Fluoride-Catalyzed Esterification of Amides

Article abstract of DOI:10.1002/chem.201800336

In recent years, it has been demonstrated that amide carbon–nitrogen bonds can be activated and selectively cleaved using transition metal catalysts. However, these methodologies have been restricted to specific amides; a one-to-one relationship exists between the catalytic system and the amides and also uses large amounts of transition-metal catalysts and ligands. Hence, we now report a general strategy for esterification of common amides using fluoride as a catalyst. This method shows high functional group tolerance, and notably it requires only a slight excess of the alcohol nucleophile, which is a rare case in transition-metal-free amide transformations. Moreover, this approach may provide a new understanding for further studies on esterification of amides and is expected to stimulate the development of alternative methods for direct functionalization of amides.

Full text of DOI:10.1002/chem.201800336

A Journal of
Accepted Article
Title: Fluoride-Catalyzed Esterification of Amides
Authors: Hongxiang Wu, Weijie Guo, Stelck Daniel, Yue Li, Chao Liu,
and Zhuo Zeng
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201800336
Link to VoR: http://dx.doi.org/10.1002/chem.201800336
Supported by

10.1002/chem.201800336
Chemistry - A European Journal
COMMUNICATION
Fluoride-Catalyzed Esterification of Amides
Hongxiang Wu[a], Weijie Guo[a], Stelck Daniel[c], Yue Li[a], Chao Liu[b], and Zhuo Zeng* [a] [b]
Abstract: In recent years, it has been demonstrated that amide
carbon-nitrogen bonds can be activated and selectively cleaved using
transition metal catalysts. However, these methodologies have been
restricted to specific amides, a one-to-one relationship exists between
the catalytic system and the amides and also use large amounts of
transition-metal catalysts and ligands. Hence, we now report a
general strategy for esterification of common amides using fluoride as
a catalyst. This method shows high functional groups tolerance, and
notably it requires only a slight excess of the alcohol nucleophile,
which is a rare case in transition-metal-free amides transformation.
Moreover, this approach may provide a new understanding for further
studies on esterification of amides and is expected to stimulate the
development of alternative methods for direct functionalization of
amides.
esterification, transamidation, Suzuki-Miyaura coupling, Negishi
couplings, etc. [8] Specifically, amides are able to be employed as
electrophiles in the decarbonylative coupling, [9] which allows the
further conversion of amides to other synthetic building blocks.
Despite the significant progress that has been achieved in
the method of esterification of amides, still there are some limits.
For instance, the use of complex catalytic systems are not
generally applicable for amide substrates, normally for secondary
benzamides (Garg’s work)[5a] or N-acyl-tert-butyl-carbamates
(Danoun’s work),[8a] and are inconvenient to handle since the
reactions must be performed under inert atmosphere. Hence, new
conceptual approaches to convert amides to esters are still
welcome to meet the intrinsic diversity of amide transformation
(Figure 1)..
Amides are ubiquitous and readily available in nature, and
represent a common structural motif in a variety of proteins,
sugars, lipids and pharmaceuticals.[1] To interconvert amides to
other functional groups is an important task in organic synthesis,
which is also challenging. Thus, to facilitate amide transformation,
many efforts have been made, including using enzymes to break
amide linkages,[2] as well as developing new reagents to convert
amides to corresponding aldehydes or ketones under harsh
reaction condition.[3] However, converting amides to esters
requires strong acidic or basic conditions, and a large excess of
the alcohol nucleophile is utilized, normally as solvent.[1d] The
short comings in the current methods of amide activation and
esterification of amides has become a longstanding challenge.
The major problem associated with amide activation is the
resonance stabilization of the amide C-N bond.[4] Consequently,
to overcome this obstacle, recent attentions have turned to the
metal-catalyzed cleavage of amide C-N bonds. In 2015, Garg and
co-workers presented a revolutionary protocol for esterification of
Figure 1. Previous studies on esterification of amides
amides, introducing
a
Nio/NHC catalyst system to amide
transformations.[5] Following the initial report, Szostak and co-
workers focused on the structural and energetic factors that
govern amide reactivity that resulted in the development of
several twisted amides.[6] Additionally, Zou’s group contributed N-
acyl-tosylamides (Ts) as a coupling partner in Suzuki coupling
reaction and subsequently employed by others. [7]
With these developments, strategically employing diverse
catalysts such as palladium, nickel, rhodium and cobalt, amides
can now be used in several important transformations, including
Here we report the first direct esterification of amides
catalyzed by cesium fluoride. The obvious characteristic of our
study includes (a) as proof of a new conceptual path for
esterification of amides via a fluoride catalyst (b) the development
of a single generic catalyst system to enable esterification of a
wide range of amides; (c) the first use of readily available, air-
stable and low-cost CsF as catalyst, avoiding the use of
expensive transition-metal catalysts and ligands. Overall, this
work demonstrates that fluoride can provide a significant
improvement in the scope of amide’s esterification, which may
facilitate the growing utilization of amides as synthons in a variety
of transformations.
To achieve the goal of esterification of amides under
transition-metal-free conditions, the possible route as shown in
(Figure 2) was proposed. Namely, we envisioned that fluoride
might be able to serve as a strong nucleophile to attack the
carbonyl group of the amide to form an acyl fluoride. The resultant
intermediate species is then trapped by another nucleophile to
generate the desired product and release the fluoride to attend
the next catalytic cycle. The amide undergoes activation by
[a]
[b]
[c]
Hongxiang Wu[a], Weijie Guo[a], Yue Li[a], Zhuo Zeng* [a]
College of Chemistry & Environment, South China Normal
University, Guangzhou 510006, Guangdong, China
E-mail: zhuoz@scnu,edu.cn
Chao Liu[b]
Shanghai Institute of Organic Chemistry, Chinese Academy of
Science, 354 Lingling Road, 200032, Shanghai, China
E-mail: chaoliu@sioc.ac.cn
Stelck Daniel[c]
Department of Chemistry, University of Idaho,
Moscow, ID 83844-2343, USA
E-mail: daniels@uidoho.edu
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

10.1002/chem.201800336
Chemistry - A European Journal
COMMUNICATION
fluoride and allows site-selective N−C Bond cleavage to convert
15
CsF
CH3CN
100
97
to ester..
With the suitable reaction conditions in hand, three classes
of amides, including N-acyl-tert-butyl-carbamates (Boc), N-acyl-
tosylamides (Ts) and di- tert-butyl N-acylimidodicarbonates were
adopted to probe the fluoride catalysis strategy (Figure 3).
Remarkably, the new catalytic systems demonstrated applicability
in the esterification of both secondary and primary amides. The
corresponding esters were formed in excellent yields, when the
above amide substrates were employed in this catalytic system.
Figure 2. Possible route of amide esterification.
To investigate our proposed transformation, amide 1a, KF
and benzyl alcohol were mixed in a solvent and the product benzyl
benzoate was observed. This preliminary result promoted us to
further investigate the hypothesis. The following table is a survey
of how the catalysts performed. The results indicate the unique
role of the fluoride in this esterification reaction. As shown in Table
1, no reaction occurred with halogen anions except fluoride were
employed in this transformation. Also, in almost every case, CsF
obtained a better yield compared to those experiments that used
other fluoride salts as catalyst. Eventually, the screening efforts,
which involved testing base, solvent, catalyst loading and
temperature, led to the best reaction conditions of this approach
(Table 1).
Figure 3. Evaluation of amide substrates
Table 1. Optimization of reaction conditions.
Entry Catalyst
solvent
T (oC)
Yield (%)
1
2
3
4
5
6
7
8
None
KF
KCl
KBr
KI
Et3N
DBU
NaF
CsF
n-Bu4NF
CsF
CsF
CsF
CsF
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
80
0
35
0
0
0
0
0
13
72
55
88
65
21
43
9
10
11
12
13
14
Figure 4. Scope of the alcohol and Ts amide substrates.
DMSO
toluene
This article is protected by copyright. All rights reserved.

10.1002/chem.201800336
Chemistry - A European Journal
COMMUNICATION
To further study the scope and limitation of this direct
esterification approach, a wide variety of alcohols were utilized to
well tolerated, in which transition-metal catalytic systems were
unable to perform. It was also shown that sterically hindered
furnish the desired products under the general reaction conditions. secondary and tertiary aliphatic amides performed smoothly
Primary alcohols were well tolerated, even those containing
olefins. Irrespective of oxygen-, sulfur- and nitrogen-containing
heterocyclic alcohols, the corresponding esters were formed in
excellent yields. These experiments revealed that furans,
thiophenes and pyrrolidines were all tolerated. This opens the
door for further application in natural product synthesis. In
addition, this methodology also can apply to secondary alcohols
and demonstrated high efficiency. Furthermore, tertiary alcohol
such as 2-methylbut-3-yn-2-ol was employed in this approach to
give the corresponding ester in 26% yield, in which previous
methods were unable to transform (Figure 4).
under these reaction conditions (Figure 4) .
In order to examine the scope of this transformation, N-acyl-
tert-butyl-carbamates (Boc) (Figure 5) and di- tert-butyl N-
acylimidodicarbonates (Figure 6) were employed to react with
varous alcohols in this catalytic system,respectively. Irrespective
of electron-donating groups and electron-withdrawing groups in
benzene ring, corresponding esters were formed in excellent
yields. Additionally, primary and secondary alcohols were all
tolerated.
Figure 7. One-pot esterification of amides
Finally, we performed a gram-scale preparation experiments
to establish a proof to our method for further application in amide
esterification. Notably, this direct transformation was carried out
in one-pot (Figure 7), starting from secondary and primary amides.
This demonstrates great application potential in amide
functionalization.
To probe our hypothesis (Figure 2) in this transformation, a
mechanism experiment was established. The 19F NMR spectrum
data (see Supporting Information) provided a direct evidence of
benzoyl fluoride intermediate (19F NMR δ = 17.09), which support
our hypothesis and designation.
Figure 5. Scope of the alcohol and Boc amide substrates.
Figure 8. Synthesis of thioester and amide
Also, propane-1,3-dithiol and phenylmethanamine were
selected as nucleophiles to trap the acyl fluoride to generate the
corresponding thioester and amide (Figure 8), respectively.
Impressively, thioester and amide can be formed in high yields,
and thioester which is unable to obtain from transition-metal-
catalyzed amide transformation and play a very important role in
peptide synthesis.10 These results indicate that this method are
Figure 6. Scope of the alcohol and di-tert-butyl N-acylimidodicarbonates
substrates
Regarding the application of phenyl derivatives, electron-
neutral as well as electron-rich and -poor phenyl-derived amides
were employed in this protocol, providing desired products in high
yields (Figure 4). Also, substrates bearing bromide groups were
This article is protected by copyright. All rights reserved.

10.1002/chem.201800336
Chemistry - A European Journal
COMMUNICATION
Yamano, S. Zhou, S. M. Anthony, N. K. Garg, Nat. Commun. 2016, 7,
11554; d) B. J. Simmons, N. A. Weires, J. E. Dander, N. K. Garg, ACS
Catal. 2016, 6, 3176-3179; e) J. E. Dander, N. A. Weires, N. K. Garg,
Org. Lett. 2016, 18, 3934-3936; f) L. Hie, E. L. Baker, S. M. Anthony, J.-
N. Desrosiers, C. Senanayake, N. K. Garg, Angew. Chem. Int. Ed. 2016,
55, 15129-15132; Angew. Chem. 2016, 128, 15353-15356. g) J. E.
Dander, N. K. Garg, ACS Catal. 2017, 7, 1413-1423; h) S. A. Ruider, N.
Maulide, Angew. Chem. Int. Ed. 2015, 54, 13856-13858; Angew. Chem.
2015, 127, 14062-14064; i) N. A. Weires, D. D. Caspi, N. K. Garg, ACS
Catal. 2017, 7, 4381-4385.
not only of theoretical significance, but also of potential application
value.
In conclusion, we have designed and presented the first
fluoride-catalyzed activation of secondary and primary amides,
which demonstrated as an efficient way to convert amides to
esters. The approach circumvents the universal problem that
transition-metal-catalyzed esterification methods have confronted.
Thus, enabling the synthesis of esters from a wide range of
amides under general reaction conditions. To be more precise,
both aromatic and aliphatic secondary and primary amides are
covered by this protocol. The methodology has demonstrated
excellent functional group tolerance and high yields under mild
conditions and only 1.2 equivalents of the alcohol nucleophile. In
brief, this diverse method of amide activation is expected to
expand the application of esterification of amides and may lead to
new discovery of amide transformation.
[6]
[7]
a) G. Meng, M. Szostak, Org. Biomol. Chem. 2016, 14, 5690-5705; b) G.
Meng, M. Szostak, Org. Lett. 2016, 18, 796-799; c) G. Meng, M. Szotak,
Angew. Chem. Int. Ed. 2015, 54, 14518-14522; Angew. Chem. 2015, 127,
14726-14730; d) G. Meng, M. Szostak, Org. Lett. 2015, 17, 4364-4367;
e) S. Shi, M. Szostak, Chem. Eur. J. 2016, 22, 10420-10424; f) C. Liu, G.
Meng, Y. Liu, R. Liu, R. Lalancette, R. Szostak, M. Szostak, Org. Lett.
2016, 18, 4194-4197.
a) X. Li, G. Zou, Chem. Commun. 2015, 51, 5089-5092; b) X. Li, G. Zou,
J. Organomet. Chem. 2015, 794, 136-145; c) C. Liu, Y. Liu, R. Liu, R.
Lalancette, R. Szostak, M. Szostak, Org. Lett. 2017, 19, 1434-1437; d)
C. W. Cheung, M. L. Ploeger, X. Hu, ACS Catal. 2017, 7, 7092-7096; e)
G. Meng, R. Lalancette, R. Szostak, M. Szostak, Org. Lett. 2017, 19,
4656-4659; g) G. Meng, R. Szostak, M. Szostak, Org. Lett. 2017, 19,
3596-3599.
Acknowledgements ((optional))
The authors gratefully acknowledge the support of Science and
Technology Planning Project of Guangdong Province
(2017A010103017), National Natural Science Foundation of
China (21272080)..
[8]
[9]
a) Y. Bourne-Branchu, C. Gosmini, G. Danoun, Chem. Eur. J. 2017, 23,
1-6; b) R. Takise, K. Muto, J. Yamaguchi, Chem. Soc. Rev. 2017, 46,
5864-5888.
a) G. Meng, M. Szostak, ACS Catal. 2017, 7, 7251-7256; b) S. Shi, M.
Szostak, Org. Lett. 2017, 19, 3095-3098; c) C. Liu, M. Szostak, Angew.
Chem. Int. Ed. 2017, 56, 12718-12722; Angew. Chem. 2017, 129,
12892-12896; d) C. Liu, G. Meng, M. Szostak, J. Org. Chem. 2016, 81,
12023-12030. e) G. Meng, M. Szostak, Org. Lett. 2016, 18, 796-799; f)
S. Shi, G. Meng, M. Szostak, Angew. Chem. Int. Ed. 2016, 55, 6959-
6963; Angew. Chem. 2016, 128, 7073-7077; g) J. Hu, M. Wang, X. Pu,
Z, Shi, Nat. Commun. 2017, 8, 14993; h) J. Hu, Y. Zhao, J. Liu, Y. Zhang,
Z. Shi, Angew. Chem. Int. Ed. 2016, 55, 8718-8722; Angew. Chem. 2016,
128, 8860-8864; i) W. Srimontree, A. Chatupheeraphat, H.-H. Liao, M.
Rueping, Org. Lett. 2017, 19, 3091-3094; j) X. Liu, H. Yue, J. Jia, L. Guo,
M. Rueping, Chem. Eur. J. 2017, 23, 11771-11775; k) H. Yue, L. Guo,
S.C. Lee, X. Liu, M. Rueping, Angew. Chem. Int. Ed. 2017, 56, 3972-
3976; Angew. Chem. 2017, 129, 4030-4034; l) H. Yue, L. Guo, H.-H. Liao,
Y. Cai, C. Zhu, M. Rueping, Angew. Chem. Int. Ed. 2017, 56, 4282-4285;
Angew. Chem. 2017, 129, 4346-4349; m) H. Wu, T. Liu, M. Cui, Y. Li, J.
Jian, H. Wang, Z. Zeng, Org. Biomol. Chem. 2017, 15, 536-540.
…
Keywords: esterification • fluoride catalysis • aliphatic amides •
generic catalyst system • metal-free
[1]
a) S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451-3479; b)
A. A. Kaspar, J. M. Reichert, Drug Discovery Today. 2013, 18, 807-817;
c) V. Ng, W. C. Chan, Chem. Eur. J. 2016, 22, 12606-12616; d) “The
Amide Linkage: Structural Significance”: Chemistry, Biochemistry and
Materials Science (Eds.: A. Greenberg, C. M. Breneman, J. F. Liebman),
Wiley-Interscience, New York, 2003.
[2]
[3]
a) S. Negoro, Appl. Microbiol. Biotechnol. 2000, 54, 461-466; b)
Proteases: Structure and Function (Eds.: K. Brix, W. StÖcker), Springer,
2013.
a) S. Nahm, S. M. Weinreb, Tetrahedron Lett. 1981, 22, 3815-3818; b) T.
A. Dineen, M. A. Zajac, A. G. Myers, J. Am. Chem. Soc. 2006, 128,
16406-16409. c) J. T. Spletstoser, J. M. White, A. R. Tunoori, G. I. Georg,
J. Am. Chem. Soc. 2007, 129, 3408-3419.
[3]
[4]
[5]
K. Ouyang, W. Hao, W. X. Zhang, Z. Xi, Chem. Rev. 2015, 115, 12045-
12090.
a) L. Hie, N. F. Fine Nathel, T. Shah, E. L. Baker, X. Hong, Y.-F. Yang,
P. Liu, K. N. Houk, N. K. Garg, Nature 2015, 524, 79-83; b) N. A. Weires,
E. L. Baker, N. K. Garg, Nat. Chem. 2016, 8, 75-79; c) E. L. Baker, M. M.
This article is protected by copyright. All rights reserved.

10.1002/chem.201800336
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
A new conceptual path for
Hongxiang Wu[a], Weijie Guo[a], Stelck
Daniel[c], Yue Li[a], Chao Liu[b], and Zhuo
Zeng* [a] [b]
esterification of amides using easily
available fluoride catalyst CsF under
mild conditions with good functional
group tolerance has been developed,
resulting in efficient synthesis of a
viariety of aliphtic esters in moderate
to good yields. This work
Page No. – Page No.
Fluoride-Catalyzed Esterification of
Amides
demonstrates that fluoride can provide
a significant improvement in the scope
of amide’s esterification, which may
facilitate the growing utilization of
amides as synthons in a variety of
transformationss
Layout 2:
COMMUNICATION
Author(s), Corresponding Author(s)*
((Insert TOC Graphic here))
Page No. – Page No.
Title
Text for Table of Contents
This article is protected by copyright. All rights reserved.