Synthesis of new thieno[2,3-d]pyrimidines, thieno[3,2-e]pyridines, and thieno[2,3-d][1,3]oxazines

Article abstract of DOI:10.1002/jhet.748

o-Aminothiophene dicarbonitrile 1 on neat reaction with cyclic ketones in anhydrous ZnCl₂ yielded mixture of fused aminopyridine 3 and iminospirooxazine 4 derivatives. Similarly, pyrimidine derivatives 5 and 8 were obtained by the reaction of this intermediate 1 with formic acid and DMF-DMA followed by hydrazine hydrate, respectively. The reaction of o-amino-thiophene dicarboxamide 2 at ambient temperature with cyclic ketones yielded spiropyrimidine 10 as a sole product in quantitative yield. The regioselective anellated pyrimidine 9, 11, and dihydropyrimidine 12 derivatives were also obtained by the reaction with aromatic aldehydes in presence of piperidine and iodine respectively. Copyright

Full text of DOI:10.1002/jhet.748

March 2012
Synthesis of New Thieno[2,3-d]pyrimidines, Thieno[3,2-e]pyridines,
and Thieno[2,3-d][1,3]oxazines
363
Shrikant B. Kanawade, Shivaraj P. Patil, Prashant S. Nikam,
Sachin A. Gangurde, Madhukar N. Jachak, and Raghunath B. Toche*
Organic Chemistry Research Center, Department of Chemistry, K.R.T. Arts, B. H. Commerce and
A. M. Science College, Affiliated to University of Pune, Nashik, MS 422 002, India
*E-mail: raghunath_toche@rediffmail.com
Received July 20, 2010
DOI 10.1002/jhet.748
Published online 31 December 2011 in Wiley Online Library (wileyonlinelibrary.com).
o-Aminothiophene dicarbonitrile 1 on neat reaction with cyclic ketones in anhydrous ZnCl2 yielded
mixture of fused aminopyridine 3 and iminospirooxazine 4 derivatives. Similarly, pyrimidine derivatives
5 and 8 were obtained by the reaction of this intermediate 1 with formic acid and DMF-DMA followed
by hydrazine hydrate, respectively. The reaction of o-amino-thiophene dicarboxamide 2 at ambient tem-
perature with cyclic ketones yielded spiropyrimidine 10 as a sole product in quantitative yield. The
regioselective anellated pyrimidine 9, 11, and dihydropyrimidine 12 derivatives were also obtained by
the reaction with aromatic aldehydes in presence of piperidine and iodine respectively.
J. Heterocyclic Chem., 49, 363 (2012).
INTRODUCTION
become well-sought privileged class of heterocyclic
compounds in drug discovery programs.
The chemistry of 2-aminothiophenes has received
much attention because of the convenient availability
through most versatile synthetic method developed by
Gewald [1]. 2-Amino-3-functionally substituted thio-
phene derivatives are useful precursor in the azo dye
industry and as intermediates for the pharmaceutically
important thieno[2,3-d]pyrimidines [2,3]. Previously,
pharmacological studies of the thienopyridine and thie-
nopyrimidine derivatives extensively showed variety of
activities such as antibacterial [4,5], antimicrobial [6],
anxiolytic [7], and psychotropic [8]. These thienopy-
ridines are also useful as potential class of VEGFR-2
kinase inhibitors [9], IjB kinase inhibitors [10], gona-
dotropin releasing hormone antagonist [11–16], and
anti-inflammatory agents, particularly for treating arthri-
tis and bone resorption inhibiting agents [17]. Conse-
quently, thienopyridines and thienopyrimidines have
In continuation of previous work aiming at the syn-
thesis of different heterocycles from the readily obtain-
able nitrile intermediates [18–22], Kandeel et al. [23,24]
and Vegh et al. [25] reported the synthesis of 5-amino-
3-phenyl and 3-heteroarylthiophene-2,4-dicarbonitrile from
phenyl- and heteroaryl-3-oxopropanenitriles, respectively.
Encouraged with this work, we report here a facile and
efficient route for the synthesis of some new thieno[2,3-
d]pyrimidine and thieno[3,2-e]pyridine derivatives from
5-amino-3-(4-chlorophenyl)thiophene-2,4-dicarbonitrile 1
and 5-amino-3-(4-chlorophenyl)thiophene-2,4-dicarboxa-
mide 2. These two precursors predominate the direction
of ring growth and generally permits direct and regio-
selective introduction of substituents in newly formed
heterocyclic ring. The required precursor 5-amino-3-(4-
chlorophenyl)thiophene-2,4-dicarbonitrile 1 was obtained
C
V
2011 HeteroCorporation

364
S. B. Kanawade, S. P. Patil, P. S. Nikam, S. A. Gangurde, M. N. Jachak, and R. B. Toche
Vol 49
by Gewald reaction [23,26] of 3-(4-chlorophenyl)-3-
oxopropanenitrile [27,28], malononitrile, and elemental
sulfur. It is well known [29,30] that the nitrile on reac-
tion with acid yielded carboxylic acid or amide depend-
ing on reaction conditions. Here, we observed that the
reaction of dicarbonitrile compound 1 with conc. H2SO4
afforded dicarboxamide compound 2 in quantitative
yield, which is our second vital precursor. In this article,
the active o-aminocarbonitrile 1 and o-aminocarbo-
xamide 2 moieties have found wide applicability for
annulation of heterocyclic ring systems and hence were
successfully utilized for syntheses of new class of
thieno[3,2-e]pyridine, thieno[2,3-d]pyrimidine, and thieno-
[2,3-d][1,3]oxazine derivatives in good yields. Acid hydro-
lysis of compound 1 at ambient temperature furnished
dicarboxamide 2, which showed three broad singlets at
d 4.82, 6.84, and 7.69 for amide NH2 and free NH2,
respectively. 13C NMR spectrum showed strong peak at
d 162.99 and 163.04 for two primary amide carbons.
Neat reaction of 5-amino-3-(4-chlorophenyl)thiophene-
2,4-dicarbonitrile 1 with cyclopentanone and/or cyclo-
hexanone in anhydrous ZnCl2 afforded mixture of fused
thienopyridines 3a–b and spirothienooxazines 4a–b,
which were separated by column chromatography elut-
ing with chloroform: methanol (9:1) in 20–25% and 68–
70% yields, respectively. The formation of major spiro-
thienooxazine products 4a–c can be explained by the
mechanism [31,32]. This mechanism actually assigned
carboxamide 2 in presence of acetonitrile and slight
excess of molecular iodine furnished thienopyrimidine
9a–c in 65–68% yield, whereas the same reaction in
ethanol and catalytic amount of piperidine afforded tet-
rahydropyrimidines 12a–c in 50–55% yield. All new
compounds were well characterized by IR, NMR,
and mass spectrometry (MS) given in ‘‘Experimental’’
section. (Scheme 2)
CONCLUSION
Acid hydrolysis of o-aminothiophenedicarbonitrile at
ambient temperature afforded o-aminothiophenedicar-
boxamide in excellent yield, which is successfully
utilized for the synthesis of regioselective annelated
thienopyrimidine derivatives.
A
new category of
thieno[2,3-d]pyrimidines, thieno[3,2-e]pyridines and
thieno[2,3-d][1,3]oxazines were obtained in good
yields from 5-amino-3-(4-chlorophenyl)thiophene-2,4-
dicarbonitrile
1 and 5-amino-3-(4-chlorophenyl)thio-
phene-2,4-dicarboxamide 2 with simple work up and
clean products.
EXPERIMENTAL
Melting points were determined on a Gallenkamp melting
point apparatus. The 1H (300 MHz) and 13C (75 MHz) NMR
spectra were recorded on a Varian XL-300 spectrometer.
Chemical shifts were reported in ppm relative to tetramethyl-
silane, and multiplicities are given as s (singlet), bs (broad
singlet), d (doublet), t (triplet), q (quartet), or m (multiplet).
Infrared spectra were recorded as KBr pellets on a Shimadzu
FTIR-408 spectrophotometer. Mass spectra were recorded on
a Shimadzu LC-MS: EI QP 2010A mass spectrometer with
an ionization potential of 70 eV. Elemental analyses were
performed on Thermo Quest Flash 1112 Series EA analyzer.
Reactions were monitored by thin layer chromatography
(TLC), carried out on 0.2 mm silica gel 60 F254 (Merck)
plates using UV light (254 and 366 nm) for detection, and
compounds were purified by column chromatography by
using silica gel of 5–20 lm (Merck, 60–120 mesh). Column
dimension is 39 ꢁ 2 cm, and elution volume used is about
200–400 mL for each product where necessary. Common rea-
gent-grade chemicals are either commercially available and
were used without further purification or were prepared by
standard literature procedures.
1
based on the IR and H NMR spectra. IR of spirooxazine
4a showed strong absorption bands at 3168 cmꢀ1 for NH,
1
2935 cmꢀ1 for CH2, and 2205 cmꢀ1 for CN groups. H
NMR of 4a showed two broad singlets at d 6.50 for
imine NH and d 4.93 for free NH, whereas, IR of 3b
showed strong absorption at 3500, 3392 cmꢀ1 for primary
1
amine NH2, and H NMR showed broad singlet for two
protons at d 4.37 for the same amine. The structures
of all new compounds were assigned based on the spec-
troscopic and analytical characterization given in the
‘‘Experimental’’ section. (Scheme 1)
An extremely convenient, environmentally benign spi-
rocyclization under solventless conditions for the prepa-
ration of spiro[cycloalkane-1,20-thieno-[2,3-d]pyrimi-
dine]-60-carboxamide 10a–b, has been successfully uti-
lized by stirring cyclopentanone and/or cyclohexanone
with o-aminodicarboxamide 2. Compound 10b showed
strong IR absorption bands at 3381–3213 cmꢀ1 and
1654 cmꢀ1 for secondary amide and carbonyl groups,
respectively, and 3288 cmꢀ1 for primary amide group.
1H NMR showed two broad singlets at d 5.37 and 8.30
for two NH protons, and 13C NMR showed quaternary
carbon at d 70.33 and secondary amide carbon at d
163.09. The reaction of acid chloride with compound 2
afforded dihydropyrimidines 11a–d in 62–70% yields.
The regioselective reaction of aldehydes with o-amino-
5-Amino-3-(4-chlorophenyl)thiophene-2,4-dicarbonitrile
(1). This compound was synthesized by the known literature
method [18,21]. This compound was recrystallized from
water/DMF (4:2) to afford faint yellow amorphous solid, mp
292–294ꢂC; IR: 3383s, 3304s, 2208m, 2198m, 1630s, 1506w,
1485w, 1421w cmꢀ1
;
1H NMR (DMSO-d6): d 7.57 (d, J ¼
8.4 Hz, 2H, Ar-H), 7.62 (d, J ¼ 8.4 Hz, 2H, Ar-H), 8.37
(bs, 2H, NH2); 13C NMR (DMSO-d6): d 85.7, 85.8, 114.9,
115.0, 129.5, 130.5, 135.2, 150.9, 198.3; ms: m/z 259 (Mþ,
100%), 261 (Mþ2, 33%). Anal. Calcd. for C12H6ClN3S
(259.00): C, 55.50; H, 2.33; N, 16.18. Found: C, 55.38; H,
2.15; N, 16.32.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis of New Thieno[2,3-d]pyrimidines, Thieno[3,2-e]pyridines,
and Thieno[2,3-d][1,3]oxazines
365
Scheme 1
(Mþ, 100%), 297 (Mþ2, 33%). Anal. Calcd. for
C12H10ClN3O2S (295.02): C, 48.73; H, 3.41; N, 14.21.
Found: C, 48.82; H, 3.62; N, 14.12.
5-Amino-3-(4-chlorophenyl)thiophene-2,4-dicarboxamide
(2). Compound 1 (2.59 g, 0.01 mol) was stirred in conc.
H2SO4 (10 mL) at room temperature for 6 h (TLC check,
chloroform: methanol, 8:2). The reaction mass was then
added to crushed ice (250 mL) and neutralized with saturated
NaHCO3 (30 mL). The crude solid separated was filtered,
washed with water, dried, and recrystallized from ethanol:
DMF (8:2) afforded pale yellow crystals, 2.65 g (90%), mp
200–202ꢂC; IR: 3327s, 3306s, 3252m, 3169m, 3475m,
General procedure for the synthesis of compounds 3a–b
and 4a–b. A mixture of 1 (0.259 g, 0.001 mol) and cyclo-
hexanone/cyclopentanone (0.001 mol) was stirred at 120–
130ꢂC in an oil bath in presence of anhydrous ZnCl2 (0.136
g, 0.001 mol) for 2–3 h (TLC check, chloroform: methanol,
9:1). The residue was dispersed in cold water and titrated to
pH 12–13 by adding 20% NaOH (5 mL). The solid product
separated was filtered, washed with water, dried, and purified
by column chromatography eluting with chloroform: metha-
nol (9:1) gave 3a–b and 4a–b in 20–25% and 68–70%
yields, respectively.
3345m, 1668s, 1672s cmꢀ1 1H NMR (DMSO-d6): d 4.82
;
(bs, 2H, amide NH2), 6.84 (bs, 2H, amide NH2), 7.38 (d, J
¼ 8.3 Hz, 2H, Ar-H), 7.56 (d, J ¼ 8.3 Hz, 2H, Ar-H), 7.69
(bs, 2H, NH2); 13C NMR (DMSO-d6): d 109.3, 114.7, 129.2,
131.1, 133.6, 134.3, 139.0, 162.9, 163.0, 166.8; ms: m/z 295
Journal of Heterocyclic Chemistry
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S. B. Kanawade, S. P. Patil, P. S. Nikam, S. A. Gangurde, M. N. Jachak, and R. B. Toche
Vol 49
Scheme 2
7.43 (d, J ¼ 8.2 Hz, 2H, Ar-H), 7.57 (d, J ¼ 8.2 Hz, 2H, Ar-
H); 13C NMR (CDCl3): d 22.3, 22.4, 22.8, 33.4, 102.5, 111.4,
114.3, 114.5, 129.6, 130.5, 131.9, 136.1, 144.4, 148.0, 159.4,
160.6; ms: m/z 339 (Mþ, 100%), 341 (Mþ2, 33%). Anal.
Calcd. for C18H14ClN3S (339.06): C, 63.62; H, 4.15; N, 12.36.
Found: C, 63.50; H, 4.24; N, 12.18.
4-Amino-3-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]-
thieno[3,2-e]pyridine-2-carbonitrile (3a). This compound was
obtained as faint brown amorphous solid, 0.081 g (25%),
mp 249–251ꢂC; IR: 3540m, 3430m, 2210m, 1626s cmꢀ1
;
1H NMR (CDCl3): d 2.12 (m, 2H, CH2), 2.73–2.98 (m, 4H,
2CH2), 5.92 (bs, 2H, NH2), 7.62 (d, J ¼ 7.8 Hz, 2H, Ar-
H), 7.69 (d, J ¼ 7.8 Hz, 2H, Ar-H); ms: m/z 325 (Mþ,
100%), 327 (Mþ2, 33%). Anal. Calcd. for C17H12ClN3S
(325.04): C, 62.67; H, 3.71; N, 12.90. Found: C, 62.53; H,
3.60; N, 12.76.
50-(4-Chlorophenyl)-40-imino-10,40-dihydrospiro[cyclopentane-
1,20-thieno[2,3-d][1,3]oxazine]-60-carbonitrile (4a). This compo-
und was obtained as an off white amorphous solid, 0.233 g
(68%), mp 244–246ꢂC; IR: 3168m, 2935s, 2205m, 1669s,
1
1620m cmꢀ1; H NMR (CDCl3): d 2.04–2.50 (m, 4H, 2CH2),
4-Amino-3-(4-chlorophenyl)-5,6,7,8-tetrahydrothieno[2,3-b]-
quinoline-2-carbonitrile (3b). This compound was obtained as
an off white amorphous solid, 0.068 g (20%), mp 260–261ꢂC;
;
IR: 3500m, 3392m, 2937s, 2208m, 1624m cmꢀ1 1H NMR
2.64–2.87 (m, 4H, 2CH2), 4.93 (bs, 1H, NH), 6.50 (bs, 1H,
NH), 7.48 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.60 (d, J ¼ 8.4 Hz,
2H, Ar-H); ms: m/z 343 (Mþ, 100%), 345 (Mþ2, 33%). Anal.
Calcd. for C17H14ClN3OS (343.05): C, 59.38; H, 4.10; N,
12.22. Found: C, 59.24; H, 4.22; N, 12.35.
(CDCl3): d 1.83–1.98 (m, 4H, 2CH2), 2.41 (t, J ¼ 5.3 Hz,
2H, CH2), 2.95 (t, J ¼ 5.3 Hz, 2H, CH2), 4.37 (bs, 2H, NH2),
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Synthesis of New Thieno[2,3-d]pyrimidines, Thieno[3,2-e]pyridines,
and Thieno[2,3-d][1,3]oxazines
367
50-(4-Chlorophenyl)-40-imino-10,40-dihydrospiro[cyclohexane-
1,20-thieno[2,3-d][1,3]oxazine]-60-carbonitrile (4b). This compo-
und was obtained as an off white amorphous solid, 0.250 g
(70%), mp 252–253ꢂC; IR: 3180m, 2934s, 2209m, 1663s,
nol, and dried to afford analytically pure pale yellow amor-
phous solid, 0.24 g (80%), mp 302–304ꢂC; IR: 3381s, 3306s,
3205m, 2200m, 1637 cmꢀ1 1H NMR (DMSO-d6): d 5.59 (s,
;
2H, NH2), 6.40 (s, 1H, NH), 7.45 (d, J ¼ 8.3 Hz, 2H, Ar-H),
7.51 (d, J ¼ 8.3 Hz, 2H, Ar-H), 8.42 (s, 1H, CH); ms: m/z 301
(Mþ, 100%), 303 (Mþ2, 33%). Anal. Calcd. for C13H8ClN5S
(301.02): C, 51.74; H, 2.67; N, 23.21. Found: C, 51.56; H,
2.51; N, 23.11.
General procedure for the synthesis of compounds 9a–c. To
a mixture of compound 2 (0.295 g, 0.001 mol) and aromatic
aldehyde (0.001 mol) in dry acetonitrile (5 mL), iodine (0.14
g, 0.0011 mol) was added. The mixture was refluxed for 8–10
h (TLC check, chloroform: methanol (8:2) as an eluent. After
reaction was completed, the mixture was cooled to room tem-
perature. An aqueous solution of sodium thiosulphate (5%,
5 mL) was added, and the resulted solid was filtered off, dried,
and washed with water. The crude product was purified by
column chromatography (silica gel 5–20 lm) in chloroform:
methanol (8:2) as an eluent.
2,5-Di(4-chlorophenyl)-3,4-dihydro-4-oxothieno[2,3-d]pyrimi-
dine-6-carboxamide (9a). This compound was obtained as
colorless amorphous solid, 0.269 g (65%), mp 340–342ꢂC;
IR: 3470m, 3330m, 3308m, 1686s, 1639m cmꢀ1 1H NMR
;
(DMSO-d6): d 6.40–6.50 (bs, 2H, amide NH2), 7.43 (d, J ¼
8.1 Hz, 2H, Ar-H), 7.52 (d, J ¼ 8.1 Hz, 2H, Ar-H), 7.53 (d,
J ¼ 8.3 Hz, 2H, Ar-H), 8.02 (d, J ¼ 8.3 Hz, 2H, Ar-H),
11.98 (bs, 1H, NH); ms: m/z 415 (Mþ, 100%), 417 (Mþ2,
65%), 419 (Mþ4, 11%). Anal. Calcd. for C19H11Cl2N3O2S
(417.01): C, 54.82; H, 2.66; N, 10.09. Found: C, 54.64; H,
2.79; N, 9.99.
1
1626m cmꢀ1; H NMR (CDCl3): d 1.80ꢀ1.85 (m, 4H, 2CH2),
2.34 (m, 2H, CH2), 2.92 (t, J ¼ 5.4 Hz, 2H, CH2), 4.04 (t, J
¼ 5.4 Hz, 2H, CH2), 5.16 (bs, 1H, NH), 6.13 (bs, 1H, NH),
7.47 (d, J ¼ 8.2 Hz, 2H, Ar-H), 7.56 (d, J ¼ 8.2 Hz, 2H, Ar-
H); ms: m/z 357 (Mþ, 100%), 359 (Mþ2, 33%). Anal. Calcd.
for C18H16ClN3OS (357.07): C, 60.41; H, 4.51; N, 11.74.
Found: C, 60.59; H, 4.71; N, 11.60.
5-(4-Chlorophenyl)-3,4-dihydro-4-oxothieno[2,3-d]pyrimidine-
6-carboxamide (5). Compound 1 (0.259 g, 0.001 mol) in for-
mic acid (5 mL) was refluxed for 12 h (TLC check, chloro-
form: methanol, 8:1). On cooling to room temperature, the
obtained residue was filtered, washed thoroughly with water,
dried, and purified by column chromatography (silica gel 5–20
lm) in chloroform: methanol (8:1) as an eluent to afford pale
yellow crystals, 0.244 g (80%), mp 265–266ꢂC; IR: 3400m,
1
3302m, 3263m, 1668s, 1641m cmꢀ1; H NMR (DMSO-d6): d
6.40–6.56 (bs, 2H, amide NH2), 7.27 (d, J ¼ 8.4 Hz, 2H, Ar-
H), 7.44 (d, J ¼ 8.4 Hz, 2H, Ar-H), 8.42 (s, 1H, CH), 11.41
(bs, 1H, NH); ms: m/z 305 (Mþ, 100%), 307 (Mþ2, 33%).
Anal. Calcd. for C13H8ClN3O2S (305.00): C, 51.07; H, 2.64;
N, 13.74. Found: C, 51.19; H, 2.79; N, 13.59.
N-(4-(4-Chlorophenyl)-3,5-dicyanothiophen-2-yl)acetamide
(6). To a mixture of 1 (0.259 g, 0.001 mol) and acetic anhy-
dride (5 mL), a drop of conc. H2SO4 was added and then
stirred at room temperature for 1 h (TLC check, chloroform:
methanol, 8:2). Resulting reaction mixture was poured over
crushed ice and stirred overnight. The separated solid was fil-
tered, washed with cold water, dried under vacuum, and crys-
tallized with ethanol: DMF (2:1) afforded pale yellow amor-
phous solid, 0.287 g (90%), mp 298–300ꢂC; IR: 3267m,
5-(4-Chlorophenyl)-3,4-dihydro-2-(2,4-dimethoxyphenyl)-4-
oxothieno[2,3-d]pyrimidine-6-carboxamide (9b). This compo-
und was obtained as off white amorphous solid, 0.299 g
(68%), mp 336–337ꢂC; IR: 3470m, 3332m, 3313m, 1688s,
1638m, 1240m cmꢀ1 1H NMR (DMSO-d6): d 3.84 (s, 3H,
;
1
2212m, 2216m, 1703s, 1625m cmꢀ1; H NMR (DMSO-d6): d
OCH3), 3.86 (s, 3H, OCH3), 6.53–7.62 (bs, 2H, amide NH2),
6.67–6.70 (m, 2H, Ar-H), 7.39 (d, J ¼ 8.5 Hz, 2H, Ar-H),
7.46 (d, J ¼ 8.5 Hz, 2H, Ar-H), 7.79 (d, 1H, Ar-H), 11.87 (s,
1H, NH); ms: m/z 441(Mþ, 100%), 443 (Mþ2, 33%). Anal.
Calcd. for C21H16ClN3O4S (441.06): C, 57.08; H, 3.65; N,
9.51. Found: C, 57.18; H, 3.59; N, 9.62.
2.31 (s, 3H, CH3), 7.64 (d, J ¼ 8.7 Hz, 2H, Ar-H), 7.73 (d, J
¼ 8.7 Hz, 2H, Ar-H), 12.63 (s, 1H, NH); 13C NMR (DMSO-
d6): d 22.3, 92.7, 96.4, 112.9, 113.7, 129.0, 129.4, 130.3,
135.0, 147.8, 153.1, 170.2; ms: m/z 301(Mþ, 100%), 303
(Mþ2, 33%). Anal. Calcd. for C14H8ClN3OS (301.10): C,
55.72; H, 2.67; N, 13.93. Found: C, 55.66; H, 2.52; N, 13.75.
(E)-N0-(4-(4-chlorophenyl)-3,5-dicyanothiophen-2-yl)-N,N-
dimethylformamidine (7). Compound 1 (0.259 g, 0.001 mol)
in dry p-xylene (5 mL) and (0.133 mL, 0.001 mol) DMF-
DMA was refluxed for 3 h (TLC check, chloroform: methanol
8:2). After evaporating the solvent in vacuo, the obtained resi-
due was stirred in hexane for 1 h and filtered, dried, and
recrystallized from ethanol: DMF (2:1) gave yellow amor-
phous solid, 0.283 g (90%), mp 210–211ꢂC; IR: 3312m,
5-(4-Chlorophenyl)-3,4-dihydro-2-(4-nitrophenyl)-4-oxo-
thieno[2,3-d]pyrimidine-6-carboxamide (9c). This compound
was obtained as yellow amorphous solid, 0.282 g (66%), mp
345–346ꢂC; IR: 3474m, 3341m, 3318m, 1684s, 1638m,
1530m, 1320s cmꢀ1 1H NMR (DMSO-d6): d 6.67–7.70 (bs,
;
2H, amide NH2), 7.41 (d, J ¼ 8.5 Hz, 2H, Ar-H), 7.48 (d, J ¼
8.5 Hz, 2H, Ar-H), 8.36 (d, J ¼ 9.0 Hz, 2H, Ar-H), 8.38 (d, J
¼ 9.0 Hz, 2H, Ar-H), 12.99 (bs, 1H, NH); ms: m/z 428 (Mþ,
100%), 430 (Mþ2, 33%). Anal. Calcd. for C19H11ClN4O4S
(428.03): C, 53.46; H, 2.60; N, 13.13. Found: C, 53.58; H,
2.49; N, 13.09.
General procedure for the synthesis of 10a–b. Stoichiometric
amounts of 2 (0.295 g, 0.001 mol) and cyclohexanone/cyclo-
pentanone (0.001 mol) in a round-bottomed flask (10 mL)
sealed with a teflon cap were vigorously stirred for 2–3 h
(TLC check, chloroform: methanol, 8:2). After standing over-
night at room temperature, the solid separated was then stirred
in diethyl ether (5 mL) for 1 h. It was then filtered, dried, and
without any further purification directly analyzed by spectro-
scopic methods.
2950s, 2208m, 2210m, 1625m cmꢀ1 1H NMR (CDCl3): d
;
3.21ꢀ3.23 (bs, 6H, 2CH3), 7.50 (d, J ¼ 8.4 Hz, 2H, Ar-H),
7.61 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.84 (s, 1H, CH); ms: m/z 315
(Mþ1, 100%), 317 (Mþ2, 33%). Anal. Calcd. for
C15H11ClN4S (314.04): C, 57.23; H, 3.52; N, 17.80. Found: C,
57.40; H, 3.41; N, 17.78.
3-Amino-5-(4-chlorophenyl)-4-imino-3,4-dihydrothieno[2,3-
d]pyrimidine-6-carbonitrile (8). A mixture of 7 (0.314 g,
0.001 mol), hydrazine hydrate (0.05 mL, 0.001 mol) in abso-
lute ethanol (10 mL) was refluxed for 6 h (TLC check, chloro-
form: methanol 8:2). The solvent was evaporated in vacuo to
give solid residue, which was filtered, washed with cold etha-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

368
S. B. Kanawade, S. P. Patil, P. S. Nikam, S. A. Gangurde, M. N. Jachak, and R. B. Toche
Vol 49
50-(4-Chlorophenyl)-30,40-dihydro-40-oxo-10H-spiro[cyclopen
(352.98): C, 47.47; H, 2.56; N, 11.86. Found: C, 47.31; H,
2.42; N, 11.76.
tane-1,20-thieno[2,3-d]pyrimidine]-60-carboxamide (10a). This
compound was obtained as white amorphous solid, 0.353 g
(98%), mp 264–265ꢂC; IR: 3490m, 3469m, 3380m, 3290m,
5-(4-Chlorophenyl)-3,4-dihydro-2-(3-chloropropyl)-4-oxo-
thieno-[2,3-d]pyrimidine-6-carboxamide (11d). This compo-
und was obtained as colorless amorphous solid, 0.247 g
(65%), mp 274–275ꢂC; IR: 3456m, 3356m, 3311m, 3169m,
3312m, 2935s, 1660s, 1630m cmꢀ1 1H NMR (DMSO-d6): d
;
1.90–1.92 (m, 4H, 2CH2), 2.18–2.24 (m, 4H, 2CH2), 6.47
(bs, 2H, amide NH2), 7.32 (d, J ¼ 8.3 Hz, 2H, Ar-H), 7.50 (d,
J ¼ 8.3 Hz, 2H, Ar-H), 7.52 (bs, 1H, NH), 8.26 (bs, 1H, NH);
ms: m/z 361 (Mþ, 100%), 363 (Mþ2, 33%). Anal. Calcd. for
C17H16ClN3O2S (361.07): C, 56.43; H, 4.46; N, 11.61. Found:
C, 56.34; H, 4.59; N, 11.51.
1672s, 1649m cmꢀ1 1H NMR (DMSO-d6): d 2.15–2.17 (m,
;
4H, 2CH2), 3.31 (m, 2H, CH2), 6.51–7.39 (bs, 2H, amide
NH2), 7.36 (d, J ¼ 8.3 Hz, 2H, Ar-H), 7.52 (d, J ¼ 8.3 Hz,
2H, Ar-H), 11.30 (bs, 1H, NH); ms: m/z 381 (Mþ, 100%),
383 (Mþ2, 65%), 385 (Mþ4, 11%). Anal. Calcd. for
C16H13Cl2N3O2S (381.01): C, 50.27; H, 3.43; N, 10.99.
Found: C, 50.19; H, 3.19; N, 10.85.
50-(4-Chlorophenyl)-30,40-dihydro-40-oxo-10H-spiro[cyclohex-
ane-1,20-thieno[2,3-d]-pyrimidine]-60-carboxamide (10b). This
compound was obtained as white amorphous solid, 0.371 g
(99%), mp 240–242ꢂC; IR: 3498m, 3473m, 3381m, 3288m,
General procedure for the synthesis of compounds 12a–c. A
mixture of compound 2 (0.295 g, 0.001 mol) and aromatic alde-
hyde (0.001 mol) in ethanol (10 mL) with catalytic amount of
piperidine was refluxed in oil bath with stirring for 10–12 h
(TLC check, chloroform: methanol, 8:2). The reaction mixture
was cooled and stirred in crushed ice (25 mL). The residue
obtained was filtered and purified by column chromatography
(silica gel 5–20 lm) in chloroform: methanol (8:2) as an eluent.
2,5-Di-(4-chlorophenyl)-1,2,3,4-tetrahydro-4-oxothieno[2,3-d]-
pyrimidine-6-carboxamide (12a). This compound was obtained
as colorless amorphous solid, 0.242 g (52%), mp 310–312ꢂC;
3213m, 2937s, 1654s, 1629m cmꢀ1 1H NMR (DMSO-d6): d
;
1.19–1.48 (m, 4H, 2 CH2), 1.76–1.87 (m, 4H, 2 CH2), 2.25 (m,
2H, CH2), 5.37 (bs, 1H, NH), 7.18–7.38 (bs, 2H, amide NH2),
7.27 (d, J ¼ 8.3 Hz, 2H, Ar-H), 7.44 (d, J ¼ 8.3 Hz, 2H, Ar-
H), 8.30 (s, 1H, NH); 13C NMR (DMSO-d6): d 20.9, 24.4,
26.3, 36.3, 41.2, 70.3, 110.1, 117.7, 127.8, 131.0, 132.3, 134.1,
139.6, 159.1, 160.3, 163.0; ms: m/z 375 (Mþ, 100%), 377
(Mþ2, 33%). Anal. Calcd. for C18H18ClN3O2S (375.08): C,
57.52; H, 4.83; N, 11.18. Found: C, 57.46; H, 4.68; N, 11.30.
General procedure for the synthesis of compounds 11a–d. A
mixture of 2 (0.295 g, 0.001 mol) and various acid chlorides
(0.001 mol) were stirred at 115ꢂC in glacial acetic acid (4 mL)
for 10–12 h (TLC check, chloroform: methanol, 8:2). Excess
acetic acid was distilled off under vacuum, and residue
obtained was poured over crushed ice (15 mL), filtered and
dried. The solid was then purified by column chromatography
(silica gel 5–20 lm) in chloroform: methanol (8:2) as an
eluent.
IR: 3475m, 3327m, 3308m, 1689s, 1641s cmꢀ1 1H NMR
;
(DMSO-d6): d 5.82 (s, 1H, CH), 6.31–6.48 (bs, 2H, amide
NH2), 7.42 (d, J ¼ 8.1 Hz, 2H, Ar-H), 7.49 (d, J ¼ 8.1 Hz,
2H, Ar-H), 7.62 (d, J ¼ 8.4 Hz, 2H, Ar-H), 8.4 (bs, 1H, NH),
8.16 (d, J ¼ 8.4 Hz, 2H, Ar-H), 12.76 (bs, 1H, NH); ms: m/z
417 (Mþ, 100%), 419 (Mþ2, 65%), 421 (Mþ4, 11%). Anal.
Calcd. for C19H13Cl2N3O2S (417.01): C, 54.56; H, 3.13; N,
10.05. Found: C, 54.64; H, 3.24; N, 9.89.
5-(4-Chlorophenyl)-1,2,3,4-tetrahydro-2-(2,4-dimethoxy-
phenyl)-4-oxothieno[2,3-d]-pyrimidine-6-carboxamide (12b). This
compound was obtained as pale green amorphous solid, 0.243
g (55%), mp 330–332ꢂC; IR: 3472m, 3330m, 3310m, 1687s,
5-(4-Chlorophenyl)-3,4-dihydro-2-methyl-4-oxothieno[2,3-d]-
pyrimidine-6-carboxamide (11a). This compound was obtained
as an off white amorphous solid, 0.207 g (65%), mp 277–
;
280ꢂC; IR: 3490m, 3470m, 1668s, 1629m cmꢀ1 1H NMR
1641m, 1242m cmꢀ1 1H NMR (DMSO-d6): d 3.84 (s, 3H,
;
(DMSO-d6): d 2.14 (s, 3H, CH3), 6.32–6.54 (bs, 2H, amide
NH2), 7.34 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.49 (d, J ¼ 8.4 Hz,
2H, Ar-H), 11.29 (bs, 1H, NH); ms: m/z 319 (Mþ, 100%), 321
(Mþ2, 33%). Anal. Calcd. for C14H10ClN3O2S (319.02): C,
52.59; H, 3.15; N, 13.14. Found: C, 52.48; H, 3.21; N, 13.21.
5-(4-Chlorophenyl)-3,4-dihydro-2-phenyl-4-oxothieno[2,3-d]-
pyrimidine-6-carboxamide (11b). This compound was obtained
as white amorphous solid, 0.236 g (62%), mp 268–270ꢂC; IR:
OCH3), 3.86 (s, 3H, OCH3), 5.86 (s, 1H, CH), 6.52–7.11 (bs,
2H, amide NH2), 6.65–6.80 (m, 2H, Ar-H), 7.72 (d, 1H, Ar-
H), 8.21 (d, J ¼ 8.3 Hz, 2H, Ar-H), 8.32 (d, J ¼ 8.3 Hz, 2H,
Ar-H), 8.50 (bs, 1H, NH), 9.78 (bs, 1H, NH); ms: m/z 441
(Mþ, 100%), 443 (Mþ2, 33%). Anal. Calcd. for
C21H18ClN3O4S (441.06): C, 56.82; H, 4.09; N, 9.47. Found:
C, 56.95; H, 4.21; N, 9.35.
5-(4-Chlorophenyl)-1,2,3,4-tetrahydro-2-(4-nitrophenyl)-4-
oxothieno[2,3-d]pyrimidine-6-carboxamide (12c). This com-
pound was obtained as yellow amorphous solid, 0.236 g
(55%), mp 329–330ꢂC; IR: 3476m, 3339m, 3315m, 1687s,
1
3488m, 3468m, 2931s, 1665s, 1624m cmꢀ1; H NMR (DMSO-
d6): d 6.31–6.56 (bs, 2H, amide NH2), 7.10–7.40 (m, 5H, Ar-
H), 7.45 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.52 (d, J ¼ 8.4 Hz, 2H,
Ar-H), 11.25 (bs, 1H, NH); ms: m/z 381 (Mþ, 100%), 383
(Mþ2, 33%). Anal. Calcd. for C19H12ClN3O2S (381.03): C,
59.76; H, 3.17; N, 11.00. Found: C, 59.68; H, 3.28; N, 11.16.
5-(4-Chlorophenyl)-3,4-dihydro-2-(chloromethyl)-4-oxothieno-
[2,3-d]pyrimidine6-carboxamide (11c). This compound was
obtained as white amorphous solid, 0.246 g (70ꢀ%1), mp 267–
1640m, 1531m, 1323s cmꢀ1 1H NMR (DMSO-d6): d 6.60–
;
7.20 (bs, 2H, amide NH2), 6.65 (s, 1H, CH), 7.25 (d, J ¼
8.4 Hz, 2H, Ar-H), 7.32 (d, J ¼ 8.4 Hz, 2H, Ar-H), 7.82 (d,
J ¼ 8.9 Hz, 2H, Ar-H), 8.16 (d, J ¼ 8.9 Hz, 2H, Ar-H),
8.52 (bs, 1H, NH), 11.08 (bs, 1H, NH); ms: m/z 429 (Mþ,
100%), 431 (Mþ2, 33%). Anal. Calcd. for C19H13ClN4O4S
(429.04): C, 53.21; H, 3.06; N, 13.06. Found: C, 53.37; H,
3.24; N, 12.90.
269ꢂC; IR: 3489m, 3468m, 1665s, 1630m cm
;
1H NMR
(DMSO-d6): d 4.56 (s, 2H, CH2), 6.35–6.58 (bs, 2H, amide
NH2), 7.36 (d, J ¼ 8.3 Hz, 2H, Ar-H), 7.52 (d, J ¼ 8.3 Hz,
2H, Ar-H), 12.04 (bs, 1H, NH); 13C NMR (DMSO-d6): d
166.0, 164.9, 163.4, 143.2, 136.8, 133.7, 133.1, 131.6, 128.9,
125.6, 120.2, 42.4; ms: m/z 353 (Mþ, 100%), 355 (Mþ2,
65%), 357 (Mþ4, 11%). Anal. Calcd. for C14H9Cl2N3O2S
Acknowledgments. The authors gratefully acknowledge the
support for this research by UGC and CSIR New Delhi and Uni-
versity of Pune for spectroscopic analysis and Principal KTHM
College, Nashik-02 for facilities.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Synthesis of New Thieno[2,3-d]pyrimidines, Thieno[3,2-e]pyridines,
and Thieno[2,3-d][1,3]oxazines
369
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