A convenient one pot synthesis of 3-cyano-9-methyl-2-methylthio-4-oxo-4H- pyrimido[2, 1-b] pyrimido [4, 5-b] quinoline and its reactions with selected nucleophiles

Article abstract of DOI:10.2174/157017809789869537

3-Amino-8-methyl pyrimido [4, 5-b] quinoline (1) in N, N-dimethyl formamide (DMF) and anhydrous potassium carbonate reacted with ethyl-2-cyano-3, 3-bismethyl thioacrylate 2 to afford novel heterocyclic compound 3-cyano-9-methyl-2-methylthio-4-oxo-4H-pyrim

Full text of DOI:10.2174/157017809789869537

544
Letters in Organic Chemistry, 2009, 6, 544-548
A Convenient One Pot Synthesis of 3-Cyano-9-methyl-2-methylthio-4-oxo-
4H- pyrimido[2,1-b] pyrimido [4,5-b] Quinoline and its Reactions with
Selected Nucleophiles
Sambhaji P. Vartale*, Vijay N. Bhosale, Sandeep V. Khansole and Ramdas N. Katapalle
Post-Graduate Research Center, Department of Chemistry, Yeshwant Mahavidyalaya, Nanded-431602, India
Received February 26, 2009: Revised March 26, 2009: Accepted April 20, 2009
Abstract: 3-Amino-8-methyl pyrimido [4,5-b] quinoline (1) in N,N-dimethyl formamide (DMF) and anhydrous
potassium carbonate reacted with ethyl-2-cyano-3,3-bismethyl thioacrylate 2 to afford novel heterocyclic compound 3-
cyano-9-methyl-2-methylthio-4-oxo-4H-pyrimido [4,5-b] quinoline 3. The latter were further reacted with selected N-, O-
and C- nucleophiles such as arylamines, substituted phenols, heterylamines and compounds with an active methylene
group.
Keywords: One pot synthesis, pyrimido quinoline, ketene dithioacetals, N,N-dimethyl formamide, ring anellation, pyrimidine
ring.
INTRODUCTION
anellated tetracyclic structure would be highly unstable and
may not exhibit any tautomerism.
Quinoline and its derivatives are an interesting class of
heterocyclic compounds with a wide range of applications as
a drug. Most of the quinoline derivatives act as analgesics
[1], antiamoebic [2-5], tryphocidal [6], antiseptic [7] and
antiserotonin [8]. In addition to these, derivatives also
exhibit good antimalarial [9, 10] antitubercular [11], antibac-
terial [12], antihistaminic [13], antineurodegerative [14],
anticonvulsants [15], antitumor [16], anticancers [17, 18] and
antiallergics [19] activities.
Scheme 1 represents a tentative mechanism pathway for
the formation of compound 3.
The compound
3 possesses a replaceable active
methylthio group at the 2-position, which is activated by the
ring 1-nitrogen atom, electron withdrawing 3-cyano group
and activation of the methylthio group is also supported by
the ring amide group of pyrimidine ring. Compound 3 was
reacted with selected N-, O- and C- nucleophiles like aryl
amines, substituted phenols, heteryl amines and compounds
containing an active methylene group. These reactions
resulted in the formation of 2-substituted derivatives of 3-
In the light of these valid observations, such fused
quinoline with pyrimidine ring would exhibit some
interesting pharmacological activities, further, the ring
anellation to amino groups containing nitrogen heterocycles
with ketene dithioacetals as reagent has been reported [20-
22]. All this prompted our interest to continue the work
directed to one pot synthesis of new heterocyclic compound
3-cyano-9-methyl-2-methylthio-4-oxo-4H-pyrimido [2,1-b]
cyano-9-methyl-2-methylthio-4-oxo-4H-pyrimido
[2,1-b]
pyrimido [4,5-b] quinoline 3. According to this method,
compound 3 independently, on reaction with p-chloro
aniline, o-chloroaniline, o-methylaniline, p-methylaniline
and p-methoxyaniline in N,N- dimethyl formamide and a
catalytic amount of anhydrous potassium carbonate, afforded
3-cyano-2-(4’-chloroanilino/2’-chloroanilino/2’-methylanili-
no/4’-methylanilino/4’-methoxyanilino)-9-methyl-4-oxo-4H-
pyrimido [2,1-b] pyrimido [4,5-b] quinoline 4a-4e
respectively (Scheme 2). Under similar experimental con-
ditions, compound 3 reacted independently with p-methyl-
phenol, o-methylphenol, p-methoxyphenol, p-chloro phenol
and o-chlorophenol, to yield 3-cyano-2-(4’-methyl phenoxy/
2’-methyl phenoxy/4’-methoxyphenoxy/4’-chlorophenoxy/
2’-chlorophenoxy)-9-methyl-4-oxo-4H-pyrimido [2,1-b]
pyr-imido [4,5-b] quinoline 5a-5e respectively (Scheme 2).
pyrimido [4,5-b] quinoline
substituted derivatives.
3 and preparation of 2-
RESULT AND DISCUSSION
Compound 3 was prepared from the reaction of 3-amino-
8-methyl pyrimido [4,5-b] quinoline 1 with ethyl -2-cyano-
3,3-bismethyl thioacrylate 2 in the presence of N,N-dimethyl
formamide and a catalytic amount of anhydrous potassium
carbonate for 4 hours in 60% yield. The structure was
established on the basis of elemental analysis, IR, PMR and
mass spectral data. Spectral studies of compounds 3 showed
that compound was stable as well as there was no linear
anellated tetracyclic system formation, since, resulting linear
3-Cyano-2-pyrrolidino/piperidino/morpholino-9-methyl-
4-oxo-4H-pyrimido[2,1-b] pyrimido [4,5-b] quinoline 6a-6c
were obtained by the condensation of compound
independently with pyrrolidine, piperidine and morpholine in
N,N-dimethyl formamide and catalytic amount of
anhydrous potassium carbonate (Scheme 2). Compound 3 on
reaction independently with acetylacetone, ethyl
3
a
*Address correspondence to this author at the Post-Graduate Research
Center, Department of Chemistry, Yeshwant Mahavidyalaya, Nanded-
431602, India; Tel: +91 2462 269616; Fax: +91 2462 253726;
E-mail: spvartale@rediffmail.com
acetoacetate, diethyl malonate and ethyl cyanoacetate in the
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

A Convenient One Pot Synthesis of Pyrimido Quinoline
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
545
H3CS
C
SCH3
N
DMF
N
Anhydrous
K2CO3
N
N
C
N
H
C
N
H5C2O
N
N
NH2
-CH3SH
C2H5O
SCH3
O
1
O
2
C
N
-C2H5OH
10
7
11
12
13
N
C
9
8
5
1
2
N
6
N
N
O
SCH3
4
3
N
Scheme 1. Ring anellation to form compound 3.
R
N
N
H2N
N
N
N
R
N
N
N
DMF/anhyd.
K2CO3
O
N
O
SCH3
H
C
N
3
C
N
4a, R = 4'-Cl
4b, R = 2'-Cl
4c, R = 2'-CH3
4d, R = 4'-CH3
4e, R = 4'-OCH3
R
N
N
OH
R
N
N
N
N
N
N
DMF/anhyd.
K2CO3
O
O
O
SCH3
C
N
3
C
N
5a, R = 4'-CH3
5b, R = 2'-CH3
5c, R = 4'-OCH3
5d, R = 4'-Cl
5e, R = 2'-Cl
N
N
H
N
N
N
N
N
N
N
DMF/anhyd.
K2CO3
O
N
O
SCH3
C
N
3
C
N
N
6a = Pyrrolidino
6b = Piperidino
6c = Morpholino
N
N
X
H2C
N
N
N
N
N
N
X
Y
DMF/anhyd.
K2CO3
O
CH
O
SCH3
C
N
3
Y
C
N
X
Y
7a -COCH3
-COCH3
7b -COOC2H5 -COCH3
7c -COOC2H5 -COOC2H5
7d -COOC2H5 -CN
Scheme 2. Nucleophilic substitution reactions with selected nucleophiles.

546 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
Vartale et al.
presence of anhydrous potassium carbonate yielded com-
pounds, characterized on the basis of their analytical and
spectral data as 3-cyano-2-(ꢀ-acetylacetonyl/ꢀ-ethylaceto-
acetyl/ꢀ-diethylmalonyl/ꢀ-ethylcyanoacetyl)-9-methyl-4-
oxo-4H- pyrimido [2-1-b] pyrimido [4,5-b] quinoline 7a-7d
respectively (Scheme 2).
(300 MHz, CDCl3, ppm): 21.3, 74.3, 114.2, 116.5, 117.2,
121.0, 123.6, 124.3, 124.8, 130.3, 130.9, 135.4, 144.8, 148.3,
163.0, 163.7, 166.1, 174.4. Found: C, 63.72; H, 2.85; N,
20.10. C22H13N6OCl. Calcd: C, 64.00; H, 3.12; N, 20.36.
4b: (2.55g, 62% yield), Mp: 175-176 oC; IR (cm-1, KBr):
3321 (NH), 2211 (CN), 1680 (CO); 1H NMR (DMSO-
d6,ppm)
: 2.6 (s,3H,Ar-CH3), 4.0(s,1H,-NH), 6.5-8.0
(m,7H,Ar-H), 8.2 (s,1H,CH=N-),8.5(s,1H,-C=CH). Found :
C, 63.72; H, 2.85; N, 20.11. C22H13N6OCl. Calcd: C, 64.00;
H, 3.12; N, 20.36.
4c: (2.66g, 68% yield ), Mp: 172-174 oC; IR (cm-1, KBr):
3330 (NH),2210 (CN), 1679 (CO); 1H NMR (DMSO-
d6,ppm) : 2.6 (s,6H, two Ar-CH3), 4.0 (s,1H,-NH), 6.4-8.0
(m,7H,Ar-H), 8.1 (s,1H,CH=N-),8.5 (s,1H,-C=CH). Found:
C, 70.00; H, 3.91; N,21.20. C23H16N6O. Calcd: C,70.05;
H,4.06; N,21.31.
4d: (2.6 g, 66% yield), Mp: 180-181 oC; IR (cm-1,KBr):
3331 (NH), 2208 (CN), 1680 (CO); 1H NMR (DMSO-
d6,ppm) : 2.6 (s,6H, two Ar-CH3), 4.0 (s,1H,-NH), 6.4-8.0
(m,7H,Ar-H), 8.1 (s,1H,CH=N-),8.5 (s,1H,-C=CH). Found:
C, 69.90; H, 4.00; N, 21.09. C23H16N6O. Calcd: C, 70.05; H,
4.06; N, 21.31.
EXPERIMENTAL
All melting points were determined in open capillary
tube and uncorrected. All the reactions were monitored by
thin layer chromatography, carried out on 0.2 mm silica gel-
G plate using iodine vapour for detection. IR spectra were
recorded in Nujol or as Potassium bromide pellets on a
1
Shimadzu IR 8400S FT infrared spectrophotometer. The H
NMR were obtained on a FT Gemino 60 (60MHz)
spectrometer with tetramethylsilane as internal standard.
Mass spectra were recorded on a FT VG-7070H mass
spectrophotometer using the EI technique at 70 eV. All
reactions were carried out under ambient atmosphere.
Elemental analysis was performed on a Heraeus CHN-O
rapid analyzer.
4e: (2.54 g, 62% yield), Mp: 176-177 oC; IR (cm-1, KBr):
3318 (NH), 2210 (CN), 1676 (CO); 1H NMR (DMSO-
d6,ppm) : 2.6 (s,3H, Ar-CH3), 3.8 (s,3H,-OCH3),4.0 (s,1H,-
NH), 6.4-8.0 (m,7H,Ar-H), 8.0 (s,1H,CH=N-),8.5 (s,1H,-
C=CH). Found: C, 67.10; H, 3.65; N, 20.18. C23H16N6O2.
Calcd: C, 67.31; H, 3.90; N, 20.48.
3-Cyano-9-methylthio-4-oxo-4H-pyrimido[2,1-b]pyrimido
[4,5-b] quinoline 3
A
mixture of 3-amino-8-methyl pyrimido [4,5-b]
quinoline 1 (2.10g, 0.01 mol) and ethyl-2-cyano-3,3-
bismethyl thioacrylate 2 (2.21 g, 0.01 mol) was refluxed in
the presence of N,N- dimethyl formamide (15 mL) and
anhydrous potassium carbonate for (10 mg) 4 h. The reaction
mixture was cooled to room temperature and poured in to ice
cold water. The separated solid was filtered, washed with
water and recrystallized from N,N- dimethyl formamide-
ethanol mixture to afford compound 3. (1.99g, 60% yield),
Mp: 118-120oC; EI-MS (m/z-RA%) : 333 (M+, 15) 332 (10),
232 (20), 157 (45), 154 (20), 138 (15), 137 (35), 79 (100); IR
General procedure for 3-cyano-2-(4’-methylphenoxy/2’-
methylphenoxy/4’-methoxy phonoxy/4’-chlorophenoxy)-
9-methylthio-4-oxo-4H-pyrimido[2,1-b]pyrimido[4,5-b]
quinoline 5a-e
A mixture of compound 3(3.33 g, 0.01 mol), N,N-
dimethyl formamide (15 mL), anhydrous potassium
carbonate (10 mg) and appropriate substituted phenols (0.01
mol) was refluxed for 6 h. The reaction mixture was cooled
to room temperature and poured into ice cold water. The
products 4a-e thus obtained were crystallized from DMF-
ethanol solvent.
1
(cm-1, KBr) : 2208 (CN), 1680 (CO); H NMR (DMSO-d6,
ppm) : 2.4 (s, 3H, SCH3), 2.6 (s, 3H, Ar-CH3), 7.2-8.0 (m,
3H, Ar-H), 8.2 (s, 1H, CH=N) 8.5 (s, 1H-C=CH quin.); 13C
NMR (300 MHz, CDCl3, ppm) 21.3, 110, 114.8, 118.3, 121,
124.9, 125.9, 130.2, 130.8, 136.2, 148.8, 162, 163.7, 165,
166.2,
176.5,
177.4.Found:
C,60.96;
H,
3.08;
5a: (2.75g, 70% yield), Mp: 275-277oC, IR (cm-1, KBr) :
N,20.88.C17H11N5OS. Calcd: C, 61.26;H,3.30.N,21.02.
1
2209 (CN), 1677 (CO); H NMR (DMSO-d6, ppm) :2.4 (s,
6H, two Ar-CH3),6.6-8.0(m,8H,Ar-H), 8.5(s,1H,CH=C
quin.); 13C NMR (300 MHz, CDCl3, ppm): 20.9, 21.3, 76.2,
114.4, 116.8, 117.2, 121.0, 124.7, 124.9, 129.8, 130.3, 130.8,
131.9, 135.4, 148.3, 153.6 , 163.0,163.2,164.0,166.1,164.0.
Found: C; 70.10; H, 3.51; N, 17.50. C23H15N5O2. Calcd: C,
70.22; H, 3.81; N, 17.81.
General procedure for 3-Cyano-2-(4’-chloroanilino/2’-
chloroanilino/2’-methyl/aniline/4’-methylanilino/4’-meth-
oxyanilino)-9-methyl-4-oxo-4H-pyrimido[2,1-b]pyrimido
[4,5-b]quinoline 4a-e
A mixture of compound 3(3.33 g, 0.01 mol), N,N-
dimethyl formamide (15 mL), anhydrous potassium
carbonate (10 mg) and appropriate substituted anilines (0.01
mol) was refluxed for 6 h. the reaction mixture was cooled to
room temperature and poured into ice cold water. The
products 4a-e thus obtained were crystallized from DMF-
ethanol solvent.
4a: (2.68g, 65% yield), Mp: 170-172oC; IR (cm-1, KBr):
3315 (NH), 2210 (CN), 1678 (CO); 1H NMR (DMSO-
d6,ppm) : 2.6 (s, 3H, Ar-CH3), 4.1 (s, 1H,-NH), 6.5-8.0 (m,
7H,Ar-H), 8.3 (s, 1H, CH=N-), 8.5 (s, 1H,-C=CH), 13C NMR
5b: (2.82g, 72% yield), Mp: 279-280oC; IR (cm-1,KBr) :
1
2211(CN), 1679 (CO); H NMR (DMSO-d6, ppm) : 2.5 (s,
6H, two Ar-CH3), 6.6-8.0 (m,8H, Ar-H), 8.5 (s,1H,CH=C
quin.); Found: C, 70.10; H, 3.61; N, 17.65.C23H15N5O2.
Calcd: C, 70.22; H, 3.81; N, 17.81.
5c: (3.02g, 74% yield ). Mp:282-283oC; IR(cm-
1,KBr):2209(CN),1681 (CO); H NMR (DMSO-d6, ppm) :
1
2.5 (s, 3H, Ar-CH3), 3.8 (s,3H,-OCH3), 6.6-7.9 (m,8H, Ar-
H), 8.5 (s,1H,CH=C quin.). Found: C, 67.13; H, 3.30; N,
17.00. C23H15N5O3 Calcd: C, 67.48; H, 3.66; N, 17.11.

A Convenient One Pot Synthesis of Pyrimido Quinoline
Letters in Organic Chemistry, 2009, Vol. 6, No. 7
547
5d: (3.24 g, 78% yield), Mp: 268-270o C; IR (cm-1, KBr)
: 2213 (CN), 1686 (CO); 1H NMR (DMSO-d6, ppm) : 2.6 (s,
3H, Ar-CH3), 6.6-7.9 (m,8H, Ar-H), 8.5 (s,1H,CH=C quin.)
Found: C, 63.61; H, 2.60; N, 16.58. C22H12N5O2Cl. Calcd: C,
63.92; H, 2.90; N, 16.94.
21.3, 22.2, 66.7, 97.0, 114.3, 117.2, 121.0, 124.7, 124.9,
130.3, 130.8, 135.4, 163.0, 163.5, 163.7, 166.1, 166.3, 167.4,
206. Found : C, 65.10; H, 3.64; N, 1.51.C21H15N5O3. Calcd:
C, 65.45; H, 3.89; N, 1.81.
7b: (3.11g, 75% yield), Mp: 285-286oC; IR (cm-1,KBr) :
5e: (3.0g, 73% yield), Mp: 272-273oC; IR(cm-1,KBr) :
2209 (CN), 1735 (CO of ester), 1684 (CO), 1678 (cyclic
1
1
2209 (CN), 1678 (CO); H NMR (DMSO-d6, ppm) : 2.6 (s,
CO), 1245 (C-O); H NMR (DMSO-d6, ppm): 1.4 (t,3H,-
3H, Ar-CH3), 6.7-8.0 (m,8H, Ar-H), 8.5 (s,1H,CH=C quin.)
Found: C, 63.69; H, 2.61; N,16.59.C22H12N5O2Cl. Calcd: C,
63.92; H, 2.90; N, 16.94.
CH3), 2.2 (s,3H,COCH3), 2.4 (s, 3H, Ar-CH3), 3.9 (s,1H,-
CH), 4.2(q,2H,-OCH2-), 7.4-8.0 (m, 4H,Ar-H), 8.5
(s,1H,CH=C quin.); Found : C, 63.30; H, 3.92; N, 16.50.
C22H17N5O4. Calcd: C, 63.61; H, 4.09; N, 16.86.
7c: (3.47g, 78% yield), m.p.251-253oC; IR (cm-1,KBr):
General procedure for 3-cyano-2-pyrrolidino/piperidino/
morpholino-9-methyl-4-oxo-4H-pyrimido [2,1-b] pyri-
mido[4,5-b] quinoline 6a-c
2211(CN), 1740 (CO of ester), 1678 (cyclic CO), 1258 (C-
1
O); H NMR (DMSO-d6, ppm): 1.4 (t,6H,two-CH3), 2.4
(s,3H,ArCH3), 3.9 (s,1H,-CH), 4.2(q, 4H,two-OCH2-), 7.4-
8.0 (m, 4H,Ar-H), 8.5 (s,1H,CH=C quin.); Found: C, 61.90;
H, 4.05; N, 15.48. C23H19N5O5 requires C, 62.02; H, 4.26; N,
15.73.
A mixture of compound 3 (3.33 g, 0.01 mol), N,N-
dimethyl formamide (15 mL), anhydrous potassium
carbonate (10 mg) and appropriate cyclic secondary amines
(0.01 mol) was refluxed for 5 h and the mixture was poured
into ice cold water. The products 6a-c thus obtained were
crystallized from DMF-ethanol solvent.
7d: (2.9g, 73% yield), Mp: 262-263oC; IR (cm-1, KBr) :
1
2211 (CN), 1739 (CO of ester), 1675 (cyclic CO); H NMR
(DMSO-d6, ppm): 1.4 (t,3H,CH3), 2.4 (s,3H,ArCH3), 4.0
(s,1H,-CH), 4.2 (q, 2H,-OCH2-), 7.4-8.0 (m, 4H,Ar-H), 8.5
(s,1H,CH=C quin.); Found: C, 63.10; H, 3.28; N, 20.90.
C21H14N6O3. Calcd: C, 63.31; H, 3.51; N, 21.10.
6a: (2.84g, 80% yield), Mp:241-242oC; IR (cm-1,KBr) :
2208 (CN), 1675 (CO); 1H NMR (DMSO-d6, ppm): 1.5
_
_
(t,4H, two -CH2 ), 2.8 (t,4H, two-NCH2 ), 2.4 (s, 3H, Ar-
CH3), 7.0-7.9 (m, 4H,Ar-H), 8.4 (s,1H,CH=C quin.); 13C
NMR (300 MHz, CDCl3, ppm): 21.3, 23.4, 46.0, 72.2, 114.0,
117.1, 121.3, 124.7, 124.9, 130.3, 130.9, 135.4, 148.2, 163.0,
163.7, 164.0, 166.1, 182.0 Found: C,67.15; H, 4.20; N,
23.32. C20H16N6O. Calcd: C, 67.41; H, 4.49; N, 23.59.
ACKNOWLEDGEMENTS
The authors are grateful to Dr. N.V. Kalyankar, Principal,
Yeshwant Mahavidyalaya, Nanded, for providing Laboratory
facilities, UGC, WRO, Pune for financial assistance for
Minor Research Project and Director, IICT, Hyderabad, for
providing spectra.
6b: (2.96g, 80% yield), Mp: 252-254oC; IR (cm-
1,KBr):2210(CN),1679(CO); 1H NMR (DMSO-d6, ppm): 1.6
(t,6H, three CH2), 2.4 (s, 3H, Ar-CH3), 2.7 (t,4H, two-
NCH2),7.3-7.9 (m, 4H,Ar-H), 8.5 (s,1H,CH=C quin.).
Found: C, 68.01; H, 4.54; N, 22.52. C21H18N6O. Calcd: C,
68.10; H, 4.86; N, 22.70.
REFERENCES
6c: (3.12g, 84% yield), Mp: 221-222oC; IR (cm-1, KBr) :
[1]
[2]
[3]
[4]
[5]
Hesse, E. Arch. Exp. Pathol. Pharmacol., 1930, 161, 249.
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63, 518, Chem. Abstr. 1990, 112, 20912 h.
1
2211 (CN), 1680 (CO). H NMR (DMSO-d6, ppm) : 2.4 (s,
_
3H, Ar-CH3), 2.6 (t,4H, -NCH2 ), 3.8 (t,4H, OCH2), 7.3-7.9
(m, 4H, Ar-H), 8.5 (s, 1H, Ar-CH=N). Found: C, 64.20; H,
4.10; N, 22.22. C20H16N6O2. Calcd: C, 64.51; H, 4.30; N,
22.58.
[6]
[7]
[8]
General procedure for 3-Cyano-2(ꢀ-acetyl acetonyl/ꢀ-
ethylacetoacetyl/ꢀ-ethylacetoacetyl/ꢀ-diethyl malonyl/ꢀ-
[9]
[10]
[11]
ethyl
cyanoacetyl)-9-methyl-4-oxo-4H-pyrimido[2,1-b]
pyrimido[4,5-b] quinoline 7a-d
[12]
Shridhar, D. R.; Shastri. C. V.; Reddy, A. K.; Rao, C. S.; Taneja,
V. Ind. J. Chem., 1979, 17, 488-99; Chem. Abstr., 1980, 93,
204422 μ.
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7a: (2.88g, 75% yield), Mp: 241-243oC; IR (cm-1,KBr) :
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1
2210 (CN), 16.78 (cyclic CO), 1685 (CO), 1248 (C-O); H
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Ar-CH3), 3.9 (s,1H,-CH), 7.4-8.0 (m, 4H,Ar-H), 8.5
(s,1H,CH=C quin.); 13C NMR (300 MHz, CDCl3, ppm):

548 Letters in Organic Chemistry, 2009, Vol. 6, No. 7
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