A new improved method for the synthesis of 2,4-diarylpyrimidines starting from 2,2,2-trichloroethylideneacetophenones

Article abstract of DOI:10.1016/j.tetlet.2013.07.075

An advantageous new approach to 2,4-diarylpyrimidines has been developed. 2,2,2-Trichloroethylideneacetophenones reacted with benzamidines leading to novel 2,6-diaryl-6-hydroxy-4-trichloromethyl-1,4,5,6-tetrahydropyrimidines in near quantitative yields. These compounds were efficiently dehydrated to obtain previously unknown 2,4-diaryl-6-trichloromethyl-1,6-dihydropyrimidines, which were able to undergo aromatisation via chloroform elimination to give 2,4-diarylpyrimidines in high yields. A main improvement of this procedure lies in circumventing the oxidative dehydrogenation of dihydropyrimidine intermediates. This preparative process has also been adapted to a one-pot protocol.

Full text of DOI:10.1016/j.tetlet.2013.07.075

Tetrahedron Letters 54 (2013) 5115–5117
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A new improved method for the synthesis of 2,4-diarylpyrimidines
starting from 2,2,2-trichloroethylideneacetophenones
⇑
Antonio Guirado , Enrique Alarcón, Yesica Vicente, Raquel Andreu
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30071 Murcia, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
An advantageous new approach to 2,4-diarylpyrimidines has been developed. 2,2,2-Trichloroethylidene-
acetophenones reacted with benzamidines leading to novel 2,6-diaryl-6-hydroxy-4-trichloromethyl-
1,4,5,6-tetrahydropyrimidines in near quantitative yields. These compounds were efficiently dehydrated
to obtain previously unknown 2,4-diaryl-6-trichloromethyl-1,6-dihydropyrimidines, which were able to
undergo aromatisation via chloroform elimination to give 2,4-diarylpyrimidines in high yields. A main
improvement of this procedure lies in circumventing the oxidative dehydrogenation of dihydropyrimi-
dine intermediates. This preparative process has also been adapted to a one-pot protocol.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 20 May 2013
Revised 5 July 2013
Accepted 9 July 2013
Available online 17 July 2013
Keywords:
Pyrimidines
Benzamidines
Chloral
Trichloroethylideneacetophenones
The chemistry of pyrimidines has been extensively reviewed.1–8
The development of preparative methods for these substances1–6,8–
has been strongly encouraged by a whole range of vital biologi-
(isolation of the targeted pyrimidine formed in mixture with
dihydrochalcone) and a long reaction time. It should also be noted
that Bignelli three-component reactions provide access to dihydro-
pyrimidines, whose oxidative dehydrogenation has received much
attention.28 Alkynones22,29 as well as enones possessing bromide
and dimethylamino groups at the b-position30–32 have also been
reported as being usable to avoid the oxidation step.
22
cal functions and important pharmacological activities.23–26 Be-
tween the approaches to pyrimidines based on condensation
processes, the method involving reactions between (+)C–C–C(+)
dielectrophilic molecules and (À)N–C–N(À) dinucleophilic re-
agents, usually called ‘common synthesis’, is very popular.7 Thus,
the reaction between 1,3-dicarbonyl compounds and amidines
provides an effective straightforward synthesis of pyrimidines.27
Chloral is an inexpensive, multipurpose starting material for
organic synthesis.33 It is able to react with amides and acetophe-
nones to yield primary intermediates from which we developed
new synthetic methods for different classes of heterocyclic com-
pounds via electrogeneration of chlorocarbanions by cathodic
cleavage of carbon-chlorine bonds. On the basis of this reduction
process we performed new preparative methods for several types
of heterocyclic compounds.34 Taking into consideration the suc-
cessful results reported for the synthesis of sulfines, isocyanates
and pyrimidinones, from trichloromethyl sulfoxides,35 trichloroac-
etamides36 and 4,4,4-trichloro-2-butenoic acid ethyl esters,37
respectively, through unusual b-elimination of chloroform, we
recognised the opportunity to improve the synthesis of pyrimi-
dines and pyrimidine derivatives starting from easily available
2,2,2-trichloroethylideneacetophenones 3 and by exploring the
behaviour of the trichloromethyl group as a good leaving group, in-
stead of acting as a good electron transfer receptor. We previously
reported38 a detailed protocol for preparing compounds 3. The key
step of new pyrimidine synthetic route is a highly effective base
catalysed b-elimination of chloroform, which allows the circum-
vention of any oxidative dehydrogenation step of dihydropyrimi-
dine intermediates (Scheme 1). In addition, this approach shows
another noteworthy advantage, since the synthesis can be carried
Readily accessible
a,b-unsaturated ketones have also been used
as dielectrophiles to react with amidines. However, this is a less
attractive option since the formation of pyrimidines requires
oxidation of previously generated dihydropyrimidines instead of
water elimination. Thus for example, reaction between equimolec-
ular amounts of benzamidine and benzalacetophenone (chalcone)
leads to 2,4,6-triphenylpyrimidine9 in low yield (33%), which
increases to 61% if an air stream is passed through the reaction
mixture for a long time under basic and high temperature condi-
tions. Nevertheless, if a similar reaction is carried out in the
absence of oxygen, but with double the amount of chalcone, the
formation of 2,4,6-triphenylpyrimidine reaches 85%, and is accom-
panied by benzylacetophenone (dihydrochalcone) (87%). This
evidences that chalcone is able to oxidise the dihydropyrimidine
intermediate involved to pyrimidine by undergoing reduction to
dihydrochalcone. The main disadvantages of this alternative proce-
dure are cost (double consumption of chalcone), practical difficulty
⇑
Corresponding author. Tel.: +34 868 887 490; fax: +34 868 884 148.
E-mail address: anguir@um.es (A. Guirado).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.075

5116
A. Guirado et al. / Tetrahedron Letters 54 (2013) 5115–5117
O
7e–g in good yields (70–73%) by reaction with commercial 3-nitro-
benzamidine and 4-methylbenzamidine.45 Compounds 7 were
subjected to GC and HPLC analyses exhibiting single peaks. Geo-
metrical characteristics of reaction products were determined by
the X-ray crystallography43 of product 7f.
O
OH
Cl3CCHO
Ar1
Ar1
CCl3
1
2
In summary, a novel and efficient synthetic method in pyrimi-
dine chemistry is reported. The described protocol improves the
interest and preparative potential of reactions between conjugated
enones and benzamidines by circumventing any oxidative dehy-
drogenation process of dihydropyrimidine intermediates. This pre-
parative strategy is operationally simple; the yields of the products
are good; and the starting materials are readily available.
- H2O
NH2
NH
Ar2
Ar2
4
HN
N
O
HO
Ar1
Ar1
CCl3
CCl3
3
5
- H2O
Acknowledgment
Ar2
Ar2
We gratefully acknowledge the financial support of the Funda-
ción Séneca of the Comunidad Autónoma de la Región de Murcia
(project 08755/PI/08).
N
NH
N
N
- CHCl3
Ar1
CCl3
Ar1
6
7
Supplementary data
Ar1
5 (%)
6 (%)
Ar2
7 (%)
entry
Supplementary data (1H and 13C NMR spectra of compounds 5,
6 and 7) associated with this article can be found, in the online ver-
sion, at http://dx.doi.org/10.1016/j.tetlet.2013.07.075.
89
93
90
93
-
a
b
c
d
e
f
4-CH3C6H4
4-ClC6H4
4-BrC6H4
4-O2NC6H4
4-CH3OC6H4
C6H5
78
78
73
68
-
79
82
90
77
72
70
73
C6H5
C6H5
C6H5
C6H5
3-O2NC6H4
3-O2NC6H4
4-CH3C6H4
References and notes
-
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2,2,2-Trichloroethylideneacetophenones 3a–d were prepared in
high to near quantitative yields38 by reaction of acetophenones 1
with chloral and subsequent dehydration of chloralacetophenones
2. Compounds 3 reacted at room temperature with commercially
available benzamidine until total conversion of starting materials
to products42 (clearly perceptible by TLC). Spectroscopic analyses
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ratio of about 3:1. The major diasteromers were isolated by crystal-
lisation. An X-ray crystallographic structural determination of 5b
showed a (4RS,6RS) configuration43 for these diastereomers. There-
fore, the configuration of the minor diasteromers was assigned to
be (4RS,6SR).
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Each diastereomeric pair of compounds 5a–d was subjected to
acidic dehydration under gentle heating44 to give the correspond-
ing dihydropyrimidines 6a–d in fair to high yields (68–78%). These
crystallised as single tautomers that were univocally identified as
2,4-diaryl-6-trichloromethyl-1,6-dihydropyrimidines by X-ray
crystallography43 of compound 6d. Room temperature treatment
of products 6a–d with potassium tert-butoxide promoted a highly
effective transformation providing single products that were iden-
tified as the targeted 2,4-diarylpyrimidines 7a–d, whose formation
clearly corresponds to an aromatisation process associated to a b-
elimination of chloroform,45 which was detected in the corre-
sponding stoichiometric amount by capillary column gas chroma-
tography. Yields were high (77–90%). After confirming the viability
of this synthetic route, we successfully carried out a one-pot con-
version of trichloroethylideneacetophenones 3e–g to pyrimidines
34. See Guirado, A.; Martiz, B.; Andreu, R.; Bautista, D. Tetrahedron 2011, 67, 5811.
and referentes cited therein.
35. Braverman, S.; Grinstein, D.; Gottlieb, H. E. Tetrahedron Lett. 1994, 35, 953.

A. Guirado et al. / Tetrahedron Letters 54 (2013) 5115–5117
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39. Dallinger, D.; Stadler, A.; Kappe, C. O. Pure Appl. Chem. 2004, 76, 1017–1024.
40. Pathak, P.; Kaur, R.; Kaur, B. ARKIVOC 2006, 160.
examples of spectroscopic properties of this class of substances: 1H NMR d
(CDCl3, 300 MHz): 7.81 (d, 2H, J = 8.1 Hz), 7.62 (d, 2H, J = 8.0 Hz), 7.42–7.36 (m,
3H), 7.14 (d, 2H, J = 7.9 Hz), 5.60 (d, 1H, J = 4.6 Hz), 4.88 (d, 1H, J = 4.8 Hz), 2.29
(s, 3H); 13C NMR d (CDCl3, 75.4 MHz): 154.29, 154.27, 138.89, 134.44, 134.42,
131.32, 129.17, 128.77, 126.95, 125.70, 105.82, 95.53, 68.41, 21.27; HRMS (ESI)
m/z: calcd for C18H16Cl3N2 (M+H)+: 365.0374, found: 365.0368; IR (Nujol):
3420, 1621, 1592, 1565, 1514, 1484, 1463, 1377, 1356, 1316, 1250, 1113, 1016,
41. Muravyova, E. A.; Desenko, S. M.; Musatov, V. I.; Knyazeva, I. V.; Shishkina, S.
V.; Shishkin, O. V.; Chebanov, V. A. J. Comb. Chem. 2007, 9, 797.
958, 808, 780, 766, 732, 714 cmÀ1
.
45. Representative procedure for the preparation of products 7: To a solution of 6
(1.0 mmol) in dry THF (25 mL) a 1.0 M solution of potassium tert-butoxide
(1.0 mmol) in dry THF was added dropwise and the mixture was stirred for 4 h.
After filtration the solvent was removed in vacuo, the solid residue was washed
with a cool ethanol (3 mL) and crystallised from ethanol: 7a mp 108–110 °C
(Lit,46 mp 109-110 °C); 7b mp 88–90 °C; 7c mp 106–108 °C (Lit,47 mp 107–
42. Representative procedure for the preparation of products 5: To a solution of 3
(1.0 mmol) in dry toluene (3 mL) a solution of 4 (1.2 mmol) in dry toluene
(3 mL) was added dropwise. The reaction mixture was stirred for 2 h at room
temperature. Then, the solvent was removed in vacuo and the solid residue
was washed with cool hexane and crystallised from hexane/chloroform (5b mp
136–137 °C; 5c mp 131–132 °C; 5d mp 185–187 °C) or hexane (5a, mp 110–
112 °C). The spectral data of product 5a are reported as representative
examples of spectroscopic properties of this class of substances: 1H NMR d
(Acetonitrile-d3, 200 MHz): 7.88–7.84 (m, 2H), 7.58–7.46 (m, 5H), 7.25 (d, 2H,
J = 8.5 Hz), 6.83 (br s, 1H), 4.46 (dd, 1H, J = 12.0 Hz, J = 3.7 Hz), 4.42 (br s, 1H),
2.55 (dd, 1H, J = 12.7 Hz, J = 3.7 Hz), 2.38 (s, 3H), 1.76 (dd, 1H, J = 12.6 Hz,
J = 12.0 Hz); 13C NMR d (Acetonitrile-d3, 50.4 MHz): 155.01, 142.60, 138.97,
136.70, 131.33, 129.95, 129.26, 127.77, 126.68, 105.60, 81.28, 69.24, 38.94,
21.10; HRMS (ESI) m/z: calcd for C18H18Cl3N2O (M+H)+: 383.0479, found:
383.0475; IR (Nujol): 3420, 3280, 1613, 1575, 1505, 1470, 1377, 1310, 1230,
108 °C); One-pot preparation: Compounds
acetonitrile (6 mL). After addition of the corresponding benzamidine
3 (1.0 mmol) were solved in
4
hydrochloride potassium carbonate (1.2 mmol) was added and the reaction
mixture was refluxed under nitrogen atmosphere for 12 h. Then, the solvent
was removed in vacuo, the residue was dissolved in chloroform (25 mL) that
was washed with water (25 mL), dried over magnesium sulfate and removed in
vacuo, leaving a residue that was crystallised from cyclohexane (7f mp 131–
132 °C; 7g mp 137–138 °C) or ethyl acetate (7e mp 170–171 °C). The spectral
data of product 7a are reported as representative examples of spectroscopic
properties of this class of substances: 1H NMR d (CDCl3, 300 MHz): 8.80 (d, 1H,
J = 5.3 Hz), 8.61–8.57 (m, 2H), 8.14 (d, 2H, J = 8.2 Hz), 7.57–7.51 (m, 4H), 7.34
(d, 2H, J = 8.0 Hz), 2.45 (s, 3H); 13C NMR d (CDCl3, 75.4 MHz): 164.43, 163.82,
157.59, 141.36, 137.89, 134.12, 130.62, 129.64, 128.48, 128.25, 127.09, 114.13,
21.45; HRMS (ESI) m/z: calcd for C17H15N2 (M+H)+: 247.1230, found: 247.1220;
IR (Nujol): 1607, 1587, 1564, 1546, 1508, 1457, 1427, 1408, 1379, 1324, 1308,
1133, 1105, 992, 900, 800, 789, 759, 701 cmÀ1
.
43. Details of the structure determination will be reported in a future full paper.
44. Representative procedure for the preparation of products 6: To a solution of 5
(1.0 mmol) in dichloromethane (15 mL) concentrated sulphuric acid
(0.3 mmol) was added and the mixture was refluxed for 12 h. Then, the
solvent was washed with aqueous sodium bicarbonate solution, dried over
magnesium sulfate, and removed in vacuo, leaving a solid residue that was
crystallised from petroleum ether/dichloromethane (6a mp 150–153 °C; 6b
mp 228–230 °C), petroleum ether (6c mp 231–234 °C) or toluene (6d mp 200–
203 °C). The spectral data of product 6a are reported as representative
1276, 1186, 1023, 834, 815, 759, 695, 650 cmÀ1
.
46. Burdeska, K.; Fuhrer, H.; Kabas, G.; Siegrist, A. E. Helv. Chim. Acta 1981,
64, 113.
47. Kumar, A.; Boykin, D. W.; Wilson, W. D.; Jones, S. K.; Bender, B. K.; Dykstra, C.
C.; Hall, J. E.; Tidwell, R. R. Eur. J. Med. Chem. 1996, 31, 767.