TMEDA-catalyzed synthesis of N-aryl-N′-ethoxycarbonyl thiourea and arene (or polymethylene)-bis-ethoxycarbonylthiourea derivatives

Article abstract of DOI:10.1080/10426500490474905

A novel and efficient method for synthesis ethoxycarbonyl isothiocyanate and ethoxycarbonyl thioureas catalyzed by TMEDA is reported. A series of N-aryl-N′-ethoxycarbonyl thioureas and arene (or polymethylene)-bis- ethoxycarbonyl thiourea derivatives have been synthesized in good-to-excellent yields via this method at room temperature.

Full text of DOI:10.1080/10426500490474905

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Phosphorus, Sulfur, and Silicon and the Related
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TMEDA-CATALYZED SYNTHESIS OF N-ARYL-N′-
ETHOXYCARBONYL THIOUREA AND ARENE (OR
POLYMETHYLENE)-BIS-ETHOXYCARBONYLTHIOUREA
DERIVATIVES
Qi Lin a , You-Ming Zhang a , Li-Ming Gao a , Tai-Bao Wei a & Hai Wang a
a Department of Chemistry, Northwest Normal University , Lanzhou, Gansu, P.R. China
Published online: 16 Aug 2010.
To cite this article: Qi Lin , You-Ming Zhang , Li-Ming Gao , Tai-Bao Wei & Hai Wang (2004) TMEDA-CATALYZED SYNTHESIS OF
N-ARYL-N′-ETHOXYCARBONYL THIOUREA AND ARENE (OR POLYMETHYLENE)-BIS-ETHOXYCARBONYLTHIOUREA DERIVATIVES,
Phosphorus, Sulfur, and Silicon and the Related Elements, 179:10, 2051-2057, DOI: 10.1080/10426500490474905
To link to this article: http://dx.doi.org/10.1080/10426500490474905
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Phosphorus, Sulfur, and Silicon, 179:2051–2057, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490474905
TMEDA-CATALYZED SYNTHESIS
OF N-ARYL-Nꢀ-ETHOXYCARBONYL THIOUREA
AND ARENE (OR POLYMETHYLENE)-
BIS-ETHOXYCARBONYLTHIOUREA DERIVATIVES
Qi Lin, You-Ming Zhang, Li-Ming Gao, Tai-Bao Wei,
and Hai Wang
Department of Chemistry, Northwest Normal University,
Lanzhou, Gansu, P.R. China
(Received January 15, 2004; accepted March 17, 2004)
A novel and efficient method for synthesis ethoxycarbonyl isothio-
cyanate and ethoxycarbonyl thioureas catalyzed by TMEDA is re-
ported. A series of N-aryl-Nꢁ-ethoxycarbonyl thioureas and arene
(or polymethylene)-bis-ethoxycarbonyl thiourea derivatives have been
synthesized in good-to-excellent yields via this method at room
temperature.
Keywords: ethoxycarbonyl isothiocyanate; ethoxycarbonyl thioureas;
TMEDA catalysis
INTRODUCTION
N-aryl-Nꢁ-ethoxycarbonyl thioureas have attracted much attention due
to their strong coordination ability.1 For example, many N-substituted-
Nꢁ-ethoxycarbonyl thioureas are commercially utilized as the collec-
tor for copper sulfides and precious metals.2 Moreover, N-aryl-Nꢁ-
ethoxycarbonyl thioureas have been found to posses high antibacte-
rial activity.3 It is also an important intermediate for synthesis of
heterocyclic compounds.4 In view of these facts, and as a part of
our work of the synthesis, biological activity, and coordination be-
havior of thiourea derivatives,5 herein we report an efficient and
novel method for synthesis N-aryl-Nꢁ-ethoxycarbonyl thioureas (4a–e)
This work was supported by Natural Science Foundation (No. 20371040) of China, the
Foundation (031-A21-004) of Gansu province, and the Foundation (No. 02-18) of North-
west Normal University, which are gratefully acknowledged.
Address correspondence to Tai-Bao Wei, Department of Chemistry, Northwest Normal
University, Lanzhou, Gansu, 730070, P.R. China. E-mail: kejichu@nwnu.edu.cn
2051

2052
Q. Lin et al.
and arene (or polymethylene)-bis-ethoxycarbonylthiourea derivatives
(5a–f) catalyzed by N,N,Nꢁ,N ꢁ-tetramethylethylenediamine (TMEDA)
under mild conditions.
The common methods for the preparation of these compounds are
via the reaction of ethoxycarbonylisothiocyanate (3) with correspond-
ing aromatic amines or arene (or polymethylene) diamines. Obviously,
the compound 3 is the key intermediate for 4 and 5. As early as 1908,
Dixon and Taylor7 reported that potassium thiocyanate (2) reacted with
ethyl chloroformate (1) in acetone solutions to gives the compound 3,
but this method gives 3 in very low yield and gives a lot of ethoxy-
carbonylthiocyanate as by-product.8 Thus it is not a good method for
preparation 3. In our earlier work, we reported that acyl isothiocyanate
could be synthesized in high yield by the reaction of benzoyl chloride
with potassium thiocyanate under solid–liquid phase-transfer catalytic
conditions;5b however, we haven’t obtained the compound 3 in high yield
using similar method.
Recently, Tomohumi Sano et al.9 reported that TMEDA could pro-
mote the acylation reaction between benzoyl chloride and alcohols
by enhancing the reactivity of benzoyl chloride. In an earlier study,
H. Kunz et al.10 also reported that pyridine could catalyze the re-
action between 2-(triphenylphosphonio)ethyl chloroformate and alco-
hols by enhancing the reactivity of 2-(triphenylphosphonio)ethyl chlo-
roformate. In view of these studies, we think TMEDA and other
amines such as pyridine can also catalyze the reaction between
1 and 2 by enhancing the reactivity of 1. As a result of these
ideas, a series of N-aryl-Nꢁ-ethoxycarbonyl thioureas (4a–e) and arene
(or polymethylene)-bis-ethoxycarbonylthiourea derivatives (5a–f) have
been synthesized in good-to-excellent yields by the catalysis of TMEDA
at room temperature.
RESULTS
TMEDA is an excellent catalyst for the synthesis of this kind of isoth-
iocyanates and thioureas. Compounds 4a–e and 5a–f were synthesized
in good-to-excellent yields at room temperature catalyzed by TMEDA.
The use of TMEDA as the catalyst has many advantages such as ex-
cellent chemical yields, high efficiency (10 mmol ethyl chloroformate
only need 0.1 mmol TMEDA), mild reaction conditions (All reactions
are performed at room temperature), and simple operation. For these
reasons, this methodology represents an important improvement for
the preparation of this kind of fine chemical.

TMEDA-Catalyzed Synthesis of Thiourea Derivatives
2053
DISCUSSION
In order to select the best reaction condition and the best catalyst for
synthesis 3, we carried out a series of experiments as follows: at first,
we estimated the reactivity of the model reaction (Scheme 1) between
1 (10 mmol) and 2 (12 mmol) under TMEDA (0.1 mmol) catalysis and
room temperature conditions in different solvents such as CH2Cl2, ace-
tone, and ethyl acetate. Because compound 3 is an oil product, after
the reaction completed we didn’t separate it, and we added the aniline
(10 mmol) slowly to the reaction mixture with constant stirring and
stirred at room temperature for 5 h. Then the solvent was evaporated
in vacuum and the precipitation was washed with 10 ml 75% EtOH
three times and 15 ml water three times. The product 4a was obtained.
The yields of 4a in different solvents are shown in Table I. From these
data we can find the ethyl acetate is the appropriate solvent for this
reaction.
SCHEME 1
In order to compare the catalytic effect of the TMEDA and other
amines, and as the second series of our experiments, we examined a sim-
ilar reaction via the use of different amines as catalysts. Because it is a
solid–liquid phase reaction, we also tested it using polyethyleneglycol

2054
Q. Lin et al.
TABLE I Yields of 4a in Different Solvents
Under the Catalysis of TMEDA
Entry
Solvents
Yields of 4a (%)
1
2
3
4
Acetone (8 ml)
CH2Cl2 (8 ml)
Ethyl acetate (8 ml)
Ethyl acetate (20 ml)
54
56
96
68
(PEG)-400 as the phase-transfer catalyst. The results are listed in
Table II. From these data we find that the TMEDA is the best cat-
alyst for this reaction, although the pyridine and other amines such
as triamyl amine could promote the reaction. We also found the
phase-transfer catalysis method couldn’t give a satisfied result for this
reaction.
Finally, we explored the general validity of the present method-
ology; different ethoxycarbonylthioreas 4a–e and 5a–f were synthe-
sized in excellent yields (Table III). The details of the reaction mech-
anism are not clear at present, but Sano et al.9 supposed that a
benzoyl chloride–TMEDA complex plays a significant role in enhanc-
ing the reactivity of benzoyl chloride. Additionally, Kunz et al.10 also
reported that the 2-(triphenylphosphonio)ethyl chloroformate-pyridine
complex is the key intermediate for enhancing the reactivity of 2-
(triphenylphosphonio)ethyl chloroformate. Therefore, we think the for-
mation of ethyl chloroformate–TMEDA complex is the key step of the
catalytic procedure. On the basis of our experimental results, we ten-
tatively propose the mechanism shown in Scheme 2.
SCHEME 2
EXPERIMENTAL
Melting points were determined in open capillaries and are uncorrected.
IR spectra were recorded in KBr on a Nicilet NEXUS 670 Fourier trans-
form infrared (FTIR) spectrophotometer, and 1H NMR spectra on a

TMEDA-Catalyzed Synthesis of Thiourea Derivatives
2055
TABLE II Yields of 4a under the Catalysis of
Different Catalysts
Entry
Catalystsa
Yields of 4a (%)
1
2
3
4
5
6
7
8
TPAb
60
80
76
96
42
68
45
74
TAAc
Pyridine
TMEDA
PEG-400d
PEG-400 + TAA
PEG-400 + Pyridine
PEG-400 + TMEDA
aThe use of each catalyst is 0.1 mmol.
bTripropyl amine.
cTriamyl amine.
dPEG-400.
FT-80A instrument using TMS as internal reference. Elemental anal-
ysis was determined on PE-2400 CHN instrument.
Typical Procedure for 4a–e and 5a–f
The synthesis of 4a–e and 5a–f were carried out by adding powdered
2 (12 mmol) to an ethyl acetate solution of 1 (10 mmol) and TMEDA
(0.1 mmol). The reaction mixture was stirred at room temperature for
5 h. Then the aromatic amine (10 mmol) to give 4a–e or arene (or
alkylene) diamine (5 mmol) to give 5a–f was slowly added to the reac-
tion mixture with constant stirring. The reaction mixture was stirred
at room temperature for 5 h again. After evaporating the solvent in
TABLE III Compounds 4a–e and 5a–f Prepared
Entry
Ar/(CH2)n
Products
Yields (%)
1
2
3
4
5
6
C6H5
4a
4b
4c
4d
4e
5a
96
88
94
80
89
76
2-CH3C6H4
3-CH3C6H4
2-ClC6H4
2-Naphthyl
7
5b
80
8
9
10
11
(CH2)2
(CH2)4
(CH2)6
(CH2)10
5c
5d
5e
5f
70
78
89
84

2056
Q. Lin et al.
vacuum, the products were obtained from washing the precipitation
with 10 ml 75% ethanol three times and 15 ml H2O three times. If nec-
essary, recrystallization 4a–e from ethanol and 5a–f from DMF-EtOH-
H2O gave the pure product.
4a. Yield, 96%; m.p. 125–126◦C. IR (KBr): ν = 3416 (NH), 3220 (NH),
1712 (C O), 1596, 1534, 1449 (C C), 1237 (C S) cm−1 1H NMR
.
(CDCl3): δH = 11.48 (s, 1H, NH), 8.29 (s, 1H, NH), 7.50 (m, 5H, ArH),
4.361 (q, 2H, CH2), 1.368, (t, 3H, CH3). Anal. Cacld. for C10H12N2O2S:
C, 53.55; H, 5.39; N, 12.49. Found: C, 53.55; H, 5.40; N, 12.54.
4b. Yield, 87%; m.p. 152–153◦C. IR (KBr): ν = 3415 (NH), 3217
(NH), 1713 (C O), 1608, 1579, 1533 (C C), 1202 (C S) cm−1. 1H NMR
(CDCl3): δH = 11.18 (s, 1H, NH), 8.33 (s, 1H, NH), 7.50 (m, 4H, ArH),
4.35 (q, 2H, CH2), 2.34 (s, 3H, CH3), 1.37 (t, 3H, CH3). Anal. Cacld. for
C11H14N2O2S: C, 55.44; H, 5.92; N, 11.76. Found: C, 55.41; H, 5.92; N,
11.78.
4c. Yield, 94%; m.p. 102–103◦C. IR (KBr): ν = 3422 (NH), 3212 (NH),
1
1714 (C O), 1603, 1538, 1474, (C C) 1242 (C S). H NMR (CDCl3):
δH = 11.43 (s, 1H, NH), 8.30 (s, 1H, NH), 7.29 (m, 4H, ArH), 4.35
(q, 2H, CH2), 2.40 (s, 3H, CH3), 1.36, (t, 3H, CH3). Anal. Cacld. for
C11H14 N O2S: C, 55.44; H, 5.92; N, 11.76. Found: C, 55.41; H, 5.92; N,
2
11.78.
4d. Yield 80%; m.p. 126–128◦C. IR (KBr): ν = 3415 (NH), 3166 (NH),
1
1723 (C O), 1559, 1539, 1477 (C C) 1246 (C S). H NMR (CDCl3):
δH = 11.65 (s, 1H, NH), 8.29 (s, 1H, NH), 7.37 (m, 4H, ArH), 4.38 (q, 2H,
CH2), 1.38 (t, 3H, CH3). Anal. Cacld. for C10H11N2O2SCl: C, 46.42; H,
4.29; N, 10.83. Found: C, 46.27; H, 4.30; N, 10.79.
4e. Yield, 89%; m.p. 159–160◦C. IR (KBr): ν = 3416 (NH), 3161 (NH),
1
1711 (C O), 1599, 1531, 1472 (C C), 1247 (C S). H NMR (CDCl3):
δH = 11.67 (s, 1H, NH), 8.44 (s, 1H, NH), 7.75 (m, 7H, ArH), 4.37 (q,
2H, CH2), 1.37 (t, 3H, CH3). Anal. Cacld. for C14H14N2O2S: C, 61.29; H,
5.14; N, 10.21. Found: C, 61.17; H, 5.20; N, 10.30.
5a. Yield, 76%; m.p. 164–165◦C. IR (KBr): ν = 3388 (NH), 3192 (NH),
1
1709 (C O), 1589, 1535, 1456 (C C), 1245 (C S). H NMR (CDCl3):
δH = 11.22 (s, 2H, NH), 8.48 (s, 2H, NH), 7.34 (m, 4H, ArH), 4.32 (q, 4H,
CH2), 1.33 (t, 6H, CH3). Anal. Cacld. for C14H18N4O4S2: C, 45.39; H,
4.90; N, 15.12. Found: C, 45.41; H, 4.86; N, 15.14.
5b. Yield, 80%; m.p. 180–181◦C. IR (KBr): ν = 3431 (NH), 3210 (NH),
1
1718 (C O), 1594, 1524, 1445 (C C), 1244 (C S). H NMR (CDCl3):
δH = 11.53 (s, 2H, NH), 8.28 (s, 2H, NH), 7.43 (m, 4H, ArH), 4.34 (q, 4H,
CH2), 1.35 (t, 6H, CH3). Anal. Cacld. for C14H18N4O4S2: C, 45.39; H,
4.90; N, 15.12. Found: C, 45.44; H, 5.06; N, 15.04.
5c. Yield, 70%; m.p. 196–197◦C. IR (KBr): ν = 3427 (NH), 3223 (NH),
1721 (C O), 1241 (C S). 1H NMR (DMSO-d6): δH = 17.74 (s, 2H, NH),

TMEDA-Catalyzed Synthesis of Thiourea Derivatives
2057
9.90 (s, 2H, NH), 4.00 (q, 4H, CH2), 3.42 (d, 4H, CH2), 1.21 (t, 6H, CH3).
Anal. Cacld. for C10H18 N O4S2: C, 37.25; H, 5.63; N, 17.38. Found: C,
4
37.36; H, 5.76; N, 17.53.
5d. Yield, 78%; m.p. 154–155◦C. IR (KBr): ν = 3402 (NH), 3296 (NH),
1702 (C O), 1256 (C S). 1HNMR (CDCl3): δH =10.85 (s, 2H, NH), 9.85
(s, 2H, NH), 4.14 (q, 4H, CH2), 3.56 (t, 4H, CH2), 1.57 (t, 4H, CH2), 1.20
(t, 6H, CH3). Anal. Cacld. for C12H22N4O4S2: C, 41.13; H, 6.33; N, 15.99.
Found: C, 41.34; H, 6.46; N, 16.03.
5e. Yield, 89%; m.p. 133–134◦C. IR (KBr): ν = 3328 (NH), 3265 (NH),
1715 (C O), 1248 (C S). 1H NMR (CDCl3): δH = 9.70 (s, 2H, NH), 8.11
(s, 2H, NH), 4.28 (q, 4H, CH2), 3.64 (q, 4H, CH2), 1.60 (t, 8H, CH2), 1.31
(t, 6H, CH3). Anal. Cacld. for C14H26N4O4S2: C, 44.42; H, 6.92; N, 14.80.
Found: C, 44.35; H, 6.91; N, 14.76.
5f. Yield, 84%, m.p. 112–113◦C. IR (KBr): ν = 3420 (NH), 3238 (NH),
1723 (C O), 1253 (C S). 1H NMR (CDCl3): δH = 9.67 (s, 2H, NH), 8.19
(s, 2H, NH), 4.27 (q, 4H, CH2), 3.64 (q, 4H, CH2), 1.38(t, 16H, CH2),
1.30 (t, 6H, CH3). Anal. Cacld. for C18H34N4O4S2: C, 49.74; H, 7.88; N,
12.89. Found: C, 49.89; H, 7.75; N, 12.98.
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