Thiol as a synthon for preparing thiocarbonyl: Aerobic oxidation of thiols for the synthesis of thioamides

Article abstract of DOI:10.1021/jo501378v

It is a constant challenge to develop an environmentally friendly, atom-economical, and step-economical method for the preparation of thioamides. Herein, we describe an oxidation method that affords the direct conversion of thiols to thioamides without the use of exogenous sulfur reagents. This is the first instance of a successful utilization of thiols as a synthon for the preparation of thioamides under economical conditions.

Full text of DOI:10.1021/jo501378v

Note
pubs.acs.org/joc
Thiol as a Synthon for Preparing Thiocarbonyl: Aerobic Oxidation of
Thiols for the Synthesis of Thioamides
Xi Wang,† Miran Ji,† Seungyeon Lim,† and Hye-Young Jang*,†,‡
†Department of Energy Systems Research, Ajou University, Suwon 443-749, Korea
‡Korea Carbon Capture & Sequestration R&D Center, Deajeon 305-343, Korea
S
* Supporting Information
ABSTRACT: It is a constant challenge to develop an environmentally friendly,
atom-economical, and step-economical method for the preparation of
thioamides. Herein, we describe an oxidation method that affords the direct
conversion of thiols to thioamides without the use of exogenous sulfur reagents.
This is the first instance of a successful utilization of thiols as a synthon for the
preparation of thioamides under economical conditions.
he thioamide functional group is commonly found in
biologically active compounds and antithyroid drugs.1 It is
made Willgerodt−Kindler-type reactions more useful for
thioamide synthesis.3b,4a,b,f,h,i,m Finally, the use of thionation
reagents to convert amides to thioamides is very selective,
efficient, and general; nonetheless, the use of excessive amounts
of sulfur transfer agents is not considered an atom-economical
and environmentally friendly method.
While our research group was investigating the oxidative
transformation of alcohols and aldehydes, we found that the
direct conversion of thiols to thiocarbonyl derivatives had never
been reported previously.5 Although a few articles proposed the
formation of a thiocarbonyl intermediate in the reaction of
disulfides,6 the direct formation of thiocarbonyl compounds
from thiols has never been reported under aerobic conditions.7
In this communication, we are pleased to report the use of
thiols as a thiocarbonyl precursor for the synthesis of
thioamides under aerobic conditions (Scheme 1). This is the
first instance of a successful conversion of thiols to
thiocarbonyls using oxygen as an oxidant. Even in the absence
of metal complexes, thioamides were formed from thiols under
aerobic oxidation conditions in reasonable yields.
T
also used as a synthetic precursor for a variety of important
thio-heterocycles and in industrial applications as vulcanization
agents and grease additives.2 Various synthetic methods for
thioamides have been subsequently reported; some of them are
(1) reactions of carbon disulfide (CS2) with nucleophiles, (2)
Willgerodt−Kindler reactions using sulfur, and (3) thionation
of amides using P4S10 and Lawesson’s reagent (Scheme 1).3,4
Scheme 1. Synthesis of Thioamides
Optimization results for thioamide formation from thiols are
given in Table 1. Initially, the mixture of benzyl mercaptan
(1a), morpholine (1b), and 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD) was subjected to aerobic conditions without the
addition of metal complexes (Table 1, entry 1). The desired
thioamide 1c was obtained in 59% yield. To accelerate the
oxidation process, we tested a variety of metal complexes with
different loading percentages. With CuCl2 loading percentages
of 1, 2, 5, and 10 mol %, the yields for 1c were 71, 82, 66, and
60%, respectively (entries 2−5). Under a nitrogen atmosphere,
1c was obtained in 10% yield (entry 3). It can be seen that
CuCl2 loadings of 5 mol % or higher even retarded the
formation of 1c. Various copper and iron complexes were also
tested with loadings of 2 mol %, and it was determined that
CuCl2 and Cu(OTf)2 gave the most favorable yields for this
The reaction of CS2 with Grignard reagents has been reported
as a classical method to form thioamides; however, it required
additional modification of the dithiocarboxylic acid to form
thioamides such as the formation of reactive thiocarbonyl
benzotriazole intermediates.4c In addition, the volatility and
toxicity of CS2 were also addressed during the experiments. The
Willgerodt−Kindler reaction using sulfur allows the direct
formation of thioamides from aldehydes and amines.
Unfortunately, it did not receive much attention for a long
time due to the harsh reaction conditions required, but recent
variations in the Willgerodt−Kindler reaction conditions such
as the use of microwave irradiation, the use of water as a
solvent, and the introduction of different aldehyde precursors
Received: June 20, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo501378v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Table 1. Optimization of the Formation of Thioamide 1c
Scheme 2. Plausible Reaction Mechanism for the Formation
of Thioamide 1c
entry
metal complex (amt, mol %)
base (amt, equiv)
yield, %
1
TBD (1)
TBD (1)
TBD (1)
TBD (1)
TBD (1)
TBD (1)
TBD (1)
TBD (1)
TBD (1)
TBD (1)
DBU (1)
59
71
2
CuCl2 (1)
a
3
CuCl2 (2)
82 (10)
4
CuCl2 (5)
66
60
67
70
79
70
71
52
5
CuCl2 (10)
CuCl (2)
6
7
CuBr2 (2)
8
Cu(OTf)2 (2)
FeCl3·6H2O (2)
FeCl2·4H2O (2)
CuCl2 (2)
9
10
11
a
Under a nitrogen atmosphere.
process (entries 6−10). In addition to TBD, 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) was utilized to afford
1c in a lower yield (52%, entry 11).
Encouraged by our initial results, we decided to probe the
reaction mechanism. On the basis of Ogata’s publication of
benzaldehyde formation from dibenzyl disulfide, we speculated
that dibenzyl disulfide might be a key intermediate.6 Under
these oxidative conditions, the formation of a disulfide
intermediate is not surprising.7 The subsequent reaction of
dibenzyl disulfide (1a′) with morpholine (1b) was conducted
in the absence of metal complexes and in the presence of CuCl2
(2 mol %). As shown in Table 2, 1c was obtained with a yield
of 54% without metal complexes, 73% with CuCl2-TBD, and
44% with CuCl2-DBU, which are comparable to the reaction
yields of 1a.
The substrate scope of the reaction was investigated further
by using diverse benzyl mercaptan derivatives and amines
(Table 3). The chloro-substituted benzyl mercaptan 2a reacted
with morpholine to form thioamide 2c in 78% yield (entry 1).
The fluoro-substituted benzyl mercaptan 3a was converted to
the corresponding amide 3c in 61% yield (entry 2). Formation
of the thioamide using electron-rich thiols (4a and 5a) and
morpholine occurred smoothly to form 4c and 5c in 78 and
74% yields, respectively (entries 3 and 4). In addition to the
reactiona of various thiols, a variety of amines were also tested
under these reaction conditions. The reactions of six-membered
heterocyclic amines 2b and 3b with benzyl mercaptan (1a)
afforded 6c and 7c in 66% and 83% yields, respectively (entries
5 and 6). The five-membered heterocyclic amine pyrrolidine
(4b) participated in the reaction to form 8c in 86% yield (entry
7). Acyclic sec-amines 5b and 6b afforded the desired products
9c and 10c in 47 and 64% yields, respectively, which are
comparable to those obtained using cyclic amines (entries 8
and 9). In comparison to the case for sec-amines, the reaction of
a primary amine, benzyl amine 7b, formed the desired product
11c in a lower yield (20%, entry 10). Finally, 1,2,3,4-
tetrahydroisoquinoline (8b) formed the desired product 12c,
in 70% yield (entry 11).
Table 2. Formation of Thioamide 1c from Dibenzyl
Disulfide 1a′
entry
metal complex (amt, mol %)
base
yield, %
1
2
3
TBD
TBD
DBU
54
73
44
CuCl2 (2)
CuCl2 (2)
In conclusion, we have reported aerobic oxidation conditions
for the synthesis of thioamides from thiols without the use of
additional sulfur compounds. A diverse range of benzyl
mercaptan derivatives reacted with morpholine to form various
thioamides in good yields. The amine nucleophiles, which
include aliphatic sec-amines, benzylic primary and sec-amines,
and tetrahydroisoquinoline, all participated in the reaction to
give good yields. A possible mechanism for the formation of
thioamides was also proposed. Overall, thiocarbonyl com-
pounds could be prepared directly from thiols; this process is
not considered a general oxidation process of thiols, unlike
alcohol oxidation. This methodology could potentially provide
a platform for the synthesis of a variety of thiocarbonyl and
thioamide derivatives under atom-economical and step-
economical conditions.
On the basis of the results in Tables 1 and 2, we propose a
plausible mechanism (Scheme 2). In the beginning, 1a
undergoes dimerization to form 1a′ under aerobic conditions.7
The deprotonation of disulfide 1a′ affords thiobenzaldehyde I,
which reacts with morpholine to form II. Analogous to the
formation of 1a′ under aerobic conditions, III was formed by
oxygen from II and 1a. Intermediate III then underwent
deprotonation by TBD to afford thioamide 1c and 1a.8 Because
1c was formed in the absence of metal complexes in 59% yield,
the proposed mechanism does not incorporate any copper
complexes. Copper complexes are presumed to accelerate the
oxidative process to form the disulfide intermediates 1a′ and
III.
B
dx.doi.org/10.1021/jo501378v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(δ) units, in parts per million (ppm) relative to the center of the triplet
at 77.00 ppm for deuteriochloroform. High-resolution mass spectra
were obtained with a magnetic sector−electric sector double-focusing
mass analyzer. IR spectra were recorded with a FT-IR spectrometer.
Caution! The experiments should be carried out in a well-ventilated
hood because thiols have a very disagreeable smell.
Table 3. Substrate Scope
General Procedure for the Reaction. Copper(II) chloride (1.3
mg, 0.01 mmol) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD; 69.6
mg, 0.5 mmol) was added to a solution of benzyl mercaptan (124.2
mg, 1.0 mmol) and morpholine (43.6 mg, 0.5 mmol) in toluene (0.5
M, 1 mL). A slow stream of O2 was passed through this solution for 10
min. Then, the reaction mixture was stirred at 100 °C for 18 h under
an O2 atmosphere. The solvent was removed under vacuum, and the
residue was purified by flash silica gel column chromatography by
using 10% ether/90% hexane as an eluent to give morpholino-
(phenyl)methanethione (1c; 85.1 mg, 82%). In larger scale reactions,
the yields of 1c were 79 and 66% using 130.8 mg (1.5 mmol) and 218
mg (2.5 mmol) of morpholine, respectively.
Representative Procedure for the Reaction of Dibenzyl
Disulfide with Morpholine. Copper(II) chloride (1.3 mg, 0.01
mmol) and 1,5,7-triazabicyclo[4.4.0] dec-5-ene (TBD; 69.6 mg, 0.5
mmol) was added to a solution of dibenzyl disulfide (123.2 mg, 0.5
mmol) and morpholine (43.6 mg, 0.5 mmol) in toluene (0.5 M, 1
mL). A slow stream of O2 was passed through this solution for 10 min.
Then, the reaction mixture was stirred at 100 °C for 4 h under an O2
atomosphere. The solvent was removed under vacuum, and the
residue was purified by flash silica gel column chromatography by
using 10% ether/hexane as an eluent to give morpholino(phenyl)-
methanethione (1c; 75.2 mg, 73%).
1
Morpholino(phenyl)methanethione (1c). Yield: 85.1 mg, 82%. H
NMR (400 MHz, CDCl3): δ 7.30 (m, 5H), 4.41 (t, 2H, J = 4.8 Hz),
3.86 (t, 2H, J = 4.8 Hz), 3.59 (m, 4H). 13C{1H} NMR (100 MHz,
CDCl3): δ 200.7, 142.3, 128.7, 128.4, 125.8, 66.8, 66.5, 52.6, 49.6. IR
(neat, cm−1): 2920, 2853, 1480, 1291, 1112. HRMS m/z (EI, [M]+):
C11H13NOS calcd 207.0718, found 207.0719.
(4-Chlorophenyl)(morpholino)methanethione (2c). Yield: 95.0
1
mg, 78%. H NMR (400 MHz, CDCl3): δ 7.31 (d, 2H, J = 8.4 Hz),
7.21 (d, 2H, J = 8.8 Hz), 4.38 (t, 2H, J = 4.4 Hz), 3.85 (t, 2H, J = 4.4
Hz), 3.59 (m, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 199.0, 140.5,
134.6, 128.6, 127.2, 66.7, 66.5, 52.7, 49.7. IR (neat, cm−1): 2949, 1474,
1289, 1114, 1033. HRMS m/z (EI, [M]+): C11H12ClNOS calcd
241.0328, found 241.0330.
(4-Fluorophenyl)(morpholino)methanethione (3c). Yield: 68.7
1
mg, 61%. H NMR (400 MHz, CDCl3): δ 7.30 (dd, 2H, J = 8.4,
5.2 Hz), 7.05 (t, 2H, J = 8.8 Hz), 4.42 (t, 2H, J = 4.4 Hz), 3.88 (t, 2H,
J = 4.4 Hz), 3.63 (d, 4H, J = 7.2 Hz). 13C{1H} NMR (100 MHz,
CDCl3): δ 199.9, 164.1, 161.7, 138.7, 128.4, 128.3, 116.0, 115.7, 67.1,
67.0, 53.2, 50.3. IR (neat, cm−1): 2983, 2920, 1601, 1485, 1292, 1228.
HRMS m/z (EI, [M]+): C11H12FNOS calcd 225.0624, found
225.0623.
(4-tert-Butylphenyl)(morpholino)methanethione (4c). Yield:
1
102.6 mg, 78%. H NMR (400 MHz, CDCl3): δ 7.36 (d, 2H, J =
7.2 Hz), 7.22 (d, 2H, J = 7.6 Hz), 4.42 (s, 2H), 3.86 (s, 2H), 3.63 (s,
4H), 1.31 (s, 9H). 13C{1H} NMR (100 MHz, CDCl3): δ 201.0, 152.1,
139.6, 125.9, 125.5, 67.1, 66.8, 52.9, 50.0, 35.1, 31.7. IR (neat, cm−1):
2963, 2860, 1473, 1259, 1114. HRMS m/z (EI, [M]+): C15H21NOS
calcd 263.1344, found 263.1345.
(4-Methoxyphenyl)(morpholino)methanethione (5c). Yield: 88.2
1
mg, 74%. H NMR (400 MHz, CDCl3): δ 7.27 (d, 2H, J = 8.4 Hz),
6.86 (d, 2H, J = 8.8 Hz), 4.40 (s, 2H), 3.86 (s, 2H), 3.81 (s, 3H), 3.65
(s, 4H). 13C{1H} NMR (100 MHz, CDCl3): δ 200.6, 159.9, 134.6,
127.8, 113.5, 66.7, 66.5, 55.5, 52.9, 50.1, 29.8. IR (neat, cm−1): 2921,
2854, 1605, 1473, 1250, 1034. HRMS m/z (EI, [M]+): C12H15NO2S
calcd 237.0824, found 237.0824.
Phenyl(piperidin-1-yl)methanethione (6c). Yield: 68.2 mg, 66%.
1H NMR (400 MHz, CDCl3): δ 7.30 (m, 5H), 4.35 (t, 2H, J = 5.6
Hz), 3.50 (t, 2H, J = 5.6 Hz), 1.77 (m, 4H), 1.56 (t, 2H, J = 5.2 Hz).
13C{1H} NMR (100 MHz, CDCl3): δ 198.9, 143.1, 128.1 (2C), 125.2,
53.2, 50.7, 27.0, 25.7, 24.3. IR (neat, cm−1): 2939, 2856, 1479, 1444,
EXPERIMENTAL SECTION
■
General Considerations. Anhydrous solvents were transferred by
an oven-dried syringe. Toluene was distilled prior to use. Proton
nuclear magnetic resonance (1H NMR) spectra were recorded with a
400 MHz spectrometer. Chemical shifts are reported in delta (δ) units,
in parts per million (ppm) downfield from trimethylsilane. Coupling
constants are reported in Hertz (Hz). 13C NMR spectra were recorded
with a 100 MHz spectrometer. Chemical shifts are reported in delta
C
dx.doi.org/10.1021/jo501378v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1244. HRMS m/z (EI, [M]+): C12H15NS calcd 205.0925, found
205.0925.
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Hz), 3.43 (t, 2H, J = 7.2 Hz), 2.04 (m, 2H), 1.93 (m, 2H). 13C{1H}
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53.5, 26.7, 24.8. IR (neat, cm−1): 2972, 2873, 1469, 1449, 1267.
HRMS m/z (EI, [M]+): C11H13NS calcd 191.0769, found 191.0765.
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1
N-Butyl-N-methylbenzothioamide (9c). Yield: 49.2 mg, 47%. H
NMR (400 MHz, CDCl3): δ 7.28 (m, 5H), 4.10 (t, 1H, J = 7.6 Hz),
3.52 (d, 1.5H, J = 1.6 Hz), 3.42 (t, 1H, J = 7.6 Hz), 3.06 (d, 1.5H, J =
1.6 Hz), 1.80 (m, 1H), 1.55 (m, 1H), 1.44 (m, 1H), 1.12 (m, 1H),
1.00 (t, 1.5H, 7.2 Hz), 0.77 (t, 1.5H, 7.2 Hz). 13C{1H} NMR (100
MHz, CDCl3): δ 200.7, 200.2, 143.6, 143.3, 128.2, 128.1 (2C), 125.4,
125.2, 55.9, 54.6, 42.1, 40.9, 30.6, 28.0, 20.4, 19.9, 14.2, 13.8. IR (neat,
cm−1): 2960, 2933, 1505, 1401, 1287, 1145. HRMS m/z (EI, [M]+):
C12H17NS calcd 207.1082, found 207.1080.
N-Benzyl-N-methylbenzothioamide (10c). Yield: 76.8 mg, 64%.
1H NMR (400 MHz, CDCl3) (two rotamers): δ 7.26 (m, 10H), 5.43
(s, 1H), 4.69 (s, 1H), 3.45 (s, 1.5H), 2.98 (s, 1.5H). 13C{1H} NMR
(100 MHz, CDCl3): δ 201.7, 143.1, 143.0, 135.2, 135.0, 128.8, 128.7,
128.4, 128.3, 128.2 (2C), 127.8 (2C), 127.7, 126.8, 125.5, 125.3, 59.5,
57.4, 41.3, 41.1. IR (neat, cm−1): 3028, 2927, 1499, 1397, 1291, 1214.
HRMS m/z (EI, [M]+): C15H15NS calcd 241.0925, found 241.0921.
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1
N-Benzylbenzothioamide (11c). Yield: 22.3 mg, 20%. H NMR
(400 MHz, CDCl3): δ 7.87 (br, 1H), 7.73 (d, 2H, J = 7.6 Hz), 7. 40
(m, 8H), 4.97 (d, 2H, J = 5.2 Hz). 13C{1H} NMR (100 MHz, CDCl3):
δ 198.7, 141.3, 136.0, 131.0, 128.9, 128.3, 128.2, 128.0, 126.6, 51.1. IR
(neat, cm−1): 3310, 3029, 2925, 1522, 1449, 1336. HRMS m/z (EI,
[M]+): C14H13NS calcd 227.0769, found 227.0768.
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1
Yield: 88.1 mg, 70%. H NMR (400 MHz, CDCl3) (two rotamers):
δ 7.13 (m, 9H), 5.40 (s, 1H), 4.69 (s, 1H), 4.51 (t, 1H, J = 6.4 Hz),
3.79 (t, 1H, J = 6.4 Hz), 3.13 (t, 1H, J = 6.0 Hz), 2.90 (t, 1H, J = 6.0
Hz). 13C{1H} NMR (100 MHz, CDCl3): δ 200.1, 199.5, 142.9, 142.8,
134.6, 133.2, 132.1, 128.6, 128.5, 128.3, 128.2, 128.1, 127.3, 126.8,
126.7, 126.6, 126.4, 125.8, 125.5, 54.0, 52.2, 50.0, 48.5, 29.9, 28.2. IR
(neat, cm−1): 3024, 2927, 1444, 1291, 1219. HRMS m/z (EI, [M]+):
C16H15NS calcd 253.0925, found 253.0927.
ASSOCIATED CONTENT
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* Supporting Information
1
Figures giving H NMR and 13C NMR spectra for 1c−12c.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
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Corresponding Author
*E-mail for H.-Y.J.: hyjang2@ajou.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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This study was supported by the Korea Research Foundation
(No. 2009-0094046 and 2013008819) and a Korea CCS R&D
Center (KCRC) grant from the Korea Government (Ministry
of Education, Science and Technology; No. 2012-0008935).
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