Two directions of the reaction of 4-bromobenzaldehyde with substituted acetophenones and urea. Synthesis of aryl-substituted pyrimidin-2-one and hexahydropyrimido[4,5-d]pyrimidin-2,7-dione

Article abstract of DOI:10.1023/B:COHC.0000027891.72906.c7

Condensation of 4-bromobenzaldehyde, urea, and 4-alkyl-substituted acetophenones gave substituted hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7- diones or 1H-pyrimidin-2-ones, depending on the substituent on the acetophenone ring and the nature of the solvent (i-PrOH, BuOH, AcOH). The corresponding 5-bromopyrimidin-2-ones were formed on bromination of these compounds. The structures of these compounds were confirmed by IR, UV, and ¹H NMR spectroscopy.

Full text of DOI:10.1023/B:COHC.0000027891.72906.c7

Chemistry of Heterocyclic Compounds, Vol. 40, No. 2, 2004
TWO DIRECTIONS OF THE REACTION OF
4-BROMOBENZALDEHYDE WITH SUBSTITUTED
ACETOPHENONES AND UREA. SYNTHESIS OF
ARYL-SUBSTITUTED PYRIMIDIN-2-ONE AND
HEXAHYDROPYRIMIDO[4,5-d]PYRIMIDIN-2,7-DIONE
V. F. Sedova and O. P. Shkurko
Condensation of 4-bromobenzaldehyde, urea, and 4-alkyl-substituted acetophenones gave substituted
hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7-diones or 1H-pyrimidin-2-ones, depending on the
substituent on the acetophenone ring and the nature of the solvent (i-PrOH, BuOH, AcOH). The
corresponding 5-bromopyrimidin-2-ones were formed on bromination of these compounds. The
structures of these compounds were confirmed by IR, UV, and 1H NMR spectroscopy.
Keywords: 4-alkylacetophenones, aminopyrimidines, 4-bromoacetaldehyde, 5-bromo-1H-pyrimidin-2-
ones, hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7-diones, 4,6-diaryl-1H-pyrimidin-2-ones, chloro-
pyrimidines, bromination, condensation.
A revived interest in the Biginelli reaction – the three component condensation of aromatic aldehydes,
ureas, and carbonyl compounds (β-keto esters, β-diketones, etc.) – which permits the preparation of
hydrogenated pyrimidin-2-ones, among which are compounds with high biological activity [1-4], is the reason
for our continuation of the investigation of the modification of the Biginelli reaction using aromatic ketones. To
synthesize hydrogenated pyrimidin-2-ones [5] we used 4-bromobenzaldehyde (1) and a series of aromatic
ketones with the aim of preparing 4-bromophenyl derivatives of pyrimidin-2-one. Acetophenone (2a),
4-methylacetophenone (2b), and 4-butylacetophenone (2c)were chosen as the aromatic ketones.
Condensation of the aldehyde 1, acetophenone 2a, and urea in a mole ratio of 1:1:4 in 2-propanol in the
presence of concentrated HCl did not give the expected products 4-(4-bromophenyl)-6-phenyl-3,4-dihydro-1H-
pyrimidin-2-one (3a) or 4-(4-bromophenyl)-6-phenyl-1H-pyrimidin-2-one (4a). The product of the reaction
under these conditions was 4,5-bis(4-bromophenyl)-8a-phenyl-3,4,4a,5,6,8a-hexahydro-1H,8H-pyrimido[4,5-d]-
pyrimidin-2,7-dione (5) (scheme 1, Table 1). Its composition ans structure were confirmed by microanalysis, IR,
1
UV, and H NMR spectra. For example, two carbonyl stretching frequencies at 1695 and 1668 cm-1 were
observed in the IR spectrum and absorptions above 260 nm were absent from the UV spectrum. The latter
indicates the presence of unconjugated aromatic groups in the molecule. When the concentration of the solution
was increased and the ratio of the reactants change to 1.5:1:3 the pyrimidinone 4a (Table 1) was isolated from
the reaction mixture in addition to compound 5.
__________________________________________________________________________________________
N. N. Vorozhstsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian
Academy of Sciences, Novosibirsk 630090; e-mail: oshk@nioch.nsc.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 2, 229-238, February, 2004. Original article submitted July 6, 2001.
194
0009-3122/04/4002-0194©2004 Plenum Publishing Corporation

Scheme 1
C6H4Br-4
C H Br-
H
4
6
4
4-BrC6H4CHO
N
HN
1
i-PrOH
+
O
N
Ph
O
N
Ph
H
+
H
4-RC6H4COMe
H
4a
3a
2a–c
R = H
+
H
H
-BrH C
C H Br-
4
4
4
6
H
6
4
NH2CONH2
i-PrOH
HN
NH
+
R = Me, Bu
H
O
N
N
O
H
H
-4
C6H4Br
Ph
5
BuOH
N
6b
7
4a + 5 + 4-RC6H4COCH=CHC6H4Br-4 (6a)
+ (4-BrC6H4CH2NH)2CO (7)
+
+
(AcOH)
O
-4
C6H4Br
N
H
4b,c
2, 4, 6 a R = H, b R = Me, c R = Bu
When the reaction was carried out in butanol the yield of compound 4a increased, but the main product
remained the pyrimidopyrimidine 5 (Table 1). 4-Bromochalcone 6a was also isolated and the formation of
1
N,N'-bis(4-bromobenzyl)urea (7) was shown by H NMR spectroscopy. Increasing the reaction time led to
decrease in the yield of 5a and an increase in the yield of the chalcone 6a which may be associated with
hydrolytic decomposition of the pyrimidopyrimidine 5. It was shown that when compound 5 was boiled in
butanol containing concentrated HCl it was converted completely into the pyrimidine 4a and the chalcone 6a (cf.
[6]).
Condensation of compounds 1, 2a, and urea in acetic acid led to the preferential formation of the
pyrimidin-2-one 4a (Table 1). This compound was also obtained from the addition of urea to chalcone 6a in acid
catalysis conditions analogous to those reported in [7, 8].
The behavior of acetophenones 2b and 2c in the three component condensations differed from that of
acetophenone 2a. The reaction products obtained were, respectively 4-(4-bromophenyl)-6-(4-tolyl)-1H-
pyrimidin-2-one (4b) and 4-(4-bromophenyl)-6-(4-butylphenyl)-1H-pyrimidin-2-one (4c), together with
disubstituted ureas 7 and the chalcone (6b) (see Scheme 1) (Table 1, experiments 6-8). Pyrimidopyrimidines
analogous to compound 5 were not isolated from these experiments.
TABLE 1. Condensation of 4-Bromobenzaldehyde (1) with Acetophenones
(2) and Urea (U)
Reaction conditions
Reaction Reagent ratio
Reaction products and yields, %
Expe- Aceto-
riment phenone
Medium
4
5
6
7
time, h
1 : 2 : U
1
2
2a
2a
2a
2a
2a
2b
2c
2c
i-PrOH/HCl
i-PrOH/HCl
BuOH/HCl
BuOH/HCl
AcOH/HCl
i-PrOH/HCl
i-PrOH/HCl
BuOH/HCl
6
6
1 : 1 : 4
1.5 : 1 : 3
1.5 : 1 : 3
1.5 : 1 : 3
1.5 : 1 : 3
1.5 : 1 : 3
1.5 : 1 : 3
1.5 : 1 : 3
—
63
49
42
25
5
—
—
13 (4a)
21 (4a)
17 (4a)
34 (4a)
48 (4b)
15 (4c)
25 (4c)
3
4
5
6
7
8
6
16 (6a)
23 (6a)
4 (6a)
10 (6b)
—
14
5
7
21
7
8
—
—
—
6
6
—
10
195

A scheme for this reaction can be proposed in agreement with data from [5, 9]. In the first stage an acid
catalysed condensation of the aldehyde with urea occurs to give an intermediate immonium ion. This ion reacts
further with the acetophenones to give an open chain intermediate which cyclizes stepwise into the
dihydropyrimidinones 3 (Scheme 2).
Scheme 2
+
4-BrC6H4CHNHCONH2
+
ArCOMe
H
+
1 + NH2CONH2
4-BrC6H4CH=NHCONH2
4-BrC6H4
H2NCONHCHC6H4Br-4
ArCOCH
ArCOCH2CH
H2NCONH
H2NCONHCHC6H4Br-4
[O]
4
3
5
Depending on the reaction conditions and the increased reactivity of the immonium ion and the
relatively low reactivity of the carbonyl groups in the intermediates diureidoalkylation may occur at the same
time as formation of compound 3 with subsequent cyclization to the pyrimidopyrimidines 5. During the reaction
the immonium ion is the hydrogen acceptor for the dehydrogenation of the dihydropyrimidinones 3 which are
converted in this way into the substituted benzyl- or dibenzylureas 7 [10].
Scheme 3
'
C6H4R -4
'
C6H4R -4
Br
N
Br2 / AcOH
N
O
N
H
R"
O
N
R"
H
8a,b,c
4a,d,e
Br2 / AcOH
4a
8a
+
25 oC
H
H
H
-BrH C
C H Br-
4
4
4
6
6
4
HN
NH
O
N
H
Ph
5
N
O
H
Br2 / AcOH
120 oC
8a
4a, 8a R' = Br, R" = Ph; 4d, 8b R' = H, R" = Ph; 4e, 8c R' = R" = H
196

TABLE 2. Characteristics of the Compounds Synthesized
Found, %
Calculated, %
——————
Empirical
Compound
mp, °С
Yield, %
formula
(solvent)
C
3
H
4
Br (Cl)
5
N
6
[M]+*, m/z
1
2
C16H11BrN2O
C17H13BrN2O
C20H19BrN2O
C24H20Br2N4O2
C16H13BrO
7
8
9
4а
4b
4c
5
58.44
58.73
3.40
3.39
24.30
24.43
8.42
8.56
326.0055
326.0055
272-275
(EtOH–dioxane)
34
47
25
63
23
21
55
57
59.98
59.83
3.76
3.84
23.50
23.42
8.49
8.21
340.0199
340.0212
335-337
(EtOH–DMF)
310-312
(EtOH–DMF)
62.57
62.67
4.86
4.99
20.40
20.85
7.19
7.31
382.0675
382.0681
51.42
51.82
3.71
3.62
29.30
28.73
9.77
10.07
*
327-329
(80% AcOH)
6b
7
62.97
63.80
4.40
4.35
27.60
26.53
—
300.0
300.0
157-159
(EtOH)
265–267 [14]
(EtOH)
C15H14Br2N2O
C16H10Br2N2O
C16H11BrN2O
45.52
45.25
3.52
3.54
39.90
40.15
6.79
7.04
395.9499
395.9474
8a
8d
47.47
47.32
2.69
2.48
39.06
39.35
6.36
6.90
403.9185
403.9161
268-272
(EtOH–dioxane)
58.43
58.73
3.44
3.39
25.10
24.43
8.79
8.56
326.0066
326.0055
246-251
(EtOH)

TABLE 2 (continued)
1
2
C10H7BrN2O
C16H10BrClN2
C17H12BrClN2
C20H18BrClN2
C16H9Br2ClN2
C21H20BrN3
3
4
5
6
7
8
9
8e
47.35
47.83
2.74
2.81
32.00
31.83
10.82
11.16
249.9741
249.9742
207-211
(EtOH)
68
74
68
50
70
75
94
88
80
9a
55.67
55.59
2.83
2.92
(10.00)
(10.26)
8.01
8.11
343.9715
343.9716
154-155
(EtOH)
9b
56.96
56.77
3.33
3.36
(10.08)
(9.86)
7.68
7.79
357.9873
357.9873
156-159
(EtOH)
9c
60.10
59.79
4.61
4.51
(9.02)
(8.82)
6.99
6.97
400.0343
400.0342
74-76
(EtOH)
205-207
(EtOH)
9d
45.74
45.26
2.37
2.14
(8.20)
(8.35)
6.40
6.60
421.8818
421.8822
10a
10b
10c
10d
64.32
63.96
5.18
5.11
20.99
20.27
10.80
10.66
393.0837
393.0841
159-161
(EtOH)
C22H22BrN3
64.08
64.71
5.28
5.43
19.20
19.57
10.42
10.29
407.0989
407.0997
178-180
(EtOH)
112-113
(EtOH)
C25H28BrN3
67.16
66.66
6.19
6.26
17.40
17.74
9.46
9.33
449.1474
449.1467
C21H19Br2N3
53.31
53.30
4.07
4.05
33.90
33.76
8.85
8.88
470.9939
470.9947
170-174
(EtOH)
_______
* High resolution mass spectra, except for compound 6b. In addition to [M+] (m/z 554), compound 5 gave a fragment ion
(m/z 327.0113), calculated for C16H12BrN2O [ M - BrC6H4CH=NHCONH2]+ m/z 327.0133.

Bromination of pyrimidine derivatives at position 5 of the ring occurred readily in the presence of donor
substituents [11]. An example of bromination of unsubstituted pyrimidin-2-one is known [12]. It was shown that
preliminary covalent hydration facilitated bromination. There are no reports of the behavior of aryl-substituted
pyrimidin-2-ones in the literature.
We have established that ready bromination of aryl-substituted pyrimidinones is a general phenomenon.
For example, 4,6-diphenyl- (4d) and 4-phenyl-1H-pyrimidin-2-ones (4e) are brominated to give the
corresponding 5-bromoderivatives 8b and 8c (Scheme 3).
Compound 5 underwent no change on treatment with bromine in chloroform. It appeared to be unstable
to bromination in acetic acid and two products which appeared to be aryl-substituted pyrimidin-2-ones were
isolated from the reaction mixture. One of these was compound 4a while the second was the product of
bromination of 4a which was confirmed by bromination of 4a. The structure 5-bromo-4-(4-bromophenyl)-6-
phenyl-1H-pyrimidin-2-one (8a) was assigned to this compound on the basis of its 1H and 13C NMR spectra. The
13
signal of the carbon atom C(5)–Br of the pyrimidine ring was observed to strong field at 101.59 ppm in the C
NMR spectrum.
The 4,6-diaryl-5R'-2-chloropyrimidines 9a-d were obtained by treatment of compounds 4a-c and 8a
with POCl3. Compounds 9a-d were converted into the 4,6-diaryl-5'-2-piperidinopyrimidines 10a-d by
nucleophilic substitution with piperidine (Scheme 4).
Scheme 4
BrC H
4-
BrC H
4-
BrC H
4-
6
4
6
4
6
4
N
N
N
N
R'
O
R'
Cl
R'
N
N
H
N
H
4-RC6H4
4a–c, 8a
RC H
4-
RC H
4-
6
4
6
4
9a–d
10a–d
9a, 10a R = R' = H, 9b,10b R = Me, R' = H, 9c, 10c R= Bu, R' = H; 9d, 10d R= H, R' = Br
We have shown that acetophenone and its 4-alkyl-substituted analogs behave differently in condensation
with 4-bromobenzaldehyde and urea. It has been established that bromination of aryl-substituted pyrimidin-2-
ones with bromine in acetic acid occurs readily and identically to give the corresponding 5-bromopyrimidin-2-
ones.
TABLE 3. Spectroscopic Characteristics of the Compounds Synthesized
IR
UV spectrum
(EtOH),
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz) in CF3COOH
spectrum,
ν
С=О, cm-1
2
λ
max, nm (log ε)
1
4а
3
4
1625
1618
278.6 (4.062), 7.74 (1H, s, C(5)–H); 7.87 (2H, d, J = 8.0, o,o'-H, p-BrC6H4);
348.4 (3.994) 8.02 (5H, s, Ph); 8.16 (2H, d, J = 8.0, m,m'-H, p-BrC6H4)
4b
7.6 (3.928),
2.66 (3H, s, CH3); 7.70 (2H, d, J = 8.0, o,o'-H, p-BrC6H4);
349.9 (3.880) 7.77 (1H, s, C(5)–H); 8.02 (4H, s, p-CH3C6H4);
8.12 (2H, d, J = 8.0, m,m'-H, p-BrC6H4)
4c
1615
7.1 (4.310),
1.08 (3H, t, J = 7.0, CH3); 1.56 (2H, m, CH2);
349.4 (4.272) 1.83 (2H, m, CH2); 2.95 (2H, t, J = 8.0, CH2);
7.72 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.78 (1H, s, C(5)–H);
7.96-8.10 (4H, m, p-C4H9C6H4); 8.15 (2H, d,
J = 8.0, m,m'-H, p-BrC6H4)
199

TABLE 3 (continued)
1
2
3
4
5*
1695,
1668
253.5 (3.336) 2.91 (1H, t, J = 6.0, ArCH–CH–CHAr); 4.21 (2H, d,
J = 6.0, Ar–CH–); 6.76 (2H, s, 2NH); 6.94 (4H, d, J = 8.5,
o,o'-H, 2p-BrC6H4); 6.99–7.01 (5H, m, m,m'-H,
p-H, C6H5, NH); 7.11-7.19 (2H, m, o,o'-H, C6H5);
7.27 (4H, d, J = 8.5, m,m'-H, 2p-BrC6H4)
6b
7
1658
225 (3.436),
317 (3.700)
2.56 (3H, s, CH3); 7.48 (2H, d, J = 8.0, o,o'-H, p-BrC6H4);
7.58-7.76 (5H, m, p-CH3C6H4, –COCH=CH–);
7.97 (1H, d, J = 15.0, –COCH=CH–); 8.01 (2H, d, J = 8.0,
m,m'-H, p-BrC6H4)
1665
1675
261 (3.070),
270 (3.070),
276 (2.861)
4.55 (4H, s, 2CH2); 7.16 (4H, d, J = 8.0, o,o'-H, 2p-BrC6H4);
7.56 (4H, d, J = 8.0, m,m'-H, 2p-BrC6H4)
8a*2
248 (4.062),
343 (3.725)
7.95 (2H, d, J = 8.0, o,o'-H, p-BrC6H4);
7.94 (2H, d, J = 7.5, o,o'-H, C6H5);
7.83 (2H, d, J = 8.0, m,m'-H, p-BrC6H4);
7.74-7.94 (3H, m, m,m'-H, p-H, C6H5)
8d
8e
9a
1668
1662
—
244 (4.110),
345 (3.844)
7.75-7.97 (6H, m, m,m'-H, p-H, 2C6H5);
7.99 (4H, d, J = 8.0, o,o'-H, 2C6H5)
228 (4.045),
338 (3.616)
257 (4.395),
313 (4.410)
7.76-7.96 (3H, m, m,m'-H, p-H, C6H5);
8.00 (2H, d, J = 8.0, o,o'-H, C6H5); 9.09 (1H, s, C(6)–H)
7.83 (2H, d, J = 7.0, o,o'-H, p-BrC6H4); 7.90–8.10 (3H, m,
m,m'-H, p-H, C6H5); 8.22 (2H, d, J = 7.0, m,m'-H, p-BrC6H4);
8.26 (2H, d, J = 8.0, o,o'-H, C6H5); 8.57 (1H, s, C(5)–H)
9b
9c
—
—
261 (4.075),
285 (3.994),
316 (4.125)
2.62 (3H, s, CH3); 7.63 (2H, d, J = 8.0, o,o'-H, p-BrC6H4);
7.93 (2H, d, J = 8.5, o,o'-H, p-CH3C6H4); 8.13 (2H, d,
J = 8.0, m,m'-H, p-BrC6H4); 8.23 (2H, d, J=8.5,
m,m'-H, p-CH3C6H4); 8.51 (1H, s, C(5)–H)
262 (4.376),
285 (4.298),
317 (4.420)
1.09 (3H, t, J = 7.0, CH3); 1.56 (2H, m, CH2);
1.83 (2H, m, CH2); 2.91 (2H, t, J = 8.0, CH2);
7.67 (2H, d, J = 8.0, o,o'-H, p-BrC6H4);
7.93 (2H, d, J = 8.5, o,o'-H, p-C4H9C6H4);
8.18 (2H, d, J = 8.0, m,m'-H, p-BrC6H4);
8.25 (2H, d, J = 8.5, m,m'-H, p-C4H9C6H4);
8.54 (1H, s, C(5)–H)
7.68-7.83 (3H, m, m,m'-H, p-H, C6H5); 7.86 (4H, s,
o,o'-H, m,m'-H, p-BrC6H4); 7.87 (2H, d,
J = 8.0, o,o'-H, C6H5)
1.98 (6H, s, 3CH2); 4.17 (4H, s, 2CH2); 7.58 (1H, s, C(5)–H);
7.74 (2H, d, J = 7.5, o,o'-H, p-BrC6H4);
7.75-7.91 (3H, m, m,m'-H, p-H, C6H5); 8.00 (2H, d,
J = 7.5, m,m'-H, p-BrC6H4); 8.08 (2H, d,
J = 8.0, o,o'-H, C6H5)
9d*2
—
—
256 (4.243),
304 (4.130)
10a
229 (4.527),
270 (4.660),
366 (3.855)
10b
10c
—
—
232 (4.399),
270 (4.453),
366 (3.710)
1.98 (6H, s, 3CH2); 2.58 (3H, s, CH3); 4.16 (4H, s, 2CH2);
7.48 (2H, d, J = 8.0, o,o'-H, p-BrC6H4); 7.57 (1H, s, C(5)–H);
7.73 (2H, d, J = 8.5, o,o'-H, p-CH3C6H4);
8.02 (2H, d, J = 8.0, m,m'-H, p-BrC6H4); 8.17 (2H, d,
J = 8.5, m,m'-H, p-CH3C6H4)
232 (4.466),
267 (4.560),
366 (3.854)
1.07 (3H, t, J = 7.5, CH3); 1.52 (2H, m, CH2);
1.77 (2H, m, CH2); 1.99 (6H, с, 3CH2);
2.88 (2H, t, J = 8.0, CH2); 4.18 (4H, с, 2CH2);
7.57 (1H, s, C(5)–H); 7.58 (2H, d, J = 8.0, o,o'-H,
p-BrC6H4); 7.84 (2H, d, J = 8.5, o,o'-H, p-C4H9C6H4);
7.93 (2H, d, J = 8.0, m,m'-H, p-BrC6H4); 8.08 (2H, d,
J = 8.5, m,m'-H, p-C4H9C6H4)
10d
—
267 (4.535),
360 (3.667)
1.94 (6H, s, 3CH2); 4.08 (4H, s, 2CH2);
7.63-7.76 (4H, m, C6H4); 7.76-7.98 (5H, m, C6H4)
_______
* 1H NMR spectrum recorded in DMSO-d6.
*2 1H NMR spectrum at 400.13 MHz.
200

EXPERIMENTAL
IR spectra of the compounds synthesized were recorded in KBr disks on a Bruker Vector 22
spectrophotometer. UV spectra of ethanol solutions were recorded on Specord M-40 spectrophotometer. Mass
1
spectra were recorded with a Finnigan MAT-8200 by direct insertion of samples into the ion source. H NMR
spectra in trifluoroacetic acid with CH2Cl2 as internal standard (5.32 ppm) were recorded on Bruker AC-200
(200 MHz) and Bruker WP-200 SY (200 MHz) instruments. The spectra of compounds 8a and 8d were recorded
with a Bruker AM-400 (400 MHz) instrument. The 13C NMR spectrum of compound 8a in DMSO-d6 was
recorded on a Bruker AM-400 spectrometer (100 MHz). The course of reactions and the purity of the
compounds obtained were monitored by TLC on Silufol UV-254 strips with CHCl3 as eluent. Data for new
compounds are cited in Tables 2 and 3.
4,5-Bis(4-bromophenyl-8a-phenyl-3,4,4q,5,6,8-hexahydro-1H,8H-pyrimido[4,5-d]pyrimidin-2,7-dione
(5) and 4-(-bromophenyl)-6-phenyl-1H-pyrimidin-2-one (4a). 4-Bromobenzaldehyde (9.2 g, 50 mmol) was
added to a solution of urea (9.0 g, 150 mmol) in 2-propanol (70 ml) and conc. HCl (5 ml). The reaction mixture
was stirred and kept at room temperature overnight. A voluminous precipitate formed. Acetophenone (6.0 g,
50 mmol) was added to the reaction mixture which was boiled for 3 h, more urea (3.0 g, 50 mmol) was added
and boiling was continued for 3 h. The precipitate was removed after cooling, and was washed successively with
methanol, NaHCO3 solution, water, and ethanol, and then dried to give the pyrimidopyrimidine 5 (6.9 g). A
further amount of 5 (1.85 g) was obtained by dilution of the filtrate with methanol or ethanol. Overall yield
8.75 g (63%) (experiment 1, Table 1).
Experiments 2-4 were carried out analogously. In experiment 2 treatment of the filtrate with ethanol
gave compound 4a (2.5 g, 13%). In experiments 3 and 4 the precipitate consisted of a mixture of compounds 4a,
5, and 6a. The precipitate was boiled with methanol (75 ml) and filtered. A precipitate of 4-bromochalcone 6a,
mp 127-129°C [13], was formed from the filtrate. An additional quantity of the chalcone was precipitated from
the methanol filtrate with water. The solid which did not dissolve in methanol was heated with 2:1 ethanol–
dioxane (50 ml) and filtered. The pyrimidine 4a precipitated from the filtrate. The insoluble residue was
dissolved on boiling in 1:2 ethanol–acetic acid. The precipitate which formed on cooling was filtered off, washed
with NaHCO3 solution, water, and ethanol, then dried to give compound 5. More 5 can be obtained by adding an
equal volume of ethanol to the filtrate.
When the reaction was carried out in acetic acid (experiment 5), the precipitate obtained was substituted
dibenzylurea 7. The precipitate obtained by addition of an equal volume of methanol to the filtrate was filtered
off and washed with methanol to give pyrimidine 4a. Water (150 ml) was added to the filtrate, the precipitate
which formed was separated, boiled with ethanol and filtered. Chalcone 6a precipitated from the ethanol filtrate.
The residue insoluble in ethanol was a mixture of compounds 5 and 7 according to the 1H NMR spectrum
4-4-Bromophenyl)-6-phenyl-1H-pyrimidinone (4a). A. A mixture of 4-bromochalcone 6a (4.6 g,
16 mmol) and urea (3.0 g, 50 mmol) in 2-propanol (30 ml) and conc. HCl (5 ml) was boiled for 7.5 h. The
precipitate was filtered off, washed with ethanol, NaHCO3 solution, water, and again with ethanol to give
pyrimidine 4a (3.0 g, 49%).
B. Compound 5 (10.0 g, 18 mmol) was boiled in butanol (60 ml) and conc. HCl (10 ml) for 13 h. The
precipitate was filtered off and washed with water to give chalcone 6a (1.1 g). Methanol (100 ml) was added to
the filtrate and further chalcone (1.2 g) precipitated. Overall yield of chalcone 6a 45%. Pyrimidine 4a (2.6 g,
44%) precipitated on addition of water (150 ml) to the methanol filtrate.
4-(4-Bromophenyl)-6-(4-tolyl)-1H-pyrimidin-2-one (4b). The reaction was carried out analogously to
experiments 1 and 2 above. A mixture (12.8 g) of pyrimidine 4b, chalcone 6b, and urea 7 (63:13:24 from
1H NMR spectroscopic data) was obtained. The residue was boiled in ethanol (50 ml) and filtered. Chalcone 6b
separated from the filtrate. Crystallization of the insoluble residue from a mixture of ethanol and DMF gave the
pyrimidine 4b.
201

4-(4-Bromophenyl)-6-(4-butylphenyl)-1H-pyrimidin-2-one (4c) was prepared analogously to
compound 4b (experiments 7 and 8, Table 1).
Bromination of Compound 5. A. Bromine (10.4 g, 65 mmol) was added dropwise to a solution of
compound 5 (18.0 g, 320 mmol) in acetic acid (90 ml) and the mixture was stirred for 8 h at room temperature.
The reaction mixture was evaporated, methanol (100 ml) and pyridine (20 ml) added, the mixture boiled for 1 h,
cooled, the precipitate filtered off and washed with water and methanol to give pyrimidine 4a (6.8 g).
An equal volume of water was added to the filtrate. The precipitate was filtered off and washed with
ethanol to give 5-bromo-4-(4-bromophenyl)-6-phenyl-1H-pyrimidin-2-one (8a) (3.0 g, 24%). 13C NMR
(100.61 MHz), DMSO-d , δ, ppm: 101.59 (C(5)), 122.44 (C-Br, C6H4Br), 127.44 (Cm,m',C6H5), 128.52 (Co,o',
6
C6H5) 128.85 (Cp, C6H5), 130.52, 130.71 (Co,o, Cm,m', C6H4Br), 137.93 (Ci, C6H4Br), 138.66 (Ci, C6H5), 158.82
(C(4)), 164.86 (C(6)), 166.16 (C=O).
B. The reaction mixture obtained by adding bromine to compound 5 in acetic acid, as in the preceding
experiment, was boiled for 0.5 h and treated analogously to give compound 8a (7.1 g, 55%).
5-Bromo-4,6-diphenyl-1H-pyrimidin-2-one (8b). A solution of bromine (0.8 g, 5 mmol) in acetic acid
(5 ml) was added to a solution of compound 4d (1.0 g, 4 mmol) in acetic acid (10 ml). A precipitate formed in
1-2 min. The mixture was boiled for 1 h, cooled, and the precipitate was filtered off. Methanol (15 ml) and
pyridine (1 ml) were added to the residue, the mixture was heated for 15 min, cooled, and 10% HCl added until
the solution was acidic. The precipitate was filtered off, washed with water and dried to give pyrimidine 8d (0.75 g).
Compounds 8a and 8c were made analogously.
2-Chloro-4-(4-bromophenyl)-6-phenylpyrimidine (9a). A mixture of pyrimidine 4a (21.0 g, 64 mmol)
and POCl3 (75 ml) was boiled for 4h, the excess of POCl3 was evaporated in vacuum, the residue was poured
onto ice, triturated, and kept for several hours at room temperature. The precipitate was filtered off, washed with
NaHCO3 solution and water to give chloropyrimidine 9a (16.4 g, 74%).
Compounds 9b,c, and d were made analogously.
4-(4-Bromophenyl)-6-phenyl-2-piperidinopyrimidine (10a). A mixture of chloropyrimidine 9a (1.0 g,
2.9 mmol), piperidine (0.8 g, 9.0 mmol), and ethanol (10 ml) was boiled for 5 h, the precipitate was filtered off
and washed with water and ethanol to give compound 10a (0.85 g, 75%).
Compounds 10b, c, and d were prepared analogously.
REFERENCES
1.
2.
3.
4.
C. O. Kappe, Molecules, 3, 1 (1998).
C. O. Kappe, Acc. Chem. Res., 33, 879 (2000).
C. O. Kappe, K. Peters, and E.-M. Peters, J. Org. Chem., 62, 3109 (1997).
D. Nagarathnam, G. Chiu, T. G. Dhar, W. C. Wong, M. R. Marzabadi, C. Gluchowski, B. Lagu,
S. Miao, PCT Int. Appl. WO 96 14846; Chem. Abstr., 125, 142759 (1996).
V. P. Mamaev and V. F. Sedova, Izv. SO AN SSSR. Ser. Khim. Nauk, No. 3, 87 (1969).
V. F. Sedova and V. P. Mamaev, Khim. Geterotsikl. Soed., 691 (1970).
G. Zigeuner, W. Nischk, and B. Juraczovits, Monatsh., B97, 1611 (1966).
G. Zigeuner, M. Rauer, F. Paltauf, and E. Fuchs, Monatsh., B98, 22 (1967).
C. O. Kappe, J. Org. Chem., 62, 7201 (1997).
5.
6.
7.
8.
9.
10.
V. F. Sedova, V. A. Samsonov, and V. P. Mamaev, Izv. SO AN SSSR. Ser. Khim. Nauk, No. 2, 112
(1972).
11.
12.
13.
14.
D. J. Brown, The Pyrimidines. Wiley, N.Y. (1994), p. 349.
O. S. Tee and S. Banerjee, J. Chem. Soc., Chem. Commun., 1032 (1972).
W. B. Black and R. E. Lutz, J. Am. Chem. Soc., 77, 5134 (1955).
A. Bakibaev, Zhur. Org. Khim., 30, 1684 (1994).
202