Synthesis of novel isoxazolyl bis-thiazolo[3,2-a]pyrimidines

Article abstract of DOI:10.1016/j.cclet.2012.06.029

A new synthetic strategy for the synthesis of novel 3-(3-(3-methyl-4- nitroisoxazol-5-yl)-2-phenyl-1-(5,7-diaryl-7H-thiazolo[3,2-a]pyrimidin-3-yl) propyl)-5,7-diaryl-7H-thiazolo[3,2-a] pyrimidines (7a-i) analogues is described. Reaction of 3-(2-(3-methyl-4-nitroisoxazole-5-yl)-1-phenylethyl)pentane-2,4- dione (3) with two moles of thiourea in presence of iodine and CuO afforded 4-(1-(2-aminothiazol-4-yl)-3-(3-methyl-4-nitroisoxazol-5-yl)-2-aryl propyl-thiazol-2-amine (5). Compound 5 on reaction with two moles of chalcone (6) furnished novel 3-(3-(3-methyl-4-nitroisoxazol-5-yl)-2-phenyl-1-(5,7-diaryl- 7H-thiazolo[3,2-a]pyrimidin-3-yl)propyl)-5,7-diaryl-7H-thiazolo[3,2-a] pyrimidines (7a-i).

Full text of DOI:10.1016/j.cclet.2012.06.029

Available online at www.sciencedirect.com
Chinese Chemical Letters 23 (2012) 899–902
www.elsevier.com/locate/cclet
Synthesis of novel isoxazolyl bis-thiazolo[3,2-a]pyrimidines
*
E. Rajanarendar , S. Ramakrishna, K. Rama Murthy
Department of Chemistry, Kakatiya University, Warangal, AP 506 009, India
Received 1 April 2012
Available online 4 July 2012
Abstract
A new synthetic strategy for the synthesis of novel 3-(3-(3-methyl-4-nitroisoxazol-5-yl)-2-phenyl-1-(5,7-diaryl-7H-thia-
zolo[3,2-a]pyrimidin-3-yl)propyl)-5,7-diaryl-7H-thiazolo[3,2-a] pyrimidines (7a–i) analogues is described. Reaction of 3-(2-
(3-methyl-4-nitroisoxazole-5-yl)-1-phenylethyl)pentane-2,4-dione (3) with two moles of thiourea in presence of iodine and CuO
afforded 4-(1-(2-aminothiazol-4-yl)-3-(3-methyl-4-nitroisoxazol-5-yl)-2-aryl propyl-thiazol-2-amine (5). Compound 5 on reaction
with two moles of chalcone (6) furnished novel 3-(3-(3-methyl-4-nitroisoxazol-5-yl)-2-phenyl-1-(5,7-diaryl-7H-thiazolo[3,2-
a]pyrimidin-3-yl)propyl)-5,7-diaryl-7H-thiazolo[3,2-a] pyrimidines (7a–i).
# 2012 E. Rajanarendar. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Isoxazolyl bis-thiazoles; Isoxazolyl bis-thiazolo[3,2-a]pyrimidines; New synthetic strategy
Thiazolopyrimidines [TAPM] have been received particular attention and widely recognized as biologically useful
systems, since they are important structural components of purine bases. Apparently, the thiazolopyrimidine scaffold
is not very frequently used in drug discovery programs. However, biological activities of certain thiazolopyrimidines
have been reported. Thaizolo[4,5-b]pyrimidine (a guanosine analogue) exhibited in vitro activity against a variety
RNA and DNA viruses [1] and also had antitumor and antimetastatic properties [2]. 2-Aminothiazolo[4,5-
b]pyrimidine acts as CXCR2 receptor antagonist [3]. Thaizolo[4,5-b]pyrimidine-5,7-dione analogues have been
reported to possess anti-inflammatory activities due to TNF inhibition [4]. Thiazolopyrimidines are also have been
found to exhibit a wide range of biological activities, such as antiviral, antibacterial, anticancer, androgenic, anabolic
and anti-human cytomegalovirus (HCMV) activities [5–9]. In addition, thiazolopyrimidines also can be utilized as
templates which have been additionally functionalized to achieve selective receptors or enzyme interactions [10].
Biological activity of substituted isoxazoles has made them a focus of medicinal chemistry over years. Isoxazoles are
potent analgesic, anti-inflammatory [11], antimicrobial [12], COX-2 inhibitory [13], anti-tubercular [14],
anticonvulsant [15] and anticancer agents [16]. Inspired with the biological profile of thiazolopyrimidine and
isoxazole nuclei and their increasing importance in pharmaceutical and biological fields, and in connection with our
search on the design and synthesis of biologically active and pharmacologically important new heterocycles linked to
isoxazoles [17], it was thought worthwhile to synthesize the title compounds with a view to obtain certain chemical
entities with active pharmachophores in a single molecular framework.
* Corresponding author.
E-mail address: rajanarendareligeti@gmail.com (E. Rajanarendar).
1001-8417/$ – see front matter # 2012 E. Rajanarendar. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2012.06.029

900
E. Rajanarendar et al. / Chinese Chemical Letters 23 (2012) 899–902
1. Experimental
All the melting points were determined on a Cintex melting point apparatus and are uncorrected. Analytical TLC
was performed on Merck precoated 60 F254 silica gel plates. Visualization was done by exposing to iodine vapor. IR
spectra (KBr pellet) were recorded on a Perkin Elmer BX series FT-IR spectrometer. 1H NMR spectra were recorded
on a Varian Gemini 300 MHz spectrometer. 13C NMR spectra were recorded on a Bruker 75 MHz spectrometer.
Chemical shift values are given in d ppm with tetramethyl silane as an internal standard. Mass spectral measurements
were carried out by EI method on a Jeol JMC-300 spectrometer at 70 eV. Elemental analyses were performed on a
Carlo Erba 106 and Perkin-Elmer model 240 analyzers.
1.1. Synthesis of 1-(2-aminothiazol-4-yl)-3-(3-methyl-4-nitroisoxazol-5-yl)-2-arylpropyl-thiazol-2-amine 5
A mixture of 3-(2-(3-methyl-4-nitroisoxazole-5-yl)-1-phenylethyl) pentane-2,4-dione (3) (0.01 mol), thiourea
(0.02 mol), iodine (0.01 mol) and CuO (0.01 mol) were taken in ethanol (15 mL). The reaction mixture was refluxed
for about 8 h. After completion of the reaction (monitored by TLC), the solvent was removed under pressure and added
30 mL water to the residue, then extracted with ethyl acetate and the residue was purified by recrystallization from
methanol to produce 5 in high yield.
1.2. Synthesis of 3-(3-(3-methyl-4-nitroisoxazol-5-yl)-2-phenyl-1-(5,7-diaryl-7H-thiazolo[3,2-a]pyrimidin-3-
yl)propyl)-5,7-diaryl-7H-thiazolo[3,2-a]pyrimidines 7
To a solution of 1-(2-aminothiazol-4-yl)-3-(3-methyl-4-nitroisoxazol-5-yl)-2-arylpropylthiazol-2-amine (5)
(0.01 mol) in dioxane (20 mL) and chalcone (0.02 mol) was added and reaction mixture was refluxed for 4 h.
After the completion of the reaction (monitored by TLC), the reaction mixture was poured onto crushed ice, separated
solid was filtered off and recrystallized from ethyl acetate to produce (7a–i) in good yields.
2. Results and discussion
The synthesis of title compounds 7 was accomplished by a new synthetic strategy and is shown in Scheme 1. The
key intermediate 3-(2-(3-methyl-4-nitroisoxazole-5-yl)-1-phenylethyl)pentane-2,4-dione 3, required for synthesis of
target compounds was obtained by Michael addition of 3-methyl-4-nitrostyrylisoxazole 1 with acetyl acetone in
refluxing triethyl amine [18]. Compound 3 on cyclocondensation reaction with two moles of thiourea under reflux in
presence of iodine and CuO in ethanol gave 4-(1-(2-aminothiazol-4-yl)-3-(3-methyl-4-nitroisoxazol-5-yl)-2-
arylpropyl-thiazol-2-amine 5 in excellent yields [19]. This is in accordance with earlier observation [20].
Compound 5 on reaction with two moles of chalcone (having a,b-unsaturated carbonyl system) in dioxane under
reflux for 4 h. resulted in the formation of 3-(3-(3-methyl-4-nitroisoxazol-5-yl)-2-phenyl-1-(5,7-diaryl-7H-
thiazolo[3,2-a]pyrimidin-3-yl)propyl)-5,7-diaryl-7H-thiazolo[3,2-a]pyrimidines 7 in excellent yields [21].
The pyrimidine ring is formed as the amino group of thiazole makes a nucleophilic attack on the b-carbon of the
]
H3C
NO2
H3C
NH2CSNH2
NO2
H3C
NO2
2
S
N
H3C
NO2
S
N
O
N
NH2
N
O
CH3COCH2COCH3
4
O
Ar
O
Ar-CH=CH-C-Ar'
2
2
CH3
N
N
N
6
I2, CuO, ethanol,
, 8h
Ph
Ar'
O
Et3N,
2h
Ph
O
Ph
H3C
Ar'
Dioxane,
, 4h
N
N
Ph
O
S
S
H2N
N
Ar
1
3
5
7
7a-i: Ar = C6H5, Ar' = C6H5; Ar = C6H5, Ar' = 4-ClC6H4; Ar = C6H5, Ar'= 4-CH3C6H4; Ar = C6H5, Ar'= 4-CH3OC6H4 ; Ar = C6H5, Ar' = 2-OHC6H4; Ar =
4-CH3C6H4, Ar' = C6H5; Ar = 4-CH3OC6H4, Ar' = C6H5; Ar = 2-ClC6H4, Ar' = C6H5; Ar = 4-ClC6H4, Ar' = C6H5
Scheme 1. 7a–i: Ar = C6H5, Ar0 = C6H5; Ar = C6H5, Ar0 = 4-ClC6H4; Ar = C6H5, Ar0 = 4-CH3C6H4; Ar = C6H5, Ar0 = 4-CH3OC6H4; Ar = C6H5,
Ar0 = 2-OHC6H4; Ar = 4-CH3C6H4, Ar0 = C6H5; Ar = 4-CH3OC6H4, Ar0 = C6H5; Ar = 2-ClC6H4, Ar0 = C6H5; Ar = 4-ClC6H4, Ar0 = C6H5.

[(Scheme_2)TD$FIG]
E. Rajanarendar et al. / Chinese Chemical Letters 23 (2012) 899–902
901
Ar
..
H3C
NO2
Ph
NH2
..
S
H3C
NO2
H3C
NO2
H3C
NO2
Ph
Ar
H
N
N
H
Ar
Ar
N
S
S
S
N
N
6
O
N
N
O
Ar'
N
N
N
N
O
O
O
O
Ar'
Ar'
OH
Ar'
Ph
Ph
Ar'
5
N
S
N
N
S
S
N
HO
S
-
H O
2
2
Ar'
O
NH
..
2
Ar'
N
..
NH
N
H
Ar'
6
Ar
Ar
Ar
O
Ar
A
B
7
Scheme 2. Plausible mechanism for pyrimidine ring formation.
of Michael type addition product Awhich is not isolated. Then, imino group of thiazole influenced by secondary amino
group attacks the carbonyl group resulting cyclocondensation product B, which spontaneously lose water to give the
title compound 7 (Scheme 2). A new synthetic strategy has been utilized for the synthesis of title compounds involving
the reaction between thiazole amine and chalcone. The structures of the products 5 and 7 have been elucidated on the
1
basis of (IR, H NMR, 13C NMR and MS) and micro analytical data.
In conclusion, we report a new synthetic strategy for the synthesis of title compounds with potential biological
activity using inexpensive and commercially available materials.
Acknowledgments
The authors are thankful to the Head, Department of Chemistry, Kakatiya University, Warangal for facilities and to
1
the Director, Indian Institute of Chemical Technology, Hyderabad for recording H NMR and MS.
References
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[19] Analytical data for compound 5: pale yellow; yield 80%, mp 156–158 8C; IR (KBr, cmꢀ1): 3350, 3325 (NH2), 1615 (C N), 1560, 1365 (NO2);
1H NMR (300 MHz, CDCl3): d 2.32 (s, 3H, CH3), 3.83 (m, 2H, CH2), 4.10 (s, 4H, 2NH2), 4.81 (m, 1H, Ar–CH), 5.25 (d, 1H, CH), 7.13 (s, 1H,
thiazole-CH), 7.20–8.00 (m, 5H, ArH). EI-MS [M]+ m/z 442. 13C NMR (75 MHz, CDCl3): d 11.41, 34.26, 48.75, 50.13, 105.36, 115.26,
124.13, 124.75, 125.35, 126.13, 126.42, 140.36, 150.38, 152.45, 159.96, 162.36. Anal. Calcd. for C19H18N6O3S2: C, 51.57; H, 4.10; N, 18.99.
Found: C, 51.52; H, 4.17; N, 19.03%.
[20] Y.P. Zhu, J.J. Yuan, Q. Zhao, et al. Tetrahedron 68 (2012) 173.

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E. Rajanarendar et al. / Chinese Chemical Letters 23 (2012) 899–902
[21] Analytical data for compounds: 7a: pale yellow; yield 82%, mp 165–167 8C; IR (KBr, cmꢀ1): 1625 (C N), 1555, 1360 (NO2); 1H NMR
(300 MHz, CDCl3): d 2.33 (s, 3H, CH3), 3.72 (m, 2H, CH2), 4.14 (m, 1H, J = 4 Hz, benzylic-H), 4.80 (m, 1H, CH), 5.23 (d, 2H, Ar–CH), 5.53
(d, 2H, J = 4 Hz, CH), 7.12 (s, 2H, thiazole-CH), 7.28–7.84 (m, 25H, ArH). EI-MS [M]+ m/z 822. 13C NMR (75 MHz, CDCl3): d 12.01,
34.56, 47.98, 50.48, 61.43, 94.28, 105.36, 115.28, 124.13, 124.21, 124.75, 125.35, 126.03, 126.13, 126.49, 126.67, 126.81, 127.01, 127.13,
127.45, 127.98, 128.11, 128.34, 135.68, 136.73, 140.36, 143.69, 150.58, 152.40, 159.78, 162.42. Anal. Calcd. for C49H38N6O3S2: C, 71.51; H,
4.65; N, 10.21. Found: C, 71.58; H, 4.58; N, 10.18%. 7b: pale yellow; yield 80%, mp 168–170 8C; IR (KBr, cmꢀ1): 1620 (C N), 1542, 1358
(NO2); 1H NMR (300 MHz, CDCl3): d 2.28 (s, 3H, CH3), 3.68 (m, 2H, CH2), 4.10 (m, 1H, J = 4 Hz, benzylic-H), 4.78 (m, 1H, CH), 5.38 (d, 2H,
Ar–CH), 5.50 (d, 2H, J = 4 Hz, CH), 7.00 (s, 2H, thiazole-CH), 7.12–7.92 (m, 23H, ArH). EI-MS [M]+ m/z 890. 13C NMR (75 MHz, CDCl3):
d 12.14, 35.56, 47.08, 51.08, 61.72, 94.18, 105.31, 115.15, 124.10, 124.28, 124.62, 125.32, 126.01, 126.10, 126.42, 126.54, 126.79, 127.11,
127.23, 127.37, 127.65, 128.14, 130.13, 134.98, 136.52, 140.13, 143.40, 150.28, 152.31, 159.16, 162.38. Anal. Calcd. for C49H36N6Cl2O3S2:
C, 65.99; H, 4.07; N, 9.42. Found: C, 65.95; H, 4.11; N, 9.38%. 7c: pale yellow; yield 84%, mp 164–166 8C; IR (KBr, cmꢀ1): 1630 (C N),
1545, 1351 (NO2); 1H NMR (300 MHz, CDCl3): d 2.29 (s, 3H, CH3), 2.81 (s, 6H, Ar–CH3), 3.52 (m, 2H, CH2), 4.06 (m, 2H, J = 4 Hz, benzylic-
H), 4.63(m, 1H, CH), 5.28 (d, 2H, Ar–CH), 5.41 (d, 2H, CH, J = 4 Hz), 7.03 (s, 2H, thiazole-CH), 7.14–8.03 (m, 23H, ArH). EI-MS [M]+ m/z
850. 13C NMR (75 MHz, CDCl3): d 12.57, 28.46, 35.16, 48.01, 51.28, 67.53, 91.38, 104.86, 117.11, 124.41, 124.63, 124.82, 125.97, 126.23,
126.41, 126.53, 126.48, 126.73, 127.11, 127.46, 127.88, 128.34, 128.56, 135.41, 136.63, 138.45, 141.06, 142.89, 151.08, 152.68, 159.67,
161.81. Anal. Calcd. for C51H42N6O3S2: C, 71.98; H, 4.97; N, 9.87. Found: C, 71.92; H, 4.99; N, 9.91%. 7d: pale yellow; yield 81%, mp 171–
173 8C; IR (KBr, cmꢀ1): 1620 (C N), 1543, 1349 (NO2); 1H NMR (300 MHz, CDCl3): d 2.21 (s, 3H, CH3), 3.41 (m, 2H, CH2), 3.61 (s, 6H,
OCH3), 4.11 (m, 1H, J = 4 Hz, benzylic-H), 4.54(m, 1H, CH), 5.31 (d, 2H, Ar–CH), 5.46 (d, 2H, J = 4 Hz, CH), 7.18 (s, 1H, thiazole-CH),
7.21–8.22 (m, 23H, ArH). EI-MS [M]+ m/z 882. 13C NMR (75 MHz, CDCl3): d 11.86, 33.97, 47.51, 50.36, 58.13, 61.43, 92.07, 106.11, 115.37,
124.26, 124.37, 124.67, 126.16, 126.34, 126.67, 126.71, 126.79, 127.11, 127.18, 127.54, 127.81, 128.00, 128.37, 135.59, 136.41, 140.71,
143.73, 150.42, 152.57, 159.81, 161.45, 162.42. Anal. Calcd. for C51H42N6O5S2: C, 69.37; H, 4.79; N, 9.52. Found: C, 69.41; H, 4.77; N,
9.48%. 7e: pale yellow; yield 79%, mp 155–157 8C; IR (KBr, cmꢀ1): 1615 (C N), 1540, 1357 (NO2); 1H NMR (300 MHz, CDCl3): d 2.23 (s,
3H, CH3), 3.33 (m, 2H, CH2), 4.20 (m, 1H, J = 4 Hz, benzylic-H), 4.43(m, 1H, CH), 5.25 (d, 2H, Ar–CH), 5.47 (d, 2H, J = 4 Hz, CH), 7.18 (s,
2H, thiazole-CH), 7.20–8.31 (m, 23H, ArH), 9.01 (bs, 2H, OH, D2O, exchangeable). EI-MS [M]+ m/z 854. 13C NMR (75 MHz, CDCl3): d
12.23, 35.41, 48.03, 50.12, 61.72, 94.10, 105.46, 115.56, 123.98, 124.10, 124.47, 125.91, 126.01, 126.23, 126.77, 126.92, 127.12, 127.29,
127.61, 127.83, 128.03, 128.54, 135.72, 136.54, 140.36, 143.51, 150.51, 152.57, 158.11, 159.67, 162.81. Anal. Calcd. for C49H38N6O5S2: C,
68.83; H, 4.48; N, 9.83. Found: C, 68.89; H, 4.51; N, 9.79%. 7f: pale yellow; yield 82%, mp 173–175 8C; IR (KBr, cmꢀ1): 1635 (C N), 1535,
1341 (NO2); 1H NMR (300 MHz, CDCl3) d: 2.30 (s, 3H, CH3), 2.83 (s, 6H, Ar–CH3), 3.50 (m, 2H, CH2), 4.16 (m, 1H, J = 4 Hz, benzylic-H),
4.58(m, 1H, CH), 5.18 (m, 2H, Ar–CH), 5.39 (d, 2H, J = 4 Hz, CH), 7.11 (s, 2H, thiazole-CH), 7.23–7.91 (m, 23H, ArH). EI-MS [M]+ m/z
850. 13C NMR (75 MHz, CDCl3): d 12.13, 29.01, 35.14, 48.41, 51.38, 67.51, 91.32, 104.86, 117.13, 124.51, 124.68, 124.73, 125.71, 126.11,
126.29, 126.42, 126.61, 126.79, 127.09, 127.25, 127.58, 128.21, 128.38, 135.35, 136.28, 138.15, 141.11, 142.68, 151.31, 152.52, 159.45,
161.69. Anal. Calcd. for C51H42N6O3S2: C, 71.98; H, 4.97; N, 9.87. Found: C, 71.94; H, 4.91; N, 9.81%. 7g: pale yellow; yield 85%, mp 169–
171 8C; IR (KBr, cmꢀ1): 1618 (C N), 1531, 1339 (NO2); 1H NMR (300 MHz, CDCl3) d 2.25 (s, 3H, CH3), 3.43 (m, 2H, CH2), 3.63 (s, 6H,
OCH3), 4.21 (m, 1H, J = 4 Hz, benzylic-H), 4.64 (m, 1H, CH), 5.38 (m, 2H, Ar–CH), 5.41 (d, 2H, J = 4 Hz, CH), 7.01 (s, 2H, thiazole-CH),
7.10–8.23 (m, 23H, ArH). EI-MS [M]+ m/z 882. 13C NMR (75 MHz, CDCl3): d 12.16, 34.17, 47.45, 50.21, 58.14, 61.31, 92.16, 106.23, 115.41,
124.11, 124.21, 124.46, 126.31, 126.42, 126.54, 126.63, 126.85, 127.30, 127.45, 127.58, 127.74, 128.07, 128.24, 135.28, 136.38, 140.51,
143.58, 150.27, 152.37, 159.69, 161.23, 161.81 Anal. Calcd. for C51H42N6O5S2: C, 69.37; H, 4.79; N, 9.52. Found: C, 69.32; H, 4.81; N,
9.47%. 7h: pale yellow; yield 80%, mp 174–176 8C; IR (KBr, cmꢀ1): 1627 (C N), 1538, 1338 (NO2); 1H NMR (300 MHz, CDCl3): d 2.30 (s,
3H, CH3), 3.52 (m, 2H, CH2), 4.21 (m, 1H, J = 4 Hz, benzylic-H), 4.61 (m, 1H, CH), 5.27 (m, 2H, Ar–CH), 5.47 (d, 2H, J = 4 Hz, CH), 7.08
(s, 2H, thiazole-CH), 7.13–7.82 (m, 23H, ArH). EI-MS [M]+ m/z 890. 13C NMR (75 MHz, CDCl3): d 12.23, 34.89, 46.88, 51.26, 61.41, 94.05,
105.10, 115.24, 124.28, 124.34, 124.57, 125.41, 126.27, 126.36, 126.58, 126.68, 126.77, 127.19, 127.31, 127.49, 127.58, 128.37, 130.31,
134.69, 136.71, 140.21, 143.38, 150.36, 152.27, 159.23, 162.46. Anal. Calcd. for C49H36N6Cl2O3S2: C, 65.99; H, 4.07; N, 9.42. Found: C,
65.92; H, 4.02; N, 9.39%. 7i: pale yellow; yield 80%, mp 170–172 8C; IR (KBr, cmꢀ1): 1631 (C N), 1528, 1315 (NO2); 1H NMR (300 MHz,
CDCl3): d 2.26 (s, 3H, CH3), 3.41 (m, 2H, CH2), 4.25 (m, 1H, J = 4 Hz, benzylic-H), 4.66 (m, 1H, CH), 5.20 (m, 2H, Ar–CH), 5.41 (d, 2H,
J = 4 Hz, CH), 7.11(s, 2H, thiazole-CH), 7.20–7.91(m, 23H, ArH). EI-MS [M]+ m/z 890. 13C NMR (75 MHz, CDCl3): d 12.31, 35.31, 47.45,
51.46, 61.51, 94.27, 105.11, 115.38, 124.22, 124.31, 124.60, 125.41, 126.06, 126.23, 126.53, 126.61, 126.81, 127.00, 127.11, 127.41, 127.53,
128.23, 130.22, 134.73, 136.45, 140.17, 143.26, 150.31, 152.38, 159.47, 162.56. Anal. Calcd. for C49H36N6Cl2O3S2: C, 65.99; H, 4.07; N, 9.42.
Found: C, 66.02; H, 4.10; N, 9.47%.