A concise synthesis of substituted thiourea derivatives in aqueous medium

Article abstract of DOI:10.1021/jo1001593

(Figure Presented) An efficient method for the synthesis of symmetrical and unsymmetrical substituted thiourea derivatives by means of simple condensation between available building blocks such as amines and carbon disulfide in aqueous medium is presented. This protocol works smoothly with aliphatic primary amines to afford various di- and trisubstituted thiourea derivatives. The present method is also useful in synthesizing various substituted 2-mercapto imidazole heterocycles. This method proceeds through a xanthate (amino dithiol deivative) intermediate, unlike isothiocyanate as in an earlier known method.

Full text of DOI:10.1021/jo1001593

pubs.acs.org/joc
A Concise Synthesis of Substituted Thiourea Derivatives in
Aqueous Medium
Mahagundappa R. Maddani and Kandikere R. Prabhu*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, Karnataka, India
prabhu@orgchem.iisc.ernet.in
Received January 29, 2010
An efficient method for the synthesis of symmetrical and unsymmetrical substituted thiourea derivatives
by means of simple condensation between available building blocks such as amines and carbon disulfide
in aqueous medium is presented. This protocol works smoothly with aliphatic primary amines to afford
various di- and trisubstituted thiourea derivatives. The present method is also useful in synthesizing
various substituted 2-mercapto imidazole heterocycles. This method proceeds through a xanthate (amino
dithiol deivative) intermediate, unlike isothiocyanate as in an earlier known method.
Introduction
Among the numerous methods for the synthesis of thiou-
reas,2a,6 condensation of primary and secondary amine with
isothiocyanate,6a thiophosgene6b or its derivatives6c con-
stitutes the most widely accepted general methods. Further,
the reaction of primary amines with carbon disulfide in the
presence of mercury acetate and the reaction of unsubsti-
tuted thioureas with primary alkyl amines7 are a few more
methods to synthesize thioureas. Despite the toxicity of the
reagents, the applications of these reagents remain inevita-
ble because of the importance of thioureas in biological
field.8 Therefore, safer, nontoxic, and user-friendly proce-
dures to synthesize thioureas are yet to be developed.
Thioureas are the subject of significant interest because
of their usefulness in medicinal chemistry due to their
biological activity as fungicides, herbicides,1 rodenticides,2
and phenoloxidase enzymatic inhibitors.3 Thiourea deriva-
tives and their metal complexes exhibit analgesic, anti-
inflammatory, antimicrobial, and anticancer activities.
Thiourea derivatives are valuable building blocks for the
synthesis of amides, guanidines, and varieties of hetero-
cycles.4 Recently, thiourea derivatives have found use in
organocatalysis.5 For these reasons, a number of proce-
dures have been reported for the synthesis of thioureas.
Results and Discussion
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The development of environmentally benign synthetic
procedures, particularly in aqueous medium, constitutes an
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Uglevodordn. Syrya 1968, 2, 101; Chem. Abstr. 1969, 71, 101668.
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5304. (b) Kasmi, S.; Hamelin, J.; Benhaoua, H. Tetrahedron Lett. 1998, 39,
8093–8096. (c) Kearney, P. C.; Fernandez, M.; Flygare, J. A. J. Org. Chem.
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S. J. Chem.;Eur. J. 2006, 12, 5418–5427. (c) Takemoto, Y. Org. Biomol.
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Int. Ed. 2004, 43, 2062–2064.
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DOI: 10.1021/jo1001593
r
Published on Web 03/04/2010
J. Org. Chem. 2010, 75, 2327–2332 2327
2010 American Chemical Society

Maddani and Prabhu
JOCArticle
SCHEME 1. Synthesis of Di- and Tri-substituted Thiourea
SCHEME 2. Synthesis of Di- and Tri-substituted Thiourea
Using Molybdenum Xanthate10
important goal in organic synthesis.9 In continuation of our
research in developing green reaction conditions, we were
interested in synthesizing these classes of compounds in
environmentally benign reaction conditions, especially in
aqueous medium. Recently, we have reported the synthesis
of thiourea derivatives by reacting primary amines with
molybdenum xanthate10 (Scheme 1).
As molybdenum xanthate11 is prepared in water, we initiated
a reaction of primary amine with in situ generated molybdenum
xanthate in aqueous medium. In this reaction, diethyl amine (1)
was treated with carbon disulfide in the presence of sodium
hydroxide as a base to form the corresponding xanthate,
followed by the addition of sodium molybdate to produce
molybdenum xanthate in water. Interestingly, when the above
solution of molybdenum xanthate was reacted with n-hexyl
amine (a) at reflux condition, the corresponding trisubstituted
thiourea 1a (1,1-diethyl-3-hexylthiourea) was obtained in
good yield (eq 1). In order to test the necessity of molybdenum
reagent, we performed a controlled reaction in the absence of
molybdenum complex. This experiment using xanthate solu-
tion with n-hexyl amine resulted in the formation of the
corresponding trisubstituted thiourea, ruling out the require-
ment of molybdenum reagent in the reaction (eq 2).
Additionally, it is documented that resin-bound N,N-
disubstituted dithiocarbamates derived from secondary
amines react with primary amines to produce a very small
amount of thioureas12 under forcing conditions. Apart from
this, there is also a report on the synthesis of trisubstituted
thiourea by the reaction of zinc dialkyldithiocarbamates
with primary aliphatic amines.13 However, zinc dialkylthio-
carbamates14 were prepared in two steps by using amines and
carbon disulfide to generate the sodium dialkylthiocarba-
mates, which were further converted to the corresponding
zinc dialkylthiocarbamates, whereas the present method
provides an easy protocol of generating the sodium di-
alkylthiocarbamates (in situ) and further reacting with several
amines. We believe that the present methodology provides
a greater flexibility of using amines (dialkyl amines and pri-
mary amines) at our convenience and is superior to other
methods.
After several experimental trials, it was optimized that
dialkyl amine (1.4 mmol) and carbon disulfide (1.5 mmol) in
aqueous NaOH (1.4 mmol) furnished the corresponding
sodium salt of dialkyldithiocarbamates. This dialkylthiocar-
bamates solution, without isolation, was heated at reflux
with primary amine (1 mmol). After the completion of the
reaction (TLC), the reaction mixture was acidified using
dilute HCl (pH = 2) to furnish the corresponding tri sub-
stituted thiourea in good to excellent yields.
A variety of di- and tri-substituted thiourea derivatives
were synthesized by using this strategy (Table 1). Secondary
amines such as diethyl amine (1), piperidine (2), and morpho-
line (3) were used to prepare the corresponding sodium
dialkylthiocarbamates in water at ambient temperature.
These in situ generated sodium dialkylthiocarbamates were
heated at reflux with primary amines such as n-hexylamine
(a), 2-phenylethyl amine (b), 1-phenylethyl amine (c), and 2-
furfuryl amine (d) to furnish the corresponding trisubstituted
thiourea in good to excellent yields.15 As seen from the
Table 1, under the optimized conditions, the in situ generated
sodium thiocarbamate of diethyl amine (1) reacted with
hexyamine (a) under the typical reaction conditions to
produce the corresponding trisubstituted thiourea 1a in
excellent yield (90%, entry 1, Table 1). Similarly, 2-phenyl-
ethyl amine (b) and 1-phenylethyl amine (c) underwent
A review of the literature for the synthesis of thiourea2a
reveals that isothiocyanate is a key intermediate in synthesiz-
ing thioureas. Therefore, the reaction of carbon disulfide
with primary amines produces the corresponding isothio-
cyanate via thiocarbamic acid. The isothiocyanate thus
produced reacts with another molecule of amine (primary
or secondary) to produce the corresponding di- or trisub-
stituted thiourea derivative (Scheme 2).
It is trivial that it is not possible to synthesize isothiocya-
nates by the reaction of secondary amines with carbon disul-
fide. Therefore, through the reaction of secondary amine
with carbon disulfide followed by the treatment with either
primary or secondary amine it is not possible to synthesize
thiourea, as there is no possibility to obtain isothiocyanate
from secondary amine under the reaction condition em-
ployed.
(12) Gomez, L.; Gellibert, F.; Wagner, A.; Mioskowski, C. J. Comb.
Chem. 2000, 2, 75–79.
(13) (a) Ramadas, K.; Janarthanan, N. J. Chem. Res. Synop. 1998, 228–
229. (b) Dirksen, A.; Nieuwenhuizen, P. J.; Hoogenraad, M.; Haasnoot,
J. G.; Reedijk J. Appl. Polym. Sci. 2000, 79, 1074–1083.
(14) Konarev, D. V.; Kovalevsky, A. Y.; Khasanov, S. S.; Saito, G.;
Lopatin, D. V.; Umrikhin, A. V.; Otsuka, A.; Lyubovskaya, R. N. Eur. J.
Inorg. Chem. 2006, 1881–1895.
(15) Although the present methodology produces the corresponding
trisubstituted thioureas as major products, trace amounts of symmetrical
thioureas were also isolated and are indicated in Tables 1 and 2.
(9) (a) Dittmer, D. C. Chem. Ind. 1997, 779–784. (b) Varma, R. S. Green
Chem. 1999, 1, 43–55. (c) Loupy, A.; Petit, A.; Hamelin, J.; Texier-Boullet,
F.; Jacqualt, P.; Mathe, D. Synthesis 1998, 1213–1234. (d) Deshayes, S.;
Marion, L.; Loupy, A.; Luche, J. L.; Petit, A. Tetrahedron 1999, 55, 10851–
10870. (e) Kidwai, M. Pure Appl. Chem. 2001, 73, 147–151.
(10) Maddani, M.; Prabhu, K. R. Tetrahedron Lett. 2007, 48, 7151–7154.
(11) Moore, F. W.; Larson, M. L. Inorg. Chem. 1967, 6, 998–1003.
2328 J. Org. Chem. Vol. 75, No. 7, 2010

Maddani and Prabhu
JOCArticle
TABLE 1. Synthesis of Tri-substituted Thiourea from Preformed
Dialkylxanthate in a One-Pot Reaction
TABLE 2. Synthesis of Symmetrical Di-substituted Thiourea Deriva-
tives
aHeated at 100 °C. bIsolated pure yields based on starting materials.
Table 2, n-hexylamine (a), 2-phenyl ethylamine (b), and 1-
phenyl ethylamine (c) furnished the corresponding symme-
trical disubstituted thiourea derivatives 4a (90%), 4b (88%),
and 4c (90%) under the reaction conditions employed in a
short period of time (entries 1-3, Table 2). 2-Furfuryl amine
(d) also afforded the corresponding symmetrical disubstitut-
ed thiourea 4d in moderate yield (65%, entry 4, Table 2) in
water at reflux conditions. Benzyl amine (e) and p-methoxy-
benzyl amine (f) produced the corresponding symmetrical
thiourea derivatives 4e (62%) and 4f (52%) in moderate
yields (entries 5 and 6, Table 2). trans-Cyclohexyl diamine (g)
produced the cyclic thiourea (4g) in moderate yield under the
reaction conditions employed (51%, entry 7, Table 2).
Our attempt to synthesize mixed disubstituted thiourea by
using the present strategy has resulted in the formation of
mixture of all possible thiourea derivatives. As seen from
Scheme 3, the xanthate of n-hexylamine (a) generated in situ
was reacted with 2-phenylethyl amine (b) at reflux tempera-
ture. As expected, mixed thiourea 5 obtained in only 32%
yield along with corresponding symmetrical disubstituted
thiourea derivatives 4a (20%) and 4b (12%) as shown in
scheme 3.
Quite interestingly, the reaction of sodium xanthate of 1
(which was generated by the reaction of 1 with CS2 and
NaOH in water) with propargyl amine at reflux condition
produced the cyclic thiozolidine9 derivative 6 in moderate
yield (45%, Scheme 4).
Tentative Reaction Mechanism. The formation of thiourea
by the present method could be explained by the involvement
of dithiol derivative as presented in Scheme 5. It is important
to note that the formation of isothiocyanate is not possible as
shown in scheme 5. We believe that the present method
aHeated at 100 °C. bIsolated pure yields based on starting materials.
cYields in paranthesis are corresponding symmetrical disubstituted
thiourea.
similar reaction with 1 to produce the corresponding thiou-
reas 1b and 1c, respectively, in good yields (entries 2 and 3,
Table 1). 2-Fufuryl amine (d) under the similar reaction with
1 produced the corresponding thiourea 1d in moderate yield
(40%, entry 4, Table 1).
Similarly, the sodium xanthate of piperidine reacted well
with n-hexylamine (a), 2-phenyl ethylamine (b), 1-phenyl
ethylamine (c), and 2-furfuryl amine (d) to furnish the
corresponding trisubstituted thioureas 2a, 2b, 2c, and 2d,
respectively, in good to excellent yields (entries 5-8, Table 1).
As expected, sodium xanthate of morpholine prepared in situ
reacted with n-hexylamine (a), 2-phenylethyl amine (b), 1-
phenylethyl amine (c), and 2-furfuryl amine (d) to produce
the corresponding substituted thiourea derivatives 3a, 3b, 3c,
and 3d under the similar reaction conditions in water (entries
9-12, Table 1).
Interestingly, several disubstituted thioureas are prepared
by the reaction of dialkyldithiocarbamate (in situ generated
by the reaction of primary alkyl amine, CS2, and NaOH)
with another molecule of primary amine. As seen from
J. Org. Chem. Vol. 75, No. 7, 2010 2329

Maddani and Prabhu
SCHEME 6. Proposed Reaction Mechanism
JOCArticle
SCHEME 3. Synthesis of Mixed Di-substituted Thiourea
SCHEME 7. Synthesis of Imidazole Derivatives
SCHEME 4. Synthesis of Cyclic Thiazolidine Derivatives
SCHEME 5. Possibility of Amino Dithiol (7) as an Intermediate
that by installing a poor leaving group in the intermediate 9,
for example, a primary amine group instead of dialkylamine,
it may be possible to obtain either a substituted heterocyclic
compound or the desired thiourea derivative. If this mechan-
ism is operating, the reaction of primary aliphatic amine,
CS2, NaOH, and propargyl amine should not produce the
thiozolidine derivative 6. Therefore, we have decided to use
an aliphatic primary amine in place of the dialkyl amine to
prepare the corresponding xanthate. Accordingly, n-hexyl-
amine (a) was converted into the corresponding xanthate by
using carbon disulfide. As anticipated, the reaction of this
xanthate with propargyl amine at reflux conditions in water
did not produce 6 but resulted in the formation of imidazole
derivative 10 as the major product in low yield (35%) along
with formation of symmetrical dihexyl thiourea (4a) in minor
amounts (24%, Scheme 7). This reaction clearly supports the
mechanism presented in Scheme 6.
Further, webelievethe presentmethod(Scheme5) proceeds
through amino dithiol derivative 7 as an intermediate. This
intermediate 7, by the expulsion of hydrogen sulfide gas,
produces the corresponding substituted thiourea as shown
in Scheme 5. The formation of the imidazole derivative
(Scheme 7) very clearly supports the mechanism presented
in Scheme 5. Therefore the formation of various imidazole
derivatives in the above reaction conditions may be explained
by the tentative reaction mechanism shown in Scheme 8.
proceeds through amino dithiol derivative 7 as an intermedi-
ate. This intermediate 7, by the expulsion of hydrogen sulfide
gas, produces the corresponding substituted thiourea. The
formation of hydrogen sulfide gas is confirmed by passing
the gas generated during the reaction of sodium xanthate
with hexylamine through the aqueous solutions of zinc
chloride and cadmium acetate.13b,16,17
On the basis of the above results of formation of trisub-
stituted thiourea from the corresponding dialkyl xanthate as
well as the formation of thiazolidine derivative (6, Scheme 4),
we have proposed a plausible reaction mechanism for the
formation of thiazolidine derivative as shown in scheme 6.
As seen from the scheme 6, the nucleophilic thio-anion
(intermediate 8) attacks the electrophilic alkyne to furnish
the corresponding five-membered intermediate 9. Later on,
elimination of diethyl amine results in the formation of
thiazolidine compound 6. In this reaction, it was envisaged
Conclusion
(16) The generation of H2S gas during the reaction was confirmed by
passing the gas generated during the reaction of the sodium salt of diethyl
xanthate and hexylamine in water through aqueous solutions of zinc chloride
and cadmium acetate, which has resulted in the formation of white and
yellow precipitates, respectively, indicating the formation of the correspond-
ing sulfides. Additionally, the H2S gas evolved during the reaction is
identified by its characteristic odor and by exposure of filter paper moistened
with lead acetate solution.
We have developed an effective and convenient method
for the synthesis of di and tri substituted thiourea derivatives
under aqueous reaction conditions in very good yields.
Present method describes the involvement of amino dithiol
moiety as an intermediate. Though this methodology is not
successful with secondary amines and aryl amines to syn-
thesize the corresponding thiourea derivatives, it works
(17) In Vogel’s Qualitative Inorganic Analysis, 7th ed.; Svehla, G., Ed.;
Longman Publishers: Singapore, 1996.
2330 J. Org. Chem. Vol. 75, No. 7, 2010

Maddani and Prabhu
JOCArticle
SCHEME 8. Proposed Mechanism for the Formation of
Imidazole Derivative
1,1-Diethyl-3-(furan-2-ylmethyl)thiourea (1d). Prepared as des-
cribed in general procedure. Rf (20% EtOAc/hexane) 0.25; yellow
liquid; yield 40%; IR (neat, cm-1) 1531, 3309; 1H NMR (CDCl3,
400 MHz) δ 1.23 (t, 3H, J = 7.2 Hz), 3.69 (q, 4H, J = 7.2 Hz), 4.87
(d, 6H, J = 4.8 Hz), 5.60 (br, 1H), 6.29-6.30 (m, 1H), 6.30-6.35
(m, 1H), 7.37-7.38 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 12.6,
42.9, 45.2, 107.8, 110.4, 142.2, 151.2, 180.1; HRESI-MS (m/z) calcd
for C10H16N2OS (M þ H) 213.1061, found (M þ H) 213.1063.
N-Hexylpiperidine-1-carbothioamide (2a). Prepared as des-
cribed in general procedure. Rf (10% EtOAc/hexane) 0.15; brown
1
viscous liquid; yield 84%; IR (neat, cm-1) 1537, 3294; H NMR
(CDCl3, 300 MHz) δ 0.89 (t, 3H, J = 5.8 Hz), 1.24-1.35 (m, 6H),
1.55-1.65 (m, 8H), 3.60-3.66 (m, 2H), 3.78-3.80 (m, 4H), 5.74
(br, 1H); 13C NMR (CDCl3, 75 MHz) δ 13.7, 22.3, 24.0, 25.2, 26.3,
29.1, 31.2, 46.0, 48.5, 180.6; HRESI-MS (m/z) calcd for C12H24N2S
(M þ Na) 251.1558, found (M þ Na) 251.1558.
N-(2-Phenylethyl)piperidine-1-carbothioamide (2b).19 Prepared
as described in general procedure. Rf (20% EtOAc/hexane) 0.25;
colorless solid; yield 82%; mp 90-94 °C; IR (neat, cm-1) 1533,
3303; 1H NMR (CDCl3, 400 MHz) δ 1.53-1.69 (m, 6H), 2.95 (t,
2H, J = 7.0 Hz), 3.68 (t, 4H, J = 5.4 Hz), 3.90-3.96 (m, 2H), 5.48
(br, 1H), 7.20-7.34 (m, 5H); 13C NMR (CDCl3, 100 MHz) δ 24.2,
25.3, 35.2, 46.8, 48.6, 126.5, 128.6, 128.8, 138.9, 180.9; HRESI-MS
(m/z) calcd for C14H20N2S (M þ Na) 271.1245, found (M þ Na)
271.1241.
smoothly with aliphatic primary amines to afford various
di and tri substituted thiourea derivatives. Unlike earlier,
present method is not successful in synthesizing amino acid
derivativatized thioureas, indicating that molybdenum xan-
thate is a useful reagent in synthesizing such class of chiral
thiourea derivatives. The present method also allows the
synthesis of substituted 2-marcaptoimidazole compounds in
moderate yields.
N-(2-Phenylethyl)morpholine-4-carbothioamide (3b). Prepared as
described in general procedure. Rf (20% EtOAc/hexane) 0.10;
colorless solid; yield 75%; mp 75-78 °C; IR (KBr, cm-1) 1534,
1
3315; H NMR (CDCl3, 400 MHz) δ 2.95 (t, 2H, J = 6.8 Hz),
3.62-3.70 (m, 8H), 3.86-3.94 (m, 2H), 5.92 (br, 1H), 7.16-7.32
(m, 5H); 13C NMR (CDCl3, 100 MHz) δ 34.8, 46.7, 47.1, 65.8,
126.3, 128.4, 128.5, 138.6, 182.0; HRESI-MS (m/z) calcd for
C13H18N2OS (M þ Na) 273.1038, found (M þ Na) 273.1039.
N-(Furan-2-ylmethyl)morpholine-4-carbothioamide (3d). Pre-
pared as described in general procedure. Rf (20% EtOAc/
hexane) 0.10; brown solid; yield 68%; mp 86-89 °C; IR (neat,
cm-1) 1538, 3271; 1H NMR (CDCl3, 400 MHz) δ 3.70-3.80 (m,
8H), 4.87 (d, 2H, J = 3.2 Hz), 5.83 (br, 1H), 6.30-6.36 (m, 2H),
7.37 (s, 1H); 13C NMR (CDCl3, 100 MHz) δ 42.9, 47.4, 66.0,
108.3, 110.5, 142.3, 150.6, 182.3; HRESI-MS (m/z) calcd for
C10H14N2O2S (M þ Na) 249.0674, found (M þ Na) 249.0675.
1,3-Dihexylthiourea (4a).20 Prepared as described in general
procedure. Rf (20% EtOAc/hexane) 0.30; colorless solid; yield 90%;
mp 35-39 °C; IR (neat, cm-1) 1555, 3260; 1H NMR (CDCl3, 300
MHz) δ 0.89 (t, 6H, J = 6.6 Hz), 1.25-1.40 (m, 12H), 1.55-1.64
(m, 4H), 3.42(br, 4H), 6.25(br, 2H);13CNMR(CDCl3, 75MHz) δ
13.8, 22.3, 26.4, 28.8, 31.3, 44.3, 181.2; HRESI-MS (m/z) calcd for
C13H28N2S (M þ Na) 267.1871, found (M þ Na) 267.1872.
1,3-Bis(furan-2-ylmethyl)thiourea (4d).21 Prepared as des-
cribed in general procedure. Rf (25% EtOAc/hexane) 0.20; pale
brown solid; yield 65%; mp 68-73 °C; IR (neat, cm-1) 1548,
3271; 1H NMR (CDCl3, 400 MHz) δ 4.62 (d, 4H, J = 3.6 Hz),
6.24-6.26 (m, 2H), 6.30-6.32 (m, 2H), 6.58 (br, 2H), 7.32-7.34
(m, 2H); 13C NMR (CDCl3, 100 MHz) δ 41.4, 108.1, 110.5,
142.3, 150.1, 182.0; HRESI-MS (m/z) calcd for C11H12N2O2S
(M þ Na) 259.0517, found (M þ Na) 259.0515.
Experimental Section
General Experimental Procedure. To a well-stirred solution
of dialkylamine (1.4 mmol) in water was added sodium hydro-
xide (1.4 mmol) followed by carbon disulfide (1.5 mmol) at
room temperature, and stirring was continued for 1 h. To this
pale yellow colored suspension was added a primary amine
(1.0 mmol), and the mixture was heated to 100 °C until the
completion of reaction (monitored by TLC). The mixture was
cooled, acidified with dilute hydrochloric acid, and extracted
into CH2Cl2 (2 ꢀ 5 mL). The combined organic layer was dried
over sodium sulfate, and the solvent was removed completely.
The residue was purified by column chromatography on silica
gel to obtain thiourea derivative.
1,1-Diethyl-3-hexylthiourea (1a).13 Prepared as described in
general procedure. Rf (10% EtOAc/hexane) 0.20; pale brown
viscous liquid; yield 90%; IR (neat, cm-1) 1532, 3309; 1H NMR
(CDCl3, 300 MHz) δ 0.89 (t, 3H, J = 6.6 Hz), 1.23 (t, 6H, J =
7.2 Hz), 1.30-1.40 (m, 6H), 1.58 1.66 (m, 2H), 3.61-3.69 (m,
6H), 5.36 (br, 1H); 13C NMR (CDCl3, 75 MHz) δ 12.6, 13.9,
22.5, 26.6, 29.3, 31.4, 44.9, 46.1, 180.0; HRESI-MS (m/z) calcd
for C11H24N2S (M þ Na) 239.1558, found (M þ Na) 239.1559.
1,1-Diethyl-3-(2-phenylethyl)thiourea (1b).18 Prepared as de-
scribed in general procedure. Rf (20% EtOAc/hexane) 0.25;
colorless solid; yield 84%; mp 67-69 °C; IR (neat, cm-1) 1530,
3318; 1H NMR (CDCl3, 300 MHz) δ 1.09 (t, 6H, J = 7.2 Hz),
2.96 (t, 2H, J = 6.6 Hz), 3.55 (q, 4H, J = 7.2 Hz), 3.85-3.96 (m,
2H), 5.28 (br, 1H), 7.21-7.34 (m, 5H); 13C NMR (CDCl3, 75
MHz) δ 12.4, 35.1, 44.9, 46.6, 126.6, 128.7, 128.8, 138.9, 180.1;
HRESI-MS (m/z) calcd for C13H20N2S (M þ Na) 259.1245,
found (M þ Na) 259.1244.
1,3-Bis(phenylmethyl)thiourea (4e).22 Prepared as described in
general procedure. Rf (25% EtOAc/hexane) 0.20; cream solid;
(19) (a) Cho, J. K; White, P. D.; Klute, W.; Dean, T. W.; Bradley, M.
Chem. Commun. 2004, 502–503. (b) Mohanta, P. K.; Dhar, S.; Samal, S. K.;
Ila, H.; Junjappa, H. Tetrahedron 2000, 56, 629–637. (c) Tisler, M. Croat.
Chem. Acta 1957, 29, 409–411.
(20) Sambrook, M. R.; Beer, P. D.; Wisner, J. A.; Paul, R. L.; Cowley,
A. R.; Szemes, F.; Drew, M. G. B. J. Am. Chem. Soc. 2005, 127, 2292–2302.
(21) McKay, A. F.; Garmaise, D. L.; Baker, H. A.; Hawkins, L. R.; Falta,
V.; Gaudry, R.; Paris, G. Y. J. Med. Chem. 1963, 6, 587–595.
(22) Hisaki, I.; Sasaki, S.; Hirose, K.; Tobe, Y. Eur. J. Org. Chem. 2007,
607–615.
(18) Vassilev, G. N. Dokl. Bulg. Akad. Nauk. 1995, 48, 51–54.
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Maddani and Prabhu
JOCArticle
yield 62%; mp 135-139 °C; IR (neat, cm-1) 1552, 3253; 1H NMR
(CDCl3, 300 MHz) δ4.60 (s, 2H), 6.20 (br, 1H), 7.15-7.35 (m, 5H);
13C NMR (CDCl3, 75 MHz) δ 48.6, 127.5, 127.9, 128.9, 136.7,
182.0; HRESI-MS (m/z) calcd for C15H16N2S (M þ Na) 279.0932,
found (M þ Na) 279.0930.
(CDCl3, 400 MHz) δ 0.88 (t, 3H, J = 6.8 Hz), 1.20-1.35 (m, 6H),
1.45-1.52 (m, 2H), 2.92 (t, 2H, J = 6.8 Hz), 3.21 (br, 2H), 3.76 (br,
2H), 5.45-6.05 (m, 2H), 7.19-7.35 (m, 5H); 13C NMR (CDCl3,
100 MHz) δ13.9, 22.4, 26.5, 28.7, 31.3, 35.2, 43.9, 45.6, 126.7, 128.7,
128.73, 138.4, 181.4; HRESI-MS (m/z) calcd for C15H24N2S (M þ
H) 265.1738, found (M þ H) 265.1734; GC-MS calcd for
C15H24N2S: 264, found 264 (Mþ).
1-Hexyl-5-methyl-1H-imidazole-2-thiol (10). Prepared as de-
scribed in general procedure. Rf (20% EtOAc/hexane) 0.10;
cream solid; yield 35%; mp 72-75 °C; IR (neat, cm-1) 1624,
3090, 3132; 1H NMR (CDCl3, 300 MHz) δ 0.89 (t, 3H, J = 6.2
Hz), 1.26-1.45 (m, 6H), 1.68-1.77 (m, 2H), 2.17 (s, 3H), 3.97 (t,
2H, J = 7.8 Hz), 6.47 (s, 1H), 11.78 (br, 1H); 13C NMR (CDCl3,
75 MHz) δ 10.2, 13.8, 22.4, 26.3, 28.5, 31.2, 44.3, 110.9, 126.2,
159.0; HRESI-MS (m/z) calcd for C10H18N2S (M þ Na)
221.1088, found (M þ Na) 221.1089.
1,3-Bis(4-methoxyphenylmethyl)thiourea (4f).23 Prepared as
described in general procedure. Rf (25% EtOAc/hexane) 0.20;
cream solid; yield 52%; mp 145-146 °C; IR (KBr, cm-1) 1551,
3305; 1H NMR (CDCl3, 400 MHz) δ 3.79 (s, 3H), 4.52 (s, 2H),
6.10 (br, 1H), 6.83 (d, 2H, J = 8.8 Hz), 7.15 (d, 2H, J = 8.8 Hz);
13C NMR (CDCl3, 100 MHz) δ 48.1, 55.3, 114.3, 128.6, 128.9,
159.3, 181.6; HRESI-MS (m/z) calcd for C17H20N2O2S (M þ
Na) 339.1143, found (M þ Na) 339.1139.
(3aS,7aS)-Octahydro-2H-benzimidazole-2-thione (4g).24 Pre-
pared as described in general procedure. Rf (30% EtOAc/hexane)
0.20; colorless solid; yield 51%; mp 180-190 °C; IR (neat, cm-1
)
1
1513, 3223; H NMR (CDCl3, 400 MHz) δ 1.28-1.38 (m, 2H),
1.43-1.55 (m, 2H), 1.77-1.87 (m, 2H), 2.05-2.08 (m, 2H),
3.25-3.35 (m, 2H); 13C NMR (CDCl3, 100 MHz) δ 23.7, 28.9,
64.7, 187.2; calcd for C7H12N2S (M þ H) 157.0799, found (M þ H)
157.0797.
1-Hexyl-3-(2-phenylethyl)thiourea (5). Prepared as described in
general procedure. Rf (20% EtOAc/hexane) 0.25; colorless solid;
yield 32%; mp 60-62 °C; IR (neat, cm-1) 1552, 3258; 1H NMR
Acknowledgment. The authors thank Indian Institute of
Science and Ray Chemicals Pvt. Ltd. for financial support of
this investigation, Dr. A. R. Ramesha for useful discussions,
and Prof. S. Chandrasekaran and Mr. Anjan Roy for
encouragements.
Supporting Information Available: Experimental proce-
1
dures and characterization data including H and 13C NMR
(23) (a) Byrne, J. J.; Vallee, Y. Tetrahedron Lett. 1999, 40, 489–490.
(b) Carr, E. L.; Young, K. C. J. Org. Chem. 1949, 14, 935–945.
(24) Davies, S. G.; Mortlock, A. A. Tetrahedron 1993, 49, 4419–4438.
spectra for thiourea derivatives. This material is available free of
charge via the Internet at http://pubs.acs.org.
2332 J. Org. Chem. Vol. 75, No. 7, 2010