Metal-Free C–S Bond Cleavage to Access N-Substituted Acrylamide and β-Aminopropanamide

Article abstract of DOI:10.1002/ejoc.201900960

Metal-free and Selectfluor-mediated C–S bond cleavage is described. This novel strategy provides a facile and efficient method to access important N-substituted acrylamide and β-aminopropanamide derivatives with good functional group tolerance and yields.

Full text of DOI:10.1002/ejoc.201900960

A Journal of
Accepted Article
Title: Metal-free C−S bond cleavage to access N-substituted
acrylamide and β-aminopropanamide
Authors: Ke Yang, Yi Li, Zhiyan Ma, Long Tang, Yue Yin, Hao Zhang,
Zhengyi Li, and Xiaoqiang Sun
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900960
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900960
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10.1002/ejoc.201900960
European Journal of Organic Chemistry
COMMUNICATION
Metal-free C−S bond cleavage to access N-substituted acrylamide
and β-aminopropanamide
Ke Yang,*[a] Yi Li,[a] Zhiyan Ma,[a] Long Tang,[a] Yue Yin,[a] Hao Zhang,[a] Zhengyi Li*[a] and Xiaoqiang
Sun*[a]
Abstract: Metal-free and Selectfluor-mediated C−S bond cleavage
is decscribed. This novel strategy provides a facile and efficient
method to access important N-substituted acrylamide and β-
aminopropanamide derivatives with good functional groups tolerance
and yields.
results on the direct synthesis of N-substituted acrylamide and
β-aminopropanamide derivatives in the presence of Selectfluor.
Results and Discussion
Table 1. Optimization of reaction conditions for N-substituted acrylamide. [a]
Introduction
The activation and transformations of organic chemical bonds
are fundamental scientific issues. Recently, C−S bond
cleavages and their transformations for the construction of C−C
bonds and C−heteroatom bonds have received tremendous
attention in the organic and petroleum chemistry.1 Among them,
thioether compounds have great potential to undergo C−S bond
cleavages to construct various important skeletons in many
natural products and pharmaceuticals.2 The most developed one
in this area relies on the insertion of a transition-metal catalyst
into the C−S bond, which leads to the corresponding C−S bond
cleavage.2a-g Although significant progress have been made in
the past decades, the development of a facile and efficient
metal-free C−S bond cleavage process is still a challenging
issue.
Entry
1
F+ reagent
Solvent
MeCN
Temperature
Yield [b]
28%
62%
21%
57%
80%
69%
62%
31%
46%
62%
40%
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (0.5 eq.)
Selectfluor (1.5 eq.)
NFSI (1.0 eq.)
110 o
110 o
110 o
110 o
110 o
100 o
120 o
110 o
110 o
110 o
110 o
C
C
C
C
C
C
C
C
C
C
C
2
MeOH
3
THF
Selectfluor
[1-chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)], as one of
the important electrophilic fluorinating reagents, has attracted
much attention due to its significant improvement in the
fluorination.3 Besides, Selectfluor can also be used as an
oxidant or Lewis acid in some other organic transformations.4
Very recently, our group demonstrated the metal-free
intramolecular N-S bond formation to construct benzoisothiazol-
3-ones.5 In our continuing studies, we found the selective C−S
bond cleavage of N-substituted 3-methylthiopropanamides could
produce N-substituted acrylamides in the presence of Selectfluor.
Inspired by this investigation, we believe that Selectfluor can
also promote the construction of important biologically active β-
aminopropanamides via an intermolecular metal-free C−S bond
cleavage and C−N formation process. Herein, we report our
4
Acetone
5
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
6
7
8
9
10
11
NFPT (1.0 eq.)
[a] Reaction conditions: 1a (0.2 mmol), F+ reagent, solvent (2.5 mL), 12 h. [b]
Isolated yields. NFSI = N-Fluorobenzenesulfonimide. NFPT = 1-Fluoro-2,4,6-
trimethylpyridinium triflate.
[a]
Dr. Ke Yang, Yi Li, Zhiyan Ma, Long Tang, Yue Yin, Hao Zhang,
Prof. Dr. Zhengyi Li, and Prof. Dr. Xiaoqiang Sun
Jiangsu Key Laboratory of Advanced Catalytic Materials &
Technology
Our initial investigation began with the reaction of 3-
(methylthio)-N-phenylpropanamide 1a in the presence of
a
School of Petrochemical Engineering
Changzhou University
1 Gehu Road, Changzhou, Jiangsu 213164, China
E-mail: keyang@cczu.edu.cn
stoichiometric amount of Selectfluor in MeCN at 110 °C , N-
phenylacrylamide 2a was detected in 28% yield (Table 1, entry
1). To our delight, the subsequent examination of other solvents
revealed that this process can be smoothly carried out in the
solvent of 1,4-dioxane in 80% yield (entries 1-5). However, the
yield of 2a could not be improved any more by increasing or
decreasing the reaction temperature or amounts of Selectfluor
Homepage:
http://che.cczu.edu.cn/2019/0304/c2960a200740/page.htm
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201900960
European Journal of Organic Chemistry
COMMUNICATION
(entries 6-9). Finally, the screening of fluorinating reagents
process (path a).9 On the other hand, substrate 1a can be
oxidized to the corresponding sulfoxide D in the presence of
Selectfluor, which is further transformed into acrylamide 2a.
Moreover, product 4a can also be prepared through the amine
substitution of sulfoxide D (path b, see Scheme S2 in Supporting
Information). 5,10
revealed that
fluorobenzenesulfonimide
a
low yield was detected with N-
(NFSI) or 1-fluoro-2,4,6-
trimethylpyridinium triflate (NFPT) (entries 10-11). With the
optimized reaction conditions in hand, the substrate scope for N-
substituted acrylamide was carried out. As shown in Scheme 1,
various N-substituted 3-methylthiopropanamides were well
tolerated and provided the desired N-substituted acrylamides
(2a-i) in good yields.
Table 2. Optimization of reaction conditions for N-substituted β-
aminopropanamide. [a]
Entry
1
F+ reagent
Solvent
1,4-dioxane
MeCN
Base
Yield [b]
trace
5%
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (1.0 eq.)
Selectfluor (0.5 eq.)
Selectfluor (1.5 eq.)
NFSI (1.0 eq.)
-
-
2
21%
9%
3
MeOH
THF
-
4
-
10%
70%
60%
35%
23%
62%
20%
34%
5
Acetone
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
-
6
K2CO3
Na2CO3
KOAc
K2CO3
K2CO3
K2CO3
K2CO3
7
Scheme 1. Substrate scope for N-substituted acrylamide. Reaction conditions:
1 (0.2 mmol), Selectfluor (0.2 mmol), 1,4-dioxane (2.5 mL), 110 oC, 12 h.
Isolated yields.
8
9
10
11
12
Based on the above results, we explored the reactions of N-
substituted 3-methylthiopropanamides and amines for the one-
pot synthesis of N-substituted β-aminopropanamides in the
presence of Selectfluor (Table 2). However, only trace desired
product 4a was obtained in the reaction of substrate 1a and
morpholine 3a under the standard conditions. After rescreening
of the reaction conditions, the results indicated that the reaction
of 1a and morpholine 3a using a stoichiometric amount of
Selectfluor and K2CO3 in the solvent of MeOH gave the desired
product 4a in 70% isolated yield.
NFPT (1.0 eq.)
[a] Reaction conditions: 1a (0.2 mmol), 3a (0.2 mmol), F+ reagent, base
(0.2 mmol), solvent (2.5 mL), 110 oC,12 h. [b] Isolated yields. NFSI = N-
Fluorobenzenesulfonimide. NFPT
triflate.
=
1-Fluoro-2,4,6-trimethylpyridinium
As shown in Scheme 2, different N-aryl substituted 3-
methylthiopropanamides including electron-donating groups (Me
and MeO) and electron-withdrawing groups (F, Cl, Br and CF3)
were investigated, and the desired N-substituted β-
aminopropanamides (4a-g) were isolated in moderate to good
yields. Notably, the well-tolerated halogens could provide further
manipulations of the initial products. Furthermore, N-benzyl
substituted substrate 1h afforded the desired product 4h in 68%
isolated yield. Next, the scope study of amine was also tested in
this system. The simple diethylamine 3b could be used to
construct the corresponding product 2g in 75% yield. Moreover,
both linear and branched aliphatic amines were tolerated and
gave the desired N-substituted β-aminopropanamides (4j-l) in
moderate yields.
Proposed mechanistic pathways have been proposed in
Scheme 3. Substrate 1a produces fluorosulfonium salt A in the
presence of Selectfluor,5-6 then salt A can be converted to the
corresponding thionium intermediate B and its isomer C.7 Next,
the intermolecular elimination of intermediate C provides the
acrylamide 2a.8 Finally, in the presence of base and morpholine,
the desired product 4a is formed through a Michael addition
Scheme 2. Substrate scope for N-substituted β-aminopropanamide.
Reaction conditions: 1 (0.2 mmol), 3 (0.2 mmol), Selectfluor (0.2 mmol),
K2CO3 (0.2 mmol), MeOH (2.5 mL), 110 oC, 12 h. Isolated yields.
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10.1002/ejoc.201900960
European Journal of Organic Chemistry
COMMUNICATION
Keywords: Selectfluor • C-S bond cleavage • Metal-free • β-
Aminopropanamide • Organic synthesis
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Scheme 3. The plausible reaction mechanism.
Conclusions
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In summary, an efficient Selectfluor-promoted C−S bond
cleavage process has been developed to access different
important N-substituted β-aminopropanamide and acrylamide
derivatives by using N-substituted 3-methylthiopropanamides as
the starting materials. This metal-free protocol is featured with
good functional group compatibility and board substrate scope.
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Experimental Section
General procedures for the synthesis of product 2. A 25 mL Schlenk
tube was charged with 3-methylthiopropanamide
1 (0.2 mmol),
Selectfluor (70.85 mg, 0.2 mmol) and 1,4-dioxane (2.5 mL). The tube
was then sealed and stirred vigorously at 110 ˚C for 12 h. After cooling to
room temperature, the reaction mixture was diluted with EtOAc (20 mL),
filtered through a pad of Celite, and the filtrate was then concentrated in
vacuo. The residue was purified by flash chromatography on silica gel to
yield the desired product 2.
General procedures for the synthesis of product 4. A 25 mL Schlenk
tube was charged with 3-methylthiopropanamide 1 (0.2 mmol), amine 3
(0.2 mmol), Selectfluor (70.85 mg, 0.2 mmol), K2CO3 (27.64 mg, 0.2
mmol) and MeOH (2.5 mL). The tube was then sealed and stirred
vigorously at 110 ˚C for 12 h. After cooling to room temperature, the
reaction mixture was diluted with EtOAc (20 mL), filtered through a pad of
Celite, and the filtrate was then concentrated in vacuo. The residue was
purified by flash chromatography on silica gel to yield the desired product
4.
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Acknowledgments
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (21572026,
21702019) and Advanced Catalysis and Green Manufacturing
Collaborative Innovation Center, Changzhou University.
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Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Selectfluor-Mediated Reactions
Ke Yang,* Yi Li, Zhiyan Ma, Long Tang,
Yue Yin, Hao Zhang, Zhengyi Li* and
Xiaoqiang Sun*
Page No. – Page No.
Metal-free C−S bond cleavage to
access N-substituted acrylamide and
β-aminopropanamide
The metal-free C−S bond cleavege process has been established to construct N-
substituted acrylamide and β-aminopropanamide derivatives in the presence of
Selectfluor.
This article is protected by copyright. All rights reserved.