Microwave-assisted simple, one-pot, four-component synthesis of 2,4,6-triarylpyrimidines under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2006.10.090

2,4,6-Triarylpyrimidines are synthesized via a simple, one-pot, four-component reaction between aryl methyl ketones, benzaldehydes, aromatic nitriles, and hydroxylamine under microwave irradiation and solvent-free conditions in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2006.10.090

Tetrahedron Letters 47 (2006) 9365–9368
Microwave-assisted simple, one-pot, four-component synthesis
of 2,4,6-triarylpyrimidines under solvent-free conditions
Mehdi Adib,a,* Niusha Mahmoodi,a Mohammad Mahdavia and Hamid Reza Bijanzadehb
aSchool of Chemistry, University College of Science, University of Tehran, PO Box 14155-6455, Tehran, Iran
bDepartment of Chemistry, Tarbiat Modarres University, Tehran, Iran
Received 9 June 2006; revised 27 September 2006; accepted 13 October 2006
Available online 13 November 2006
Abstract—2,4,6-Triarylpyrimidines are synthesized via a simple, one-pot, four-component reaction between aryl methyl ketones,
benzaldehydes, aromatic nitriles, and hydroxylamine under microwave irradiation and solvent-free conditions in good to excellent
yields.
Ó 2006 Published by Elsevier Ltd.
Pyrimidines are of chemical and pharmacological inte-
rest.1,2 Compounds containing a pyrimidine ring system
have been shown to possess antitumor, antibacterial,
antifungal, antimalarial, and anticonvulsant activi-
ties.1–5 Some examples are valuable drugs in the treat-
ment of hyperthyroidism, acute leukemia in children
and adult granulocytic leukemia.1 Furthermore, some
pyrimidines are used in polymer and supramolecular
chemistry.6,7 Conjugated molecules which have a pyrimi-
dine core as the key unit have recently received much
attention and they are prospective candidates for light-
emitting devices8 and molecular wires.9
dimerization–oxidative fragmentation of aryl-b-aryl-
vinylimines,12 one-pot condensation of b-dicarbonyl
compounds, NH4OAc and aldehydes,13 condensation
of phenacyldimethylsulfonium salts, aldehydes, and
ammonia,14 reaction of alkynes and nitriles in the pres-
ence of TfOH,15 rearrangement of 2,4,5-trisubstituted
imidazolines,16 one-pot, three-component reaction of
aryl halides, terminal propargyl alcohols and amidinium
salts based upon a coupling-isomerization–cycloconden-
sation sequence,17 arylation of halogenated pyrimidines
via a Suzuki coupling reaction,18 reaction of a,a-di-
bromo oxime ethers with Grignard reagents,19 micro-
wave-assisted reaction of amidines and alkynones,20
and sequential assembly of aryl groups onto a pyrimi-
dine core (2-methylthiopyrimidine).21 However, in some
these methods the reactants such as amidines, unsatu-
rated ketones, aryl-b-arylvinylimines, sulfonium salts,
imidazoline derivatives, and dihalo oxime ethers have
to be synthesized initially, hence these methods are rela-
tively expensive and time consuming.
So far the most common synthetic methods for the
preparation of pyrimidine ring systems involve: (i) trans-
formation of another ring and, (ii) cyclizations classified
on the basis of the number of ring atoms in each of the
components being cyclized: (iia) from six ring atoms, by
N1–C2 or N3–C4 bond formation; (iib) by formation of
two bonds, from [5+1], [4+2], or [3+3] atom fragments;
and (iic) by formation of three bonds, from [2+2+2] or
[3+2+1] atom fragments.1,2,10
Due to the unique properties of pyrimidine derivatives,
the development of synthetic methods which enable a
facile access to this heterocycle are desirable. As part
of our ongoing program to develop efficient methods
for the preparation of widely used organic compounds
from readily available building blocks, we report a
simple, versatile and solvent-free route to 2,4,6-triaryl-
pyrimidines. Thus, aryl methyl ketones 1, aromatic alde-
hydes 2, aromatic nitriles 3, and hydroxylamine 4
undergo a one-pot, four-component reaction (by the
formation of four bonds from [2+1+2+1] atom
2,4,6-Trisubstituted pyrimidines have been synthesized
using various methods and procedures including the
reaction of amidines with a,b-unsaturated ketones,11
Keywords: 2,4,6-Triarylpyrimidines; Four-component reactions;
Solvent-free synthesis; Microwave irradiation.
*
Corresponding author. Tel./fax: +98 21 66495291; e-mail: madib@
khayam.ut.ac.ir
0040-4039/$ - see front matter Ó 2006 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2006.10.090

9366
M. Adib et al. / Tetrahedron Letters 47 (2006) 9365–9368
Table 1. Microwave-assisted solvent-free synthesis of 2,4,6-triarylpyrimidines
Ar"
1. powdered NaOH (cat.),
O
r.t., 2.5 h
N
N
+
Ar'CHO
Ar
CH3
2. Ar"CN (3) (1.2 equiv),
NH2OH (4) (1.2 equiv),
Ar
Ar'
AcOH (cat.), r.t., 2.5 h
1
2
5
3. MW, 150 ºC, 3 min
°
5
a
Ar
Ar0
Ar00
% Yielda
90
Mp Cb (lit.)
185–186 (184–185)19
235–237 (237)20
b
c
89
93
Br
Cl
219–221 (219–220)17
d
e
93
95
172–174
Cl
129–131 (128)20
CH3O
f
94
86
149–151 (148–150)13
173–174 (176–177)13
CH3
CH3
g
CH3
h
i
92
87
92
87
171–173 (174–175)17
139–141
CH3
Cl
CH3O
CH3O
CH3O
Cl
j
134–136 (135–138)13
135–137 (132–136)13
CH3O
k
l
89
160–161
Cl
m
n
91
89
195–197
Cl
Cl
209–210 (212–213)22
O2N
o
p
91
86
153–155 (154–155)14
130–133 (132–133)12a
q
90
153–155 (153–154)12a
a Isolated yields.
b Recrystallized from absolute EtOH.

M. Adib et al. / Tetrahedron Letters 47 (2006) 9365–9368
9367
Ar"
O
O
NaOH
AcOH
Ar'"'
NH2OH +
C
N
+ Ar'CHO
H2N
NOH
Ar
CH3
Ar'
Ar
_
H2O
6
7
MW, 150 ºC
_
2 H2O
Ar"
N
N
Ar
Ar'
5
Scheme 1.
fragments) under solvent-free conditions and microwave
irradiation to produce 2,4,6-triarylpyrimidines 5a–q in
86–95% yields (Table 1).
References and notes
1. Undheim, K.; Benneche, T. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. V.
F., Eds.; Pergamon Press: London, 1996; Vol. 6, Chapter
2, pp 93–231, and references cited therein.
2. Brown, D. J.; Evans, R. F.; Cowden, W. B. In The
Pyrimidines; Taylor, E. C., Weissberger, A., Eds.; John
Wiley: New York, 1994; Vol. 52.
3. Johar, M.; Manning, T.; Kunimoto, D. Y.; Kumar, R.
Bioorg. Med. Chem. 2005, 13, 6663.
4. Azas, N.; Rathelot, P.; Djekou, S.; Delmas, F.; Gellis, A.;
Di Giorgio, C.; Vanelle, P.; Timon-David, P. Il Farmaco
2003, 58, 1263.
The reactions were carried out by first mixing the ketone
and the aldehyde, in the presence of powdered sodium
hydroxide at room temperature. After a few hours and
nearly complete conversion to the corresponding chal-
cone, 6, as indicated by TLC monitoring, the nitrile,
hydroxylamine and acetic acid (catalytic amount, but
more than the amount of NaOH used)23 were added
to the reaction mixture and stirring continued for
further 2.5 h.24 The nitrile and hydroxylamine are
converted in situ to the corresponding amidoxime, 7.
Next, the reaction mixture was irradiated in a micro-
5. Agarwal, A.; Srivastava, K.; Puri, S. K.; Chauhan, P. M.
S. Bioorg. Med. Chem. 2005, 13, 4645.
1
6. Gompper, R.; Mair, H.-J.; Polborn, K. Synthesis 1997,
696; Kanbara, T.; Kushida, T.; Saito, N.; Kuwajima, I.;
Kubota, K.; Yamamoto, T. Chem. Lett. 1992, 583.
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Baum, G.; Fenske, D. Angew. Chem., Int. Ed. 1997, 36,
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hedron Lett. 2005, 46, 7889; Kappe, C. O. Acc. Chem. Res.
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Marzinzik, A. L.; Felder, E. R. J. Org. Chem. 1998, 63,
723.
wave oven25 at 150 °C for 3 min. H NMR analysis of
the reaction mixtures clearly indicated the formation
of pyrimidine derivatives 5 (Scheme 1). After optimiza-
tion, treatment of the in situ prepared chalcones with
1.2 equiv each of the nitrile and hydroxylamine afforded
the corresponding 2,4,6-triarylpyrimidines in 86–95%
yields (Table 1).
The structures of the isolated products were confirmed
by comparison of their mps and their spectral data
(high-field 1H and 13C NMR spectra) with those of
authentic samples.26
In conclusion, we have developed a microwave-assisted,
simple, one-pot, four-component and solventless proce-
dure for the preparation of 2,4,6-triarylpyrimidines of
potential synthetic and pharmacological interest. The
use of commercial materials, and the one-pot and sol-
vent-free conditions are the main advantages of this
method. This method appears to have a broad scope
with respect to variation in substitution at the pyrimi-
dine 2-, 4-, and 6-positions.
12. Forrester, A. R.; Gill, M.; Thomson, R. H. J. Chem. Soc.,
Perkin Trans. 1 1979, 616.
13. Weis, A. L.; Rosenbach, V. Tetrahedron Lett. 1981, 22,
1453.
Acknowledgement
14. Gupta, K. C.; Manglum, P. Curr. Sci. 1989, 58, 1196.
This research was supported by the Research Council of
the University of Tehran as a research project (6102036/
1/02).
´
15. Martınez, A. G.; Fernandez, A. H.; Alvarez, R. M.;
Losada, M. C. S.; Vilchez, D. M.; Subramanian, L. R.;
Hanack, M. Synthesis 1990, 881.

9368
M. Adib et al. / Tetrahedron Letters 47 (2006) 9365–9368
16. Seki, M.; Kubota, H.; Matsumoto, K.; Kinumaki, A.;
Da-te, T.; Okamura, K. J. Org. Chem. 1993, 58, 6354.
17. Muller, T. J. J.; Braun, R.; Ansorge, M. Org. Lett. 2000, 2,
1967.
18. Schomaker, J. M.; Delia, T. J. J. Org. Chem. 2001, 66,
7125.
19. Kakiya, H.; Yagi, K.; Shinokubo, H.; Oshima, K. J. Am.
Chem. Soc. 2002, 124, 9032.
20. Bagley, M. C.; Hughes, D. D.; Taylor, P. H. Synlett 2003,
259.
Calcd for C22H15ClN2 (342.83): C, 77.08; H, 4.41; N, 8.17.
Found: C, 77.2; H, 4.5; N, 8.1. 1H NMR (500.1 MHz,
CDCl3): d 7.44–7.49 (2H, m, 2CH), 7.52–7.58 (6H, m,
6CH), 8.02 (1H, s, CH), 8.26 (4H, dd, J = 7.8 and 2.0 Hz,
4CH), 8.60 (1H, d, J = 6.8 Hz, CH), 8.69 (1H, br s, CH).
13C NMR (125.8 MHz, CDCl3): d 110.70, 126.57, 127.26,
128.47, 128.94, 129.67, 130.54, and 130.91 (8CH), 134.55,
137.21, and 139.97 (3C), 163.20 and 164.86 (2C–N).
Compound 5i: Colorless crystals. MS, m/z (%): 234 (3),
191 (3), 132 (100), 118 (16). Anal. Calcd for C23H17ClN2O
(372.85): C, 74.09; H, 4.60; N, 7.51. Found: C, 74.1; H,
21. Itami, K.; Yamazaki, D.; Yoshida, J. J. Am. Chem. Soc.
2004, 126, 15396.
1
4.7; N, 7.5. H NMR (500.1 MHz, CDCl3): d 3.84 (3H, s,
22. Heine, H. W.; Weese, R.; Cooper, R.; Durbetaki, A. J.
J. Org. Chem. 1967, 32, 2708.
23. The best results were obtained when the catalytic amount
of acetic acid added during the second stage of the
reaction was greater than that of the NaOH employed in
the first stage.
24. We were concerned regarding the reaction between chal-
cones and hydroxylamine. However, when a mixture of
1,3-diphenyl-2-propen-1-one, 6: Ar = Ar0 = C6H5, and
hydroxylamine was stirred at 25 °C, the chalcone was
recovered almost unchanged after 5 h.
25. The reactions were performed using a microwave oven
(ETHOS 1600, Milestone) with a power of 600 W specially
designed for organic synthesis.
OCH3), 7.00 (2H, d, J = 8.4 Hz, 2CH), 7.46 (2H, d,
J = 8.2 Hz, 2CH), 7.50–7.53 (3H, m, 3CH), 7.79 (1H, s,
CH), 8.15 (2H, d, J = 8.4 Hz, 2CH), 8.18 (2H, dd, J = 7.9
and 1.5 Hz, 2CH), 8.59 (2H, d, J = 8.2 Hz, 2CH). 13C
NMR (125.8 MHz, CDCl3): d 55.28 (OCH3), 109.21,
114.09, 127.10, 128.44, 128.62, and 128.74 (6CH) 129.50
(C), 129.69 and 130.61 (2CH), 136.51, 136.71, and 137.32
(3C), 161.87 (C–O), 163.07, 163.93, and 164.18 (3C–N).
Compound 5l: Colorless crystals. MS, m/z (%): 344 (M+
37Cl, 1), 342 (M+ 35Cl, 3), 238 (8), 204 (7), 136 (83), 103
(100), 77 (99), 63 (19), 51 (78). Anal. Calcd for
C22H15ClN2 (342.83): C, 77.08; H, 4.41; N, 8.17. Found:
1
C, 77.1; H, 4.5; N, 7.9. H NMR (500.1 MHz, CDCl3): d
7.49 (2H, d, J = 8.3 Hz, 2CH), 7.50–7.55 (6H, m, 6CH),
7.95 (1H, s, CH), 8.22 (2H, d, J = 8.3 Hz, 2CH), 8.27 (2H,
dd, J = 7.8 and 2.0 Hz, 2CH), 8.69 (2H, dd, J = 7.9 and
1.6 Hz, 2CH). 13C NMR (125.8 MHz, CDCl3): d 109.78,
127.23, 128.43, 128.45, 128.48, 128.87, 129.05, 130.71, and
130.84 (9CH) 135.83, 136.91, 137.27, and 137.94 (4C),
163.31, 164.44, and 164.79 (3C–N). Compound 5m:
Colorless crystals. MS, m/z (%): 377 (M+ 37Cl, 1), 375
(M+ 35Cl, 5), 277 (2), 238 (10), 204 (8), 163 (5), 137 (100),
102 (8), 51 (44). Anal. Calcd for C22H14Cl2N2 (377.27): C,
70.04; H, 3.74; N, 7.43. Found: C, 69.9; H, 3.8; N, 7.2. 1H
NMR (500.1 MHz, CDCl3): d 7.49 (2H, d, J = 8.4 Hz,
2CH), 7.52 (2H, d, J = 8.4 Hz, 2CH), 7.53–7.56 (3H, m,
3CH), 7.96 (1H, s, CH), 8.21 (2H, d, J = 8.4 Hz, 2CH),
8.25 (2H, d, J = 7.6 Hz, 2CH), 8.63 (2H, d, J = 8.4 Hz,
2CH). 13C NMR (125.8 MHz, CDCl3): d 110.03, 127.24,
128.49, 128.65, 128.95, 129.15, 129.78, and 130.99 (8CH),
135.70, 136.42, 136.93, 137.12, and 137.13 (5C), 163.51,
163.57, and 164.98 (3C–N).
26. The procedure for the preparation of 2,4,6-triphenylpyri-
midine (5a) is described as an example. A mixture of
acetophenone (0.48 g, 4 mmol), benzaldehyde (0.42 g,
4 mmol), and powdered NaOH (0.01 g, 0.25 mmol) was
stirred at 25 °C for 2.5 h. After a nearly complete
conversion to the corresponding chalcone, as indicated
by TLC monitoring, benzonitrile (0.49 g, 4.8 mmol), 50%
hydroxylamine (0.32 g, 4.8 mmol), and acetic acid (a
catalytic amount, but greater than 0.25 mmol) were added
to the reaction mixture and stirring continued at 25 °C for
a further 2.5 h. The reaction was then irradiated in a
microwave oven at 150 °C for 3 min. Aqueous work-up
and purification by column chromatography (4:1 n-
hexane–EtOAc as the eluent, Merck silica gel 60 mesh)
afforded 2,4,6-triphenylpyrimidine 5a in a 90% yield. The
selected data for 2,4,6-triarylpyrimidines; 5d: Colorless
crystals. MS, m/z (%): 344 (M+ 37Cl, 29), 342 (M+ 35Cl,
100), 265 (6), 126 (7), 103 (10), 98 (11), 77 (9), 50 (4). Anal.