A simple route for the synthesis of symmetrical thiourea derivatives and amidinium cations by reaction between isocyanides, amines and carbon disulfide

Article abstract of DOI:10.1080/17415993.2012.724419

Reaction between primary amines and CS₂ promoted by alkyl isocyanides in ethanol as solvent provides a simple and efficient route for the synthesis of symmetrical thiourea derivatives. The reaction of secondary amines with carbon disulfide and alkyl isocyanides afforded new amidinium cations in good yields.

Full text of DOI:10.1080/17415993.2012.724419

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A simple route for the synthesis of
symmetrical thiourea derivatives
and amidinium cations by reaction
between isocyanides, amines and
carbon disulfide
Mohammad Anary-Abbasinejad a , Nadia Karimi a , Hossein Mehrabi
a & Reza Ranjbar-Karimi a
a Department of Chemistry, Vali-e-Asr University of Rafsanjan,
Rafsanjan, 77176, Iran
Version of record first published: 18 Sep 2012.
To cite this article: Mohammad Anary-Abbasinejad, Nadia Karimi, Hossein Mehrabi & Reza Ranjbar-
Karimi (2012): A simple route for the synthesis of symmetrical thiourea derivatives and amidinium
cations by reaction between isocyanides, amines and carbon disulfide, Journal of Sulfur Chemistry,
33:6, 653-659
To link to this article: http://dx.doi.org/10.1080/17415993.2012.724419
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Journal of Sulfur Chemistry
Vol. 33, No. 6, December 2012, 653–659
SHORT COMMUNICATION
A simple route for the synthesis of symmetrical thiourea
derivatives and amidinium cations by reaction between
isocyanides, amines and carbon disulfide
Mohammad Anary-Abbasinejad*, Nadia Karimi, Hossein Mehrabi and Reza Ranjbar-Karimi
Department of Chemistry, Vali-e-Asr University of Rafsanjan, Rafsanjan 77176, Iran
(Received 14 July 2012; final version received 21 August 2012)
Reaction between primary amines and CS2 promoted by alkyl isocyanides in ethanol as solvent provides a
simple and efficient route for the synthesis of symmetrical thiourea derivatives. The reaction of secondary
amines with carbon disulfide and alkyl isocyanides afforded new amidinium cations in good yields.
S
R' NH2
+
RNHCSH
R
R'NH
X
HNR'
ethanol, r.t.
CS2
+
R
N
C
X
NH
S
S
H N
N
N
X
H
Keywords: thiourea; isocyanide; multi-component reaction; amidinium cations; carbon disulfide
1. Introduction
Thiourea derivatives are biologically active compounds existing as fungicides, herbicides (1) and
antibacterial agents (2). They are also key intermediates in organocatalysis (3a) and references
cited therein (3b–f ). There are several routes for the synthesis of thioureas, which requires the
use of hazardous and toxic reagents (4). For example, thioureas have been prepared by the reac-
tion between primary and secondary amines and thiophosgene or isothiocyanates (5), which are
hazardous compounds. Furthermore, the reaction of amines with carbon disulfide in the presence
of mercury acetate and the reaction of unsubstituted thioureas with primary alkyl amines (6) have
been utilized for the synthesize of thioureas. The reactions between carbon disulfide and amines
have been reported utilizing a ZnO/Al2O3 composite as catalyst at high temperature (100◦C) to
afford thiourea derivatives (7). The reaction between carbon disulfide and primary amines was also
reported in hot water to afford symmetrical thiourea derivatives in the absence of any catalyst (8).
*Corresponding author. Email: mohammadanary@yahoo.com
ISSN 1741-5993 print/ISSN 1741-6000 online
© 2012 Taylor & Francis
http://dx.doi.org/10.1080/17415993.2012.724419
http://www.tandfonline.com

654 M. Anary-Abbasinejad et al.
A similar reaction has been reported between carbon disulfide and primary or secondary amines
in a boiling solution of sodium hydroxide in water to form di- and tri-substituted thioureas (9).
In continuation of our previous works on isocyanide-based multi-component reactions (10–13),
we wish to report here the reaction between amines, carbon disulfide and alkyl isocyanides to
form thiourea derivatives or amidinium salts.
2. Results and discussion
The reaction between cyclohexyl isocyanide 1a, primary amine 2 and carbon disulfide (3) in
ethanol, after 3 h stirring at room temperature, afforded thiourea derivatives 4 in high yields
(Figure 1). To show the role of the isocyanide in the formation of thiourea derivatives from
the reaction between amines and carbon disulfide, the reaction between aniline and CS2 was
conducted in the absence of isocyanide and only the salt PhNHCSS− PhNH3+ was isolated in
80% yield after 12 h stirring at room temperature. As shown in Table 1, the reaction is compatible
with aromatic and aliphatic amines. In all cases, the reaction was clean and complete after 3 h
stirring at room temperature and the products were readily purified by evaporating the solvent and
washing the precipitated solids with diethyl ether. All products in Table 1 are known compounds
and their structures were proved by comparison of the melting points and IR and NMR data with
the reported data (7).
S
S
H
ethanol
r.t., 3h
+
CS
+
2 RNH
RNH C HNR
Cy N CH
Cy N C
+
2
2
1a
2
3
4
5
Figure 1. Synthesis of thiourea derivatives by reaction between primary amines and CS2, promoted by cyclohexyl
isocyanide.
Table 1. Preparation of thioureas from primary amines, CS2 and isocyanide.
Entry
1
Amine 2
Product 4
Yield%∗
94
S
−
Ph NH2
PhNHCNHPh
(4-MeC6H4NH)2CS
(4-ClC6H4NH)2CS
(PhCH2NH)2CS
(C6H11NH)2CS
2
3
4
5
4-MeC6H4NH2
4-ClC6H4NH2
PhCH2NH2
95
97
90
95
C6H11NH2
H
N
NH2
NH2
6
93
S
N
H
H
N
NH2
NH2
NH2
7
92
S
N
H
NH
8
90
CS
2
∗Isolated yields.

Journal of Sulfur Chemistry 655
S
N
H
Cy
C
H
R NH2
+
CS2
N C SH
R
2
3
6
S
S
H
H
+
Cy N CH
R N C S C N Cy
R N C S
9
7
8
S
S
H
H
H
R NH2
+ Cy N CH
R N C S
R N C N R
10
5
4
Figure 2. Suggested mechanism for the formation of compound 4 by the reaction of primary amine, isocyanide and CS2.
A reasonable mechanism for the formation of thiourea from the reaction between isocyanide
1, primary amine 2 and CS2 is presented in Figure 2. The addition of amine to CS2 leads to
carbodithioic acid intermediate 6, which protonates the alkyl isocyanide 1 to form nitrilium
cation 8. The addition of carbodithioate anion 7 to nitrilium cation 8 leads to intermediate 9 that
converts to isothiocyanate 10 by loss of a molecule of CyNHCSH 5.Addition of another molecule
of amine to isothiocyanate 10 affords the product 4.
To investigate the reaction between isocyanide, CS2 and secondary amines, pyrrolidine was
reacted with CS2 and t-butyl isocyanide (Figure 3 and Table 2). After stirring the reaction mixture
at room temperature for 3 h and removing the solvent at reduced pressure, a solid product was
1
obtained. The H NMR spectrum of this product exhibited the presence of the skeleton of one
molecule of t-butyl isocyanide and two molecules of pyrrolidine. The elemental analysis also
showed the presence of one molecule of CS2 in the structure of the product. So, a four-component
reaction has occurred between t-butyl isocyanide, pyrrolidine and CS2. On the basis of the ele-
mental analysis and IR and NMR spectral data, structure 12a was considered for the product.
The IR spectrum shows a strong peak at 1694 cm−1, indicating the existence of iminium cation
+
1
+
(C N ), which was further confirmed by H NMR spectrum (δ = 8.38 ppm, NCH N ) and 13C
=
=
+
1
=
NMR spectrum (δ = 151.4 ppm, NCH N ). The H NMR spectrum of 12a exhibited a singlet at
1.36 ppm for t-butyl protons. A singlet that integrated for one hydrogen was observed at 8.38 ppm
and a D2O-exchangable signal was observed at 8.79 ppm. The 13C NMR spectrum showed a sig-
nal at 209.7 ppm which is assigned to the NCS2 carbon and a signal (CH) at 151.4 ppm which is
−
−
attributed to N CH N carbon atom (on the basis of DEPT NMR data). This value is similar to
δ = 149.4 (14, 15) in amidine carbocations and indicates significant stabilization of the cationic
carbon. The 13C NMR spectrum of 12a showed signals related to the t-butyl group at 29.9 and
55.2 ppm. One of the pyrrolidine rings showed two signals at 53.4 and 25.0 ppm. The other pyrol-
lidine ring that possesses a positively charged nitrogen showed thr+ee signals at 26.4, 51.9 and
=
47.5 ppm. This is attributed to the restricted rotation about the C N bond, desymmetrizing the
methylene groups of the ring. The same behavior was observed for the two pyrrolidine rings in
the 1H NMR spectrum of compound 12a, one ring showing two signals at 3.64 and 1.80 ppm for
the four methylene groups and the positively charged ring showing four broad signals at 3.73,
3.38, 1.96 and 1.85 ppm for methylene groups of the ring.
To investigate the scope of the reaction, different secondary amines were treated with CS2 and
cyclohexyl isocyanide or t-butyl isocyanide and related products were obtained in good yields
(Table 2). It is noteworthy that the restricted rotations about CN bonds of NCHN moiety may also
result in the presence of two rotational isomers. For example, the 1H NMR spectrum of compound
12e shows that it exists at solution as two rotamers (Figure 4).

656 M. Anary-Abbasinejad et al.
Table 2. Amidinium cations from secondary amines, CS2 and isocyanides.
Entry
Amine
R’
Product
Yield%∗
95
H
N
S
S
N
N
1
t-Bu
NH
H
12a
H
S
S
N
N
N
2
3
Cy
90
90
NH
NH
H
12b
H
N
S
n-Bu
N
N
S
H
12c
H
N
S
O
N
O
N
4
5
6
t-Bu
Cy
75
71
80
O
NH
NH
S
12d
H
H
S
O
N
O
N
O
N
S
12e
H
H
S
N
t-Bu
NH
N
N
12f
S
H
∗Isolated yields.
A suggested mechanism for the formation of compound 12a is presented in Figure 5. As shown
in Figure 2, the treatment of amine, isocyanide and CS2 leads to the formation of intermediate 13,
this cannot be converted to isothiocyanate intermediate in the case of secondary amines. Addition
X
S
R'
H
N
H
Ethanol
r.t., 3h
X
NH
CS2
+
+
R' N C
N
X
N
S
12
Figure 3. Synthesis of amidinium cations by reaction between secondary amines, CS2 and isocyanides.
O
O
O
H
N
N
H
N
H
N
H
N
H
N
H
E-isomer
Z-isomer
Figure 4. Resonance forms and rotational isomers of compound 12e.
12e

Journal of Sulfur Chemistry 657
S
S
NH
S
N
H
N
H
N
N
S
N
H
13
14
12a
Figure 5. Suggested mechanism for the formation of compound 12 by the reaction of pyrrolidine, t-Butyl isocyanide
and CS2.
of another molecule of pyrrolidine to intermediate 13 affords compound 14, which then ionizes
to product 12a.
3. Conclusions
In summary, we reported herein a simple and efficient route for the synthesis of thiourea derivatives
by reaction between primary amines and CS2 promoted by alkyl isocyanides. The reactions are
conducted under neutral conditions and are clean and complete at room temperature after 3 h. The
reaction of secondary amines with carbon disulfide and alkyl isocyanides afforded amidinium
cations in good yields. In all the experiments, products were purified by simple washing with
diethyl ether and were obtained in high yields.
4. Experimental section
4.1. General
All melting points are uncorrected. Elemental analyses were performed using a Heraeus CHN-
O-Rapid analyzer. Mass spectra were recorded on a Finnigan-MAT 8430 mass spectrometer
operating at an ionization potential of 70 eV. IR spectra were recorded on a Shimadzu IR-470
spectrometer. 1H and 13C NMR spectra were recorded on Bruker DRX-500 Avance spectrometer
at 500.1 and 125.8 or 75 MHz, respectively. 1H and 13C NMR spectra were obtained on solution
in DMSO-d6 using TMS as internal standard. The chemicals used in this work were purchased
from Fluka (Buchs, Switzerland) and were used without further purification.
4.2. General procedure for the preparation of compounds 4a–4j and 12a–12f
Isocyanide (1 mmol) was added to a mixture of amine (2 mmol) and carbon disulfide (1 mmol)
in ethanol (10 ml) and the mixture was stirred at room temperature for 3 h. Solvent was removed
under reduced pressure and the solid residue was washed with diethyl ether (5 ml) to give the
pure product. All products in Figure 1 are known compounds and their structures were proved
by comparison of the melting points and IR and NMR data with the reported data. Compounds
12a–12f are new and their structures were proved by IR and NMR spectroscopy and analyti-
cal data.
4.2.1. 12a
White powder (0.29 g, 95%). mp: 161–163◦C. FT-IR (KBr): νmax (cm−1) = 3190 (NH), 1693
+
=
(C N ). Anal. Calcd for C14H27N3S2 (301.2): C, 55.8; H, 9.0; N, 13.9; S, 21.3%. Found: C,

658 M. Anary-Abbasinejad et al.
1
55.7; H, 9.1; N, 13.9; S, 21.2%. H NMR (500 MHz; DMSO-d6): δ = 1.36 (s, 9H, t-butyl),
1.8 (m, 4H, 2 CH2 of pyrrolidine), 1.85 and 1.96 (2 broad m, 4H, 2 CH2 of positively charged
pyrrolidine), 3.38 and 3.73 (2 broad m, 4H, 2NCH2 of positively charged pyrrolidine), 3.66 (m,
4H, 2 CH2 of pyrrolidine), 8.38 (s, 1H, CH), 8.79 (broad s, 1H, NH). 13C NMR (75 MHz, DMSO-
d6): δ = 25.0 (2 CH2), 26.4 (2 CH2), 29.9 (3 CH3 of t-butyl), 47.5 and 51.9 (2NCH2 of positively
charged pyrrolidine), 53.4 (2NCH2 of pyrrolidine), 55.2 (C of t-butyl), 151.4 (NCHN), 209.7
=
(C S).
4.2.2. 12b
White powder (0.29 g, 90%). mp: 189–191◦C; FT-IR (KBr): νmax (cm−1) = 3197 (NH), 1681
+
=
(C N ). Anal. Calcd for C16H29N3S2 (327.2): C, 58.7; H, 8.9; N, 12.8; S, 19.6%. Found: C,
1
58.7; H, 9.0; N, 12.8; S, 19.4%. H NMR (500 MHz; DMSO-d6): δ = 1.08, 1.22, 1.24, 1.38,
1.41, 1.57 and 1.86 (6m, 10H, 5 CH2 of cyclohexyl), 1.75 (m, 4H, 2 CH2 of pyrrolidine), 1.79 and
1.94 (2 broad m, 4H, 2 CH2 of positively charged pyrrolidine), 3.38 (m, 3H, CH of cyclohexyl
and CH2 of positively charged pyrrolidine), 3.65 (m, 6H, 3 CH2), 8.46 (m, 1H, CH), 8.95 (broad
s, 1H, NH); 13C NMR (75 MHz, DMSO-d6): δ = 25.0, 25.3, 26.4, 33.5, 47.3, 51.7, 53.4, 57.0,
=
153.2 (NCHN), 209.6 (C S).
4.2.3. 12c
White powder (0.27 g, 90%). mp 108–110◦C. FT-IR (KBr): νmax (cm−1) = 3184 (NH), 1690
+
1
=
(C N ). H NMR (300 MHz; DMSO-d6): δ = 0.9 (t, 3H, CH3 of n-Bu), 1.31 (sextet, 2H, CH2
of n-Bu), 1.59 (quintet, 2H, CH2 of n-Bu), 1.85–3.68 (m, 8H, 4 CH2 of pyrrolidine rings), 3.42–
3.68 (2m, 8H, 4 CH2 of pyrrolidine rings), 8.60 (m, 1H, CH), 9.24 (broad s, 1H, NH). 13C NMR
(75 MHz, DMSO-d6): δ = 14.2, 19.6, 32.6 and 53.4 (carbons of n-Butyl), 25.0, 26.3, 46.7, 47.3
=
and 51.7 (2 pyrrolidine rings), 154.3 (NCHN), 209 (C S).
4.2.4. 12d
White powder (0.25 g, 75%). mp: 161–163◦C. FT-IR (KBr): νmax (cm−1) = 3192 (NH), 1689
+
1
=
(C N ). H NMR (500 MHz; DMSO-d6): δ = 1.34 (s, 9H, t-butyl), 3.33 and 4.29 (2t, j = 5.2 Hz,
8H, 4 CH2 of morpholine), 3.69, 3.79 and 3.10 (broad signals, 4 CH2 of positively charged
morpholine), 8.12 (s, 1H, CH), 9.29 (broad s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): δ = 29.7
and 55.5 (carbons of t-Butyl), 50.2 and 66.7 (4 CH2 of morpholine), 43.8, 45.7, 64.5 and 66.1
=
(4 CH2 of positively charged morpholine), 152.9 (NCHN), 214.6 (C S).
4.2.5. 12e
White powder (0.25 g, 71%). mp: 204–209◦C. FT-IR (KBr): νmax (cm−1) = 3426 (NH), 1691
+
1
=
(C N ). H NMR (500 MHz; DMSO-d6): δ = 1.09–2.36 (6m, 10H, 5 CH2 of cyclohexyl),
3.36 and 4.20 (broad signals, 8 CH2 of morpholine rings and CH of cyclohexyl), 7.83 and 8.14
(2s, 1H, CH of two isomers), 9.4 and 9.54 (2 broad s, 1H, NH of two isomers).
4.2.6. 12f
White powder (0.29 g, 80%). mp 155–157◦C; FT-IR (KBr): νmax (cm−1) = 3150 (NH), 1680
+
1
=
(C N ). H NMR (500 MHz, DMSO-d6): δ = 0.86 (d, J = 7 Hz, 6H, 2 CH3), 1.11 (m, 2H, 2

Journal of Sulfur Chemistry 659
CH), 1.33 (s, 9H, t-Bu), 1.67, 2.49, 3.20, 3.91, 4.35 (broad signals, 8 CH2 of piperidine rings,
7.72 (s, 1H, NCHN), 7.97 (broad s, 1H, NH). 13C NMR (75 MHz, DMSO-d6): δ = 21.2, 21.3,
=
29.7, 30.1, 30.8, 32.8, 33.4, 34.0, 34.3, 46.5, 50.7, 52.5, 53.1, 56.0, 150.0 (NCHN), 212.6 (C S).
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