18-Crown-6 Catalyzed Microwave-mediated Synthesis of Symmetric Bis-Heterocyclic Compounds under Solvent-free Condition

Article abstract of DOI:10.1002/jhet.2162

An efficient, solvent-free and 18-crown-6 catalyzed method for the synthesis of N-alkyl-4-(4-(5-(2-(alkyl-amino)thiazol-4-yl)pyridin-3-yl)phenyl)thiazol-2-amine, N-alkyl-4-(5-(2-alkyamino)thiazol-4-yl)pyridine-3-yl)thiazol-2-amine, and 4,4′-bis-{2-[amino]-4-thiazolyl}biphenyl bis-heterocyclic derivatives via microwave accelerated cyclization is presented.

Full text of DOI:10.1002/jhet.2162

Month 2014
18-Crown-6 Catalyzed Microwave-mediated Synthesis of Symmetric
Bis-Heterocyclic Compounds under Solvent-free Condition
a
b
c
a
Rathnasamy Rishikesan, Kamalakannan Prabakaran, Rajamani Murugesan, * Ramaswamy Venkataraman,
d
e
f
Pakkath Karuvalam Ranjith, Sivasubramanian Arvind, and Sathiah Thennarasu *
a
Department of Chemistry, PG and Research Centre, Sri Paramakalyani College, Alwarkurichi, Tirunelveli, 627412, Tamil
Nadu, India
b
Organic Chemistry Division, School of Advanced Sciences, VIT University, Vellore, 632014, Tamil Nadu, India
c
Department of Chemistry, T.D.M.N.S. College T. Kallikulam, Tirunelveli, 627113, Tamil Nadu, India
d
School of Chemical Sciences, Kannur University, Kannur, 670567, Kerala, India
e
Department of Chemistry, School of Chemical and Biotechnology, SASTRA University, Thanjavur, 613401, Tamil
Nadu, India
f
Organic Chemistry Laboratory, CSIR-Central Leather Research Institute, Chennai, 600020, Tamil Nadu, India
*
E-mail: rmuru2006@yahoo.co.in; thennarasu@gmail.com
Received October 4, 2013
DOI 10.1002/jhet.2162
Published online 00 Month 2014 in Wiley Online Library (wileyonlinelibrary.com).
An efficient, solvent-free and 18-crown-6 catalyzed method for the synthesis of N-alkyl-4-(4-(5-(2-(alkyl-
amino)thiazol-4-yl)pyridin-3-yl)phenyl)thiazol-2-amine, N-alkyl-4-(5-(2-alkyamino)thiazol-4-yl)pyridine-3-yl)
thiazol-2-amine, and 4,4′-bis-{2-[amino]-4-thiazolyl}biphenyl bis-heterocyclic derivatives via microwave
accelerated cyclization is presented.
J. Heterocyclic Chem., 00, 00 (2014).
INTRODUCTION
ketones with mono substituted thioureas [22], or by modified
Hantzsch’s methodologies via the reaction of in situ generated
α-λ -iodanyl ketones with thioureas [23,24]. Aminothiazoles
Thiazole derivatives are prominent heterocyclic
compounds in medicinal chemistry as well as in pharma-
ceutical research [1,2]. Typically, 2-aminothiazole
heterocyclic compounds have shown a wide variety of
pharmacological properties such as antibacterial [3],
anti-inflammatory [4], antitumor [5], antimicrobial [6],
antithrombotic activities [7], and have been used to treat
conditions like HIV infections [8] and schizophrenia [9].
The structure activity studies on 2-aminothiazoles have
proved their remarkable potential in counteracting tau-
induced cytotoxicity in a human neuronal cell line model
3
are also prepared by the reaction of α-thiocyanato carbonyl
compounds with aromatic or aliphatic amine hydrochlo-
rides [25]. The Kodomari’s group has reported the
synthesis of 2-aminothiazoles from α-bromo ketones
using the supported reagents KSCN/SiO –RNH OAc/
2
3
Al O [26]. Recently, Meshram et al. have reported
2
3
the synthesis of 2-aminothiazoles by the reaction of α-
haloketone carbonyls with ammonium thiocyanate in the
presence of N-methylimidazole [27]. Despite these
procedures, novel and widely applicable green methodol-
ogies for the synthesis of 2-aminothiazole derivatives are
still in demand.
Bis-heterocyclic compounds offer enhanced pharmaco-
logical utility especially when two pharmacologically
active heterocyclic moieties are present in the same
molecule. In this report, we describe solvent-free routes
for the synthesis of bis-heterocyclic compounds containing
2-aminothiazole moiety. One of the key intermediates 3,
5-diacetyl pyridine was prepared using Stille coupling
method. 3-acetyl-5-(4-acetylphenyl)pyridine was prepared
using Mayura-Suzuki coupling. Consequently, three
diacetyl derivatives were converted into the corresponding
[
10]. 2-aminothiazole derivatives have also shown high
affinity for the neuropeptide Y5 (NPY5) receptor, useful
for the treatment of eating disorders such as obesity and
hyperphagia [11]. Besides, thiazoles are also synthetic
intermediates and common substructures in numerous
biologically active natural products [12]. Aminothiazole
analogs are known to be ligands of estrogen receptors
13], adenosine receptor antagonists [14], and as
schistosomicidal and anthelmintic drugs [15].
The pervasiveness and eminence of 2-aminothiazole
moiety have led to the development of many synthetic
approaches [16–21]. Generally, 2-aminothiazoles are
prepared by Hantzsch’s cyclocondensation of α-halo
[
©
2014 HeteroCorporation

R. Rishikesan, K. Prabakaran, R. Murugesan, R. Venkataraman, P. K. Ranjith,
S. Arvind, and S. Thennarasu
Vol 000
bis(α-bromo ketones) and utilized for the efficient synthe-
sis of novel bis-heterocyclic compounds using 18-crown-
3c was purchased from Sigma-Aldrich, USA. The
controlled α-bromination of the diketo compounds 3a–c
6
phase transfer catalyst and microwave irradiation under
was achieved using Br and 40% HBr in acetic acid, which
2
solvent-free conditions [28].
afforded the corresponding bis(α-bromo ketones) 4a–c in
high yield (Scheme 3).
Having synthesized the bis(α-bromo ketone) intermedi-
ates 4a–c, we then focused on their synthetic utility as
building blocks for the construction of bis-heterocyclic
compounds as outlined in Scheme 4. Various substituted
arylthiourea derivatives, 5a–h were chosen for cyclization
with bis(α-bromo ketone) intermediates 4a–c as the amino
and mercapto groups in the thiourea moiety serve as
nucleophilic centers [34]. In an attempt to minimize the
RESULTS AND DISCUSSION
Considering the synthetic utility of α-bromo ketones in
cross aldol condensations, enaminoketones, Favorskii
rearrangements, and a variety of heterocyclic compounds,
we set out to synthesize three bis(α-bromo ketones)
bridged by a pyridine, pyridin-3-yl-phenyl or biphenyl
system. In the first part of the study, the synthesis of one
of the key substrates, 3,5-diacetyl pyridine, was prepared
by Stille coupling [29–31] of 3-bromo-5-acetyl pyridine
Scheme 3. Synthesis of Bis(α-bromo ketone) 4a–c.
(
1a) with ethoxyethene-tributyltin in 1,4-dioxane at 80°C.
The resultant intermediate 1-(3-(1-ethoxyethyl)pyridyl)
ethanone was quenched in aq. 1.5 N HCl to obtain 3,5-
diacetyl pyridine (3a) in good yield as depicted in
Scheme 1. The other diacetyl substrate 3-acetyl-5-(4-
acetylphenyl)pyridine (3b) was prepared from 4-
bromoacetophenone in two steps using Mayura-Suzuki
coupling method [32,33] as depicted in Scheme 2. The first
step was the preparation of 1-(4-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)phenyl)ethanone (2b) using 4,4,5,5-
tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)-1,3,2-dioxaborolane, Pd(dppf) Cl , and potassium
2
2
Scheme 4. Synthesis of Bis-heterocyclic compounds.
acetate in 1,4-dioxane. In the second step, 2b was coupled
with 1-(5-bromopyridin-3-yl)ethanone (1a) using Pd(PPh3)4
catalyst and Na CO in 1,4-dioxane/water 1:1 mixture to
2
3
obtain the diacetyl compound 3b. The 4,4-diacetylbiphenyl
Scheme 1. Synthesis of 3,5-Diacetyl pyridine 3a.
Scheme 2. Synthesis of 3-Acetyl-5-(4-acetylphenyl)pyridine, 3b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
18-Crown-6 Catalyzed Microwave-mediated Synthesis of Symmetric
Bis-Heterocyclic Compounds under Solvent-free Condition
useof organic solvents, solvent-free microwave accelerated
reaction conditions in the presence of a catalyst were opti-
mized. For this purpose, the efficiency of different catalysts
at room temperature was screened and the results are de-
scribed in Table 1. The cyclization reaction in water or etha-
nol solvent without any catalyst showed a lower yield
Further optimization of the reaction conditions was
carried out using 1-(2-fluorophenyl)thiourea 2 with and
without solvent, and the results are summarized in
Table 2. As seen in Table 2, the cyclization reaction
proceeds in the presence and absence of solvents, and
the best yields are obtained only under solvent-free
condition and in the presence of the phase transfer
catalyst 18-Crown-6.
(Entries 1 and 2, Table 1). As it is clear from Table 1, when
ethanol is used as the solvent, the phase transfer catalysts
TBAF and 18-crown-6 provide better yields under micro-
wave irradiation (2–3 min) conditions.
Having optimized a solvent-free reaction condition, we set
out to synthesize three different series of bis-heterocyclic com-
pounds viz., N-alkyl-4-(5-(2-alkyamino)thiazol-4-yl)pyridine-
3-yl)thiazol-2-amine (6a–h), N-alkyl-4-(4-(5-(2-(alkyl-amino)
Table 1
a
thiazol-4-yl)pyridin-3-yl)phenyl)thiazol-2-amine (7a–e),
and 4,4′-bis-{2-[amino]-4-thiazolyl}biphenyl (8a–l)
derivatives as depicted in Scheme 5. In almost all the
Cyclization of bromoethanones, 4, with 1-(2-fluorophenyl)thiourea, 5.
b
Bis-α-bromo
ketone
Catalyst
10 mol%
LC–MS purity
Entry
Solvent
(area %)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
No catalyst
No catalyst
Imidazole
DMAP
DABCO
3
Et N
DIPEA
TBAF
18-crown-6
18-crown-6
18-crown-6
water
61%
67%
65%
69%
66%
64%
62%
80%
83%
84%
89%
Scheme 5. Synthesis of N-Alkyl-4-(5-(2-alkyamino)thiazol-4-yl)pyridine-
3-yl)thiazol-2-amine (6a–h), N-Alkyl-4-(4-(5-(2-(alkyl-amino)thiazol-4-yl)
pyridin-3-yl)phenyl)thiazol-2-amine (7a-e), and 4,4′-Bis-{2-[amino]-4-
thiazolyl}biphenyl (8a–l) derivatives.
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
10
1
1
a
Reaction condition: bis-α-bromo ketone, 4 (1 mmol), 1-(2-fluoro phenyl)
thiourea, 5 (2 mmol), with or without catalyst in the solvent indicated and
agitated at room temperature for 12 h.
b
LC–MS purity.
Table 2
Cyclization of bromoethanones, 1, with 1-(2-fluorophenyl)thiourea, 2.
a
b
Entry
Bis-α-bromo ketone
Catalyst
Solvent
Time (in min)
LC–MS purity (area %)
1
2
3
4
5
6
7
8
9
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
No catalyst
No catalyst
No catalyst
Imidazole
DMAP
DABCO
3
Et N
DIPEA
TBAF
Basic alumina
18-crown-6
Imidazole
DMAP
Water
2
1
2
2
2
2
2
2
2
3
2
2
2
2
2
2
2
3
2
2
2
2
81%
79%
81%
74%
83%
89%
75%
78%
85%
85%
90%
81%
78%
86%
79%
83%
90%
82%
80%
99%
99%
98%
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Water
Water
Water
Water
Water
Water
Water
Water
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
DABCO
Et
3
N
DIPEA
TBAF
Basic alumina
18-crown-6
18-crown-6
18-crown-6
18-crown-6
Solvent-free
Solvent-free
Solvent-free
a
Reaction condition: bis-α-bromo ketone, 4 (1 mmol), 1-(2-fluoro phenyl) thiourea, 5 (2 mmol), with or without catalyst and/or solvent. Microwave ir-
radiation (120 W) at100°C for 3 min.
b
LC–MS purity.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Rishikesan, K. Prabakaran, R. Murugesan, R. Venkataraman, P. K. Ranjith,
S. Arvind, and S. Thennarasu
Vol 000
Table 3
a
Condensation reaction of 4a with various aryl thioureas, 5.
b
Entry
1
Substituted thiourea 5
Product, 6
Yield (%)
82
2
3
4
5
6
7
84
88
80
91
90
92
8
83
a
Reaction condition: bis-α-bromo ketone, 4a (1 mmol), substituted thiourea, 5 (2 mmol), 18-crown-6 (10 mol%), microwave irradiation (120 W) at100°C for 3 min;
Isolated yield.
b
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
18-Crown-6 Catalyzed Microwave-mediated Synthesis of Symmetric
Bis-Heterocyclic Compounds under Solvent-free Condition
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Rishikesan, K. Prabakaran, R. Murugesan, R. Venkataraman, P. K. Ranjith,
S. Arvind, and S. Thennarasu
Vol 000
Table 5
a
Condensation reaction of 4c with various substituted thiourea, 5.
b
Entry
1
Substituted thiourea 5
Product, 8
Yield (%)
86
2
3
4
5
6
80
82
80
86
82
7
8
9
90
84
92
1
1
0
1
88
90
12
86
a
Reaction condition: bis-α-bromo ketone, 4c (1 mmol), substituted thiourea, 5 (2 mmol), 18-crown-6 (10 mol%) microwave irradiation (120 W) at100°C
for 3 min.
b
Isolated yield.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
18-Crown-6 Catalyzed Microwave-mediated Synthesis of Symmetric
Bis-Heterocyclic Compounds under Solvent-free Condition
phenyl), 7.32–7.38 (m, 2H, phenyl), 7.43–7.45 (d, 2H,
J = 8.4 Hz, phenyl), 7.77–7.80 (d, 2H, 3.6 Hz, phenyl), 7.98
cases, very good yields were obtained in less than 3 min
under solvent-free microwave irradiation condition as
summarized in Tables 3, 4, and 5. All the compounds were
characterized using NMR, mass, and elemental analyses.
(
s, 2H, thiazole), 9.21 (m, 3H, pyridyl), 10.75 (s, 2H, NH-
13
proton). C-NMR (DMSO-d
6
): δ = 104.17, 104.44, 108.25,
08.46, 109.50, 113.46, 131.01, 131.11, 133.00, 135.38,
39.94, 142.81, 142.93, 145.15, 161.85, 164.14, 164.25. LC–
1
1
MS (ESI) m/z: 464.0 (M + 1) for C H F N S requires 463.53.
Elemental analysis, calculated for C23H F N S : C, 59.60; H,
15 2 5 2
2
3 15 2 5 2
CONCLUSION
In conclusion, we have presented 18-crown-6 catalyzed,
microwave-mediated solvent-free reaction condition for
the efficient synthesis of three classes of bis-heterocyclic
compounds viz. N-alkyl-4-(4-(5-(2-(alkyl-amino)thiazol-
3.26; F, 8.20; N, 15.11; S, 13.84%. Found: C, 59.86; H, 3.31;
N, 15.28; S, 13.94%.
N-(3-Bromo-5-fluorophenyl)-4-(5-(2-(3-bromo-5-fluoropheny-
lamino)thiazol-4-yl)pyridin-3-yl)thiazol-2-amine (6c). Yellowish
1
brown solid; yield: 88%; H-NMR (DMSO-d
6
): δ = 7.14–7.17
4
-yl)pyridin-3-yl)phenyl)thiazol-2-amine, N-alkyl-4-(5-(2-
alkyamino)thiazol-4-yl)pyridine-3-yl)thiazol-2-amine, and
,4′-bis-{2-[amino]-4-thiazolyl}biphenyl derivatives. In
(
m, 2H, 3-bromo-phenyl), 7.26–7.30 (t, 2H, J = 8.0 Hz 3-
bromo-phenyl), 7.70–7.73 (m, 2H, 3-bromo-phenyl), 7.98
(s, 2H, thiazole), 8.06–8.07 (s, 2H, pyridyl), 9.18–9.21 (m, 3H,
4
1
3
addition, a three-step protocol for the preparation of
symmetric bis(α-bromo ketones) bridged by a pyridine or
pyridin-3-yl-phenyl system, is also presented. The biologi-
cal and photophysical properties of these compounds are
being explored.
pyridyl, phenyl), 10.73 (s, 2H, NH-proton). C-NMR (DMSO-
d
1
6
): δ = 109.72, 116.39, 119.84, 122.39, 124.53, 131.45,
33.12, 135.69, 139.40, 142.69, 144.92, 164.04. LC–MS (ESI)
m/z: 583.9 (M-1) for C H Br N S requires 585.34.
2
3
15
2 5 2
Elemental analysis, calculated for C H Br N S : C, 47.19; H,
2
3
15
2 5 2
2
2
.58; Br, 27.30; N, 11.96; S, 10.96%. Found: C, 47.28; H,
.65; N, 12.00; S, 11.07%.
N-(3-Chlorophenyl)-4-(5-(2-(3-chlorophenylamino)thiazol-
EXPERIMENTAL
4
-yl)pyridin-3-yl)thiazol-2-amine (6d).
Yellow solid; yield:
1
All the reagents were purchased from Sigma-Aldrich and used
80%; H-NMR (DMSO-d ): δ = 7.31–7.35 (m, 2H, 3-Chloro-
6
1
13
without further purification. The H-NMR and C-NMR spectra
were recorded on a Bruker Spectrospin Avance DPX400
spectrometer. Mass spectra were obtained using Agilent mass
spectrometry 1200 series. Microwave irradiation was performed
in a Biotage microwave oven operating at 20 kHz with the
output power set at 120 W. The China Health and Nutrition
Survey analysis was done on a Vario Micro elemental analyser.
General procedure for the synthesis of 2-Aminothiazole
phenyl), 7.70–7.73 (m, 2H, 3-chloro-phenyl), 7.89 (s,
2H, thiazole), 7.99–8.04 (m, 3H, 3-Chloro-phenyl, pyridyl),
8.79–8.84 (m, 2H, 3-Chloro-phenyl), 9.29 (s, 2H, pyridyl),
1
3
10.69 (s, 2H, NH-proton). C-NMR (DMSO-d ): δ = 108.84,
6
116.59, 119.84, 122.39, 124.53, 131.45, 133.12, 135.69,
139.41, 142.69, 144.93, 164.04. LC–MS (ESI) m/z: 498.0
(M + 2) for
analysis, calculated for C23
C
23
H
15Cl
2
N
5
S
H
2
requires 496.43. Elemental
15Cl N S : C, 55.65; H, 3.05; Cl,
2 5 2
derivatives.
A mixture of bis-α-bromo ketone (4a or 4b or
14.28; N, 14.11; S, 12.92%. Found: C, 55.73; H, 3.12; N,
14.20; S, 13.00%.
4
c, 1.0 mmol), N-substituted thiourea 5 (2.0 mmol), and 18-
crown-6 (catalyst, 10 mol%) was taken in 8 mL vials and
irradiated in a Biotage Microwave Oven at 100°C for 2–3 min.
The reaction progress was monitored by TLC. Upon completion
of the reaction, the reaction mixture was cooled to ambient
temperature and quenched with water, and the solid obtained
was filtered off, dried under reduced pressure, and then
crystallized in methanol or methanol-DMSO mixture to obtain
pure bis-2-aminothiazole derivatives (6a–h, 7a–e, 8a–l). All
N-(3-(Trifluoromethyl)phenyl)-4-(5-(2-(3-(trifluoromethyl)
phenylamino)thiazol-4-yl)pyridin-3-yl)thiazol-2-amine (6e). Yellow
1
solid; yield: 91%; H-NMR (DMSO-d
): δ = 7.30–7.32 (d, 2H,
6
J = 7.6 Hz, 3-CF
- phenyl), 7.55–7.59 (t, 2H, J = 8.0 Hz,
3
phenyl), 7.77 (s, 2H, 3-CF
3
-phenyl), 7.89–7.91 (d, 2H,
J = 9.6 Hz, phenyl), 8.36 (s, 2H, thiazole), 8.88 (s, 1H, pyridyl),
9.122–9.12 (d, 2H, J = 2.0 Hz, pyridyl), 10.81 (s, 2H, NH-
1
3
proton). C-NMR (DMSO-d ): δ = 104.44, 108.25, 108.46,
6
1
13
the compounds were characterized using H-NMR, C-NMR,
LC–MS, and elemental analysis techniques, and the analytical
data are given below.
109.36, 109.62, 113.46, 118.13, 121.03, 123.31, 126.02,
130.37, 130.67, 131.09, 132.78, 133.08, 139.70, 140.27,
141.84, 142.80, 145.07, 145.25, 164.02, 164.14. LC–MS (ESI)
m/z: 564.0 (M + 1) for C H F N S requires 563.54.
N-(2-Fluorophenyl)-4-(5-(2-(2-fluorophenylamino)thiazol-
2
3 15 6 5 2
4
8
7
7
-yl)pyridin-3-yl)thiazol-2-amine (6a). Yellow solid; yield:
Elemental analysis, calculated for C H F N S : C, 53.28; H,
2.68; F, 20.23; N, 12.43; S, 11.38%. Found: C, 53.35; H, 2.73;
N, 12.42; S, 11.45%.
23 15 6 5 2
1
2%; H-NMR (DMSO-d ): δ = 7.43–7.47 (t, 2H, 2-fluoro-phenyl),
6
.57–7.59 (m, 2H, 2-fluoro-phenyl), 7.94 (s, 2H, thiazole),
.97–7.99 (m, 2H, phenyl), 8.49 (s, 2H, pyridyl), 9.20–9.21
N-(3,5-Bis(trifluoromethyl)phenyl)-4-(5-(2-(3,5-bis(trifluoro-
13
(
bs, 3H, pyridyl, phenyl), 10.74 (s, 2H, NH-proton). C-NMR
methyl)phenylamino)thiazol-4-yl)pyridin-3-yl)thiazol-2-amine
1
(
DMSO-d ): δ = 109.15, 118.17, 121.65, 122.86, 129.78, 132.03,
(6f). Yellow solid; yield: 90%; H-NMR (DMSO-d ): δ = 7.57
6
6
1
(
33.00, 134.96, 139.64, 141.43, 144.96, 164.28, 167.79. LC–MS
ESI) m/z: 464.0 (M + 1) for C23 requires 463.53.
Elemental analysis, calculated for C23 : C, 59.60; H,
.26; F, 8.20; N, 15.11; S, 13.84%. Found: C, 59.84; H, 3.33; N,
5.30; S, 13.94%.
(s, 2H), 7.85 (s, 2H), 8.43 (s, 4H), 8.94 (s, 1H), 9.11–9.12 (m, 2H,
pyridyl), 11.18 (s, 2H, NH-proton). C-NMR (DMSO-d ):
6
δ = 104.44, 113.46, 118.14, 121.04, 123.31, 126.02, 130.37,
130.67, 131.09, 132.78, 133.08, 139.70, 140.27, 141.84, 142.81,
145.07, 145.25, 164.02, 164.14. LC–MS (ESI) m/z: 700.0 (M + 1)
13
H
15
F
2
N
F
5
S
2
H
15
2
N
5
S
2
3
1
N-(3-Fluorophenyl)-4-(5-(2-(3-fluorophenylamino)thiazol-4-
for C27
for C27
H
H
13
F
12
N
5
S
2
requires 699.54. Elemental analysis, calculated
: C, 46.36; H, 1.87; F, 32.59; N, 10.01; S,
yl)pyridin-3-yl)thiazol-2-amine (6b).
Yellowish brown solid;
13
F
12
N
5
S
2
1
yield: 84%; H-NMR (DMSO-d
6
): δ = 6.78–6.82 (m, 2H,
9.17%. Found: C, 46.35; H, 1.94; N, 10.08; S, 9.20%.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Rishikesan, K. Prabakaran, R. Murugesan, R. Venkataraman, P. K. Ranjith,
S. Arvind, and S. Thennarasu
Vol 000
N-(Methylbenzoate)-4-(5-(2-((methylbenzoate)amino)thiazol-
-yl)pyridin-3-yl)thiazol-2-amine (6g). Brown solid; yield:
): δ = 3.82 (s, 6H, methyl ester),
.42–7.46 (t, 2H, phenyl), 7.54–7.56 (d, 2H, J = 8.0 Hz, phenyl),
.91–7.94 (m, 2H, phenyl), 7.98 (s, 2H, thiazole), 8.61-8.62
3.79; N, 19.39; S, 12.68%. Found: C, 64.07; H, 3.81; N, 19.40;
S, 12.77%.
4
9
7
7
1
2%; H-NMR (DMSO-d
6
N-(3,5-Bis(trifluoromethyl)phenyl)-4-(5-(4-(2-(3,5-bis(trifluoro-
methyl)phenylamino)thiazol-4-yl)phenyl) pyridin-3-yl)thiazol-2-
1
amine (7d).
Yellowish brown solid; yield: 90%; H-NMR
(
d, 2H, J = 1.6 Hz, pyridyl), 9.18–9.22 (m, 3H, pyridyl, phenyl),
(DMSO-d ): δ = 7.64–7.65 (m, 2H, phenyl), 7.74 (s, 1H,
6
1
3
1
1
1
0.77 (s, 2H, NH-proton). C-NMR (DMSO-d ): δ = 52.62,
thiazole), 7.98–8.03 (m, 3H, phenyl, thiazole), 8.10–8.12
(m, 2H, phenyl), 8.50 (m, 4H, phenyl), 8.87 (s, 1H, pyridyl),
9.10–9.11 (m, 1H, pyridyl), 9.20 (s, 1H, pyridyl), 11.13 (s, 1H,
6
09.20, 117.95, 121.87, 122.49, 129.87, 130.82, 132.95,
35.07, 139.78, 141.54, 145.07, 164.06, 166.66. LC–MS (ESI)
1
3
m/z: 544.0 (M + 1) for C H N O S requires 543.62.
NH-proton), 11.24 (s, 1H, NH-proton). C-NMR (DMSO-d ):
2
7
21
5
4
2
6
Elemental analysis, calculated for C H N O S : C, 59.65; H,
δ = 102.20, 109.21, 117.91, 121.88, 122.46, 129.87, 130.88,
132.95, 135.07, 139.78, 141.55, 145.07, 164.16, 166.66. LC–
2
7 21 5 4 2
3
.89; N, 12.88; O, 11.77; S, 11.80%. Found: C, 59.71; H, 3.90;
N, 12.89; S, 11.87%.
MS (ESI) m/z: 776.0 (M + 1) for C33 requires
H
17
F
12
N
5
S
2
N-(4-(5-(2-(Pyridin-4-ylamino)thiazol-4-yl)pyridin-3-yl)thiazol-
775.63. Elemental analysis, calculated for C33H F N S : C,
17 12 5 2
2
-yl)pyridin-4-amine (6h). Yellowish brown solid; yield: 83%;
51.10; H, 2.21; F, 29.39; N, 9.03; S, 8.27%. Found: C, 51.24;
H, 2.27; N, 9.10; S, 8.35%.
1
H-NMR (DMSO-d ): δ = 7.43–7.47 (t, 2H, J = 8.0 Hz, phenyl),
6
7.57–7.60 (m, 2H, phenyl), 7.94 (s, 2H, thiazole), 7.97–8.00 (m,
N-(3(Methybenzoate))-4-(4-(5-(2-(phenylamino)thiazol-4-yl)
2
H, phenyl), 8.49–8.50 (bs, 2H, phenyl), 9.20–9.21 (3H, pyridyl,
pyridin-3-yl)methybenzoate) thiazol-2-amine (7e).
White
1
3
1
phenyl), 10.75 (s, 2H, NH-proton). C-NMR (DMSO-d
6
) δ:
09.15, 118.17, 121.65, 122.87, 129.78, 132.03, 133.00, 134.97,
39.64, 141.44, 144.96, 164.27, 167.79. LC–MS (ESI) m/z: 430.0
solid; yield: 91%; H-NMR (DMSO-d ): δ = 3.85 (s, 3H, methyl
6
1
1
ester), 3.91 (s, 3H, methyl ester), 7.50–7.63 (m, 5H, phenyl,
thiazole), 7.86–7.93 (m, 2H, phenyl), 8.05–8.10 (m, 3H,
phenyl, thiazole), 8.19–8.21 (m, 2H, phenyl), 8.70–8.75
(m, 2H, phenyl), 9.12 (s, 1H, pyridyl), 9.19 (s, 1H, pyridyl),
9.25 (s, 1H, pyridyl), 10.61 (s, 1H, NH-proton), 10.77 (s, 1H,
(M + 1) for C21
H
15
N
7
S
2
requires 429.52. Elemental analysis,
2
S : C, 58.72; H, 3.52; N, 22.83; S,
calculated for C21
H
15
N
7
14.93%. Found: C, 58.71; H, 3.57; N, 22.89; S, 15.00%.
1
3
N-(2-Fluorophenyl)-4-(5-(4-(2-(2-fluorophenylamino)thiazol-
NH-proton). C-NMR (DMSO-d ): δ = 52.73, 105.79, 117.82,
6
4
-yl)phenyl)pyridin-3-yl)thiazol-2-amine (7a).
Yellowish
121.68, 122.03, 122.24, 122.62, 128.34, 129.86, 129.96,
130.85, 133.52, 136.15, 141.91, 149.52, 163.32, 164.13,
1
brown solid; yield: 86%; H-NMR (DMSO-d
6
): δ = 6.94–6.98
(
m, 2H, phenyl), 7.44–7.50 (m, 4H, phenyl), 7.66 (s, 1H,
25 5 4 2
166.76. LC–MS (ESI) m/z: 620.0 (M + 1) for C33H N O S
thiazole), 8.04–8.06 (m, 2H, phenyl), 8.12–8.13 (m, 3H,
phenyl, thiazole), 8.16–8.26 (m, 2H, phenyl), 9.17–9.25
requires 619.71. Elemental analysis, calculated for
C H N O S : C, 63.96; H, 4.07; N, 11.30; O, 10.33; S,
3
3 25 5 4 2
(
m, 3H, pyridyl), 10.73 (s, 1H, NH-proton), 10.90 (s, 1H, NH-
10.35%. Found: C, 64.07; H, 4.07; N, 11.37; S, 10.37%.
1
3
proton). C-NMR (DMSO-d
1
1
m/z: 540.0 (M + 1) for C H F N S requires 539.62.
Elemental analysis, calculated for C29
6
) δ: 105.79, 117.82, 117.94,
26.85, 128.34, 129.86, 129.96, 130.85, 133.52, 136.15,
41.56, 141.91, 149.56, 163.32, 164.23, 166.66. LC–MS (ESI)
4,4′-Bis-{2-[amino]-4-thiazolyl}biphenyl (8a). White solid;
1
yield: 86 %; H-NMR (DMSO-d
6
) δ: 5.56 (s, 2H, –NH
2
proton,
exchanged with water), 7.09 (s, 1H, thiazole), 7.96–7.98 (d, 2H,
J = 8.4 Hz, biphenyl), 8.12–8.14 (d, 2H, J = 8.4 Hz, biphenyl);
2
9
19
2
5
2
13
H
19
F
2
N
5
S
2
: C, 64.55; H,
6
C-NMR (DMSO-d ) δ: 103.57, 126.85, 126.95, 127.62,
3
.55; F, 7.04; N, 12.98; S, 11.88%. Found: C, 64.66; H, 3.59;
127.77, 127.96, 128.08, 128.26, 128.69, 128.84, 129.05,
129.90, 134.60, 139.24, 140.02, 140.50, 167.84, 170.77; LC–
MS (ESI) m/z: 351.0 (M + 1) for C H N S requires 350.46.
N, 13.02; S, 12.00%.
N-(Acetyl)-4-(5-(4-(2-(acetylamino)thiazol-4-yl)phenyl)pyridin-
18 14 4 2
3
8
7
-yl)thiazol-2-amine (7b).
2%; H-NMR (DMSO-d
.82 (s, 1H, thiazole), 7.99–8.14 (m, 4H, phenyl), 8.31 (s, 1H,
Yellowish brown solid; yield:
): δ = 2.19–2.21 (bs, 6H, acetyl),
Elemental analysis, calculated for C H N S : C, 61.69; H,
4.03; N, 15.99; S, 18.30%. Found: C, 61.73; H, 3.97; N, 16.05;
S, 18.25%.
18 14 4 2
1
6
thiazole), 9.18–9.25 (m, 3H, pyridyl), 12.28 (s, 1H, NH-
proton), 12.43 (s, 1H, NH-proton). C-NMR (DMSO-d6):
4,4′-Bis-{2-[Methyl-amino]-4-thiazolyl}biphenyl (8b). White
1
3
1
solid; yield: 80%; H-NMR (DMSO-d ) δ: 3.02 (s, 6H, methyl),
6
δ = 24.08, 113.42, 116.36, 116.59, 119.67, 120.15, 120.23,
7.28 (s, 2H, thiazole), 7.84–7.86 (dd, 4H, J = 8.8 Hz, biphenyl),
13
1
1
1
21.90, 121.96, 122.23, 126.70, 127.00, 130.58, 132.09,
32.34, 133.23, 141.44, 144.38, 148.41, 156.98, 159.39,
62.48, 162.52. LC–MS (ESI) m/z: 436.2 (M + 1) for
7.89–7.91 (dd, 4H, J = 8.4 Hz, biphenyl), 8.82 (s, 2H, –NH); C-
NMR (DMSO-d ) δ: 27.37, 101.36, 121.02, 125.30, 126.17,
6
128.03, 129.12, 142.74, 153.77, 165.39; LC–MS (ESI) m/z: 379.4
C H N O S requires 435.52. Elemental analysis, calculated
(M+ 1) for C H N S requires 378.51. Elemental analysis,
2
1
17
5
2
2
20 18 4 2
for C21
H
17
N
5
O
2
S
2
: C, 57.91; H, 3.93; N, 16.08; O, 7.35; S,
18 4 2
calculated for C20H N S : C, 63.46; H, 4.79; N, 14.80; S,
1
4.72%. Found: C, 58.00; H, 4.00; N, 16.10; S, 14.80%.
16.94%. Found: C, 63.51; H, 4.74; N, 14.85; S, 16.89%.
N-(4-(5-(4-(2-(Pyridin-4-ylamino)thiazol-4-yl)phenyl)pyridin-
4,4′-Bis-{2-[propyl-amino]-4-thiazolyl}biphenyl (8c). White
1
3
8
7
-yl)thiazol-2-yl)pyridin-4-amine (7c).
Yellow solid; yield:
solid; yield: 82%; H-NMR (DMSO-d ) δ: 0.93 (t, 3H,
6
1
4%; H-NMR (DMSO-d ): δ = 7.48–7.52 (m, 2H, phenyl),
J = 7.6 Hz, n-propyl), 1.62 (m, 2H, n-propyl), 3.22 (q, 2H,
J = 6.8 Hz, n-propyl), 7.11 (s, 1H, thiazole), 7.68–7.71 (t, 1H,
J = 8.0 Hz, –NH), 7.71–7.73 (dd, 2H, J = 8.4 Hz, biphenyl),
6
.56–7.61 (m, 3H, phenyl, thiazole), 7.96–8.11 (m, 5H, phenyl,
thiazole), 8.18–8.20 (m, 2H, phenyl), 8.41–8.50 (m, 2H, phenyl),
.23–9.26 (m, 3H, pyridyl), 10.57 (s, 1H, NH-proton), 10.76
1
3
9
(
1
6
7.91–7.93 (dd, 2H, J = 8.4 Hz, biphenyl); C-NMR (DMSO-d )
1
3
s, 1H, NH-proton). C-NMR (DMSO-d ): δ = 110.42, 113.36,
δ: 11.59, 25.37, 51.03, 101.36, 121.02, 125.30, 126.17, 128.03,
129.12, 142.74, 153.77, 165.39; LC–MS (ESI) m/z: 435.2
6
13.59, 116.67, 117.15, 117.23, 130.58, 132.09, 132.34, 133.23,
1
41.44, 144.38, 148.41, 156.88, 159.39, 162.48, 162.58. LC–MS
(M + 1) for C24
calculated for C24
14.76%. Found: C, 66.37; H, 5.97; N, 12.84; S, 14.81%.
H
26
N
4
S
2
requires 434.62. Elemental analysis,
(
ESI) m/z: 506.5 (M + 1) for C27
19
H N
S
7 2
requires 505.62.
26 4 2
H N S : C, 66.32; H, 6.03; N, 12.89; S,
Elemental analysis, calculated for C27
19 7 2
H N S : C, 64.14; H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2014
18-Crown-6 Catalyzed Microwave-mediated Synthesis of Symmetric
Bis-Heterocyclic Compounds under Solvent-free Condition
4
,4′-Bis-{2-[isopropyl-amino]-4-thiazolyl}biphenyl (8d).
White
4,4′-Bis-{2-[3-(trifluoromethyl)-phenyl-amino]-4-thiazolyl}
1
1
solid; yield: 80%; H-NMR (DMSO-d ) δ: 1.24–1.25 (d, 12H,
biphenyl (8i). White solid; yield: 92%; H-NMR (DMSO-d )
6
6
J = 6.4 Hz, isopropyl) 3.9 (m, 2H, isopropyl), 7.17 (s, 2H,
δ: 7.31–7.33 (d, 2H, J = 8 Hz, phenyl), 7.54 (s, 2H, thiazole),
7.59–7.62 (t, 2H, J = 8.0 Hz, phenyl), 7.85–7.90 (m, 6H,
biphenyl and phenyl), 8.03–8.05 (dd, 4H, J = 8.4 Hz,
thiazole), 7.78–7.80 (d, 4H, J = 8.4 Hz, biphenyl), 7.88–7.90
1
3
(
d, 4H, J = 8.4 Hz, biphenyl); C-NMR (DMSO-d
6
) δ: 24.59,
1
3
5
0.99, 101.01, 120.48, 124.89, 134.87, 142.10, 153.98, 166.41;
biphenyl), 8.41(s, 2H, phenyl) 10.71 (s, 2H, –NH); C-NMR
LC–MS (ESI) m/z: 435.2 (M + 1) for C H N S requires
(DMSO-d ) δ: 105.13, 105.49, 108.30, 109.63, 113.54,
2
4
26
4
2
6
4
6
34.62. Elemental analysis, calculated for C24
6.32; H, 6.03; N, 12.89; S, 14.76%. Found: C, 66.36; H, 5.97;
H
26
N
4
S
2
: C,
127.42, 131.02, 131.12, 133.24, 140.56, 140.95, 141.84,
142.79, 142.90, 144.73, 161.83, 164.25; LC–MS (ESI) m/z:
638.9 (M + 1) for C H F N S requires 638.65. Elemental
N, 12.85; S, 14.82%.
,4′-Bis-{2-[phenyl-amino]-4-thiazolyl}biphenyl (8e). White
solid; yield: 86%; H-NMR (DMSO-d
phenyl), 7.36–7.38 (m, 4H, phenyl), 7.40–7.43 (s, 2H,
thiazole), 7.76–7.78 (d, 4H, J = 8.4 Hz, phenyl), 7.82–7.84 (dd,
4
3
2
20
6
4 2
4
analysis, calculated for C H F N S : C, 60.18; H, 3.16; F,
32 20 6 4 2
1
6
) δ: 6.97–7.01 (m, 2H,
17.85; N, 8.77; S, 10.04%. Found: C, 60.25; H, 3.14; N, 8.74;
S, 10.09%.
4,4′-Bis-{2-[5-bromo-3-fluoro-phenyl-amino]-4-thiazolyl}
1
H, J = 8.4 Hz, biphenyl), 8.03–8.05 (dd, 4H, J = 8.4 Hz,
biphenyl (8j). White solid; yield: 88%; H-NMR (DMSO-
1
3
biphenyl), 10.32 (s, 2H, –NH); C-NMR (DMSO-d ) δ:
d6) δ: 7.47–7.51 (4H, phenyl, thiazole), 7.58–7.62 (m, 2H,
phenyl), 7.80–7.82 (dd, 4H, J = 2.4 Hz, phenyl), 8.02–8.04
(dd, 4H, J = 8.4 Hz, biphenyl), 8.66–8.70 (m, 2H, phenyl),
6
1
1
1
03.67, 117.37, 117.70, 121.74, 122.32, 126.74, 126.88,
27.06, 127.16, 127.32, 127.92, 128.94, 129.50, 129.58,
39.08, 141.05, 141.68, 150.13, 162.40, 163.66; LC–MS (ESI)
1
3
6
10.26–10.27 (s, 2H, -NH); C-NMR (DMSO-d ) δ: 92.96,
m/z: 503.0 (M + 1) for C H N S requires 502.65. Elemental
112.85, 112.94, 118.74, 118.96, 121.40, 126.86, 127.03,
127.30, 128.13, 128.43, 133.10, 139.55, 146.85, 150.64,
153.11, 161.97; LC–MS (ESI) m/z: 730.2 (M + 1) for
3
0 22 4 2
analysis, calculated for C H N S : C, 71.68; H, 4.41; N,
3
0 22 4 2
1
1
1.15; S, 12.76%. Found: C, 71.73; H, 4.36; N, 11.11; S,
2.80%.
C
30
H
18Br
2
Cl
2
N
4
S
2
requires 729.33. Elemental analysis,
Cl : C, 49.40; H, 2.49; Br,
4
,4′-Bis-{2-[2-fluorophenylamino]-4-thiazolyl}biphenyl (8f). White
calculated for C30
H
18Br
2
2 4 2
N S
1
solid; yield: 82%; H-NMR (DMSO-d ) δ: 6.44–6.49 (m, 2H,
21.91; Cl, 9.72; N, 7.68; S, 8.79%. Found: C, 49.51; H, 2.46;
N, 7.66; S, 8.84%.
6
fluorophenyl), 7.01–7.31 (m, 4H, fluorophenyl), 7.47 (s, 2H,
thiazole), 7.81–7.83 (d, 4H, J = 8.4 Hz, biphenyl), 8.01–8.04 (d,
4,4′-Bis-{2-[3,5-Bis(trifluoromethyl)phenyl-amino]-4-thiazolyl}
1
4
H, J = 8.4 Hz, biphenyl), 8.63–8.67 (t, 2H, J = 8.4 Hz,
biphenyl (8k). White solid; yield: 90%; H-NMR (DMSO-d
6
)
1
3
fluorophenyl), 10.13 (s, 2H, –NH); C-NMR (DMSO-d ) δ:
δ: 7.63–7.64 (m, 4H, phenyl, thiazole), 7.88–8.15 (m, 8H,
6
13
1
1
1
04.90, 105.04, 115.51, 115.69, 120.35, 122.69, 125.20, 122.70,
26.88, 127.15, 127.32, 128.90, 129.47, 129.58, 132.97, 134.01,
39.07, 139.76, 149.78, 150.98, 153.41, 162.48, 163.79; LC–MS
biphenyl), 8.49 (s, 4H, phenyl), 11.08 (s, 2H, –NH); C-NMR
(DMSO-d ) δ: 104.16, 104.43, 108.28, 108.49, 109.65, 113.52,
6
127.41, 131.02, 131.12, 133.23, 140.55, 140.95, 141.83,
142.79, 142.90, 144.71, 161.82, 164.15; LC–MS (ESI) m/z:
775.0 (M + 1) for C H F N S requires 774.64. Elemental
(
20 2 4 2
ESI) m/z: 539.0 (M + 1) for C30H F N S requires 538.63.
Elemental analysis, calculated for C H F N S : C, 66.90; H,
3
0
20
2
4
2
34 18 12 4 2
3
1
.74; F, 7.05; N, 10.40; S, 11.91%. Found: C, 66.97; H, 3.70; N,
0.39; S, 11.95%.
analysis, calculated for C H F N S : C, 52.72; H, 2.34; F,
29.43; N, 7.23; S, 8.28%. Found: C, 52.79; H, 2.30; N, 7.21; S,
8.26%.
34 18 12 4 2
4
,4′-Bis-{2-[3-bromo-phenyl-amino]-4-thiazolyl}biphenyl (8g). White
1
solid; yield: 90%; H-NMR (DMSO-d
phenyl), 7.31–7.35 (m, 2H, phenyl), 7.51 (s, 2H, thiazole),
.66–7.68 (m, 2H, phenyl), 7.84–7.87 (dd, 4H, J = 8.4 Hz,
biphenyl), 8.02–8.04 (dd, 4H, J = 8.4 Hz, biphenyl), 8.14–8.15
6
) δ: 7.15–7.17 (m, 2H,
4,4′-Bis-{2-[4-Fluoro-benzylamino]-4-thiazolyl}biphenyl
1
(8l).
White solid; yield: 86%; H-NMR (DMSO-d ) δ: 4.57
6
7
(s, 4H, benzylic), 7.19–7.23 (m, 6H, fluorophenyl, thiazole),
7.46–7.50 (m, 4H, fluoro phenyl), 7.77–7.80 (dd, 4H, J = 8.4 Hz,
biphenyl), 7.89–7.91 (dd, 4H, J = 8.4 Hz, biphenyl), 8.72–8.85
1
3
(
m, 2H, phenyl), 10.53 (s, 2H, –NH); C-NMR (DMSO-d
6
) δ:
13
1
1
1
1
04.44, 104.58, 116.11, 116.41, 119.59, 119.88, 122.37,
6
(bs, 2H, –NH); C-NMR (DMSO-d ) δ: 48.25, 103.05, 115.48,
24.08, 124.66, 126.67, 126.89, 127.07, 127.19, 127.36,
28.87, 131.38, 132.92, 133.97, 134.18, 138.89, 139.10,
39.74, 142.48, 143.12, 147.19, 150.15, 161.85, 163.08; LC–
115.64, 115.85, 126.80, 127.11, 127.24, 127.78, 128.93, 130.04,
130.12, 130.24, 130.32, 131.40, 134.07, 135.36, 139.56, 146.70,
160.82, 163.23, 166.90, 169.34; LC–MS (ESI) m/z: 567.0 (M+ 1)
MS (ESI) m/z: 661.0 (M + 1) for C30
H
20Br
2
N
4
S
2
requires
for C32
24
2 4 2
H F N S requires 566.69. Elemental analysis, calculated
6
5
60.44. Elemental analysis, calculated for C H Br N S : C,
4.56; H, 3.05; Br, 24.20; N, 8.48; S, 9.71%. Found: C, 54.61;
for C H F N S : C, 67.82; H, 4.27; F, 6.71; N, 9.89; S,
11.32%. Found: C, 67.88; H, 4.25; N, 9.91; S, 11.36%.
3
0
20
2
4
2
32 24
2 4 2
H, 3.00; N, 8.45; S, 9.74%.
,4′-Bis-{2-[3-chloro-phenyl-amino]-4-thiazolyl}biphenyl (8h). White
4
1
solid; yield: 84%; H-NMR (DMSO-d
phenyl), 7.37–7.41 (m, 2H, phenyl), 7.51 (s, 2H, thiazole),
.61–7.63 (m, 2H, phenyl), 7.84–7.86 (dd, 4H, J = 8.4 Hz,
biphenyl), 8.01–8.02 (dd, 4H, J = 8.4 Hz, biphenyl), 10.55
6
) δ: 7.02–7.04 (m, 2H,
Acknowledgment. The authors wish to express their gratitude to
the Sophisticated Analytical Instruments Facility (SAIF), Indian
Institute of Science, Bangalore, for supporting in NMR and
LC–MS analyses.
7
1
3
(
s, 2H, –NH);
6
C-NMR (DMSO-d ) δ: 104.46, 115.77,
1
1
16.71, 121.19, 126.67, 127.19, 131.07, 133.84, 133.95,
39.08, 142.99, 150.10, 163.13; LC–MS (ESI) m/z: 572.0
REFERENCES AND NOTES
(
M + 1) for C H Cl N S requires 571.54. Elemental
3
0
20
2
4
2
analysis, calculated for C30
H
20Cl
2
N
4
S
2
: C, 63.04; H, 3.53;
[1] Gorczynski, J. M.; Leal, M. R.; Mooberry, L. S.; Bushweller,
Cl, 12.41; N, 9.80; S, 11.22%. Found: C, 63.10; H, 3.48;
N, 9.76; S, 11.26%.
H. J.; Brown, L. M. J Bioorg Med Chem 2004, 12, 1029.
[2] Tsuji, K.; Ishikawa, H. Bioorg Med Chem Lett 1994, 4, 1601.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

R. Rishikesan, K. Prabakaran, R. Murugesan, R. Venkataraman, P. K. Ranjith,
S. Arvind, and S. Thennarasu
Vol 000
[
[
3] More, P. G.; Bhalvankar, R. B. J Indian Chem Soc 2006, 83, 113.
4] Bekhit, A. A.; Fahmy, H. T. Y.; Rostom, S. A.; Bekhit,
[17] Corrao, S. L.; Macielag, M. J.; Turchi, I. J Org Chem 1990, 55,
4484.
[18] Burger, K.; Hoess, E.; Geith, K. Synthesis 1990, 4, 357.
[19] Thompson, M. J.; Heal, W.; Chen, B. Tetrahedron Lett 2006,
47, 2361.
A. E. D. Eur J Med Chem 2010, 45, 6027.
5] Komar, Y.; Green, R.; Wise, D.; Worting, L. L. J Med Chem
988, 23, 501.
6] Sivakumar, A.; Martinez, R.; Canney, J. D.; Eidem, T.; Dunman,
M. P.; Abou-Gharbia, M. Bioorg Med Chem Lett 2012, 22, 7719.
7] Badorc, A.; Borders, M.-F.; de Cointet, P.; Savi, P.; Bernat, A.;
Lale, A.; Petitou, M.; Maffrand, J.-P.; Herbert, J.-M. J Med Chem 1997,
0, 3393.
8] Venkatachalam, T. K.; Sudbeck, E. A.; Mao, C.; Uckum, F. M.
Bioorg Med Chem Lett 2001, 11, 523.
9] Jaen, J. C.; Wise, L. D.; Caprathe, B. W.; Tecle, H.;
[
1
[20] Li, Y.; Giulianotti, M.; Houghten, A. R. Tetrahedron Lett
[
2010, 51, 5637.
[21] Hameed, S.; Akhtar, T. Current Org Chem 2011, 15, 694.
[
[22] Hantzsch, A.; Weber, J. H. Ber Dtsch Chem Ges 1887,
20, 3118.
[23] Ochiai, E.; Kashida, Y. J Pharm Soc Jpn 1942, 62, 97.
[24] Ochiai, E.; Haginiwa, J. J Pharm Soc Jpn 1947, 67, 138.
[25] Lagoja, I.; Pannecouque, C.; Griffioen, G.; Wera, S.;
Rojasdelaparra, M. V.; Van Aerschot, A. Eur J Med Chem 2011,
43, 386.
4
[
[
Bergmeier, S.; Humblet, C. C.; Heffiner, T. G.; Meltzner, L. T.; Pugsley,
T. A. J Med Chem 1990, 33, 311.
[
10] Mathivanan, P.; Coate, H.; Mahesh, D.; Jimenez, N. H.;
[26] Aoyama, T.; Murata, S.; Arai, I.; Araki, N.; Takido, T.;
Suzuki, Y.; Kodomari, M. Tetrahedron 2006, 62, 3201.
[27] Meshram, H. M.; Thakur, B. P.; MadhuBabu, B.; Bangade,
M. V. Tetrahedron Lett 2012, 53, 5265.
Reinhard, J. E.; Jubian, J. V.; Marzabadi, R. M.; Chandrasena, G.;
Wolinski, C. T.; Walker, W. M.; Andersen, K. Bioorg Med Chem Lett
011, 21, 6500.
2
[
11] Parker, E.; Van Heek, M.; Stamford, A. Eur J Pharmacol 2002,
[28] Lidstrom, P.; Tierney, J.; Wathey, B.; Westman, J.
Tetrahedron 2001, 57, 9925.
4
40, 173.
[12] De Souza, M. V. N. J Sulfur Chem 2005, 26, 429.
[29] Mitchell, T. N. Synthesis 1992, 9, 803.
[
13] Fink, B. A.; Mortensen, D. S.; Stauffer, S. R.; Aron, Z. D.;
[30] Huang, C.-W.; Shanmugasundaram, M.; Chang, H.-M.;
Cheng, C.-H. Tetrahedron 2003, 59, 3635.
[31] Lerebours, R.; Camacho-Soto, A.; Wolf, C. J Org Chem 2005,
70, 8601.
[32] Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett 1979,
36, 3437.
[33] Miyaura, N.; Suzuki, A. Chem Rev 1995, 95, 2457.
[34] Combellas, C.; Dellerue, S.; Mathey, G.; Thiébault, A.
Tetrahedron Lett 1997, 38, 539.
Katzenellenbogen, J. A. Chem Biol 1999, 6, 205.
14] Van Muijlwijk-Koezen, J. E.; Timmerman, H.; Vollinga,
R. C.; Von DrabbeKunzel, J. F.; De Groote, S.; Ijzerman, A. P. J Med Chem
001, 44, 749.
15] Metzger, J. V. Comprehensive Heterocyclic Chemistry I;
Pergamon: New York, 1984; Vol 6, pp 328.
16] Golankiewicz, B.; Januszczyk, P.; Gdaniec, M.; Kosturkiewicz, Z.
Tetrahedron 1985, 41, 5989.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet