-
based
154
catalysts. In the 1970s, Inoue and co-workers
112,155
first reported the homogeneous carbon
dioxide hydrogenation to formate salts using a series of transition-metal complexes (including Pd,
Fe, Co, Ni, Ru, Rh, and Ir) in combination with alcohols and amines as cocatalysts. In 2009, Nozaki
and co-workers
132
reported an extremely impressive turnover frequency (TOF) of 150,000 h
-1
at
200 °C under 50 bar H2/CO2 (1:1) and the highest turnover number (TON) of 3,500,000 at 120 °C
under 60 bar gas pressure for the hydrogenation of carbon dioxide employing a newly developed
iridium trihydride PNP
1
pincer catalyst [PNP
1
= 2,6-bis(di-iso-propylphosphinomethyl)pyridine]
(Figure 4.4, a) in the presence of KOH and THF. This catalytic system improved the
aforementioned values (TOF. and TON) 1.5 times and 15 times, respectively, over activities of
previous catalysts under similar reaction conditions. Later, an even higher TOF of 1,100,000 h
-1
at
120 °C under 40 bar pressure (3H2/1CO2) was obtained by Pidko and co-workers
110
in 2014 using
a ruthenium PNP
2
[2,6-bis(di-tert-butylphosphinomethyl)-pyridine] pincer complex (Figure 4.4,
b) bearing hydride, chloro, and carbon monoxide ligands, which is the most efficient catalyst
system to date for the hydrogenation of carbon dioxide. More recently, parallel to the work by the
groups of He,
135
Heldebrant,
156,157
and Leitner,
121
the group of Prakash and Olah
158
demonstrated
that the efficient amine-promoted capture and subsequent in situ hydrogenation of CO2 to formates
proceed smoothly using well-defined iron PNP pincer complex (Figure 4.4, c) as a catalyst, which
208
is previously utilized as an effective catalyst for the selective dehydrogenation of methanol by
Beller and co-workers.
159
In this report, a biphasic solvent system for homogeneous FA synthesis
from carbon dioxide was also performed and coupled with the investigation of catalyst
recyclability, giving an overall TON for formate > 7,000 in five consecutive cycles. Over the
years, the homogeneous carbon dioxide hydrogenation to FA or its salts has been investigated
under a broad range of conditions, such as using both precious and nonprecious metal catalysts,
testing a variety of solvents including water, in the presence of organic and inorganic bases, as
well as in the absence of basic promoters. All these studies have been summarized in a series of
reviews, where both the tremendous advances in the field and the scientific and technological
challenges that remain to be addressed are highlighted and discussed in details.
56,160–167
Figure 4.4 Structure of metal pincer catalysts active in CO2 hydrogenation in basic media.
Concurrently, varied combinations of transition metals and stabilizing ligands have been
studied as highly active catalysts to enhance the selectivity of the FA decomposition to hydrogen
and carbon dioxide. In the early 1910s, the first report on the catalytic decomposition of FA
utilizing heterogeneous catalysts was published by Sabatier and Mailhe.
168,169
Since then, a large amount of heterogeneous catalysts, for example SiO2, Al2O3, TiO2, MgO, ZnO,
Fe3O4, Cr2O3, and ThO2, were investigated for the formic acid dehydrogenation. However, harsh
Ir
N
H
(
i
Pr)
2
P P(
i
Pr)
2
H
H
Ru
N
CO
(
t
Bu)
2
P P(
t
Bu)
2
Cl
H
Fe
Br
CO
HN
P(
i
Pr)
2
(
i
Pr)
2
P
H
a b c
209
temperature condition (around 300 °C) was required for these catalysts to provide high conversions
of FA to hydrogen.
170
Only a smaller quantity of heterogeneous catalysts, for instance, a Ag-Pd
core-shell nanocatalyst, was required under mild conditions for FA decomposition with no
detectable CO in the gaseous products,.
171
In addition to the development of homogeneous
catalysts, a variety of ruthenium-,
95,105,110,172–176
iridium-,
101,177–188
rhodium-,
139,189–191
and iron-
containing
99,192,193
complexes as homogeneous catalysts were also tested for selective hydrogen
generation from formic acid. It is worth mentioning the results obtained by Fukuzumi,
189
Wills,
194,195
Puddephatt and co-workers
117,196
as well as the work of Laurenczy et al.
95,98
who
demonstrated the possibility of using ruthenium catalysts in combination with the water soluble
TPPTS ligand [TPPTS = tris-(meta-sulfonatophenyl)phosphine] for selective hydrogen release
from formic acid in an aqueous solution of HCOOH/HCOONa (9:1). In parallel, Beller and co-
workers
100
reported another highly efficient ruthenium catalyst formed by adding triethylamine
(TEA) and PPh3 to RuX3 (X = Cl, Br), exhibiting an outstanding TOF of 3630 h
-1
at 40 °C after
20 min. In 2011, our group
25
not only reinvestigated H2 evolution from FA/HCOONa aqueous
solution using RuCl3 as the catalyst precursor in the absence of ligand but also presented
FA/HCOONa dehydrogenation using synthesized [Ru4(CO)12H4] as catalyst in DMF, resulting in
CO-free hydrogen production under atmospheric pressure. In a subsequent investigation,
3
selective
FA decomposition for H2 generation was carried out applying the same catalyst precursor (RuCl3)
with a diversity of stabilizing phosphine ligands. To further develop the approach for renewable
hydrogen storage, our group integrated the selective FA/HCOONa dehydrogenation in presence
of IrCl3 and N-donor ligands (Scheme 4.2) with a H2/air proton exchange membrane (PEM) fuel
cell, providing a stable and continuous conversion of chemical energy to electricity. In recent years,
Himeda and co-workers
101
reported an exceptional TOF of 228,000 h
-1
at 90 °C for the
210
dehydrogenation of formic acid using a [(Ir(Cp*)(Cl))2(thbpym)]
2+
catalyst (Cp* =
pentamethylcyclopentadienide, thbpym = 4,4’,6,6’-tetrahydroxy-2,2’-bipyrimidine).
Subsequently, an improved TOF of 322,000 h
-1
at 100 °C was achieved by the same group
employing a [Cp*Ir(2,4-(HO)2-pm-imidazoline)(OH2)]SO4 complex, which includes 6-(4,5-
dihydro-1H-imidazol-2-yl)- pyrimidine-2,4-diol as a ligand.
188
Many review articles have already
summarized the development of selective FA decomposition for hydrogen storage using a vast
scope of catalysts, and also have disclosed the current challenges and the perspectives in this field
at their respective times.
2,50,53,56,103,106
Scheme 4.2 Hydrogen generation from FA decomposition in the presence
of IrCl3 and selective N-donor ligands
HCOOH H
2
+ CO
2
IrCl
3
, ligand, H
2
O
HCOONa, 90-100 °C
ligands:
N
N N
N N
N
N
N
N N
NH
N
N
N
N
NH
N
HN
N
N
N
py bpy phen
TMEDA PMDETA
IndH PAPH
2
211
Although these hydrogen-storage systems for hydrogenation of CO2 or dehydrogenation of FA
with excellent performance have been widely reported, it remains a challenge for the practical
adoption of these systems because of the relatively high prices of the catalysts. In addition to this,
basic additives such as the volatile amines reported to enhance the CO2 hydrogenation step for
storage or to be indispensable for hydrogen generation by FA decomposition may contaminate the
gaseous products, which complicates the construction of practical H2 charge/discharge devices.
The major concerns are caused by the loss of amine additives during hydrogen liberation from
formates or adducts and the necessity for an extra gas purification unit.
3
Despite much effort
devoted to overcoming these problems, the development of a cost-effective hydrogen-storage
system consisting of operational simplicity and environmental compatibility is highly desired as a
long-term goal, suggesting the absence of additives and organic solvents. For the broad practical
application of the hydrogen-storage system constructed by FA formation and decomposition, it is
essential to develop novel, practical and efficient catalyst with less expensive and stable ligands
that can be synthesized in large scales, which could lead to significant improvements in terms of
catalytic activity, selectivity, stability, recyclability, and energy efficiency.
3,56
Scheme 4.3 Structure of the ligand PAPH2
N
N
HN
HN
N
N
N
NH
N
HN
N
N
1: PAPH
2
a b
212
Herein, we report for the first time the synthesis, structure determination and characterization
of several new molybdenum, ruthenium and tungsten complexes of the tetradentate N-donor ligand,
1,4-di(2′-pyridyl)aminophthalazine (PAPH2, 1) (Scheme 4.3). In the present work, single crystals
suitable for X-ray crystallography have been obtained. Furthermore, we also present an initial
investigation on the catalytic reactivity of these new complexes in hydrogenation of carbon dioxide
(storage) and hydrogen production from FA decomposition as well as some other potential organic
transformation for their application in the carbon neutral chemical energy storage.
4.2 Results and discussion
Synthesis and Characterization of [Mo(PAPH2)(CO)4] (2)
Complex 2 was isolated as an orange-red solid by the reaction of Mo(CO)6 with the tetradentate
N-donor ligand PAPH2 in a methanol and toluene solvent under carbon monoxide pressure, as
summarized in Scheme 4.4.
Scheme 4.4 Preparation of [Mo(PAPH2)(CO)4]
In its infrared spectrum, two N-H stretching absorptions occur at 3314 and 3335 cm
-1
,
indicating the presence of two types of the NH grouping. One of the NH groups bound to an
exocyclic amine nitrogen exhibits coupled C=N stretching vibrations above1600 cm
-1
(1621 and
Mo
CO
CO
CO
CO
OC
OC
+
N
N
HN
HN
N
N
5ml MeOH
5ml Toluene
50 spi CO
6 h, 100 °C
N
N
HN
HN
N
N
Mo
CO
CO
CO
CO
2
213
1608 cm
-1
). Therefore, the PAPH2 ligand is expected to exist in the tautomeric form (Scheme 4.3,
a). Similar structure of this ligand were also obtained for iron complexes.
197,198
Meanwhile, this
complex exhibits pyridine ring breathing mode vibrations above 1000 cm
-1
, suggesting that the
ligand PAPH2 behaves in a tetradentate fashion because of the coordination of the pyridine
ring.
199,200
In addition, the peaks at 1885, 1850, 1800, and 1775 cm
-1
could be attributed to the four
different CO stretching modes, respectively, demonstrating the CO coordination to molybdenum.
Table 4.1 Analytic data of [Mo(CO)4(PAPH2)] by CHNS analysis
% Calculated Found Percent Errors/%
N 16.09 15.8458 1.52
C 50.588 49.9689 1.22
H 2.7016 2.6766 0.92
According to the HRMS result of complex 2, the formula of this crystal is C22H14N6O4Mo.
MH
+
peak was found at around 527 (m/z). The peaks at 497.0, 468.0, 441.0, 413.0 m/z can be
attributed to the sequential loss of CO molecules, respectively. The intensive peak at 315.1 m/z is
due to the PAPH3
+
formation. In the
13
C NMR spectrum, the triplet peak at 225.3 ppm also shows
the existence of CO structure in [Mo(PAPH2)(CO)4]. Furthermore, the results of CHNS elemental
analysis illustrate that the accurate composition of this orange complex 2 is MoC22H14N6O4 as well
(Table 4.1).
X-ray crystal structure of complex [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH
Complex 2 has been further structurally characterized by crystallization at low temperature and
X-ray crystallography. The molecular structure and atom numbering scheme of this compound is
shown in Figure 4.5. Crystallographic data and details of the structure determination are given in
Table 4.2, and selected bond lengths and angles are listed in Table 4.3.
214
Figure 4.5 Molecular structure of complex [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH. The
solvent molecules have been omitted for clarity. Thermal ellipsoids are drawn at the 50%
probability level.
This complex is a mono-molybdenum compound which is coordinated by one phthalazine (N1)
and one pyridine (N6) nitrogen atom of the aminophthalazine ligand and by four CO groups. The
Mo center is in a distorted octahedral environment, which is evidenced by all the angles around
the metal centers deviating from 80° to 180°. The PAPH2 ligand performs as a bidentate ligand
existing in a tautomeric form (Scheme 4.3, a). This contrasts with the molecular structure of the
free ligand compound, where only one hydrogen atom is on the exocyclic nitrogen atom (N5)
while the other hydrogen is on the phthalazine nitrogen atom (N2) (Scheme 4.3, b).
197,201
The C12-
N1 bond length in the phthalazine ring of 1.317 Å is shorter than that of the exocyclic nitrogen
atom, where the C12-N5 bond length is 1.389 Å. The distances betwen these corresponding atoms
were observed in the same pattern for both reported copper and iron complexes of the PAPH2
ligand.
197,202,203
The bond lengths of Mo-COterminal are all around 2 Å, which are typical and in
215
agreement with the results of similar molybdenum carbonyl complexes.
204–206
The four carbonyl
ligands around Mo are asymmetric demonstrated by the various bond lengths of Mo-C and C-O as
well as the bond angles of Mo-C-O. The Mo-N bond lengths of 2.232 and 2.273 Å are similar to
the reported complexes with the same sterically hindered phthalazine ligand.
198,207
Table 4.2 Crystallographic parameters for [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH
Compound reference [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH
Chemical formula C26.5 H22 Mo N6 O5
Formula weight 600.44
Crystal system Monoclinic
a/Å 9.2190(4)
b/Å 19.6008(9)
c/Å 15.3072(7)
α/° 90
β/° 93.4329(7)
γ/° 90
Dcalcd (g/cm
3
) 1.444
Crystal size (mm) 0.241 x 0.175 x 0.115
Unit cell volumn/Å
3
2761.04
Temperature/K 100.(2)
Space group P 21/n
Number of formula units per unit cell, Z 4
Radiation type MoK\α
Absorption coefficient, μ/mm
−1
0.521
No. of reflections measured 8412
No. of independent reflections 7100
Rint 0.0344
Final R1 values (I > 2σ(I)) 0.0496
Final wR values (I > 2σ(I)) 0.1427
Final R1 values (all data) 0.0603
Final wR values (all data) 0.1505
Goodness of fit 1.062
216
Table 4.3 Selected bond lengths (Å) and angles (°) for [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH
Bond lengths (Å) Bond angles (°)
Mo1-C1 2.024 C1-Mo1-C2 170.7(1)
Mo1-C2 2.047 C1-Mo1-C3 88.1(1)
Mo1-C3 1.965 C1-Mo1-C4 84.2(1)
Mo1-C4 1.964 C1-Mo1-N1 92.8(1)
Mo1-N1 2.232 C1-Mo1-N6 98.4(1)
Mo1-N6 2.273 C2-Mo1-C3 88.3(1)
N1-N2 1.380 C2-Mo1-C4 87.2(1)
N1-C12 1.317 C2-Mo1-N1 91.4(1)
N2-C5 1.308 C2-Mo1-N6 90.5(1)
C12-N5 1.389 C3-Mo1-C4 90.3(1)
C5-N3 1.381 C3-Mo1-N1 176.4(1)
C18-N5 1.390 C3-Mo1-N6 97.1(1)
C13-N3 1.397 C4-Mo1-N1 93.3(1)
N4-C13 1.346 C4-Mo1-N6 172.2(1)
N6-C18 1.343 N1-Mo1-N6 79.34(9)
N4-C17 1.340 C12-N1-Mo1 122.7(2)
N6-C22 1.359 C18-N6-Mo1 120.2(2)
C1-O1 1.147 C12-N5-C18 125.7(2)
C2-O2 1.148 C5-N3-C13 130.4(2)
C3-O3 1.161 Mo1-C1-O1 171.3(3)
C4-O4 1.158 Mo1-C2-O2 173.5(3)
Mo1-C3-O3 179.4(3)
Mo1-C4-O4 177.5(3)
Synthesis and Characterization of [W(PAPH2)(CO)4] (3)
Complex 3 was synthesized as a bright orange solid by the reaction of equimolar amounts of
W(CO)6 and the tetradentate N-donor ligand PAPH2 in a mixed methanol and toluene solvent
under lower carbon monoxide pressure compared to the synthesis of complex 2, as presented in
Scheme 4.5.
217
Scheme 4.5 Preparation of [W(PAPH2)(CO)4]
In its infrared spectrum, similar to complex 2, two N-H stretching absorptions occur at 3320
and 3339 cm
-1
, indicating the presence of two types of the NH group. One of the NH group bound
to an exocyclic amine nitrogen exhibits coupled C=N stretching vibrations above1600 cm
-1
(1625
and 1610 cm
-1
). Therefore, the PAPH2 ligand is expected to exist in the tautomeric form (Scheme
4.3, a). Similar structure of this ligand were also obtained for iron complexes as well as complex
2.
197,198
Meanwhile, this complex exhibits pyridine ring breathing mode vibrations above 1000
cm
-1
, indicating that the ligand PAPH2 behaves in a tetradentate fashion because of the
coordination of the pyridine ring.
199,200
In addition, the bands at 1997, 1900, 1842, and 1779cm
-1
could be attributed to the asymmetric carbonyl stretching vibration, suggesting the remained CO
coordination to tungsten. These values are in good agreement with those reported tungsten
carbonyl complexes.
208–210
Furthermore, the results of CHNS elemental analysis illustrate that the
accurate formula of this orange complex 3 is WC22H14N6O4 (Table 4.4).
Table 4.4 Analytic data of [W(CO)4(PAPH2)] by CHNS analysis
% Calculated Found Percent Errors/%
N 13.77 13.5566 1.55
C 43.302 42.8560 1.03
H 2.3079 2.2883 0.85
W
CO
CO
CO
CO
OC
OC
+
N
N
HN
HN
N
N
5ml MeOH
5ml Toluene
10 psi CO
6 hours
100 °C
N
N
HN
HN
N
N
W
CO
CO
CO
CO
218
X-ray crystal structure of complex [W(PAPH2)(CO)4]•0.5PhMe•MeOH
Complex 3 has been further crystallized at low temperature as a clear orange-red color crystal
and then structurally characterized by X-ray crystallography. The molecular structure and atom
numbering scheme of this compound is shown in Figure 4.6. Crystallographic data and details of
the structure determination are given in Table 4.5, and selected bond lengths and angles are listed
in Table 4.6. The complex is a mono-tungsten compound, which is coordinated by one phthalazine
(N1) and one pyridine (N3) nitrogen atom of the aminophthalazine ligand and by four CO ligand
groups. The W center is in a distorted octahedral environment, which is evidenced by all the angles
around the metal centers deviating from 80° to 180°. The PAPH2 ligand serves as a bidentate ligand
existing in a tautomeric form (Scheme 4.3, a). This contrasts with the molecular structure of the
free ligand compound, where only one hydrogen atom is on the exocyclic nitrogen atom (N5)
while the other hydrogen is on the phthalazine nitrogen atom (N2) (Scheme 4.3, b).
197,201
The C12-
N1 bond length in the phthalazine ring of 1.317 Å is shorter than that of the exocyclic nitrogen
atom, where the C12-N5 bond length is 1.389 Å. The distances of these corresponding atoms were
observed in the same pattern for both reported copper and iron complexes of the PAPH2
ligand.
197,202,203
The bond lengths of W-COterminal are all around 2 Å, which are typical and in good
agreement with the results of similar tungsten carbonyl complexes.
208,208,210
The four carbonyl
ligands around tungsten are asymmetric evidenced by the various bond lengths of W-CO and C-O
as well as the bond angles of W-C-O. The W-N bond lengths of 2.226 and 2.259 Å are similar to
the reported complexes with the same sterically hindered phthalazine ligand.
211,212
Overall, the
crystal structure of tungsten complex 3 is very close to that of molybdenum complex 2.
Nevertheless, they may behave differently with various reactivity and applicability due to the
different metal centers.
219
Figure 4.6 Molecular structure of complex [W(PAPH2)(CO)4]•0.5PhMe•MeOH. The solvent
molecules have been omitted for clarity. Thermal ellipsoids are drawn at the 50% probability level.
Table 4.5 Crystallographic parameters for [W(PAPH2)(CO)4]•0.5PhMe•MeOH
Compound reference [W(PAPH2)(CO)4]•0.5PhMe•MeOH
Chemical formula C26.5 H22 W N6 O5
Formula weight 688.35
Crystal system Monoclinic
a/Å 9.2246(4)
b/Å 19.6392(9)
c/Å 15.2149(7)
α/° 90
β/° 93.1090(7)
220
γ/° 90
Dcalcd (g/cm
3
) 1.661
Crystal size (mm) 0.254 x 0.181 x 0.158
Unit cell volumn/Å
3
2752.33
Temperature/K 100.(2)
Space group P 21/n
Number of formula units per unit cell, Z 4
Radiation type MoK\α
Absorption coefficient, μ/mm
−1
4.243
No. of reflections measured 8408
No. of independent reflections 6932
Rint 0.0489
Final R1 values (I > 2σ(I)) 0.0341
Final wR values (I > 2σ(I)) 0.0883
Final R1 values (all data) 0.0463
Final wR values (all data) 0.0940
Goodness of fit 1.058
Table 4.6 Selected bond lengths (Å) and angles (°) for [W(PAPH2)(CO)4]•0.5PhMe•MeOH
Bond lengths (Å) Bond angles (°)
W1-C1 1.964 C1-W1-C2 88.5(2)
W1-C2 2.036 C1-W1-C3 91.0(2)
W1-C3 1.962 C1-W1-C4 88.2(2)
W1-C4 2.018 C1-W1-N1 96.5(1)
W1-N3 2.226 C1-W1-N6 175.9(1)
W1-N1 2.259 C2-W1-C3 87.2(2)
N3-N4 1.380 C2-W1-C4 171.0(2)
N3-C10 1.317 C2-W1-N1 90.7(1)
N4-C17 1.306 C2-W1-N6 91.2(1)
C10-N2 1.390 C3-W1-C4 84.5(2)
221
C17-N5 1.381 C3-W1-N1 172.1(2)
C9-N2 1.387 C3-W1-N6 93.1(1)
C18-N5 1.394 C4-W1-N1 98.0(1)
N1-C9 1.343 C4-W1-N6 92.6(1)
N6-C18 1.347 N1-W1-N6 79.4(1)
N1-C5 1.361 C9-N1-W1 120.3(2)
N6-C22 1.347 C10-N3-W1 122.9(2)
C1-O1 1.167 C9-N2-C10 125.2(3)
C2-O2 1.157 C17-N5-C18 130.4(3)
C3-O3 1.162 W1-C1-O1 179.0(4)
C4-O4 1.154 W1-C2-O2 173.8(3)
W1-C3-O3 177.2(4)
W1-C4-O4 172.0(4)
Synthesis and Characterization of [Ru4(PAP)2(CO)8]• C6H5CH3 (4)
The tetranuclear ruthenium (I) complex 4 was synthesized and crystallized as a clear orange
crystal by the reaction of Ru3(CO)12 with the tetradentate N-donor ligand PAPH2 using toluene as
solvent under carbon monoxide pressure followed by crystallization of the reaction mixture at low
temperature (0-4°C) for two days, as described in Scheme 4.6.
Scheme 4.6 Preparation of [Ru4(PAP)2(CO)8]• C6H5CH3
N
N
N
N
N
N
N
N
N
N
N
N
Ru
CO
OC
Ru
Ru
Ru
CO
OC
CO
OC
CO
OC
Ru
3
(CO)
12
+ 1.5
N
N
HN
HN
N
N
10ml Toluene
10 spi CO
5 h, 130 °C
4
222
In the infrared spectrum of complex 4, no single N-H stretching absorption is observed above
3000 cm
-1
, indicating the absence of the NH group. This contrasts with the structure of the neutral
ligand PAPH2 in complexes 2 and 3. In addition, the corresponding vibrations of the coupled C=N
bonds in complex 4 are anionic and have exocyclic imine moieties typically found between 1600
and 1500 cm
-1
instead of above 1600 cm
-1
. The complex 4 showed no bands between 1700 and
1600 cm
-1
but strong bands in the latter region (1599, 1582, and 1541 cm
-1
). Therefore, it supports
that the ligand is existing in the PAP format for anionic coordination of the metal center. Similar
structure of this ligand were also obtained for several copper-, cobalt- and nickle-based
complexes.
199,207,213
Meanwhile, this complex exhibits pyridine ring breathing mode vibrations
above 1000 cm
-1
, suggesting that the ligand PAP behaves in a tetradentate fashion because of the
coordination of the pyridine ring.
199,200
In addition, the peaks at 2051, 2035, 2010, 1985, 1966,
1930, and 1919 cm
-1
could be attributed to the variety of CO stretching modes, demonstrating the
CO coordination to ruthenium. These values are in good agreement with those reported results of
the similar ruthenium carbonyl complexes.
214–216
Besides, this suggests that more carbonyl
terminal ligands are obtained in complex 4 when compared to complexes 2 and 3.
Table 4.7 Analytic data of [Ru4(PAP)2(CO)8]• C6H5CH3 by CHNS analysis
% Calculated Found Percent Errors/%
N 12.4578 12.3796 0.63
C 45.401 46.1115 1.56
H 2.68945 2.5999 3.33
According to the HRMS result of complex 4, the formula of this crystal is C51H32N12O8Ru4.
MH
+
peak was found at around 1345 (m/z) (molecular ion plus toluene). The peaks around 1257
m/z indicate the loss of toluene molecule. The peaks at 1228, 1120 m/z can be attributed to the
223
sequential loss of 2 CO molecules, respectively. The peaks around 629 m/z indicate it becomes
half of the original crystal which should be [Ru2(PAP)(CO)4H
+
]. 546 m/z peak shows the loss of
three CO molecules. Peaks around 415 m/z indicate the loss of one Ru atom and one CO molecule.
Furthermore, the results of CHNS elemental analysis illustrate that the accurate composition of
this orange complex 4 is C51H32N12O8Ru4 as well within really reasonable measurement errors
(Table 4.7).
X-ray crystal structure of complex [Ru4(PAP)2(CO)8]•C6H5CH3
Cmplex 4 has been further structurally characterized by X-ray crystallography. The molecular
structure and partial atom numbering scheme of this compound is shown in Figure 4.7.
Crystallographic data and details of the structure determination are given in Table 4.8, and selected
bond lengths and angles are listed in Table 4.9. As shown in Figure 4.7, the complex 4 is a
tetranuclear ruthenium compound where the four ruthenium centers are coordinated by various
types of nitrogen atom such as phthalazine (N3, N4, N9, N10), pyridine (N1, N6, N7, N12) and
anionic (N5, N11) nitrogen atom from two aminophthalazine ligands and by eight CO groups in
total. The four ruthenium centers are arranged in a curved line and connected by three Ru-Ru bonds
with varying bond length, 2.892, 2.677, 2.911 Å for Ru1-Ru2, Ru2-Ru3, Ru3-Ru4, respectively.
Ru1 or Ru4 center is coordinated with two pyridine (N1, N12 for Ru1 and N6, N7 for Ru4) nitrogen
atom from each of the two PAP ligands, one phthalazine (N3 for Ru1 and N9 for Ru4) nitrogen
atom and two terminal carbonyl ligands. Concurrently, Ru2 and Ru3 are coordinated with the same
types of nitrogen atoms and CO ligands. However, the structure of the complex 4 is asymmetric.
Each ruthenium center is in a distorted octahedral environment, which is evidenced by all the
angles around the metal centers deviating from 80° to 180°. The PAP ligand behaves as the
224
deprotonated structure of the free ligand compound where only one hydrogen atom is on the
exocyclic nitrogen atom (N5) while the other hydrogen is on the phthalazine nitrogen atom (N2)
(Scheme 4.3, b).
197,201
Therefore, the bond lengths of N-N in complex 4 (1.393 and 1.390 Å) are
longer than the ones in the complex 2 and 3 where the N-N bond lengths are both 1.380 Å. The
bond lengths of Ru-COterminal are all between 1.85 to 1.89 Å, which are typical and agree well with
the results of similar ruthenium carbonyl complexes.
217–220
The carbonyl ligands around Ru are
also asymmetric demonstrated by the various bond lengths of Ru-C and C-O as well as the bond
angles of Ru-C-O. The Ru-N bond lengths all around 2.1~2.2 Å are similar to the reported
complexes with the close sterically hindered phthalazine ligand.
198,207
Figure 4.7 Molecular structure of complex [Ru4(PAP)2(CO)8]•C6H5CH3. The
hydrogen atoms and solvent molecules have been omitted for clarity. Two ligands
use different but similar colors of its nitrogen and carbon atoms for clarity. Thermal
ellipsoids are drawn at the 20% probability level.
225
Table 4.8 Crystallographic parameters for [Ru4(PAP)2(CO)8]•C6H5CH3
Compound reference [Ru4(PAP)2(CO)8]•C6H5CH3
Chemical formula C51 H32 N12 O8 Ru4
Formula weight 1345.16
Crystal system Monoclinic
a/Å 15.8998(8)
b/Å 14.9046(8)
c/Å 20.4785(11)
α/° 90
β/° 97.6840(10)
γ/° 90
Dcalcd (g/cm
3
) 1.858
Crystal size (mm) 0.322 x 0.130 x 0.080
Unit cell volumn/Å
3
4809.4(4)
Temperature/K 100.(2)
Space group P 21/n
Number of formula units per unit cell, Z 4
Radiation type MoK\α
Absorption coefficient, μ/mm
−1
1.303
No. of reflections measured 14682
No. of independent reflections 12190
Rint 0.0343
Final R1 values (I > 2σ(I)) 0.0287
Final wR values (I > 2σ(I)) 0.0637
Final R1 values (all data) 0.0407
Final wR values (all data) 0.0704
Goodness of fit 1.060
226
Table 4.9 Selected bond lengths (Å) and angles (°) for [Ru4(PAP)2(CO)8]•C6H5CH3
Bond lengths (Å) Bond angles (°)
Ru1-C1 1.868 C1-Ru1-C2
90.2(1)
Ru1-C2 1.880 C1-Ru1-N1
95.4(1)
Ru2-C3 1.857 C1-Ru1-N3
86.6(1)
Ru2-C4 1.871 C1-Ru1-N12
175.7(1)
Ru3-C5 1.866 C1-Ru1-Ru2
95.76(9)
Ru3-C6 1.865 C2-Ru1-N1
98.5(1)
Ru4-C7 1.882 C2-Ru1-N3
172.85(9)
Ru4-C8 1.866 C2-Ru1-N12
89.46(9)
Ru1-N1 2.147 C2-Ru1-Ru2
106.97(8)
Ru1-N3 2.114 N1-Ru1-N3
88.18(8)
Ru1-N12 2.196 N1-Ru1-N12
88.94(8)
Ru2-N4 2.110 N1-Ru1-Ru2
152.07(6)
Ru2-N11 2.170 N3-Ru1-N12
93.21(8)
Ru3-N5 2.165 N3-Ru1-Ru2
67.04(5)
Ru3-N10 2.104 N12-Ru1-Ru2
80.19(6)
Ru4-N6 2.199 C3-Ru2-C4
87.5(1)
Ru4-N7 2.159 C3-Ru2-N4
96.0(1)
Ru4-N9 2.120 C3-Ru2-N11
172.6(1)
Ru1-Ru2 2.892 C3-Ru2-Ru1
101.71(8)
Ru2-Ru3 2.677 C3-Ru2-Ru3
92.99(8)
Ru3-Ru4 2.911 C5-Ru3-C6
91.0(1)
N3-N4 1.390 C5-Ru3-N5
95.20(9)
N9-N10 1.393 C5-Ru3-N10
172.98(9)
C1-O1 1.140 C5-Ru3-Ru2
94.88(8)
C2-O2 1.144 C5-Ru3-Ru4
107.64(8)
C3-O3 1.143 C7-Ru4-C8
89.1(1)
C4-O4 1.147 C7-Ru4-N6
88.5(1)
C5-O5 1.151 C7-Ru4-N7
98.4(1)
C6-O6 1.148 C7-Ru4-N9
172.6(1)
C7-O7 1.142 C7-Ru4-Ru3
107.33(9)
C8-O8 1.134 O1-C1-Ru1
176.9(3)
N8-C32 1.335 O2-C2-Ru1
176.0(2)
N11-C39 1.374 O3-C3-Ru2
177.4(2)
227
N2-C14 1.331 O4-C4-Ru2
175.1(2)
N5-C21 1.371 O5-C5-Ru3
177.0(2)
O6-C6-Ru3
178.4(2)
O7-C7-Ru4
174.9(3)
O8-C8-Ru4
176.2(2)
Catalytic hydrogen generation and storage
In order to further investigate the applications of these newly developed complexes, their
catalytic performances of hydrogen production from formic acid decomposition and
hydrogenation of carbon dioxide and methyl trans-cinnamate toward a carbon neutral chemical
energy storage were also tested. In the present study, the ability of our complexes to catalyze the
dehydrogenation of FA with sodium dodecyl sulfate as an additive was first explored and the
results from the experiments are summarized in Table 4.10. Unfortunately, the expected gaseous
products evolved from FA in the course of the dehydrogenation reaction such as hydrogen and
carbon dioxide were not measured using complex 2, 3, or 4 as the catalyst.
Table 4.10 Chemical composition of gaseous products from FA decomposition in the
presence of complex 2, 3, or 4 as a catalyst
Gas composition (%)
b
Entry
a
Catalyst H2 CO2 CO
1 [Mo(PAPH2)(CO)4] nd nd nd
2 [W(PAPH2)(CO)4] nd nd nd
3 [Ru4(PAP)2(CO)8]•C6H5CH3 nd nd nd
a
0.04 mmol catalyst, [FA] = 3.6 M, [HCOONa] = 0.4 M, 0.6 mmol Me(CH 2) 11OSO 3Na, 25
mL aqueous solution, T = 100 °C.
b
Determinded by gas chromatography using thermal
conductivity (TCD); nd: not detected.
228
Next, the hydrogenation of CO2 in combination with the complexes as catalysts was also
studied. The results from the experiments of CO2 hydrogenation were selectively exhibited in
Table 4.11. This reaction was carried out and tested with a variety of reaction temperatures and
several solvents including DMF, toluene and dioxane as well as in the absence of amine additives.
However, no change in the pressure of the reaction system was observed for each entry in Table
4.11, indicating catalytic inefficiency of our complexes in hydrogenation of CO2. Besides, several
experiments for hydrogenation of methyl trans-cinnamate in the presence of these complexes were
also investigated and presented in Table 4.12. Nonetheless, the hydrogenated product was not
obtained in the protocols of using complexes 2, 3, and 4 as catalysts.
Table 4.11 Hydrogenation of CO2 in the presence of complex 2, 3, or 4 as a catalyst
Entry
a
Catalyst
p(H2)/p(CO2)
[bar]
T
[°C]
Solvent Result
1 2 35/35 75 DMF no change in pressure
2 2 35/35 100 Toluene no change in pressure
3
b
2 35/35 100 Dioxane no change in pressure
4 3 35/35 100 Toluene no change in pressure
5
b
3 35/35 100 Dioxane no change in pressure
6 4 35/35 90 Toluene no change in pressure
7 4 35/35 90 Dioxane no change in pressure
a
0.03 mmol catalyst, 5 mL solvent, t = 12 h.
b
5 mmol Pentaethylenehexamine (PEHA) was
added.
Table 4.12 Hydrogenation of methyl trans-cinnamate in the presence
of complex 2, 3, or 4 as a catalyst
CO
2
CH
3
H
2
(35 bar), Cat (3 mol %)
MeOH (0.0617 M), 12 h, T
CO
2
CH
3
229
Entry
a
Catalyst
T
[°C]
Solvent Result
1 2 75 MeOH no change in pressure
2 2 90 MeOH no change in pressure
3
3 100 MeOH no change in pressure
4 4 110 MeOH no change in pressure
a
0.617 mmol methyl trans-cinnamate (1 equiv, 100 mg), 0.02 mmol catalyst
(3 mol %), 10 mL solvent, t = 12 h.
4.3 Conclusion
For the first time, we have developed three new molybdenum, tungsten, and tetranuclear
ruthenium(I) complexes with 1,4-di(2’-pyridyl)aminophthalazine ligand, [Mo(PAPH2)(CO)4] (2),
[W(PAPH2)(CO)4] (3), and [Ru4(PAP)2(CO)8]•C6H5CH3 (4). These complexes were also
structurally characterized by elemental analysis, HRMS, and IR spectroscopy. In addition, the
single crystals of all three complexes were grown for an X-ray diffraction study. The structure
analysis of X-ray crystallography has suggested that the coordination geometry around the
molybdenum and tungsten atom as well as the ruthenium(I) ion is distorted octahedral.
Furthermore, the catalytic activity of these new complexes was also investigated on the
hydrogenation of carbon dioxide and methyl trans-cinnamate (hydrogen storage) and hydrogen
generation from FA decomposition toward a carbon neutral chemical energy storage, albeit
excellent catalytic abilities for these transformations were not observed. Further studies on the
scope of these complexes as safe and efficient catalyst or reagent systems for various other
synthetic transformations are currently underway in our laboratory.
230
4.4 Experimental details
4.4.1 General information
Material information. Unless otherwise stated, all the chemicals were purchased from
commercial sources such as Sigma-Aldrich, Alfa Aesar, Fisher Scientific, Frontier Scientific, TCI,
and Oakwood, and used without further purification. Hydrogen gas (Gilmore, ultra high pure
grade), carbon dioxide gas (Gilmore, instrument grade), 1:1 H2/CO2 gas (Airgas, grade = certified
standard-spec), nitrogen (Airgas, pre-purified grade), and carbon monoxide (Gilmore, chemically
pure grade) were used as received without any purification. Ligand 1,4-di-(2'-
pyridyl)aminophthalazine (PAPH2) was synthesized according to a modified procedure of
Thompson and co-workers.
221
Equipment Information. The catalytic reactions for energy storage appliction were carried out in
a 125 mL Monel Parr reactor. The Parr autoclave was heated in an oil bath. The internal
temperature and pressure of the reactor were recorded utilizing LabVIEW 8.6. except for the
preparation of ligand PAPH2. The gas mixture was analyzed using a Thermo gas chromatograph.
The column used is Supelco, Carboxen 1010 plot, 30 m x 0.53 mm, equipped with a TCD detector
(detection limit: 0.099 v/v%). The infrared spectra of the prepared complexes 2, 3, and 4 were
obtained using a Jasco FT-IR 4600 instrument.
1
H and
13
C nuclear magnetic resonance (NMR)
spectra were recorded on 400 MHz, 500 MHz or 600 MHz Varian NMR spectometers. NMR data
are represented as follows: chemical shift (d), multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet), coupling constant in Hertz (Hz), and integration.
1
H NMR chemical shifts
were determined relative to CDCl3 as the internal standard at 7.26 ppm.
13
C NMR chemical shifts
were determined relative to
13
C signal of CDCl3 solvent at 77.16 ppm.
231
4.4.2 Synthesis of ligand PAPH2 (1)
2
In a round-bottomed flask, 3.2 g (25 mmol, 2 equiv) phthalonitrile and 1.177 g (12.5 mmol, 1
equiv) 2-aminopyridine were mixed with a magnetic bar and heated to 200 °C. This temperature
was maintained for 8 hours and then the hot and still molten reaction mixture was poured quickly
into 200 mL ethanol. After filtration, the crude product was recrystallized from boiling ethanol
giving 6.08 g of fluffy green solid IndH in 81.5% yield. Subsequently, 2.06 g (9 mmol) of IndH
was dissolved in 170 mL methanol under reflux in a round-bottom flask. The flask was removed
from the oil bath and 0.96 mL hydrazine hydrate was added into the homogeneous brown solution
dropwise. Then the solution was heated under reflux for 12 hours. The reaction mixture was
allowed to cool down to room temperature giving a yellow precipitate. Recrystallization of the
precipitate from boiling ethanol provided nice shiny yellow crystals of 1.35 g in 47.8% yield.
4.4.3 Preparation of [Mo(PAPH2)(CO)4] complex (2)
63mg (0.238 mmol) molybdenum hexacarbonyl, 75 mg PAPH2 (0.238 mmol) (Mo:PAPH2=1:1),
5 mL MeOH and 5 mL toluene were mixed in a 15 mL pressure tube equipped with a pressure
gauge and pressure relief valve. The reaction mixture was stirred under a CO pressure of 10 psi at
100 °C for 6 hours giving a dark red solution and a few amounts of brown solid. After the reaction,
232
the obtained suspension was vacuum filtered giving a brown solid and orange red filtrate. During
the vacuum filtration, some orange precipitate was formed from filtrate in the side-arm Erlenmeyer
flask. The filtrate was vacuum filtered giving 74.1 mg orange powder (yield 59.6%). FTIR (ATR,
cm
-1
) nCO = 3335, 3314, 2007, 1885, 1850, 1800, 1775, 1621, 1608, 1589, 1578, 1540, 1503, 1471,
1430. HRMS: C22 H14 N6 O4 Mo, MH
+
peak was found at around 527 (m/z).
4.4.4 Preparation of [W(PAPH2)(CO)4] complex (3)
67.1 mg (0.191 mmol) tungsten hexacarbonyl, 60 mg PAPH2 (0.191 mmol) (W:PAPH2=1:1), 5
mL MeOH and 5 mL toluene were mixed in a 15 mL pressure tube equipped with a pressure gauge
and pressure relief valve. The reaction mixture was stirred under a CO pressure of 10 psi at 100 °C
for 6 hours giving a dark red solution. The heating was turned off but the reactor was left in the oil
bath in order to prevent a fast cooling and the formation of microcrystalline products. The dark red
solution was kept in the fridge (0-4 °C) for two days giving red orange crystals. The obtained big
orange crystals were vacuum filtered giving a mass of 90.9 mg (yield 66.2%). FTIR(ATR, cm
-1
)
nCO = 3339, 3320, 1997, 1900, 1842, 1779, 1625, 1610, 1594, 1578, 1543, 1504, 1470, 1458, 1429.
HRMS: C22 H14 N6 O4 W, MH
+
peak was found at around 610 (m/z).
4.4.5 Preparation of [Ru4(PAP)2(CO)8]•CH3C6H5 complex (4)
67.8 mg (0.106 mmol) Ru3(CO)12, 50 mg (0.159 mmol) PAPH2 (1:1.5 of Ru3(CO)12:PAPH2), 10
mL toluene were mixed in a 15 mL pressure tube equipped with a pressure gauge and pressure
relief valve. The reaction mixture was stirred under a CO pressure of 10 psi at 130 °C for 5 hours
giving a dark red solution. The red solution was kept in the fridge (0-4 °C) for two days giving red
orange crystals. The obtained big orange crystals were vacuum filtered giving a mass of 36.5 mg
(yield 34.1%). C51 H32 N12 O8 Ru4 FTIR(ATR, cm
-1
) nCO = 2051, 2035, 2010, 1985, 1966, 1930,
233
1919, 1599, 1582, 1541, 1496, 1471, 1457, 1426. HRMS: C22 H14 N6 O4 W, MH
+
peak was
found at around 1345 (m/z).
4.4.6 X-ray Crystallography
Preparation for single crystals of [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH
84 mg (0.318 mmol) molybdenum hexacarbonyl, 50 mg PAPH2 (0.159 mmol) (Mo:PAPH2=2:1),
5 mL MeOH and 5 mL toluene were mixed in a 15 mL pressure tube equipped with a pressure
gauge and pressure relief valve. The reaction mixture was stirred under a CO pressure of 50 psi at
100 °C for 19 hours giving a dark red solution and a few amounts of brown solid. The obtained
system was kept in the fridge (0-4 °C) for one day. Since no crystals were formed, then it was put
into the freezer -20 °C. After several days, orange crystals were formed. Instead of directly putting
the mixture into the fridge then freezer, the obtained suspension from the other identical reaction
was vacuum filtered giving a brown solid and an orange red filtrate. Then the filtrate was passed
through a syringe filter (13 mm w/ 0.45 μm PTFE Membrane). The orange filtrate was kept in a
fridge (0-4 °C) for one day. Similarly, the orange crystals were isolated.
Crystal Structure Determinations
The X-ray intensity data for [Ru4(PAP)2(CO)8]•C6H5CH3, [W(PAPH2)(CO)4]•0.5PhMe•MeOH,
and [Mo(PAPH2)(CO)4]•0.5PhMe•MeOH were measured on a Bruker APEX II CCD system
equipped with a TRIUMPH curved-crystal monochromator and a MoKα fine-focus tube (λ =
0.71073 Å). The frames were integrated with the Bruker SAINT software package using a SAINT
V8.34C algorithm (Bruker AXS, 2013). Data were corrected for absorption effects using the multi-
scan method (SADABS 2014/5, Bruker AXS, 2014). The structures were solved and refined in F
2
using the Bruker SHELXTL Software Package (Bruker AXS, 2014). All non-hydrogen atoms were
refined anisotropically.
234
4.4.7 HRMS spectra
HRMS analysis of [W(CO)4(PAPH2)]:
235
236
HRMS analysis of W(CO)4(PAPH2)]:
237
238
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Abstract (if available)
Abstract
This dissertation mainly explored two areas of research. The first three chapters focus on the development of novel, practical and efficient organic synthetic methodologies for functional group transformations. The last chapter of this thesis describes my effort towards designing and synthesizing new transition metal based heterogeneous catalysts for potential applications in energy storage. ? Chapter one reports the preparation of poly(4-vinylpyridine) supported solid bromine/iodine complexes. These complexes with a catalytic amount of additive are found to be safe, convenient and efficient reagent systems for the ipso-bromination/iodination of arylboronic acids. The reactions occur under mild conditions and tolerate various functional groups resulting in products with high selectivity and yields. The use of the PVP-Br?/I? complexes as thermally stable halide sources and potential recycled reagents, and a simple isolation procedure of the method result in an overall efficient and green protocol for synthesis of aryl halides. ? Chapter two demonstrates the investigation of a fast and practical method for the palladium-catalyzed selective reduction of carboxylic acids to aldehydes using a phosphine-based reagent system with commodity chemicals (PPh?, NBS, Et?SiH). This protocol presents high functional group compatibility, chemoselectivity and scalability under mild reaction conditions, affording products in good yields with no overreduction to alcohols. The key reaction intermediate, acyloxyphosphonium ion, has been studied by NMR spectroscopic analysis. Direct reduction of bio-active pharmaceutical compounds has been demonstrated. This methodology allows access to deuterated aryl aldehydes using a Et?SiD reagent. ? Chapter three delivers the first efficient method for the ipso-nitration of arylsilanes under mild reaction conditions employing readily available starting materials. The transformation employs nitrate salts in combination with TMSCl as an activator, affording nitroarenes in good yields and a regioselective manner. The scope and limitations of the protocol have also been presented. ? Chapter four conveys the synthesis and structural characterization of three new transition metal based catalysts, [Mo(PAPH?)(CO)?], [W(PAPH?)(CO)?], and [Ru?(PAP)?(CO)?]•C?H?CH?. These catalysts have also been investigated on the hydrogenation of carbon dioxide and methyl trans-cinnamate, and hydrogen production from formic acid decomposition toward a carbon neutral hydrogen storage.
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Asset Metadata
Creator
Fu, Fang
(author)
Core Title
Novel methods for functional group interconversions in organic synthesis and structural characterization of new transition metal heterogeneous catalysts for potential carbon neutral hydrogen storage
School
College of Letters, Arts and Sciences
Degree
Doctor of Philosophy
Degree Program
Chemistry
Degree Conferral Date
2021-08
Publication Date
07/23/2021
Defense Date
04/26/2021
Publisher
University of Southern California
(original),
University of Southern California. Libraries
(digital)
Tag
functional group transformations,ipso-halogenation,ipso-nitration,methodology development,OAI-PMH Harvest,organic synthesis,reduction of carboxylic acids,transition metal catalysts
Format
application/pdf
(imt)
Language
English
Contributor
Electronically uploaded by the author
(provenance)
Advisor
Prakash, Surya G. K. (
committee chair
), Sharada, Shaama Mallikarjun (
committee member
), Takahashi, Susumu (
committee member
)
Creator Email
fangfu@usc.edu
Permanent Link (DOI)
https://doi.org/10.25549/usctheses-oUC15619461
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UC15619461
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etd-FuFang-9844
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Dissertation
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Fu, Fang
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Tags
functional group transformations
ipso-halogenation
ipso-nitration
methodology development
organic synthesis
reduction of carboxylic acids
transition metal catalysts