Efficient and accessible silane-mediated direct amide coupling of carboxylic acids and amines

Article abstract of DOI:10.1039/d0gc02833a

A straightforward method for the direct synthesis of amides from amines and carboxylic acids without exclusion of air or moisture using diphenylsilane with N-methylpyrrolidine has been developed. Various amides are made efficiently, and broad functional group compatibility is shown through a Glorius robustness study. A gram-scale synthesis demonstrates the scalability of this method. This journal is

Full text of DOI:10.1039/d0gc02833a

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DOI: 10.1039/D0GC02833A
COMMUNICATION
Efficient and Accessible Silane-Mediated Direct Amide Coupling of
Carboxylic Acids and Amines
a
a
a
Melissa C. D’Amaral, Nick Jamkhou, and Marc J. Adler*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
A straightforward method for the direct synthesis of amides from impractical for the general synthesis of amides or peptides,
amines and carboxylic acids without exclusion of air or moisture specifically those with sensitive functionalities.
using diphenylsilane with N-methylpyrrolidine has been
A variety of alternative approaches to amide bond
developed. Various amides are made efficiently, and broad formation have been developed to circumvent this issue. One
functional group compatibility is shown through a Glorius route is through the use of more electrophilic carboxylic acid
robustness study. A gram-scale synthesis demonstrates the derivatives, including acid chlorides. However, such derivatives
2
scalability of this method.
are highly reactive, which can result in unwanted reactivity,
and they require additional synthetic steps to access them from
naturally occurring sources. In situ preactivation of the
carboxylic acid using stoichiometric coupling reagents is the
Introduction
The amide is a cornerstone functional group in organic
chemistry. Amide-containing molecules are crucial in a variety
of fields: 25% of drugs on the market contain an amide bond
2
most widely used method for amide bond formation. The most
common
coupling
reagents
include
carbodiimides,
uronium/phosphonium salts, or benzotriazoles. Despite high
efficiency, these reagents result in poor atom economy and
toxic by-products, and they can require harsh conditions,
(including all peptidic and each of the top six selling small-
molecule drugs) and polyamides represent one of the most
2
,6
1
-4
expensive reagents, and/or challenging purifications.
versatile and functional classes of synthetic polymers. In
these applications and others, amide bonds are ubiquitous and
vital, and because of this amidation reactions are among the
most frequently performed transformations in organic
chemistry. Although there has been significant effort dedicated
to the development of methods for amidation and great
advances have been made, the need for greener approaches
remain a high priority in the synthetic organic chemistry
Furthermore, recent reports have linked widely used uronium
coupling reagents (e.g. HATU) for peptide synthesis to the
development of severe allergies as a result of extended
exposure. Catalytic methods have also been explored for
direct amidation in an effort to improve atom economy and
1
0
9
,11
reduce waste; catalysts include organoboron species
and
1
2
metal complexes. In spite of their promise, various pitfalls –
including inefficiency, water-sensitivity, narrow substrate
scopes, and metal toxicity – have prevented these methods
community.4–6 Accordingly, the ACS Green Chemistry Institute
Pharmaceutical Roundtable (GCIPR) listed sustainable direct
amide bond formation as one of their ten key green chemistry
6
,13
from being widely adopted
and leave stoichiometric
6
,13,14
7
methods as the state-of-the-art.
Therefore, the
development of green, safe, efficient, and practical
stoichiometric coupling reactions are of high interest.
research areas in 2018.
The most direct way to make amides is through the
condensation of a carboxylic acid with an amine. These
substrates are the precursors of choice for amide synthesis due
to their large abundance and only water as waste upon forming
the amide bond. However, in the absence of other reagents or
catalysts, the elimination of water will not proceed except
under harsh, forcing conditions due to spontaneous formation
Organosilanes are highly attractive reagents for organic
synthesis from a green perspective and have historically shown
1
5
sporadic promise as stoichiometric amide coupling reagents.
Silicon is the second most abundant surface element on earth
1
6
and is environmentally benign. Silanes are relatively inert,
1
7
2
,8,9
making them safer to handle and easily stored. Their
unreactive natures renders them compatible with many
common functional groups and a wide range of reaction
conditions; for this reason they are often used as protecting
groups. Because of these favourable attributes and versatile
reactivity, organosilanes are widely commercially available and
well-established as tools in organic synthesis.
of an ammonium carboxylate salt.
Such conditions are
a. Department of Chemistry & Biology, Ryerson University, Toronto, ON, M5B 2K3,
Canada.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
18
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COMMUNICATION
Journal Name
The development of efficient methods that utilize (Figure 1). The requirement of anhydrous VieawnAdrticleinOenlrinte-
organosilanes in amide coupling reactions could be atmospheric conditions and extended DrOeIa: c10ti.o10n39t/iDm0GesC0l2im83i3tAs
transformative for the field. For this reason, interest and practicality. The use of elevated temperatures (particularly
exploration in the field of silane-mediated coupling has applied for long periods) means it may not be suitable for use
1
9-23
increased over the past few years (Figure 1).
Tetramethyl with molecules possessing certain sensitive functionalities.
orthosilicate (TMOS) was reported by Braddock and Lickiss et al. Some further suffer from limited reported scope, and it is worth
1
9
19
as a highly efficient coupling reagent for direct amidation.
noting in particular that TMOS is a highly dangerous reagent.
and Blanchet groups We were, however, inspired by these works and sought to
or intermediates.20,21 Charette utilize the ideas that were brought forth to develop a greener
and co-workers disclosed two highly efficient methods using 9- method for coupling amines and unactivated carboxylic acids
2
0-22
23
Phenylsilane was used by the Denton
2
2,23
to form amides as products
2
4
25
silafluorenyl dichlorides and diphenylsilane (Figure 1), using silanes. Herein, we report a straightforward and efficient
respectively, as amide coupling reagents. Their advancement organosilane-mediated amidation reaction without rigorous
from the bespoke silafluorenyl reagent to commercially exclusion of air or water; this method is metal-free and
2
available diphenylsilane for this protocol improved atom generates H and a siloxane as by-products (Figure 1). We
economy and avoided the production of a protic acid, which can additionally probe the scope and general compatibility of the
be problematic for peptide synthesis. A highlight of these proposed method.
reactions is the 1:1:1 stoichiometry of amine:carboxylic
acid:silane coupling reagent; this waste-minimizing ratio lies in
stark contrast to state-of-the-art peptide synthesis that usually
Results and Discussion
requires large excesses of both coupling reagents and one of the
A key, simple issue we noted in our early studies is that
when we mixed our trial substrates (benzylamine and 2-
phenylacetic acid) an insoluble ammonium carboxylate salt
formed. This is problematic for the reaction for two reasons: 1)
removing the reactants from solution could hamper their ability
to interact with each other and thus react, 2) protonation of the
amine substrate decreases the nucleophilicity of the amine. To
address these issues and facilitate the reaction, we added an
exogenous base, N-methylpyrrolidine (NMPi), which then
afforded the amide product in good yield (Table 1). The tertiary
amine base serves to deprotonate the carboxylic acid moiety to
make the ammonium carboxylate salt more soluble and
maintain the nucleophilicity of the amine coupling partner.
NMPi is a waste product of the process, however, if desired it
could be recycled after the reaction is complete. We observed
that performing the reaction without rigorous exclusion of air
or water was optimal under each of the three sets of explored
conditions (Table 1), which sets this apart from other methods
using organosilicon reagents where water exclusion was
1
5g,19,23-25
necessary for productive reaction.
Trace water seemed
2
6
to be beneficial, but adding one equivalent of water proved to
detrimental under all investigated conditions. Additionally,
although microwave irradiation was unsuccessful in reducing
2
5
reaction times for Charette’s diphenylsilane-based method ,
we found that it can be used to reduce reaction times (see ESI,
Table S1). Accordingly, microwave conditions were generally
used to optimize this method.
Table 1 Role of air and moisture.
two coupling partners to get high conversion.
Figure 1 Recent silane-mediated amide coupling reactions.
The methods disclosed to date show great promise for the
approach of using silane coupling reagents; however, they each
suffer from drawbacks that preclude their widespread adoption
2
| J. Name., 2012, 00, 1-3
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COMMUNICATION
Acetonitrile was found to be the optimal solvent (Table 3, entry
Conditions[a]
Yield (%)[b]
View Article Online
RT,
Overnight
80˚C (MW),
5 mins
21
9), and increasing concentration (Table 3
DOenI:
,
t
10
r
y
.1
9
03-1
9
1
/D
)
0imGC
p
0
ro
2
833A
ve
d
Anhydrous?
+base?
80˚C, 20 mins
[
c]
yield. Running the reaction neat was not as productive (Table 3,
entry 12). Thus, under microwave conditions, the reaction was
optimal at 10 M in MeCN and we reached a maximum yield at
No
Yes
No
No
No
Yes
Yes
Yes
0
0
41
40
14
[
d]
d]
[d]
[d]
63
44
84
77
1
20˚C for 5 minutes (entry 13). Running the reaction for just 30
[
Yes
56
31
52
22
seconds gave a slightly decreased yield of 74% (ESI, Table S8).
No[
e]
0
[
a]
Reaction conditions: 4 M in MeCN with NMPi as base at indicated temperature
Table 3 Final optimizations in the microwave.
[
b]
and time, unless otherwise stated. NMR yield using EtOAc as an internal standard
[
c]
[d]
unless otherwise stated. Reaction run in dichloromethane (CH
NO
used as an internal standard. [e]1 equivalent of water was added to this
reaction mixture.
2 2
Cl ) at 4 M. Ph-
2
We investigated the effect of various bases on the reaction
See ESI, Table S1). K CO did not affect the reaction beneficially,
Entry
Solvent
EtOAc
Acetone
[C] (M)
1
1
1
1
1
1
1
1
1
4
10
-
10
Yield (%)[a]
(
2
3
1
2
3
4
5
6
7
8
9
0
0
0
but tertiary amine bases did shorten reaction times and
improve yields. NMPi provided the highest yield of amide
product in the microwave (77%) and can be catalytic: 0.5
equivalents gave the same yield of product as 1.0 equivalents.
Diphenylsilane was the optimal coupling agent of the
2
H O
iPrOH
Pyridine
THF
0
21
34
50
51
57
2
5
screened commercially available silanes (Table 2, entry 7). No
evidence of amide formation was observed using other silanes
DMF
CH
2
Cl
2
MeCN
MeCN
MeCN
No solvent
MeCN
(entry 1-4, 6) with triethylamine as the base. A low yield was
[
[
[
b]
b]
b]
1
1
1
1
0
1
2
3
77
84
42
obtained using 1-hydrosilatrane when pyrrolidine was the
amine substrate (Table 1, entry 5). It was determined that a
stoichiometric amount of diphenylsilane is needed in this
reaction when using NMPi as the base (Table 1, entry 8).
89[c]
[
a]
NMR yield using Ph-NO
2
as an internal standard unless otherwise stated. [b]EtOAc
as an internal standard. 120˚C in the microwave.
[
c]
Table 2 Investigation of silanes as coupling reagents.[a]
For the thermal reactions (Table 4), as the temperature
increased from 80˚C to 100˚C the yield predictably increased,
however the yield at 120˚C (entry 5) was not significantly
different from the yield at 100˚C so temperatures higher than
that were not explored. The reactions completed in the absence
of NMPi had a significantly lower yield compared to the
reactions with the amine base even after a longer reaction time,
indicating that the inclusion of NMPi is beneficial under thermal
conditions. A reaction time of 20 minutes was required for
complete reaction (see ESI, Table S12).
Entry
Silane
PhSiH
Ph SiH
Base
TEA
TEA
Yield (%)[b]
1
2
3
4
5
6
7
8
9
3
< 1
0
3
Hydrosilatrane
Hydrosilatrane
Hydrosilatrane
PMHS
TEA
0
0[
c]
NMPi
NMPi
TEA
15[d]
0
Table 4 Final optimizations under thermal conditions.
Ph
2
Ph
2
Ph
2
Ph
2
SiH
SiH
SiH
SiH
2
2
2
2
TEA
45
[
e]
NMPi
NMPi
NMPi
77
[
e],[f]
19
[
e],[g]
1
0
60
[
a]
Reaction conditions in microwave: 1M in MeCN and ran for 5 mins at 80˚C, unless
[
b]
otherwise noted. NMR yield using nitrobenzene (Ph-NO
[
2
) as an internal standard.
c]Heated at 100˚C in an oil bath for 20 mins. [d]Pyrrolidine substrate used as the
Deviation from standard conditions
Yield (%)[a]
[
e]
[f]
amine and heated at 100˚C in an oil bath for 4 hrs. 4 M reaction. 0.2 eq of
diphenylsilane. 1.2 eq of diphenylsilane.
[
g]
-
91
84
87
8
0˚C
120˚C
We then probed the reaction solvent, temperature, and
time in the microwave. Polar protic and several polar aprotic
solvents did not allow the reaction to proceed with any amide
product (Table 3, entry 1-4). We tried pyridine (Table 3, entry 5)
to explore whether a basic solvent would improve the reaction,
but the yield significantly decreased. Other polar aprotic
solvents (Table 3, entry 6-8) resulted in moderate yields.
b]
no NMPi
h, no NMPi
RT, 20 h
51[
1
65[b]
81
[
a]
NMR yield using Ph-NO as an internal standard unless otherwise stated. [b]EtOAc
2
used as an internal standard.
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The scope and limitations of this method were then synthesized amides both 1) in the microwave anVdiew2)AratictlerOonolimne
explored (Scheme 1). For accessibility (as not every lab is temperature. Microwave reactions to synDtOhIe: s10iz.1e0a39m/Did0eGsC10a28, 313gA,
equipped with a microwave synthesizer) and time-efficiency (as 1h, 2a, 2c, 3b, 3d, 3f, and 3g were explored to improve yield
the room temperature reactions must run for an extended (ESI, Table S9). Good yields were obtained in synthesizing 1a,
period of time), we demonstrated the scope comprehensively 1g, 2a, 2c, 3b, and 3d in the microwave and the yields compare
using the optimized thermal conditions. Many substrates were favourably to the thermal reactions. Microwave reaction of
further examined using the microwave and/or room phenylacetic acid with aniline afforded the corresponding
temperature methods to establish the generality of these amide 1h in low yield, however, it did enhance the reaction
alternative approaches. The reaction was briefly re-optimized compared to the thermal reaction for 20 minutes. In the
for both 1) aromatic carboxylic acid substrates (see ESI, Table synthesis of 3f and 3g, though products were formed in
S14) and 2) secondary aliphatic amines (see ESI, Table S15). reasonable yields in the microwave, it did not enhance the
Several amides comprising a range of classes were synthesized reaction. As room temperature reactions provide mild
in good to excellent yield with the optimized reaction conditions, we were interested in seeing if the developed
conditions.
method can be used to synthesize amides at room temperature
Aliphatic carboxylic acids coupled to primary aliphatic overnight (ESI, Table S16). These reactions gave low-yielding
amines were produced in moderate to excellent yields (1a-1g). results for 1h, 2a and 3g; however, 2c was synthesized in an
The reaction of 2-phenylacetic acid with benzylamine excellent 85% yield and 3d resulted in a 33% yield, which is
proceeded smoothly. Bulkier pivalic acid and α- comparable to the microwave reaction that yielded 34% of
methylbenzylamine were not as efficient substrates under product.
these reaction conditions giving lower yields of their amide
The tertiary amine base is a key aspect to this method and
product (1c and 1g, respectively) when coupled to benzylamine has shown to improve the efficiency of this reaction. To further
and phenylacetic acid, respectively. A longer reaction time and demonstrate the role of the tertiary amine base in improving
2
.0 equivalents of benzylamine was needed to afford amide 1c the reaction, we chose four amides (1a, 2d, 2e, and 3a) from
in a moderate yield of 37%. A long chain carboxylic acid Scheme and ran the reaction without base under
hexanoic acid) and alkyl amine (hexylamine) were converted to complimentary reaction conditions. Amides 1a and 3a showed
1
(
their corresponding amides (1b and 1e, respectively) in good an improved yield when NMPi was added. However, when more
yields. N-protected amino acid (tert-butoxycarbonyl)-L-alanine) nucleophilic amines like piperidine and morpholine were used
and 2-aminothiophene afforded their corresponding amides to make 2d and 2e, respectively, the amine base is not required
efficiently (1d and 1f, respectively). Aniline was not a suitable to improve yields.
substrate for this reaction as amide 1h was not able to be made
using this method in 20 minutes, however, when reaction time
increased to 4 h a modest yield was obtained. The synthesis of
a dipeptide was explored to demonstrate that this method can
be used for peptide coupling. An N-protected amino acid (tert-
butoxycarbonyl)-L-alanine) and an amino ester (L-alanine ethyl
ester hydrochloride) (1i) were coupled to investigate this
reaction. This reaction is a proof of concept and further
optimization will be needed to establish a genuine protocol for
peptide coupling; however, these reactions show that the
stereochemical fidelity at the crucial position α to the amide is
1
maintained as only a single diastereomer is observed in the H
NMR spectra of the product (see ESI).
Secondary amines were also coupled to phenylacetic acid
(
2a-2e) in moderate to good yields, though longer reaction
times were needed. Sterically hindered acyclic amines in 2a and
b resulted in modest yields, while cyclic amines worked well
2
using these reaction conditions (2c-2e).
Finally, the method was expanded to aromatic carboxylic
acids (3a-3g). Benzoic acid reacted with benzylamine to form 3a
in good yield. Electron-rich p-anisic acid gave 3b in a moderate
yield of 51%. Electron-poor 4-nitrobenzoic acid reacted with
benzylamine to form amide 3f in 86% yield. Heterocyclic acids
of pyridine (3c), furan (3e and 3g), indole (3h), and imidazole
(3i) were compatible with this method, and an iodophenyl-
derived amide (3d) was also synthesized in moderate yield.
To demonstrate the versatility of this method, we explored
complimentary related approaches to several of the
4
| J. Name., 2012, 00, 1-3
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5
minutes, 10 M, 1.5 mmol of acid, and 1.0 mmol of amine, silaVnieew, aAnrdticbleaOsen.liRneT
conditions: room temperature, 20 h, 1 M in CH
of amine, silane, and base. [i]4 M reaction.
2
Cl
2
, 1.5 mmol of acid, and 1.0 mmol
DOI: 10.1039/D0GC02833A
Many important amides exist in molecules that are large and
complex with diverse functionality. A general coupling reaction
to synthesize amide-containing molecules requires a method
that is unreactive toward a wide range of functional groups. To
examine the functional group tolerance of this method we
2
7
conducted a Glorius robustness study. 16 additives that each
contain a different functional group were added into the
reaction each at 1 equivalent to probe any limitations with
respect to functional group compatibility of the developed
2
7
method. The experimental results are presented in Table 5,
and a table of all the experimental results and spectra can be
seen in the ESI (Table S19). The reaction was robust in the
presence of most of the additives, demonstrating good general
applicability of this method. Lower yields of the amide product
were observed upon the addition of 4H-chromen-4-one,
undecane-6-one, 1-nonanol, and benzaldehyde, and the
amount of additive remaining varied significantly. The crude
reaction mixture with 4H-chromen-4-one was subjected to
1
column chromatography and H NMR analysis of the separated
fractions indicated that conjugate addition of benzylamine to
2
8
1
4
H-chromen-4-one occurred. The H NMR of the reaction
mixture of undecane-6-one shows some evidence of imine
1
formation. Finally, the H NMR spectra of the reaction with
2
9
benzaldehyde showed imine formation had occurred. In each
of these cases, the deleterious reactivity was due to the amine
coupling partner, which is a general feature of amidation
reactions and not specific to this method. The one additive that
seemed to be not fully compatible with the actual method was
1
-nonanol; the GC-MS of this crude reaction mixture revealed
silyl ether formation due to the high oxophilicity of silicon.
Table 5 Glorius robustness study.
Scheme 1 Substrate scope. Yields reported as NMR yield, with isolated yields listed
in parentheses, if obtained. [a]Thermal reaction conditions: 1 mmol of acid, amine,
silane, and base 100˚C in oil bath for 20 minutes. Microwave (MW) conditions:
1
20˚C in the microwave, 5 minutes, 10 M, 1.0 mmol of acid, amine, silane, and
base. RT conditions: room temperature, 20 h, 4 M, 1.0 mmol of acid, amine, silane,
and base. [b]2.0 mmol of amine and reaction time of 1 h. [c]Reaction run at 1 M. [d]4
h reaction time. [e] 2 mmol of base and reaction time of 1 h. [f] 2.0 mmol of base at
8
1
1
0˚C. [g]Thermal reaction conditions: 1.0 mmol of acid, amine, silane, and base.
00˚C in an oil bath for 4 h. Microwave (MW) conditions: 120˚C in the microwave,
0 minutes, 4 M, 1.0 mmol of acid, amine, silane, and base. RT conditions: room
temperature, 20 h, 4 M, 1.0 mmol of acid, amine, silane, and base. [h]Thermal
reaction conditions: 1.5 mmol of acid, and 1.0 mmol of amine, silane, and base.
1
00˚C in an oil bath for 1 h. Microwave (MW) conditions: 120˚C in the microwave,
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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temperature. In the present work, the method is readily
Product Yield (Relative
Product Yield) (%)[a]
91
Additive Remaining
(%)[b]
View Article Online
Additive
DO
I
: 1
0
.1
0
3
9/
D0
G
C
0
2
833A
scalable up to at least 10 mmol and it is r
obu
st
t
ow
ar
ds
v
arious
none
undecane-6-one
benzaldehyde
common organic functional groups. Due to its simplicity in
execution, reliance on readily available reagents, and the other
aforementioned positive attributes, this method will be of
immediate utility to those seeking to make small-molecule
amides.
27 (30)
29 (32)
34 (37)
49 (54)
92
11
0[c]
57
80
1
-nonanol
4
H-chromen-4-one[d]
trans-chalcone
67 (74)
1
-dodecene
69 (76)
86
2
-n-butylfuran
76 (84)
79 (87)
75 (82)
40
quant.
95
Conflicts of interest
There are no conflicts to declare.
decanenitrile
acetanilide[e]
benzaldehyde
dimethyl acetal
benzothiazole
N-benzylpyrrole
7
9 (87)
quant.
Acknowledgements
The authors thank Ryerson University and the Natural Sciences
and Engineering Research Council of Canada (NSERC) for
supporting this work.
78 (86)
78 (86)
81 (89)
81 (89)
79 (87)
78 (86)
96
98
quant.
94
98
obs.[f]
3
,5-lutidine
aniline
dec-1-yne
bromobenzene
[a]Yield of product as 1H NMR yield using EtOAc as an internal standard unless
otherwise stated. Relative H NMR yield to 91% of amide product with no additive
Notes and references
1
shown in parentheses (green: 80-100%, yellow: 50-80%, red: <50%), EtOAc internal
1
(a) N. A. McGrath, M. Brichacek, J. T. Njardarson, A Graphical
Journey of Innovative Organic Architectures That Have
Improved Our Lives, J. Chem. Ed. 2010, 87, 1348. (b) J.
Njardarson et al., Top 200 Pharmaceuticals by Retail Sales in
[
b] 1
standard unless otherwise stated.
H NMR yield using EtOAc as an internal
[
c]
[d]
standard unless otherwise stated. Yield determined by GC-MS. Average of 2
[
e]
Ph-NO
2
used as an internal standard. [f] No evidence to suggest that
runs.
bromobenzene was consumed, however, we were not able to quantify the amount
of bromobenzene. It was present in GC-MS in significant amount, and no new
products were observed.
2
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demand in the pharmaceutical industry. To demonstrate the
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.36 g of phenylacetic acid and 1.09 mL of benzylamine, 1.63
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Conclusions
We have developed a simple and fast organosilane-
mediated amide coupling reaction of unactivated carboxylic
acids and amines. Using diphenylsilane in the presence of NMPi
in a setup that does not require rigorous exclusion of air or
water, amidation is enabled and a diverse range of amides can
be synthesized in good to high yields. The reaction is highly
practical and advantageous over previously reported
diphenylsilane-mediated coupling as it 1) is optimal without
energy- and time-consuming exclusion of air or water, 2)
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