Simple microwave-assisted method for the synthesis of primary thioamides from nitriles

Article abstract of DOI:10.1055/s-2004-834812

Primary thioamides are prepared in excellent yield from the corresponding nitrile by treatment with ammonium sulfide in methanol, at room temperature for electron-deficient aromatic nitriles or under microwave irradiation at 80 °C or 130 °C in 15-30 minutes for other aromatic and aliphatic nitriles. This procedure avoids the use of gaseous H₂S under high pressure, proceeds in the absence of base and provides thioamides usually without the need for chromatographic purification.

Full text of DOI:10.1055/s-2004-834812

LETTER
2615
Simple Microwave-Assisted Method for the Synthesis of Primary Thioamides
from Nitriles
Synthesis of Primary
T
a
hioamides
r
from
N
it
k
rile
s
C. Bagley,* Krishna Chapaneri, Christian Glover, Eleanor A. Merritt
Cardiff School of Chemistry, Cardiff University, PO Box 912, Cardiff, CF10 3TB, UK
Fax +44(29)20874030; E-mail: Bagleymc@cf.ac.uk
Received 16 July 2004
used microwave-assisted methods in the synthesis of the
Abstract: Primary thioamides are prepared in excellent yield from
the corresponding nitrile by treatment with ammonium sulfide in
methanol, at room temperature for electron-deficient aromatic ni-
triles or under microwave irradiation at 80 °C or 130 °C in 15–30
sulfur-containing heterocyclic domain of the cyclic thi-
azolylpeptide amythiamicin19 and the acidic methanolysis
product of the sulfomycins, dimethyl sulfomycinamate,20
minutes for other aromatic and aliphatic nitriles. This procedure we set out to establish a predictable method for the con-
avoids the use of gaseous H2S under high pressure, proceeds in the
version of both aliphatic and aromatic nitriles to primary
absence of base and provides thioamides usually without the need
thioamides using microwave irradiation.
for chromatographic purification.
Initially, an electron-deficient aromatic substrate, 2-
cyanopyridine (1a), was reacted with either sodium hy-
Key words: thioamides, nitriles, microwaves
drosulfide or ammonium sulfide under a range of different
conditions (Table 1). Although reactions with sodium
The use of thioamides as building blocks in the Hantzsch
hydrosulfide, the less unpleasant-smelling of the two
thiazole synthesis has found broad applicability in many
sulfides, failed to give appreciable yields of the product
areas of chemistry.1 In general, two strategies may be
even under microwave irradiation (entries 1–4), all reac-
adopted for the synthesis of thioamides: the thionation of
tions conducted with ammonium sulfide on the highly
reactive electron-deficient aromatic nitrile 1a provided
thioamide 2a in essentially quantitative yield after an
the corresponding amide with an electrophilic reagent,2
such as Lawesson’s reagent3 or phosphorus pentasulfide,4
or reaction with a nucleophilic thionating reagent, by elec-
aqueous work up without any need for further purification
trophilic activation of either an amide5 or, more simply,
(entries 5–8).
by using the corresponding nitrile.6 The latter conversion,
The facile nature of this transformation, which proceeded
which requires the use of hydrogen sulfide with triethyl-
at room temperature without the use of high pressures,
amine or pyridine as a catalyst at atmospheric pressure,
was at first surprising, even though the precursor was an
proceeds well for aromatic nitriles but is highly problem-
atic for the synthesis of aliphatic thioamides and inevita-
Table 1 Synthesis of Pyridine-2-thiocarboxamide (2a)
bly, with a toxic gaseous reagent, experimentally can be
somewhat involved.7 The use of alkali-metal hydrogen
Sulfide
NaSH
Conditions
Yield (%)
26b
sulfides or ammonium sulfide can simplify the procedure
considerably,8 but usually requires high pressures9 and is
restricted to very electron-deficient aromatic nitriles.10
More convenient sources of hydrogen sulfide, such as
thioacids11 and thioacetamide,12 and alternative reagents,
such as Dowex SH–,13 (P4S11)Na214 or sodium trimethylsi-
lanethiolate,15 all of which require initial preparation,
have been explored. However, the challenge of establish-
ing a simple method that is successful for a wide range of
different substrates and proceeds under straightforward
experimental conditions using commercially available
non-gaseous reagents remains.
1
Et3N, MeOH–H2O (3:2), r.t.,
18 h
2
3
NaSH
NaSH
MeOH, r.t., 18 h
24
46
MeOH, MWa (80 °C, 100 W),
30 min
4
5
NaSH
MeOH, MWa (130 °C, 130 W),
30 min
30
(NH4)2S
Et3N, MeOH–H2O (3:2), r.t.,
18 h
>98
6
7
(NH4)2S
(NH4)2S
MeOH, r.t., 18 h
>98
>98
Microwave dielectric heating has emerged as a valuable
alternative to conventional conductive heating methods in
recent years16 and has been used in the three-component
combinatorial Kindler synthesis of thioamides from alde-
hydes, amines and elemental sulfur17 and to accelerate
amide thionations using Lawesson’s reagent.18 Having
MeOH, MWa (80 °C, 100 W),
15 min
8
(NH4)2S
MeOH, MWa (130 °C, 130 W),
30 min
>98
a MW = microwave irradiation (hold temperature, initial power)
conducted in a sealed tube in a CEM Discover synthesizer.
b Purification by column chromatography was required.
SYNLETT 2004, No. 14, pp 2615–2617
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834812; Art ID: D19504ST
© Georg Thieme Verlag Stuttgart · New York

2616
M. C. Bagley et al.
LETTER
electron-deficient aromatic substrate, and represents a Table 2 Reaction of Nitriles 1a–j and Ammonium Sulfide
simple experimental procedure for the synthesis of prima-
ry thioamides that avoids the use of hydrogen sulfide gas.
Entry Substrate
Product Mp (°C)a
Yield (%)b
1
2
3
2a
2b
2c
137–138
(138–139)
>98 (A)
>98 (B)
>98 (C)
In order to establish the scope of these new methods, a
range of aliphatic and aromatic nitriles 1a–j was reacted
with ammonium sulfide in methanolic solvent at room
temperature (method A)21 and under microwave-assisted
conditions at either 80 °C (method B)22 or 130 °C (method
C, Scheme 1, Table 2). With electron-deficient aromatic
nitriles, the thionation reaction proceeded in essentially
quantitative yield without heating, additional base or any
subsequent purification, although microwave irradiation
did dramatically accelerate these transformations. Most
aliphatic and electron-rich aromatic nitriles failed to give
any yield of the product at room temperature, but when ir-
radiated generated the corresponding thioamide 2 in poor
or near quantitative yield.
N
CN
CN
4
5
186–189
191–192
(190–192)
>98 (A)
>98 (B)
N
6
7
8
MeCN
MeCN
MeCN
121–122
113–114
(108–109)6
0 (A)
53 (B)
39 (C)
9
10
2d
2e
171–172
(169–170)
0 (A)
>98 (B)
CN
11
12
13
0 (A)
8 (B)c
HO
Cl
40 (C)c
CN
(NH4)2S, MeOH
Method A) r.t., 18 h (37% to quant.)
S
14
15
2f
2g
2h
2i
116–117
129–130
(129–130)
>98 (A)
>98 (B)
R
C
N
or MW, 80–130 °C,
R
NH2
2a–j
Method B) 80 °C, 15 min (8% to quant.)
Method C) 130 °C, 30 min (35% to quant.)
CN
1a–j
16
17
18
111–112
98–99
0 (A)
21 (B)c
93 (C)c
Scheme 1 Facile methods for synthesis of primary thioamides 2a–j
(145–147)23
MeO
CN
19
20
21
114–116
110–115
(116)24
0 (A)
35 (B)
35 (C)d
Although this simple procedure often generates the prima-
ry thioamides in excellent yield, in particular for electron-
deficient nitriles, a number of substrates performed poorly
under these conditions. The thionation of 4-cyanophenol
(1e) did not go to completion even under microwave irra-
diation (entries 11–13) and a number of nitriles failed to
give any of the required thioamide product under all of the
conditions investigated (Figure 1).26,27 In spite of these re-
strictions on substrate tolerance, this method does provide
facile access to primary thioamides without the use of
base or gaseous reagents.
CN
22
23
24
PhCN
PhCN
PhCN
112–114
(117–118)
0 (A)
90 (B)
82 (C)d
25
26
(EtO)2CHCN
(EtO)2CHCN
2j
94–95
37 (A)
>98 (B)
(81–82)25
a The range in parentheses refers to literature melting points (ref.13,
unless stated otherwise).
b Isolated yield of pure product. The letter in parentheses refers to re-
action conditions. Method A: r.t., 18 h. Method B: microwave irradi-
ation at 80 °C (100 W) for 15 min. Method C: microwave irradiation
at 130 °C (130 W) for 30 min.
O
CN
CN
CN
CN
c Not isolated yield but based on 1H NMR analysis of crude reaction
mixture.
MeO
d Purification by column chromatography on silica was required.
Figure 1 Nitriles that failed to give the corresponding thioamide 2
when reacted with ammonium sulfide both at ambient temperature
and under microwave irradiation.
In conclusion, ammonium sulfide in methanol either at
room temperature or under microwave irradiation repre-
sents an extremely simple method for the synthesis of
primary thioamides from nitriles that is effective for both
electron-deficient27 and some electron-rich aliphatic and
aromatic substrates, giving the product without any need
for purification28 and, often, in quantitative yield.
References
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Acknowledgment
(7) Fairfull, A. E. S.; Lowe, J. L.; Peak, D. A. J. Chem. Soc.
1952, 742.
We thank CEM (Microwave Technology) Ltd and Chris J. Mason
for valuable assistance.
Synlett 2004, No. 14, 2615–2617 © Thieme Stuttgart · New York

LETTER
Synthesis of Primary Thioamides from Nitriles
2617
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stirred at r.t. for 18 h, evaporated in vacuo and partitioned
between EtOAc (10 mL) and H2O (10 mL). The aqueous
layer was further extracted with EtOAc (2 × 5 mL) and the
organic extracts were combined, washed with brine (10 mL),
dried (Na2SO4) and evaporated in vacuo to give thioamide 2.
(22) General Procedure for Microwave-Assisted Reaction of
Nitriles 1 and Ammonium Sulfide (Method B). A solution
of nitrile 1 (0.5 mmol, 1 equiv) and (NH4)2S (0.5 mmol, 1
equiv; 50 wt.% in H2O) in MeOH (5 mL) was irradiated for
15 min in a self-tunable CEM microwave Discover
synthesizer at 80 °C (initial power 100 W) and then cooled
using a flow of compressed air, evaporated in vacuo and
partitioned between EtOAc and H2O. The aqueous layer was
further extracted with EtOAc (2 × 5 mL) and the organic
extracts were combined, washed with brine (10 mL), dried
(Na2SO4) and evaporated in vacuo to give thioamide 2.
(23) Feiring, A. E. J. Org. Chem. 1976, 41, 148.
(24) Walter, W.; Curts, J. Chem. Ber. 1960, 93, 1511.
(25) Inami, K.; Shiba, T. Bull Chem. Soc. Jpn. 1985, 58, 352.
(26) The nitriles depicted in Figure 1 gave only unreacted starting
material under ambient and microwave-assisted conditions,
according to methods A and B, respectively, except for
acrylonitrile which instead reacted by conjugate addition
with ammonium sulfide.
(27) The reaction of 2-cyanopyridine(1a) with ammonium
sulfide according to method A has been conducted on a
larger scale (10 mmol) to give thioamide 2a without any
reduction in yield.
(28) With a volatile aliphatic nitrile, such as 1c, evaporation in
vacuo after an aqueous work-up removed unreacted starting
material. For reactions that were not quantitative,
(20) Bagley, M. C.; Dale, J. W.; Xiong, X.; Bower, J. Org. Lett.
2003, 5, 4421.
(21) General Procedure for Reaction of Nitriles 1 and
Ammonium Sulfide at Room Temperature (Method A).
A solution of nitrile 1 (0.5 mmol, 1 equiv) and (NH4)2S (0.5
mmol, 1 equiv; 50 wt.% in H2O) in MeOH (5 mL) was
purification by column chromatography on silica was
usually required. For experiments that gave >98% yield
(Table 2, entries 1–5, 10, 14, 15, and 26), no purification on
silica or recrystallisation of the product was necessary.
Synlett 2004, No. 14, 2615–2617 © Thieme Stuttgart · New York