Facile and odorless one-pot process for the synthesis of N-substituted thioamides via TsCl-mediated Beckmann rearrangement of ketoximes

Article abstract of DOI:10.1055/s-0030-1259720

A facile and odorless one-pot thionation process for the synthesis of N-substituted thioamides using chemically stable and inexpensive thiourea reagent via the Beckmann rearrangement of ketoximes, has been described. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1259720

LETTER
979
Facile and Odorless One-Pot Process for the Synthesis of N-Substituted
Thioamides via TsCl-Mediated Beckmann Rearrangement of Ketoximes
Thioamidesg Liu, Na An, Hong-Jun Pi, Jun Ying, Wenting Du,* Wei-Ping Deng*a
a
a
a
a
a,b
F
L
acile and Odor
i
less
O
n
-
e
-Pot
S
F
N
-S
e
ubstitute
d
n
a
School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, P. R. of China
Fax +86(21)64252431; E-mail: weiping_deng@ecust.edu.cn; fax +86(21)64252431; E-mail: ddwwtt@163.com
b
Department of Pharmacy, Zhejiang Medical College, 481 Binwen Road, Hangzhou 310053, P. R. of China
Received 26 October 2010
Dedicated to Prof. Xiyan Lu and Prof. Lixin Dai
sulfonates, which then generate the reactive iminocar-
bocation intermediates via the well-known Beckmann re-
arrangement pathway. The nucleophilic attack to the
iminocarbocation by benzotriazole (BtH) affords the N-
imidoylbenzotriazoles (Scheme 1). In order to further ex-
tend the scope of this process, we then envisaged that the
use of a stable, odorless and environment friendly thion-
ation reagent instead of BtH would ideally provide us a
straightforward and environmentally benign process for
the synthesis of thioamides. As aforementioned, com-
monly used thio sources often suffer from the unpleasant
odor, and instability in some cases. Thiourea is a chemi-
cally stable, odorless and inexpensive reagent, which
could be the ideal candidate as thionation reagent. To our
best knowledge, there is not a single report on the thion-
ation using thiourea for the synthesis of thioamides to
Abstract: A facile and odorless one-pot thionation process for the
synthesis of N-substituted thioamides using chemically stable and
inexpensive thiourea reagent via the Beckmann rearrangement of
ketoximes, has been described.
Key words: Beckmann rearrangement, thioamides, tosyl chloride,
ketoximes
Thioamides, serving as versatile synthetic precursors for
the preparation of biologically valuable five- and six-
1
,2
membered S-containing heterocycles, especially the thi-
1
a
azolines and thiazoles, have been extensively employed
1
2
in the field of organic and medicinal chemistry. As a
consequence, many efforts have been made to develop
versatile, highly efficient and environmentally benign
synthetic procedures, which can be classified into two
main strategies. The first one is the thionation of corre-
sponding amides using electrophilic reagents, such as
14
date. Herein, we present our preliminary result on odor-
less one-pot thionation process using thiourea reagent for
the synthesis of a variety of N-substituted thioamides via
the Beckmann rearrangement of ketoximes.
3
4
5
Lawesson reagent, P S and PSCl3 etc. The second
4
10
method is the reaction of activated amides or nitriles with
6
nucleophilic thionation reagents, such as (TMS) S and
2
7
N
(
NH ) S. Recently, Pathak et. al reported a new and high-
4
2
N
OH
R2
ly efficient synthesis of N-substituted thioamides from ke-
N
N
N
N
MsCl, Et3N
H
toximes via PSCl -mediated Beckmann rearrangement
3
N
R1
8
solvent, 0 °C
reflux
pathway. In this procedure, PSCl not only was used to
3
induce the Beckmann rearrangement, but also served as a
nucleophile to capture in situ formed reactive iminocar-
N
R1
R2
bocation intermediate. However, PSCl is a fuming, cor-
3
Scheme 1 The one-pot synthesis of N-imidoylbenzotriazoles
rosive and moisture-sensitive reagent with a pungent
odor, which makes this procedure neither operational nor
environmentally benign. Nevertheless, it provided us with
a new idea for the construction of thioamides.
Initially, acetophenone oxime (1a) was chosen as the sub-
strate of model reaction and several common solvents
such as THF, dioxane and MeCN were tested in the pres-
Over the past several years, we have enjoyed continued
success in the field of Beckmann rearrangement of ke-
toximes. We found that a variety of reagents can promote
the Beckmann rearrangement smoothly in catalytic
ence of Et N and MsCl, respectively. In view of the com-
3
mercial availability and chemical stability, TsCl was also
used for the optimization of reaction condition. To our de-
light, as expected, the reaction proceeded smoothly and
generated the desired N-substituted thioamide, and the op-
timal result was obtained in the presence of TsCl and in
MeCN to afford thioamide 2a in 90% yield (Table 1, entry
9
amount, such as BOPCl, tetraaminophthalocyanine
1
0
11
12
(
TAPC), TsCl and AlCl . Recently, we developed a
3
highly efficient MsCl-mediated one-pot procedure for the
synthesis of N-imidoylbenzotriazoles via the Beckmann
4
).
1
3
rearrangement of corresponding ketoximes. In that pro-
cedure, MsCl firstly reacts with ketoximes to form oxime
Having established the optimized reaction condition, we
then examined the generality and scope of substrates by
using arylalkyl ketoximes 1a–h, diaryl ketoxime 1i, di-
alkyl ketoximes 1j–m and cycloketoximes 1n and 1o. As
shown in Table 2, most of the arylalkyl ketoximes (1a–g)
SYNLETT 2011, No. 7, pp 0979–0981
x
x.
x
x.
2
0
1
1
Advanced online publication: 10.03.2011
DOI: 10.1055/s-0030-1259720; Art ID: W01010ST
©
Georg Thieme Verlag Stuttgart · New York

9
80
L.-F. Liu et al.
LETTER
Table 1 Screening of Solvents for Model Reactiona
product 2i in 71% yield. Dialkyl ketoximes 1j–l were
found to be less effective to give the corresponding thioa-
mides 2i–l in low to moderate yields (24–48%). Interest-
ingly, when dicyclopropyl ketoxime was used for this
reaction, the corresponding thioamide 2m was obtained in
a good yield (76%). For cycloketoximes, cyclohexanone
oxime (1o) gave a higher yield of the corresponding prod-
uct than cyclododecanone oxime (1n), which may be at-
tributed to the size of the ring.
S
OH
N
S
TsCl, Et3N
H2N
NH2
Ph
Ph
solvent, 0 °C to r.t.
reflux, 2 h
N
H
1a
2
a
Entry
Solvent
THF
Yield (%)b
57 (60)
64 (36)
46 (38)
90 (75)
53
1
2
3
4
Based on the aforementioned assumption, as depicted in
Scheme 2, we propose that the formation of oxime sul-
fonates A takes place in situ by reaction of the oximes 1
with sulfonyl chloride in the presence of base, followed by
smooth Beckmann rearrangement of oxime sulfonate A to
form the iminocarbocation species, which is subjected to
simultaneous nucleophilic attack by thiourea to generate
the intermediate B. The hydrolysis of B finally forms the
N-substituted thioamides 2 accompanied by the formation
of urea.
dioxane
toluene
MeCN
CH Cl
5
2
2
a
Reaction conditions: (i) ketoxime (1.0 equiv), Et N (2.2 equiv), TsCl
3
(
1.1 equiv), solvent (5 mL), ice bath, then r.t. for 30 min; (ii) thiourea
2.0 equiv), reflux for 2 h.
Yields in parentheses were obtained when MsCl was used instead of
(
b
TsCl.
R2
N
S
R1
+
Table 2 One-Pot Synthesis of N-Substituted Thioamides
TsO
OH
OTs
N
N
NH2
S
TsCl
Et3N
OH
N
S
R1
R2
R1
R2
TsCl, Et3N
H2N
NH2
NH2
R1
R1
R2
R2
MeCN, 0 °C to r.t.
reflux, 2 h
N
1
Et3NHCl
A
H
1
2
24–90% yields
NH2
NH
O
S
Product
R1
R2
Yield (%)
90
2
H O
R1
+
S
N
R2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
a
b
c
d
e
f
Ph
Me
H2N
NH2
H
H+
R2
N
R1
2
Ph
Et
82
B
4-MeC H
Me
88
6
4
Scheme 2 Proposed reaction pathway
4-MeOC H
Me
78
6
4
4
4
In conclusion, we have developed a facile, odorless and
practical synthetic method15 to produce N-substituted
thioamides in 24–90% yield in a one-pot process from the
corresponding ketoximes using the chemically stable, in-
expensive thiourea reagent. Further studies focusing on
the application of this process to the synthesis of biologi-
cally important products and synthetically useful interme-
diates are in progress in our laboratory.
2-MeOC H
Me
87
6
3-MeOC H
Me
89
6
g
h
i
4-ClC H
Me
85
6
4
4-NO C H
4
Me
38
2
6
Ph
Ph
71
j
Me
Bn
Me
24
k
l
Bn
45
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
C(CH3)3
Me
48
m
n
o
cyclopropyl
(CH2)11
cyclopropyl
76
Acknowledgment
35
This work was financially supported by the Shanghai Committee of
Science and Technology (No. 064319022), the New Century Excel-
lent Talents in University, the Ministry of Education, China (No.
NCET-07-0283), the Natural Science Foundation of China (No.
NSFC 20602011), and the ‘111’ Project (No. B07023).
(CH2)5
69
gave the corresponding thioamides in good to excellent
yields regardless the electronic effect of substituents on
aromatic ring. Interestingly, 1-(4-nitrophenyl)ethanone
oxime (1h) was not very ideal and afforded the corre- References and Notes
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(
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(
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Synlett 2011, No. 7, 979–981 © Thieme Stuttgart · New York

LETTER
Facile and Odorless One-Pot Synthesis of N-Substituted Thioamides
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(
2
2
5
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1
(
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3
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(
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