A Simple and Convenient Method for the Synthesis of 3,5-disubstituted 1,2,4-thiadiazoles via Oxidative Dimerization of Primary Thioamides

Article abstract of DOI:10.1002/jhet.2627

A simple and efficient protocol has been developed for the preparation of 3,5-diaryl-1,2,4-thiadiazoles in high yields through the oxidative dimerization of primary thioamides in aqueous medium at room temperature.

Full text of DOI:10.1002/jhet.2627

Month 2016
A Simple and Convenient Method for the Synthesis of 3,5-disubstituted
1,2,4-thiadiazoles via Oxidative Dimerization of Primary Thioamides
D. Subhas Bose* and K. Raghavender Reddy
Organic and Biomolecular Chemistry Division, Fine Chemicals Laboratory, CSIR-Indian Institute of Chemical
Technology, Tarnaka, Hyderabad 500 007, T. S., India
*
E-mail: boseiict@gmail.com; dsb@iict.res.in
Received November 4, 2015
DOI 10.1002/jhet.2627
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
A simple and efficient protocol has been developed for the preparation of 3,5-diaryl-1,2,4-thiadiazoles in
high yields through the oxidative dimerization of primary thioamides in aqueous medium at room
temperature.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
1,2,4-thiadiazoles have generally been synthesized by intra-
molecular oxidative cyclization of amidinithioureas [14]
and 1,3-dipolar cycloaddition of nitrile sulfides to nitriles
[15]. The most common approach to the synthesis of 1,2,4-
thiadiazoles involves the oxidative dimerization of primary
thioamides by using different oxidizing reagents, such as ni-
trous acid [16], t-butyl hypochlorite [17], N-bromosuc-
cinimide [18], dimethyl sulfoxide-electrophilic reagents
[19], organohypervalent iodine reagents [20], 2,3-dichloro-
5,6-dicyano-p-benzoquinone [21], polymer-supported diaryl
selenoxide and telluroxide [22], Oxone [23]. However, some
of these methods are not quite satisfactory in view of using
large excess of reagents, long reaction times, harsh reaction
conditions, and the formation of nitriles and isothiocyanates
as byproducts [24]. Consequently, there is a need to develop
a convenient, rapid, and enironmentally friendly method for
the synthesis of these important heterocyclic compounds.
Nitrogen-containing ring systems are present in widely
bioactive natural and synthetic products. The synthesis of
the 1,2,4-thiadiazole ring has been the subject of consider-
able interest as several derivatives of this heterocyclic unit
have been found in several natural products to possess useful
bilogical activities [1]. Although, currently, the only com-
mercial 1,2,4-thiadiazole drug is the antibiotic cefozopran
[2], there are a number of derivatives related to this system
often endowed with a wide range of biological activities such
as for treatment of human leukemmia cell [3], acetylcholin-
esterase inhibitory activity [4], G-protein-coupled receptors
[5], cardiovascular system [6], central nervous system [4],
inflammation [7], or antibiotic activity [8]. In addition to
their use as pharmacophores, thiadiazoles are used as thiol
trapping agents [9] and the first non-adenosine triphosphate
(ATP) competitive glycogen synthase kinase 3β inhibitors
[10]. The development of mild and effective methods for
the synthesis of symmetrically 3,5-disubstituted 1,2,4-
thiadiazoles is thus important in organic synthesis.
RESULTS AND DISCUSSION
Thioamides are widely used as versatile building blocks in
organic synthesis and especially in the construction of
heterocyclic compounds [11]. They have been used as im-
portant synthons in the synthesis of five, and six-membered
heterocycles [12]. Among them, primary thioamides are
good intermediates for the synthesis of wide variety of
thiazole and thiadiazole derivatives [13]. Traditional
methods utilized for the synthesis of 3,5-diaryl-1,2,4-
thiadiazoles may be broadly divided into three categories,
which include intramolecular cyclization, intermolecular
cyclization of two different molecules, and oxidative dimer-
ization of thioamides. 3,5-Unsymmetrically disubstituted
In recent years, trichloroisocyanuric acid (1,3,5-trichloro-
1,3,5-triazinane-2,4,6-trione, TCCA) is used widely as an in-
dustrial disinfectant, bleaching agent, and innocuous oxidant
with high stability. TCCA has been employed in various or-
ganic transformations [25] that include oxidation of alcohols
to their corresponding carbonyl compounds, conversion of
alcohols into alkyl halides, dihalogenation of olefins, and ha-
logenation because of its ready availability, inexpensive, and
environmentally benign nature. Herein, we wish to report an
efficient and practical method by employing TCCA-water as
a new promoter system for the one-pot synthesis of 3,5-
diaryl-1,2,4-thiadiazoles from arylthioamides as shown in
© 2016 Wiley Periodicals, Inc.

D. Subhas Bose and K. Raghavender Reddy
Vol 0000
Scheme 1. The protocol affords a potential route for the ac-
cess of the target products with wide substrate scope. How-
ever, to the best of our knowledge, there is no report on the
oxidative dimerization of thioamides to 1,2,4-thiadiazoles
with TCCA as catalyst.
The development of environmentally friendly protocols
is very important in chemical research at present, with
water emerging as a useful solvent for organic chemistry
in recent years [26]. Water is an abundant, inexpensive,
and environmentally friendly solvent but also exhibits
new reactivity and selectivity, which is different from that
of conventional organic solvents [27]. Therefore, we first
investigated the optimization of the reaction conditions
using thiobenzamide as a model substrate, and the role of
various conditions on the reaction system with respect to
reagents, appropriate solvents, temperature, and the molar
ratio was carried out (Table 1).
Scheme 1
Table 1
Optimization of reagents and reaction conditions.a
Among the various organic solvents studied (EtOH,
MeOH, CH3CN, PEG-400, N,N-dimethyacetamide, and
water), water was found to be the most suitable solvent
for this reaction. We found that the optimum ratio of
thioamide/TCCA/water is about 1:0.3:5 (Table 1, entry
8). Further investigations revealed that reducing the
loading of TCCA to 0.25 equiv gave the desired product
in a lower yield of 75% (Table 1, entry 6). The use of
5.0 equiv of H2O was also found to be necessary for this
transformation to proceed smoothly; when H2O was re-
duced to 2.5 equiv, a slightly lower yield of 68% product
was obtained (Table 1, entry 5). In the similar category,
its bromo analog, namely, tribrimoisocyanuric acid, has
also been found to be an effective oxidant for this pur-
pose (Table 1, entries 1 and 2). The experiments were
run from 0 to 25°C. We found that those conducted at
room temperature (23–25°C) were obtained in high
yields, whereas at 0°C led to a reduced yield of the prod-
uct. Under the optimized reaction conditions, we exam-
ined the substrate scope for the present oxidative
dimerization using 0.3 mmol of TCCA. Various types
of primary thioamides including aromatic, heterocyclic,
and aliphatic ones could be converted into the corre-
sponding 3,5-disubstituted 1,2,4-thiadiazoles in high
Reagent
(equiv)
Time
(min)
Entry
Solventb
MeOH
MeOH
EtOH
Yield (%)c
1.
2.
3.
4.
5.
6.
7.
8.e
9.
TCCA (0.1)
TBCA (0.1)
TCCA (0.2)
TBCA (0.2)
TCCA (0.25) H2O
TCCA (0.25) EtOH
TCCA (0.3)
TCCA (0.3)
TCCA (0.3)
2
6
4
5
8
2
8
2
10
72
74
81
CH3CN
83
68
75,68d
81
H2O
PEG-400
N,N-Dimenthyl
acetamide
95,76f
84
10.
TCCA (0.3)
10
78
TCCA, 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione; TBCA,
tribrimoisocyanuric acid.
aReactions were carried out on a 5-mmol scale in water at room temper-
ature with TCCA/TBCA.
b2 mL
cIsolated yield after column chromatography.
dReaction was performed at 0°C.
eOptimum reaction conditions.
f2.5 equiv of H2O used.
Table 2
Oxidative dimerization of thioamides to symmetrically 3,5-disubstituted 1,2,4-thiadiazoles.a
Entry
1.
Thioamide (1)
Time (min)b
4
Product (2)
mp °C (lit)
Yield (%)c
92
90–91 (lit. [18] 89–90)
2.
2
137–138 (lit. [18] 139–140)
96
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Simple and Convenient Method for the Synthesis of 3,5-disubstituted 1,2,4-
Thiadiazoles via Oxidative Dimerization of Primary Thioamides
Table 2
(Continued)
Entry
3.
Thioamide (1)
Time (min)b
8
Product (2)
mp °C (lit)
Yield (%)c
95
91–92
4.
5.
6
2
129–130 (lit. [18] 135–137)
93
91
80–81
6.
7.
2
4
185–186
125–127
90
88
8.
4
97–98
90
9.
8
4
201–202 (lit. [16] 198–199)
86
89
10.
185–186
11.
12.
4
8
179–180 (lit. [28] 180–180.5)
132–134 (lit. [16] 136–137)
92
87
(Continued)
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Subhas Bose and K. Raghavender Reddy
Vol 0000
Table 2
(Continued)
Entry
13.
Thioamide (1)
Time (min)b
Product (2)
mp °C (lit)
Yield (%)c
14
—
82
mp, melting point.
aAll products were characterized by mp’s, 1H and 13C NMR, and mass spectral data.
bThe reaction times were optimized after several experiments.
cYields refer to pure isolated products.
Scheme 2
yields; the results are summarized in Table 2. The exper-
imental procedure for this conversion is straightforward
and does not require the use of toxic organic solvents
or inert atmosphere. Thiobenzamide derivatives, which
contain eletron-donating as well as electron-withdrawing
substituents on the aromatic rings, efficiently proceeded
to afford the corresponding 3,5-disubstituted 1,2,4-
thiadiazoles in high yields without formation of nitriles
and isothiocyanates as byproducts [1,24]. The results in-
dicate that no remarkable electronic effects of the sub-
stituent on the aromatic ring were observed.
Based on the literature reports, we propose that a tentative
mechanism for the condensation of two molecules of the
arylthioamides 1 to give 3,5-disubstituted 1,2,4-thiadiazoles
2 via nucleophilic attack by sulfur of another molecule of
thioamide gives the intermediate (A), which on further oxi-
dation obtained the product (Scheme 2).
the oxidative dimerization of thiobenzamides using TCCA-
water as readily available, inexpensive, short reaction times,
safe, and environmentally benign oxidant under esentially
mild conditions and this protocol should be of further interest
in synthetic organic chemistry.
EXPERIMENTAL
Reagents and chemicals were obtained from commercial
suppliers and used without further purification. Melting
points were determined in open capillaries with a precision
digital melting point Veego VMP-DS apparatus and are un-
corrected. IR spectra were recorded on a thermo Nicolet
1
Nexus 670 FT-IR spectrophotometer. H and 13C NMR
spectra were recorded on either a Bruker Avance 300
1
(Bruker, Germany; 300.132MHz for H, 75.473 for 13C)
or Varian FT-200MHz (Gemini) spectrometer in CDCl3.
The chemicals shifts (δ) and coupling constants (J) quoted
in hertz are reported in parts per million relative to
tetramethylsilane (δ=0.00ppm) (for 1H) as an internal stan-
dard. The resonances of residual proton and those of carbons
in deuterated solvents CDCl3 (δH =7.26ppm, δc = 77.0 ppm)
CONCLUSIONS
In conclusion, a facile and efficient method is described
for the synthesis of 3,5-disubstituted 1,2,4-thiadiazoles by
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Simple and Convenient Method for the Synthesis of 3,5-disubstituted 1,2,4-
Thiadiazoles via Oxidative Dimerization of Primary Thioamides
and DMSO-d6 (δH =2.50ppm, δc =39.52ppm) were used as
internal standards. Elemental analyses were performed on an
Elementar Vario EL microanalyzer. Low-resolution mass
spectra (ESI-MS) and HRMS were recorded on Quattro
LC, Micromass, and Q STAR XL, Applied Biosystems, re-
spectively. Column chromatography was performed using
silica gel (Acme’s 60–120mesh). Solvents for chromatogra-
phy (n-hexane, acetonitrile, cyclohexane, and EtOAc) were
distilled prior to use. For analytical thin-layer chromatogra-
phy, Merck pre-coated silica gel 60F-254 plates were used;
the plates were visualized using UV light (254nm) or iodine
vapor or by dipping the plates in phosphomolybdic acid ceric
(IV)sulfate-sulphuric acid (PMA) solution and heating the
plates at 100°C.
1465, 1406, 1321, 1110, 839, 709 cmÀ1 1H NMR
;
(300 MHz, CDCl3): δ 8.32 (d, J = 8.6 Hz, 2H), 7.98 (d,
J = 8.6 Hz, 2H), 7.61–7.46 (m, 4H), 1.39 (S, 18H); 13C
NMR (75 MHz, DMSO-d6): δ 165.4, 152.2, 150.3,
140.75, 120.4, 111.0, 107.3, 56.5, 56.4, 53.0. HRMS:
Calcd. for C22H26N2S = 351.1889 [M + H]+. Found:
351.1886.
3,5-Bis(4-methylphenyl)-1,2,4-thiadiazole (2d).
White
solid, mp 129–130°C (lit.18 135–137°C); IR (KBr) νmax
3040, 2957, 2863, 1605, 1475, 1406, 1321, 1110, 839,
709cmÀ1 1H NMR (300MHz, CDCl3): δ 8.29 (d,
:
;
J=8.2Hz, 2H), 7.94 (d, J=8.2Hz, 2H), 7.35–7.24 (m,
4H), 2.43 (s, 3H); 13C NMR (CDCl3): δ 187.9, 173.7,
142.4, 140.4, 130.3, 129.8, 129.3, 128.2, 127.4, 21.6, 21.5.
HRMS: Calcd for C16H14N2S=267.0950. Found: 267.0946.
General procedure for the synthesis of 3,5-disubstituted
1,2,4-thiadiazoles [29]. To a stirred solution of arylthioamide
(5.0 mmol) in water (0.5mL) at room temperature was
added TCCA (3.88 g, 1.67mmol) in one portion. The color
of the reaction solution changed to yellow at the beginning
of the reaction and it was disappeared after few seconds.
The reaction mixture was stirred magnetically at room
temperature for the specified time (Table 1) until
arylthioamide was completely disappeared (the progress of
the reaction was monitored by thin-layer chromatography).
After completion of the reaction, the reaction mixture was
extracted with ethyl acetate (3 ×5mL) followed by brine
(5mL). The organic layer was dried over anhy.Na2SO4 and
concentrated under reduced pressure to give crude product,
which was purified by silica gel column chromatography
using petroleum ether and ethyl acetate (95:5) to afford
analytically pure substituted thiadiazoles in 82–96% yield.
3,5-Bis(3-chlorolphenyl)-1,2,4-thiadiazole (2g).
White
solid, mp 125–127°C; IR (KBr) νmax: 3046, 2950, 2863,
1605, 1470, 1406, 1321, 1110, 839, 709 cmÀ1; H NMR
1
(300 MHz, CDCl3): δ 8.41 (d, J = 1.8 Hz, 1H), 8.28 (dd,
J = 7.0 Hz, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.92 (d,
J = 7.5 Hz, 1H), 7.57–7.43 (m, 4H); 13C NMR (CDCl3): δ
186.9, 172.5, 135.4, 134.7, 134.2, 131.9, 130.6, 130.5,
130.0, 128.5, 127.3, 126.4, 125.6; ESI MS: m/z 307 [M
+ H]+. Anal. Calcd. for C14H8Cl2N2S: C, 54.74; H, 2.61;
N, 9.12; S, 10.45. Found: C, 54.68; H, 4.22.61; N, 9.10;
S, 10.43.
3,5-Bis(4-nitrophenyl)-1,2,4-thiadiazole (2i). Pale yellow
solid, mp 201–202°C (lit.16 198–199°C); IR (KBr) νmax
:
3075, 2950, 2863, 1605, 1535, 1470, 1406, 1321, 839,
709 cmÀ1 1H NMR (300MHz, CDCl3): δ 8.60 (d,
;
J = 8.2 Hz, 1H), 8.45–8.33 (m, 4H), 8.25 (d, J =8.2 Hz,
1H), 7.88 (d, J = 8.2 Hz, 2H); 13C NMR (CDCl3): δ
191.5, 169.5, 157.1, 154.8, 152.9, 148.7, 147.9, 144.2,
143.7, 143.5, 137.8, 136.2; ESI MS: m/z 328 [M +H]+.
Anal. Calcd. for C14H8N4O4S: C, 51.22; H, 2.46; N,
17.07; S, 9.77. Found: C, 51.25; H, 2.42; N, 17.02; S, 9.81.
3,5-Bis(5-bromofuran-2-yl)-1,2,4-thiadiazole (2j). White
solid, mp 185–186°C; IR (KBr) νmax: 3060, 2965, 2863,
3,5-Diphenyl-1,2,4-thiadiazole (2a).
White solid, mp
90–91°C (lit.18 89–90°C); IR (KBr) νmax: 3045, 1590,
1475 cmÀ1 1H NMR (300 MHz, CDCl3): δ 8.45–8.38
;
(m, 2H), 8.12–8.04 (m, 2H), 7.60–7.48 (m, 6H); 13C
NMR (75 MHz, CDCl3): δ 188.0, 173.7, 132.8, 131.9,
130.6, 130.3, 129.2, 128.6, 128.3, 127.4; ESI MS: m/z
239 [M + H]+. Anal. Calcd. for C14H10N2S: C, 70.56; H,
4.23; N, 11.76; S, 13.46. Found: C, 70.59; H, 4.24; N,
11.74; S, 13.44.
1605, 1535, 1470, 1406, 1321, 839, 709 cmÀ1; H NMR
1
(300 MHz, CDCl3): δ 7.22 (d, J = 3.6 Hz, 1H), 7.16 (d,
J = 3.5 Hz, 1H), 6.57 (d, J = 3.6 Hz, 1H), 6.50 (d,
J = 3.5 Hz, 1H); 13C NMR (CDCl3): δ 175.9, 149.7,
126.9, 125.2, 115.1, 114.9, 114.8, 113.8; ESI MS: m/z
376 [M + H]+. Anal. Calcd. for C10H4Br2N2O2S: C,
31.94; H, 1.06; N, 7.45; S, 8.53. Found: C, 31.89; H,
1.02; N, 7.38; S, 8.48.
3,5-Bis(4-methoxyphenyl)-1,2,4-thiadiazole (2b). White
solid, mp 137–138°C (lit.18 139–140°C); IR (KBr) νmax
:
2923, 2851, 1607, 1579, 1519, 1475, 1419, 1307, 1275,
1
1250, 1168, 1027 cmÀ1. H NMR (300 MHz, CDCl3): δ
8.33 (d, J = 8.6 Hz, 2H), 7.98 (d, J = 8.6 Hz, 2H), 7.02
(d, J = 8.5 Hz, 4H), 3.89 (S, 6H); 13C NMR (75 MHz,
CDCl3): δ 187.3, 173.3, 162.4, 161.2, 129.8, 129.1,
126.0, 123.6, 114.5, 113.9, 55.5, 55.3. HRMS: Calcd.
3,5-Cyclohexylmethyl-1,2,4-thiadiazole (2m).
liquid; 1H NMR (300 MHz, CDCl3):
Colorless
δ 2.96 (d,
for
C16H14O2N2S = 299.0849
[M + H]+.
Found:
J = 6.5 Hz, 1H), 2.84 (d, J = 7.2 Hz, 1H), 1.74 (dt,
J = 18.3, 8.5 Hz, 10H), 1.37–0.93 (m, 12H), 1.39 (S,
18H); 13CNMR (75 MHz, CDCl3): δ 190.0, 176.4, 40.5,
38.7, 38.6, 37.4, 33.0, 32.9, 30.1, 29.6, 26.0, 25.9.
HRMS: Calcd. for C16H26N2S = 279.1889 [M + H]+.
Found: 279.1882.
299.0845. Anal. Calcd. for C16H14O2N2S: C, 63.98; H,
5.37; N, 9.33; S, 10.67. Found: C, 63.93; H, 5.36; N,
9.31; S, 10.69.
3,5-Bis(4-(t-butyl)phenyl)-1,2,4-thiadiazole (2c). White
solid, mp 91–92°C; IR (KBr) νmax: 2957, 2863, 1605,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. Subhas Bose and K. Raghavender Reddy
Vol 0000
[11] Jagodzinski, T. S. Chem Rev 2003, 103, 197.
Acknowledgment. This work was supported by Council of
Scientific and Industrial Research, New Delhi, Republic of,
India under XII Five Year Plan CSC0108-ORIGIN. One of
the authors (K.R.R.) thanks Council of Scientific and
Industrial Research, New Delhi, Republic of India, for
financial support of this work.
[12] Orazio, A. A.; De Crescentini, L.; Foresti, E.; Galarini, R.;
Santeusanio, S.; Serra-Zanetti, F. Synthesis 1995 1397.
[13] Katritzky, A. R.; Fan, W.-Q. J Heterocycl Chem 1993, 30,
1679.
[14] Castro, A.; Castano, A.; Encinas, A.; Porcal, W.; Gil, C.
Bioorg Med Chem 2006, 14, 1644.
[15] Kihara, Y.; Kabashima, S.; Uno, K.; Okawara, T.; Yamasaki,
T.; Furukawa, M. Synthesis 1990 1020.
[16] Cronyn, M. W.; Nakagawa, T. W. J Am Chem Soc 1952,
74, 3693.
REFERENCES AND NOTES
[17] El-Wassimy, M. T. M.; Jorgensen, K. A.; Lawesson, S. O. Tet-
rahedron 1983, 39, 1729.
[18] Xu, Y.; Chen, J.; Gao, W.; Jin, H.; Ding, J.; Wu, H. J Chem
Res 2010 151.
[19] (a) Takikawa, Y.; Shimada, K.; Sato, K.; Sato, S. Bull Chem
Soc Jpn 1985, 58, 995; (b) Khosropour, A. R.; Noei, J. H. J Heterocyclic
Chem 2011, 48, 226.
[20] (a) Thorat, P. B.; Bhong, B. Y.; Karade, N. N. Synlett 2013,
24, 2061; (b) Patil, P. C.; Bhalerao, D. S.; Dangate, P. S.; Akamanchi,
K. G. Tetrahedron Lett 2009, 50, 5820.
[21] Cheng, D.; Luo, R.; Zheng, W.; Yan, J. Synth Commun 2012,
42, 2007.
[22] Hu, N. X.; Aso, Y.; Otsubo, T.; Ogura, F. Bull Chem Soc Jpn
1988, 61, 2117.
[23] Yoshimura, A.; Todora, A. D.; Kastern, B. J.; Koski, S. R.;
Zhdankin, V. V. Eur J Org Chem 2014 5149.
[24] Bahadir, M.; Nitz, S.; Parlar, H.; Korte, F. Z. Naturforsch.
1979, 34, 768.
[25] Tilstam, U.; Weinmann, H. Org Process Res Dev 2002, 6, 384.
[26] Breslow, R. Acc Chem Res 1991, 24, 159.
[27] Grieco, P. A. Organic Synthesis in Water; Blackie Academic
and professional: London, 1998.
[28] Boeini, H. Z. J Iran Chem Soc 2009, 6, 547.
[29] It is note worthy to mention here that during the preparation of
primary thioamide from the corresponding primary amide by using
Lawesson’s reagent, toluene reflux, we have observed that there is no for-
mation of 3,5-disubstituted 1,2,4-thiadiazoles.
[1] (a) Li, Y.; Geng, J.; Liu, Y.; Yu, S.; Zhao, G. ChemMedChem
2013, 8, 27; (b)Wilkins, D. Comprehensive Heterocyclic Chemistry III;
Katritzky, A. R.; Ramsden, C. A.; Scriven, E. F. V.; Taylor, R. J. K.;
Zhdankin, V. V., Eds.; Elsevier, Oxford, U.K., 2008; Vol. 5, pp 487.
[2] Izawa, Y.; Okonogi, K.; Hayashi, R.; Iwahi, T.; Yamazaki, T.;
Imada, A. Antimicrob Agents Chemother 1993, 37, 100.
[3] Romagnoli, R.; Baraldi, P. G.; Carrion, M. D.; Cruzlopez, O.;
Preti, D.; Tabrizi, M. A.; Fruttarolo, F.; Heilmann, F.; Bermejo, J.;
Estevez, F. Bioorg Med Chem Lett 2007, 17, 2844.
[4] Martinez, A.; Fernandez, E.; Castro, A.; Conde, S.; Rodriguez-
Franco, I.; Banos, J. E.; Badia, A. E. Eur J Med Chem 2000, 35, 913.
[5] Lanzafame, A.; Christopoulos, A. J Pharmacol Exp Ther 2004,
308, 830.
[6] Shen, L.; Zhang, Y.; Wang, A.; Sieber-McMaster, E.; Chen,
X.; Pelton, P.; Xu, J. Z.; Yang, M.; Zhu, P.; Zhou, L.; Reuman, M.; Hu,
Z.; Russell, R.; Gibbs, A. C.; Ross, H.; Demarest, K.; Murray, W. V.;
Kuo, G.-H. J Med Chem 2007, 50, 3954.
[7] Song, Y. T.; 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.
[8] Ishikawa, T.; Lizawa, Y.; Okonogi, K.; Miyake, A. J Antibiotic
2000, 53, 1053.
[9] Tam, T. F.; Leung-Toung, K.; Li, W.; Spino, M.; Karimian, K.
Mini Rev Med Chem 2005, 5, 367.
[10] Martinez, A.; Alonso, M.; Castro, A.; Perez, C.; Moreno, F. J.
J Med Chem 2002, 45, 1292.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet