An environmentally benign method for the synthesis of symmetrical N,N′-disubstituted thioureas in a water medium

Article abstract of DOI:10.1080/104265090968082

An environmentally benign method for the synthesis of symmetrical N,N′-disubstituted thioureas in a water medium using poly(ethylene glycol)-400 (PEG-400) as a catalyst and a microwave as a heating source is described. Diaryl- and dialkyl-thioureas efficiently are synthesized by the reactions of thiourea with a variety of amines. This protocol has advantages of (a) no use of hazardous reagents and volatile organic solvents, (b) a rapid reaction rate, (c) a high yield, and (d) a simple work-up procedure. Copyright Taylor & Francis Inc.

Full text of DOI:10.1080/104265090968082

This article was downloaded by: [Mount Allison University 0Libraries]
On: 22 April 2013, At: 03:33
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
An Environmentally Benign
Method for the Synthesis
of Symmetrical N, N ′-
Disubstituted Thioureas in a
Water Medium
Zheng Li a , Zhi-Yuan Wang a , Yan-Long Zhao a , Yu-
Lin Xing a & Wei Zhu a
a Gansu Key Laboratory of Polymer Materials,
College of Chemistry and Chemical Engineering,
Northwest Normal University, Lanzhou, Gansu,
People's Republic of China
Version of record first published: 19 Aug 2006.
To cite this article: Zheng Li , Zhi-Yuan Wang , Yan-Long Zhao , Yu-Lin Xing & Wei Zhu
(2005): An Environmentally Benign Method for the Synthesis of Symmetrical N, N ′-
Disubstituted Thioureas in a Water Medium, Phosphorus, Sulfur, and Silicon and the
Related Elements, 180:12, 2745-2750
To link to this article: http://dx.doi.org/10.1080/104265090968082
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.

The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 180:2745–2750, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090968082
An Environmentally Benign Method for the Synthesis
ꢀ
of Symmetrical N,N -Disubstituted Thioureas
in a Water Medium
Zheng Li
Zhi-Yuan Wang
Yan-Long Zhao
Yu-Lin Xing
Wei Zhu
Gansu Key Laboratory of Polymer Materials, College of Chemistry and
Chemical Engineering, Northwest Normal University, Lanzhou, Gansu,
People’s Republic of China
An environmentally benign method for the synthesis of symmetrical N,Nꢀ-
disubstituted thioureas in a water medium using poly(ethylene glycol)-400 (PEG-
400) as a catalyst and a microwave as a heating source is described. Diaryl- and
dialkyl-thioureas efficiently are synthesized by the reactions of thiourea with a va-
riety of amines. This protocol has advantages of (a) no use of hazardous reagents
and volatile organic solvents, (b) a rapid reaction rate, (c) a high yield, and (d) a
simple work-up procedure.
ꢀ
Keywords Environmentally benign; microwave irradiation; N,N -disubstituted
thiourea; PEG-400; water medium
INTRODUCTION
Thioureas are of importance in medicinal chemistry due to their bio-
logical activities, e.g., anti-HIV,1 antituberculosis2 and antiarrhythmic
activities,3 and in connection with biomimetic models.4 Thioureas are
valuable building blocks for the synthesis of five- and six-membered
heterocycles.5
Treatment of 2 equivalents of a primary or secondary amine with
thiophosgene is the easiest and most general method of making
symmetrical disubstituted thioureas.6 However, this method is haz-
ardous due to the toxic properties of thiophosgene. Hence, numerous
Received February 15, 2005; in final form March 4, 2005.
Address correspondence to Zheng Li, Northwest Normal University, College of Chem-
istry and Chemical Engineering, Lanzhou, Gansu 730070, People’s Republic of China.
E-mail: lizheng@nwnu.edu.cn
2745

2746
Z. Li et al.
alternative methods have been developed for the synthesis of sym-
metrical thioureas avoiding the use of thiophosgene. Thus, symmet-
rical thioureas are formed by (i) either the direct7 or catalyzed8 reac-
tion of carbon disulfide and amines; (ii) the reaction of carbodiimides
with hydrogen sulfide;9 (iii) the reaction of 2-chloropyridinium salts
with sodium trithiocarbonate and amines;10 or (iv) the reaction of 1,1ꢀ-
thiocarbonyldiimidazole with amines.11 However, these methods still
suffer from the following practical limitations: the use of flammable
and volatile organic solvents, harsh reaction conditions, poor yields,
and many side reactions.
Organic reactions in an aqueous medium have been the subject of
considerable attention in terms of achieving more environmentally
friendly synthetic transformations.12 In an effort to develop aqueous
reactions, in this article, we wish to report an environmentally friendly
aqueous method suitable to symmetrical N,Nꢀ-diaryl and dialkyl sub-
stituted thioureas, which utilizes an industrial commodity chemical
thiourea as a starting material, inexpensive PEG-400 as a catalyst,
and microwave irradiation as a heating source.
RESULTS AND DISCUSSION
Synthesis of N,N ꢀ-Diphenylthiourea Using Different Catalysts
In the course of our investigation, we selected the synthesis of N,Nꢀ-
diphenylthiourea by reaction of thiourea with aniline as a model reac-
tion. When the mixture of 2 equiv. of aniline and 1 equiv. of thiourea was
refluxed in water at 100◦C for 24 h, no reaction product was formed (en-
try 1, Table I). However when the reaction was catalyzed by 2% equiv.
ꢀ
of different catalysts, N,N -diphenylthiourea was obtained in varying
yields: β-Cyclodextrin (β-CD) as a supramolecular catalyst for this re-
action gave 26% yield (entry 2, Table I); Sodium n-dodecylsulfonate as
a micellar catalyst gave 51% yield (entry 3, Table I); some quater-
nary ammonium salts as phase transfer catalysts also gave moderate
yields (entries 4–6, Table I). In contrast, PEG-400 as a catalyst af-
forded the highest yield (entry 7, Table I). Subsequent tests confirmed
that PEG-400 was the most efficient catalyst for the synthesis of N,Nꢀ-
diphenylthiourea in water medium (Scheme 1).
SCHEME 1

Thioureas
2747
TABLE I Synthesis of
N,N ꢀ-Diphenylthiourea in a Water
Medium Using Different Catalysts
Entry
Catalyst
Time (h) Yield (%)
1
2
3
4
5
6
7
None
β-CD
24
24
24
24
24
24
24
0
26
51
37
49
56
80
n-C12H25SO3Na
(n-C4H9)4NBr
(n-C4H9)4NI
n-C16H33N(CH3)3Br
PEG-400
PEG-400 Catalyzed Synthesis of N,N ꢀ-Disubstituted Thiourea
Under Microwave Irradiation
We found that the PEG-400 catalyzed synthesis of N,Nꢀ-
diphenylthiourea in water could be accelerated efficiently by mi-
crowave irradiation. A reaction could be completed within 2 min at
650W microwave power to afford the product in a 94% yield. There-
fore, we extended this protocol to other symmetrically disubstituted
thioureas.
The mixture of 2 equiv. of primary aromatic amines and 1 equiv.
of thiourea was irradiated in water for 2 min to give symmetrical di-
aryl thioureas 1a–j in 77–97% yields after cooling to room tempera-
ture and filtration (Scheme 1, Table II). The symmetrical di(thiazol-
2-yl) thiourea (1k) was obtained under a similar condition in an 87%
yield. The reactions of 2 equiv. of primary aliphatic amines with 1 equiv.
of thiourea could be completed within much shorter time (30 s) to af-
ford the corresponding products in high yields (93–96%) (1m–o). It is
noteworthy to mention that this procedure is efficiently applicable to all
primary amines to produce N,Nꢀ-disubstituted thioureas in very high
selectivity. No side reactions were observed.
Hypothesized Mechanism for the Synthesis of Symmetrically
Disubstituted thioureas
A plausible reaction mechanism for the title reactions is illustrated in
Scheme 2. Thiourea reacts with one molecule of amine, librating one
molecule of ammonia, and is transformed to monosubstituted thiourea
2. Subsequently, the monosubstituted thiourea is converted to an isoth-
iocyanate 3 with the loss of another molecule of ammonia. Then the

2748
Z. Li et al.
SCHEME 2
isothiocyanate reacts with another amine molecule to produce N,Nꢀ-
disubstituted thiourea.
In conclusion, we have successfully developed an environmen-
tally friendly method that can be applicable to diaryl- and dialkyl-
substituted thioureas. This method utilizes industrial-commodity pri-
mary amines and thiourea as starting materials, inexpensive PEG-400
as a catalyst, microwave as a heating source, and water as the reaction
medium. This protocol has advantages of (a) not using flammable and
volatile organic solvents of rapid reaction rate, (b) high yield, and (c) a
simple work-up procedure.
EXPERIMENTAL
General Procedure for Symmetrical N,N ꢀ-Disubstituted
Thioureas Under Microwave Irradiation
To a solution of thiourea (0.76 g, 10 mmol) dissolved in H2O (0.5 mL),
primary amines (20 mmol) and PEG-400 (0.08 g, 0.2 mmol) were added.
Then the mixture was placed in a modified microwave oven and sub-
jected to microwave irradiation at a power of 650 W for 2 min or 30 s
(Table II). After the reactions were complete, the resulting mixture was
cooled to room temperature, and the products were isolated either by
filtration and washing with water (1a, 1b, 1d, 1f, 1h, 1i, 1j 1l, and 1o),
or by extraction with EtOAc (3 × 20 mL) and concentration under re-
duced pressure (1c, 1e, 1g, 1k, 1m, and 1n). Analytical samples were
obtained by recrystallization from EtOH or EtOAc.

Thioureas
2749
TABLE II Synthesis of Symmetrically Disubstituted Thioureas in a
Water Medium Under MW Irradiation
Entry
Amine
Disubstituted thioureaa
Time Yield (%)b
1a
2 min
2 min
94
97
1b
1c
1d
2 min
2 min
86
96
1e
1f
2 min
2 min
77
94
1g
1h
2 min
2 min
93
92
1i
1j
2 min
2 min
90
84
1k
1l
2 min
30 s
30 s
30 s
30 s
87
96
96
95
93
1m
1n
1o
aAll products were identified by 1H NMR, IR, and elemental analyses and in
comparison with authentic samples.
bYields refer to the isolated products.

2750
Z. Li et al.
All products were identified by 1H NMR, IR, and elemental analyses,
and m.p. and were compared with authentic samples.
REFERENCES
[1] T. K. Venkatachalam, E. A. Sudbeck, C. Mao, and F. M. Uckun, Bioorg. Med. Chem.
Lett., 11, 523 (2001).
[2] S. Karakus and S. Rollas, Farmaco, 57, 577 (2002).
[3] E. G. Chalina and L. Chakarova, European J. Med. Chem., 33, 975 (1998).
[4] (a) Y. Tobe, S. Sasaki, K. Hirose, and K. Naemura, Tetrahedron Lett., 38, 4791 (1997);
(b) J. Smith, J. L. Liras, S. E. Schneider, and E. V. Anslyn, J. Org. Chem., 61, 8811
(1996).
[5] U. Heinelt, D. Schultheis, S. Jager, M. Lindenmaier, A. Pollex, and H. S. Beckmann,
Tetrahedron, 60, 9883 (2004).
[6] S. Sharma, Synthesis, 803 (1978).
[7] J. Vazquez, S. Bernes, Y. Reyes, M. Moya, P. Sharma, C. Alvarez, and R. Gutierrez,
Synthesis, 1955 (2004).
[8] (a) N. Yamazaki, F. Higashi, and T. Iguchi, Tetrahedron Lett., 15, 1191 (1974);
(b) M. Ballabeni, R. Ballini, F. Bigi, R. Maggi, M. Parrini, G. Predieri, and G. Sartori,
J. Org. Chem., 64, 1029 (1999).
[9] F. Kurzer and K. Douraghi-Zadeh, Chem. Rev., 67, 107 (1967).
[10] Y. Takikawa, N. Inoue, R. Sato, and S. Takizawa, Chem. Lett., 11, 641 (1982).
[11] H. A. Staab, Angew. Chem., Int. Ed. Engl., 1, 351 (1962).
[12] C. J. Li and T. H. Chan, Organic Reactions in Aqueous Media (Wiley, Chichester,
1997).