Dithiocarbamate as an efficient intermediate for the synthesis of 2-amino-1,3,4-thiadiazoles in water

Article abstract of DOI:10.1016/j.tetlet.2009.11.100

A new and facile protocol for the synthesis of 2-amino-1,3,4-thiadiazoles in water is described. Reaction of acid hydrazides with easily prepared dithiocarbamates gives the corresponding thiadiazoles in moderate to excellent yields. 2-Amino-1,3,4-oxadiazoles were not observed as side products using this procedure.

Full text of DOI:10.1016/j.tetlet.2009.11.100

Tetrahedron Letters 51 (2010) 790–792
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dithiocarbamate as an efficient intermediate for the synthesis
of 2-amino-1,3,4-thiadiazoles in water
a,
Fezzeh Aryanasab a, Azim Ziyaei Halimehjani b, , Mohammad R. Saidi
*
*
a Department of Chemistry, Sharif University of Technology, PO Box 11465-9516, Tehran, Iran
b Faculty of Chemistry, Tarbiat Moallem University, 49 Mofateh St., Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 7 June 2009
Revised 20 October 2009
Accepted 24 November 2009
Available online 27 November 2009
A new and facile protocol for the synthesis of 2-amino-1,3,4-thiadiazoles in water is described. Reaction
of acid hydrazides with easily prepared dithiocarbamates gives the corresponding thiadiazoles in moder-
ate to excellent yields. 2-Amino-1,3,4-oxadiazoles were not observed as side products using this
procedure.
Ó 2009 Elsevier Ltd. All rights reserved.
The synthesis of organic molecules via green, mild, and simple
procedures is currently receiving considerable attention. Also,
reducing or eliminating the use and generation of hazardous sub-
stances is a goal of green chemistry. In this context, water is the
preferred choice as a solvent. Reactions in aqueous media are gen-
erally environmentally safe, devoid of any carcinogenic effects, are
simple to handle, cheaper to operate, and are especially important
in industry.1
The development of efficient methods for the synthesis of 1,3,4-
thiadiazoles has attracted significant interest. Substituted 1,3,4-
thiadiazoles have become very useful compounds in medicine,
agriculture, and in many fields of technology such as dyes,2 lubri-
cating compositions,3 optically active liquid crystals,4 photo-
graphic materials5, and many others. Also, applications of 1,3,4-
thiadiazoles in agriculture as herbicides,6 fungicides7, and bacte-
riocides8 have been patented. Acetazolamide (acetazol), a carbonic
anhydrase inhibitor launched in 1954, is a well-known drug based
on the 1,3,4-thiadiazole ring.9 Also, 1,3,4-thiadiazole derivatives
have shown anti-inflammatory activity.10
A variety of synthetic methods for the preparation of 1,3,4-thi-
adiazoles have been reported. One of the most common procedures
involves the cyclization of a 1,2-diacylhydrazine or its thia analog
in the presence of a coupling agent such as SOCl2 or POCl3, and a
strong mineral acid.11 Several recent publications have reported
milder cyclization methods using (PhO)2P(O)Cl, Ph3P, TMSCl, and
Lawesson’s reagent for the synthesis of 1,3,4-thiadiazoles.12 There
are many reports on the multi-step synthesis of thiadiazoles,13
however, one-pot or one-step syntheses are rare. Varma and co-
workers reported the first one-pot, one-step, solvent-free proce-
dure for the synthesis of substituted 1,3,4-thiadiazoles using acid
hydrazides and triethylorthoalkanoates in the presence of P4S10/
Al2O3 under microwave irradiation.14 Solid-phase synthesis of 2-
amino-1,3,4-thiadiazole derivatives via selective, reagent-based
cyclization of acyldithiocarbazate resins was reported by Gong.12a
Also, Lau and co-workers reported the synthesis of 2-amino-
1,3,4-thiadiazole derivatives via reaction of a thiosemicarbazide
bound to a resin and an aldehyde, followed by cyclization of the
resulting thiosemicarbazone with a solution of iron(III) chloride
in dichloromethane/methanol.15
Werecentlyreportedseveral green, one-pot, andsimplemethods
for the synthesis of dithiocarbamates from amines, CS2, and different
nucleophile acceptors, such as alkyl halides, activated olefins, and
epoxides, under solvent-free and aqueous conditions.16 In continua-
tion of our interest in the synthesis of novel dithiocarbamates and
the use of these intermediates in organic transformations,17 we have
focused our attention on the reaction of dithiocarbamate 1 with acid
hydrazide 2 (Scheme 1). We found that compound 3 was the only
product and no cyclization product was observed. Also, on refluxing
the reaction mixture in high boiling point solvents such as benzene,
toluene, and DMF, acyclic product 3 was formed. Surprisingly, we
found that the reaction of the dithiocarbamate and acid hydrazide
in the presence of triethylamine or pyridine in water and under
reflux, afforded the substituted 2-amino-1,3,4-thiadiazole 4 in
S
H
R1
H
N
R3
solvent-free
Et3N, 60oC
N
N
H
3
S
O
O
R1
H
R2
H2N
+
N
S
N
R3
H
Et3N, H2O
reflux
N N
R1
1
2
R3
N
S
4
H
* Corresponding authors.
E-mail addresses: azimkzn@yahoo.com (A.Z. Halimehjani), saidi@sharif.edu
Scheme 1. Reaction of dithiocarbamate 1 with acid hydrazide 2 in water and under
(M.R. Saidi).
solvent-free conditions.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.100

F. Aryanasab et al. / Tetrahedron Letters 51 (2010) 790–792
791
excellent yield. When the reaction was carried out at low tempera-
ture over a short reaction time, compound 3 was detected as a side
product. No oxadiazole was observed as a by-product. After synthe-
sizing the starting dithiocarbamates and acid hydrazides, optimiza-
tion of the reaction conditions was achieved by varying the number
of equivalents of dithiocarbamate, acid hydrazide, and triethyl-
amine, the temperature and the solvent. We obtained excellent
yields when one equivalent of each of dithiocarbamate and acid
hydrazide in water was heated under reflux in the presence of
2 equiv of triethylamine.
presence of water and triethylamine. The corresponding 2-ami-
no-1,3,4-thiadiazole was obtained in high yield (Scheme 3).
Scheme 4 shows a possible pathway for the reaction between
the dithiocarbamate and acid hydrazide. It is thought that the reac-
tion occurs by an elimination–addition mechanism, involving
elimination of an alkylthiol with the formation of an isothiocya-
nate, which immediately undergoes addition to the acid hydrazide,
to give a thiosemicarbazide. This mechanism also shows why
dithiocarbamates prepared from secondary amines did not give
the expected products.
Next, the scope and limitations of this process were explored
using a wide range of acid hydrazides and dithiocarbamates. As
shown in Table 1, dithiocarbamates derived from primary aliphatic
and aromatic amines underwent the reaction in water to afford thi-
adiazoles 4 in moderate to excellent yields without using any cycli-
zation promoters. Moderate to excellent yields were obtained with
aliphatic and aromatic acid hydrazides. Optically active 1,3,4-thi-
adiazoles were synthesized by reaction of a chiral dithiocarbamate
with acid hydrazides in moderate to excellent yields (Table 1, en-
tries 21–25). The stereogenic center of these compounds remained
intact and the ees were the same as those of the starting materials
as shown by the use of a chiral shift reagent (R/S ꢀ 98:2). Also thi-
adiazoles, which are used in coordination chemistry, were synthe-
sized from ortho hydroxy acid hydrazides in good yields (Table 1,
entries 5, 8, 14, 17, and 25). Similarly, a 1,3,4-thiadiazole contain-
ing an adamantyl group was prepared in excellent yield (Table 1,
entry 26). Reactions with dithiocarbamates derived from second-
ary amines were not possible. The structures of the products were
elucidated from their IR, 1H and 13C NMR, and mass spectra. In
DMSO-d6, the 1H NMR spectra showed broad peaks for the NH of
the amine group at 10–13 ppm. In CDCl3 this peak was shifted to
6–9 ppm. The 13C NMR spectra clearly showed that the thiadiazole
was the only product, the chemical shifts of C-2 at 151–154 ppm
and C-5 at 168–172 ppm were in the ranges reported in the litera-
ture.12a Also mass spectrometry confirmed the molecular formula.
To show that the reaction occurs via intermediate 3a, we per-
formed the cyclization reaction with the freshly prepared thiosem-
icarbazide under the same reaction conditions. The 2-amino-1,3,4-
thiadiazole 4a was obtained in excellent yield (Scheme 2).
H
O2N
Et3N, H2O
S
O
S
N
N
N N
H H
N N
reflux
O2N
H
89%
4a
3a
Scheme 2. Synthesis of 2-amino-1,3,4-thiadiazole from thiosemicarbazide 3a in
water.
H
S
N
Et3N, H2O
N C S
O
H2N
N N
N
reflux
O2N
O2N
H
78%
Scheme 3. Synthesis of
hydrazide with an isothiocyanate.
a 2-amino-1,3,4-thiadiazole via reaction of an acid
O
O
S
Heat
R1
R2
S
+
R1N=C=S
+
H2N N R3
R3 N NH3+ R2S
N
H
H
H
O
+ R2SH
R3 N NH2
H
S
O
R1
H
N
N N R3
H H
To investigate the efficiency of the reaction medium, we studied
the reaction of an acid hydrazide with an isothiocyanate in the
Scheme 4. Proposed mechanism for the synthesis of thiosemicarbazides.
Table 1
Synthesis of 5-substituted-2-amino-1,3,4-thiadiazoles using dithiocarbamates and acid hydrazides in water18
S
O
N N
S
Et3N
R1
H
R1
H
R2
R3
N
N
S
H2N N R3
H2O/ reflux
H
1
2
4
Entry
r1
R2
R3
Yielda,b,c (%)
Entry
R1
R2
R3
Yield (%)a,b,c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Ph
Ph
Ph
Ph
–CH2CH2CN
–CH2CH2CN
–CH2CH2CN
–CH2CH2CN
Ph
PhCH2
9513g
96
15
16
17
18
19
20
21
22
23
24
25
26
n-Bu
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
4-Pyridine
Ph
2-HOC6H4
4-MeC6H4
4-Pyridine
PhCH2
Ph
PhCH2
4-MeC6H4
4-Pyridine
2-HOC6H4
4-MeC6H4
68
PhCH2
PhCH2
PhCH2
PhCH2
PhCH2
(R)-1-Phenylethyl
(R)-1-Phenylethyl
(R)-1-Phenylethyl
(R)-1-Phenylethyl
(R)-1-Phenylethyl
Adamantyl
8913g
84
4-MeC6H4
4-Pyridine
2-HOC6H4
4-MeC6H4
Ph
2-HOC6H4
4-Pyridine
PhCH2
9213g
7513
68
88
Ph
–CH2CH2CN
8813g
82
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
3,4-Cl2C6H3
n-Bu
n-Bu
n-Bu
n-Bu
Et
Et
Et
Et
Et
Et
Et
Et
Et
97
89
95d
90d
98d
40d
92d
95
51
7113
91
Ph
4-MeC6H4
PhCH2
81
88
63
80
2-HOC6H4
a
b
c
Isolated yield.
Reaction conditions: acid hydrazide (1 mmol), dithiocarbamate (1 mmol), Et3N (2 mmol), and H2O (4 mL).
References are given for known compounds.
Ees determined by GC and found to be the same as those of the starting materials (R/S ꢀ 98:2).
d

792
F. Aryanasab et al. / Tetrahedron Letters 51 (2010) 790–792
OH-
Labanauskas, L.; Kalcas, V.; Udrenaite, E.; Gaidelis, P.; Brukstus, A.; Dauksas,
Et3NH+
+
Et3N
+ H2O
A. Pharmazie 2001, 56, 617–619; (e) Boschelli, D. H.; Connor, D. T.; Bornemeier,
D. A.; Dyer, R. D.; Kennedy, J. A.; Kuipers, P. J.; Okonkwo, G. C.; Schrier, D. J.;
Wright, C. D. J. Med. Chem. 1993, 36, 1802–1810.
S
O
S
O
S
O
R1
H
R1
R1
H
N
N N R3
H2O
+
11. (a) Sun, X. W.; Hui, X. P.; Chu, C. H.; Zhang, Z. Y. Indian J. Chem., Sect. B 2001, 40,
15–19; (b) Xu, P. F.; Yang, Y. P.; Wu, S. Z.; Zhang, Z. Y. Indian J. Chem., Sect. B
1998, 37, 127–131; (c) Borg, S.; Estennebouhton, G.; Luthman, K.; Csoregh, I.;
Hesselink, W.; Hacksell, U. J. Org. Chem. 1995, 60, 3112–3120; (d) Mavrova, A.
T.; Wesselinova, D.; Tsenov, Y. A.; Denkova, P. Eur. J. Med. Chem. 2009, 44, 63–
69.
N N R3
OH
+
N
N N R3
N
H
H
H H
H
5
3
N NH
S
N N
S
R1
H2O
N NH
O
-H2O
R1
R1
H
OH
R3
N
N
OH
+
N
12. (a) Hwang, J. Y.; Choi, H.-S.; Lee, D.-H.; Gong, Y.-D. J. Comb. Chem. 2005, 7, 816–
819; (b) Kaleta, Z.; Makowski, B. T.; Sos, T.; Dembinski, R. Org. Lett. 2006, 8,
1625–1628; (c) Rusmussen, P. B.; Pedersen, U.; Thompson, I.; Yde, B. S.;
Lawesson, O. Bull. Soc. Chim. Fr. 1985, 62–65.
R3
S
H
R3
H
4
7
6
Scheme 5. Proposed mechanism for the synthesis of 2-amino-1,3,4-thiadiazoles in
water.
13. (a) Kilburn, J. P.; Lau, J.; Jones, R. C. F. Tetrahedron Lett. 2003, 44, 7825–7828; (b)
Shih, M.-H.; Wu, C.-L. Tetrahedron 2005, 61, 10917–10925; (c) Okuma, K.;
Nagakura, K.; Nakajima, Y.; Kubo, K.; Shioji, K. Synthesis 2004, 1929–1931; (d)
Jensen, K. A.; Pederson, C. Acta Chem. Scand. 1961, 5, 1124; (e) Huisgen, R.;
Sturm, H. J.; Seidel, M. Chem. Ber. 1961, 94, 1555; (f) Le, V.-D.; Rees, C. W.;
Sivadasan, S. J. Chem. Soc., Perkin Trans. 1 2002, 1543–1547; (g) Linganna, N.;
Lokanatha, K. M. Synth. Commun. 1998, 28, 4611–4617.
14. Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49, 879–883.
15. (a) Severinsen, R.; Kilburn, J. P.; Lau, J. F. Tetrahedron 2005, 61, 5565–5575; (b)
Werber, G.; Buccheri, F.; Gentile, M.; Librici, L. J. Heterocycl. Chem. 1977, 14,
853–855.
16. (a) Azizi, N.; Aryanasab, F.; Saidi, M. R. Org. Lett. 2006, 8, 5275–5277; (b) Azizi,
N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org. Chem. 2006, 71,
3634–3635; (c) Ziyaei, A.; Saidi, M. R. Can. J. Chem. 2006, 84, 1515–1519; (d)
Azizi, N.; Ebrahimi, F.; Akbari, E.; Aryanasab, F.; Saidi, M. R. Synlett 2007, 2797–
2800; (e) Azizi, N.; Pourhasan, B.; Aryanasab, F.; Saidi, M. R. Synlett 2007, 1239–
1242.
A plausible mechanism for the synthesis of 2-amino-1,3,4-thi-
adiazoles is shown in Scheme 5. The reaction of triethylamine with
water gave a mild basic media in which the thiosemicarbazide 3
can be converted into anion 5, and then cyclization via nucleophilic
attack of sulfur on the carbonyl group produces compound 7. Aro-
matization of 7 proceeds with elimination of water. Water may
play a dual role in this mechanism: producing the hydroxide ion
and activating the carbonyl group via hydrogen bonding.
In conclusion, we have developed an efficient method for the
synthesis of 1,3,4-thiadiazoles from readily prepared S-alkyl
dithiocarbamates and acid hydrazides. We have also shown that
substituted 2-amino-1,3,4-thiadiazoles can be synthesized by the
reaction of dithiocarbamates prepared from aliphatic and aromatic
primary amines and acid hydrazides in water in good to excellent
yields. This protocol represents a one-pot, one-step, simple, and
green procedure using mild reaction conditions, and has general
applicability. It avoids hazardous organic solvents and toxic cata-
lysts, especially in the cyclization step.
17. Ziyaei Halimehjani, A.; Pourshojaei, Y.; Saidi, M. R. Tetrahedron Lett. 2009, 50,
32–34.
18. General Procedure for the one-pot reaction of acid hydrazides and
dithiocarbamates in the presence of water: In
a round-bottomed flask
equipped with a magnetic stirrer, acid hydrazide (1 mmol), dithiocarbamate
(1 mmol), triethylamine (2 mmol), and H2O (4 mL) were added. The mixture
was heated at reflux for 18 h with vigorous stirring until conversion of the
starting material was complete (TLC, EtOAc/petroleum ether; 1:2). The reaction
mixture was cooled to room temperature and the product was collected by
filtration, and washed with H2O and hot petroleum ether to afford the pure
product. For entries 2, 13, 19, 22, 23, and 25 in Table 1, extraction with EtOAc
from aqueous media, washing with 1 N HCl, and evaporation of the solvent
gave the product in high purity. All compounds were characterized on the basis
of 1H NMR, 13C NMR, and mass spectroscopy. Table 1, entry 9: mp 232–235 °C.
1H NMR (500 MHz, DMSO-d6): d (ppm) = 7.35 (d, J = 5.8 Hz, 2H), 7.43 (dd,
J = 8.5, 2.0 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 2.1 Hz, 1H), 8.64 (d,
Acknowledgments
We are grateful to the research council of Sharif University of
Technology for financial support. We also thank the Faculty of
Chemistry of Tarbiat Moallem University for supporting this work.
J = 5.8 Hz, 2H), 14.1 (br s, 1H, -NH). 13C NMR (125 MHz, DMSO-d6):
d
(ppm) = 122.9, 130.1, 131.9, 132.3, 132.5, 133.5, 133.8, 134.9, 149.1, 151.1,
170.0. Anal. Calcd for C13H8Cl2N4S: C, 48.29; H, 2.47; N, 17.33. Found: C, 47.95;
H, 2.43; N, 17.42. Table 1, entry 11: mp 124–127 °C. 1H NMR (500 MHz,
acetone-d6): d (ppm) = 0.78 (t, J = 7.8 Hz, 3H), 1.19 (m, 2H), 1.62 (m, 2H), 4.10
(t, J = 7.8 Hz, 2H), 7.56–7.23 (m, 5H), 12.76 (br s, 1H, –NH). 13C NMR (125 MHz,
acetone-d6): d (ppm) = 12.5, 19.0, 30.9, 43.5, 128.1, 128.6, 130.0, 132.6, 151.4,
168.3. Anal. Calcd for C12H15N3S: C, 61.80; H, 6.44; N, 18.02. Found: C, 61.64; H,
6.33; N, 17.89. Table 1, entry 12: 1H NMR (500 MHz, CDCl3): d (ppm) = 0.89 (t,
J = 7.4 Hz, 3H), 1.29 (m, 2H), 1.73 (m, 2H), 2.47 (s, 3H), 4.12 (t, J = 7.8 Hz, 2H),
7.34 (d, J = 7.9 Hz, 2H), 7.49 (d, J = 7.9 Hz, 2H), 12.45 (br s, 1H). 13C NMR
(125 MHz, CDCl3): d (ppm) = 13.9, 20.1, 21.9, 30.7, 45.0, 123.5, 128.9, 130.2,
141.8, 152.6, 167.8. MS (EI): m/z = 248 (20) [M+1]+, 214 (100), 191 (58), 118
(33), 91 (28), 41 (27). Anal. Calcd for C13H17N3S: C, 63.16; H, 6.88; N, 17.00.
Found: C, 63.48; H, 6.91; N, 16.83. Table 1, entry 17: mp 178–181 °C. 1H NMR
(300 MHz, acetone-d6): d (ppm) = 5.34 (s, 2H), 6.85-7.38 (m, 9H), 9.32 (br s, 1H,
–OH), 12.86 (br s, 1H, –NH). 13C NMR (75 MHz, acetone-d6): d (ppm) = 47.8,
114.5, 116.9, 120.6, 127.5, 128.2, 128.9, 132.0, 134.6, 136.9, 151.1, 156.3, 169.6.
Anal. Calcd for C15H13N3OS: C, 63.60; H, 4.59; N, 14.84. Found: C, 63.18; H,
4.76; N, 15.15. Table 1, entry 18: mp 179–182 °C. 1H NMR (300 MHz, acetone-
d6): d (ppm) = 2.36 (s, 3H), 5.39 (s, 2H), 7.11–7.43 (m, 9H), 12.85 (br s, 1H, –
NH). 13C NMR (75 MHz, acetone-d6): d (ppm) = 21.3, 48.0, 124.5, 127.4, 128.2,
129.1, 129.3, 129.8, 137.1, 141.8, 152.9, 170.5. Anal. Calcd for C16H15N3S: C,
68.33; H, 5.34; N, 14.95. Found: C, 68.67; H, 5.42; N, 14.73. Table 1, entry 19:
mp 197–200 °C.) 1H NMR (300 MHz, acetone-d6): d (ppm) = 5.57 (s, 2H), 7.14–
7.32 (m, 5H), 7.55 (d, 2H, J = 5.8 Hz), 8.63 (d, 2H, J = 5.8 Hz), 13.14 (br s, 1H, –
NH). 13C NMR (75 MHz, acetone-d6): d (ppm) = 48.0, 123.1, 127.6, 128.5, 129.4,
134.6, 136.6, 150.6, 151.3, 171.1. Anal. Calcd for C14H12N4S: C, 62.69; H, 4.48;
N, 20.89. Found: C, 62.38; H, 4.62; N, 20.68. Table 1, entry 22: mp 118–121 °C.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.100.
References and notes
1. (a)Organic Synthesis in Water; Grieco, P. A., Ed.; Blackie Academic and
Professional: London, 1998; Li, C. J.; Chang, T. H. Organic Reactions in Aqueous
Media; Wiley: New York, 1997; (b) Li, C. J. Chem. Rev. 2005, 105, 3095–3166.
2. Zareba, S. Pharmazie 1993, 48, 782–783.
3. Gao, Y. J.; Zhang, Z. J.; Xue, Q. J. Mater. Res. Bull. 1999, 34, 1867–1874.
4. Choi, U. S.; Kim, T. W.; Jung, S. W.; Kim, C. J. Bull. Korean Chem. Soc. 1998, 19,
299–307.
5. Chen, S. L.; Ji, S. X.; Zhu, Z. H.; Yao, Z. G. Dyes Pigments 1993, 23, 275–283.
6. Jin, G. Y.; Hou, Z.; Zhao, G. F.; Cao, C. Y.; Li, Y. C. Chem. J. Chin. Univ. 1997, 18,
409–412.
7. Lu, S. M.; Chen, R. Y. Org. Prep. Proced. Int. 2000, 32, 302–306.
8. Hui, X. P.; Zhang, L. M.; Zhang, Z. Y.; Wang, Q.; Wang, F. Indian J. Chem., Sect. B
1999, 38, 1066–1069.
9. (a) Brezeanu, M.; Marinescu, D.; Badea, M.; Stanica, N.; Iles, M. A.; Supuran, C. T.
Rev. Roum. Chim. 1997, 42, 727–732; (b) Scozzafava, A.; Supuran, C. T. J. Enzyme
Inhib. 1998, 13, 103–123; (c) Supuran, C. T.; Clare, B. W. Eur. J. Med. Chem. 1999,
34, 41–50.
½ ꢁ
a 2D0 100.0 (c 1, CHCl3), 1H NMR (300 MHz, acetone-d6): d (ppm) = 1.67 (d, 3H,
J = 7.3 Hz), 3.65 (s, 2H), 6.43 (1H, m), 6.95 (dd, 2H, J = 7.5, 2.0 Hz), 7.21–7.48 (m,
8H), 12.62 (br s, 1H, –NH). 13C NMR (75 MHz, acetone-d6): d (ppm) = 14.3, 32.8,
53.6, 126.9, 127.4, 128.0, 128.9, 129.2, 129.5, 135.8, 139.7, 151.8, 169.7. Anal.
Calcd for C17H17N3S: C, 69.15; H, 5.76; N, 14.24. Found: C, 68.92; H, 5.32; N,
14.05.
10. (a) Kumar, H.; Javed, S. A.; Khan, S. A.; Amir, M. Eur. J. Med. Chem. 2008, 43,
2688–2698; (b) Mullican, M. D.; Wilson, M. W.; Connor, D. T.; Kostlan, C. R.;
Schrier, D. J.; Dyer, R. D. J. Med. Chem. 1993, 36, 1090–1099; (c) Song, Y.;
Connor, D. T.; Sercel, A. D.; Sorenson, R. J.; Doubleday, R.; Unangst, P. C.; Roth, B.
D.; Beylin, V. G.; Gilbertsen, R. B.; Chan, K.; Schrier, D. J.; Guglietta, A.;
Bornemeier, D. A.; Dyer, R. D. J. Med. Chem. 1999, 42, 1161–1169; (d)