Microwave-assisted synthesis of some BI- and tricyclic pyrimidine derivatives

Article abstract of DOI:10.1080/10426500307886

Pyrimidine derivatives 4a-4c was prepared by a Biginelli cyclocondensation of β-ketoesters, aryl aldehydes, and thiourea derivatives under microwave irradiation. A simple and fast synthesis of bicyclic pyrimidine derivatives 6a-6c was performed by microwave-assisted reaction of 4a-4c with bromomalononitrile (5). Reaction of bicyclic pyrimidines 6a-6c with HCO₂H and HONH₃Cl under microwave irradiation gave tricyclic pyrimidines 7a-7c and 8a-8c respectively.

Full text of DOI:10.1080/10426500307886

This article was downloaded by: [University of Haifa Library]
On: 16 September 2013, At: 00:56
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Phosphorus, Sulfur, and Silicon and the Related
Elements
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Microwave-Assisted Synthesis of Some Bi- and Tricyclic
Pyrimidine Derivatives
N. Foroughifar a , A. Mobinikhaledi a , H. Fathinejad Jirandehi a & S. Memar a
a Arak University, Arak, Iran
Published online: 27 Oct 2010.
To cite this article: N. Foroughifar , A. Mobinikhaledi , H. Fathinejad Jirandehi & S. Memar (2003) Microwave-Assisted
Synthesis of Some Bi- and Tricyclic Pyrimidine Derivatives, Phosphorus, Sulfur, and Silicon and the Related Elements, 178:6,
1269-1276, DOI: 10.1080/10426500307886
To link to this article: http://dx.doi.org/10.1080/10426500307886
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any
form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 178:1269–1276, 2003
C
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print
DOI: 10.1080/10426500390200558
MICROWAVE-ASSISTED SYNTHESIS OF SOME
BI- AND TRICYCLIC PYRIMIDINE DERIVATIVES
N. Foroughifar, A. Mobinikhaledi, H. Fathinejad Jirandehi,
and S. Memar
Arak University, Arak, Iran
(Received October 15, 2002; accepted November 19, 2002)
Pyrimidine derivatives 4a–4c was prepared by a Biginelli cyclocon-
densation of -ketoesters, aryl aldehydes, and thiourea derivatives
under microwave irradiation. A simple and fast synthesis of bi-
cyclic pyrimidine derivatives 6a–6c was performed by microwave-
assisted reaction of 4a–4c with bromomalononitrile (5). Reaction
of bicyclic pyrimidines 6a–6c with HCO2H and HONH3Cl under
microwave irradiation gave tricyclic pyrimidines 7a–7c and 8a–8c
respectively.
Keywords: Bromomalononitrile; microwave; neutral alumina;
pyrimidine
Pyrimidine is known as a versatile heterocyclic compound, which has
been subjected to a various structural modifications in order to pre-
pare some derivatives with different biological effects. Some of pyrim-
15
idines possess remarkable pharmacological efficiency.1
Microwave
irradiation is a nonconventional energy source whose application in or-
19
ganic synthesis has been increased recently16
and technologically
is becoming more popular. Some of the more salient features of this
method are the rapid reaction rates and simple and cleaner reaction
conditions.6,16,19
Therefore, due to the versatile biological properties of pyrimidine
derivatives, we have extended the microwave-assisted cyclocondensa-
tion reactions in order to synthesize some novel bicyclic and tricyclic
pyrimidine derivatives in high yield.
Address correspondence to N. Foroughifar, Chemistry Department, Arak University,
Dr. Beheshti Ave., Arak, Iran. E-mail: N Foroughifar@yahoo.com
1269

1270
N. Foroughifar et al.
RESULTS AND DISCUSSION
Starting materials 4(a–c) were synthesized on the basis of already
reported procedure. -ketoester 1, aryl aldehyde 2, (thio)urea 3, and
polyphosphate ester (PPE) were reacted under microwave irradiation
to give the corresponding pyrimidine derivatives 4a–4c in high yields
(Table I) according to Scheme 1.
SCHEME 1
Reactions of 4(a–c) with bromomalononitrile (5) under microwave
irradiation lead to the formation of corresponding bicyclic pyrimidine
compounds 6(a–c) in high yields (Table II).

Microwave-Assisted Synthesis of Some Bi- and Tricyclic Pyrimidine Derivatives 1271
TABLE I Pyrimidine Derivatives 4a–4c
Entry
R
X
Yield
4a
4b
4c
Et
Et
Et
H
p-CH3
p-N(CH3)2
85
71
81
1H NMR, IR, and mass spectroscopies were used to identification of
these compounds. In the IR spectra of compounds 6(a–c) the sharp ab-
1
sorption at 2180–2202 cm indicate the existence of the nitrile group.
1
Also the absorption at 3203–3379 cm in IR spectra were assigned
1
1
to the NH2 group which is supported by the H NMR data. The H
NMR spectra 6(a–c) show a singlet signal at 7.6–7.7 ppm due to NH2
group. The multiplet signal at 6.5–7.3 ppm and the singlet signal at
6.2–6.3 ppm are due to resonance of aryl and pyrimidine ring protons
respectively.
Reactions of bicyclic pyrimidines 6(a–c) with HCO2H under mi-
crowave irradiation afforded tricyclic pyrimidines 7a–7c (Table III).
1H NMR of compounds 7a–7c could not be obtained due to their
insolubility in DMSO. However the IR and mass spectroscopies data
suggested these compounds should be pure. The IR spectra of these
1
compounds have an absorption in the region 3327–3340 cm which is
the characteristic of secondary amines.
Compounds 8a–8c (Table IV) were synthesized by reaction of bicyclic
1
pyrimidines 6(a–c) with HONH3Cl under microwave irradiation. H
NMR measurements of compounds 8a–8c confirmed their purity to be
1
more than 95%. In H NMR spectra the sharp singlet signal at 2.2–
2.5 ppm is assigned to resonance of CH3 group on the pirimidine ring.
Resonance at 6.50–7.69 ppm is attributed to aromatic protons of the
phenyl and pyrimidine rings. The two different singlet signals in the
regions 7.90–8.50 and 9.00–9.20 ppm, respectively, are due to resonance
of NH and NH2 groups of five-member heterocyclic ring containing
two nitrogens. This was supported by IR spectra, which included signals
1
in the region 3160–3526 cm
.
TABLE II Pyrimidine Bicyiclic Derivatives
6a–6c
Entry
R
X
Yield
6a
6b
6c
Et
Et
Et
H
p-CH3
p-N(CH3)2
83
75
86

1272
N. Foroughifar et al.
TABLE III Pyrimidine Tricyiclic Derivatives 7a–7c
Entry
R
X
Yield (%)
7a
7b
7c
Et
Et
Et
H
p-CH3
p-N(CH3)2
75
70
82
We also have made a comparison of time scales and yields on
the formation of pyrimidines 6–8 using microwave irradiation and
conventional heating method. It can be concluded that synthesis of bi-
cyclic and tricyclic pyrimidine derivatives under microwave irradiation
is quite faster (20–1080 times) and the yields are higher than conven-
tional heating methods (Table V).
In conclusion the rapid heating induced by microwave irradiation not
only avoids the force conditions and the decomposition of the reagents
but also results in formation of clean product under mild conditions,
thus increasing the yield.
EXPERIMENTAL
An Electrothermal digital melting point apparatus was used to deter-
mination of melting points. IR spectra were recorded on a Galaxy series
1
FT-IR 5000 spectrophotometer by using KBr pellets. H NMR spectra
were recorded on Bruker 400 and 500 MHz spectrometers with using
Me4Si (TMS) as an internal standard. Mass spectra were obtained from
an EI (70 eV)+Q1MSLMR up LP spectrometer. Reaction courses and
product mixtures were monitored by thin layer chromatography.
General Procedure for Preparation (4a---4c)
The mixture of aryl aldehyde (2 mmol), ethylacetoacetate (2.2 mmol),
thiourea (6.0 mmol), and polyphosphate ester (PPE, 0.30 g) were placed
in 25-ml glass beaker and stirred for 3–4 min with a magnetic stir-
rer. The reaction container was inserted into a 200-ml pyrex beaker
filled with neutral alumina (100–290 mesh) and irradiated in the mi-
crowave oven at 50% power level for 90 s. After cooling and addition of
H2O (5 mL) the mixture was stirred at room temperature for 2 h. The
TABLE IV Pyrimidine Tricyiclic Derivatives 8a–8c
Entry
R
X
Yield (%)
8a
8b
8c
Et
Et
Et
H
p-CH3
p-N(CH3)2
65
60
70

Microwave-Assisted Synthesis of Some Bi- and Tricyclic Pyrimidine Derivatives 1273
TABLE V Comparison of Time and Yields on the Formation
of Some Pyrimidine Derivatives Using Microwave Irradiation
and Conventional Heating
Microwave Irradiation
Conventional Heating
t/min Yield (%) tc/tmw
Entry
Power/W%
t/min
Yield (%)
6a
6b
6c
7a
7b
7c
8a
8b
8c
50
50
50
100
100
100
100
100
100
1.5
1.5
1.5
2/3
2/3
2/3
1
83
75
86
75
70
82
65
60
70
30
30
30
600
720
720
300
300
360
65
63
65
65
60
65
67
65
65
20
20
20
900
1080
1080
300
300
360
1
1
solid products were filtered, washed with H2O and subsequently dried
(Table I).
Preparation of Bromomalononitrile (5)
A mixture of malononitrile (0.825 g, 0.025 mmol) and water (8 ml) were
placed in a 50-ml narrow-neck flask. The mixture was put on an ice-
bath and stirred for 2–3 min with a magnetic stirrer. Then Br2 (1.275 ml,
0.025 mmol) was added as small portions. After the completion of the re-
action, 0.025 mmol of malononitrile was added and the mixture shacked
for 10 min at room temperature. The mixture was kept at 4 C for
overnight and the white crystals precipitated, filtered, washed with
H2O, and subsequently dried.
General Procedure for Preparation of Thiazole
Pyrimidine (6a---6c)
A mixture of pyrimidine derivative (4a–4c) (0.01 mmol), bromoma-
lononitrile (0.011 mmol) and PPE (0.3 g) were placed in a 25-ml beaker.
The reaction container was inserted into a 200-ml pyrex beaker filled
with neutral alumina (100–290 mesh). This set-up was irradiated in
the microwave oven 50% power level for 90s (one-step). The result was
then cooled at room temperature for 2 h and filtered. The precipitate
was crystallized from dilute DMF.
General Procedure for Preparation of (7a---7c)
A mixture of formic acid (1.2 mmol) and appropriate pyrimidine thiazole
derivatives, 6a–6c, (1 mmol) into a 25-ml glass beaker were stirred for

1274
N. Foroughifar et al.
2 min. The reaction container was inserted into a 200-ml pyrex beaker
filled with neutral alumina (alumina bath). This set-up was subjected
to microwave irradiation (100% power level) for 40 s. Then the result
was cooled for 4 h and recrystallized from ethanol.
General Procedure for Preparation (8a---8c)
A mixture of appropriate thiazole pyrimidine derivative, 6a–6c,
(0.01 mmol), hydroxylamin chloride (0.012 mmol) and PPE (0.6 g) were
stirred in a 50-ml glass beaker for 2 min. The reaction container was
inserted into a 200-ml pyrex beaker filled with neutral alumina and
subjected to microwave irradiation (100% power level) for 60 s. Then
result mixture was cooled at room temperature for 4 h. The result solid
was stirred in H2O, filtered, and recrystallized from ethanol.
Ethyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (4a)
Yield 85%, m.p. 206–207 C.
1
IR (KBr): v = 3340, 3180, 3100, 2990, 1676 cm
.
1H NMR (DMSO-d6), = 1.1 (t, j = 7.2 Hz, 3H, CH3), 2.3 (s,3H, CH3),
4.0 (q, j = 7.2 Hz, 2H, CH2), 5.3 (d, 1H, H-4), 7.3 (m, 5H, Haromat),
9.6, 10.3 (s, 1H, NH).
Ethyl 6-methyl-4-(4-methylphenyl)-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (4b)
Yield 71%, m.p. 186–187 C.
1
IR (KBr): v = 3325, 3177, 3109–2924, 1674 cm
.
1H NMR (DMSO-d6): = 1.0 (t, j = 7.2 Hz, 3H, CH3), 2.3 (s, 6H,
2CH3), 4.0 (q, j = 7.2 Hz, 2H,CH2), 5.2 (d, 1H, H-4), 7.2 (s, 4H,
H
aromat), 9.5 (bs, 1H, NH), 10.2 (s, 1H, NH).
Ethyl 6-methyl-4-(4-dimethylamino phenyl)-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (4c)
Yield 81%, m.p. 197–198 C.
1
IR (KBr): v = 3320, 3160, 3100, 2920, 1720 cm
.
1H NMR (DMSO-d6): = 1.2 (t, j = 7.2 Hz, 3H, CH3), 2.3 (s, 3H, CH3),
2.9 (s, 6H, CH3), 4.1 (q, j = 7.2 Hz, 2H, CH2), 5.2 (d, 1H, H-4),
6.6–7.2 (m, 4H, Haromat), 7.2, 7.9 (bs, 1H, NH).
Ethyl-3-amino-5-phenyl-2-cyano-7-methyl-5H-thiazolo[a-2,3]py-
rimidine-6-carboxylate (6a)
Yield 83%, m.p. 231–232 C.
1
IR (KBr): v = 3369–3271, 3115, 2980, 2191, 1705, 1680 cm
.
1H NMR (DMSO-d6): = 1.2 (t, 3H, CH3), 2.3 (s, 3H, CH3), 4.09 (q,
2H, CH2), 6.2 (s, 1H, H-4), 7.3 (s, 5H, Haromat), 7.7 (s, 2H, NH2).
MS: m/z (%) = 340 (M+, 100), 292 (83), 267(56), 263 (33).

Microwave-Assisted Synthesis of Some Bi- and Tricyclic Pyrimidine Derivatives 1275
Ethyl-3-amino-5-(4-methyl phenyl)-2-cyano-7-methyl-5H-thia-
zolo[a-2,3] pyrimidine-6-carboxylate (6b)
Yield 75%, m.p. 216–218 C.
1
IR (KBr): v = 3379–3291, 3146, 2985, 2202, 1709, 1651 cm
.
1H NMR (DMSO-d6): = 1.2 (t, j = 7.2 Hz, 3H, CH3), 2.3 (s, 6H,
2CH3), 4.0 (q, 2H, CH2), 6.3 (s, 1H, H-4), 7.2 (m, 4H, Haromat),
7.8 (s, 2H, NH2).
MS: m/z (%) = 354 (M+, 100), 324 (22), 306 (63), 281 (60), 263 (23).
Ethyl-3-amino-5-(4-dimethyl aminophenyl)-2-cyano-7-methyl-
5H-thiazolo[a-2,3]pyrimidine-5-carboxylate (6c)
Yield 86%, m.p. 209–210 C.
1
IR (KBr): v = 3303–3215, 3070, 2980, 2180, 1655 cm
.
1H NMR (DMSO-d6): = 1.2 (t, 3H, CH3), 2.3 (s, 6H, CH3), 4.0 (q,
2H, CH2), 6.2 (s, 1H, H-4), 6.5–7.2 (m, 4H, Haromat), 7.6 (s, 2H, NH2).
MS: m/z (%) = 383 (M+, 100), 336 (46), 310 (97), 263 (25).
Ethyl-9-phenyl-4-oxo-7-methyl-9H-3,4 dihydrothiazolo[a-2,3;, b-
4,5] dipyrimidine-8-carboxylate (7a)
Yield 75%, m.p. 206–207 C.
1
IR (KBr): v = 3340, 3140, 2980, 1680, 1630 cm
.
MS: m/z (%) = 368 (M+, 80), 339 (32), 323 (10), 295 (17), 291 (100).
Ethyl-9-(4-methyl phenyl)-4-oxo-7-methyl-9H-3,4-dihydrothia-
zolo [a-2,3: b-5,4] dipyrimidine-8-carboxylate (7b)
Yield 70%, m.p. 202–204 C.
1
IR (KBr): v = 3327, 3140, 2980, 1678, 1625 cm
.
MS: m/z (%) = 382 (78), 353 (32), 309 (82), 291 (100).
Ethyl-9-(4-dimethyl amino phenyl)-4-oxo-7-methyl-9H-3,4-dihy-
dropyrimidine-8-carboxylate (7c)
Yield 82%, m.p. 181–182 C.
1
IR (KBr): v = 3337, 3136, 2980, 1668, 1630 cm
.
MS: m/z (%) = 411 (29), 389 (25), 338 (100), 291 (85).
Ethyl-3-amino-8-phenyl-6-methyl-1H,8H-pyrazole [d-3,4] thia-
zole [a-2,3]pyrimidine-7-carboxylate (8a)
Yield 65%, m.p. 202–204 C.
1
IR (KBr): v = 3526–3160, 3120, 2972, 1710, 1525 cm
.
1H NMR (DMSO-d6): = 1.2 (t, 3H, CH3), 2.5 (s, 3H, CH3), 3.5 (q,
2H, CH2), 6.7 (s, 1H, H-4), 7.2–7.6 9 (m, 5H, Haromat), 7.9 (s, 1H,
NH), 9.0 (s, 2H, NH2).
MS: m/z (%) = 355 (M+, 21), 310 (38), 280 (100), 278 (42).
Ethyl-3-amino-8-(4-methylphenyl)-6-methyl-1H,8H-pyrazole [d-
3,4] thiazole[a-2,3]pyrimidine-7-carboxylate (8b)
Yield 60%, m.p. 182–183 C.
1
IR (KBr): v = 3480, 3180, 3125, 2980, 1699, 1525 cm
.
1H NMR (DMSO-d6): = 1.2 (t, 3H,CH3), 2.3 (s, 6H, 2CH3), 4.0 (q,

1276
N. Foroughifar et al.
2H, CH2), 5.2 (s, 1H, H-4), 6.7–7.4 (m, 4H, Haromat), 8.5 (s, 1H, NH),
9.2 (s, 2H, NH2).
Ethyl-3-amino-8-(4-dimethylaminophenyl)-6-methyl-1H,
8H-
pyrazole[d-3,4] thiazole [a-2,3] pyrimidine-7-carboxylate (8c)
Yield 70%, m.p. 176–178 C.
1
IR (KBr): v = 3380, 3212, 3060, 2958, 1650 cm
.
1H NMR (DMSO-d6): = 1.2 (t, 3H, CH3), 2.2 (s, 3H, CH3), 2.8 (s, 6H,
CH3), 4.0 (q, 2H, CH2), 6.2 (s, 1H, H-4), 6.5–7.2 (m, 4H, Haromat),
8.0 (s, 1H, NH), 9.0 (s, 2H, NH2).
REFERENCES
[1] C. O. Kappe, Tetrahedron, 49, 6937 (1993).
[2] H. Cho, M. Ueda, K. Shima, et al., J. Med. Chem., 32, 2399 (1989).
[3] K. S. Atwal, B. N. Swanson, S. E. Unger, et al., J. Med. Chem., 34, 806 (1991).
[4] C. G. Rovnyak, K. S. Atwal, A. Hedberg, et al., J. Med. Chem., 35, 3254 (1992).
[5] E. L. Khania, G. O. Sillinietse, Ya. Ya. Ozel, G. Dabur, and A. A. Yakimenis, Khim.
Pharm. Zh., 78, 1321 (1978).
[6] R. S. Varma, Green Chem., 43 (1999).
[7] G. C. Rovnyak, S. D. Kimball, B. Bever, et al., J. Med. Chem., 38, 119 (1995).
[8] A. Loupy, A. Petit, J. Hamelin, et al., Synthesis, 1213 (1998).
[9] C. O. Kappe, F. S. Falsone, Synlett., 718 (1998).
[10] G. C. Rovnyak, K. S. Atwal, A. Hedberg, et al., J. Med. Chem., 35, 3254 (1992).
[11] G. J. Grover, S. Dzwonczyk, D. M. McMullen, et al., Pharmacol., 26, 289 (1995).
[12] R. A. Abramovich, Org. Proceed Int., 23, 683 (1991).
[13] N. Foroughifar and A. Mobinikhaledi, Asian Journal of Chemistry, 14, 614 (2002).
[14] A. K. Bose, B. K. Banik, N. Lavlinskaia, M. Jayaraman, and M. S. Manhas,
Chemtech., 27, 18 (1997).
[15] M. A. Bruce, G. S. Pointdexter, G. Johnson, PCT Int. WO 98 33, 791.
[16] S. Caddick, Tetrahedron, 51, 1403 (1995).
[17] C. R. Strauss and R. W. Trainor, Aust. J. Chem., 48, 1665 (1995).
[18] F. Langa. P. de la Cruz, A.de la hoz, A. Diaz-Ortiz, and E. Diez-Barra, Contemp.
Org. Synth., 4, 373 (1997).
[19] N. Foroughifar, A. Mobinikhaledi, S. M. Shariatzadeh, and M. Masoudnia, Asian
Journal of Chemistry, 14, 782 (2002).