A simple and efficient one-pot synthesis of multifunctional 5-aryl-5H-thiazolo[3,2-a]pyrimidines

Article abstract of DOI:10.1002/jhet.831

One-pot economical and efficient synthesis of multifunctional 5H-thiazolo[3,2-a]pyrimidines by the reaction of 4-aryl dihydrothiopyrimidines with propargyl bromide in the presence of inorganic base has been reported in very short time.

Full text of DOI:10.1002/jhet.831

600
A Simple and Efficient One-Pot Synthesis of Multifunctional
5-Aryl-5H-thiazolo[3,2-a]pyrimidines
Vol 49
*
Seerat Fatima, Anindra Sharma, Rahul Sharma, and Rama P. Tripathi
Medicinal and Process Chemistry Division, Central Drug Research Institute (CSIR), Lucknow 226001,
Uttar Pradesh, India
This article is a CDRI communication (No. 8007).
*
E-mail: rpt.cdri@gmail.com
Received October 18, 2010
DOI 10.1002/jhet.831
View this article online at wileyonlinelibrary.com.
One-pot economical and efficient synthesis of multifunctional 5H-thiazolo[3,2-a]pyrimidines by the
reaction of 4-aryl dihydrothiopyrimidines with propargyl bromide in the presence of inorganic base has been
reported in very short time.
J. Heterocyclic Chem., 49, 600 (2012).
INTRODUCTION
preparation and isolation of a-haloketones or haloalde-
hydes required for synthesis in the laboratory is hazardous
in nature and sometimes they are commercially unavail-
able also. Therefore, developments of new, simple, and
practically efficient synthesis of these molecules are
highly desirable.
The discovery of Biginelli reaction and its subsequent
modifications have led to access a variety of dihydropyrimidines
of great synthetic and chemotherapeutic significance [1–5].
The dihydropyrimidinones and thiodihydropyrimidinones
in particular have been used as the key substrates to develop
several synthetic molecules as drugs or potent leads in
medicinal chemistry. Among various derivatives of thiodi-
hydropyrimidines, the thiazolo[3,2-a]pyrimidine derivatives
are of great significance because of their wide range of
biological activities such as calcium channel blocking
activity [6], antimalarial and antitubercular activity [7],
acetylcholine esterase inhibitory activity [8], glutamate
receptor antagonistic activity [9], 5-HT2a receptor
antagonistic activity [10], antiH5N1 activity [11], anticancer
activity [12], kinase inhbitory activity [13] and so on.
Typically they have been synthesized by the condensation
of an aminothiazole with a malonate derivative followed by
intramolecular cycloacylation [14–16]. The protocols for the
synthesis of these molecules, reported so far, suffer the
drawbacks of heating at high temperatures, prolonged reaction
times and low yields. Very recently a two-step high-yield
process involving the condensation of 2-aminothiazole and
diethylmalonate followed by intramolecular cyclization with
Eaton’s reagent (a mixture of 7.7 wt % phosphorus pentoxide
solution in methanesulfonic acid) at low temperature has been
disclosed [17]. Reactions of 1,4-dihydropyrimidine-thiones
with haloketones have also been reported to give various
thiazolo[3,2-a]pyrimidine derivatives [15,18,19]. These
synthetic methodologies too are plagued with drawbacks,
as 2-aminothizole preparation via Hantzsch synthesis
involves thioureas and a-haloketones or aldehydes. The
Recently such a highly efficient synthesis of thiazolo
[3,2-a]-pyrimidinones has been reported [20] by reacting
alkynyl bromides with thiopyrimidinones under micro-
wave irradiation at 130ꢀC using K2CO3 as a base. The
scope of their study was limited to only-alkyl substituted
thiopyrimidinones, and the scope of this reaction with
thiopyrimdines was not fully investigated. The scope of
study was also limited to microwave at higher tempera-
ture. Encouraged by this report and to fulfill our quest
to develop new chemotherapeutic agents from dihydro-
pyrimidines [21,22], we were interested to synthesize
library of thiazolo[3,2-a]pyrimidines using safer and
better yielding routes. Because propargyl bromide has
been considered to be equivalent to a-bromoacetones
[23], and it is commercially available in plenty; we have
carried out reaction of thiodihydropyrimidines with
propargyl bromide in presence of base to get the desired
thizolo[3,2-a]-pyrimidines with ester and ketone groups.
Our method of synthesis is quite simple, rapid, eco-
friendly, economical, and high yielding.
RESULT AND DISCUSSION
To optimize the reaction condition initially we have carried
out reaction of 5-carbmethoxy-6-methyl-4-(4-fluorophenyl)
dihydropyrimidine-2-thione with propargyl bromide in the
© 2012 HeteroCorporation

May 2012
A Simple and Efficient One-Pot Synthesis of Multifunctional
5-Aryl-5H-thiazolo[3,2-a]-pyrimidines
601
Scheme 1. Reaction of 1 with propargyl bromide in different bases and
solvents at different temperature.
the reaction product in comparatively lower yields (entries
6 and 7) when compared with carbonates and alkoxides.
Thus, NaOMe as base and MeOH as solvent or NaOEt as base
and EtOH as solvent and heating the reaction mixture at 80ꢀC
was found to be the most optimum reaction condition.
Out of the two possibilities of 7H-thiazolo[3,2-a]-and
5H-[3,2-a]-pyrimidines A and B (Fig. 1), the product obtained
in the above reaction was found to be methyl 5-(4-fluorophenyl)-
3,7-dimethyl-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate
(2). The structure was elucidated on the basis of spectro-
1
scopic data and analysis. In the H-NMR spectrum of
presence of various catalysts at different temperatures in a
wide variety of solvents (Scheme 1), and the results are shown
in Table 1.
compound 2, the methyl proton of the thiazole ring
appeared as singlet at d 2.07, whereas the other methyl pro-
ton of the pyrimidine ring appeared as singlet at d 2.36 ppm.
The methyl proton of the ester group appeared as singlet at
d 3.71 ppm. The CH proton of the dihydropyrimidine ring
appeared as singlet at d 6.14 whereas that of the thiazole ring
appeared at d 5.96 ppm. The aromatic protons were observed
at their usual chemical shift values. The detailed NOESY and
HSQC spectra of compound 2 revealed the position of differ-
ent susbtitutents in the molecule. As evident from the
NOESY spectrum, the thizolyl methyl protons show interac-
tion with H-2 and H-5 protons and no interaction with
7-methyl protons (Fig. 2). The regioselectivity in the
above reaction of thiodihydropyrimdines with propargyl
bromide may be explained in terms of difference in the
electron density at N3 and N1 position. The higher
basicity of the N3 results in preferential nucleophilic at-
tack at the thiopropargylic moiety to give the N3-regio-
slective product. Such observations were earlier reported
in the reaction of dihydropyrimdines in literature
[18,24,25] by different workers.
As shown in Table 1, with organic bases such as Et3N,
DBU, and DABCO, reaction did not proceed, even after
prolonged heating (entries 11, 12, and 14 Table 1).
Reaction preceded by the use of inorganic bases carbonates
(K2CO3, Na2CO3 in protic and aprotic solvents, entries 1,
2, 3, 4, 17, 18, 20 Table 1). However, CsCO3 proved to
be an unsuccessful catalyst (entry13) with only 5% yield.
The reaction with K2CO3 was successful even in aprotic
solvent acetonitrile. However, by using NaOMe, or NaOEt
in their respective alcohol solvents, compounds were
obtained in good yields. Reaction was completed in about
8 h in the presence of NaOMe in methanol (entry 9) at
ambient temperature, whereas on heating at 80ꢀC, it was
completed in only 30 min (entry 8). With ethylene glycol,
reaction was sluggish, and the product formation was <5%
(TLC) as most of the starting material was recovered. With
NaHCO3 as base and acetone as solvent, the yield of the
reaction was only 10% (entry19). KOH as catalyst gave
Table 1
Optimization of reaction conditions for the formation of 2.
Entry
Catalyst (base)
Solvent
Temperature (ꢀC)
Time
Yield (%)
1
2
3
4
5
6
7
8
K2CO3
K2CO3
K2CO3
K2CO3
KOH
KOH
KOH
NaOMe
NaOMe
NaOEt
Et3N
Acetone
RT
80ꢀC
80ꢀC
80ꢀC
RT
10 h
8 h
10 h
8 h
70
80
20
<5
50
85
40
94
90
50
0
0
5
0
85
88
75
10
10
70
Acetone
Methanol
Ethylene glycol
Methanol
Methanol
Water
Methanol
Methanol
Ethanol
Ethanol
Acetone
Acetone
Acetone
THF
8 h
80ꢀC
80ꢀC
80ꢀC
RT
40 min
40 min
30 min
8 h
2 h
8 h
8 h
12 h
8 h
40 min
45 min
8 h
9
10
11
12
13
14
15
16
17
18
19
20
80ꢀC
RT
RT
RT
RT
DBU
Cs2CO3
DABCO
NaOMe
NaOMe
K2CO3
Na2CO3
NaHCO3
K2CO3
80ꢀC
80ꢀC
80ꢀC
80ꢀC
80ꢀC
80ꢀC
ArCN
ArCN
Acetone
Acetone
THF
8 h
8 h
8 h
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

602
S. Fatima, A. Sharma, R. Sharma, and R. P. Tripathi
Vol 49
Scheme 2. Synthesis of multifunctional 5H-thiazolo[3,2-a]-pyrimidines.
intermediate III, which again isomerises to the product IV.
Botta and coworkers have hypothesized Path A for the
reaction as only mild base K2CO3 was used for the
reaction where the formation of allene is not feasible
easily. However, we have carried out reactions in the
presence of both mild and strong base. Under K2CO3-
catalyzed reaction, the yields were comparatively low,
but we observed allene formation by NMR studies of
one of the reaction mixture.
In summary, we have developed a simple, economical, and
high yield process for the preparation of multifunctional
5H-thiazolo[3,2-a]pyrimidines by the reaction of 4-aryl
thiopyrimidines with propargyl bromide in presence of
inorganic base. These compounds are of great synthetic
and chemotherapeutic importance. Application of these
compounds in designing of new biologically important
molecules is underway.
Figure 1. The chemical structure of two possible regioisomer.
Having established the standard reaction condition to access
thizolopyrimidine, we have investigated the scope of this
reaction with different substrates. Thus, a wide variety of thio-
dihydropyrimidines with carbmethoxy, carbethoxy, and acetyl
groups at C-3 and substituted phenyl ring at C-4 were reacted
with propargyl bromide to get the desired 5H-thiazolo[3,2-a]
pyrimidines (Scheme 2), and the results are shown in Table 2.
As shown in Table 2, the reaction was successful
with a wide range of thiodihydropyrimidines having
acetyl, carbethoxy, and carbmethoxy susbtitutents at C-5.
Further, substitution in the 4-phenyl ring either with
electron-donating or electron-withdrawing substituents
does not alter the course of reaction as the yields are
comparable. Thus, it is equally applicable in all kinds of
5-(carbmethoxy/carbethoxy/acetyl)-4-phenyl-1,4-dihy-
dropyrimidines. Structures of these compounds were
established on the basis of their spectroscopic data
and microanalyses.
Formation of the above thiazolo[3,2-a]-pyrimidines could
be rationalized via a mechanism similar to that proposed by
Botta and coworkers [20] (Fig. 3). The S-propargylation
of the thiodihydromidine I results in the intermediate com-
pound II. The latter may undergo cylization adopting either
of the two pathways, (i) path A consists in exo-dig cyclization
via nucleophilic attack of imine on to the triple bond to give an
intermediate III, which isomerizes to the desired thiazolo
[3,2-a]-pyrimidine (IV) or (ii) path B in isomerization consists
of triple bond to allene intermediate V followed by attack of
imine nitrogen on to the central carbon atom leading to
EXPERIMENTAL
Commercially available reagent grade chemicals were used as
received. TLC was carried out with E. Merck Kieselgel 60 F254
,
Spots were visualized under UV light, I2 vapors and by spraying
with a 20% aq. KMnO4. Column chromatography was performed
on silica gel (60–120 mesh, E. Merck). IR spectra were recorded
as thin films or in KBr solution with a Perkin–Elmer Spectrum
1
RX-1 (4000–450 cmÀ1) spectrophotometer. The H-NMR (200
and 300 MHz) and 13C-NMR (50 MHz) spectra were recorded
on a Brucker DRX-300 in CDCl3. Chemical shift values are reported
in ppm relative to TMS as internal reference, unless otherwise stated;
s (singlet), d (doublet), t (triplet); J in Hz. FAB mass spectra were
performed using a mass Spectrometer Jeol SX-102 and ESI mass
spectra with Quattro II (Micromass). Elemental analyses were
performed on a Perkin–Elmer 2400 II elemental analyzer.
General procedure for the synthesis of multifunctional
5H-thiazolo[3,2-a]-pyrimidines. To a stirred solution of 4-
pheyl-2-thio-dihydropyrimidines (1.0 equiv), propargyl bromide (1.1
equiv), and in ethanol/ methanol appropriate base was added and
stirring continued at 80ꢀC till the disappearance of the
starting thiodihydropyridmine (TLC). The reaction mixture
was cooled and neutralized by 4% aq. HCl solution and
concentrated in vacuum to evaporate the solvent. Then, the
reaction mixture was extracted by ethyl acetate/water. The
organic layer was dried over sodium sulphate (Na2SO4) and
concentrated under reduced pressure. The product was
purified by either by crystallization with appropriate solvent
or by column chromatography on a short column of silica
gel (60–120 mesh) using hexane: ethylacetate as eluant to
give the desired thiazolo[3,2-a]pyrimidine derivatives.
Figure 2. Possible NOE interactions.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
A Simple and Efficient One-Pot Synthesis of Multifunctional
5-Aryl-5H-thiazolo[3,2-a]-pyrimidines
603
Table 2
Synthesis of multifunctional 5H-thiazolo[3,2-a]-pyrimidines from different thiodihdropyrimidines with propargyl bromide.
Entry
R1
R2
Product
Time
Isolated yield (%)
1
2
3
4
5
6
7
8
Phenyl
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
OCH2CH3
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
40
4p
4q
4r
4s
30
25
30
25
25
30
35
9h
8h
8h
9h
30
25
30
35
30
30
35
30
35
30
30
92
91
93
93
92
88
90
85
86
82
84
94
90
93
94
93
92
90
94
89
90
92
4-Methoxy phenyl
4-Bromo phenyl
4-Chloro phenyl
3-Chloro phenyl
4-Fluoro phenyl
3-Nitrophenyl
2-Naphthyl
Phenyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
4-Fluoro phenyl
3,4-Dimethoxy phenyl
Phenyl
4-Methoxy phenyl
1-Naphthyl
2-Naphthyl
2-Chloro phenyl
3-Chloro phenyl
4-Chloro phenyl
3,4-Dimethoxy phenyl
3-Methoxy-4-hydroxy phenyl
2,3,4-Trimethoxy phenyl
4-Benzloxy phenyl
4t
4u
4v
OCH3
OCH3
aTo a stirred solution of thiodihydropyrimidines (1.0 equiv), propargyl bromide (1.1 equiv) in ethanol, NaOEt (1.1 eq) was added and stirring continued at
80ꢀC till the disappearance of the starting.
bTo a stirred solution of thiodihydropyrimidines (1.0 equiv), propargyl bromide (1.1 equiv) in acetone K2CO3 (1.5 eq) was added and stirring continued at
80ꢀC till the disappearance of the starting.
cTo a stirred solution of thiodihydropyrimidines (1.0 equiv), propargyl bromide (1.1 equiv) in methanol, NaOMe (1.1 eq) was added and stirring continued
at 80ꢀC till the disappearance of the starting.
Methyl 5-(4-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (2). This compound was obtained
as yellow solid, yield 92%; mp 138–140ꢀC; Rf = 0.5 (6:4 hexane/
ethylacetate); IR (KBr): 3432, 3121, 3036, 2945, 1694, 1600, 1474,
(s, 3H, CH3), 2.07 (s, 3H, CH3); 13C-NMR (50 MHz, CDCl3 + CCl4,):
d = 166.9, 166.5, 156.1, 139.1, 139.0, 135.0, 128.1, 128.0, 115.8,
115.4, 100.3, 99.9, 57.0, 50.8, 23.9, 13.9; ms (ESI+): m/z: 319 [M+H]+.
Anal. Calcd. for C16H15FO2N2S (318.37): C, 60.36; H, 4.75; N, 8.80.
Found: C, 60.33; H, 4.76; N, 8.78.
1
1360, 1215, 1080, 971, 829 cmÀ1; H NMR (200 MHz, CDCl3
Ethyl 3,7-dimethyl-5-phenyl-5H-thiazolo[3,2-a]pyrimidine-
6-carboxylate (4a). This compound was obtained as yellow
+ CCl4): d = 7.32–7.26 (m, 2H, ArH), 7.02–6.93 (m, 2H, ArH),
6.14 (s, 1H, CH), 5.96 (s, 1H, CH), 3.71 (s, 3H, OCH3), 2.36
Figure 3. Reaction mechanism proposed.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

604
S. Fatima, A. Sharma, R. Sharma, and R. P. Tripathi
Vol 49
solid, yield 92%, mp 110–111ꢀC, Rf = 0.5 (6:4 hexane/
Ethyl 5-(4-fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4f). It was obtained as yellow solid,
yield 88%, mp 100–101ꢀC; Rf = 0.5 (6:4 hexane/ethylacetate);
ir (KBr): 3520, 3398, 3019, 2928, 2358, 1661, 1481, 1218, 795,
ethylacetate); ir (KBr): 3355, 2932, 2365, 1665, 1590, 1481,
1219, 1084, 765 cmÀ1 1H-NMR (300 MHz, CDCl3 + CCl4):
;
d = 7.30–7.26 (m, 5H, ArH), 6.16 (s, 1H, CH), 5.92 (s, 1H,
CH), 4.19 (q, J = 7.20 Hz, 2H, OCH2), 2.37 (s, 3H, CH3),
2.07 (s, 3H, CH3), 1.32 (t, J = 7.05 Hz, 3H, CH3); 13C nmr
(50 MHz, CDCl3 + CCl4,): d = 166.7, 166.5, 155.9, 143.1,
135.2, 128.7, 128.1, 126.4, 100.1, 100.0, 59.6, 57.7, 23.9,
14.4, 14.0; ms (ESI+): m/z: 315 [M+H]+. Anal. Calcd. for
C17H18N2O2S (314.40): C, 64.94; H, 5.77; N, 8.91. Found: C,
64.90; H, 5.73; N, 8.90.
669 cmÀ1 1H-NMR (200 MHz, CDCl3+CCl4): d = 7.34–7.27
;
(m, 2H, ArH), 7.03–6.93 (m, 2H, ArH), 6.14 (s, 1H, CH), 5.95
(d, J = 1.2 Hz, 1H, CH), 4.21 (q, J = 7.0 Hz, 2H, OCH2), 2.37
(s, 3H, CH3), 2.07 (d, J = 1.2 Hz, 3H, CH3), 1.33 (t, J = 7.1 Hz,
3H, CH3); 13C-NMR (50 MHz, CDCl3+CCl4,): d = 166.5, 166.3,
155.8, 139.1, 139.0, 135.0, 128.2, 128.1, 115.8, 115.4, 100.2,
100.1, 59.7, 57.0, 23.9, 14.4, 13.9; ms (ESI+): m/z: 333 [M+H]+.
Anal. Calcd. for C17H17FN2 O2S (332.39): C, 61.43; H, 5.16; N,
8.43. Found: C, 61.40; H, 5.18; N, 8.42.
Ethyl 5-(4-methoxyphenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4b). It was obtained as yellow solid,
yield 91%, mp 112–113ꢀC; Rf = 0.4 (6:4 hexane/ethylacetate); IR
Ethyl 3,7-dimethyl-5-(3-nitrophenyl)-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4g). It was obtained as yellow
solid, yield 90%, mp 151–152ꢀC; Rf = 0.4 (6:4 hexane/
ethylacetate); IR (KBr): 3406, 2357, 1665, 1478, 1218, 1083,
1
(KBr): 3430, 3019, 1658, 1481, 1217, 762 cmÀ1; H-NMR (200
MHz, CDCl3 + CCl4): d = 7.30–7.20 (m, 2H, ArH), 6.82–6.76 (m,
2H, ArH), 6.08 (s, 1H, CH), 5.92 (d, J = 1.2 Hz, 1H, CH), 4.19
(q, J = 7.0 Hz, 2H, OCH2), 3.77 (s, 3H, OCH3), 2.36 (s, 3H,
CH3), 2.08 (d, J = 1.1 Hz, 3H, CH3), 1.32 (t, J = 7.12 Hz, 3H,
CH3); 13C-NMR (50 MHz, CDCl3+CCl4,): d = 166.6, 166.3,
159.3, 155.5, 135.6, 135.2, 127.7, 113.9, 100.4, 99.8, 59.5,
57.2, 55.0, 23.8, 14.4, 14.0; ms (ESI+): m/z: 345 [M+H]+.
Anal. Calcd. for C18H20N2O3S (344.43): C, 62.77; H, 5.85; N,
8.13. Found: C, 62.74; H, 5.87; N, 8.12.
770 cmÀ1 1H-NMR (200 MHz, CDCl3+CCl4): d = 8.15–8.11
;
(m, 2H, ArH), 7.66–7.62 (m, 1H, ArH), 7.52–7.45 (m, 1H, ArH),
6.28 (s, 1H, CH), 6.01 (d, J = 1.1 Hz, 1H, CH), 4.20 (q, J = 6.9
Hz, 2H, OCH2), 2.36 (s, 3H, CH3), 2.07 (d, J = 1.1 Hz, 3H,
CH3), 1.34 (t, J = 7.1 Hz, 3H, CH3); 13C-NMR (50 MHz,
CDCl3+CCl4,): d = 166.6, 166.3, 156.9, 148.2, 144.8, 134.6,
132.4, 130.0, 123.1, 121.2, 100.9, 99.1, 60.0, 57.1, 23.9,
14.4, 14.0; ms (ESI+): m/z: 360 [M+H]+. Anal. Calcd. for
C17H17O4N3S (359.40): C, 56.81; H, 4.77; N, 11.69. Found:
C, 56.80; H, 4.79; N, 11.67.
Ethyl 5-(4-bromophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4c). It was obtained as yellow solid,
yield 93%, mp 115–116ꢀC; Rf = 0.5 (6:4 hexane/ethylacetate);
IR (KBr): 3397, 3016, 1810, 1663, 1480, 1218, 1028, 762 cmÀ1
;
1-(3,7-dimethyl-5-(naphthalen-2-yl)-5H-thiazolo[3,2-a]
pyrimidin-6-yl)ethanone (4h). It was obtained as yellow viscous
liquid, yield 85%; Rf = 0.5 (6:4 hexane/ethylacetate); IR (Neat):
1H-NMR (300 MHz, CDCl3+CCl4): d = 7.44–7.41(m, 2H, ArH),
7.28–7.21 (m, 2H, ArH), 6.14 (s, 1H, CH), 5.97 (s, 1H, CH),
4.19 (q, J = 7.53 Hz, 2H, OCH2), 2.38 (s, 3H, CH3), 2.05 (s, 3H,
CH3), 1.31 (t, J = 7.11 Hz, 3H, CH3); 13C-NMR (50 MHz,
CDCl3+CCl4,): d = 166.5, 166.4, 156.1, 142.0, 134.9, 131.8,
128.1, 122.2, 100.2, 99.7, 59.7, 57.2, 23.9, 14.4, 13.9; MS
(ESI+): m/z: 394 [M+H]+. Anal. Calcd. for C17H17Br N2O2S
(393.30): C, 51.92; H, 4.36; N, 7.12. Found: C, 51.91; H, 4.38; N, 7.10.
Ethyl 5-(4-chlorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4d). It was obtained as yellow
solid, yield 93%, mp 117–118ꢀC; Rf = 0.5 (6:4 hexane/
ethylacetate); IR (KBr): 3776, 3423, 3019, 2928, 2363, 1662,
3749, 3021, 2398, 1705, 1217, 763, 670 cmÀ1 1H-NMR
;
(200 MHz, CDCl3+CCl4): d = 7.79–7.70 (m, 4H, ArH), 7.50–7.30
(m, 3H, ArH), 6.59 (s, 1H, CH), 6.04 (s, 1H, CH), 2.43 (s, 3H,
CH3), 2.41 (s, 3H, CH3), 2.15 (s, 3H, CH3); 13C-NMR (50 MHz,
CDCl3+CCl4,): d = 193.8, 166.8, 155.8, 140.0, 136.1, 133.1,
133.0, 128.8, 128.3, 127.5, 126.1, 125.0, 124.5, 111.8, 100.8, 56.9,
31.6, 25.4, 14.0; ms (ESI+): m/z: 335 [M+H]+. Anal. Calcd. for
C20H18N2OS (334.43): C, 71.83; H, 5.42; N, 8.38. Found: C,
71.80; H, 5.44; N, 8.36.
1-(3,7-dimethyl-5-phenyl-5H-thiazolo[3,2-a]pyrimidin-6-yl)
ethanone (4i). It was obtained as yellow viscous liquid, yield
86%; Rf = 0.5 (6:4 hexane/ethylacetate); IR (Neat): 3419, 3020,
1
1590, 1481, 1217, 1084, 766, 670 cmÀ1; H-NMR (200 MHz,
CDCl3+CCl4): d = 7.25–7.22 (m, 4H, ArH), 6.09 (s, 1H, CH),
5.91 (d, J = 1.22 Hz, 1H, CH), 4.16 (q, J = 7.10 Hz, 2H,
OCH2), 2.32 (s, 3H, CH3), 2.02 (d, J = 1.2 Hz, 3H, CH3), 1.29
(t, J = 7.12 Hz, 3H, CH3); 13C-NMR (50 MHz, CDCl3+CCl4,):
d = 166.6, 166.5, 156.0, 141.5, 135.0, 134.1, 128.9, 127.8,
100.3, 99.8, 59.8, 57.1, 23.9, 14.4, 14.0; MS (ESI+): m/z: 349
[M+H]+. Anal. Calcd. for C17H17ClO2N2S (348.85): Calcd. C,
58.53; H, 4.91; N, 8.03 Found: C, 58.50; H, 5.92; N, 8.00.
Ethyl 5-(3-chlorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4e). It was obtained as yellow
viscous liquid yield 92%; Rf = 0.5 (6:4 hexane/ethylacetate); IR
2366, 1728, 1468, 1219, 769 cmÀ1 1H-NMR (200 MHz,
;
CDCl3+CCl4): d = 7.27–7.23 (m, 5H, ArH), 6.40 (s, 1H, CH),
6.00 (s, 1H, CH), 2.38 (s, 6H, 2 X CH3), 2.10 (s, 3H, CH3);
ms (ESI+): m/z: 285 [M+H]+. Anal. Calcd. for C16H16N2OS
(284.38): C, 67.58; H, 5.67; N, 9.85. Found: C, 67.55; H, 5.66; N, 9.81.
1-(5-(4-Fluorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidin-6-yl)ethanone (4j). It was obtained as yellow solid,
yield 82%, mp 135–136ꢀC; Rf = 0.4 (6:4 hexane/ethylacetate); IR
(KBr): 3427, 3019, 2368, 1604, 1467, 1219, 768 cmÀ1; 1H-NMR
(300 MHz, CDCl3+CCl4): d = 7.28–7.23 (m, 2H, ArH),
6.96–6.90 (m, 2H, ArH), 6.36 (s, 1H, CH), 6.01 (s, 1H, CH),
2.37 (s, 6H, 2 X CH3), 2.08 (s, 3H, CH3); 13C-NMR (50 MHz,
CDCl3+CCl4,): d = 193.7, 166.6, 155.8, 138.7, 138.6, 135.8, 128.1,
128.0, 115.6, 115.3, 111.9, 100.8, 56.0, 31.5, 25.3, 13.8; ms(ESI+):
m/z: 303 [M+H]+. Anal. Calcd for C16H15FN2OS (302.37): C,
63.56; H, 5.00; N, 9.26. Found: C, 63.55; H, 5.05; N, 9.23.
(Neat): 3571, 2928, 2387, 1688, 1479, 1218, 1082, 767 cmÀ1
;
1H-NMR (200 MHz, CDCl3+CCl4): d = 7.32–7.20 (m, 4H,
ArH), 6.17 (s, 1H, CH), 6.00 (d, J = 1.2 Hz, 1H, CH), 4.24 (q,
J = 7.14 Hz, 2H, OCH2), 2.39 (s, 3H, CH3), 2.10 (d, J = 1.2
Hz, 3H, CH3), 1.37 (t, J = 7.12 Hz, 3H, CH3); 13C-NMR (50
MHz, CDCl3+CCl4,): d = 166.4, 156.3, 144.8, 134.9, 134.5,
130.1, 128.4, 126.5, 124.5, 100.4, 99.5, 59.8, 57.2, 23.9, 14.4,
14.0; ms (ESI+): m/z: 349 [M+H]+. Anal. Calcd. for
C17H17ClO2N2S (348.85): C, 58.53; H, 4.91; N, 8.03. Found:
C, 58.51; H, 4.92; N, 8.00.
1-(5-(3,4-dimethoxyphenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidin-6-yl)ethanone (4k). It was obtained as yellow solid,
yield 84%, mp 129–130ꢀC; Rf = 0.4 (6:4 hexane/ethylacetate);
ir (KBr): 3463, 3019, 2364, 1599, 1465, 1218, 765 cmÀ1. 1H-NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
A Simple and Efficient One-Pot Synthesis of Multifunctional
5-Aryl-5H-thiazolo[3,2-a]-pyrimidines
605
(200 MHz, CDCl3+CCl4): d = 6.87 (s, 1H, ArH), 6.70 (s, 2H, ArH),
6.31 (s, 1H, CH), 5.98 (s, 1H, CH), 3.81 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 2.36 (s, 6H, 2 X CH3), 2.09 (s, 3H, CH3); 13C-NMR
(50 MHz, CDCl3+CCl4,): d = 194.0, 166.6, 155.6, 149.0,
148.6, 136.1, 135.6, 128.1, 128.0, 118.2, 115.6, 115.3, 112.0,
111.0, 109.7, 100.8, 100.5, 56.3, 55.8, 55.7, 31.6, 25.3, 13.9;
ms (ESI+): m/z: 345 [M+H]+. Anal. Calcd. for C18H20N2O3S
(344.43): C, 62.77; H, 5.85; N, 8.13. Found: C, 62.75; H,
5.87; N, 8.10.
Methyl 3,7-dimethyl-5-phenyl-5H-thiazolo[3,2-a]pyrimidine-6-
carboxylate (4l). It was obtained as yellow solid, yield 94%, mp
120–121ꢀC; Rf = 0.5 (6:4 hexane/ethylacetate); IR (KBr): 3567,
2914, 2337, 1673, 1492, 1220, 1089, 976, 697 cmÀ1; 1H-NMR (200
MHz, CDCl3+CCl4): d = 7.32–7.26 (m, 5H, ArH), 6.16 (s, 1H, CH),
5.94 (d, J = 0.9 Hz, 1H, CH), 3.71 (s, 3H, OCH3), 2.37 (s, 3H,
CH3), 2.07 (s, 3H, CH3); 13C-NMR (50 MHz, CDCl3+CCl4,):
d = 167.0, 166.6, 156.1, 143.1, 135.2, 128.7, 128.1, 126.3,
100.0, 99.8, 57.7, 50.8, 23.9, 14.0; ms (ESI+): m/z: 301 [M+H]+.
Anal. Calcd. for C16H16O2N2S (300.38): C, 63.98; H, 5.37; N, 9.33.
Found: C, 63.95; H, 5.30; N, 9.31.
7.35–7.21 (m, 3H, ArH), 6.58 (s, 1H, CH), 5.90 (s, 1H, CH), 3.67
(s, 3H, OCH3), 2.43 (s, 3H, CH3), 2.17 (s, 3H, CH3); 13C-NMR
(50 MHz, CDCl3+CCl4,): d =166.6, 166.4, 156.4, 141.7, 135.7,
130.5, 130.3, 129.5, 128.2, 99.8, 99.7, 54.6, 50.6, 23.5, 14.5; ms
(ESI+): m/z: 335 [M+H]+. Anal. Calcd for C16H15ClN2O2S
(334.82): C, 57.40; H, 4.52; N, 8.37. Found: C, 57.38; H, 4.53;
N, 8.35.
Methyl 5-(3-chlorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4q). It was obtained as yellow
viscous liquid, yield 92%; Rf = 0.5 (6:4 hexane/ethylacetate); ir
(Neat): 3378, 3022, 2366, 2264, 1880, 1662, 1590, 1478, 1217,
1
763, 671 cm-1; H nmr (200MHz, CDCl3+CCl4): d = 7.30-7.22
(m, 4H, ArH), 6.18 (s, 1H, CH), 6.01 (d, J = 1.2 Hz, 1H, CH),
3.75 (s, 3H, OCH3), 2.39 (s, 3H, CH3), 2.11(d, J = 1.2 Hz, 3H,
CH3); 13C nmr (50MHz, CDCl3+CCl4,): d = 166.9, 166.5,
144.8, 134.9, 134.7, 130.1, 128.4, 126.4, 124.4, 100.5, 57.2,
50.9, 23.8, 14.0; ms (ESI+): m/z: 335 [M+H]+. Anal. Calcd for
C16H15ClN2O2S (334.82): C, 57.40; H, 4.52; N, 8.37. Found:
C, 57.37; H, 4.50; N, 8.33.
Methyl 5-(4-chlorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4r). It was obtained as yellow
viscous liquid, yield 90%; Rf = 0.5 (6:4 hexane/ethylacetate); IR
(Neat): 3468, 3366, 3021, 2364, 1579, 1477, 1217, 767,
Methyl 5-(4-methoxyphenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4m). It was obtained as yellow solid,
yield 90%, mp 126–127ꢀC; Rf = 0.4 (6:4 hexane/ethylacetate); IR
(KBr): 3417, 2930, 1626, 1480, 1218, 1088, 765, 699 cmÀ1
;
670 cmÀ1 1H-NMR (200 MHz, CDCl3+CCl4): d = 7.37–7.28
;
1H-NMR (200 MHz, CDCl3+CCl4): d = 7.28–7.19 (m, 2H, ArH),
6.79–6.76 (m, 2H, ArH), 6.06 (s, 1H, CH), 5.90 (s, 1H, CH),
3.75 (s, 3H, OCH3), 3.68 (s, 3H, OCH3), 2.34 (s, 3H, CH3),
2.05 (s, 3H, CH3); 13C-NMR (50 MHz, CDCl3+CCl4,):
d = 167.0, 166.3, 159.4, 155.5, 135.5, 135.2, 127.6, 114.0, 100.3,
100.0, 57.2, 55.0, 50.7, 23.7, 13.9; MS (ESI+): m/z: 331 [M+H]+.
Elemental Anal. Calcd for C17H18O3N2S: C, 61.80; H, 5.49; N, 8.48.
Found: C, 61.75; H, 5.46; N, 8.42.
(m, 4H, ArH), 6.16 (s, 1H, CH), 5.98 (d, J = 1.2 Hz, 1H, CH),
3.73 (s, 3H, OCH3), 2.37 (s, 3H, CH3), 2.09(d, J = 1.2 Hz, 3H,
CH3); 13C-NMR (50 MHz, CDCl3+CCl4,): d = 167.0, 166.5,
156.1, 141.5, 135.0, 134.1, 128.9, 127.7, 100.4, 99.6, 57.1,
50.9, 23.9, 13.8; ms (ESI+): m/z: 335 [M+H]+. Anal. Calcd for
C16H15ClN2O2S (334.82): C, 57.40; H, 4.52; N, 8.37. Found:
C, 57.38; H, 4.51; N, 8.36.
Methyl 5-(3,4-dimethoxyphenyl)-3,7-dimethyl-5H-thiazolo
[3,2-a]pyrimidine-6-carboxylate (4s). It was obtained as yellow
solid, yield 94%, mp 167–168ꢀC; Rf = 0.4 (6:4 hexane/
ethylacetate); IR (KBr): 3572, 3020, 2396, 1685, 1516, 1217, 767,
Methyl 3,7-dimethyl-5-(naphthalen-1-yl)-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4n). It was obtained as yellow solid,
yield 93%, mp 164–165ꢀC; Rf = 0.4 (6:4 hexane/ethylacetate); IR
(KBr): 3392, 3020, 2930, 2370, 1662, 1481, 1217, 765, 670 cmÀ1
;
670 cmÀ1; H-NMR (200 MHz, CDCl3+CCl4): d = 6.87–6.72
1
1H-NMR (200 MHz, CDCl3+CCl4): d = 8.48 (d, J = 8.52 Hz,
1H, ArH), 7.84–7.75 (m, 3H, ArH), 7.63–7.39 (m, 3H, ArH), 6.98
(s, 1H, CH), 5.80 (d, J = 1.2 Hz, 1H, CH), 3.51 (s, 3H, OCH3),
2.43 (s, 3H, CH3), 1.88 (d, J = 1.2 Hz, 3H, CH3); 13C-NMR
(50 MHz, CDCl3+CCl4,): d = 166.9, 166.6, 155.5, 140.9,
135.7, 133.3, 129.2, 129.1, 128.7, 127.2, 126.4, 126.1, 125.5,
123.4, 100.8, 99.7, 53.5, 50.5, 23.8, 14.6; MS (ESI+): m/z: 351 [M+H]+.
Anal. Calcd for C20H18N2O2S (350.43): C, 68.55; H, 5.18; N, 7.99.
Found: C, 68.52; H, 5.19; N, 7.94.
(m, 3H, ArH), 6.10 (s, 1H, CH), 5.94 (d, J = 1.2 Hz, 1H, CH),
3.85 (s, 3H, OCH3), 3.83 (s, 3H, OCH3), 3.72 (s, 3H, OCH3),
2.36 (s, 3H, CH3), 2.09(d, J = 1.0 Hz, 3H, CH3); 13C-NMR
(50 MHz, CDCl3+CCl4,): d = 167.1, 166.5, 155.8, 149.2,
148.9, 135.8, 135.3, 118.4, 111.0, 109.4, 100.1, 99.9, 57.4,
55.7, 50.8, 23.9, 14.0; ms (ESI+): m/z: 361 [M+H]+. Anal.
Calcd. for C18H20N2O4S (360.43): C, 59.98; H, 5.59; N, 7.77.
Found: C, 59.95; H, 5.60; N, 7.74.
Methyl 5-(4-hydroxy-3-methoxyphenyl)-3,7-dimethyl-5H-
thiazolo[3,2-a]pyrimidine-6-carboxylate (4t). It was obtained
as yellow viscous liquid, yield 89%; Rf = 0.4 (6:4 hexane/
ethylacetate); ir (Neat): 3427, 3021, 2363, 1660, 1593, 1217,
Methyl 3,7-dimethyl-5-(naphthalen-2-yl)-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4o). It was obtained as yellow solid,
yield 94%, mp 124–125ꢀC; Rf = 0.4 (6:4 hexane/ethylacetate); IR
(KBr): 3380, 3021, 2364, 2173, 1659, 1216, 766, 671 cmÀ1
;
766, 671 cm-1; H nmr (200MHz, CDCl3+CCl4): d = 6.96-6.78
1
1H-NMR (200 MHz, CDCl3+CCl4): d = 7.83–7.72 (m, 4H,
ArH), 7.51–7.30 (m, 3H, ArH), 6.33 (s, 1H, CH), 5.92 (s, 1H,
CH), 3.71 (s, 3H, OCH3), 2.40 (s, 3H, CH3), 2.08 (s, 3H,
CH3); 13C-NMR (50 MHz, CDCl3+CCl4,): d = 167.0, 166.6,
156.1, 140.3, 135.3, 133.1, 128.9, 128.3, 127.5, 126.2, 125.0,
124.4, 100.1, 99.8, 58.0, 50.8, 23.9, 14.0; ms (ESI+): m/z: 351
[M+H]+. Anal. Calcd for C20H18N2O2S (350.43): C, 68.55; H,
5.18; N, 7.99. Found: C, 68.50; H, 5.15; N, 7.93.
(m, 3H, ArH), 6.12 (s, 1H, CH), 5.97 (s, 1H, CH), 4.73 (d, J = 2.30
Hz, 1H, OH), 3.84 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 2.37 (s, 3H,
CH3), 2.03(s, 3H, CH3); 13C nmr (50MHz, CDCl3+CCl4,): d = 167.1,
166.5, 155.8, 149.8, 146.8, 137.0, 135.3, 118.2, 114.0, 109.8, 100.1,
100.0, 57.3, 55.7, 50.8, 23.8, 14.0; ms (ESI+): m/z: 347 [M+H]+. Anal.
Calcd. for C17H18O4N2S (346.40): C, 58.94; H, 5.24; N, 8.09. Found:
C, 58.90; H, 5.26; N, 8.05.
Methyl 3,7-dimethyl-5-(2,3,4-trimethoxyphenyl)-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4u). It was obtained as yellow viscous
liquid, yield 90%; Rf = 0.4 (6:4 hexane/ethylacetate); IR (Neat):
Methyl 5-(2-chlorophenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4p). It was obtained as yellow solid,
yield 93%, mp 118–120ꢀC; Rf = 0.5 (6:4 hexane/ethylacetate); IR
3367, 3022, 2364, 2077, 1660, 1592, 1327, 1213, 762, 671 cmÀ1
;
(KBr): 3370, 2950, 2366, 1480, 1218, 1090, 769, 670 cmÀ1
;
1H-NMR (200 MHz, CDCl3+CCl4): d = 7.30 (s, 1H, ArH), 6.51
(s, 2H, ArH), 6.13 (s, 1H, CH), 5.99 (d, J = 1.2 Hz, 1H, CH), 3.83
1H-NMR (200 MHz, CDCl3+CCl4): d = 7.69–7.64 (m, 1H, ArH),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

606
S. Fatima, A. Sharma, R. Sharma, and R. P. Tripathi
Vol 49
[7] Geist, J. G.; Lauw, S.; Illarionova, V.; Illarionov, B.; Fischer,
M.; Grawert, T.; Rohdich, F.; Eisenreich, W.; Kaiser, J.; Groll, M.;
Scheurer, C.; Wittlin, S.; Alonso-Gómez, J. L.; Schweizer, W. B.; Bacher,
A. Chem Med Chem 2010, 5, 1092.
[8] Liu, S.; Yang, L.; Jin, Z.; Huang, E.; Wan, D. C. C.; Lin, H.;
Hua, C. ARKIVOC 2009, x, 333.
[9] Wichmann, J.; Adam, G.; Kolczewski, S.; Mutel, V.; Woltering, T.
Bioorg Med Chem Lett 1999, 9, 1573.
[10] Awadallah, F. M. Sci Pharm 2008, 76, 415.
[11] Rashad, A. E.; Shamroukh, A. H.; Abdel-Megeid, R. E.;
Kandeil, A. M.; Mostafa, A.; Elshesheny, R.; Ali, M. A.; Banert, K. Eur
J Med Chem 2010, 11, 5251.
[12] Shridhar, D. R.; Jogibhukta, M.; Krishnan, V. S. H. Indian J
Chem B 1986, 25, 345.
[13] Munchhof, M. J.; Beebe, J. S.; Casavant, J. M.; Cooper, B. A.;
Doty, J. L.; Higdon, R. C.; Hillerman, S. M.; Soderstrom, C. I.; Knauth, E.
A.; Marx, M. A.; Rossi, A. M. K.; Sobolov, S. B.; Sun, J. Bioorg Med
Chem Lett 2004, 14, 21.
[14] Balkan, A.; Uma, S.; Ertan, M.; Wiegrebe, W. Pharmazie
1992, 47, 687.
[15] Wichmann, J.; Adam, G.; Kolczewski, S.; Mutel, V.; Woltering, T.
Bioorg Med Chem Lett 1999, 9, 1573.
(s, 12H, 3 X OCH3), 3.76 (s, 3H, OCH3), 2.38 (s, 3H, CH3), 2.12
(s, 3H, CH3); 13C-NMR (50 MHz, CDCl3+CCl4,): d = 167.2,
166.6, 153.9, 138.4, 135.4, 128.8, 103.0, 100.1, 99.9, 60.6, 57.6,
56.0, 50.9, 23.8, 14.0; ms (ESI+): m/z: 391 [M+H]+. Anal. Calcd.
for C19H22O5N2S (390.45): C, 58.45; H, 5.68; N, 7.17. Found: C,
58.42; H, 5.66; N, 7.16.
Methyl 5-(4-(benzyloxy)phenyl)-3,7-dimethyl-5H-thiazolo[3,2-a]
pyrimidine-6-carboxylate (4v). It was obtained as yellow solid, yield
92%, mp 198–199ꢀC; Rf = 0.4 (6:4 hexane/ethylacetate); IR (KBr):
3512, 2398, 2367, 1700, 1484, 1213, 1079, 1012, 748, 546 cmÀ1
;
1H-NMR (200 MHz, CDCl3+CCl4): d = 7.44–7.26 (m, 7H, ArH),
6.95–6.89 (m, 2H, ArH), 6.13 (s, 1H, CH), 5.96 (d, J = 1.3 Hz, 1H,
CH), 5.04 (s, 2H, OCH2), 3.72 (s, 3H, OCH3), 2.41 (s, 3H, CH3),
2.09(d, J = 1.2 Hz, 3H, CH3); 13C-NMR (50 MHz, CDCl3+CCl4,):
d = 167.3, 166.7, 158.7, 156.0, 136.8, 135.9, 135.4, 128.6, 128.0,
127.7, 127.5, 114.9, 100.2, 100.1, 70.0, 57.2, 50.9, 23.9, 14.0; ms
(ESI+): m/z: 407 [M+H]+. Anal. Calcd. for C23H22O3N2S (406.50):
C, 67.96; H, 5.46; N, 6.89. Found: C, 67.95; H, 5.43; N, 6.85.
[16] Shridhar, D. R.; Jogibhukta, M.; Joshi, P. P.; Rao, C.; Seshagiri, J.
A. Y. Indian J Chem B 1984, 23, 492.
[17] Ahmad, N. M.; Jones, K. Tetrahedron lett 2010, 51, 3263.
[18] Quan, Z.; Zhang, Z.; Wang, J.; Wang, X.; Liu, Y.; Ji, P.-Y.
Heteroatom Chem 2008, 19, 149.
[19] Al-Rashood, K. A.; Abdel-Aziz, H. A. Molecules 2010, 15, 3775.
[20] Castagnolo, D.; Pagano, M.; Bernardini, M.; Botta, M. Synlett
2009, 13, 2093.
Acknowledgments. The authors thank CSIR and DRDO, New
Delhi for financial assistance. Seerat and Anindra are thankful to
CSIR New Delhi for their SRF and Rahul is thankful to DRDO
New Delhi for PA. The authors also thank SAIF staff for
providing the spectral data and microanalysis.
REFERENCES AND NOTES
[21] Singh, B. K.; Mishra, M.; Saxena, N.; Yadav, G. P.; Maulik, P.
R.; Sahoo, M. K.; Gaur, R. L.; Murthy, P. K.; Tripathi, R. P. Eur J Med
Chem 2008, 43, 2717.
[22] Katiyar, D.; Tiwari, V. K.; Tripathi, R. P.; Srivastava, A.;
Chaturvedi, V.; Srivastava, R.; Srivastava, B. S. Bioorg Med Chem
2003, 11, 4369.
[23] Mahalingam, S. M.; Aidhen, I. S. J Org Chem 2006, 71, 349.
[24] Wang, X.; Quan, Z.; Wang, J. K.; Zhang, Z.; Wang, M. Bioorg
Med Chem Lett 2006, 16, 4592.
[1] Biginelli, P. Gazz Chim Ital 1893, 23, 360.
[2] Kappe, C. O. Tetrahedron 1993, 49, 6937.
[3] Kappe, C. O. Acc Chem Res 2000, 33, 879.
[4] Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999, 1799
and references cited therein.
[5] Simon, C.; Constantieux, T.; Rodriguez, J. Eur J Org Chem
2004, 4957 and references cited therein.
[6] Kappe, C. O. QSAR Comb Sci 2003, 22, 630.
[25] Dallinger, D.; Gorobets, N. Y.; Kappe, C. O. Org Lett 2003, 5, 1205.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet