Facile conversion of thioamides into the corresponding amides in the presence of tetrabutylammonium bromide

Article abstract of DOI:10.1055/s-0030-1258154

Desulfurization of thioamides was accomplished using a semicatalytic amount of Bu₄NBr. The corresponding amides were obtained in high yields, with good functional group compatibility. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258154

PAPER
3087
Facile Conversion of Thioamides into the Corresponding Amides in the
Presence of Tetrabutylammonium Bromide
D
esulfurization of
i
Thioca
y
rbonyl Compoounds 4
U
sin
f
N
B
u
r
mi Inamoto,* Mitsugu Shiraishi, Kou Hiroya, Takayuki Doi*
Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, Sendai, 980-8578, Japan
Fax +81(22)7956864; E-mail: inamoto@mail.pharm.tohoku.ac.jp; E-mail: doi_taka@mail.pharm.tohoku.ac.jp
Received 13 April 2010; revised 14 May 2010
under an argon atmosphere (entry 12). This suggests that
oxygen is involved in this transformation.2b,7
Abstract: Desulfurization of thioamides was accomplished using a
semicatalytic amount of Bu4NBr. The corresponding amides were
obtained in high yields, with good functional group compatibility.
Table 1 Optimization of Reaction Parameters
Key words: desulfurization, thioamides, amides, tetrabutylammo-
nium bromide, thioketones
H
H
air
Bu4NBr
N
Ph
N
Ph
N
S
Ph
S
solvent
(0.05 M)
O
Amide groups occur widely in nature, and a large number
of biologically active molecules, including drugs, natural
products, and peptides possess amide groups. The devel-
opment of methods for the efficient synthesis of amide
bond containing molecules is therefore of great impor-
tance. Desulfurization of thioamides produces amides,
and a number of methods for this transformation have
been reported.1,2 However, most of these methods suffer
from several drawbacks such as harsh reaction conditions,
use of a stoichiometric amount or an excess of toxic and/
or expensive (metal) reagents, and a narrow substrate
scope.3 Consequently, development of more efficient
methods for conversion of thioamides to amides is desir-
able. In this study, we report a simple, highly practical
method for this conversion using Bu4NBr as the sole re-
agent. Various amides are produced from the correspond-
ing thioamides, generally in high yields, in the presence of
a semicatalytic amount of Bu4NBr, which is an inexpen-
sive, easy-to-handle reagent of low toxicity.
100 °C, time
1
2
3
Entry Bu4NBr Solvent
(equiv)
Time Yield (%)
(h)a of 2, 3
1
2
2
DMF
15
15
22
19
17
5
0, 0 (quant)b
trace, 0 (quant)b
0, 0 (quant)b
64, 21
2
NMP
3
2
DMSO
4
2
NMP–DMSO (1:1)
NMP–DMSO (1:1)
NMP–DMSO (1:1)
NMP–DMSO (1:1)
5
1
61, 17
6
0.5
0.2
0.5
0.5c
0.5d
0
67, 17
7
5
48, <10 (16)b
77, 15
8
NMP–DMSO–DMF (1:1:1) 16
NMP–DMSO–DMF (1:1:1) 12
NMP–DMSO–DMF (1:1:1) 12
NMP–DMSO–DMF (1:1:1) 12
NMP–DMSO–DMF (1:1:1) 12
9
10, 0 (82)b
3, 0 (93)b
18, 0 (77)b
0, 0 (95)b
10
11
12
First, we studied the reaction of thiobenzanilide (1) in the
presence of two equivalents of Bu4NBr in air (Table 1).
Although the use of DMF, NMP, or DMSO as the sole sol-
vent resulted in quantitative recovery of starting material
1 (entries 1–3), the NMP–DMSO solvent system surpris-
ingly provided the desired benzanilide (2) in fairly good
yield (entry 4). 2-Phenylbenzothiazole (3) was also ob-
tained in 21% yield.4 Interestingly, the amount of Bu4NBr
could be reduced to 0.5 equivalent without causing a re-
duction in the yield (entries 4 and 5 vs 6). Further studies
revealed that the use of DMF as an additional co-solvent
gave the best results, with formation of 77% of 2 (entry
8).5 Bu4NCl and Bu4NI turned out to be much less effi-
cient than Bu4NBr as catalysts for the desulfurization pro-
cess (entries 9 and 10), and only small amounts of product
were formed in the absence of Bu4NBr (entry 11).6 No
product was obtained when the reaction was performed
0.5e
a Reaction time was not optimized.
b Yield of recovered starting material 1 in parentheses.
c Bu4NCl was used instead of Bu4NBr.
d Bu4NI was used instead of Bu4NBr.
e Under argon atmosphere.
Once we had established the optimal reaction conditions,
we examined the substrate scope of the reaction (Table 2).
From a series of thiobenzanilides 4 with various substitu-
ents on one or both of the benzene rings, we obtained the
corresponding benzanilides 5 in good to high yields. It is
worth noting that various functional groups such as cyano
(entries 1, 9, and 12), nitro (entry 2), or alkoxycarbonyl
(entry 3) groups, as well as halogen atoms (entries 6–8,
10), are well tolerated in the reaction.8
SYNTHESIS 2010, No. 18, pp 3087–3090
x
x.
x
x
.
2
0
1
0
Advanced online publication: 07.07.2010
DOI: 10.1055/s-0030-1258154; Art ID: F06710SS
© Georg Thieme Verlag Stuttgart · New York

3088
K. Inamoto et al.
PAPER
Table 2 Substrate Scope in the Desulfurization of Thioamides
H
R2
H
R2
air
N
N
Bu4NBr (0.5 equiv)
R1
R1
NMP–DMSO–DMF
(1:1:1, 0.05 M)
100 °C, 12–17 h
S
O
4
5
Entry
1
4
Product
5
Yield (%)
92
R1 = 4-CN
R2 = H
H
N
5a
O
NC
R1 = 4-NO2
R2 = H
H
N
2
3
5b
5c
82
86
O
O2N
R1 = 4-CO2Et
R2 = H
H
N
O
EtO2C
R1 = 4-OMe
R2 = H
H
N
4
5d
5e
5f
75
13
66
74
O
MeO
MeO
R1 = 3-OMe
R2 = H
H
N
5
O
R1 = 3-Br
R2 = H
H
6a
Br
N
O
F
R1 = 2-F
R2 = H
H
N
7a
5g
O
R1 = 4-I
R2 = H
H
N
8
9
5h
5i
83
59
59
84
O
I
CN
Cl
R1 = H
H
N
R2 = 4-CN
O
R1 = H
H
N
10
11
5j
R2 = 4-Cl
O
O
OMe
R1 = H
H
N
5k
R2 = 4-OMe
Synthesis 2010, No. 18, 3087–3090 © Thieme Stuttgart · New York

PAPER
Desulfurization of Thiocarbonyl Compounds Using Bu4NBr
3089
Table 2 Substrate Scope in the Desulfurization of Thioamides (continued)
H
R2
H
R2
air
N
N
Bu4NBr (0.5 equiv)
R1
R1
NMP–DMSO–DMF
(1:1:1, 0.05 M)
100 °C, 12–17 h
S
O
4
5
Entry
12
4
Product
5
Yield (%)
93
OMe
R1 = 4-CN
H
5l
R2 = 4-OMe
N
O
NC
a Amount of Bu4NBr = 0.75 equiv.
EtOAc (3 × 10 mL) and the combined organic layers were washed
with brine (3 × 10 mL), and then dried (MgSO4). The solvent was
removed under reduced pressure and the residue was purified by sil-
ica gel column chromatography to give the desired compound.
Physical and spectroscopic data for selected products are shown be-
low.
Although thioamides 6a–c, which were derived from ben-
zylamines, did not react at all in air, use of an oxygen at-
mosphere greatly enhanced the process, resulting in
formation of the corresponding amides 7a–c in high yields
(Scheme 1).
In conclusion, we have developed a facile method for de-
sulfurization of thioamides, producing the corresponding
amides, generally in high yields. The sole reagent required
is 0.5 equivalent of Bu4NBr. A solvent combination such
as NMP–DMSO–DMF is crucial for this process. This re-
action proceeds under metal-free, neutral, and relatively
mild conditions, and has good functional group compati-
bility. Further studies to disclose the precise reaction
mechanism, as well as to broaden the substrate scope, are
under way.
N-(4-Cyanophenyl)benzamide (5a)
Colorless prisms: mp 164–165 °C (hexane–acetone) (Lit.9 mp 170–
170.5 °C).
IR (film): 3340, 2226, 1685, 1659, 1592, 1522, 1407, 1318 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.50 (t, J = 7.3 Hz, 2 H), 7.59 (t,
J = 7.3 Hz, 1 H), 7.65 (d, J = 8.8 Hz, 2 H), 7.79 (d, J = 8.8 Hz, 2 H),
7.87 (d, J = 7.3 Hz, 2 H), 8.04 (br, 1 H).
13C NMR (100 MHz, CDCl3): d = 107.3, 118.8, 119.9, 127.1, 128.9,
132.4, 133.2, 134.0, 142.0, 165.8.
MS (EI): m/z (%) = 222 (28, [M]+), 105 (100).
All reactions were carried out under an air atmosphere unless other-
wise noted. Bu4NBr was crystallized from benzene–hexane. Anhyd
1-methyl-2-pyrrolidinone (NMP), DMSO, and DMF were pur-
chased from Sigma-Aldrich. Thiocarbonyl compounds were pre-
pared from the reaction of the corresponding amides with
Lawesson’s reagent. Melting points were measured with a Yazawa
micro melting point apparatus. 1H NMR spectra were recorded on
JEOL JNM-AL400 (400 MHz) using TMS as an internal standard.
Chemical shifts (d) are given from TMS (0 ppm) and coupling con-
stants are expressed in Hertz (Hz). 13C NMR spectra were recorded
on JEOL JNM-AL400 (100 MHz) and chemical shifts (d) are given
from 13CDCl3 (77.0 ppm). Mass spectra and high-resolution mass
spectra were measured on JEOL JMS-DX303 and MS-AX500 in-
struments, respectively.
HRMS: m/z calcd for C14H10N2O: 222.0793; found: 222.0778.
N-(4-Ethoxycarbonylphenyl)benzamide (5c)
Colorless prisms; mp 147–148 °C (hexane–acetone) (Lit.10 mp 137
°C).
IR (film): 3331, 1713, 1659, 1601, 1528, 1407, 1322, 1280, 1176,
1104 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.40 (t, J = 7.1 Hz, 3 H), 4.37 (q,
J = 7.1 Hz, 2 H), 7.49 (t, J = 7.3 Hz, 2 H), 7.57 (t, J = 7.3 Hz, 1 H),
7.74 (d, J = 8.8 Hz, 2 H), 7.87 (d, J = 7.3 Hz, 2 H), 8.01 (br, 1 H),
8.06 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 14.4, 60.9, 119.1, 126.1, 127.0,
128.8, 130.8, 132.1, 134.4, 141.9, 165.7, 166.0.
MS (EI): m/z (%) = 269 (72, [M]+), 105 (100).
Desulfurization of Thioamides; General Procedure
A mixture of the respective thioamide 4 (0.23 mmol) and Bu4NBr
(36 mg, 0.11 mmol) in NMP–DMSO–DMF (1:1:1, 4.5 mL, 0.05 M)
was stirred at 100 °C. The reaction mixture was extracted with
HRMS: m/z calcd for C16H15NO3: 269.1052; found: 269.1045.
3
3
O2
Bu4NBr (0.5 equiv)
4
2
4
2
R3
R3
H
H
N
NMP–DMSO–DMF
(1:1:1, 0.05 M)
100 °C, 13–18 h
N
S
O
7a R3 = H, 92%
6a–c
7b R3 = 4-OMe, 97%
7c R3 = 2-Br, 98%
Scheme 1
Synthesis 2010, No. 18, 3087–3090 © Thieme Stuttgart · New York

3090
K. Inamoto et al.
PAPER
K. Monatsh. Chem. 2004, 135, 411. (e) Mohammadpoor-
N-(4-Cyanophenyl)-4-methoxybenzamide (5l)
Colorless needles; mp 155–156 °C (hexane–acetone).
Baltork, I.; Memarian, H. R.; Hajipour, A. R.; Bahrami, K.
Bull. Korean Chem. Soc. 2003, 24, 1002.
IR (film): 3333, 2224, 1658, 1605, 1592, 1512, 1407, 1320, 1247,
1176 cm–1.
1H NMR (400 MHz, CDCl3): d = 3.87 (s, 3 H), 6.97 (d, J = 8.8 Hz,
2 H), 7.62 (d, J = 8.8 Hz, 2 H), 7.78 (d, J = 8.8 Hz, 2 H), 7.84 (d,
J = 8.8 Hz, 2 H), 8.06 (br, 1 H).
13C NMR (100 MHz, CDCl3): d = 55.5, 107.0, 114.1, 118.8, 119.8,
126.1, 129.0, 133.2, 142.2, 162.9, 165.2.
(f) Mohammadpoor-Baltork, I.; Khodaei, M. M.; Nikoofar,
K. Tetrahedron Lett. 2003, 44, 591. (g) Mohammadpoor-
Baltork, I.; Sadeghi, M. M.; Esmayilpour, K. Synth.
Commun. 2003, 33, 953. (h) Movassagh, B.; Lakouraj, M.
M.; Ghodrati, K. Synth. Commun. 2000, 30, 2353.
(3) Indeed, only little is known about the functional-group
compatibility of this kind of desulfurization process in
previous reports.
(4) (a) Although the precise reaction mechanism of this
cyclization affording 2-phenylbenzothiazole (3) is not clear
at this point, tetrabutylammonium cation mediated
Hugershoff-type reaction might be occurring, see: Metzger,
J. In Comprehensive Heterocyclic Chemistry, Vol. 6;
Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984, 323. (b) We recently reported a synthetic
method for 2-arylbenzothiazoles via Pd-catalyzed C–H
functionalization, see: Inamoto, K.; Hasegawa, C.; Hiroya,
K.; Doi, T. Org. Lett. 2008, 10, 5147.
(5) MeCN and DMA had a yield-improving effect similar to
DMF (75% and 73% yield of 2, respectively). Use of other
solvents, such as 1,4-dioxane, toluene, and 2-BuOH resulted
in lower yields.
(6) For previous reports on the use of Bu4NBr in oxidation
reactions of hydrocarbons, see: Harustiak, M.; Hronec, M.;
Ilavsky, J. React. Kinet. Catal. Lett. 1988, 37, 215; and
references cited therein.
MS (EI): m/z (%) = 252 (7, [M]+), 135 (100).
HRMS: m/z calcd for C15H12N2O2: 252.0899; found: 252.0885.
Anal. Calcd for C15H12N2O2: C, 71.42; H, 4.79; N, 11.10. Found: C,
71.45; H, 4.81; N, 11.12.
N-(2-Bromobenzyl)benzamide (7c)
Colorless prisms; mp 135–139 °C (EtOH) (Lit.11 mp 141–142 °C).
IR (film) 3293, 1641, 1539, 1489, 1465, 1441, 1414, 1309 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.69 (d, J = 6.0 Hz, 2 H), 6.75 (br,
1 H), 7.15 (td, J = 7.6, 1.5 Hz, 1 H), 7.27 (td, J = 7.6, 1.4 Hz, 1 H),
7.39–7.51 (m, 4 H), 7.55 (dd, J = 7.6, 1.4 Hz, 1 H), 7.78 (d, J = 7.6
Hz, 2 H).
13C NMR (100 MHz, CDCl3): d = 44.3, 123.8, 127.0, 127.7, 128.6,
129.2, 130.5, 131.6, 132.8, 134.2, 137.2, 167.3.
MS (EI): m/z (%) = 289 (0.62, [M]+), 210 (100).
HRMS: m/z calcd for C14H1279BrNO: 289.0102; found: 289.0085.
(7) The reaction mechanism of this desulfurization process is
not yet clear at present. There are several reports on the
desulfurization of thiocarbonyl compounds using molecular
oxygen with photoirradiation, see for example:
(a) Ramnath, N.; Ramesh, V.; Ramamurthy, V. J. Org.
Chem. 1983, 48, 214. (b) Suzuki, N.; Sano, K.; Wakatsuki,
S.; Tani, N.; Izawa, Y. Bull. Chem. Soc. Jpn. 1982, 55,
3351. (c) Tamagaki, S.; Akatsuka, R.; Nakamura, M.;
Kozuka, S. Tetrahedron Lett. 1979, 38, 3665. (d)Ishibe,N.;
Odani, M.; Sunami, M. J. Chem. Soc., Chem. Commun.
1971, 118.
(8) Unfortunately, an aliphatic thioamide such as N-phenyl-
thioacetamide did not undergo the desulfurization, the
reaction of which resulted in the recovery of a large amount
of the starting material.
(9) Bogert, M. T.; Wise, L. E. J. Am. Chem. Soc. 1910, 32, 1494.
(10) Solak, N.; Rollas, S. ARKIVOC 2006, (xii), 173.
(11) Bowman, W. R.; Heaney, H.; Jordan, B. J. Tetrahedron
1991, 47, 10119.
Anal. Calcd for C14H12BrNO: C, 57.95; H, 4.17; N, 4.83. Found: C,
57.93; H, 4.83; N, 4.20.
Acknowledgment
This work was supported in part by a Grant-in-Aid for Young Sci-
entists (B) from the Japan Society for the Promotion of Science
(JSPS).
References
(1) For a review, see: Corsaro, A.; Pistarà, V. Tetrahedron 1998,
54, 15027.
(2) For selected recent reports, see: (a) Bahrami, K.; Khodaei,
M. M.; Tirandaz, Y. Synthesis 2009, 369. (b) Shibahara, F.;
Suenami, A.; Yoshida, A.; Murai, T. Chem. Commun. 2007,
2354. (c) Pourali, A. R. Monatsh. Chem. 2005, 136, 733.
(d) Mohammadpoor-Baltork, I.; Memarian, H. R.; Bahrami,
Synthesis 2010, No. 18, 3087–3090 © Thieme Stuttgart · New York