A convenient synthesis of 5- and 6-substituted 2-phenyl-3H-pyrimidin-4-ones

Article abstract of DOI:10.1055/s-2008-1032032

A simple and convenient one-pot procedure for the synthesis of 5- and 6-substituted 2-phenyl-3H-pyrimidin-4-ones by the condensation of 4-alkoxy-1,1,1-trichloroalk-3-en-2-ones with benzamidine hydrochloride is described. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1032032

358
PAPER
A Convenient Synthesis of 5- and 6-Substituted 2-Phenyl-3H-pyrimidin-4-ones
S
ynthesis of 5- and
i
6-Sub
l
stituted
o
2-Phenyl-3
H
-pyri
Z
midin-4-one
s
anatta,* Leonardo Fantinel, Rogério V. Lourega, Helio G. Bonacorso, Marcos A. P. Martins
Núcleo de Química de Heterociclos (NUQUIMHE), Departamento de Química, Universidade Federal de Santa Maria,
97105-900 Santa Maria, RS, Brazil
Fax +55(55)2208031; E-mail: zanatta@base.ufsm.br
Received 22 August 2007; revised 16 November 2007
compounds; iii) they allow one to introduce a wider range
Abstract: A simple and convenient one-pot procedure for the syn-
thesis of 5- and 6-substituted 2-phenyl-3H-pyrimidin-4-ones by the
condensation of 4-alkoxy-1,1,1-trichloroalk-3-en-2-ones with
benzamidine hydrochloride is described.
of substituents on the final product than compared with
most of the methods cited above; iv) the yields are usually
higher; and v) uses milder reaction conditions. Thus, in
this study we report a simple and efficient one-pot method
to obtain a wide scope of 5- and 6-substituted 2-phenyl-
3H-pyrimidin-4-ones from the reaction of the readily
available 4-alkoxyvinyl trichloromethyl ketones and
benzamidine hydrochloride. To our knowledge, 4-alkoxy-
vinyl trichloromethyl ketones have not been used for the
synthesis of 2-phenyl-3H-pyrimidine-4-ones. The syn-
thetic versatility of 4-alkoxyvinyl trichloromethyl ketones
has been recently demonstrated by the preparation of 3-
aminomethylenedihydrofuran-2-ones,15 pyrazoles and
pyrazolium chlorides,16 furan-3-carboxylic acids and de-
rivatives,17 pyrazolecarboxamide,18 azolylmethylpyrimi-
din-2-ones,19 and 4-trichloromethyl-2-methanesulfanyl
pyrimidines.20 The synthesis and applications of 4-
alkoxy-1,1,1-trichloroalk-3-en-2-ones have also been the
subject of a recent review.21
Key words: pyrimidines, 2-phenylpyrimidin-4-ones, trichloro-
methylated enones, benzamidine hydrochloride, Sildenafil
The 2-phenyl(aryl)-substituted pyrimidine-4-ones moiety
is present in important biological active compounds such
as azapurine,1 an efficient anti-allergic substance, and
Sildenafil2 used for men’s dysfunction erection. Since the
discovery of the biological properties of Sildenafil and its
analogues, there was an increasing interest to develop
shorter and more reliable synthetic method to obtain these
molecules to search for new biological active compounds.
2-Phenyl-3H-pyrimidin-4-ones have been synthesized by
the reaction of: i) acetylacetone, acetylacetophenone, and
ethyl acetoacetate with amidoximes catalyzed by rutheni-
um carbon monoxide under a carbon monoxide pressure
of 5 kg cm–2;3 ii) ethylacetophenones with benzamidine
hydrochloride in the presence of DMF and potassium hy-
droxide or potassium tert-butoxide;4 iii) acetylacetone,
methylacetonate, and dimethyl malonate with benzami-
dine;5 iv) ethyl a-bromocinnamates with benzamidine in
the presence of an excess of triethylamine in anhydrous
benzene;6 and v) 3-aminocrotonamide with benzonitrile in
methanol and sodium methoxide.7 2-Phenylpyrimidine-4-
ones have also been synthesized by the derivatization and
chemical transformation of the substituents from other py-
rimidines.5,8–10
Scheme 1 outlines the synthesis of a series of 5- or 6-sub-
stituted 2-phenyl-3H-pyrimidin-4-ones from the reactions
of the enones 1a–o with benzamidine hydrochloride. In
order to obtain better yields, three methods were tested
(Scheme 1). Table 1 presents the optimized results ob-
tained after each reaction was carried out by the three
methods. It is important to mention that method A was the
method of choice for most reactions, because it furnished
better yields and purity and allowed for an easier isolation
of the products than the other methods studied. We spec-
ulate that method B was not adequate because sodium
methoxide is a base strong enough to decompose the
enones 1.22 Method C exhibited better results only for the
reaction of enone 1h with benzamidine hydrochloride to
furnish 2h. Product 2h is important, because the bromo-
methyl substituent on the 6-position of the pyrimidine ring
allows for further derivatizations.23 It was observed that
the reaction of the 4-aryl-substituted enones 1i–l with
benzamidine hydrochloride furnished the desired pyrimi-
din-4-ones 2i–l as the major compound (55–90%), but mi-
nor amounts (5–8%) of 4-trichloromethyl pyrimidine 3i–
l, were also obtained. The major compounds 2i–l were
separated from their corresponding minor compounds 3i–
l by recrystallization.
One can observe from the examples cited above that there
are only few methods available for the synthesis of 5- or
6-substituted 2-phenyl-3H-pyrimidin-4-ones. In addition,
some of these methods are of restricted scope,3,5 result in
low yields,6,11 or entail a multi-step synthesis.12 Further-
more, the synthetic potential of 4-alkoxy-1,1,1-trichloro-
alk-3-ene-2-ones 1a–o as precursors of 2-phenyl-3H-
pyrimidin-4-ones has not been tested yet. Enones 1a–o
have the following advantage over the traditional methods
to prepare 2-phenyl-3H-pyrimidin-4-ones: i) they are eas-
ily prepared by acylation of enol ethers13 and acetals;14 ii)
the reactions are more regioselective than 1,3-dicarbonyl
SYNTHESIS 2008, No. 3, pp 0358–0362
x
x
.
x
x
.2
0
0
8
Advanced online publication: 10.01.2008
DOI: 10.1055/s-2008-1032032; Art ID: M06407SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 5- and 6-Substituted 2-Phenyl-3H-pyrimidin-4-ones
359
O
O
CCl3
N
R1
OR2
R
R1
H
R1
R
H
R1
R
methods
A, B, and C
N
N
;
;
O
R2O
N
Ph
N
Ph
N
Ph
CCl3
1a–o
2a–l
3i–l
4m–o
Scheme 1
Table 1 Compounds 2–4 Prepared
The reaction of enones 1m–o, which bear a substituent at
the a-carbonyl position, with benzamidine hydrochloride
furnished 2-phenyldihydropyrimidin-4-ones 4m–o, in
good yields. The presence of a substituent at the 5-posi-
tion of the pyrimidine ring stabilizes the dihydropyrimi-
dine probably due to the steric effect between the 5-
substituent and the trichloromethyl group. The elimina-
tion of the 6-alkoxy and 4-hydroxy groups can be
achieved by using dehydrating agents such as sulfuric acid
or phosphorous pentoxide.24 Compounds obtained in this
Comp. R
R1
R2
Methoda Yield Product
(%)b
1a
1a
1b
1c
1d
1e
1f
H
H
Et
A
B
A
A
A
A
A
A
A
B
C
A
A
A
A
A
A
A
64
2a
c
c
H
H
Et
–
–
Me
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
80
86
87
87
76
85
2b
2c
2d
2e
2f
Et
H
1
study were analyzed by H and 13C NMR, GC-MS, and
Pr
H
elemental analysis.
Bu
H
The mechanism of formation of 2-phenyl-3H-pyrimidin-
4-ones 2 probably involves the addition of a nitrogen atom
from benzamidine to the b-carbon of the b-alkoxyvinyl
ketones 1 (Structure I, Scheme 2) followed by the tau-
tomerization of the hydroxyl hydrogen with the a-carbon
and restoration of the carbonyl group (Structure II,
Scheme 2). The ether function (OR2) is stable under basic
condition. In the second step, the other nitrogen of benz-
amidine undergoes intramolecular nucleophilic addition
to the carbonyl group generating a quaternary carbon and
closing a six-membered pyrimidine ring (Structure III).
On the presence of a base, the carbonyl is restored and the
trichloromethyl group is eliminated to furnish the dihy-
dropyrimidines 4m–o. Next, the base removes the H-5,
causing the elimination of the alkoxy group leading to
i-Bu
H
1g
1h
1h
1h
1i
Ph
H
2g
c
c
CH2Br
CH2Br
CH2Br
4-BrC6H4
4-ClC6H4
4-MeC6H4
4-MeOC6H4
H
H
–
–
c
c
H
–
–
H
60
2h
H
90/5
65/7
70/8
55/5
70
2i/3i
2j/3j
2k/3k
2l/3l
4m
1j
H
1k
1l
H
H
1m
1n
1o
Me
the 2-phenyl-3H-pyrimidin-4-ones
2
according to
Scheme 2.15,25
H
-(CH2)2-
-(CH2)3-
63
4n
In conclusion, we have described a simple and convenient
one-pot procedure for the synthesis of 5- or 6-substituted
2-phenyl-3H-pyrimidin-4-ones from the condensation re-
action of 4-alkoxy-1,1,1-trichloroalk-3-en-2-ones with
benzamidine hydrochloride, under mild conditions and in
good yields. In addition, a simple method to obtain the 6-
bromomethylpyrimidine, which is an important interme-
diate for further derivatizations, has been presented.
H
72
4o
a Method A: Benzamidine hydrochloride, NaOH (1 M), CH2Cl2, 15
min, 20–25 °C; Method B: Benzamidine hydrochloride, Na, MeOH,
24 h, reflux; Method C: Benzamidine hydrochloride, NaH, THF, 24 h,
reflux.
b Yields after purification.
c Complex mixture of unidentified compounds.
OR2
H
OR2
R1
R1
R1
OR2
R
R
R
H2N
HN
B–
Cl3C
H
Cl3C
Ph
NH
Ph
N
O
H
O
O
CCl3
HN
O
HN
Ph
1
I
II
O
B–
H
R1
O
CCl3
H
R1
– R2OH
H
H
H
– CHCl3
N
N
R1
R
N
R
N
Ph
N
Ph
R2O
R
N
Ph
R2O
III
4m–o
2
Scheme 2
Synthesis 2008, No. 3, 358–362 © Thieme Stuttgart · New York

360
N. Zanatta et al.
PAPER
The syntheses of compounds 1a–o are reported in the literature.13,14
All melting points were determined on a Kofler Reichert Thermovar
or on a MQAPF-301 apparatus and are uncorrected. The CHN mi-
croanalyses were performed on a PerkinElmer 2400 elemental ana-
lyzer from the Department of Chemistry of the São Paulo
University (USP), São Paulo, SP, Brazil. Mass spectra were regis-
tered in a HP 5973 MSD connected to a HP 6890 GC. The GC was
equipped with a split-splitless injector, auto-sampler, cross-linked
HP-5 capillary column (30 m, 0.32 mm of internal diameter), and
helium was used as the carrier gas. 1H and 13C NMR spectra were
acquired on a Bruker DPX200 or DPX400 spectrometer in DMSO-
d6 with TMS as the internal reference.
Anal. Calcd for C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C,
71.66; H, 5.71; N, 13.68.
2-Phenyl-6-propylpyrimidin-4(3H)-one (2d)
Mp 146–148 °C (hexane–CHCl3, 1:3).
1H NMR (200 MHz, CDCl3): d = 1.00 (t, J = 7.4 Hz, 3 H, CH3), 1.78
(sext, J = 7.4 Hz, 2 H, CH2), 2.59 (t, J = 7.4 Hz, 2 H, CH2), 6.29 (s,
1 H, H-5), 7.49–7.53, 8.21–8.26 (m, 5 H, C6H5), 13.36 (br s, 1 H,
NH).
13C NMR (50 MHz, CDCl3): d = 13.6 (CH3), 21.1 (CH2), 39.6
(CH2), 110.2 (C-5), 127.8, 128.7, 131.7, 132.3 (C6H5), 156.4 (C-2),
165.6 (C-4), 169.8 (C-6).
GC-MS (EI 70 eV): m/z (%) = 214 (M+, 10), 186 (100), 158 (23),
104 (43), 77 (25).
5- and 6-Substituted 2-Phenyl-3H-pyrimidin-4-ones 2 and 4;
General Procedure
Method A: A solution of enone 1 (1.0 mmol) in CH2Cl2 (0.5 mL)
was added to a vigorously stirred mixture of benzamidine hydro-
chloride (0.19 g, 1.0 mmol) in aq 1 M solution of NaOH (1.0 mL),
at r.t. The mixture was stirred for 15 min at r.t. and during the stir-
ring a precipitate was formed. The precipitate was collected by fil-
tration and the solid was washed with H2O (10 mL) to remove the
salt formed during the reaction. The solid was washed with hexane
(10 mL) and dried in a desiccator containing P2O5 under vacuum.
Products 2a–g and 4m–o were recrystallized from a mixture of hex-
ane–CHCl3 (1:3). The mixture of compounds 2i–l and 3i–l were re-
crystallized from a mixture of CHCl3–MeOH (5:1). By this
recrystallization, the major products 2i–l crystallized and were re-
covered by filtration and the minor products 3i–l were recovered
from the mother liquor.
Anal. Calcd for C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found: C,
72.47; H, 6.67; N, 12.89.
6-Butyl-2-phenylpyrimidin-4(3H)-one (2e)
Mp 218–220 °C (hexane–CHCl3, 1:3).
1H NMR (200 MHz, CDCl3): d = 0.89 (t, J = 7.4 Hz, 3 H, CH3), 1.35
(sext, J = 7.0 Hz, 2 H, CH2), 1.66 (quint, J = 7.6 Hz, 2 H, CH2), 2.55
(t, J = 7.6 Hz, 2 H, CH2), 6.22 (s, 1 H, H-5), 7.45–7.48, 8.12–8.17
(m, 5 H, C6H5), 13.07 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 13.8 (CH3), 22.2 (CH2), 30.0
(CH2), 37.3 (CH2), 109.9 (C-5), 127.8, 128.6, 131.5, 132.6 (C6H5),
156.7 (C-2), 166.0 (C-4), 170.0 (C-6).
GC-MS (EI 70 eV): m/z (%) = 229 (M+, 3), 186 (100), 156 (42), 104
(42), 77 (23).
2-Phenylpyrimidin-4(3H)-one (2a)
Mp 205–207 °C (hexane–CHCl3, 1:3).
Anal. Calcd for C14H16N2O: C, 73.66; H, 7.06; N, 12.20. Found: C,
73.47; H, 7.02; N, 11.99.
1H NMR (200 MHz, DMSO-d6): d = 6.34 (d, J = 6.6 Hz, 1 H, H-5),
7.45–7.62, 7.09–8.13 (m, 5 H, C6H5), 8.05 (d, J = 6.6 Hz, 1 H, H-6),
12.69 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 112.7 (C-5), 127.7, 128.6,
131.6, 132.7 (C6H5), 154.5 (C-6), 158.1 (C-2), 163.4 (C-4).
GC-MS (EI 70 eV): m/z (%) = 172 (M+, 100), 144 (17), 104 (86), 69
(46).
6-Isobutyl-2-phenylpyrimidin-4(3H)-one (2f)
Mp 163–168 °C (hexane–CHCl3, 1:3).
1H NMR (400 MHz, CDCl3): d = 0.95 (d, J = 6.5 Hz, 6 H, 2 CH3),
2.14 (m, 1 H, CH), 2.37 (d, J = 7.0 Hz, 2 H, CH2), 5.90 (s, 1 H, H-
5), 7.36–7.56, 7.77–8.10 (m, 5 H, C6H5), 9.28 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 22.4 (2 CH3), 27.2 (CH), 46.2
(CH2), 108.3 (C-5), 127.5, 127.8, 128.7, 138.4 (C6H5), 161.9 (C-2),
165.0 (C-4), 172.7 (C-6).
Anal. Calcd for C10H8N2O: C, 69.76; H, 4.68; N, 16.27. Found: C,
70.01; H, 4.75; N, 16.69.
GC-MS (EI 70 eV): m/z (%) = 229 (M+, 9), 186 (100), 158 (21), 104
(34), 77 (21).
6-Methyl-2-phenylpyrimidin-4(3H)-one (2b)
Mp 220–221 °C (hexane–CHCl3, 1:3).
Anal. Calcd for C14H16N2O: C, 73.66; H, 7.06; N, 12.20. Found: C,
73.51; H, 7.01; N, 11.95.
1H NMR (400 MHz, DMSO-d6): d = 2.29 (s, 3 H, CH3), 6.22 (s, 1
H, H-5), 7.50–7.60, 8.11–8.13 (m, 5 H, C6H5), 12.51 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 24.2 (CH3), 110.8 (C-5), 127.8,
2,6-Diphenylpyrimidin-4(3H)-one (2g)
Mp 299–300 °C (hexane–CHCl3, 1:3).
1H NMR (400 MHz, DMSO-d6): d = 6.92 (s, 1 H, H-5), 7.51–7.62,
8.17–8.28 (m, 10 H, C6H5), 12.76 (br s, 1 H, NH).
128.9, 131.8, 132.1 (C6H5), 156.5 (C-2), 165.3 (C-6), 163.4 (C-4).
GC-MS (EI 70 eV): m/z (%) = 186 (M+, 100), 158 (24), 104 (81), 83
(36).
13C NMR (100 MHz, DMSO-d6): d = 106.6 (C-5), 126.9, 127.9,
128.6, 128.7, 130.5, 131.6 132.9, 136.3 (C6H5), 157.3 (C-2), 160.8
(C-6), 164.2 (C-4).
GC-MS (EI 70 eV): m/z (%) = 248 (M+, 100), 220 (19), 149 (48),
104 (64), 77 (43).
Anal. Calcd for C11H10N2O: C, 70.95; H, 5.41; N, 15.04. Found: C,
70.45; H, 5.39; N, 15.03.
6-Ethyl-2-phenylpyrimidin-4(3H)-one (2c)
Mp 158–162 °C (hexane–CHCl3, 1:3).
1H NMR (400 MHz, DMSO-d6): d = 1.22 (t, J = 7.2 Hz, 3 H, CH3),
2.57 (q, J = 7.2 Hz, 2 H, CH2), 6.20 (s, 1 H, H-5), 7.51–7.57, 8.14–
8.17 (m, 5 H, C6H5), 11.93 (br s, 1 H, NH).
Anal. Calcd for C16H12N2O: C, 77.40; H, 4.87; N, 11.28. Found: C,
77.24; H, 5.00; N, 11.40.
13C NMR (100 MHz, DMSO-d6): d = 12.0 (CH3), 29.8 (CH2), 108.3
(C-5), 127.6, 128.4, 131.3, 132.8 (C6H5), 157.0 (C-2), 164.0 (C-4),
169.0 (C-6).
GC-MS (EI 70 eV): m/z (%) = 200 (M+, 79), 171 (44), 104 (100), 77
(89), 51 (54).
6-(4-Bromophenyl)-2-phenylpyrimidin-4(3H)-one (2i)
Mp 304–307 °C (CHCl3–MeOH, 5:1).
1H NMR (400 MHz, DMSO-d6): d = 6.94 (s, 1 H, H-5), 7.54–7.71,
8.11–8.24 (m, 9 H, C6H5), 12.80 (br s, 1 H, NH).
Synthesis 2008, No. 3, 358–362 © Thieme Stuttgart · New York

PAPER
Synthesis of 5- and 6-Substituted 2-Phenyl-3H-pyrimidin-4-ones
361
13C NMR (100 MHz, DMSO-d6): d = 108.8 (C-5), 123.8, 127.6,
128.0, 128.3, 128.7, 131.3, 135.4, 135.7 (2 C6H5), 163.5 (C-2),
165.3 (C-6), 166.5 (C-4).
13C NMR (100 MHz, DMSO-d6): d = 95.9 (CCl3), 109.1 (C-5),
128.1, 128.9, 129.1, 129.5, 131.8, 134.2, 135.9, 136.0 (2 C6H5),
163.5 (C-6), 165.3 (C-4), 166.7 (C-2).
GC-MS (EI 70 eV): m/z (%) = 326 (M+, 100), 300 (20), 182 (14),
GC-MS (EI 70 eV): m/z (%) = 382 (M+, 85), 349 (58), 245 (48), 162
104 (78), 77 (49), 51 (21).
(72), 136 (43), 104 (93), 75 (33).
Anal. Calcd for C16H11BrN2O: C, 58.74; H, 3.39; N, 8.56. Found: C,
58.63; H, 3.26; N, 9.05.
2-Phenyl-4-(p-tolyl)-6-(trichloromethyl)pyrimidine (3k)
Mp 151–154 °C (CHCl3–MeOH, 5:1).
6-(4-Chlorophenyl)-2-phenylpyrimidin-4(3H)-one (2j)
Mp 301–304 °C (CHCl3–MeOH, 5:1).
1H NMR (400 MHz, DMSO-d6): d = 2.44 (s, 3 H, CH3), 6.88 (s, 1
H, H-5), 7.31–7.85, 8.05–8.58 (m, 9 H, C6H5).
1H NMR (400 MHz, DMSO-d6): d = 6.96 (s, 1 H, H-5), 7.55–7.63,
13C NMR (100 MHz, DMSO-d6): d = 20.7 (CH3), 95.9 (CCl3), 108.2
(C-5), 126.5, 127.3, 128.2, 128.6, 129.5, 131.3, 135.9, 141.5 (2
C6H5), 163.3 (C-6), 165.6 (C-4), 166.2 (C-2).
GC-MS (EI 70 eV): m/z (%) = 362 (M+, 100), 327 (54), 245 (47),
142 (78), 115 (74), 104 (58), 76 (19).
8.21–8.26 (m, 9 H, C6H5), 13.42 (br s, 1 H, NH).
13C NMR (50 MHz, DMSO-d6): d = 108.9 (C-5), 127.7, 128.1,
128.4, 129.3, 131.6; 135.4, 135.8, 136.8 (2 C6H5), 163.5 (C-2),
165.2 (C-6), 166.5 (C-4).
GC-MS (EI 70 eV): m/z (%) = 282 (M+, 100), 254 (26), 179 (17),
138 (18), 104 (56), 77 (36).
4-(4-Methoxyphenyl)-2-phenyl-6-(trichloromethyl)pyrimidine
(3l)
Mp 154–157 °C (CHCl3–MeOH, 5:1).
1H NMR (400 MHz, DMSO-d6): d = 3.89 (s, 3 H, OCH3), 7.16 (s, 1
H, H-5), 7.57–7.61, 8.33–8.57 (m, 9 H, C6H5).
13C NMR (100 MHz, DMSO-d6): d = 55.2 (OCH3), 96.0 (CCl3),
107.6 (C-5), 127.6, 127.9, 128.2, 128.8, 129.2, 131.2, 136.0, 162.3
(2 C6H5), 163.2 (C-6), 165.8 (C-4), 166.0 (C-2).
Anal. Calcd for C16H11ClN2O: C, 67.97; H, 3.92; N, 9.91. Found: C,
66.29; H, 3.99; N, 9.83.
2-Phenyl-6-(p-tolyl)pyrimidin-4(3H)-one (2k)
Mp 290–292 °C (CHCl3–MeOH, 5:1).
1H NMR (200 MHz, DMSO-d6): d = 2.38 (s, 3 H, CH3), 6.89 (s, 1
H, H-5), 7.31–7.63, 8.10–8.58 (m, 9 H, C6H5), 12.73 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 20.6 (CH3), 105.8 (C-5),
126.8, 127.8, 128.6, 128.9, 129.3, 131.5, 133.5, 140.3 (2 C6H5),
157.5 (C-2), 160.7 (C-6), 164.7 (C-4).
GC-MS (EI 70 eV): m/z (%) = 262 (M+, 100), 234 (25), 104 (29), 77
(26).
GC-MS (EI 70 eV): m/z (%) = 378 (M+, 100), 344 (31), 245 (22),
158 (68), 104 (47), 76 (17).
6-Ethoxy-5-methyl-2-phenyl-5,6-dehydropyrimidin-4(3H)-one
(4m)
Mp 120–124 °C (hexane–CHCl3, 1:3).
1H NMR (400 MHz, CDCl3): d = 1.30 (t, J = 7.2 Hz, 3 H, CH3), 1.32
(d, J = 7.2 Hz, 3 H, CH3), 2.59 (dq, J = 11.4, 7.2 Hz, 1 H, H-5), 3.66
(dq, J = 12.0, 7.2 Hz, 1 H, CH2), 4.17 (dq, J = 12.0, 6.8 Hz, 1 H,
CH2), 4.67 (d, J = 11.4 Hz, 1 H, H-6), 7.42–7.53, 7.89–7.90 (m, 5
H, C6H5), 9.36 (br s, 1 H, NH).
13C NMR (100 MHz, CDCl3): d = 10.3 (CH3), 15.0 (OCH2CH3),
39.6 (C-5), 63.2 (OCH2), 90.6 (C-6), 126.4, 128.6, 132.0, 132.9
(C6H5), 149.1 (C-2), 174.7 (C-4).
Anal. Calcd for C17H14N2O: C, 77.84; H, 5.38; N, 10.68. Found: C,
77.44; H, 5.51; N, 10.87.
6-(4-Methoxyphenyl)-2-phenylpyrimidin-4(3H)-one (2l)
Mp 251–258 °C (CHCl3–MeOH, 5:1).
1H NMR (200 MHz, DMSO-d6): d = 3.89 (s, 3 H, OCH3), 6.85 (s, 1
H, H-5), 7.05–7.64, 8.15–8.59 (m, 9 H, C6H5), 12.72 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 55.5 (OCH3), 107.9 (C-5),
114.5, 127.7, 128.1, 128.5, 129.5, 131.6, 136.2, 162.5 (2 C6H5),
163.3 (C-2), 165.4 (C-6), 166.2 (C-4).
GC-MS (EI 70 eV): m/z (%) = 278 (M+, 100), 235 (18), 104 (32), 77
(26).
GC-MS (EI 70 eV): m/z (%) = 232 (M+, 3), 203 (64), 104 (100), 77
(35).
Anal. Calcd for C13H16N2O2:C, 67.22; H, 6.94; N, 12.06. Found: C,
66.82; H, 6.54; N, 12.51.
4-(4-Bromophenyl)-2-phenyl-6-(trichloromethyl)pyrimidine
(3i)
Mp 162–165 °C (CHCl3–MeOH, 5:1).
1H NMR (400 MHz, DMSO-d6): d = 7.38 (s, 1 H, H-5), 7.61–7.82,
8.37–8.57 (m, 9 H, C6H5 + Ar).
13C NMR (100 MHz, DMSO-d6): d = 95.9 (CCl3), 109.0 (C-5),
125.9, 128.1, 128.9, 129.7, 130.5, 131.1, 132.1, 135.8 (2 C6H5),
163.4 (C-6), 165.4 (C-4), 166.6 (C-2).
3-Phenyl-5,6-dihydrofuro[2,3-d]pyrimidin-4(3H,4aH,7aH)-one
(4n)
Mp 132–135 °C (hexane–CHCl3, 1:3).
1H NMR (400 MHz, DMSO-d6): d = 1.94–2.09 (m, 2 H, H-5), 2.53–
2.61 (m, 1 H, H-4a), 4.03 (m, 2 H, H-6), 4.95 (d, J = 7.2 Hz, 1 H, H-
7a), 7.44–7.54, 7.86–7.88 (m, 5 H, C6H5), 10.72 (br s, 1 H, NH).
13C NMR (100 MHz, DMSO-d6): d = 21.8 (C-5), 43.9 (C-4a), 66.4
(C-6), 93.4 (C-7a), 127.3, 128.3, 131.2, 132.6 (C6H5), 151.9 (C-2),
172.2 (C-4).
GC-MS (EI 70 eV): m/z (%) = 426 (M+, 45), 394 (64), 247 (40), 208
(45), 127 (72), 104 (100), 76 (45).
GC-MS (EI 70 eV): m/z (%) = 214 (M+, 5), 188 (100), 160 (76), 104
(90), 77 (43).
4-(4-Chlorophenyl)-2-phenyl-6-(trichloromethyl)pyrimidine
(3j)
2-Phenyl-4a,5,6,7-tetrahydro-3H-pyrano[2,3-d]pyrimidin-
4(8aH)-one (4o)
Mp 181–185.5 °C (hexane–CHCl3, 1:3).
1H NMR (200 MHz, DMSO-d6): d = 1.46 (m, 2 H, H-6), 2.24 (m, 2
H, H-5), 3.47 (m, 1 H, H-4a), 3.97 (t, J = 11.2 Hz, 2 H, H-7), 4.67
(d, J = 12.4 Hz, 1 H, H-8a), 7.41–7.56, 7.86–7.90 (m, 5 H, C6H5),
10.81 (br s, 1 H, NH).
Mp 145–148 °C (CHCl3–MeOH, 5:1).
1H NMR (400 MHz,DMSO-d6): d = 6.90 (s, 1 H, H-5), 7.60–7.69,
8.45–8.58 (m, 9 H, C6H5).
Synthesis 2008, No. 3, 358–362 © Thieme Stuttgart · New York

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N. Zanatta et al.
PAPER
13C NMR (50 MHz, DMSO-d6): d = 22.2 (C-5), 24.7 (C-6), 41.2 (C-
4a), 66.2 (C-7), 89.2 (C-8a), 127.3, 128.3, 131.1, 132.6 (C6H5),
149.4 (C-2), 172.6 (C-4).
(5) (a) Katritzky, A. R.; Yousaf, T. I. Can. J. Chem. 1986, 64,
2087. (b) Hamper, B. C.; Gan, K. Z.; Owen, T. J.
Tetrahedron Lett. 1999, 40, 4973.
(6) Marsura, A.; Luu Duc, C. Synthesis 1982, 595.
(7) Kato, T.; Chiba, T.; Sasaki, M. Heterocycles 1981, 16, 577.
(8) Gallemaers, J.-P.; Christophe, D.; Promel, R. Tetrahedron
Lett. 1976, 693.
(9) Yamamoto, Y.; Ohnishi, S.; Azuma, Y. Chem. Pharm. Bull.
1983, 31, 1929.
GC-MS (EI 70 eV): m/z (%) = 230 (M+, 25), 201 (38), 173 (100),
104 (88), 77 (43), 55 (33).
Anal. Calcd for C13H14N2O2:C, 67.81; H, 6.13; N, 12.17. Found: C,
67.47; H, 6.20; N, 12.43.
6-(Bromomethyl)-2-phenylpyrimidin-4(3H)-one (2h); Typical
Procedure
(10) Hirai, Y.; Egawa, H.; Shoko, Y.; Yamazaki, T. Heterocycles
1983, 20, 1243.
Method C: To a stirred solution of benzamidine hydrochloride (0.16
g, 1.0 mmol) in anhyd THF (10 mL) kept in an ice-bath was added
NaH (36.0 mg, 1.5 mmol). To this mixture was added dropwise a
solution of the enone 1h (0.29 g, 1.0 mmol) in anhyd THF (1.0 mL)
through an addition funnel. After the addition, the water bath was
removed and the mixture was allowed to warm to r.t. and then re-
fluxed for 16 h. At the end of the reaction, the NaCl formed was fil-
tered off and the solvent was removed on a rotavapor to obtain a
brown solid. The product 2h was purified by recrystallization from
MeOH; yield: 0.16 g (60%); mp 132–135 °C (MeOH).
1H NMR (200 MHz, DMSO-d6): d = 4.47 (s, 2 H, CH2), 6.52 (s, 1
H, H-5), 7.48–7.63, 8.09–8.14 (m, 5 H, C6H5).
13C NMR (100 MHz, DMSO-d6): d = 62.2 (CH2), 109.8 (C-5),
127.8, 128.3, 131.6, 131.9 (C6H5), 157.5 (C-6), 163.9 (C-2), 167.1
(C-4).
(11) (a) Tice, C. M.; Bryman, L. M. Tetrahedron 2001, 57, 2689.
(b) Chang, L. C. W.; Spangersberg, R. F.; von Frijtag
Drabbe Künzel, J. K.; Mulder-Krieger, T.; van den Hout, G.;
Beukers, M. W.; Brussee, J.; Ijzerman, A. P. J. Med. Chem.
2004, 47, 6529.
(12) Hamper, B. C.; Gan, K. Z.; Owen, T. J. Tetrahedron Lett.
1999, 40, 4973.
(13) Colla, A.; Martins, M. A. P.; Clar, G.; Krimmer, S.; Fisher,
P. Synthesis 1991, 483.
(14) (a) Martins, M. A. P.; Siqueira, G. M.; Flores, A. F. C.; Clar,
G.; Zanatta, N. Quím. Nova 1994, 17, 24. (b) Martins, M.
A. P.; Bastos, G. P.; Bonacorso, H. G.; Zanatta, N.; Flores,
A. F. C.; Siqueira, G. M. Tetrahedron Lett. 1999, 40, 4309.
(15) Zanatta, N.; Barichello, R.; Pauletto, M.; Bonacorso, H. G.;
Martins, M. A. P. Tetrahedron Lett. 2003, 44, 961.
(16) Martins, M. A. P.; Pereira, C. M. P.; Beck, P.; Machado, P.;
Moura, S.; Teixeira, M. V. M.; Bonacorso, H. G.; Zanatta, N.
Tetrahedron Lett. 2003, 44, 6669.
GC-MS (EI 70eV): m/z (%) = 264 (M+, 59), 157 (29), 104 (100), 77
(38), 51 (21).
(17) Zanatta, N.; Faoro, D.; Silva, S. C.; Bonacorso, H. G.;
Martins, M. A. P. Tetrahedron Lett. 2004, 45, 5689.
(18) Martins, M. A. P.; Emmerich, D.; Beck, P.; Cunico, W.;
Pereira, C. M. P.; Sinhorin, A. P.; Brondani, S.; Peres, R. L.;
Teixeira, M. V. M.; Bonacorso, H. G.; Zanatta, N. Synth.
Commun. 2004, 34, 1915.
(19) Zanatta, N.; Flores, D. C.; Amaral, S. S.; Bonacorso, H. G.;
Martins, M. A. P.; Flores, A. F. C. Synlett 2005, 3079.
(20) Zanatta, N.; Flores, D. C.; Madruga, C. C.; Flores, A. F. C.;
Bonacorso, H. G.; Martins, M. A. P. Tetrahedron Lett. 2006,
47, 573.
Anal. Calcd for C11H9BrN2O: C, 49.84; H, 3.42; N, 10.57. Found:
C, 50.04; H, 3.53; N, 10.78.
Acknowledgment
The authors thank the financial support from the Fundação de
Apoio à Pesquisa do Estado do Rio Grande do Sul (FAPERGS) and
Conselho Nacional de Desenvolvimento Científico e Tecnológico
(CNPq - Universal grant No. 476634/06-7), and fellowships from
CAPES (to L. Fantinel and R. V. Lourega).
(21) Martins, M. A. P.; Cunico, W.; Pereira, C. M. P.; Sinhorin,
A. P.; Flores, A. F. C.; Bonacorso, H. G.; Zanatta, N. Curr.
Org. Synth. 2004, 1, 391.
References
(22) Zanatta, N.; Cortelini, M. F. M.; Carpes, M. J. S.; Bonacorso,
H. G.; Martins, M. A. P. J. Heterocycl. Chem. 1997, 34, 509.
(23) Zanatta, N.; Flores, D. C.; Madruga, C. C.; Flores, A. F. C.;
Bonacorso, H. G.; Martins, M. A. P. Tetrahedron Lett. 2006,
47, 573.
(24) Zanatta, N.; Fagundes, M. B.; Ellensohn, R.; Marques, M.;
Bonacorso, H. G.; Martins, M. A. P. J. Heterocycl. Chem.
1998, 35, 451.
(1) Murphy, R.; Kung, H. F.; Kung, M.; Billings, J. J. Med.
Chem. 1990, 33, 171.
(2) (a) Langtry, H. D.; Markham, A. Drugs 1999, 57, 967.
(b) Moreland, R. B.; Goldstein, I.; Kim, N. N.; Traish, A.
Trends Endocrinol. Metab. 1999, 44, 153.
(3) Akazome, M.; Kondo, T.; Watanabe, Y. J. Mol. Catal. 1993,
80, 383.
(4) Burdeska, K.; Fuhrer, H.; Kabas, G.; Siergrist, A. E. Helv.
Chim. Acta 1981, 64, 113.
(25) Zanatta, N.; Faoro, D.; Silva, S. C.; Bonacorso, H. G.;
Martins, M. A. P. Tetrahedron Lett. 2004, 45, 5689.
Synthesis 2008, No. 3, 358–362 © Thieme Stuttgart · New York