Efficient synthesis of N,N′-dialkyl-N″-dialkylaminocarbothioyl thioureas from cyclic secondary amines, CS2, and N,N′-dialkyl carbodiimides in water

Article abstract of DOI:10.1016/j.tetlet.2008.04.158

A mild, convenient, and practical one-pot procedure for direct synthesis of N,N′-dialkyl-N″-dialkylaminocarbothioyl thioureas is described via three-component reaction of cyclic secondary amines, CS₂, and N,N′-dialkyl carbodiimides in water at room temperature.

Full text of DOI:10.1016/j.tetlet.2008.04.158

Tetrahedron Letters 49 (2008) 4239–4241
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Tetrahedron Letters
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Efficient synthesis of N,N0-dialkyl-N00-dialkylaminocarbothioyl thioureas
from cyclic secondary amines, CS2, and N,N0-dialkyl carbodiimides in water
*
Issa Yavari , Nargess Hosseini, Loghman Moradi, Anvar Mirzaei
Chemistry Department, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
mild, convenient, and practical one-pot procedure for direct synthesis of N,N0-dialkyl-N00-di-
Article history:
A
Received 12 February 2008
Revised 23 April 2008
Accepted 29 April 2008
Available online 2 May 2008
alkylaminocarbothioyl thioureas is described via three-component reaction of cyclic secondary amines,
CS2, and N,N0-dialkyl carbodiimides in water at room temperature.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Dithiobiuret
Carbodiimide
Secondary amine
Aqueous media
Carbon disulfide
Acylureas and biurets are acyclic compounds with anticonvul-
sant activity. Replacement of one or both oxygen atoms of these
compounds with sulfur results in the formation of thiobiurets
and dithiobiurets. This modification increases the lipophilicity
and possibly the biological activity of these compounds. The struc-
tural similarity of dithiobiuret to biurets has allowed researchers
to test several analogues for their antifungal and insecticide
activities.1 Some dithiobiurets were synthesized as male insect
chemosterilants.2 Also these compounds are useful reagents or
intermediates in the synthesis of heterocycles and polymers with
biological properties.3 Dithiobiurets are (S,S)-bidentate ligands
and are used widely in coordination chemistry.4,5 Several
approaches for the synthesis of dithiobiurets have been
described.1–7
Me
N
Me
H2N
S
S
1
S
Ph
N
S
Ph
S
Ph
N
S
Ph
N
SH
Ph
S
Ph
3
2
Scheme 1.
It has been shown that the reaction of primary amines with CS2
in Et2O or THF leads to thioureas and/or isothiocyanates.8 Also,
using N-methylcyclohexylamine or diphenylamine as secondary
amines, in Et2O or pyridine, results in salt 1 or compound 2, respec-
tively. Compound 3 is readily oxidized to the disulfide 2 in the
presence of oxygen8 (Scheme 1).
and primary amines (benzylamine, tert-butylamine), a complex
reaction mixture was obtained.
The reaction of 4, CS2, and 5 proceeded smoothly in H2O, and
was complete within 5 h. The 1H NMR and 13C NMR spectra of
the reaction mixtures after work-up clearly indicated the forma-
tion of N,N0-dialkyl-N00-dialkylaminocarbothioyl thioureas 6a–6h
in 87–96% yields (Table 1).
The structures of compounds 6a–6h were apparent from their
mass spectra, which displayed, in each case, the molecular ion peak
at the appropriate m/z value. The 1H and 13C NMR spectroscopic
data, as well as the IR spectra, were in agreement with the pro-
posed structures. For example, the 1H NMR spectrum of 6a showed
characteristic multiplets for the methylene (d = 1.05–2.00 and
3.83) and methine (d = 4.27–4.34 and 4.93–4.99) protons, together
with a doublet (d = 6.03, 3J = 7.5) for the NH group. The 13C NMR
Herein we report a three-component reaction between cyclic
secondary amines 4 and CS2 in the presence of N,N0-dialkyl carbo-
diimides
5
in water,9,10 which leads to N,N0-dialkyl-N00-di-
alkylaminocarbothioyl thioureas 6 in excellent yields (Scheme 2).
When these reactions were carried out in the presence of acyclic
secondary amines (dibenzylamine, diethylamine, dimethylamine)
* Corresponding author. Tel.: +98 21 88001001; fax: +98 21 88006544.
E-mail address: yavarisa@modares.ac.ir (I. Yavari).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.158

4240
I. Yavari et al. / Tetrahedron Letters 49 (2008) 4239–4241
S
S
R
S
S
NR
C
NH
C
H2O
rt
+
5
+
NH
Z
+
CS2
N
N
R
NHR
CS2
N
S
4
N
SH
R
+
Z
Z
Z
NR
N
R
4
6
5
8
9
7
Scheme 2.
S
HN
6
N
S
NR
Table 1
Reaction of cyclic secondary amines 4, CS2, and N,N0-dialkyl carbodiimides 5 in H2O
Z
Entry
4
R in 5
6
Yielda (%)
10
Scheme 3.
S
S
S
S
N
N
N
N
H
a
Cyclohexyl
91
NH
NH
of the present procedure over existing methods is that the reaction
is performed in aqueous media and under solvent-free conditions
by simple mixing of the starting materials.
6a
N
S
N
H
b
c
i-Pr
89
92
References and notes
6b
S
1. Pandeya, S. N.; Kumar, A.; Singh, B. N.; Mishra, D. N. Pharm. Res. 1987, 4,
321.
2. Oliver, J. E.; Chang, S. C.; Brown, R. T.; Borkovec, B. J. Med. Chem. 1971, 14, 772.
3. Kenawy, E.; Worley, S. D.; Broughton, R. Biomacromolecules 2007, 8, 1359.
4. Crane, J. D.; Herod, A. Inorg. Chem. Commun. 2004, 7, 38.
N
N
N
NH
Cyclohexyl
H
6c
5. Billson, T. S.; Crane, J. D.; Sinn, E.; Teat, S. J.; Wheeler, E.; Young, N. A. Inorg.
Chem. Commun. 1999, 2, 527.
S
S
6. McGrady, J. E.; Mingos, D. M. P. J. Chem. Soc., Perkin Trans. 2 1996, 355.
7. Shibuya, I.; Nakanishi, H. Bull. Chem. Soc. Jpn. 1987, 1381.
8. Jochims, J. C. Chem. Ber. 1968, 101, 1746.
9. Chan, T. H. Organic Reactions in Aqueous Media; Willey: New York, 1997.
10. Jun-Li, C. Chem. Rev. 2005, 105, 3095.
11. Williams, A.; Ibrahim, I. T. Chem. Rev. 1981, 81, 589.
N
N
N
NH
d
e
f
i-Pr
95
87
93
95
H
6d
S
S
12. Kurzer, F.; Douraghi-Zadeh, K. Chem. Rev. 1967, 67, 107.
N
N
N
N
H
13. Typical procedure for the synthesis of 6: Amine (2 mmol) was added slowly to a
mixture of CS2 (2 mmol) and N,N0-dialkyl carbodiimide (2 mmol) in 5 ml of
water at rt. The reaction mixture was stirred for 5 h. After completion of the
reaction, the resulting solid was filtered off, dried and analyzed by 1H NMR, and
13C NMR. In some cases, further purification was carried out by
recrystallization from CH3CN. Compound 6a:White powder, mp 130–134 °C,
0.33 g, yield 91%. IR (KBr) (mmax/cmꢀ1): 3330, 2905, 1511, 1473, 1433, 1384,
1350, 1314, 1228, 1131. MS (EI, 70 eV): m/z (%) = 367 (M+, 6), 128 (60), 98
(100), 84 (46), 55 (78), 41 (62). Anal. Calcd for C19H33N3S2 (367.61): C, 62.08; H,
9.05; N, 11.43. Found: C, 61.97; H, 8.90; N, 11.25. 1H NMR (500.1 MHz, CDCl3):
d 1.05–1.22 (m, 4H, 2CH2), 1.30–1.43 (m, 4H, 2CH2), 1.56–1.77 (m, 14H, 7CH2),
1.92–2.00 (m, 4H, 2CH2), 3.83 (br, 4H, 2CH2), 4.27–4.34 (m, 1H, CH), 4.93–4.99
(m, 1H, CH), 6.03 (d, 3J = 7.5, 1H, NH). 13C NMR (125.7 MHz, CDCl3): d 24.2
(CH2), 25.0 (2CH2), 25.8 (CH2), 25.9 (CH2), 26.1 (2CH2), 26.3 (2CH2), 30.7
(2CH2), 33.1 (2CH2), 51.6 (2CH2), 53.7 (CH), 60.9 (CH), 179.0 (C@S), 183.4
(C@S). Compound 6b: Yellow powder, mp 166–170 °C, 0.25 g, yield 89%. IR
(KBr) (mmax/cmꢀ1): 3320, 2940, 1612, 1561, 1514, 1242. Anal. Calcd for
C13H25N3S2 (287.48): C, 54.31; H, 8.78; N, 14.62. Found:C, 54.11; H, 8.52; N,
14.52. 1H NMR (500.1 MHz, CDCl3): d 1.20 (d, 3J = 6.5, 6H, 2CH3), 1.34 (d,
3J = 6.6, 6H, 2CH3), 1.68 (br, 6H, 3CH2), 4.08 (br, 4H, 2CH2), 4.55–4.62 (m, 1H,
1CH), 5.35–5.40 (m, 1H, CH), 5.87 (d, 3J = 6.5, 1H, NH). 13C NMR (125.7 MHz,
CDCl3): d 20.2 (CH2), 22.4 (2CH3), 23.8 (2CH3), 25.6 (2CH2), 42.1 (2CH2), 46.8
(CH), 52.7 (CH), 179.0 (C@S), 182.7 (C@S). Compound 6c: White powder, mp
152–155 °C, 0.32 g, yield 92%. IR (KBr) (mmax/cmꢀ1): 3330, 2905, 1514, 1475,
1435, 1314. Anal. Calcd for C18H31N3S2 (353.58): C, 61.14; H, 8.84; N, 11.88.
Found: C, 61.09; H, 8.80; N, 11.79. 1H NMR (500.1 MHz, CDCl3): d 1.04–1.25 (m,
4H, 2CH2), 1.30–1.43 (m, 4H, 2CH2), 1.56–1.62 (m, 4H, 2CH2), 1.72–1.82 (m, 4H,
2CH2), 1.88–1.90 (m, 2H, CH2), 1.97 (br, 6H, 3CH2), 3.46–3.56 (br, 2H, CH2),
3.57–3.87 (br, 2H, CH2), 4.31–4.37 (m, 1H, CH), 4.90–4.95 (m, 1H, CH), 5.85 (d,
3J = 6.9, 1H, NH). 13C NMR (125.7 MHz, CDCl3): d 24.5 (2CH2), 24.9 (2CH2), 25.4
(CH2), 25.5 (CH2), 25.9 (3CH2), 30.4 (2CH2), 32.7 (2CH2), 33.9 (CH2), 53.0 (CH),
60.3 (CH), 178.4 (C@S), 181.6 (C@S). Compound 6d: Yellow powder, mp 132–
136 °C, 0.26 g, yield 95%. IR (KBr) (mmax/cmꢀ1): 3305, 2940, 1516, 1439, 1384,
1311, 1283, 1248, 1210, 1162, 1122, 1077. Anal. Calcd for C12H23N3S2 (273.45):
C, 52.71; H, 8.48; N, 15.37. Found: C, 52.67; H, 8.39; N, 15.30. 1H NMR
(500.1 MHz, CDCl3): d 1.17 (d, 3J = 6.5, 6H, 2CH3), 1.33 (d, 3J = 6.7, 6H, 2CH3),
1.98 (br, 4H, 2CH2), 3.44–3.93 (br d, 4H, 2CH2), 4.56–4.65 (m, 1H, CH), 5.26–
5.34 (m, 1H, CH), 5.68 (d, 3J = 6.5, 1H, NH). 13C NMR (125.7 MHz, CDCl3): d 20.6
(2CH3), 22.5 (2CH3), 22.6 (2CH2), 46.6 (CH), 52.4 (2CH2), 52.5 (CH), 178.6 (C@S),
181.0 (C@S). Compound 6e: White powder, mp 147–150 °C, 0.32 g, yield 87%.
IR (KBr) (mmax/cmꢀ1): 3325, 2900, 1508, 1474, 1427, 1388, 1350, 1312, 1266,
1226, 1110. 1043. Anal. Calcd for C18H31N3OS2 (369.58): C, 58.50; H, 8.45; N,
11.37. Found: C, 58.41; H, 8.39; N, 11.28. 1H NMR (500.1 MHz, CDCl3): d 1.05–
Cyclohexyl
O
NH
O
6e
S
S
S
N
N
N
H
i-Pr
NH
O
O
6f
S
N
N
g
Cyclohexyl
H
NH
HO
HO
6g
S
S
N
N N
NH
H
h
Cyclohexyl
96
HO
OH
6h
a
Isolated yield.
spectrum of 6a showed 11 distinct resonances (d = 24.2–60.9) in
the aliphatic region of the spectrum, together with two signals at
d = 179.0 and 183.4 ppm for the C@S groups.
A tentative mechanism for this transformation is proposed in
Scheme 3. It is conceivable that the initial event is the formation
of the SH-acidic intermediate 7 from 4 and CS2 that can protonate
5 to afford 9. Subsequent nucleophilic attack of the sulfur anion 8
on 9 results in 10, which undergoes a well-documented rearrange-
ment11,12 to produce 6.13
In conclusion, we have described a novel system that is effective
for the synthesis of N,N0-dialkyl-N00-dialkylaminocarbothioyl thio-
ureas in high yields at room temperature in water. The advantage

I. Yavari et al. / Tetrahedron Letters 49 (2008) 4239–4241
4241
1.21 (m, 4H, 2CH2), 1.29–1.42 (m, 4H, 2CH2), 1.56–1.69 (m, 4H, 2CH2), 1.69–
1.77 (m, 4H, 2CH2), 1.87–1.90 (br, 2H, CH2), 1.97–2.00 (br, 2H, CH2), 3.65–3.75
(m, 4H, 2CH2), 3.88 (br, 4H, 2CH2), 4.26–4.33 (m, 1H, CH), 4.91–4.98 (m, 1H,
CH), 5.92 (d, 3J = 7.5, 1H, NH). 13C NMR (125.7 MHz, CDCl3): d 24.5 (2CH2), 25.3
(CH2), 25.4 (CH2), 25.8 (2CH2), 30.2 (2CH2), 32.7 (2CH2), 50.1 (2CH2), 53.2 (CH),
60.5 (CH), 65.9 (2CH2), 178.9 (C@S), 184.2 (C@S). Compound 6f: White powder,
mp 123–127 °C, 0.27 g, yield 93%. IR (KBr) (mmax/cmꢀ1): 3315, 2945, 2830, 1514,
Found: C, 59.21; H, 8.49; N, 10.79. 1H NMR (500.1 MHz, CDCl3): d 1.01–1.14 (m,
4H, 2CH2), 1.25–1.32 (m, 4H, 2CH2), 1.50–1.71 (m, 10H, 5CH2), 1.82–1.89 (m,
6H, 3CH2), 2.30 (br, 1H, OH), 3.78 (br, 2H, 2CH), 3.98 (br, 3H, 3CH), 4.20 (br, 1H,
CH), 4.85 (br, 1H, CH), 5.95 (d, 3J = 7.1, 1H, NH). 13C NMR (125.7 MHz, CDCl3): d
24.5 (2CH2), 25.2 (CH2), 25.4 (CH2), 25.9 (3CH2), 30.2 (CH2), 32.6 (2CH2), 32.3
(2CH2), 46.6 (2CH2), 53.3 (CH), 60.6 (CH), 64.7 (CH), 178.5 (C@S), 183.1 (C@S).
Compound 6h: Pale brown powder, mp 115–120 °C, 0.37 g, yield 96%. IR (KBr)
(mmax/cmꢀ1): 3340, 2905, 1521, 1472, 1328, 1270, 1214, 1128. Anal. Calcd for
C19H33N3OS2 (383.61): C, 59.49; H, 8.67; N, 10.95. Found: C, 59.20; H, 8.51; N,
10.80. 1H NMR (500.1 MHz, CDCl3): d 1.03–1.14 (m, 6H, 3CH2),1.15–1.22 (m,
2H, CH2), 1.23–1.36 (m, 6H, 3CH2), 1.62–1.81 (m, 4H, 2CH2), 1.83–1.93 (m, 2H,
CH2), 1.94–1.99 (m, 4H, 2CH2), 2.97 (br, 1H, OH), 3.39–3.99 (br, 4H, 2CH2), 4.00
(br, 1H, CH), 4.23–4.25 (br, 1H, CH), 4.85–4.89 (br, 1H, CH), 6.17 (d, 3J = 6.9, 1H,
NH). 13C NMR (125.7 MHz, CDCl3): d 24.6 (2CH2), 25.3 (2CH2), 25.4 (2CH2), 25.8
(CH2), 25.9 (2CH2), 29.5 (CH2), 29.9 (CH2), 30.3 (CH2), 32.4 (CH2), 32.5 (CH2),
49.1 (CH), 56.2 (CH), 60.7 (CH), 178.2 (C@S), 184.4 (C@S).
1456, 1427, 1383, 1313, 1263, 1220, 1117. Anal. Calcd for
C12H23N3OS2
(289.45): C, 49.79; H, 8.01; N, 14.52. Found: C, 49.70; H, 7.96; N, 14.49. 1H NMR
(500.1 MHz, CDCl3): d 1.15 (d, 3J = 6.5, 6H, 2CH3), 1.29 (d, 3J = 6.7, 6H, 2CH3),
3.67 (t, 3J = 4.9, 4H, 2CH2), 3.84 (br, 4H, 2CH2), 4.51–4.55 (m, 1H, CH), 5.27–5.33
(m, 1H, CH), 5.72 (d, 3J = 7.0, 1H, NH). 13C NMR (125.7 MHz, CDCl3): d 20.2
(2CH3), 22.5 (2CH3), 46.9 (CH), 50.0 (2CH2), 52.7 (CH), 65.9 (2CH2), 179.2 (C@S),
183.8 (C@S). Compound 6g: Pale yellow powder, mp 59–61 °C, 0.36 g, yield
95%. IR (KBr) (mmax/cmꢀ1): 3335, 2905, 1504, 1477, 1437, 1377, 1338, 1258,
1216, 727. Anal. Calcd for C19H33N3OS2 (383.61): C, 59.49; H, 8.67; N, 10.95.