Phenysilane and Silicon Tetraacetate: Versatile Promotors for Amide Synthesis

Article abstract of DOI:10.1002/ejoc.201901660

Phenylsilane was reevaluated as a useful coupling reagent for amide synthesis. At room temperature, a wide range of amides and peptides were obtained in good to excellent yields (up to 99 %). For the first time, Weinreb amides synthesis mediated by a hydrosilane were also documented. Comparative experiments with various acetoxysilanes suggested the involvement of a phenyl-triacyloxysilane. From this mechanistic study, silicon tetraacetate was shown as an efficient amine acylating agent.

Full text of DOI:10.1002/ejoc.201901660

A Journal of
Accepted Article
Title: Phenysilane and Silicon Tetraacetate: Versatile Promotors for
Amide Synthesis
Authors: Eléonore Morisset, Aurélien Chardon, Jacques Rouden, and
Jérôme Blanchet
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901660
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10.1002/ejoc.201901660
European Journal of Organic Chemistry
COMMUNICATION
Phenysilane and Silicon Tetraacetate: Versatile Promotors for
Amide Synthesis.
Eléonore Morisset[a], Aurélien Chardon[a], Jacques Rouden[a] and Jérôme Blanchet*[a]
Abstract: Phenylsilane was reevaluated as a useful coupling reagent
for amide synthesis. At room temperature, a wide range of amides
and peptides were obtained in good to excellent yields (up to 99%).
For the first time, Weinreb amides synthesis mediated by a
hydrosilane were also documented. Comparative experiments with
various acetoxysilanes suggested the involvement of a phenyl-
triacyloxysilane. From this mechanistic study, silicon tetracetate was
shown as an efficient amine acylating agent.
Figure 1. Reported silicon coupling agents.
Introduction
In 2018, Braddock reported a simple and efficient procedure
Amide bonds are ubiquitous in chemical science. From natural
products to polymers, amide is one of the most popular and useful
functional groups in chemistry.[1] In biological systems, the
importance of the amide bond lies in sustaining life by linking
amino acids together thus forming proteins.[2] Therefore, it is not
surprising that amide bond formation is the most frequently
performed transformations in the chemist’s toolbox.[3] The use of
chlorinating, diimide or onium based coupling reagents (SOCl2,
DCC, EDCI, HATU…) are highly predictable methodologies to
combine carboxylic acids and amines.[4] Nevertheless, some
issues are still associated with these reagents, related to partial
racemization, waste, toxicity or chemoselectivity.[5] Within this
context, novel methodologies for amides and peptides synthesis
are in great demand and stimulated global efforts in the area of
amide synthesis.[6]
however relying on highly toxic tetramethylorthosilicate
(TMOS).[11]
Within this framework, hydrosilanes are appealing considering
low toxicity and that hydrogen gas and silanols are expected as
only side products. However, the use of hydrosilanes appears
underinvestigated: only two reports mention it so far. In 2006,
phenylsilane (PhSiH3) was examined as a mild coupling reagent
using a high-throughput screening of various amines and
carboxylic acids.[12] Driven by initial success in homogeneous
solution, further solid phase syntheses were carried out using
large excess of phenylsilane at room temperature.[13]
Later, Charette documented diphenylsilane (Ph2SiH2) as an
effective coupling reagent for amide and peptide synthesis.[14]
Under the reported conditions (DMAP 0.5 equiv., DIPEA 1 equiv.,
acetonitrile, 80 °C), an array of dipeptides were synthesized albeit
considerable epimerization was observed in the case of N-Boc-
phenylglycine (e.r. 61:39). Moreover, Fmoc protecting group was
found incompatible with the reported reaction conditions.
Surprisingly, upon screening the nature of the hydrosilane,
phenylsilane was found less reactive. Intrigued by this result, we
decided to reassess phenylsilane potential as coupling reagent
for peptide and Weinreb amide synthesis.
Alongside tremendous progresses in metal- and boron-catalyzed
methodologies[7,8], there has been a steep rise in the development
and implementation of silicon-based reagents as a useful
alternative to recently developed coupling reagents.[9] Pioneered
by Chan in 1969,[10a,b] the use of silicon active reagents derived
from SiCl4 was later investigated by Liskamp (Me2SiCl2) and
Mukaiyama to culminate recently with the development of a 9-
silafluorenyl dichloride by Charette (Figure 1).[10c-h] Although a
useful scope was accomplished with the later, this methodology
required a large excess of a Brønsted base as hydrogen chloride
scavenger. This resulted in large chemical wastes and
enantiomeric erosion of substrate, notably in the presence of
sensitive phenylglycine derivatives.
Results and Discussion
Our investigation began by examining a model reaction involving
morpholine and phenylacetic acid. A stoichiometric amount of
both partners in methylene chloride afforded a promising 50%
yield after one hour at room temperature (Table 1, entry 1).
[a]
E. Morisset, Dr A. Chardon, Pr. J. Rouden, Dr J. Blanchet
Laboratoire de Chimie Moléculaire et Thio-organique, Normandie
Univ, ENSICAEN, UNICAEN, CNRS, 14000 Caen, France.
jerome.blanchet@ensicaen.fr.
https://www.lcmt.ensicaen.fr/cv-jerome-blanchet/
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
Table 1. Optimization of amide synthesis with phenylsilane.
Entry
1 : 2 : PhSiH3
t
NMR conv.[a]
1
2
3
4
5
6
7
1:1:1
1:1:3
1 h
1 h
50 %
39 %
1:1:1
5 h
68 %
1:1.5:1.5
1.5:1:1.5
2:1:1.5
2:1:1.5
5 h
74 %
2 h
84 %
2 h
100 %
100 %[b]
Scheme 1. Substrate scope of phenylsilane promoted amide synthesis.
Reaction of 1 (2 mmol), 2 (1 mmol) and PhSiH3 (1.5 mmol) were carried out in
MeCN (1 mL) at 20 °C.
30 min
[a] Determined using 1,3,5-trimethoxybenzene as internal standard. [b]
Reaction carried out in MeCN.
As expected, electron rich 2-furancarboxylic acid and less
nucleophilic aniline were found to be challenging substrates and
moderate 64-61% yields were obtained after a prolonged reaction
time. Also, a limitation was identified with highly hindered mesityl
carboxylic acid that gave no detectable amount of amide product.
More challenging peptides couplings were then examined using
phenylsilane. Surprisingly, a solvent change to methylene
chloride was required, as slightly lower yield of Boc-Phe-Phe-
OMe 7a was obtained with acetonitrile. Additives such as DMAP,
DMAPO[16] or sodium bisulfite[17] did not improve the yield. Only
one equivalent of potassium cyanide was found to barely improve
the yield of the reaction but the acute toxicity of such additive
excluded further investigations.
When α-amino ester hydrochloride was used as a substrate in the
presence of added triethylamine, the yield of Boc-Phe-Phe-OMe
7a dropped to 29%. Therefore we investigated the scope of the
reaction using α-amino esters as free amine. All the reactions
proceeded smoothly to afford the desired dipeptides 7 in good to
moderate yields. Boc-glycine was efficiently coupled to methyl α-
amino esters of phenylalanine, proline, valine, methionine,
aspartic acid and sarcosine (7b-g, Scheme 2). More significantly,
other N-protected α-amino acids derived from proline,
phenylalanine and tryptophan performed equally well with 62-
83% isolated yields (7h-n, Scheme 2). Under our mild reaction
conditions, usual protecting groups were well tolerated, including
the versatile Fmoc group as illustrated by the synthesis of Fmoc-
Phe-Phe-OMe in 75% yield (7m, Scheme 2). Strongly hindered
O-protected Boc-threonine and valine delivered peptides 7o and
7p, albeit in moderate 55-56% yields (Scheme 2). In contrast, a
control reaction with Boc-threonine bearing an unprotected
hydroxyl group failed to deliver the corresponding peptide.
Importantly, no epimerization was detected when using chiral N-
protected α-amino acids even in the presence of sensitive Boc-
phenylglycine as demonstrated with the synthesis of 7q in 57%
yield (Scheme 2).
In sharp contrast with previous study[14], an extra amount of
phenylsilane appeared detrimental for the amide bond formation
(Table 1, entry 2). Longer reaction time associated to amine
excess led to an improved conversion of 74% (Table 1, entry 4).
However, a substantial acceleration was observed in the
presence of a two-fold excess of phenylacetic acid and a
quantitative conversion was reached in only two hours at room
temperature (Table 1, entry 6). Additional solvent screening led to
an even faster reaction in acetonitrile, giving a complete
conversion in only 30 minutes (Table 1, entry 7). Control reactions
with other hydrosilanes (Et3SiH, PhMe2SiH, PMHS, TMDS,
Ph2SiH2) did not produce any amide 3. Only hexylsilane was
found less reactive providing a 33% conversion under similar
reaction conditions. Efforts to identify a more efficient coupling
reagent prompted us to investigate the reactivity of phenylsilane
derivatives 4a-4e, synthesized according to known procedures
(Figure 2).[15]
Figure 2. Considered phenylsilane derivatives.
Unfortunately, monitoring reaction progress using 1H NMR,
slightly lower performance were showed for hydrosilanes 4a and
4b and an absence of reactivity with 4c and 4d (see supporting
information Figure S1). In our hands, 4e was found surprisingly
too volatile to be evaluated.
Using optimal reaction conditions, various aliphatic, aromatic and
heteroaromatic carboxylic acids (1a-f) derivatives were smoothly
coupled with primary amines or cyclic secondary amines
(Scheme 1).
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10.1002/ejoc.201901660
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COMMUNICATION
Scheme 3. Substrate scope of phenylsilane promoted Weinreb amide synthesis.
The less electrophilic 2-methoxybenzoic acid reacted sluggishly
due to a combination of unfavorable electronic and steric factors
(Scheme 3).
The mechanism of amide synthesis involving hydrosilanes is still
unclear. Charette conducted a brief mechanistic study and
proposed a chemical ligation pathway requiring the addition of
both amine and carboxylic acid at the silicon atom followed by the
intramolecular addition of silylamine
silylester.[10h,14] However, such mechanism involving the formation
of silanone was later determined thermodynamically
9
to neighboring
a
unfavorable using DFT calculations.[19] A related study by Denton
supported that phenylsilylester 10 (Figure 3) is effective for amide
synthesis however in refluxing toluene and with a moderate yield
of 64%.[20a] The observation that an excess of carboxylic acid
significantly bolstered the reaction kinetic suggested than a
putative polysilylester intermediate might be responsible for the
high reactivity observed at room temperature. Therefore we
hypothesized that diester 11 or triester 12, readily formed by a
two-fold or three-fold dehydrogenative addition of carboxylic acid
to phenylsilane, might be responsible for the reactivity observed
at room temperature.
Scheme 2. Substrate scope of phenylsilane promoted peptide synthesis.
Reaction of N-protected α-amino acid 1 (2 mmol), α-amino ester 2 (1 mmol) and
PhSiH3 (1.5 mmol) were carried out in dry CH2Cl2 (1 mL) for 16 hours at 20 °C.
[a] d.e. > 99%. HPLC data available in supporting information.
Unfortunately, as the peptide chain extend yields plummeted and
tripeptides 7r and 7s were obtained in moderate 48% and 55%
yields, respectively. However, those yields are in line with
Charette‘s study[14] while reactions were run at ambient
temperature in our case.
As a case study, Weinreb amide synthesis was also investigated.
To the best of our knowledge hydrosilane mediated synthesis of
such useful intermediates is unreported and so might represent a
useful alternative to well-known procedures.[18] As expected, the
use of N,O-dimethylhydroxylamine was found unreliable since the
free amine readily decomposed. As a consequence the reaction
was optimized with the corresponding hydrochloride salt. Several
aliphatic and electron depleted aromatic carboxylic acids gave the
corresponding Weinreb amides in good to moderate 86-44%
yields (8a-e, Scheme 3).
Figure 3. Possible reactive intermediate involved in hydrosilanes mediated
amide synthesis.
However, in our hands any effort to isolate reactive esters 11 and
12 failed and systematically ended with polysiloxanes formation.
As a surrogate, the acetylation of morpholine 2a was investigated
with various commercially available silyl acetates 13a-c (Scheme
4).
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Most amines and anilines gave high yields at room
temperature (14a-l, 75-99% isolated yields) and only electron
poor or N-substituted anilines required mild heating to reach
reasonable to excellent yields (14m-o, Scheme 5). Additional
chiral alpha amino ester were also acetylated without noticeable
racemization (14p-r, Scheme 5).
Scheme 4. Silyl acetate reactivity in acetylation reaction. [a] NMR conversion
determined using 1,3,5-trimethoxybenzene as internal standard. [b] Conversion
after 5 h at room temperature. [c] Isolated yield.
Conclusions
Interestingly, diacetoxydimethylsilane 13a was found not
productive at all: even after 5 hours at room temperature, no trace
of amide product was detected by H NMR (Scheme 4). On the
In conclusion, phenylsilane was reassessed as an efficient
amide and peptide coupling reagent. A large scope of dipeptides
and two tripeptides was achieved with good to moderate yields. It
is worth noting that no side reaction such as epimerization was
observed even with phenylglycine derivatives. Comparative
experiments using various acetoxysilanes pointed towards
phenyltriacyloxysilane as reactive intermediate. Finally, silicon
tetraacetate was introduced as an interesting acetylating reagent
for amines and anilines that operate in mild conditions and in
absence of base.
1
contrary, triacetoxy(methyl)silane 13b displayed a moderate
conversion of 26% at 0 °C and more than two-fold increased at
room temperature (Scheme 4). Finally, silicon tetraacetate 13c
reacted quantitatively and almost immediately at 0 °C. While a
direct comparison is arguable, such results suggest that silicon
esters 10 and 11 are not responsible for the reactivity observed
at room temperature. Indeed it appeared clearly that added
acetate groups at the silicon significantly boosted the
electrophilicity of the acetyl moiety. This prompted us to
rationalize that phenylsilane mediated amide synthesis is likely to
occur through putative ester 12.[20b]
Acknowledgements
The authors thank the CNRS, Labex Synorg (ANR-11-LABX-
0029) for AC fellowship, Normandie université, the Conseil
Régional de Normandie and the European FEDER fundings for
financial support.
Keywords: hydrosilane • amide • peptide • acetylation • coupling
reagent
[1]
a) A. Greenberg, C. M. Breneman, J. F. Liebman in The Amide Linkage:
Structural Significance in Chemistry, Biochemistry, and Materials
Science, Wiley-Interscience, New York, 2000. b) A. R. Chamberlin,
Chem. Rev. 1997, 97, 2243–2266. c) K. E. Schwieter, J. N. Johnston J.
Am. Chem. Soc. 2016, 138, 14160–4169.
[2]
[3]
T. Wieland, M. Bodanszky, in The World of Peptides: A Brief History of
Peptide Chemistry, Springer, 1991.
a) S. D.; Roughley, Jordan, A. M. J. Med. Chem. 2011, 54, 3451–3479.
b) M. C. Bryan, P. J. Dunn, D. Entwistle, F. Gallou, S. G. Koenig, J. D.
Hayler, M. R. Hickey, S. Hughes, M. E. Kopach, G. Moine, P. Richardson,
F. Roschangar, A. Steven, F. J. Weiberth, Green Chem. 2018, 20, 5082–
5103.
[4]
For recent reviews about peptides synthesis see: a) F. Albericio, A. El-
Faham, Org. Process Res. Dev. 2018, 22, 760–772. b) S. C. Stolzewand,
M. Kaiser, Synthesis 2012, 44, 1755–1777. c) V. Made, S. Els-Heindl, A.
G. Beck-Sickinge, Beilstein J. Org. Chem. 2014, 10, 1197–. d) E. Valeur,
M. Bradley, Chem. Soc. Rev. 2009, 38, 606–631. e) S. B. H. Kent, Chem.
Soc. Rev. 2009, 38, 338–351. f) A. El-Faham, F. Albericio, Chem. Rev.
2011, 111, 6557–6602.
[5]
[6]
V. R. Pattabiraman, J. W. Bode, Nature 2011, 480, 471-479.
Scheme 5. Substrate scope of silicon tetraacetate promoted acetamide
synthesis. Reaction times are not optimized for individual substrates. [a] e.e. >
99%. HPLC data available in supporting information.
For recent reviews about amide bond formation see: a) H. Lunberg, F.
Tinnis, N. Selander, H. Adolfsson, Chem. Soc. Rev. 2014, 43, 2714–
2742. b) R. Marcia de Figueiredo, J.-S. Suppo, J.-M. Campagne, Chem.
Rev. 2016, 116, 12029–12122. c) A. Ojeda-Porras, D. Gamba-Sanchez,
J. Org. Chem. 2016, 81, 11548–11555. d) M. T. Sabatini, L. T. Boulton,
H. F. Sneddon, T. D. Sheppard, Nat. Catal. 2019, 2, 10–17. e) K.
To the best of our knowledge, silicon tetraacetate has never
been considered so far as a general acetylating reagent of amines.
Therefore, its versatility was demonstrated by the synthesis of a
range of acetamides under mild conditions and in absence of any
base (Scheme 5).
Hollanders, B. U. W. Maes, S. A. Ballet, Synthesis 2019, 51, 2261–2277.
a) T. Krause, S. Baader, B. Erb, L. J. Gooßen, Nat. Commun. 2016, 7,
11732–. b) H. Lundberg, F. Tinnis, H. Adolfsson, Appl. Organomet.
Chem. 2019, 33, e5062. c) H. Lundberg, F. Tinnis, N. Selander, H.
Adolfsson, Chem. Soc. Rev. 2014, 43, 2714–2742.
[7]
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[8]
For key references in boron-catalysed amide synthesis see: a) K.
Ishihara, S. Ohara, H. Yamamoto, J. Org. Chem. 1996, 61, 4196–4197.
b) R. M. Al Zoubi, O. Marion, Hall, D. G. Angew. Chem. Int. Ed. 2008, 47,
2876–2879. c) N. Gernigon, R. M. Al Zoubi, D. G. Hall, J. Org. Chem.
2012, 77, 8386–8400. d) E. K. W. Tam, Rita, L. Y. Liu, A. Chen, Eur. J.
Org. Chem. 2015, 5, 1100–1107. e) T. Mohy El Dine, W. Erb, Y. Berhault,
J. Rouden, J. Blanchet, J. Org. Chem. 2015, 80, 4532–4544. f) T. Mohy
El Dine, J. Rouden, J. Blanchet, Chem. Commun. 2015, 51, 16084–
16087. g) H. Noda, M. Furutachi, Y. Asada, N. Kumagai, M. Shibasaki,
Nature Chem. 2017, 9, 571–577. h) C. R. Opie, H. Noda, M. Shibasaki,
N. Kumagai, Chem. Eur. J. 2019, 25, 4648–4653. i) H. Noda, Y. Asada,
M. Shibasaki, N. Kumagai, J. Am. Chem. Soc. 2019, 141, 1546–1554. j)
Z. Liu, H. Noda, M. Shibasaki, N. Kumagai, Org. Lett. 2018, 20, 612–615.
k) D. N. Sawant, D. B. Bagal, S. Ogawa, K. Selvam, S. Saito, Org. Lett.
2018, 20, 4397–4400. l) N. Shimada, M. Hirata, M. Koshizuka, N. Ohse,
R. Kaito, K. Makino, Org. Lett. 2019, 21, 4303–4308. m) M. T. Sabatini,
L. T. Boulton, T. D. Sheppard, Sci. Adv. 2017, 3, e1701028.
[9]
L. Hu, S. Xu, Z. Zhao, Y. Yang, Z. Peng, M. Yang, C. Wang, J. Zhao, J.
Am. Chem. Soc. 2016, 138, 13135–13138.
[10] a) T.-H. Chan, L. T. L. Wong, J. Org. Chem. 1969, 34, 2766–2767. b)
T.-H. Chan, L. T. L. Wong, J. Org. Chem. 1971, 36, 850–853. c) S. H.
Van Leeuwen, P. J. L. M. Quaedflieg, Q. B. Broxterman, R. M. J.
Liskamp, Tetrahedron Lett. 2002, 43, 9203–9207. d) T. Tozawa, Y.
Yamane, T. Mukaiyama, Chem. Lett. 2005, 34, 1586–1587. e) T. Tozawa,
Y. Yamane, T. Mukaiyama, Chem. Lett. 2005, 34, 734–735. f) T. Tozawa,
Y. Yamane, T. Mukaiyama, Chem. Lett. 2005, 34, 1334–1335. g) T.
Tozawa, Y. Yamane, T. Mukaiyama, Heterocycles 2006, 67, 629–641.
h) S. J. Aspin, S. Taillemaud, P. Cyr, A. B. Charette, Angew. Chem. Int.
Ed. 2016, 55, 13833–13837.
[11] D. C. Braddock, P. D. Lickiss, B. C. Rowley, D. Pugh, T. Purnomo, G.
Santhakumar, J. F. Fussell, Org. Lett. 2018, 20, 950–953.
[12] Z. Ruan, R. M. Lawrence, C. B. Cooper, Tetrahedron Lett. 2006, 47,
7649–7651. The title « Phenylsilane as an active amidation reagent for
the preparation of carboxamides and peptides » is misleading since no
peptide synthesis is reported there (following IUPAC peptide definition
as “amides derived from two or more amino carboxylic acid molecules”).
[13] Typically, 10 equiv of amines and 20 equiv of PhSiH3 were used.
[14] M. Sayes, A. B. Charette, Green Chem. 2017, 19, 5060–5064.
[15] M. D. Visco, J. M. Wieting, A. E. Mattson, Org. Lett. 2016, 18, 2883–2885.
[16] I. Shiina, H. Ushiyama, Y. Yamada, Y. Kawakita, K. Nakata, Chem. Asian
J. 2008, 3, 454–461.
[17] B. Iorga, J.-M. Campagne, Synlett 2004, 10, 1826–1828.
[18] a) J. I. Levin, E. Turos, S. M. Weinreb, Synth. Commun. 2006, 12, 989–
993. b) I. Maugras, J. Ponchet, P. Jouin, Tetrahedron 1990, 46, 2807–
2816. c) P. A. Jacobi, W. Zheng, Tetrahedron Lett. 1991, 32, 1279–1282.
[19] a) Y. Y. Jiang, L. Zhu, Y. Liang, X. Man, S. Bi, J. Org. Chem. 2017, 82,
9087–9096. b) B. Hu, Y.-Y. Jiang, P. Liu, R.-X. Zhang, Q. Zhang, T.-T.
Liu, S. Bi, Org. Biomol. Chem. 2019, 17, 9232–9242.
[20] a) K. G. Andrews, R. M. Denton, Chem. Commun. 2017, 53, 7982–7985.
A more recent NMR study concluded that amide synthesis did not directly
involve monoester 9 or 10. see b) P. B. White, S. J. Rijpkema, R. P.
Bunschoten, J. Mecinović, Org. Lett. 2019, 21, 1011–1014.
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COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Amides synthesis
Eléonore Morisset[a], Aurélien
Chardon[a], Jacques Rouden[a] and
Jérôme Blanchet[a]
Page No. – Page No.
Phenysilane and Silicon Tetraacetate:
Versatile Promotors for Amide
Synthesis.
Phenylsilane as been reassed as useful coupling reagent for amides synthesis.
Peptides and Weinreb amides are easily obtained under mild conditions in absence
of epimzerization even with challenging substrates such as phenylglycine. Further
investigation regarding the reactivity of stable acetoxysilanes supported
phenylpolyacyloxysilane as key intermediate.
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