A novel microwave-assisted green synthesis of condensed 2-substituted-pyrimidin-4(3H)-ones under solvent-free conditions

Article abstract of DOI:10.1002/jhet.30

A rapid microwave-assisted green chemical synthesis of condensed 2-substituted-pyrimidin-4(3H)-ones 3, 4, and 5 involving the condensation of a variety of nitriles with o-aminoesters of thiophene 2a-e, benzene 2f, dimethoxybenzene 2g and quinazolinone 2h in the presence of catalytic amount of HCl alone or with the Lewis acid AlCl₃ under solvent-free conditions, is described for the first time. This novel and clean one-pot methodology, which is characterized by very short reaction times and easy workup procedures, can be exploited to generate a diverse library of condensed pyrimidine heterocycles.

Full text of DOI:10.1002/jhet.30

178
A Novel Microwave-Assisted Green Synthesis of Condensed
2-Substituted-pyrimidin-4(3H)-ones Under Solvent-Free Conditions
Vol 46
Kishor S. Jain,* Jitender B. Bariwal, Manisha S. Phoujdar,
Madhuri A. Nagras, Rakesh D. Amrutkar, Manoj K. Munde, Riyaj S. Tamboli,
Samrat A. Khedkar, Rahul H. Khiste, Nikhil C. Vidyasagar,
Vinit V. Dabholkar, and M. K. Kathiravan
Department of Pharmaceutical Chemistry, Sinhgad College of Pharmacy, Pune 411 041, India
*E-mail: kishor.s.jain@gmail.com
Received May 8, 2008
DOI 10.1002/jhet.30
Published online 23 March 2009 in Wiley InterScience (www.interscience.wiley.com).
A rapid microwave-assisted green chemical synthesis of condensed 2-substituted-pyrimidin-4(3H)-
ones 3, 4, and 5 involving the condensation of a variety of nitriles with o-aminoesters of thiophene 2a–e,
benzene 2f, dimethoxybenzene 2g and quinazolinone 2h in the presence of catalytic amount of HCl alone
or with the Lewis acid AlCl3 under solvent-free conditions, is described for the first time. This novel and
clean one-pot methodology, which is characterized by very short reaction times and easy workup proce-
dures, can be exploited to generate a diverse library of condensed pyrimidine heterocycles.
J. Heterocyclic Chem., 46, 178 (2009).
INTRODUCTION
time. The regularly employed synthetic methodologies
involve annelation of the pyrimidine ring on an appro-
priately substituted carbocycle or heterocycle [3].
Pyrimidines and condensed pyrimidines have a long
and distinguished history of their numerous biological
and medicinal applications [1]. The synthesis and bio-
logical evaluation [2] of potentially bioactive condensed
pyrimidines, appropriately functionalized, especially at
the 2- and 4-positions have attracted considerable atten-
tion of medicinal chemists worldwide. Therefore, the
synthesis of condensed pyrimidines has been a very
important process, subject to improvement, from time to
Of these the most popularly used synthetic methodology
is the ‘‘Principal Pyrimidine Synthesis’’, which involves
mainly the cyclocondensation of o-aminocarbonyl sub-
strates with reagents like amidines, ureas, thiourea or imi-
dates [3]. Alternatively use of nitriles as reagents for cyclo-
condensation with o-aminocarbonyl substrates is relatively
less exploited and is reported under basic [4,5] as well as
C
V
2009 HeteroCorporation

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A Novel Microwave-Assisted Green Synthesis of Condensed 2-Substituted-pyrimidin-
4(3H)-ones Under Solvent-Free Conditions
179
Scheme 1
acidic [6,7] conditions. The direct use of nitriles in these
cyclocondensations is attractive as it offers more flexibility
and generates a variety of 2-substituents in the resultant con-
densed pyrimidines. Nitriles often being the precursors for ami-
dines are also more economical than the amidines (Scheme 1).
It would be very interesting to adopt this reaction for
high throughput synthesis in order to generate diverse
libraries of condensed pyrimidines of type 1 with four
diverse points for further functionalization.
intermediate. This interesting reaction has been developed
as a synthetic method of general applicability to obtain a
variety of condensed 2-substituted-4-functionalized pyri-
midines. The reaction generally takes 8–12 h for comple-
tion and typically involves bubbling of dry HCl gas
through the reaction mixture in dioxane (Scheme 2).
The direct use of the electrophilic properties of nitriles
in such syntheses, though previously reported [8], has
received only scant attention. Shishoo and coworkers
[6,7,9–15] have exploited the reactions of a variety of
nitriles with a host of o-aminocarbonyl substrates, under
the influence of dry HCl gas under conventional conditions
to obtain a wide range of 2-substituted-4-oxo/4-amino/4-
chloro and 4-aryl condensed pyrimidines (Scheme 2).
These reactions are known to proceed via the imidoyl ha-
lide intermediate, whose carbon is highly electrophilic.
The cyclocondensation proceeds via the transient amidine
Scheme 2
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K. S. Jain, J. B. Bariwal, M. S. Phoujdar, M. A. Nagras, R. D. Amrutkar, M. K. Munde, R. S. Tamboli, Vol 46
S. A. Khedkar, R. H. Khiste, N. C. Vidyasagar, V. V. Dabholkar, and M. K. Kathiravan
Scheme 3
Reactions that are adaptable for high speed through-
vent-free conditions for generating compound libraries
of condensed pyrimidines of type 1.
put syntheses have become an important component of
the modern medicinal chemist’s armory, as a great num-
ber of compounds can be produced through such rapid
parallel synthetic programs [16]. Synthetic methods that
enable the rapid production of an array of heterocycles,
useful for the identification of new lead structures are of
critical importance from the point of new drug dis-
covery. Moreover, quinazolines, thienopyrimidines and
other condensed pyrimidine scaffolds are important
heterocyclic building blocks and have been shown to
possess significant pharmacological activity against a
variety of molecular targets [17].
Herein, we report for the first time a rapid micro-
wave-assisted green synthesis of condensed 2-substitu-
tedpyrimidin-4(3H)-ones, 3, 4, and 5 involving the con-
densation of a variety of nitriles with o-aminoesters of
thiophene 2a–e, benzene 2f, dimethoxybenzene 2g and
quinazolinone 2h in the presence of catalytic amount of
HCl alone or with the Lewis acid, AlCl3 under solvent-
free conditions (Scheme 3).
RESULTS AND DISCUSSION
Our encouraging results in the MWI-based syntheses
of thiophene o-aminoesters involving Gewald reaction
[18], as well as, thienopyrimidine bioisosteres of gefiti-
nib [19] under microwave irradiation conditions, moti-
vated us to assess whether the use of MWI could be
extended to the single pot cyclocondensation of the
nitriles with various o-aminoester substrates under sol-
We started the experiments using different nitriles
such as acetonitrile, chloroacetonitrile and acrylonitrile.
The conventional methods for the synthesis of the
target condensed 2-substitutedpyrimidin-4(3H)-ones are
through the cyclization of appropriate o-amino esters 2
with these nitriles under acidic conditions in the solvent,
1,4-dioxane at 0–5ꢀC. This particular reaction requires
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A Novel Microwave-Assisted Green Synthesis of Condensed 2-Substituted-pyrimidin-
4(3H)-ones Under Solvent-Free Conditions
181
Table 1
Physical data of 2-substituted-thieno[2,3-d]pyrimidin-4(3H)-ones 3a–e, 4a–e, and 5a–e
Conventional method
Microwave-assisted method
R1
R2
R3
ACH3
ACH3
ACH3
Yield (%)
mp (ꢀC)
Time (h)
Yield (%)
mp (ꢀC)
Time (min)
3a
ACH2)4A
66
76
93
71
69
84
85
91
85
94
77
83
88
86
90
300–302a
286–288b
243–245
260–262c
262–264d
218–220
199–200
167–168
165–167
267–268
257–259f
246–247g
246–248
243–245h
208–210i
8–10
10–12
8–10
8–10
8–10
8–10
20–24
10–12
8–10
8–10
6–8
68
89
94
85
75
96e
99
92e
88
96
90
91
93
95
91
298
286
248
262
264
218
201
169
167
267
258
256
249
225
214
75
60
55
40
65
45
50
35
20
45
30
25
40
10
35
3b
3c
3d
3e
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
ACH3
4-CH3C6H4A
ACH3
ACH3
AH
ACOOC2H5
AH
ACH3
ACH3
AC6H5
A(CH2)4A
ACH2CH2Cl
ACH2CH2Cl
ACH2CH2Cl
ACH2CH2Cl
ACH2CH2Cl
ACH2Cl
ACH2Cl
ACH2Cl
ACH2Cl
ACH2Cl
CH3
4-CH3C6H4A
ACH3
ACH3
AH
ACOOC2H5
AC6H5
AH
A(CH2)4A
ACH3
4-CH3C6H4A
CH3
ACH3
AH
ACOOC2H5
AH
8–10
6–8
6–8
6–8
AC6H5
a Reported m.p. 300–302ꢀC [10].
b Reported m.p. 286–288ꢀC [10].
c Reported m.p. 260–262ꢀC [6].
d Reported m.p. 262–264ꢀC [20].
e Catalytic amount of anhydrous. AlCl3 was added to the reaction mixture as per General Procedure B (experimental section).
f Reported m.p. 257–259ꢀC [21].
g Reported m.p. 246–247ꢀC [9].
h Reported m.p. 243–245ꢀC [12].
i Reported m.p. 208–210ꢀC [12].
bubbling of dry HCl gas in the reaction mixture for 8–
12 h, which is the time taken to complete the reaction
depending upon the nature of nitrile used. Interestingly,
these same reactions under microwave irradiation at
350 W were accomplished by using catalytic amount
of concentrated HCl (33% w/v, 5.0 mL) in very short
time periods. The physical data for the 2-substituted-
thieno[2,3-d]pyrimidin-4(3H)-ones 3a–e, 4a–e, 5a–e
synthesized under MWI is presented in Table 1 and that
for the 2-substitutedquinazolines 3f–h, 4f, and 5f–h is
recorded in Table 2. The reaction time varied depending
upon the type of nitrile used. The reactions with acetoni-
trile were completed in 40–75 min to obtain the con-
densed 2-methylpyrimidin-4(3H)-ones 3a–h with iso-
lated yields ranging from 68–94%. The reactions with
acrylonitrile were completed in 20–50 min and afforded
the condensed 2-chloroethylpyrimidin-4(3H)-ones 4a-f
in 85–96% yields (Scheme 3).
Interestingly, when the reactive nitrile, chloroacetoni-
trile was used, the reaction went to completion in just
10–40 min and afforded the corresponding 2-chlorome-
thylpyrimidin-4(3H)-ones 5a–h in generally excellent
isolated yields (>90%). Thus, in all the aforementioned
cases, there is considerable reduction in the reaction
times, when conventional heating is replaced by micro-
wave-assisted heating, i.e., from 6–12 h to 10–75 min,
respectively. Considerable improvement in yields was
also observed.
A very important and noteworthy fact is that all the
reactions depicted in Scheme 3 failed to proceed in the
absence of HCl. This indicates that these reactions under
MWI, may also be involving the imidoyl chloride inter-
mediates [22,23]. Further, in a few typical cases, only
catalytic amount of HCl failed to bring about the com-
pletion of the reaction. This was observed in the reac-
tion of 2a and 2c with acrylonitrile to prepare
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K. S. Jain, J. B. Bariwal, M. S. Phoujdar, M. A. Nagras, R. D. Amrutkar, M. K. Munde, R. S. Tamboli, Vol 46
S. A. Khedkar, R. H. Khiste, N. C. Vidyasagar, V. V. Dabholkar, and M. K. Kathiravan
Table 2
Physical data of other 2-substitutedpyrimidin-4(3H)-ones 3f–h, 4f, and 5f–h
Conventional method
Microwave-assisted method
R1
AH
R2
AH
R3
ACH3
ACH3
ACH3
ACH2CH2Cl
ACH2Cl
ACH2Cl
ACH2Cl
Yield (%)
mp (ꢀC)
Time (h)
Yield (%)
mp (ꢀC)
Time (min)
3f
70
62
52
80
90
65
53
240–242a
239–241
243–245
200–202
246–248b
242–244
240–242
8–10
8–10
8–10
8–10
6–8
80
70
71
83
94
70
66
240
240
243
202
241
242
241
45
45
20
30
30
25
20
3g
3h
4f
5f
5g
5h
AOCH3
AOCH3
–
–
AH
AH
AOCH3
AH
AH
AOCH3
6–8
8–10
a Reported m.p. 240–242ꢀC [10].
b Reported m.p. 246–248ꢀC [10].
compounds 4a and 4c, respectively. However, addition
of catalytic amount of a Lewis acid, anhydrous AlCl3
along with conc. HCl, accomplished the successful com-
pletion of the aforementioned reactions to afford the tar-
get condensed 2-substitutedpyrimidin-4(3H)-ones 4a and
4c in excellent isolated yields (Table 1). Thus, the
Lewis acid AlCl3, has forwarded the reactions, probably
by way of forming the electrophilic nitrile-metal halide,
hydrohalide complex as shown below (Scheme 4) [24].
involves the cyclocondensation of a variety of nitriles
with o-aminoesters of thiophene 2a-e, benzene 2f, dime-
thoxybenzene 2g and quinazolinone 2h in the presence
of catalytic amount of conc. HCl alone or with the
Lewis acid, AlCl3. This novel synthesis involving
nitriles as the building blocks, under microwave irradia-
tion for these condensed 2-substitutedpyrimidin-4(3H)-
ones requires only 10–75 min as compared to the con-
ventional heating protocols requiring 6–12 h, thereby
showing a significant acceleration in reaction rates
(Tables 1 and 2). The reaction proceeds through the
same activated electrophilic nitrile derivatives, the imi-
doyl halide intermediate and affords the products in
yields superior to that by the conventional protocols.
Coupled with simple workup procedures and superior
yields the methodology is eminently suitable for the gen-
eration of diverse libraries of condensed 2-substituted-
pyrimidin-4(3H)-ones employing parallel synthesis
procedures.
CONCLUSION
A novel microwave-assisted green synthesis of the
condensed 2-substitutedpyrimidin-4(3H)-ones 3, 4, and 5
under solvent-free conditions has been reported for the
first time. The unusually rapid synthetic methodology
Scheme 4
EXPERIMENTAL
Microwave synthesizer (Questron Technologies, Canada;
model: Q-Pro M) having monomode open-vessel was used for
the synthesis. All the chemicals used in the synthesis were of
laboratory grade. The melting points were determined in open
capillary on Veego (VMP-D) electronic apparatus and are
uncorrected. The IR spectra of synthesized compounds were
recorded on Perkin Elmer BX2 FT-IR Spectrophotometer in
KBr and reported in cmꢁ1 1H NMR spectra were measured
.
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A Novel Microwave-Assisted Green Synthesis of Condensed 2-Substituted-pyrimidin-
4(3H)-ones Under Solvent-Free Conditions
183
on a Varian Mercury YH-300 FT NMR spectrometer in
DMSO-d6 with chemical shifts (d) given in ppm relative to
TMS as internal standard. Thin layer chromatography was per-
formed on precoated silica plates (Merck Silicagel F254) using
hexane-ethyl acetate-glacial acetic acid (4.5 mL:0.5
mL:2drops), chloroform-methanol (4.5 mL:0.5 mL) as the sol-
vent systems and the spots were visualized by exposure to
iodine vapors or under ultra violet (UV) light. The HCl used
was 33% w/v aqueous and was of LR grade.
1H, 3-NH). Anal. Calcd. for C9H8N2O: C, 67.44; H, 5.02.
Found: C, 67.63; H, 5.42.
6,7-Dimethoxy-2-methylquinazolin-4(3H)-one
compound was obtained according to the aforementioned gen-
eral procedure; IR (potassium bromide): CO 1669 cmꢁ1 1H
(3g). This
;
NMR: d 2.55 (s, 3H, 2-CH3), 3.99 (s, 6H, 6- and 7-OCH3),
7.02–7.55 (m, 2H, phenyl protons), 10.87 (s, 1H, 3-NH). Anal.
Calcd. for C11H12N2O3: C, 59.90; H, 5.41. Found: C, 58.99;
H, 5.72.
2-Methyl-3H-[1,2,4]triazino[6,1-b]quinazolin-4,10-dione (3h).
This compound was obtained according to the aforementioned
General procedure A.
Reaction of 2-amino-3-carbethoxysubstrates 2 with nitriles
(in presence of only conc. HCl). A mixture of the appropriate
2-amino-3-carbethoxy substrate 2 (0.02 moles), nitrile (0.022
moles) and catalytic amount of HCl (33% w/v, 5.0 mL) was
irradiated at 350 W for 10–75 min in a microwave synthesizer.
The progress of reaction was monitored (using TLC) after 5-
min intervals. The reaction mixture was allowed to cool to
room temperature, and after completion of the reaction poured
into ice-water. The resulting precipitated solid was collected
by filtration, washed with chilled water and dried. The crude
product on recrystallization from methanol-chloroform mixture
yielded the appropriate condensed 2-substitutedpyrimidin-4-
(3H)-ones 3a–h, 4b, 4d–f, and 5a–h.
2-Methyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-d]pyri-
midin-4-one (3a). This compound was obtained according to
the aforementioned general procedure; IR (potassium bro-
mide): CO 1659 cmꢁ1 1H NMR: d 1.77 (s, 4H, 6- and 7-
;
CH2), 2.30 (s, 3H, 2-CH3), 2.70 (s, 2H, 5-CH2), 2.83 (s, 2H,
8-CH2). Anal. Calcd. for C11H12N2OS: C, 59.90; H, 5.47.
Found: C, 59.66; H, 5.38.
general procedure; IR (potassium bromide): CO 1680 cmꢁ1
;
1H NMR: d 2.37 (s, 3H, 2-CH3), 7.72–8.22 (m, 4H, phenyl
protons). Anal. Calcd. for C11H8N4O2: C, 57.90; H, 3.51.
Found: C, 57.69; H, 3.71.
2-(2-Chloroethyl)-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-
one (4b). This compound was obtained according to the afore-
mentioned general procedure; IR (potassium bromide): CO 1669
; d 2.38 (s, 3H, 5-CH3), 2.47 (s, 3H,
cmꢁ1 1H NMR:
6-CH3), 3.19 (t, 2H, 2-CH2CH2Cl, J ¼ 7.5 Hz), 3.97 (t, 2H,
2-CH2CH2Cl , J ¼ 7.2 Hz), 12.34 (s, br, 1H, 3-NH). Anal. Calcd.
for C10H11ClN2OS: C, 49.40; H, 4.53. Found: C, 49.14; H, 4.35.
Ethyl 2-(2-chloroethyl)-3,4-dihydro-5-methyl-4-oxothieno
[2,3-d]pyrimidin 6-carb-oxylate (4d). This compound was
obtained according to the aforementioned general procedure;
IR (potassium bromide): CO 1719, 1670 cmꢁ1 1H NMR: d
;
1.41 (t, 3H, 6-COOCH2CH3, J ¼ 7.3 Hz), 2.9 (s, 3H, 5-CH3),
3.24 (t, 2H, 2-CH2CH2Cl, J ¼ 6.7 Hz), 4.29 (t, 2H, 2-
CH2CH2Cl, J ¼ 7.3 Hz CH2), 4.3 (q, 2H, 6-COOCH2CH3, J
¼
7.1 Hz), 12.30 (s, 1H, 3-NH). Anal. Calcd. for
C11H13ClN2O2S: C, 47.93; H, 4.35. Found: C, 47.97; H, 4.42.
2-(2-Chloroethyl)-5-phenylthieno[2,3-d]pyrimidin-4(3H)-one
(4e). This compound was obtained according to the aforemen-
tioned general procedure; IR (potassium bromide): CO
2,5,6-Trimethylthieno[2,3-d]pyrimidin-4(3H)-one (3b). This
compound was obtained according to the aforementioned gen-
;
eral procedure; IR (potassium bromide): CO 1665 cmꢁ1 1H
NMR: d 2.37 (s, 3H, 2-CH3), 2.46 (s, 3H, 5-CH3), 2.51 (s, 3H,
6-CH3), 12.04 (s, br, 1H, 3-NH). Anal. Calcd. for C9H10N2OS:
C, 55.64; H, 5.15. Found: C, 55.81; H, 5.52.
1685cmꢁ1
;
1H NMR: d 3.19 (t, 2H, 2-CH2CH2Cl, J ¼ 7.2
Hz), 4.02 (t, 2H, 2-CH2CH2Cl, J ¼ 7.5 Hz), 7.30–7.50 (m,
6H, phenyl protons and 6-H), 12.40 (s, br, 1H, 3-NH). Anal.
Calcd. for C14H11ClN2OS: C, 57.83; H, 3.81. Found: C, 57.74;
H, 3.89.
2-Methyl-5-(4-methylphenyl)thieno[2,3-d]pyrimidin-4(3H)-one
(3c). This compound was obtained according to the aforemen-
tioned general procedure; IR (potassium bromide): CO 1670
1
cmꢁ1; H NMR: d 2.39 (s, 3H, 2-CH3), 2.47 (s, 3H, ArACH3),
2-(2-Chloroethyl)quinazolin-4(3H)-one (4f). This compound
was obtained according to the aforementioned general proce-
;
dure; IR (potassium bromide): CO 1678 cmꢁ1 1H NMR: d
3.18 (t, 2H, 2-CH2CH2Cl, J ¼ 6.3, 7.2 Hz), 4.06 (t, 2H, 2-
CH2CH2Cl, J ¼ 6.3, 7.2 Hz), 7.44–8.07 (m, 4H, phenyl pro-
tons), 10.25 (s, 1H, 3-NH). Anal. Calcd. for C10H9ClN2O: C,
57.55; H, 4.37. Found: C, 57.49; H, 4.80.
7.04 (s, 1H, 6-H), 7.16–7.48 (m, 4H, phenyl protons), 11.90 (s,
1H, 3-NH). Anal. Calcd. for C14H14N2OS: C, 65.66; H, 4.73.
Found: C, 65.76; H, 4.52.
Ethyl 3,4-dihydro-2,5-dimethyl-4-oxothieno[2,3-d]pyrimidin
6-carboxylate (3d). This compound was obtained according to
the aforementioned general procedure; IR (potassium bro-
mide): CO 1718, 1667 cmꢁ1 1H NMR: d 1.40 (t, 3H, 6-
;
COOCH2CH3, J ¼ 7.3 Hz), 2.55 (s, 3H, 2-CH3), 2.94 (s, 3H,
5-CH3), 4.36(q, 2H, 6-COOCH2CH3, J ¼ 7.1 Hz,); 10.95 (1H,
s, 3-NH). Anal. Calcd. for C10H11N2O2S: C, 52.37; H, 4.74.
Found: C, 52.56; H, 4.97.
2-Methyl-5-phenylthieno[2,3-d]pyrimidin-4(3H)-one (3e). This
compound was obtained according to the aforementioned gen-
;
eral procedure; IR (potassium bromide): CO 1671 cmꢁ1 1H
NMR: d 3.36 (s, 3H, 2-CH3), 7.31–7.50 (m, 5H, phenyl pro-
tons and 6-H), 12.28(s, 1H, 3-NH). Anal. Calcd. for
C13H10N2OS: C, 64.46; H, 4.12. Found: C, 64.15; H, 4.46.
2-Methylquinazolin-4(3H)-one (3f). This compound was
obtained according to the aforementioned general procedure;
IR (potassium bromide): CO 1666 cmꢁ1; H NMR: d 2.50 (s,
2H, 2-CH3), 7.38–7.74 (m, 4H, phenyl protons), 12.13 (s, br,
2-Chloromethyl-5,6,7,8-tetrahydro-3H-benzo[4,5]thieno[2,3-
d]pyrimidin-4-one (5a). This compound was obtained accord-
ing to the aforementioned general procedure; IR (potassium
1
bromide): CO 1663 cmꢁ1; H NMR: d 1.86 (s, 4H, 6- and 7-
CH2), 2.79 (s, 2H, 5-CH2), 3.02 (s, 2H, 8-CH2), 4.55 (s, 2H,
2-CH2Cl), 10.65 (s, br, 1H, 3-NH). Anal. Calcd. for
C11H11ClN2OS: C, 51.87; H, 4.30. Found: C, 57.69; H, 4.25.
2-Chloromethyl-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-
one (5b). This compound was obtained according to the afore-
mentioned general procedure; IR (potassium bromide): CO 1662
cmꢁ1 1H NMR: d 2.39 (s, 3H, 5-CH3), 2.47 (s, 3H, 6-CH3),
;
4.51 (s, 2H, 2-CH2Cl), 10.03(s, br, 1H, 3-NH). Anal. Calcd. for
C9H9ClN2OS: C, 47.20; H, 3.95. Found: C, 47.30; H, 3.40.
2-Chloromethyl-5-(4-methylphenyl)thieno[2,3-d]pyrimidin-
4(3H)-one (5c). This compound was obtained according to the
1
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K. S. Jain, J. B. Bariwal, M. S. Phoujdar, M. A. Nagras, R. D. Amrutkar, M. K. Munde, R. S. Tamboli, Vol 46
S. A. Khedkar, R. H. Khiste, N. C. Vidyasagar, V. V. Dabholkar, and M. K. Kathiravan
aforementioned general procedure; IR (potassium bromide):
CO 1651 cmꢁ1 1H NMR: d 2.39 (s, 3H, Ar-CH3), 4.53 (s,
aforementioned general procedure; IR (potassium bromide):
1
;
CO 1672 cmꢁ1; H NMR: d 2.40 (3H, s, Ar-CH3), 3.06 (2H, t,
2-CH2CH2Cl, J ¼ 7.0 Hz,), 3.87 (t, 2H, 2-CH2CH2Cl, J ¼ 7.0
Hz, 7.06 (s, 1H, 6-H), 7.15–7.45 (m, 4H, aryl protons), 12.99
(s, 1H, 3-NH). Anal. Calcd. for C15H15ClN2OS: C, 59.10; H,
4.33; Found: C, 59.25; H, 4.20.
2H, 2-CH2Cl), 7.13 (s, 1H, 6-H), 7.19–7.46 (m, 4H, phenyl
protons), 10.43 (s, 1H, 3-NH). Anal. Calcd. for
C14H13ClN2OS: C, 57.89; H, 3.80. Found: C, 57.79; H, 3.87.
Ethyl
2-chloromethyl-3,4-dihydro-5-methyl-4-oxothieno
[2,3-d]pyrimidine 6-carboxylate (5d). This compound was
General procedure C: Conventional method. A stream of
dry hydrogen chloride gas was bubbled through an ice-cold
mixture of the appropriate 2-amino-3-carbethoxysubstrate, 2a–
h (0.06 mole) and appropriate nitrile (0.09 mole) in dry diox-
ane (60 mL) for 8–12 h while maintaining the temperature
below 10ꢀC. The reaction mixture was allowed to stand there-
after at room temperature for 12 h. The reaction was then
heated on a water bath for 2–3 h, cooled to room temperature
and poured onto ice-water mixture (150–200 mL) and neutral-
ized with strong ammonium hydroxide solution (50%v/v). The
solid that separated was collected by filtration, washed with
water, dried and recrystallized from appropriate solvent.
obtained according to the aforementioned general procedure;
IR (potassium bromide): CO 1725, 1670 cmꢁ1 1H NMR: d
;
1.41 (t, 3H, 6-COOCH2CH3 J ¼ 7.0 Hz,), 2.95 (s, 3H, 5-CH3),
4.38 (q, 2H, 6-COOCH2CH3, J ¼ 7.0 Hz), 4.57 (s, 2H,
2-CH2Cl), 10.62 (s, 1H, 3-NH). Anal. Calcd. for
C10H11ClN2O2S: C, 46.04; H, 3.86. Found: C, 46.10; H, 3.92.
2-Chloromethyl-5-phenylthieno[2,3-d]pyrimidin-4(3H)-one
(5e). This compound was obtained according to the aforemen-
tioned general procedure; IR (potassium bromide): CO 1663
cmꢁ1 1H NMR: d 4.58 (s, 2H, 2-CH2Cl), 7.31–7.52 (m, 5H,
;
aryl protons and 6-H), 12.69 (s, br, 1H, 3-NH). Anal. Calcd. for
C13H9ClN2OS: C, 56.49; H, 3.23. Found: C, 56.62; H, 3.33.
2-Chloromethylquinazolin-4(3H)-one (5f). This compound
was obtained according to the aforementioned general proce-
;
dure; IR (potassium bromide): CO 1697 cmꢁ1 1H NMR: d
4.53 (s, 2H, 2-CH2Cl), 7.49–7.82 (m, 4H, aryl protons), 12.56
(s, br, 1H, 3-NH). Anal. Calcd. for C9H7ClN2O: C, 55.50; H,
3.64. Found: C, 55.62; H, 3.24.
Acknowledgments. The authors are thankful to the Indian
Council of Medical Research (ICMR) for providing financial as-
sistance to Mr. Jitender B. Bariwal and Mr. M. K. Kathiravan to
carry out this work. They are also grateful to Sinhgad Technical
Education Society, Pune for providing facilities to carry out this
work.
2-Chloromethyl-6,7-dimethoxyquinazolin-4(3H)-one (5g).
This compound was obtained according to the aforementioned
REFERENCES AND NOTES
general procedure; IR (potassium bromide): CO 1668 cmꢁ1
;
1H NMR: d 4.0 (s, 6H, 6- and 7-OCH3), 4.57 (s, 2H, 2-
CH2Cl), 7.01–7.59 (m, 2H, aryl protons) 9.75 (s, 1H, 3-NH).
Anal. Calcd. for C11H11ClN2O3: C, 51.85; H, 4.36. Found: C,
51.66; H, 4.20.
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1
CO 1690 cmꢁ1; H NMR: d 4.59 (s, 2H, 2-CH2Cl), 7.53–7.79
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Reaction of 2-amino-3-carbethoxythiophenes 2a and 2c
with acrylonitrile (in presence of conc. HCl and AlCl3). A
mixture of appropriate 2-amino-3-carbethoxythiophene 2a or 2c
(0.02 moles), acrylonitrile (0.022 moles), aq. HCl (33% w/v, 5.0
mL) and anhydrous AlCl3 (0.1–0.25 g) was irradiated at 350 W
for 35–45 min in a microwave synthesizer. After completion of
reaction, the reaction mixture was allowed to cool to room tem-
perature then was poured into ice-water. The resulting precipi-
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nol–chloroform mixture yielded the appropriate condensed
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009
A Novel Microwave-Assisted Green Synthesis of Condensed 2-Substituted-pyrimidin-
4(3H)-ones Under Solvent-Free Conditions
185
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