An efficient synthesis of some novel 3-cyano-4-imino-2-(methylthio)4H- pyrido[1,2-a]pyrimidine and their derivatives

Article abstract of DOI:10.1002/jhet.1565

Pyrazolo pyrimido pyrimidine (4a-k) was prepared by the reaction of compound 3-cyano-4-imino-2-(methylthio)4H-pyrido[1,2-a]pyrimidine (3) with hydrazine hydrate, phenyl hydrazine, 2-hydrazino benzothiazole, and 6-substituted hydrazine benzothiazole in N,N-dimethylformamide and anhydrous potassium carbonate. These synthesized compounds were characterized by elemental analysis IR, ¹H NMR, and mass spectral data.

Full text of DOI:10.1002/jhet.1565

March 2013
An Efficient Synthesis of Some Novel 3-Cyano-4-imino-2-(methylthio)
4H-pyrido[1,2-a]pyrimidine and Their Derivatives
351
*
Sambhaji P. Vartale, Nilesh K. Halikar, Shivraj B. Sirsat, and Yogesh D. Pawar
P.G. Research Centre, Department of Chemistry, Yeshwant Mahavidyalaya, Nanded, Maharashtra 431602, India
*
E-mail: spvartale@gmail.com
Received June 20, 2011
DOI 10.1002/jhet.1565
Published online 29 March 2013 in Wiley Online Library (wileyonlinelibrary.com).
N
SCH3
DMF / Anhy. K2CO3
-CH3SH
N
N
SCH3
DMF / Anhy. K2CO3
H3CS
NC
NH2
R
N
N
+
N
-CH3SH
N
CN
NH2
CN
R NH-NH2
NH
NH
1
2
4
3
Pyrazolo pyrimido pyrimidine (4a–k) was prepared by the reaction of compound 3-cyano-4-imino-2-
(methylthio)4H-pyrido[1,2-a]pyrimidine (3) with hydrazine hydrate, phenyl hydrazine, 2-hydrazino benzothiazole,
and 6-substituted hydrazine benzothiazole in N,N-dimethylformamide and anhydrous potassium carbonate.
These synthesized compounds were characterized by elemental analysis IR, 1H NMR, and mass spectral data.
J. Heterocyclic Chem., 50, 351 (2013).
INTRODUCTION
RESULTS AND DISCUSSION
A novel method was successfully demonstrated
toward the synthesis of pyrido[1,2-a]pyrimidines. The
fused pyrimidines exhibit promising antiviral [1],
antibacterial [2], anti-AIDS [3], and antinociceptive
[4] activities. Fused pyrimidines are extensively used
in neurology, particularly in the treatment of neurode-
generative disorders such as Parkinson’s disease [5],
anti-anxiety disorders [6], and depression [7]. Fused
pyrimidines are selective inhibitors for multidrug resistance
[8]. Folate metabolism has long been recognized as an
attractive target for cancer chemotherapy because of
indispensable role of fused pyrimidine antifolates as antitumor
agents [9]. Risperidone is a derivative of pyrido[1,2-a]pyrimi-
dines [10,11]. These compounds showed antipsychotic
activity [12] and were used as a2 antagonists [13–15]. They
exhibit a high affinity for a2-adrenoceptor with high
selectivity versus the a-receptor and possess potent in vivo
central activity [16,17]. Wamho and Korte [18,19] have
reported the synthesis of pyrido[1,2-a]pyrimidines by using
2-amino heterocyclic compounds and a-acetyl-g-butyrolac-
tone by refluxing dioxane or using PPA and have observed
the formation of mixture of products. After a successful
literature survey, it stimulated us to synthesize 3-amino-
4-imino-2-(6′-substituted benzothiazolyl)pyrazolo[3,4-b]
pyrido[1,2-a]pyrimidine (4) by using 3-cyano-4-imino-2-
(methylthio)4H-pyrido[1,2-a]pyrimidine (3) and 2-hydrazino
benzothiazole by refluxing N,N-dimethylformamide and
anhydrous potassium carbonate with new method and
improved yield.
In the present communication, we have developed a new
methodology toward the synthesis of 3-amino-4-imino-2-
(6′-substituted benzothiazolyl)pyrazolo[3,4-b] pyrido[1,2-a]
pyrimidine (4), as shown in Scheme 1. Our method gives a
single product with high yield. The reaction started
with 2-aminopyridines (1) and bis(methylthio)methylene
malononitrile (2) refluxed in N,N-dimethylformamide in
the presence of catalytic amount of anhydrous
potassium carbonate to afford (3).
Compound (3) possesses replaceable active methylthio
group at the 2-position, which is activated by the ring
1-nitrogen atom, electron withdrawing 3-cyano group.
Compound (3) reacted with hydrazine hydrate in the
presence of N,N-dimethylformamide, and the catalytic
amount of anhydrous potassium carbonate afforded
compound (4a) in 78% yield. The subsequent compound
(3) was independently heated with phenyl hydrazine, 4-nitro
phenyl hydrazine, 2,4-dinitro phenyl hydrazine, 2-hydrazino
benzothiazole, 6-methyl 2-hydrazino benzothiazole, 6-meth-
oxy 2-hydrazino benzothiazole, 6-chloro 2-hydrazino
benzothiazole, 6-nitro 2-hydrazino benzothiazole, 2,4-
dimethyl 2-hydrazino benzothiazole, and 6,7-chloro,fluoro
2-hydrazino benzothiazole to obtain 3-amino-4-imino-2-
(6′-substituted benzothiazolyl)pyrazolo[3,4-b] pyrido[1,2-a]
pyrimidine derivatives (4a–k), respectively, as shown in
Scheme 2.
The structure of these newly synthesized compounds
was established on the basis of elemental analysis, IR,
PMR, and mass spectral data; spectral studies of all
© 2013 HeteroCorporation

352
S. P. Vartale, N. K. Halikar, S. B. Sirsat, and Y. D. Pawar
Vol 50
Scheme 1. Formation of fused pyrido[1,2-a]pyrimidine.
H
N
SCH3
H3CS
SCH3
CN
NH2
DMF / Anhy. K2CO3
+
-CH3SH
N
N
NC
CN
NC
1
2
N
SCH3
N
CN
NH
3
benzothiazole, 6-methoxy 2-hydrazino benzothiazole, 6-chloro
2-hydrazino benzothiazole, 6-nitro 2-hydrazino benzothiazole,
2,4-dimethyl 2-hydrazino benzothiazole, and 6,7-chloro,fluoro
2-hydrazino benzothiazole (0.001 mol) in 15 mL of N,N′-
dimethylformamide and anhydrous potassium carbonate
(10 mg) was refluxed for 5 h. The reaction mixture was cooled
to room temperature and poured into ice-cold water. The
separated solid product was filtered, washed with water, and
recrystallized from a N,N′-dimethylformamide–ethanol mixture
to give pure (4a–k).
compounds show that compounds are stable and do not
exhibit any tautomerism.
In conclusion, we have developed a new methodology
toward the synthesis of 3-amino-4-imino-2-(6′-substituted
benzothiazolyl)pyrazolo[3,4-b]pyrido[1,2-a]pyrimidine by
using a reaction of 2-aminopyridines and bis(methylthio)
methylene malononitrile in DMF as a solvent in the
presence of a catalytic amount of anhydrous potassium
carbonate.
3-Cyano-4-imino-2-(methylthio)4H-pyrido[1,2-a]pyrimidine
(3). Orange powder, yield 60%, mp 230 ꢀC (dec.). IR (KBr/
cmÀ1) 3350 (═NH), 2225 (CN). 1H NMR (400 MHz, DMSO-
d6): 2.59 (s, 3H, SCH3), 6.4–6.5 (d, 2H, J=8Hz), 6.1–6.3 (d, 2H,
J=7.5–8Hz), 9.2 (br s, 1H, ═NH). EI-MS (m/z: RA %): 217
(M + I), 100%, 215 (35). 13C NMR (300 MHz, DMSO-d6): d 16,
40, 79, 109, 115, 122, 134, 138, 151, 165. Anal. Calcd for
C10H8N4S; C, 60.35; H, 3.55; N, 24.85. Found: C, 60.30; H, 3.50;
N, 24.80.
EXPERIMENTAL
Melting points were determined by open capillary tubes and
were uncorrected. All the reactions were monitored by thin-layer
chromatography, carried out on 0.2-mm silica gel-C plates using
iodine vapors for detection. Infrared spectra were recorded in
Nujol or as potassium bromide pellets on an infrared spectropho-
tometer; nuclear magnetic resonance spectra were obtained on
Brukner avance spectrophotometer; 400 MHz mass spectra were
recorded on FT-VC-7070H mass spectrometer with the use of
the EI technique at 70 eV. All the reactions were carried out under
ambient atmosphere. Elemental analysis was performed on a
Heraeus CHN-O rapid analyzer.
3-Amino-4-imino-2-(2H)pyrazolo[3,4-b]pyrido[1,2-a]pyrimidiÀn1e
(4a). Brown powder, yield 75%, mp 187 ꢀC (dec.). IR (KBr/cm
)
3380 (═NH), 3321 cmÀ1 (NH2 asym.), 3213 cmÀ1 (NH2 sym.). 1H
NMR (400 MHz, DMSO-d6): 4.0 (s, 2H, x-NH2), 5.1–5.3
(d, 2H J=7.3–8Hz), 6.1–6.5 (d, 2H, J=7.8–8Hz), 9.2 (br s, 1H,
═NH), 13.6 (s, 1H, NH). Anal. Calcd for C9H8N6: C, 53.99; H,
4.03; N, 41.98. Found: C, 53.32; H, 3.61; N, 41.30.
General procedure.
3-Cyano-4-imino-2-(methylthio)4H-pyrido[1,2-a]pyriidine (3). A
mixture of 2-aminopyridine (2) (0.01 mol) and (methylthio)
methylene malononitrile (1) (0.01 mol) in 15mL of N,N′-
dimethylformamide and anhydrous potassium carbonate (10 mg)
was refluxed for 5 h. The reaction mixture was cooled to room
temperature and poured into ice-cold water. The separated solid
product was filtered, washed with water, and recrystallized from a
N,N′-dimethylformamide–ethanol mixture to give pure (3).
3-Amino-4-imino-2-(6′-substituted benzothiazolyl)pyrazolo
3-Amino-4-imino-2-(phenyl)pyrazolo[3,4-b]pyrido[1,2-a]
pyrimidine (4b). Brown powder, yield 62%, mp 140ꢀC (dec.).
IR (KBr/cmÀ1
)
3370 (═NH), 3327 cmÀ1 (NH2 asym.),
3217 cmÀ1 (NH2 sym.). 1H NMR (400 MHz, DMSO-d6): 4.9
(s, 2H, –NH2), 5.1–6.5 (d, 4H, J = 7–8 Hz), 7.4–7.6 (m, 5H), 9.8
(s, 1H, ═NH). Anal. Calcd for C15H12N6: C, 65.21; H, 4.38; N,
30.42. Found: C, 64.78; H, 3.03; N, 30.02.
3-Amino-4-imino-2-(4′-nitro phenyl)pyrazolo[3,4-b]pyrido
[1,2-a]pyrimidine (4c). Brown powder, yield 79%, mp 156 ꢀC
(dec.). IR (KBr/cmÀ1) 3380 (═NH), 3335 cmÀ1 (NH2 asym.),
3220 cmÀ1 (NH2 sym.). 1H NMR (400 MHz, DMSO-d6): 4.4
(s, 2H, –NH2), 5.9–6.4 (d, 4H, J= 6.7 Hz), 7.3 (d, 2H, J=8Hz), 7.4
(d, 2H, J= 7.5 Hz), 9.1 (br s, 1H, ═NH). Anal. Calcd for
[3,4-b]pyrido[1,2-a]pyrimidine (4a–k). A mixture of
3
(0.001 mol) and independently with hydrazine hydrate (80%),
phenyl hydrazine, 4-nitro phenyl hydrazine, 2,4-dinitro phenyl
hydrazine, 2-hydrazino benzothiazole, 6-methyl 2-hydrazino
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2013
An Efficient Synthesis of Some Novel
353
3-Cyano-4-imino-2-(methylthio)4H-pyrido[1,2-a]pyrimidine and Their Derivatives
Scheme 2. 3-Amino-4-imino-2-(6′-substituted benzothiazolyl)pyrazolo[3,4-b]pyrido[1,2-a]pyrimidine derivatives (4a–k).
R
Comp.No
H
N
SCH3
4a
4b
N
N
H
H
R
H
N
+
C
N
N
H
3
4
c
O2N
O2N
4d
NO2
S
H
SCH3
C
4e
N
N
N
N
H
H
R
N
N
N
H3C
4f
S
N
H
H3CO
g
4
S
H
N
N
S
R
N
N
h
4
Cl
H
N
C
N
N H
N
N
O2N
S
i
4
H
N
N
N
R
N
H3C
j
S
N
4
NH
N
NH
CH3
F
N
N
R
k
4
N
Cl
S
NH2
NH
N
(4a-k)
C15H11N7O2: C, 56.07; H, 3.45; N, 30.52. Found: C, 53.32; H, 3.61;
N, 30.01.
4.2 (s, 2H, –NH2), 5.4–6.7 (d, 4H, J = 6.5 Hz), 7.4–8.3
(d, 4H, J = 8.5 Hz), 8.6 (br s, 1H, ═NH). Anal. Calcd for
C16H11N7S: C, 57.64; H, 3.33; N, 29.41. Found: C, 57.06; H,
2.67; N, 28.90.
3-Amino-4-imino-2-(2′,4′-dinitro phenyl)pyrazolo[3,4-b]pyrido
[1,2-a]pyrimidine (4d). Brown powder, yield 68%, mp 168 ꢀC
(dec.). IR (KBr/cmÀ1) 3380 (═NH), 3343 cmÀ1 (NH2 asym.),
3213 cmÀ1 (NH2 sym.). 1H NMR (400 MHz, DMSO-d6): 4.3
(s, 2H, –NH2), 5.6–6.5 (d, 4H, J = 6.5–7.5 Hz,), 7.3 (s, 1H), 7.2
(d, 2H, J = 8 Hz), 8.4 (br s, 1H, ═NH). Anal. Calcd for
C15H10N8O4: C, 49.19; H, 2.75; N, 30.59. Found: C, 48.60; H,
2.21; N, 30.02.
3-Amino-4-imino-2-(2′-benzothiazolyl)pyrazolo[3,4-b]pyrido
[1,2-a]pyrimidine (4e). Brown powder, yield 74%, mp 192 ꢀC
(dec.). IR (KBr/cmÀ1) 3367 (═NH), 3336 cmÀ1 (NH2 asym.),
3226 cmÀ1 (NH2 sym.). 1H NMR (400 MHz, DMSO-d6):
3-Amino-4-imino-2-(6′-methyl-2′-benzothiazolyl)pyrazolo
[3,4-b] pyrido[1,2-apyrimidine (4f). Brown powder, yield 68%,
mp 150 ꢀC (dec.). IR (KBr/cmÀ1) 3380 (═NH), 3321 cmÀ1 (NH2
1
asym.), 3213cmÀ1 (NH2 sym.). H NMR (400 MHz, DMSO-d6):
4.4 (s, 2H, –NH2), 5.4–6.7 (d, 4H), J = 7–8 Hz, 7.1 (s, 1H),
7.2–8.3 (d, 2H, J = 7.2–7.5 Hz), 2.4 (s, 3H, Ar–CH3), 9.1 (br s,
1H, ═NH). Anal. Calcd for C17H13N7S: C, 58.77; H, 3.77; N,
28.22. Found: C, 58.23; H, 3.20; N, 27.60.
3-Amino-4-imino-2-(6′-methoxy-2′-benzothiazolyl)pyrazolo
[3,4-b]pyrido[1,2-a]pyrimidine (4g). Brown powder, yield 72%,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

354
S. P. Vartale, N. K. Halikar, S. B. Sirsat, and Y. D. Pawar
Vol 50
mp 183 ꢀC (dec.). IR (KBr/cmÀ1) 3435 (═NH), 3321cmÀ1 (NH2
Acknowledgments. The authors are grateful to Dr N.V. Kalyankar,
Principal, Yeshwant Mahavidyalaya, Nanded, for providing
laboratory facilities; to UGC New Delhi for financial assistance
under major research project (F.N 39-834/2010 (SR)); and to the
Director of the Indian Institute of Chemical Technology,
Hyderabad, for providing spectral data.
1
asym.), 3213cmÀ1 (NH2 sym.), 2208 (CN). H NMR (400 MHz,
DMSO-d6): 3.9 (s, 3H, Ar–OCH3), 4.4 (s, 2H, NH2), 5.1–5.4
(d, 2H, J = 6.5–7 Hz), 6.2–6.7 (d, 2H, J = 7.3–8 Hz), 7.0–7.7
(d, 2H), 8.3 (s, 1H), 9.7 (br s, 1H, ═NH). EI-MS (m/z: RA %):
364 (M+ I), 261, 236 (100), 231, 216, 178, 165, 122. Anal. Calcd
for C17H13N7OS: C, 56.19; H, 3.61; N, 26.98. Found: C, 55.74;
H, 3.02; N, 26.32.
3-Amino-4-imino-2-(6′-chloro-2′-benzothiazolyl)pyrazolo
[3,4-b]pyrido[1,2-a]pyrimidine (4h). Brown powder, yield
67%, mp 260 ꢀC (dec.). IR (KBr/cmÀ1) 3368 (═NH), 3334 cmÀ1
(NH2 asym.), 3216cmÀ1 (NH2 sym.). 1H NMR (400 MHz,
DMSO-d6): 4.2 (s, 2H, NH2), 5.2–5.6 (d, 2H, J = 6.5–7.3 Hz),
6.1–6.7 (d, 2H, J = 6.5–7 Hz), 7.6 (s, 1H), 8.0–8.3 (d, 2H,
J = 7.5–8 Hz), 9.2 (br s, 1H, ═NH). EI-MS (m/z: RA %): 368
(M+ I), 353, 336. Anal. Calcd for C16H10ClN7S: C, 52.25; H,
2.74; N, 26.66. Found: C, 51.72; H, 2.15; N, 26.10.
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3-Amino-4-imino-2-(6′-nitro-2′-benzothiazolyl)pyrazolo[3,4-b]
pyrido[1,2-a]pyrimidine (4i). Brown powder, yield 67%, mp
above 300 ꢀC (dec.). IR (KBr/cmÀ1) 3342 (═NH), 3230cmÀ1
(NH2 asym.), 3213 cmÀ1 (NH2 sym.). 1H NMR (400 MHz,
DMSO-d6): 4.7 (s, 2H, NH2), 5.2–5.5 (d, 2H, J = 6.3–7 Hz),
6.0–6.6 (d, 2H, J = 6.5–7 Hz), 8.0–8.3 (d, 2H, J = 7–8 Hz), 9.2
(s, 1H), 8.8 (br s, 1H, ═NH). Anal. Calcd for C16H10N8O2S:
C, 50.79; H, 2.66; N, 29.61. Found: C, 53.32; H, 3.61; N, 41.30.
3-Amino-4-imino-2-(4′,6′-dimethyl-2′-benzothiazolyl)pyrazolo
[3,4-b]pyrido[1,2-a]pyrimidine (4j). Brown powder, yield
74%, mp 130 ꢀC (dec.). IR (KBr/cmÀ1) 3386 (═NH), 3342 cmÀ1
(NH2 asym.), 3224 cmÀ1 (NH2 sym.). Anal. Calcd for
C18H14N6S: C, 62.41; H, 4.07; N, 24.26. Found: C, 61.84; H,
3.69; N, 23.85.
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3-Amino-4-imino-2-(6′,7′-chloro,floro-2′benzothiazolyl)pyrazolo
[3,4-b]pyrido[1,2-a]pyrimidine (4k). Brown powder, yield 48%, mp
195 ꢀC (dec.). IR (KBr/cmÀ1) 3380 (═NH), 3321 cmÀ1 (NH2
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1
asym.), 3213 cmÀ1 (NH2 sym.). H NMR (400MHz, DMSO-d6):
4.2 (s, 2H, NH2), 5.0–5.6 (d, 2H, J = 6.3–7 Hz), 6.3–6.9 (d, 2H,
J = 7–8 Hz), 7.3–7.9 (d, 2H, J = 7.5–8 Hz), 9.1 (br s, 1H, ═NH)
Anal. Calcd EI-MS (m/z: RA %): 385 (M), 217, 216 (100). For
C16H9ClFN6S: C, 51.83; H, 2.35; N, 22.67. Found: C, 51.32; H,
1.61; N, 22. 03.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet