A new convenient synthetic approach to diarylpyrimidines

Article abstract of DOI:10.1016/j.tet.2016.05.018

A new synthetic method in pyrimidine chemistry has been developed. 2,2,2-Trichloroethylideneacetophenones, easily available from chloral and acetophenones, reacted with benzamidines to provide novel 2,6-diaryl-6-hydroxy-4-trichloromethyl-1,4,5,6-tetrahydr

Full text of DOI:10.1016/j.tet.2016.05.018

Accepted Manuscript
A new convenient synthetic approach to diarylpyrimidines
Antonio Guirado, Enrique Alarcón, Yesica Vicente, Raquel Andreu, Delia Bautista,
Jesús Gálvez
PII:
S0040-4020(16)30391-X
10.1016/j.tet.2016.05.018
TET 27745
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 24 February 2016
Revised Date: 28 April 2016
Accepted Date: 6 May 2016
Please cite this article as: Guirado A, Alarcón E, Vicente Y, Andreu R, Bautista D, Gálvez J, A new
convenient synthetic approach to diarylpyrimidines, Tetrahedron (2016), doi: 10.1016/j.tet.2016.05.018.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
A new convenient synthetic approach to diarylpyrimidines
Antonio Guiradoa*, Enrique Alarcóna, Yesica Vicentea, Raquel Andreua, Delia
Bautistaa, Jesús Gálvezb
aDepartamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de
Espinardo, 30071 Murcia, Spain
bDepartamento de Química Física, Facultad de Química, Universidad de Murcia, Campus de Espinardo,
30071 Murcia, Spain
Corresponding author. Tel.: +34 868 887 490; fax: +34 868 884 148
E-mail address: anguir@um.es
Keywords: Chloral; Acetophenones; Trichloroethylideneacetophenones, Benzamidines; Pyrimidines
Abstract- A new synthetic method in pyrimidine chemistry has been developed. 2,2,2-
Trichloroethylideneacetophenones, easily available from chloral and acetophenones,
reacted with benzamidines to provide novel 2,6-diaryl-6-hydroxy-4-trichloromethyl-
1,4,5,6-tetrahydropyrimidines in near quantitative yields. Efficient dehydration of these
compounds
gave
previously
unknown
2,4-diaryl-6-trichloromethyl-1,6-
dihydropyrimidines, which were found able to undergo base-induced chloroform
elimination to give 2,4-diarylpyrimidines in high yields. Molecular structures for final
and intermediate compounds were determined by single crystal X-ray diffraction. A
main improvement of this procedure lies in circumventing the oxidative aromatization
of dihydropyrimidine intermediates through a chloroform elimination process. The
diarylpyrimidines were also found directly accessible by a fair yield one-pot procedure.
1. Introduction
As a result of our research project on the synthesis of heterocyclic compounds based on
the chemistry and electrochemistry of chloral derivatives,1-3 we recently reported a
preliminary communication4 demonstrating that 2,2,2-trichloroethylideneacetophenones
3 are helpful intermediates to prepare novel 2,6-diaryl-6-hydroxy-4-trichloromethyl-
1,4,5,6-tetrahydropyrimidines
5
and
2,4-diaryl-6-trichloromethyl-1,6-
dihydropyrimidines 6, which were found to be easily convertible to 2,4-
diarylpyrimidines 7. In this paper, we report full details of this synthetic process, as well
as spectroscopic properties and X-ray crystallographic molecular structures of
1

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compounds 5,6 and 7.
Concerning the goal of this work, it should be noted that the high interest of pyrimidines
has been excellently documented in numerous reviews.5-16 Many members of this
family of heterocyclic compounds exhibit important properties and applications from a
whole range of vital biological functions and pharmacological activities,7,9,13,17-20 which
strongly encourage the search of good preparative procedures.5-9,11-16,21-38
A classical method to prepare pyrimidines uses reactions between (+)C-C-C(+)
dielectrophilic molecules and (-)N-C-N(-) dinucleophilic reagents.12 For example, 1,3-
dicarbonyl compounds and amidines easily undergo double condensation being an
effective straightforward synthesis of pyrimidines.39 3-Oxopropiophenones and 3,3-
dimethoxypropiophenones have also been used in reactions with benzamidines to give
2,4-diarylpyrimidines.40 A related highly attractive preparative method involves a
palladium catalyzed carbonylation Heck reaction affording 1-aryl-3-butoxy-2-
propenones, which act as excellent 1,3-ketoaldehyde synthons able to react with
benzamidines yielding 2,4-diarylpyrimidines, as well as with other dinucleophilic
agents to give different significant classes of heterocyclic compounds.41 Readily
accessible α,β-unsaturated ketones are also good dielectrophilic molecules to react with
amidines. However, these reactions provide dihydropyrimidines whose conversion to
pyrimidines requires oxidation instead of easier water elimination.21 Therefore, this
alternative procedure is to be considered less attractive in general.4 It should also be
noted that Biginelli three-component reactions provide access to dihydropyrimidines,
whose oxidative dehydrogenation has received much attention.42 Alkynones,30,43,44 as
well as certain enones possessing bromo and dimethylamino substituents at the β-
position,35,45-47 have been reported as being usable to avoid the oxidation step. An
interesting one-pot method48 for preparing 2,4-diarylpyrimidines and other heterocyclic
compounds has been reported recently. It consists of a selective oxidation of a
propargylamine followed by spontaneous rearrangement providing an enaminone which
in the presence of an amidine, a hydrazine, hydroxylamine, etc., reacts to give the
corresponding pyrimidine, pyrazole, isoxazole, etc. It was also been reported that Cbz-
protected β-enaminones, generated by isomerization of the corresponding Cbz-protected
propargylic hydroxylamines, are able to react with amides leading to pyrimidines.49
In this line of work we envisioned that readily available 2,2,2-
trichloroethylideneacetophenones 3 could offer a plausible opportunity to develop a new
and convenient approach to pyrimidines starting from chloral, which is an inexpensive
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multipurpose starting material for organic synthesis.50 It reacts with acetophenones to
afford the corresponding aldol-type adducts (commonly called chloralacetophenones) in
near quantitative yields,51 whose subsequent dehydrations lead to compounds 3 in high
yields. We previously reported experimental details for preparing this class of
substances when developed the first synthesis of 1-aryl-4,4-dichlorobut-3-en-1-ones51 in
order to make available hitherto unknown 3-aryl-5-dichloromethyl-2-pyrazolines2 and
3-aryl-5-dichloromethyl-2-isoxazolines.1 In that cases the trichloromethyl group played
a crucial role as electrophore in reductive electrochemical processes. Taking into
consideration the successful results reported for the synthesis of sulfines, isocyanates
and pyrimidinones, from trichlomethyl sulfoxides,52 trichloroacetamides,53 and 4,4,4-
trichloro-2-butenoic acid ethyl esters,54 respectively, through unusual β-elimination of
chloroform, we recognised the chance to work in exploring a promising method for the
synthesis of pyrimidines and pyrimidine derivatives starting from compounds 3, in this
occasion attempting to exploit the behaviour of the trichloromethyl group as a good
leaving group instead of acting as an electrophore one.
2. Results and discussion
2,2,2-Trichloroethylideneacetophenones 3a-d were readily prepared in near quantitative
yields from chloral and acetophenones following our previously described protocol
(Scheme 1).51 These compounds were treated with commercially available benzamidine
under mild experimental conditions. Clean and near quantitative addition processes
operated (89-93%) in all cases occurring without be followed by spontaneous
dehydration. Each of these reactions led to two isomeric compounds whose elemental
and spectroscopic analyses were consistent with a diastereomeric mixture of previously
unknown 6-aryl-6-hydroxy-2-phenyl-4-trichloromethyl-1,4,5,6-tetrahydropyrimidines
5a-d/5a’-d’ (ratio a/a’ of about 3:1).
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O
O
OH
O
-
H2O
Cl3CCHO
Ar1
Ar1
CCl3
Ar1
CCl3
1
2
3
Ar2
Ar2
NH2
NH
-
H2O
HN
N
Ar2
N
NH
3
HO
Ar1
4
CCl3
Ar1
CCl3
5
6
Ar2
N
N
-
CHCl3
6
Ar1
7
Scheme 1. Synthesis of 2,4-diarylpyrimidines.
The major components of each diastereomeric pair could be isolated by fractional
crystallization. Crystallization of diastereomer 5b in DMF/water provided single
crystals solvated by DMF that were suitable for a crystallographic analysis. The
molecular structure determined is displayed in Fig. 1, evidencing a (4RS,6RS)
configuration for products 5a-d. Therefore, the configuration of the minor diastereomers
5a’-d’was assignable to be (4RS,6SR).
Fig. 1. Molecular structure of 5b, showing the crystallographic numbering system used. Ellipsoids
represent 50% probability levels.
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When diastereomeric pairs 5a-d/5a’-d’ were subjected to acidic dehydration, under
gentle heating, they provided unprecedented 4-aryl-2-phenyl-6-trichloromethyl-1,6-
dihydropyrimidines 6a-d in high yields (68-78%), which crystallized as single
tautomers whose structure was fully confirmed by X ray crystallography of compound
6d. The molecular structure determined is shown in Fig. 2.
Fig. 2. Molecular structure of 6d, showing the crystallographic numbering system used. Ellipsoids
represent 50% probability levels.
Finally, aromatization of products 6a-d was successfully promoted by treatment with
potassium tert-butoxide. The expected 4-aryl-2-phenylpyrimidines 7a-d were obtained
in high yields (77-90%), whose formation clearly corresponds to a β-elimination of
chloroform, which was detected in the expected stoichiometric amount by capillary
column gas chromatography.
The results of this stepwise preparative procedure are summarized in Table 1. In
addition to the successful synthesis of pyrimidines 7, it should be considered the
noteworthy advantage that it makes feasible the isolation in high yields of the novel
classes of tetrahydro- and dihydropyrimidines 5,6 of potential biological interest.42,55-57
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Table 1. Products 5-7 and yields.
Ar1
5 (%)
6 (%)
Ar2
7 (%)
entry
89
93
90
93
a
b
c
d
4-CH3C6H4
4-ClC6H4
78
78
73
68
79
82
90
77
C6H5
C6H5
C6H5
C6H5
4-BrC6H4
4-O2NC6H4
In the effort for improving the practical utility of this synthetic method if neither
intermediate product is targeted, we focused interest in the search of a one-pot protocol
able to provide pyrimidines 7 directly, therefore avoiding the previous isolation of
intermediates 5 and 6. Satisfactory results were obtained when mixtures of starting
materials 3 and 4 and potassium carbonate were heated in refluxing acetonitrile. Results
of twelve fair yield reaction examples are displayed in Table 2. Structural characteristics
of compound 7m were determined by single crystal X ray diffraction (Fig. 3).
Table 2. Products 7e-p and yields
Ar1
Ar2
yield (%)
7
67
62
70
57
56
72
73
70
66
71
67
51
e
f
C6H5
4-MeC6H4
4-ClC6H4
C6H5
g
h
i
C6H5
3-O2NC6H4
4-MeC6H4
4-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
2-C10H7
2-C10H7
2-C10H7
4-PhC6H4
4-PhC6H4
4-PhC6H4
j
3-O2NC6H4
4-MeC6H4
4-ClC6H4
k
l
m
n
o
p
3-O2NC6H4
4-MeC6H4
4-ClC6H4
3-O2NC6H4
6

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Fig. 3. Molecular structure of 7m, showing the crystallographic numbering system used. Ellipsoids
represent 50% probability levels.
In contrast to that observed in the stepwise preparations, the one-pot processes also
generated small amounts of minor products that were detected by HPLC. Some
reactions afforded appreciable quantities (about 5%) enough to allow the isolation and
identification of these products, they corresponding to 2,6-diaryl-4-
dichloromethylpyrimidines 8. The molecular structure of 4-dichloromethyl-6-(2-
naphthyl)-2-(3-nitrophenyl)pyrimidine 8m was determined by X ray crystallography
(Fig. 4).
The formation of these products can reasonably be explained by unlike competence
between two elimination processes from intermediates 6: hydrogen chloride elimination
followed by rearrangement to form products 8, and a much faster chloroform
elimination process to give the main reaction products 7 (Scheme 2).
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Ar2
CHCl3
N
N
Ar2
Ar1
7
N
NH
Ar2
Ar2
Ar1
CCl3
N
N
HCl
N
NH
6
Ar1
CHCl2
Ar1
CCl2
8
Scheme 2. Generation of compounds 7 and 8.
Fig. 4. Molecular structure of 8m, showing the crystallographic numbering system used. Ellipsoids
represent 50% probability levels.
3. Conclusions
In conclusion, a novel, facile and effective synthetic method in pyrimidine chemistry is
reported, which improves the interest and the preparative potential of reactions between
conjugated enones and bezamidines avoiding oxidative dehydrogenation of
dihydropyrimidine intermediates. Both, the stepwise and the one-pot procedures are
operationally simple; the yields of the products are good; and the starting materials are
readily available.
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4. Experimental Section
4.1. General
NMR spectra were determined on Bruker AV-200, Bruker AV-300 or Bruker AV-400
with tetramethylsilane as internal reference. High-resolution mass spectra (HRMS) were
obtained using a time-of-flight (TOF) instrument equipped with electrospray ionization
(ESI). IR spectra were recorded on a Nicolet Impact 400 Spectrometer. Microanalyses
were performed on a Carlo Erba EA- 1108 analyzer. Melting points were determined on
a
Büchi
Melting
point
B-540,
and
are
uncorrected.
2,2,2-
Trichloroethylideneacetophenones were prepared as previously described.51
Benzamidine hydrochlorides were purchased from Sigma-Aldrich.
4.2. General procedure for the synthesis of 6-aryl-6-hydroxy-2-phenyl-4-
trichloromethyl-1,4,5,6-tetrahydropyrimidines 5a-d
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 or hexane/chloroform.
4.2.1. (4RS,6RS)-6-Hydroxy-6-(4-methylphenyl)-2-phenyl-4-trichloromethyl-1,4,5,6-
tetrahydropyrimidine (5a). Pale yellow powder (hexane). Mp: 110-112 ºC. (Found C
1
56.26; H 4.54; N 7.38; C18H17Cl3N2O requires C 56.34; H 4.47; N 7.30); H NMR δ
(CD3CN, 200 MHz): 1.76 (dd, 1H, J = 12.6 Hz, J = 12.0 Hz), 2.38 (s, 3H), 2.55 (dd, 1H,
J = 12.7 Hz, J = 3.7 Hz), 4.42 (br s, 1H), 4.46 (dd, 1H, J = 12.0 Hz, J = 3.7 Hz), 6.83
(br s, 1H), 7.24-7.28 (m, 2H), 7.46-7.58 (m, 5H), 7.84-7.89 (m, 2H); 13C NMR δ
(CD3CN, 50.4 MHz): 21.10, 38.94, 69.25, 81.28, 105.60, 126.68, 127.77, 129.26,
129.95, 131.33, 136.70, 138.97, 142.60, 155.01; HRMS (ESI): m/z (M+H)+: calcd
383.0479, found 383.0480; IR (nujol): 3420, 3280, 1613, 1575, 1505, 1470, 1377, 1310,
1230, 1133, 1105, 992, 900, 800, 789, 759, 701 cm-1.
4.2.2. (4RS,6RS)-6-(4-Chlorophenyl)-6-hydroxy-2-phenyl-4-trichloromethyl-1,4,5,6-
tetrahydropyrimidine (5b). White needles (hexane/chloroform). Mp: 136-137 ºC.
1
(Found C 50.22; H 3.65; N 6.99; C17H14Cl4N2O requires C 50.53; H 3.49; N 6.93); H
NMR δ (CD3CN, 400 MHz): 1.77 (dd, 1H, J = 12.7 Hz, J = 12.0 Hz), 2.54 (dd, 1H, J =
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12.7 Hz, J = 3.7 Hz), 4.44 (dd, 1H, J = 12.0 Hz, J = 3.7 Hz), 4.52 (br s, 1H), 6.91 (br s,
1H), 7.42-7.51 (m, 5H), 7.64-7.67 (m, 2H), 7.83-7.85 (m, 2H); 13C NMR δ (CD3CN,
100.8 MHz): 38.71, 69.06, 81.09, 105.40, 127.78, 128.79, 129.24, 129.26, 131.39,
134.44, 136.57, 144.43, 154.98; HRMS (ESI): m/z (M+H)+: calcd 402.9933, found
402.9927; IR (nujol): 34 48, 1635, 1620, 1570, 1508, 1482, 1465, 1377, 1288, 1091,
975, 803, 757, 701 cm-1.
4.2.3. (4RS,6RS)-6-(4-Bromophenyl)-6-hydroxy-2-phenyl-4-trichloromethyl-1,4,5,6-
tetrahydropyrimidine (5c). White powder (hexane/chloroform). Mp: 131-132 ºC.
(Found C 45.68; H 3.19; N 6.33; C17H14BrCl3N2O requires C 45.52; H 3.15; N 6.33); 1H
NMR δ (CD3CN, 400 MHz): 1.77 (dd, 1H, J = 12.7 Hz, J = 12.0 Hz), 2.55 (dd, 1H, J =
12.7 Hz, J = 3.7 Hz), 4.44 (dd, 1H, J = 12.0 Hz, J = 3.7 Hz), 5.06 (br s, 1H), 6.91 (br s,
1H), 7.43-7.51 (m, 3H), 7.58-7.59 (m, 4H), 7.83-7.85 (m, 2H); 13C NMR δ (CD3CN,
100.8 MHz): 38.38, 68.85, 80.87, 105.15, 122.37, 127.50, 128.85, 128.99, 131.11,
131.97, 136.30, 144.61, 154.66; HRMS (ESI): m/z (M+H)+: calcd 446.9428, found
446.9424; IR (nujol): 3449, 1619, 1570, 1510, 1481, 1464, 1377, 1288, 1099, 1075,
1003, 976, 804, 784, 755, 700 cm-1.
4.2.4. (4RS,6RS)-6-Hydroxy-6-(4-nitrophenyl)-2-phenyl-4-trichloromethyl-1,4,5,6-
tetrahydropyrimidine (5d). White needles (hexane/chloroform). Mp: 185-187 ºC.
(Found C 49.36; H 3.33; N 10.00; C17H14Cl3N3O3 requires C 49.24; H 3.40; N 10.13);
1H NMR δ (DMSO-d6, 200 MHz): 1.65 (t, 1H, J = 12.3 Hz), 2.45 (dd, 1H, J = 12.3 Hz,
J = 3.3 Hz), 4.46 (dd, 1H, J = 11.8 Hz, J = 3.3 Hz), 6.81 (br s, 1H), 7.43-7.48 (m, 3H),
7.86-7.96 (m, 4H), 8.24-8.29 (m, 2H), 8.54 (br s, 1H); 13C NMR δ (DMSO-d6, 50.4
MHz): 38.69, 67.47, 79.62, 105.15, 123.50, 127.30, 127.73, 128.15, 130.38, 135.42,
147.23, 152.53, 153.91; MS (ESI): m/z (M+H)+: calcd 414.0, found 414.1; IR (nujol):
3427, 3393, 1614, 1574, 1513, 1481, 1464, 1377, 1352, 1291, 1100, 975, 854, 765, 715
cm-1.
4.3. X-ray structure determination of compound 5b
Crystal data: C20H21Cl4N3O2 (C17H14Cl4N2O1,C3H7N1O1), Mr = 477.20, triclinic, space
group P-1, a = 9.7103(9) b = 10.0995(9) c = 11.6856(11) Å, α = 85.318(2)°, β =
88.816(2)º, γ = 70.722(2)°, U = 1078.11(17) Å3 at –173°C; Z = 2, Dx = 1.470 g cm–3,
F(000) = 492, µ = 0.571 mm–1. Data collection: A colourless block 0.34 × 0.223 × 0.12
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mm was mounted in inert oil on a glass fibre and transferred to the cold gas stream of
the diffractometer (Bruker SMART APEX CCD). Measurements were performed to
2θmax 56° with monochromated Mo-Kα radiation. Of 19506 measured reflections, 7533
were unique (Rint = 0.066) and were used for all calculations. Structure refinement: The
structures were refined anisotropically against F (program SHELXL-97).58 The
2
hydrogen atoms were refined using rigid methyl groups or a riding model and the NH
and OH as free. The final wR2 value was 0.1170 for all reflections and 272 parameters,
with R1 0.0461 for reflections with I > 2σ(I); max. ∆ρ 0.56 e/Å3, S 1.10.
Complete crystallographic data (excluding structure factors) have been deposited at the
Cambridge Crystallographic Data Centreunder number CCDC 1431492. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
4.4. General procedure for the synthesis of 4-aryl-6-trichloromethyl-2-phenyl-1,6-
dhydropyrimidines 6a-d
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,
petroleum ether/dichloromethane or toluene.
4.4.1. 4-(4-Methylphenyl)-6-trichloromethyl-2-phenyl-1,6-dihydropyrimidine
(6a).
White needles (pet ether/dichloromethane). Mp: 150-153 ºC. (Found C 59.01; H 4.15; N
7.58; C18H15Cl3N2 requires 59.12; H, 4.13; N 7.66); 1H NMR δ (CDCl3, 300 MHz): 2.30
(s, 3H), 4.88 (d, 1H, J = 4.8 Hz), 5.60 (d, 1H, J = 4.6 Hz), 5.70 (br s, 1H), 7.13-7.15 (m,
2H), 7.36-7.44 (m, 3H), 7.61-7.63 (m, 2H), 7.80-7.82 (m, 2H); 13C NMR δ (CDCl3, 75.4
MHz): 21.27, 68.41, 95.53, 105.82, 125.70, 126.95, 128.77, 129.17, 131.33, 134.08,
134.43, 138.89, 145.08, 154.27; HRMS (ESI): m/z (M+H)+: calcd 365.0374, found
365.0368; IR (nujol): 3420, 1621, 1592, 1565, 1514, 1484, 1463, 1377, 1356, 1316,
1250, 1113, 1016, 958, 808, 780, 766, 732, 714 cm-1.
4.4.2. 4-(4-Chlorophenyl)-6-trichloromethyl-2-phenyl-1,6-dihydropyrimidine
(6b).
White needles (pet ether/dichloromethane). Mp: 228-230 ºC. (Found C 52.95; H 3.07; N
7.33; C17H12Cl4N2 requires 52.88; H 3.13; N 7.26); 1H NMR δ (CDCl3, 400 MHz): 4.86
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(d, 1H, J = 4.5 Hz), 5.82 (d, 1H, J = 4.5 Hz), 6.38 (br s, 1H), 7.28-7.30 (m, 2H), 7.40-
7.47 (m, 3H), 7.79-7.85 (m, 4H); 13C NMR δ (CDCl3, 100.8 MHz): 67.08, 97.07,
105.60, 126.93, 127.37, 128.40, 128.86, 131.52, 134.38, 134.47, 136.47, 147.11,
154.58; HRMS (ESI): m/z (M+H)+: calcd 384.9827, found 384.9828; IR (nujol): 3425,
1621, 1565, 1512, 1488, 1463, 1377, 1351, 1091, 1012, 846, 827, 808, 770, 734 cm-1.
4.4.3. 4-(4-Bromophenyl)-6-trichloromethyl-2-phenyl-1,6-dihydropyrimidine
(6c).
Orange powder (pet ether). Mp: 231-234 ºC. (Found C 47.39; H 2.86; N 6.62;
C17H12BrCl3N2 requires 47.42; H 2.81; N 6.51); 1H NMR δ (CDCl3, 200 MHz): 4.95 (d,
1H, J = 5.0 Hz), 5.83 (d, 1H, J = 5.0 Hz), 5.95 (br s, 1H), 7.49-7.55 (m, 5H), 7.75-7.79
(m, 2H), 7.89-7.94 (m, 2H); 13C NMR δ (CDCl3, 50.4 MHz): 67.52, 96.91, 105.51,
122.89, 126.92, 127.60, 128.84, 131.44, 131.52, 134.27, 136.50, 146.31, 154.53; HRMS
(ESI): m/z (M+H)+: calcd 428.9322, found 428.9314; IR (nujol): 3420, 1624, 1591,
1560, 1510, 1487, 1464, 1396, 1350, 1312, 1069, 1007, 806, 773, 732, 647 cm-1.
4.4.4. 4-(4-Nitrophenyl)-6-trichloromethyl-2-phenyl-1,6-dihydropyrimidine
(6d).
Yellow needles (toluene). Mp: 200-203 ºC. (Found C 51.57; H 3.13; N 10.67;
1
C17H12Cl3N3O2 requires 51.48; H 3.05; N 10.59); H NMR δ (CDCl3, 400 MHz): 5.00
(d, 1H, J = 5.2 Hz), 6.04 (d, 1H, J = 4.8 Hz), 6.59 (br s, 1H), 7.50-7.59 (m, 3H), 7.93-
13
7.95 (m, 2H), 8.08-8.10 (m, 2H), 8.25-8.27 (m, 2H); C NMR δ (CDCl3, 75.4 MHz):
67.02, 99.84, 105.05, 123.54, 126.77, 126.91, 128.90, 131.77, 133.88, 143.95, 146.21,
147.81, 154.97; HRMS (ESI): m/z (M+H)+: calcd 396.0068, found 396.0065; IR
(nujol): 3219, 1621, 1593, 1557, 1515, 1492, 1463, 1377, 1348, 1319, 1288, 1111, 975,
857, 817, 783, 726 cm-1.
4.5. X-ray structure determination of compound 6d
Crystal data: C17H12Cl3N3O2, Mr = 396.65, triclinic, space group P-1, a = 10.0289(8), b
= 11.1558(8), c = 15.6453(12) Å, α = 101.153(2)°, β = 92.528(2)°, γ = 100.639(2)°, U =
1682.0(2) Å3 at –173°C; Z = 4, Dx = 1.566 g cm–3, F(000) = 808, µ = 0.561 mm–1. Data
collection: A yellow needle 0.19 × 0.17 × 0.04 mm was mounted in inert oil on a glass
fibre and transferred to the cold gas stream of the diffractometer (Bruker SMART
APEX CCD). Measurements were performed to 2θmax 56° with monochromated Mo-Kα
radiation. Of 19506 measured reflections, 7533 were unique (Rint = 0.066) and were
12

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used for all calculations. Structure refinement: The structures were refined
58
2
anisotropically against F (program SHELXL-97). The hydrogen atoms were refined
using rigid methyl groups or a riding model and the NH as free. The final wR2 value
was 0.1277 for all reflections and 459 parameters, with R1 0.0685 for reflections with I
> 2σ(I); max. ∆ρ 0.45 e/Å3, S 1.07.
Complete crystallographic data (excluding structure factors) have been deposited at the
Cambridge Crystallographic Data Centreunder number CCDC 1431489. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
4.6. General procedure for the synthesis of 4-aryl-2-phenyl-pyrimidines 7a-d
To a solution of 6 (1.0 mmol) in dry THF (25 mL) a 1.0M 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.
4.6.1. 4-(4-Methylphenyl)-2-phenylpyrimidine (7a). Brown prisms (ethanol). Mp: 108-
110 ºC (Lit,59 mp 109-110 °C). (Found C 82.99; H 5.85; N 11.42 C17H14N2 requires
1
82.90; H 5.73; N 11.37); H NMR δ (CDCl3, 300 MHz): 2.45 (s, 3H), 7.33-7.36 (m,
2H), 7.51-7.58 (m, 4H), 8.13-8.15 (m, 2H), 8.58-8.61 (m, 2H), 8.81 (d, 1H, J = 5.3 Hz);
13C NMR δ (CDCl3, 75.4 MHz): 21.45, 114.14, 127.09, 128.25, 128.48, 129.64, 130.62,
134.12, 137.89, 141.36, 157.59, 163.82, 164.43; HRMS (ESI): m/z (M+H)+: calcd
247.1230, found 247.1220; IR (nujol): 1607, 1587, 1564, 1546, 1508, 1457, 1427, 1408,
1379, 1324, 1308, 1276, 1186, 1023, 834, 815, 759, 695, 650 cm-1.
4.6.2. 4-(4-Chlorolphenyl)-2-phenylpyrimidine (7b). Brown plates (ethanol). Mp: 98-
90 ºC (Lit,35 mp 69-72 °C). (Found C 72.01; H 4.20; N 10.58 C16H11ClN2 requires
1
72.05; H 4.16; N 10.50); H NMR δ (CDCl3, 200 MHz): 7.49-7.58 (m, 6H), 8.15-8.21
13
(m, 2H), 8.54-8.60 (m, 2H), 8.85 (d, 1H, J = 5.3 Hz); C NMR δ (CDCl3, 50.4 MHz):
114.21, 128.27, 128.48, 128.56, 129.18, 130.85, 135.35, 137.22, 137.58, 157.96,
162.70, 164.62; HRMS (ESI): m/z (M+H)+: calcd 267.0684, found 267.0681; IR
(nujol): 1587, 1563, 1543, 1491, 1462, 1430, 1403, 1377, 1090, 823, 752, 692 cm-1.
13

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4.6.3. 4-(4-Bromophenyl)-2-phenylpyrimidine (7c). Yellow needles (ethanol). Mp:
106-108 ºC (Lit,60 mp 107-108 °C). (Found C 61.81; H 3.66; N 9.01 C16H11BrN2
1
requires 61.76; H 3.56; N 9.00); H NMR δ (CDCl3, 200 MHz): 7.51-7.57 (m, 4H),
13
7.64-7.70 (m, 2H), 8.07-8.14 (m, 2H), 8.54-8.60 (m, 2H), 8.84 (d, 1H, J = 5.3 Hz); C
NMR δ (CDCl3, 50.4 MHz): 114.16, 125.62, 128.25, 128.54, 128.67, 130.82, 132.13,
135.81, 137.61, 158.04, 162.70, 164.67; HRMS (ESI): m/z (M+H)+: calcd 311.0178,
found 311.0171; IR (nujol): 1587, 1562, 1540, 1487, 1456, 1428, 1399, 1376, 1069,
1008, 825, 816, 751, 691 cm-1.
4.6.4. 4-(4-Nitrophenyl)-2-phenylpyrimidine (7d). Orange prisms (ethanol). Mp: 158-
159 ºC). (Found C 69.20; H 4.04; N 15.00 C16H11N3O2 requires 69.31; H 4.00; N
1
15.15); H NMR δ (CDCl3, 200 MHz): 7.53-7.56 (m, 3H), 7.66 (d, 1H, J = 5.2 Hz),
13
8.38-8.42 (m, 4H), 8.56-8.60 (m, 2H), 8.94 (d, 1H, J = 5.2 Hz); C NMR δ (CDCl3,
100.8 MHz): 115.05, 124.10, 128.14, 128.38, 128.65, 131.13, 137.33, 142.87, 149.42,
158.56, 161.51, 165.08; HRMS (ESI): m/z (M+H)+: calcd 278.0924, found 278.0916;
IR (nujol): 1607, 1586, 1560, 1549, 1524, 1457, 1428, 1408, 1376, 1347, 1108, 858,
831, 820, 744, 688 cm-1.
4.7. One-pot general procedure for the synthesis of 2,4-diarylpyrimidines 7e-p
Compounds 3 (1.0 mmol) were solved in acetonitrile (6 mL). After addition of the
corresponding benzamidine 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 appropriate solvent.
4.7.1. 2-(4-Methylphenyl)-4-phenylpyrimidine (7e). Yellow needles (hexane). Mp: 91-
92 ºC (Lit,59 mp 91-94 °C). (Found C 82.55; H 5.98; N 11.42; C17H14N2 requires C
1
82.90; H 5.73; N 11.37); H NMR δ (CDCl3, 300 MHz): 2.45 (s, 3H), 7.32-7.36 (m,
2H), 7.53-7.56 (m, 4H), 8.21-8.25 (m, 2H), 8.48-8.53 (m, 2H), 8.81 (d, 1H, J = 5.4 Hz);
13C NMR δ (CDCl3, 75.4 MHz): 21.47, 114.17, 127.13, 128.19, 128.85, 129.25, 130.83,
135.11, 136.98, 140.89, 157.71, 163.70, 164.56; MS (EI) m/z (%): 246 (M+, 100), 247
(38), 231 (4), 169 (6), 129 (30), 117 (32), 102 (59); IR (KBr): 1583, 1547, 1492, 1452,
1426, 1406, 1382, 1277, 1175, 830, 765, 688 cm−1.
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4.7.2. 2-(4-Chlorophenyl)-4-phenylpyrimidine (7f). Yellow needles (hexane). Mp:
114-116 ºC (Lit,25 mp 115-117 °C). (Found C 72.01; H 4.28; N 10.41; C16H11ClN2
1
requires C 72.05; H 4.16; N 10.50); H NMR δ (CDCl3, 400 MHz): 7.46-7.50 (m, 2H),
7.52-7.56 (m, 3H), 7.57 (d, 1H, J = 5.2 Hz), 8.17-8.22 (m, 2H), 8.51-8.55 (m, 2H), 8.79
13
(d, 1H, J = 5.2 Hz); C NMR δ (CDCl3, 100.8 MHz): 114.61, 127.13, 128.68, 128.92,
129.59, 131.03, 136.30, 136.70, 136.86, 157.79, 163.54, 163.87; MS (EI) m/z (%): 266
(M+, 100), 268 (55), 267 (44), 269 (13), 231 (M+−Cl, 8), 189 (6), 137 (68), 129 (96),
103 (55), 102 (98), 76 (33); IR (KBr): 1582, 1546, 1492, 1450, 1428, 1401, 1377, 1321,
1275, 1188, 1168, 1089, 1012, 828, 768, 690 cm−1.
4.7.3. 2-(3-Nitrophenyl)-4-phenylpyrimidine (7g). White plates (cyclohexane). Mp:
131-132 ºC. (Found C 69.05; H 4.32; N 15.25; C16H11N3O2 requires C 69.31; H 4.00; N
15.15); 1H NMR δ (CDCl3, 300 MHz): 7.54-7.56 (m, 3H), 7.63-7.68 (m, 2H), 8.19-8.22
(m, 2H), 8.32 (ddd, 1H, J = 8.1 Hz, J = 2.4 Hz, J = 1.2 Hz), 8.84 (d, 1H, J = 5.1 Hz),
8.89 (ddd, 1H, J = 7.8 Hz, J = 1.5 Hz, J = 1.2 Hz), 9.39 (t, 1H, J = 1.8 Hz); 13C NMR δ
(CDCl3, 75.4 MHz): 115.38, 123.19, 125.07, 127.15, 129.01, 129.39, 131.30, 133.91,
136.21, 139.57, 148.66, 157.97, 162.21, 164.11; MS (EI) m/z (%): 277 (M+, 76), 278
(47), 231 (95), 232 (51), 129 (82), 115 (44), 102 (100), 77 (43); IR (KBr): 1615, 1586,
1566, 1547, 1526, 1494, 1481, 1420, 1373, 1349, 1085, 773, 734, 694, 685, 623 cm−1.
4.7.4. 4-(4-Methoxyphenyl)-2-(4-methylphenyl)pyrimidine (7h). Yellow needles
(hexane). Mp: 122-123 ºC. (Found C 78.20; H 5.99; N 10.16; C18H16N2O requires C
1
78.24; H 5.84; N 10.14); H NMR δ (CDCl3, 300 MHz): 2.44 (s, 3H), 3.88 (s, 3H),
7.01-7.04 (m, 2H), 7.31-7.34 (m, 2H), 7.47 (d, 1H, J = 5.4 Hz), 8.18-8.21 (m, 2H), 8.46-
13
8.49 (m, 2H), 8.74 (d, 1H, J = 5.1 Hz); C NMR δ (CDCl3, 75.4 MHz): 21.45, 55.34,
113.31, 114.17, 128.13, 128.65, 129.20, 129.37, 135.24, 140.75, 157.40, 161.92,
163.17, 164.37; MS (EI) m/z (%): 276 (M+, 100), 277 (41), 261 (22), 245 (M+−OCH3,
3), 233 (9), 159 (27), 138 (22), 132 (65), 117 (51), 116 (52), 89 (39); IR (KBr): 1608,
1582, 1560, 1544, 1510, 1435, 1413, 1379, 1329, 1307, 1283, 1250, 1173, 1116, 1028,
825, 790 cm−1.
4.7.5. 2-(4-Chlorophenyl)-4-(4-methoxyphenyl)pyrimidine (7i). Yellow needles
(hexane). Mp: 122-124 ºC. (Found C 68.99; H 4.77; N 9.54; C17H13ClN2O requires C
68.81; H 4.42; N 9.44); 1H NMR δ (CDCl3, 400 MHz): 3.88 (s, 3H), 7.01-7.04 (m, 2H),
15

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13
7.46-7.49 (m, 3H), 8.15-8.17 (m, 2H), 8.50-8.52 (m, 2H), 8.72 (d, 1H, J = 5.6 Hz); C
NMR δ (CDCl3, 100.8 MHz): 55.38, 113.73, 114.27, 128.63, 128.68, 129.11, 129.55,
136.48, 136.73, 157.47, 162.13, 163.36, 163.38; MS (EI) m/z (%): 296 (M+, 100), 298
(63), 297 (50), 299 (15), 281 (21), 253 (11), 218 (6), 189 (7), 159 (38), 137 (45), 132
(83), 117 (46), 102 (37), 89 (53); IR (KBr): 1607, 1581, 1560, 1543, 1513, 1439, 1253,
1173, 822, 789 cm−1.
4.7.6. 4-(4-Methoxyphenyl)-2-(3-nitrophenyl)pyrimidine (7j). Yellow needles (ethyl
acetate). Mp: 170-171 ºC. (Found C 66.86; H 4.42; N 13.72; C17H13N3O3 requires C
1
66.44; H 4.26; N 13.67); H NMR δ (CDCl3, 400 MHz): 3.90 (s, 3H), 7.03-7.06 (m,
2H), 7.55 (d, 1H, J = 5.2 Hz), 7.64 (t, 1H, J = 8.0 Hz), 8.16-8.19 (m, 2H), 8.30 (ddd,
1H, J = 8.0 Hz, J = 2.0 Hz, J = 0.8 Hz), 8.76 (d, 1H, J = 5.6 Hz), 8.87 (dt, 1H, J = 8.0
Hz, J = 1.6 Hz), 9.38 (t, 1H, J = 2.0 Hz); 13C NMR δ (CDCl3, 100.8 MHz): 55.43,
114.50, 114.54, 123.28, 124.90, 128.82, 128.92, 129.29, 133.87, 140.03, 149.00,
157.67, 162.32, 162.55, 163.85; MS (EI) m/z (%): 307 (M+, 100), 308 (44), 261 (96),
262 (23), 246 (36), 218 (57), 217 (35), 190 (8), 129 (30), 117 (23), 102 (52), 89 (46); IR
(KBr): 1607, 1583, 1567, 1530, 1514, 1447, 1428, 1374, 1347, 1313, 1285, 1250, 1185,
1084, 1028, 828, 806, 789, 742, 727, 716, 688, 580 cm−1.
4.7.7. 2-(4-Methylphenyl)-4-(2-naphthyl)pyrimidine
(7k).
Yellow
needles
(cyclohexane). Mp: 137-138 ºC. (Found C 85.06; H 5.63; N 9.41; C21H16N2 requires C
85.11; H 5.44; N 9.45); 1H NMR δ (CDCl3, 200 MHz): 2.47 (s, 3H), 7.34-7.38 (m, 2H),
7.52-7.61 (m, 2H), 7.67 (d, 1H, J = 5.4 Hz), 7.88-8.03 (m, 3H), 8.32 (dd, 1H, J = 8.8
Hz, J = 1.8 Hz), 8.52-8.56 (m, 2H), 8.70 (d, 1H, J = 1.0 Hz), 8.83 (d, 1H, J = 5.2 Hz);
13C NMR δ (CDCl3, 50.4 MHz): 21.53, 114.42, 124.03, 126.56, 127.36, 127.40, 127.76,
128.27, 128.65, 129.03, 129.32, 133.22, 134.31, 134.62, 135.19, 140.97, 157.74,
163.66, 164.67; MS (EI) m/z (%): 296 (M+, 100), 281 (3), 179 (32), 153 (33), 151 (82),
148 (18), 126 (19), 116 (21), 117 (16); IR (KBr): 1600, 1580, 1550, 1471, 1427, 1403,
1390, 1375, 1174, 1016, 870, 818, 784, 754, 720, 685 cm−1.
4.7.8. 2-(4-Chlorophenyl)-4-(2-naphthyl)pyrimidine
(7l).
Yellow
prisms
(cyclohexane). Mp: 148-149 ºC. (Found C 75.61; H 4.28; N 8.82; C20H13ClN2 requires
C 75.83; H 4.14; N 8.84); 1H NMR δ (CDCl3, 400 MHz): 7.49-7.52 (m, 2H), 7.54-7.60
(m, 2H), 7.68 (d, 1H, J = 5.6 Hz), 7.89-7.91 (m, 1H), 7.96-8.01 (m, 2H), 8.28 (dd, 1H, J
16

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= 8.8 Hz, J = 2.0 Hz), 8.55-8.58 (m, 2H), 8.66 (d, 1H, J = 0.8 Hz), 8.81 (d, 1H, J = 5.2
Hz); 13C NMR δ (CDCl3, 100.8 MHz): 114.80, 123.87, 126.62, 127.43, 127.47, 127.75,
128.71, 129.01, 129.63, 133.16, 133.94, 134.65, 136.32, 136.89, 157.77, 163.58,
163.76; MS (EI) m/z (%): 316 (M+, 71), 318 (39), 317 (32), 319 (9), 281 (M+−Cl, 3),
179 (35), 153 (36), 151 (100), 137 (36), 126 (27), 102 (20); IR (KBr): 1594, 1581,
1551, 1428, 1403, 1390, 1376, 1088, 1011, 871, 820, 786, 758, 679 cm−1.
4.7.9. 4-(2-Naphthyl)-2-(3-nitrophenyl)pyrimidine (7m). Yellow needles (ethyl
acetate). Mp: 182-183 ºC. (Found C 73.02; H 4.15; N 12.93; C20H13N3O2 requires C
73.38; H 4.00; N 12.84); 1H NMR δ (CDCl3, 300 MHz): 7.54-7.61 (m, 2H), 7.69 (t, 1H,
J = 7.8 Hz), 7.79 (d, 1H, J = 5.1 Hz), 7.90-8.03 (m, 3H), 8.30-8.36 (m, 2H), 8.70 (s,
1H), 8.89 (d, 1H, J = 4.8 Hz), 8.95 (d, 1H, J = 7.8 Hz), 9.45 (s, 1H); 13C NMR δ
(CDCl3, 75.4 MHz): 115.66, 123.39, 123.88, 125.11, 126.78, 127.66, 127.67, 127.83,
128.92, 129.11, 129.42, 133.32, 133.77, 133.99, 134.91, 139.86, 148.99, 158.04,
162.57, 164.32; MS (EI) m/z (%): 327 (M+, 83), 328 (48), 281 (100), 282 (33), 279
(30), 152 (67), 153 (40), 151 (43), 140 (59), 129 (40), 126 (28), 102 (59); IR (KBr):
1615, 1586, 1564, 1550, 1526, 1480, 1423, 1389, 1375, 1346, 826, 815, 793, 756, 710,
699, 475, 467 cm−1.
4.7.10. 4-(4-Biphenylyl)-2-(4-methylphenyl)pyrimidine (7n). Yellow needles (ethyl
acetate). Mp: 185-187 ºC. (Found C 85.70; H 5.99; N 8.76; C23H18N2 requires C 85.68;
1
H 5.63; N 8.69); H NMR δ (CDCl3, 300 MHz): 2.46 (s, 3H), 7.34-7.37 (m, 2H), 7.41
(t, 1H, J = 7.2 Hz), 7.50 (t, 2H, J = 6.9 Hz), 7.58 (d, 1H, J = 5.4 Hz), 7.67-7.70 (m, 2H),
13
7.75-7.78 (m, 2H), 8.29-8.32 (m, 2H), 8.50-8.53 (m, 2H), 8.82 (d, 1H, J = 5.1 Hz); C
NMR δ (CDCl3, 75.4 MHz): 21.50, 114.05, 127.11, 127.53, 127.59, 127.84, 128.22,
128.88, 129.28, 135.14, 135.82, 140.20, 140.92, 143.60, 157.72, 163.29, 164.61; MS
(EI) m/z (%): 322 (M+, 100), 307 (3), 245 (4), 205 (21), 178 (65), 179 (26), 176 (33),
160 (16), 151 (29), 152 (26), 117 (34), 116 (28), 89 (12); IR (KBr): 1605, 1567, 1555,
1541, 1518, 1485, 1431, 1404, 1375, 1174, 820, 783, 767, 730, 690, 503, 428 cm−1.
4.7.11. 4-(4-Biphenylyl)-2-(4-chlorophenyl)pyrimidine (7o). Yellow needles (ethyl
acetate). Mp: 205-206 ºC. (Found C 77.01; H 4.33; N 8.04; C22H15ClN2 requires C
1
77.08; H 4.41; N 8.17); H NMR δ (CDCl3, 300 MHz): 7.41 (t, 1H, J = 7.2 Hz), 7.47-
7.51 (m, 4H), 7.61 (d, 1H, J = 5.1 Hz), 7.66-7.69 (m, 2H), 7.75-7.79 (m, 2H), 8.26-8.30
17

ACCEPTED MANUSCRIPT
13
(m, 2H), 8.54-8.58 (m, 2H), 8.81 (d, 1H, J = 5.1 Hz); C NMR δ (CDCl3, 75.4 MHz):
114.50, 127.16, 127.64, 127.65, 127.94, 128.74, 128.93, 129.72, 135.72, 136.52,
136.99, 140.27, 143.95, 157.83, 163.63, 163.78; MS (EI) m/z (%): 342 (M+, 100), 344
(58), 343 (41), 345 (13), 307 (3), 205 (39), 178 (88), 176 (32), 152 (28), 137 (41), 102
(18); IR (KBr): 1596, 1582, 1568, 1556, 1541, 1486, 1433, 1404, 1376, 1089, 1012,
1003, 822, 786, 769, 732, 710, 690, 684, 504, 494, 427 cm−1.
4.7.12.
4-(4-Biphenylyl)-2-(3-nitrophenyl)pyrimidine
(7p).
Yellow
needles
(dichloromethane). Mp: 221-225 ºC. (Found C 74.13; H 4.43; N 11.74; C22H15N3O2
requires C 74.78; H 4.28; N 11.89); 1H NMR δ (CDCl3, 300 MHz): 7.40 (t, 1H, J = 7.2
Hz), 7.49 (t, 2H, J = 7.2 Hz), 7.66-7.72 (m, 4H), 7.78-7.82 (m, 2H), 8.29-8.36 (m, 3H),
8.88 (d, 1H, J = 5.1 Hz), 8.94 (dt, 1H, J = 7.8 Hz, J = 1.2 Hz), 9.45 (t, 1H, J = 1.8 Hz);
13C NMR δ (CDCl3, 75.4 MHz): 115.34, 123.45, 125.11, 127.22, 127.77, 127.80,
128.05, 128.99, 129.42, 133.98, 135.42, 139.99, 140.27, 144.36, 149.16, 158.08,
162.69, 164.13; MS (EI) m/z (%): 353 (M+, 93), 354 (51), 307 (100), 308 (37), 305
(16), 229 (6), 178 (70), 179 (24), 176 (32), 154 (50), 152 (39), 129 (50), 102 (65); IR
(KBr): 1614, 1604, 1585, 1565, 1542, 1525, 1481, 1449, 1423, 1371, 1350, 924, 893,
832, 816, 794, 770, 739, 708, 686 cm−1.
4.8. X-ray structure determination of compound 7m
Crystal data: C20H13N3O2, Mr = 327.33, Orthorhombic, space group Pca2(1), a =
32.730(5), b = 5.8020(8), c = 7.9291(11)Å, U = 1505.7(4) Å3 at –173°C; Z = 4, Dx =
1.444 g cm–3, F(000) = 680, µ = 0.096 mm–1. Data collection: A colourless needle 0.20
× 0.09 × 0.07 mm was mounted in inert oil on a glass fibre and transferred to the cold
gas stream of the diffractometer (Bruker SMART APEX CCD). Measurements were
performed to 2θmax 56° with monochromated Mo-Kα radiation. Of 9407 measured
reflections, 1960 were unique (Rint = 0.036) and were used for all calculations. Structure
2
refinement: The structures were refined anisotropically against F (program SHELXL-
97).58 The hydrogen atoms were refined using a riding model. The final wR2 value was
0.1356 for all reflections and 226 parameters, with R1 0.0617 for reflections with I >
2σ(I); max. ∆ρ 0.43 e/Å3, S 1.22.
Complete crystallographic data (excluding structure factors) have been deposited at the
Cambridge Crystallographic Data Centreunder number CCDC 1431490. These data can
18

ACCEPTED MANUSCRIPT
be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
4.9. Isolation of 2,6-diaryl-4-dichloromethylpyrimidines 8k-m
The mother liquors of crystallisation of compounds 7k-m were concentrated under
reduced pressure leaving solid residues whose column chromatography (silica gel TLC,
ethyl acetate/hexane 4:1) provided small amounts of highly pure products 8k-m (5%)
that were crystallised from cyclohexane or ethyl ether.
4.9.1. 4-Dichloromethyl-2-(4-methylphenyl)-6-(2-naphthyl)pyrimidine (8k). Yellow
needles (cyclohexane). Mp: 120-122 ºC. (Found C 69.46; H 4.73; N 7.79; C22H16Cl2N2
requires C 69.67; H 4.25; N 7.39); 1H NMR δ (CDCl3, 200 MHz): 2.46 (s, 3H), 6.76 (s,
1H), 7.33-7.37 (m, 2H), 7.56-7.61 (m, 2H), 7.90-8.07 (m, 3H), 8.15 (s, 1H), 8.38 (d, 1H,
J = 8.6 Hz), 8.51-8.56 (m, 2H), 8.77 (s, 1H); HRMS (ESI) m/z (M+H)+: calcd 379.0763,
found 379.0766.
4.9.2. 2-(4-Chlorophenyl)-4-dichloromethyl-6-(2-naphthyl)pyrimidine (8l).
Yellow prisms (cyclohexane). Mp: 141-142 ºC. (Found C 63.41; H 3.49; N 6.89
C21H13Cl3N2 requires C 63.10; H 3.28; N 7.01); 1H NMR δ (CDCl3, 200 MHz): 6.75 (s,
1H), 7.47-7.54 (m, 2H), 7.56-7.63 (m, 2H), 7.89-7.94 (m, 1H), 7.98-8.06 (m, 2H), 8.16
(s, 1H), 8.33 (dd, 1H, J = 8.6 Hz, J = 1.8 Hz), 8.55-8.61 (m, 2H), 8.73 (d, 1H, J = 1.4
Hz); MS (EI) m/z (%): 398 (M+, 72), 400 (68), 402 (31), 399 (20), 401 (20), 403 (6),
364 (8), 315 (4), 247 (6), 226 (13), 199 (35), 190 (53), 178 (100), 151 (65), 137 (42),
126 (27), 102 (25), 73 (32).
4.9.3. 4-Dichloromethyl-6-(2-naphthyl)-2-(3-nitrophenyl)pyrimidine (8m). White
powder (ethyl ether). Mp: 174-175 ºC. (Found C 61.25; H 3.01; N 10.20;
C21H13Cl2N3O2 requires C 61.48; H 3.19; N 10.24); 1H NMR δ (CDCl3, 200 MHz): 6.79
(s, 1H), 7.54-7.64 (m, 2H), 7.71 (t, 1H, J = 8.0 Hz), 7.89-7.94 (m, 1H), 7.99-8.06 (m,
2H), 8.23 (s, 1H), 8.31-8.40 (m, 2H), 8.73 (d, 1H, J = 1.2 Hz), 8.96 (dt, 1H, J = 7.8 Hz,
J = 1.2 Hz), 9.42 (t, 1H, J = 1.8 Hz); MS (EI) m/z (%): 409 (M+, 100), 411 (66), 410
(21), 412 (14), 413 (12), 375 (14), 363 (20), 328 (36), 292 (14), 199 (22), 190 (42), 178
(37), 164 (39), 152 (48), 151 (43), 146 (32), 126 (26), 102 (26), 75 (27).
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4.10. X-ray structure determination of compound 8m
Crystal data: C21H13Cl2N3O2, Mr = 410.24, monoclinic, space group P2(1)/n , a =
9.0311(11), b = 9.2142(11), c = 1521.760(3) Å, β = 97.162(2)°, U = 1796.7(4) Å3 at –
173°C; Z = 4, Dx = 1.517 g cm–3, F(000) = 840, µ = 1.517 mm–1. Data collection: A
colourless needle 0.28 × 0.07 × 0.06 mm was mounted in inert oil on a glass fibre and
transferred to the cold gas stream of the diffractometer (Bruker SMART APEX CCD).
Measurements were performed to 2θmax 56° with monochromated Mo-Kα radiation. Of
20964 measured reflections, 4394 were unique (Rint = 0.039) and were used for all
calculations. Structure refinement: The structures were refined anisotropically against
58
2
F (program SHELXL-97). The hydrogen atoms were refined using rigid methyl
groups or a riding model. The final wR2 value was 0.117 for all reflections and 253
parameters, with R1 0.0535 for reflections with I > 2σ(I); max. ∆ρ 0.46 e/Å3, S 1.17.
Complete crystallographic data (excluding structure factors) have been deposited at the
Cambridge Crystallographic Data Centreunder number CCDC 1431491. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
We gratefully acknowledge the financial support of the Fundación Séneca of the
Comunidad Autónoma de la Región de Murcia (project 19249/PI/14).
Supplementary data
Supplementary data related to this article can be found in the online version, at
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