Facile synthesis of thioamides via P2S5-mediated beckmann rearrangement of oximes

Article abstract of DOI:10.1002/cjoc.201200448

A facile and efficient approach to the synthesis of secondary thioamides from ketoximes via Beckmann rearrangement has been established, using phosphorus pentasulfide as a dehydrating and thiating agent. It is also efficient for the preparation of primary thiobenzamide from benzaldoxime. This approach features simple-operation, easy-control and good to excellent yields.

Full text of DOI:10.1002/cjoc.201200448

COMMUNICATION
DOI: 10.1002/cjoc.201200448
Facile Synthesis of Thioamides via P2S5-Mediated Beckmann
Rearrangement of Oximes
Li, Jiangsheng*(李江胜)
Li, Zhiwei*(李志伟) Cai, Feifei(蔡菲菲)
Cheng, Chao†(程超)
Xue, Yuan(薛媛)
Zhang, Xinrui(张馨睿)
Liu, Weidong(刘卫东)
Hunan Provincial Key Laboratory of Materials Protection for Electric Power and Transportation, School of
Chemistry and Biological Engineering, Changsha University of Science & Technology, Changsha,
Hunan 410114, China
A facile and efficient approach to the synthesis of secondary thioamides from ketoximes via Beckmann rear-
rangement has been established, using phosphorus pentasulfide as a dehydrating and thiating agent. It is also effi-
cient for the preparation of primary thiobenzamide from benzaldoxime. This approach features simple-operation,
easy-control and good to excellent yields.
Keywords thioamides, oximes, phorphorus pentasulfide, Beckmann rearrangement, iminocarbocation
Introduction
S
R1
P2S5
N
R1
OH
(1)
R2
N
R2
Thioamides are widely used in biochemistry and
medicine as major drugs for treatment of thyrotoxicosis
and hyperthyroidism, and have been incorporated into
peptides as isosteres for the amide bond as thiopeptide
antibiotics.[1] Also, thioamides are synthetically versa-
tile molecules, being key components in various trans-
formations, especially in the preparation of many useful
heterocycles.[2]
Although a variety of methods for the synthesis of
thioamides have been developed to date, most of these
procedures are limited to the use of amides, ketones or
nitriles as precursors.[3] Only a few examples of the
synthesis of thioamides from oximes or their esters via
Beckmann rearrangement have been reported.[4]
H
1
2
Results and Discussion
Initially, treatment of an acetophenone oxime 1a
with P2S5 was chosen as a model reaction. When
acetophenone oxime reacted with equimolar P2S5 in dry
acetonitrile at ambient temperature for 7 h, the
thioacetanilide 2a was generated in 32% yield (Table 1,
Entry 1). To further optimize the reaction conditions,
several solvents, temperatures and oxime/P2S5 ratios
were evaluated. As shown in Table 1, when DCM
replaced MeCN, the yield was not significantly
enhanced (Table 1, Entry 2), but when aromatic solvents
such as xylene, toluene, and benzene were used instead,
the yields increased dramatically to 75%—85% (Table
1, Entries 3, 5 and 6). Benzene as a solvent gave the
best result (Table 1, Entry 6), although the longer
reaction times in these solvents were required. It is
noteworthy that with acetone as solvent none of the
desired product was generated and the oxime could be
quantitatively recovered. Elevation of the reaction tem-
perature remarkably shortened the reaction time and
slightly augmented the yield (Table 1, Entries 7—9).
When refluxing in benzene, the yield was increased to
90% and the time shortened to only 0.5 h. After lower-
ing the ratio of oxime/P2S5, it was found that the use of
Although a one-pot method has been recently
reported in which PSCl3 is used to transform oximes
[4b]
to thioamides in the absence of extra activating and
thionating reagents, these methods require complicated
operations or prior oxime activation such as the forma-
tion of sulfonate esters. Recognition of these drawbacks
prompted us to design an alternative approach to the
direct conversion of oximes to thioamides. In this paper,
we demonstrate a facile and highly efficient one-pot
synthesis of thioamides via Beckmann rearrangement of
oximes using only the commonly available reagent P2S5
under mild conditions (Eq. 1).
*
E-mail: js_li@yahoo.com.cn (Dr. J. S. Li); lizwhn@126.com (Dr. Z. W. Li)
Equal contribution with the first author.
†
Received May 8, 2012; accepted May 29, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201200448 or from the author.
Chin. J. Chem. 2012, 30, 1687—1689 © 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Li et al.
COMMUNICATION
0.5 equivalents of P2S5 could afford 90% yield in the
same reaction time (Table 1, Entry 9). However, when
0.33 equiv. P2S5 was used, a considerable amount of
oxime (40%) was recovered (Table 1, Entry 10).
cation B and its counteranion C via the Beckmann rear-
rangement pathway. Nucleophilic attack on B by C pro-
vides the thioamide 2, with the elimination of phospho-
rus oxide-sulfide. This oxide-sulfide further reacts with
another oxime to undergo this transformation. In this
reaction, P2S5 probably works in a manner similar to the
conversion of amides to thioamides.
Table 1 Optimization of the reaction conditionsa
Entry Solventb
Temp./℃
Time/h
7
Yieldc/%
1
MeCN
30
30
30
30
30
30
50
80
80
80
32
Table 2 P2S5-mediated Beckamann rearrangement of ketoxi-
mesa
2
CH2Cl2
xylene
72
41
3
72
80
Product R1
R2
Time/h
0.5
0.5
3
Yieldb/%
90
4
acetone
toluene
benzene
benzene
benzene
benzene
benzene
7
—
2a
2b
2c
2d
2e
2f
Ph
Me
Ph
5
＞72
72
75
Ph
85
6
85
4-BrC6H4
4-ClC6H4
4-MeC6H4
3-NO2C6H4
naphthyl-2
naphthyl-1
3-ClC6H4
Me
Me
Me
Me
Me
Me
Et
75
7
2
88
3
80
8
9d
10e,f
0.5
0.5
4
90
0.5
5
90
90
68
50
2g
2h
2i
2.5
2
75
a Reaction conditions: Acetophenone oxime 1a (1 mmol), P2S5 (1
81
mmol), solvent (10 mL), air atmosphere unless otherwise stated.
2.5
2
80
b
c
Dried with standard methods. Isolated yield based on the
oxime. d Molar ratio 1a/P2S5 1∶0.5. e Oxime 1a (40%) was not
converted. f Molar ratio 1a/P2S5 1∶0.33.
2j
2,4-(EtO)2C6H3 Me
83
2k
2l
2-BnOC6H4
4-CF3C6H4
4-BrC6H4
Me
Me
2.5
4
75
65
Under the most favorable reaction conditions, we
investigated the generality and scope of this rearrange-
ment using various ketoximes and the results are sum-
marized in Table 2. All the substrates tested smoothly
underwent conversion to the corresponding thioamides
in good to excellent yields (65%—90%), and, as ex-
pected, exclusive anti migration, was observed. As is
customary in Beckmann rearrangements of ketoximes,
electron-releasing groups on the aromatic ring facilitate
the reaction giving higher yields (Table 2, Entries 2e
and 2j), while electron-withdrawing groups retard the
rearrangement resulting in relatively lower yields (Table
2, Entries 2c, 2d, 2f, 2i and 2l). The conversion also
proceeds effectively with a variety of substituents, such
as methylthio, on the aromatic rings of the ketoximes. It
should be noted that 1-p-tolylethanone oxime 2e gave
90% yield using the established standard conditions
whereas no desired product was obtained using the
PSCl3 method.[4b] Also, with the P2S5 method,
1-(3-chlorophenyl)-propan-1-one oxime 2i gave 80%
yield whereas with the PSCl3 method the analogous
propiophenone oxime did not produce the desired
thioamide.[4b] Aliphatic ketoximes were also converted
to their corresponding thioamides in good yields (Table
2, Entries 2o—2q). For cyclohexanoxime 1o, azepane-
2-thione 2o was initially obtained in only 40% yield
accompanied by 30% of the ε-caprolactam. However,
using freshly disilled benzene as solvent, the yield of 2o
was increased to 65%.
2m
MeSCH2
MeS(Me)
CH
1
72
2n
Ph
1
70
2o
2p
(CH2)5
(CH2)11
Me
2
2
2
65
80
83
2q
Me
a
Reaction conditions: oxime 1 (1 mmol), P2S5 (0.5 mmol), dry
benzene (10 mL) at 80 ℃ under air atmosphere. b Isolated yield.
The major side product was the corresponding amide.
OH
R2
S
P
SH
P
S
N
S
S
R1
P2S5
N
O
R1
R2
1
A
S
N R1
R2
R1
R2
N
H
B
2
S
P
S
P
S
S
S
1
P
P
S
S
S
O
S
OH
C
Figure 1 Plausible mechanism for P2S5-mediated formation of
thioamides from ketoximes
In addition, treatment of benzaldoxime under the es-
tablished route led to only a small amount of thioben-
zamide together with benzonitrile. When the equivalent
of P2S5 was increased to 1.0, a yield of 90% was
achieved (Eq. 2). Presumably, the excess P2S5 converted
benzonitrile to thiobenzamide.[5] Compared to the syn-
On the basis of the Beckmann rearrangement, a ten-
tative mechanism is presented in Figure 1. Firstly, P2S5
reacts with ketoxime 1 to furnish the activated interme-
diate ester A, which genrates the reactive iminocarbo-
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 1687—1689

Facile Synthesis of Thioamides via P2S5-Mediated Beckmann Rearrangement of Oximes
thesis using PSCl3,[4d] this approach features greater
S 23.22; found C 39.08, H 3.71, N 5.13, S 23.13.
generality, being easy use for transformation of aldoxi-
mes to primary thioamides simply by increasing the
amount of P2S5.
Acknowledgement
This work was financially supported by Hunan Pro-
vincial Science and Technology Project (2011WK3038),
the Scientific Research Fund of Hunan Provincial Edu-
cation Department (10W017), Changsha Municipal
Science and Technology Project (K1104066-31), the
Hunan Provincial Key Laboratory of Materials Protec-
tion for Electric Power and Transportation (No.
2012CL03), Changsha University of Science & Tech-
nology, P. R. China. We should especially thank Pro-
fessor Jim Simpson at University of Otago for his kind
help with English polishing .
S
P2S5 (1.0 eq.)
(2)
N
NH2
OH
H
Conclusions
In summary, a facile and efficient procedure for the
synthesis of secondary thioamides via Beckmann rear-
rangement of the corresponding ketoximes has been
developed. The reaction is mediated by the commer-
cially available and cheap reagent P2S5 and occurs in
one step. This approach has been successfully extended
to the transformation of benzaldoximes to thioben-
zamides. Further applications of this new procedure are
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ketoximes 1 to thioamides 2: To a solution of ketoxime
(1.0 mmol) in dried benzene (10 mL) was added P2S5 in
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Chin. J. Chem. 2012, 30, 1687—1689
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