Ammonium phosphorodithioate: A mild, easily handled, efficient, and air-stable reagent for the conversion of amides into thioamides

Article abstract of DOI:10.1055/s-0031-1289859

A simple, efficient, and new method has been developed for the synthesis of thioamides from amides. As described below, the reaction of a variety of aromatic and aliphatic amides in the presence of ammonium phosphorodithioate as an efficient reagent proceeded effectively to afford the corresponding thioamides in high yields. This method is easy, rapid, and high-yielding for the synthesis of thioamides from amides using an easily handled reagent. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289859

LETTER
2807
Ammonium Phosphorodithioate: A Mild, Easily Handled, Efficient, and
Air-Stable Reagent for the Conversion of Amides into Thioamides
N
ovel Conversion
a
of
A
mide
b
s
into Thioam
a
ides k Kaboudin,* Leila Malekzadeh
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), Gava Zang, Zanjan 45137-66731, Iran
Fax +98(241)4249023; E-mail: kaboudin@iasbs.ac.ir
Received 9 August 2011
amides, the conversion of amides into thioamides has so
far received comparatively more attention. Recently,
Rhee and co-workers have also developed a new proce-
dure for the conversion of amides into thioamides using
Abstract: A simple, efficient, and new method has been developed
for the synthesis of thioamides from amides. As described below,
the reaction of a variety of aromatic and aliphatic amides in the pres-
ence of ammonium phosphorodithioate as an efficient reagent pro-
ceeded effectively to afford the corresponding thioamides in high P4S10 in dimethicone.15 However, all of these reagents
yields. This method is easy, rapid, and high-yielding for the synthe-
have problems, including drastic reaction conditions, ex-
sis of thioamides from amides using an easily handled reagent.
pensive reagents and starting materials, a longer reaction
Key words: thioamides, amides, phosphorodithioates, thionation
time, and yield side products. Therefore, the development
of novel methods for the synthesis of important biologi-
cally active molecules in an efficient, practical, economi-
cal, and environmentally benign fashion still remains an
active ongoing research area. Despite a wide range of re-
agents for the conversion of amides into thioamides, no at-
tempt has been made to use readily accessible ammonium
phosphorodithioate for this conversion. Recently, we
have reported a new method for the preparation of ammo-
nium phosphorodithioates and used it as a suitable reagent
for the conversion of epoxides into thiiranes.16 Further in-
vestigation of the application of this mixture, we found
that ammonium phosphorodithioate is a suitable reagent
for the conversion of nitriles into thioamides under mild
reaction conditions. In this paper, we wish to provide an
efficient and simple procedure for the preparation of thio-
amides from amides using ammonium phosphorodithio-
ate.
Thioamides are an important class of bioactive molecules
in the field of drugs and pharmaceuticals. These com-
pounds are valuable intermediates in organic synthesis
that have been used advantageously in the Hantzsch thia-
zole synthesis as building blocks that are applicable in
many areas of chemistry.1 Some thioamide derivatives
have been shown to possess potent opioid activity at m-
and d-receptors,2 immunosuppressive activity and
DHODH inhibitory properties,3 activity against parasitic
nematodes,4 and antituberculotic activity.5 Renau et al.
have reported the design, synthesis, and activity of non-
phosphorylable analogues of toyocamycin, sangiva-
mycin, and thiosangivamycin against human cyto-
megalovirus.6 A series if thioamides has also been shown
to be potent inhibitors of HIV-1 reverse transcriptase.7
They can also act as ligands to transition metals for asym-
metric synthesis.8
Initially, we have carried out the experiment with benz-
amide (1a) as a model compound, in the presence of O,O-
diethyl ammonium phosphorodithioate salt in a variety of
solvents. The progress of the reaction was monitored by
TLC, and the experimental data for the screening condi-
tions are listed in Table 1 (Scheme 1).
Many effective methods have been reported in the litera-
ture for the preparation of thioamides. These methods im-
ply: 1) thiohydrolysis of nitriles involve heating in an
alcoholic solution in the presence of an alkali metal hy-
drogen sulfide or ammonium sulfide under pressure in a
closed reactor or using (P4S11)Na2 (prepared in situ by re-
action of phosphorus decasulfide and sodium sulfide),9 2)
one-pot condensation of amines with aldehydes in the
presence of sulfur and sodium sulfide at high temperature
(120 °C),10 3) conversion of the oxo group of amides into
the corresponding thio derivatives using Lawesson’s re-
agent (LR)11, (NH4)2S in Tf2O at –40 °C,12 or a mixture of
PSCl3, H2O, and Et3N,13 and 4) one-pot reaction between
carboxylic acids and amines in the presence of dithiophos-
phoric acid.14 Although many different methods have
been reported in the literature for the preparation of thio-
As shown in Table 1 conversion of benzamide (1a) into
thiobenzamide (2a) was generally completed in toluene
after 24 hours compared to chlorinated and other solvents.
In the case of DMF as solvent, compound N,N-dimethyl
thioformamide was obtained as major product. We found
that reaction of benzamide with O,O-diethyl ammonium
phosphorodithioate under reflux conditions for four hours
gave thiobenzamide in 91% yield.
To study the scope and limitation of the reaction, various
amides were subjected to treatment with O,O-diethyl am-
O
C
S
S
C
solvent
H2NS P(OEt)2
NH2
NH2
+
reflux, 24 h
SYNLETT 2011, No. 19, pp 2807–2810
Advanced online publication: 09.11.2011
x
x
.x
x
.2
0
1
1
1a
2a
DOI: 10.1055/s-0031-1289859; Art ID: D25711ST
Scheme 1
© Georg Thieme Verlag Stuttgart · New York

2808
B. Kaboudin, L. Malekzadeh
LETTER
R2 R3
N
R2 R3
N
S
R2
R3
S
S
C
O
C
O
O
C
R2
R3
R2
R3
H4NS P(OEt)2
R1
N
R1
C
S
P(OEt)2
R1
N
+
HS P(OEt)2
R1
N
R1
C
O
S
– NH3
OEt
OEt
OH
P
1
2
SH
Scheme 2
monium phosphorodithioate in refluxing toluene
(Table 2).17 As shown in Scheme 2 and Table 2, the reac-
tion of a mixture of aromatic amides with O,O-diethyl am-
monium phosphorodithioate in refluxing toluene afforded
the corresponding thioamides 2b,c in good yields. The re-
actions also proceeded with other N-substituted and N,N-
disubstituted amides using O,O-diethyl ammonium phos-
phorodithioate in toluene under reflux to give the corre-
sponding thioamides 2h–m in good to high yield.
Acetamide also reacted to give the thioacetamide 2n in
good yield. The reactions were clean with no tar forma-
tion.
Table 1 Reaction of Benzamide with O,O-Diethyl Ammonium
Phosphorodithioate in Various Solventsa
Solvent
CH2Cl2
EtOH
THF
Yield (%)
–
–
–
H2O
–
toluene
91
a Reaction conditions: benzamide (5 mmol), O,O-diethyl ammonium
phosphorodithioate (10 mmol), solvent (5 mL), reflux, 24 h.
Table 2 Conversion of Amides into Thioamides Using O,O-Diethyl Ammonium Phosphorodithioate in Refluxing Toluene
Entry
Compound 1
Product 2
Time (h)
Yield (%)a
Mp (°C) [lit.]b,c
S
C
O
C
110–113
1
4
91
NH2
NH2
[117–118]10
NH2
NH2
2a
Cl
Cl
O
S
C
64–66
2
6
87
[62–65]10
C
2b
Cl
Cl
S
C
112–114
O
3
4
5
6
10
10
86
70
72
[112–114]10
NH2
C
NH2
2c
S
C
O
C
H
N
103–105
[102]7
H
N
2d
Et
Et
S
C
O
C
H
N
104–106
H
N
2e
2f
S
C
O
C
H
N
132–134
[135]10
H
N
6
7
8
10
10
6
91
80
90
OMe
Br
OMe
Br
S
C
O
C
H
N
138–140
[140]18
H
N
2g
2h
S
C
O
C
H
N
88–90
H
N
[91–92]19
Synlett 2011, No. 19, 2807–2810 © Thieme Stuttgart · New York

LETTER
Novel Conversion of Amides into Thioamides
2809
Table 2 Conversion of Amides into Thioamides Using O,O-Diethyl Ammonium Phosphorodithioate in Refluxing Toluene (continued)
Entry
9
Compound 1
Product 2
Time (h)
6
Yield (%)a
71
Mp (°C) [lit.]b,c
143–14520
Cl
Cl
O
S
C
H
N
H
N
C
2i
2j
S
C
Me
Me
O
C
Me
Me
63–65
10
11
12
N
6
6
6
90
81
91
[66.0–66.8]21
N
S
Me
Me
O
C
Me
Me
107–11322
88–90
Me
C N
Me
N
2k
S
Me
Me
O
Me
Me
Cl
C N
Cl
C N
2l
Me
Me
S
C
Me
Me
O
Me
Me
13
14
6
4
90
86
yellow oil
N
C
N
2m
S
H
H
O
C
H
H
110–112
Me
C
N
[113–114]23
Me
N
2n
a Yields refers to the isolated pure products after column chromatography.
b Literature references.
c Melting points are uncorrected.
In summary, we have developed a simple, practical, and
possible industrial process for the synthesis of thioamides
under mild conditions. Thioamides can be synthesized in
good to excellent yields under the treatment of amides
with easily prepared and air-stable O,O-diethyl ammoni-
um phosphorodithioate salt in toluene. This method is
quite useful, in comparison with previously reported
methods, because it allows the use of readily available in-
expensive O,O-diethyl ammonium phosphorodithioate
salt. In addition, by carrying out this method, we achieved
thioamides without any additives such as base, acid, or
catalyst. In addition, the other advantages of this environ-
mentally benign and safe protocol include a simple reac-
tion setup, not requiring specialized equipment, very mild
reaction conditions, and good to excellent yields. Many of
the pharmacologically relevant substitution patterns on
the aromatic ring could be introduced with high efficiency
by using this procedure. All of the products were charac-
terized by 1H NMR and 13C NMR spectroscopy.17
References and Notes
(1) (a) Oare, D. A.; Sanner, M. A.; Heathcock, C. H. J. Org.
Chem. 1990, 55, 132. (b) Heathcock, C. H.; Davidson, S. K.;
Mills, S. G.; Sanner, M. A. J. Org. Chem. 1992, 57, 2531.
(c) Magnus, P.; Mendoza, J. S.; Stamford, A.; Ladlow, M.;
Willis, P. J. Am. Chem. Chem. Soc. 1992, 114, 10232.
(d) Kim, G.; Chu-Moyer, M. Y.; Danshefsky, S. J.; Schulte,
G. K. J. Am. Chem. Soc. 1993, 115, 30. (e) Takahata, H.;
Banba, Y.; Mozumi, M.; Yamazaki, T. Heterocycles 1986,
24, 947. (f) Takahata, H.; Yamazaki, T. Heterocycles 1988,
27, 1953. (g) Hurd, R. N.; Delmater, G. T. Chem. Rev. 1961,
61, 45. (h) Roth, H. J.; Kleemann, A. Drug Synthesis, In
Pharmaceutical Chemistry, Vol. 1; Wiley: New York,
1988. (i) Hoeg-Jensen, T. Phosphorus, Sulfur Silicon Relat.
Elem. 1996, 108, 1.
(2) Sherman, D. B.; Spatola, A. F.; Wire, W. S.; Burks, T. F.;
Nguyen, T. M.-D.; Schiller, P. W. Biochem. Biophys. Res.
Commun. 1982, 162, 1126.
(3) Albert, A.; Knecht, H.; Andersen, E.; Hungerford, V.;
Schreier, M. H.; Papageorgiou, C. Bioorg. Med. Chem.
1988, 8, 2203.
(4) Jeschke, P.; Harder, A.; Etzel, W.; dau, W.; Thielking, G.;
Bonse, G.; Linuma, K. Pest Manag. Sci. 2001, 57, 1000.
(5) Cynamon, M. H.; Gimi, R.; Gyenes, F.; Sharpe, C. A.;
Bergmann, K. E.; Han, H. J.; Gregor, L. B.; Rapolu, R.;
Luciano, G.; Welch, T. J. Med. Chem. 1995, 38, 3902.
(6) Renau, T. E.; Ludwig, M. S.; Drach, J. C.; Townsend, L. B.
Bioorg. Med. Chem. Lett. 1992, 2, 1755.
Acknowledgment
The authors gratefully acknowledge support by the Institute for Ad-
vanced Studies in Basic Sciences (IASBS) Research Council under
grant No. G2010IASBS120.
(7) Mehanna, A. S.; Belani, J. D.; Kelley, C. J.; Pallansc, L. A.
Med. Chem. 2007, 3, 513.
Synlett 2011, No. 19, 2807–2810 © Thieme Stuttgart · New York

2810
B. Kaboudin, L. Malekzadeh
LETTER
(8) Suzyki, Y.; Yazaki, R.; Kumagai, N.; Shibasaki, M. Angew.
Chem. Int. Ed. 2009, 48, 5026.
Hz), 8.87 (br, 1 H, NH). 13C NMR (100.65 MHz, CDCl3): d
= 14.4, 24.5, 126.8, 127.4, 128.5, 128.7, 129.2, 131.5, 137.0,
139.8, 142.2, 200.0.
(9) (a) Kindler, K. Justus Liebigs Ann. Chem. 1923, 431, 187.
(b) Zbruyev, O. I.; Stiasni, N.; Kapper, C. O. J. Comb. Chem.
2003, 5, 145. (c) Wang, C.-H.; Hwang, F.-Y.; Horng, J.-M.;
Chen, C.-T. Heterocycles 1979, 12, 1191. (d) Albert, A.
Ber. Dtsch. Chem. Ges. 1915, 48, 470. (e) Taylor, E. C.;
Zoltewicz, J. A. J. Am. Chem. Soc. 1960, 82, 2656.
(f) Liboska, R.; Zyka, D.; Bobek, M. Synthesis 2002, 1649.
(g) Benner, S. A. Tetrahedron Lett. 1981, 22, 1851.
(h) Benner, S. A. Tetrahedron Lett. 1981, 22, 1855.
(i) Shiao, M. J.; Lai, L. L.; Ku, W. S.; Lin, P. Y.; Hwu, J. R.
J. Org. Chem. 1993, 58, 4772. (j) Brillon, D. Synth.
Commun. 1992, 22, 1397.
(10) Okamoto, K.; Yamamoto, T.; Kanbara, T. Synlett 2007,
2687.
(11) For selected articles, see: (a) Ozturk, T.; Ertas, E.; Mert, O.
Chem. Rev. 2007, 107, 5210. (b) Varma, R. S.; Kumar, D.
Org. Lett. 1999, 1, 697. (c) Curphey, T. J. J. Org. Chem.
2002, 67, 6461.
N-(4-Methoxyphenyl)thiobenzamide (2f)
1H NMR (400 MHz, CDCl3): d = 3.88 (s, 3 H), 7.01 (d, 2 H,
J = 7.2 Hz), 7.45 (t, 2 H, J = 7.6 Hz), 7.53 (t, 1 H, J = 7.2
Hz), 7.66 (d, 2 H, J = 7.2 Hz), 7.89 (d, 2 H, J = 7.2 Hz), 8.97
(br, 1 H, NH). 13C NMR (100.65 MHz, CDCl3): d = 55.5,
114.2, 125.6, 126.7, 128.7, 129.2, 131.3, 131.9, 143.0,
158.2, 198.2.
N-(4-Bromophenyl)thiobenzamide (2g)
1H NMR (400 MHz, CDCl3): d = 7.40–7.65 (m, 5 H), 7.74
(d, 2 H, J = 7.2 Hz), 7.87 (d, 2 H, J = 7.2 Hz), 8.98 (br, 1 H,
NH). 13C NMR (100.65 MHz, CDCl3): d = 119.9, 125.1,
128.8, 129.2, 131.5, 132.2, 137.9, 198.0.
N-Cyclohexylthiobenzamide (2h)
1H NMR (400 MHz, CDCl3): d = 1.19–1.60 (m, 5 H), 1.62–
1.85 (m, 3 H), 2.17–2.25 (m, 2 H), 4.48–4.61 (m, 1 H), 7.36
(t, 2 H, J = 7.6 Hz), 7.44 (t, 1 H, J = 7.2 Hz), 7.54 (br, 1 H,
NH), 7.70 (d, 2 H, J = 7.2 Hz). 13C NMR (100.65 MHz,
CDCl3): d = 24.7, 25.5, 31.6, 55.0, 126.7, 128.4, 130.9,
142.3, 197.6.
(12) Charette, A. B.; Gernon, M. J. Org. Chem. 2003, 68, 5792.
(13) Pathak, U.; Pandey, L. K.; Tank, R. J. Org. Chem. 2008, 78,
2890.
(14) Borthakur, N.; Goswami, A. Tetrahedron Lett. 1995, 36,
6745.
2-Chloro-N-cyclohexylthiobenzamide (2i)
1H NMR (400 MHz, CDCl3): d = 1.19–1.60 (m, 5 H), 1.62–
1.85 (m, 3 H), 2.17–2.25 (m, 2 H), 4.48–4.62 (m, 1 H), 7.27–
7.40 (m, 3 H, NH), 7.50–7.40 (m, 1 H), 7.57–7.62 (m, 1 H).
13C NMR (100.65 MHz, CDCl3): d = 24.6, 25.5, 31.3, 54.8,
127.0, 128.3, 129.9, 130.1, 130.3, 142.2, 195.5.
N,N-Dimethylthiobenzamide (2j)
(15) Cho, D.; Ahn, J.; De Castro, K. A.; Ahn, H.; Rhee, H.
Tetrahedron 2010, 66, 5583.
(16) (a) Kaboudin, B.; Norouzi, H. Synthesis 2004, 2035.
(b) Kaboudin, B.; Elhamifar, D. Synthesis 2006, 224.
(c) Kaboudin, B.; Elhamifar, D.; Farjadian, F. Org. Prep.
Proced. Int. 2006, 38, 412.
1H NMR (400 MHz, CDCl3): d = 3.03 (s, 3 H), 3.47 (s, 3 H),
7.15–7.29 (m, 5 H). 13C NMR (100.65 MHz, CDCl3): d =
43.2, 44.2, 125.7, 128.3, 128.5, 143.3, 200.7.
4-Methyl-N,N-dimethylthiobenzamide (2k)
1H NMR (400 MHz, CDCl3): d = 2.34 (s, 3 H), 3.16 (s, 3 H),
3.57 (s, 3 H), 7.13 (d, 2 H, J = 8.0 Hz), 7.20 (d, 2 H, J = 8.0
Hz). 13C NMR (100.65 MHz, CDCl3): d = 21.3, 43.4, 44.3,
125.9, 128.9, 138.7, 140.6, 201.4.
4-Chloro-N,N-dimethylthiobenzamide (2l)
CAS No. 15563-46. 1H NMR (400 MHz, CDCl3): d = 3.19
(s, 3 H), 3.60 (s, 3 H), 7.26 (d, 2 H, J = 8.4 Hz), 7.34 (d, 2 H,
J = 8.4 Hz). 13C NMR (100.65 MHz, CDCl3): d = 43.3, 44.2,
127.3, 128.6, 134.6, 141.6, 199.8.
(17) The amide (5 mmol) was added to a mixture of O,O-diethyl
ammonium phosphorodithioate salt (10 mmol, 2.03 g)16a and
toluene (5 mL), and the reaction mixture was stirred for 4–
10 h at reflux. After stirring for a known period (Table 2),
the mixture was evaporated under reduced pressure. The
resulting mixture was subjected to column chromatography
on silica gel with EtOAc–n-hexane (1:9), and evaporation of
the solvent under reduced pressure gave pure products in 70–
91% yields. All products gave satisfactory spectral data in
accord with the assigned structures and literature reports.9–
16,18–22
Thiobenzamide (2a)
3-Methyl-N,N-dimethylthiobenzamide (2m)
1H NMR (400 MHz, CDCl3): d = 2.34 (s, 3 H), 3.14 (s, 3 H),
3.57 (s, 3 H), 7.05 (d, 1 H, J = 7.6 Hz), 7.12 (d, 2 H, J = 6.0
Hz), 7.22 (d, 1 H, J = 8.0 Hz). 13C NMR (100.65 MHz,
CDCl3): d = 21.4, 43.2, 44.2, 122.6, 126.3, 128.2, 129.3,
138.1, 143.4, 201.4.
1H NMR (400 MHz, CDCl3): d = 7.29 (br, 1 H, NH2), 7.43
(t, 2 H, J = 8.0 Hz), 7.54 (t, 1 H, J = 8.0 Hz), 7.89 (d, 2 H,
J = 8.0 Hz), 7.90 (br, 1 H, NH2). 13C NMR (100.65 MHz,
CDCl3): d = 126.9, 128.5, 132.1, 139.2, 202.2.
2-Chlorothiobenzamide (2b)
1H NMR (400 MHz, CDCl3): d = 7.35 (br, 1 H, NH2), 7.28–
7.48 (m, 3 H), 7.62 (d, 1 H, J = 8.0 Hz), 8.45 (br, 1 H, NH2).
13C NMR (100.65 MHz, CDCl3): d = 127.1, 128.2, 130.1,
130.2, 131.0, 140.4, 201.5.
Thioacetamide (2n)
CAS No. 62-55-5. 1H NMR (400 MHz, CDCl3): d = 3.34 (s,
3 H), 8.90–9.20 (br, 2 H, NH2). 13C NMR (100.65 MHz,
CDCl3): d = 31.0, 206.1.
3-Chlorothiobenzamide (2c)
(18) Habibi, M.; Habibi, M. H.; Tangestaninejad, S.; Fallah-
Shojaie, A.; Mohammadpoor-Baltork, I.; Tayyari, S. F.;
Emtiazi, G.; Hamidimotlagh, R. J. Coord. Chem. 2005, 58,
955.
1H NMR (400 MHz, CDCl3): d = 7.29 (br, 1 H, NH2), 7.37
(t, 1 H, J = 8.0 Hz), 7.50 (d, 1 H, J = 8.0 Hz), 7.72 (d, 1 H,
J = 8.0 Hz), 7.88 (s, 1 H), 7.92 (br, 1 H, NH2). 13C NMR
(100.65 MHz, CDCl3): d = 124.8, 127.3, 131.9, 134.6, 140.8,
201.1.
(19) Alliger, G.; Smith, G. E. P.; Carr, E. L.; Stevens, H. P.
J. Org. Chem. 1949, 14, 962.
N-Phenylthiobenzamide (2d)
(20) Rauf, M. K.; Bolte, M.; Badshah, A. Acta Crystallogr., Sect.
E: Struct. Rep. Online 2009, 65, 01265.
(21) Hori, T.; Otani, Y.; Kawahata, M.; Yamaguchi, K.; Ohwada,
T. J. Org. Chem. 2008, 73, 9102.
(22) Scheibye, S.; Pedersen, B. S.; Lawesson, S.-O. Bull. Soc.
Chim. Belg. 1978, 78, 229.
1H NMR (400 MHz, CDCl3): d = 7.23–7.90 (m, 10 H), 9.03
(br, 1 H, NH). 13C NMR (100.65 MHz, CDCl3): d = 123.6,
126.7, 127.0, 128.7, 129.1, 131.3, 138.9, 143.3, 198.3.
N-(2-Ethylphenyl)thiobenzamide (2e)
1H NMR (400 MHz, CDCl3): d = 1.29 (t, 3 H, J = 7.6 Hz),
2.71 (q, 2 H, J = 7.6 Hz), 7.23–7.45 (m, 3 H), 7.47 (t, 2 H,
J = 7.6 Hz), 7.57 (t, 2 H, J = 7.2 Hz), 7.93 (d, 2 H, J = 7.2
(23) Bagley, M. C.; Chapaneri, K.; Glover, C.; Merritt, E. A.
Synlett 2004, 2615.
Synlett 2011, No. 19, 2807–2810 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.