Diphenylsilane as a coupling reagent for amide bond formation

Article abstract of DOI:10.1039/c7gc02643a

A simple procedure for amide bond formation using diphenylsilane as a coupling reagent is described. This methodology enables the direct coupling of carboxylic acids with primary and secondary amines, releasing only hydrogen and a siloxane as by-products. Only one equivalent of each partner is needed, providing a more sustainable amidation method producing minimal wastes. This methodology was also extended to the synthesis of peptides and lactams by addition of Hünig's base (DIPEA) and 4-dimethylaminopyridine (DMAP).

Full text of DOI:10.1039/c7gc02643a

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Diphenylsilane as a Coupling Reagent for Amide Bond Formation
Morgane Sayes and André B. Charettea *
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A
simple procedure for amide bond formation using activated α-aminoesters8g) with carboxylic acids. Although
diphenylsilane as coupling reagent is described. This efficient and elegant, these methods require
a
methodology enables the direct coupling of carboxylic acids with prefunctionalization of one of the coupling partners or the use
primary and secondary amines, releasing only hydrogen and a of an alternative functional group to carboxylic acids or
siloxane as by-products. Only one equivalent of each partner is amines. An interesting strategy is the direct amide formation
needed, providing
a more sustainable amidation method from carboxylic acids and amines, which can be achieved by
producing minimal wastes. This methodology was also extended using organoboron derivatives,9 a zirconium catalyst10 or
to the synthesis of peptides and lactams by addition of Hünig’s fluorouronium reagents.11 However, methods using boronic
base (DIPEA) and 4-dimethylaminopyridine (DMAP).
acids, for instance, generally require harsh conditions (high
temperature).
Amide bonds are prevalent in nature as the backbone of
proteins and are also found in high-added-value products, such
as pharmaceuticals and polymers, due to the high bond
polarity and stability. Indeed, amide bond formation is the
most commonly used reaction for the synthesis of
pharmaceuticals, accounting for 16% of all reactions; the
amide bond can be found in 25% of pharmaceuticals currently
on the market.1 Traditional methods to form amide bonds
require preactivation of the carboxylic acid moiety and the use
of stoichiometric coupling reagents with additives.2 These
methods are general; however, some drawbacks include poor
atom economy, high cost and reagents or by-products that are
both toxic and hazardous.3 Consequently, amide bond
formation has been recognized as one of the most important
reactions used in industry requiring more efficient and
sustainable procedures.4
We have already developed a direct amidation procedure
using 9-silafluorenyl dichlorides as coupling reagents.12
A
similar strategy was first reported in 1969 by Chan, who
described silicon tetrachloride as an efficient coupling reagent
for amide bond formation.13 Furthermore, Liskamp reported
the use of dichlorodialkyl silanes for the synthesis of amides by
a protection-activation strategy.14 Our previously developed
method enables the synthesis of a range of dipeptides in
excellent yields with minimal epimerization. However, 9-
silafluorenyl dichlorides are not commercially available and are
moisture-sensitive reagents (glovebox storage necessary).
Furthermore, significant quantities of base are needed to
neutralize the HCl formed during the reaction.
Herein we describe the use of commercially available and
stable diphenylsilane as coupling reagent for direct amide
bond formation (Scheme 1).
Over the last decades, many alternatives have been
developed,5 such as the use of carboxylic acid surrogates
Scheme 1 Amide Bond Formation by Si-Ligation.
(thioacids,6a,b
aldehydes,6g,h
esters,6c,d
alcohols,6e,f
α-keto
acids,6k
functionalized
potassium
a) Previous work
1) Et3N (5 equiv)
ketones,6i,j
R2
O
R2
DMAP (0.5 equiv)
2) R3R4SiCl2 (1 equiv)
O
acyltrifluoroborates (KATs),6l nitriles,6m,n alkynes6o,p), α-bromo
nitroalkanes7 with amines, or the use of amine surrogates
(isocyanates,8a,b isonitriles,8c azides,8d sulfonamides,8e,f CDI-
BocHN
BocHN
+
OH
ClH•H2N
CO2Me
N
CO2Me
H
R1
THF, 60 °C
R1
(1.1 equiv)
(1.1 equiv)
65-99%
b) This work
Ph2SiH2 (1 equiv)
Base, additive
O
O
R2
R3
R2
a.Université de Montréal, Centre in Green Chemistry and Catalysis, Department of
Chemistry, Faculty of Arts and Sciences, P.O. Box 6128, Station Downtown,
Québec, Canada H3C 3J7.
R1
OH
+
R1
N
N
H
ACN, 80 °C
R3
(1 equiv)
(1 equiv)
E-mail : andre.charette@umontreal.ca
Electronic Supplementary Information (ESI) available: experimental procedures
and characterization data (PDF). See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Phenylsilane has already been reported as a coupling reagent Notably, using a higher concentration (2.5 M) afforded the
for amide synthesis.15 However, 10 equivalents of the amine desired amide in good yield (entry 6). A high concentration is
partner and 20 equivalents of phenylsilane were needed, and ideal for greener procedures.
no mechanism was proposed. In the present method, To gain mechanistic insights, we studied different silanes:
preactivation of either partner is not required and, in the case monohydrosilanes, dihydrosilanes and phenylsilane (entries 8–
of simple amides, additional additives are not needed. This 12). Phenylsilane gave a similar yield to the one obtained with
simple and atom-economical procedure releases only diphenylsilane (entry 4 vs 8). As with our previously developed
dihydrogen and a siloxane as by-products, enabling the method using dichlorosilanes, we postulate a chemical ligation
formation of amide bonds in a more sustainable manner with pathway whereby a silicon intermediate linked to both
minimal waste.
partners can rearrange upon heating to form the amide bond
Dihydrosilanes are commonly used as reducing agents, (Scheme 2a). However, amide formation was also observed
generally with metals.16 Notably, they have been used for with monohydrosilanes, albeit in much lower yields (entries 9–
alkylation and formylation of amines with carboxylic acids or 10). Therefore, it is probable that the reaction can also
carbon dioxide.17 In an alkylation reaction using proceed via a competitive pathway involving simple activation
methylphenylsilane as a hydride source, Minakawa reported of the carboxylic acid followed by nucleophilic attack by the
that “no amide side products were observed” under the amine, leading to the same final product (Scheme 2b). Upon
reported
phenylacetamide formation while optimizing
alkylation of amines with carboxylic acids with Karstedt’s bond that can act as a hydride donor.19 Despite our efforts, we
catalyst.17c
were unable to observe the putative intermediate . However,
conditions.17b
However,
Beller
observed nucleophilic attack of the carboxylate, a pentacoordinate
a
direct N- silicon intermediate can be formed, thus weakening the Si–H
A
B
As ruthenium complexes are often used to activate Si–H a series of control experiments showed that diphenylsilane
bonds,17b,18 we first attempted to couple acetic acid with reacts with both partners independently, supporting its
benzylamine in presence of [RuCl2(p-cymene)]2 catalyst and formation.20 In a recent publication, Denton described a
diphenylsilane without solvent (Table 1, entry 1). Significant H2 similar intermediate in
a mechanistic study of catalytic
release was observed, and the product was obtained in Staudinger amidation.21 Next, we investigated the influence of
excellent yield in a really clean manner. While performing varying the silicon substituents (entries 11–12). When
control experiments, we were pleased to observe that no triethylsilane was used, we observed a dramatic decrease in
catalyst was needed (entry 2). As most carboxylic acids are yield from 86% to 14% (entry 11 vs 4). Indeed, aromatic groups
solids, we chose phenylacetic acid as coupling partner for the are required to stabilize intermediate
A. Exchanging an alkyl
optimization. Based on our previously developed method with group for an aromatic group provided an improved yield (entry
dichlorosilanes, tetrahydrofuran (THF) was first employed, 12).
affording the desired product in moderate yield (entry 3). The Next, we explored the scope of the reaction. First, neat
use of acetonitrile to solubilize starting materials enabled acetylations of different amines were performed in good to
amide bond formation in excellent yield (entry 4). However, excellent yields (Scheme 3, 1a-d). Then, several amides were
when these conditions were applied to a secondary amine, the synthesized with the developed method in good yields.
product was obtained in a low yield (entry 5).
Various acids including benzylic (1e), aromatic (1f) and
aliphatics (1g-h) can be used with good to excellent yields. SFC
traces showed minimal epimerization (3%) for the
stereocenter containing acid (1g). Alkenes and alkynes are
tolerated (1i-j), as well as a furan ring (1k). Tertiary amides can
also be obtained in good to excellent yields from disubstituted
or cyclic amines (1l–n). Unfortunately, when using benzoic
acid, a lower yield is observed (1q).
Table 1 Optimization of amide formation
O
O
silane (1 equiv)
R2
R1
OH
+
R1
N
Ph
N
H
Ph
solvent (x M)
16 h, 80 °C
R2
(1 equiv)
(1 equiv)
Entry
R1
Me
Me
Bn
R2
Silane
Solvent
[C] (M)
Yield (%)a
1b
Me
Me
H
Ph2SiH2
Ph2SiH2
Ph2SiH2
-
-
-
94
98
61
Scheme 2 Postulated mechanism
2
-
R2
R3
Ph
O
Ph
O
O
3
THF
0.5
0.5
N
H2
Si
R2
H
O
Si
H
R1
R3
H
R2
R3
O
Si
H
R1
H
H
Bn
H
R1
O
N
H
4
5
Ph2SiH2
Ph2SiH2
Ph2SiH2
Ph2SiH2
PhSiH3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
86
36
78
90
81
32
50
14
76
Ph
H
Ph
Ph
N
b
Ph
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Me
Me
H
0.5
2.5
2.5
0.5
0.5
0.5
0.5
0.5
H2
a
A
6
a) Chemical ligation pathway:
7
O
Ph Ph
Si
O
Ph
R3
R2
Ph
O
R3
8
H
Si
Product + (Ph2SiO)n
R1
N
O
N
R1
9
H
Me2PhSiH
Ph3SiH
H
H
R2
H2
B
10
11
12
H
b) Carboxylic acid activation pathway:
H
Et2SiH2
O
R2
O
H
MePhSiH2
R3
Product + (Ph2SiO)n
R1
N
H
Si
H
a
b
Ph
Ph
NMR yield using 1,3,5-trimethoxybenzene as internal standard. [RuCl2(p-
H2
cymene)]2 used as catalyst (1 mol %).
2 | J. Name., 2012, 00, 1-3
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(
2a–c). Moreover, the reaction can be scaled up to 2 mmol
Scheme 3 Amide formation.a,b
without any decrease in yield (2b).
O
O
Ph2SiH2 (1 equiv)
R2
R3
R2
R1
N
Table 2 Optimization of conditions for peptide coupling reaction
N
H
R1
OH
+
MeCN (2.5 M)
16 h, 80 °C
R3
Ph2SiH2 (1 equiv)
DIPEA (1 equiv)
Additive (0.5 equiv)
(1 equiv)
(1 equiv)
O
O
R
O
BocHN
BocHN
OMe
ClH•H2N
+
Neat reactions:
OH
N
OMe
H
MeCN (0.5 M)
O
R
O
O
O
O
(1 equiv)
(1 equiv)
N
Ph
N
Ph
N
N
H
Yield
(%)a
0
O
Entry
R
Base
Additive
Time (h)
T (° C)
1a
80%
1b
94%
1c
88%
1d
83%
1
2
H
H
-
-
-
16
16
60
60
Acid variation:
DIPEA
68
O
O
O
O
3
4
H
DIPEA
Et3N
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
Pyridine
Pyridine
16
16
16
16
16
42
42
42
60
60
60
80
100
80
80
80
99
78
42
66
58
91
90
39
Ph
BnO
H
N
Ph Ph
N
Ph
N
Ph
N
Ph
H
H
H
H
BocN
5
Bn
Bn
Bn
Bn
Bn
Bn
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
-
1e
84%
1f
74%
1g
65%
1h
72%
6
7
8b
O
O
O
O
9
10c
N
Ph
Ph
N
Ph
N
Ph
H
H
H
Ph
1i
54%
1j
70%
1k
70%
a
NMR yield using 1,3,5-trimethoxybenzene as internal standard. b Reaction run
on a 2-mmol scale. c 1.5 equiv of pyridine used.
Amine variation:
O
O
O
O
However, employing more hindered carboxylic acids was more
challenging: using Boc–(L)Ala–OH, Boc–(L)Phe–OH or Boc–
(L)PheGly–OH decreased reactivity. Still, corresponding
dipeptides were obtained in moderate yields (2d–f).
Ph
Ph
Ph
Ph
Ph
N
N
Ph
N
N
H
O
1l
70%
1m
77%
1n
91%
1o
46%
Finally, we wanted to apply our method to tripeptide
O
O
O
O
synthesis. After
a simple deprotection at both ends
Ph
Ph
N
Ph
N
N
N
independently, Boc–Gly–(L)Phe–OMe was coupled to NH2–
Gly–OMe•HCl (for the Boc deprotected residue) and to Boc–
Gly–OH (for the ester hydrolyzed residue) (2g–h). C to N
synthesis (2g) as well as N to C synthesis (2h) gave a moderate
50% yield. For the C to N synthesized tripeptide 2g, this low
yield can be attributed to steric hindrance from the carboxylic
acid residue as observed previously. In the case of N to C
synthesis, considering the steric hindrance of both partners,
tripeptide 2h should have been obtained in higher yield. This
moderate yield can be attributed to product inhibition that we
observed during our studies.23 It should be pointed out that
these conditions led to significant product epimerization when
N–Boc–phenylglycine was used as the coupling partner (see
Electronic Supplementary Information). However, only one
diastereoisomer was observed for 2d. This methodology also
H
O
O
MeO2C
1p
1q
1r
67%c
1s
63%
61%
49%
a Reaction run on a 0.5-mmol scale. b Isolated yield. c 42-h reaction time.
However, a longer reaction time (1r) or the use of an electron-
withdrawing group (1s) gave better yields. Next, we focused
on the more challenging peptide coupling reaction.
We began our studies with the simplest coupling between
Boc–Gly–OH and NH2–Gly–OMe•HCl (Table 2). Unfortunately,
no product was obtained using our previous conditions (entry
1). After a quick optimization, we demonstrated that the
dipeptide could be obtained in excellent yield (entry 3) by
adding Hünig’s base and DMAP. However, when the more
hindered NH2–(L)Phe–OMe•HCl was used, the yield dropped
significantly (entry 5). Increasing temperature to 80 °C and
provided small lactams in good yields (3a–c).
reaction time to 42 h was beneficial to the reaction (entries 6– Scheme 4 Peptide and lactam synthesis.a,b
8) and afforded the desired dipeptide in 90% yield (entry 8).22
Microwave heating was unsuccessfully employed to reduce
reaction time. Gratifyingly, DMAP, an expensive reagent, could
be replaced by pyridine with no modification in yield (entry 9).
Nevertheless, pyridine cannot be used as base due to its lower
pKa (entry 10).
With these new conditions in hand, dipeptide formation was
investigated (Scheme 4). When Boc–Gly–OH was used as the
carboxylic acid partner, good to excellent yields were obtained
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Ph2SiH2 (1 equiv)
DIPEA (1 equiv)
DMAP (0.5 equiv)
3
4
K. D. Wehrstedt, P. A. Wandrey and D. Heitkamp, J Hazard
Mater. 2005, 126, 1.
D. J. C. Constable, P. J. Dunn, J. D. Hayler, G. R. Humphrey, J.
L., Jr. Leazer, R. J. Linderman, K. Lorenz, J. Manley, B. A.
Pearlman, A. Wells, A. Zaks and T. Y. Zhang, Green Chem.
O
O
O
R2
BocHN
ClH•H2N
BocHN
OMe
+
OH
OMe
N
MeCN (0.5 M)
42 h, 80 °C
H
R1
(1 equiv)
R2
(1 equiv)
R1
O
2007, 9, 411.
Boc-(L)Phe-Gly-OMe
Boc-Gly-Gly-OMe
2a, 90% (16 h)
2b, 84%c
2e, 57%
2f, 52%
5
6
(a) V. R. Pattabiram and J. W. Bode, Nature, 2011, 480, 471;
(b) R. Marcia de Figueiredo, J.-S. Suppo and J.-M. Campagne,
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2009, 48, 2355; (c) B. C. Ranu and P. Dutta, Synth. Commun.
2003, 33, 297; (d) M. Movassaghi and M. Schimdt, Org. Lett.
Boc-Gly-(L)Phe-OMe
Boc-Gly-(L)Val-OMe
Boc-(L)PheGly-Gly-OMe
Boc-Gly-(L)Phe-Gly-OMe
Boc-Gly-Gly-(L)Phe-OMe
2c, 91%
2d, 54%
2g, 51%
2h, 50%
Boc-(L)Ala-(L)Ala-OMe
O
O
O
BocHN
BocHN
CbzHN
NH
NH
NH
3a, 78%
3b, 90%
3c, 72%
2005, 7, 2453; (e) L. U. Nordstrom, H. Vogt and R. Madsen, J.
a Reaction run on a 0.25-mmol scale. b Isolated yield. c Reaction run on a 2-mmol scale.
Am. Chem. Soc. 2008, 130, 17672; (f) C. Gunanathan, Y. Ben-
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Notably, this method is compatible with both Boc and Cbz
protecting groups. However, the Fmoc protecting group was
cleaved under reaction conditions.
Conclusions
In summary, we have developed
a simple and more
sustainable amidation procedure. Despite long reaction times,
this methodology offers an atom-economical and
environmentally attractive way to form amide bonds
compared to traditional methods. Commercially available
unactivated carboxylic acids and amines can be coupled in
good yields using one equivalent of inexpensive and stable
diphenylsilane. The only by-products of this reaction are H2
and a siloxane that can be filtered off, providing a clean crude
product that can be easily purified by a rapid flash column
chromatography. This study provides a proof of concept that
dihydrosilanes can be used without any metals to form amide
7
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bonds through
a putative chemical ligation pathway.
Moreover, this methodology can be applied to dipeptide and
lactam synthesis by adding Hünig’s base and DMAP or
pyridine.
9
We
Engineering
Grant RGPIN-06438, the Canada Foundation
gratefully
Research Council of Canada (NSERC) Discovery
for Innovation
thank
the
Natural
Science
and
ꢀ
ꢀ
9
and N. Kumagai, Nature Chem. 2017, , 571.
, 1320; (e) H. Noda, M. Furutachi, Y. Asada, M. Shibasaki
9
Leaders Opportunity Funds 227346, the Canada Research Chair
Program CRC-227346, the FRQNT Centre in Green Chemistry
and Catalysis (CGCC) Strategic Cluster RS-171310, and
Université de Montréal. M. S. is grateful to Université de
Montréal for postgraduate scholarship.
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Adolfsson, J. Am. Chem. Soc. 2017, 139, 2286.
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Conflicts of interest
There are no conflicts to declare.
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1
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4 | J. Name., 2012, 00, 1-3
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COMMUNICATION
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20 See ESI for control experiments.
21 K. G. Andrews and R. M. Denton, Chem. Commun. 2017, 53
7982.
,
22 Free amine can also be used instead of HCl salt, giving similar
yields (80% yield without DIPEA and 87% yield with DIPEA).
23 When 1 equivalent of Boc–Gly–Gly–OMe was added at the
beginning of reaction, for the coupling of Boc-Gly-OH with
NH2-(L)Phe-OMe•HCl, the desired dipeptide was obtained in
only 52% yield compared to the 91% yield obtained in
standard conditions.
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TOC
O
O
Ph2SiH2
R2
R2
R3
R1
OH
+
R1
N
N
H
MeCN, 80 °C
R3
Metal-free procedure
Commercially available coupling partner
H2 and a siloxane as by-products
A simple amidation procedure enabling the direct coupling of carboxylic acids to amines using
one equivalent of diphenysilane is reported.