Heterocyclization of amidophenacylation products of uracil

Article abstract of DOI:10.1023/A:1025162619589

When uracil is reacted with benzoylamino(chloro)acetophenone, we obtain two amidophenacylation products depending on the condensation conditions. The first product contains an amidophenacyl moiety at the N¹ center, and in the second product two such moieties are located at the N¹ and N³ centers of the uracil. Treatment of these accessible uracil derivatives with phosphorus oxychloride, thionyl chloride, or phosphorus pentasulfide leads to cyclization of the amidophenacyl side group, which is used to synthesize a number of modified pyrimidine bases with 2,5-diphenyloxazole or 2,5-diphenylthiazole residues.

Full text of DOI:10.1023/A:1025162619589

Chemistry of Heterocyclic Compounds, Vol. 39, No. 5, 2003
HETEROCYCLIZATION OF AMIDO-
PHENACYLATION PRODUCTS OF URACIL
B. M. Khutova, S. V. Klyuchko, L. P. Prikazchikova, S. V. Iksanova, and B. S. Drach
When uracil is reacted with benzoylamino(chloro)acetophenone, we obtain two amidophenacylation
products depending on the condensation conditions. The first product contains an amidophenacyl
moiety at the N1 center, and in the second product two such moieties are located at the N1 and N3
centers of the uracil. Treatment of these accessible uracil derivatives with phosphorus oxychloride,
thionyl chloride, or phosphorus pentasulfide leads to cyclization of the amidophenacyl side group,
which is used to synthesize a number of modified pyrimidine bases with 2,5-diphenyloxazole or
2,5-diphenylthiazole residues.
Keywords: oxazole, thiazole, uracil, amidophenacylation, heterocyclization.
Reaction of uracil (1) with benzoylamino(chloro)acetophenone (2) at 0°C in the presence of sodium
hydroxide leads to formation of the N1-amidophenacylation product 3 [1]. Furthermore, at 20°C for a 1:2:2 mole
ratio of the indicated reagents, we obtain the N1,N3-di(amidophenacylation) product 4 in high yield. As we see
from the scheme, both these accessible uracil derivatives 3, 4 could be used to obtain a series of novel modified
pyrimidine bases 5-9 containing substituted azolyl moieties in the 1 position or in the 1 and 3 positions.
Thus when substrate 3 is treated with phosphorus oxychloride in DMF, the Vilsmeier reaction does not
occur but rather intermediate 5 is formed, which after hydrolysis is converted to 1-(2,5-diphenyloxazol-4-yl)-
uracil (6). The latter is not formed when we try to carry out heterocyclization in excess thionyl chloride; we note
that SOCl2 in the presence of POCl3 displays not only a condensing effect but also a chlorinating effect,
converting uracil 3 to a mixture of compounds 5 and 6 [2]. Furthermore, the reaction of substrate 4 with thionyl
chloride occurs without complications and leads to 1,3-bis(2,5-diphenyloxazol-4-yl)uracil (7).
The conversions 3 → 5 and 4 → 7 are special cases of the Robinson–Gabriel synthesis of substituted
1
oxazoles [3]. The occurrence of these cyclocondensations is supported by H NMR spectra, which allow us to
follow the disappearance of the resonance signals from the =CH–NH– moiety after treatment of substrates 3 and
4 with condensing agents.
Reactions of nucleophilic substitution of the chlorine atom in compound 5 are described below. The
halogen in the 4 position of compound 5 is rather mobile, as shown by the example of reactions with amines of
different basicity (5 → 8 conversions). It is quite possible that substrate 5 could also be used in condensations
with O- and S-nucleophiles.
And finally, we have shown that it is possible to obtain 1,3-bis(2,5-diphenylthiazol-4'-yl)-4-thiouracil
(9) when substrate 4 is reacted with phosphorus pentasulfide. Thionation is directed toward the 4 position, as is
supported by the shift of the signal from the (5-H) proton in compound 9 compared with compound 4.
Thionation does not occur at the 2 position of the ring, which is probably connected with steric factors.
__________________________________________________________________________________________
Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Kiev
02094; e-mail: Drach@bpci.kiev.ua. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5,
pp. 761-764, May, 2003. Original article submitted June 19, 2000.
660
0009-3122/03/3905-0660$25.00©2003 Plenum Publishing Corporation

Cl
Cl
O
PhCOCHNHCOPh,
2 PhCOCHNHCOPh,
2
NH
2
0
2 NaOH, 20 0C
NaOH, 0 C
O
N
H
1
Ph
O
N
O
O
N
O
O
POCl3/ DMF
NH
N
N
H
Ph
O
O
Ph
NH
Ph
NH
O
O
Ph
O
Ph
3
4
1. SOCl2 (excess)
2. H2O
SOCl2 (excess)
Ph
Cl
P2S5 (excess)
O
N
O
N
NH
O
H2O
N
O
N
O
N
Ph
N
N
N
O
N
Ph
Ph
Ph
Ph
O
5
O
6
Ph
Ph
O
7
1
2RR NH
Ph
N
S
S
1
N
RR
Ph
N
N
N
O
N
O
N
N
Ph
Ph
Ph
Ph
S
O
9
8a–e
a RR1N = MeNH, b RR1N = Et2N, c RR1N = PhNH,
1
1
RR N
e
=
O
RR N
d
=
,
N
N
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker WP-200 spectrometer (200 MHz) in DMSO-d6
solutions, internal standard TMS.
661

TABLE 1. Characteristics of Synthesized Compounds 4-9
Found, %
——————
Com-
pound
Empirical
formula
Calculated, %
mp, °С Yield, %
С
H
N
S
Cl
—
С34H26N4O6
C19H12ClN3O2
C19H13N3O3
C34H22N4O4
C20H16N4O2
C23H22N4O2
C25H18N4O2
C24H22N4O2
C23H20N4O3
C34H22N4OS3
69.87
69.62
4.38
4.47
9.48
9.55
—
196-197
249-252
304-306
293-295
262-263
241-243
265-268
228-229
239-240
236-237
79
58
97
61
41
38
83
67
81
83
4
65.08
3.54
11.97
9.91
5
—
—
—
—
—
—
—
—
65.24
3.46
12.01
10.15
68.99
68.88
4.02
3.95
12.36
12.68
6
—
—
—
—
—
—
—
—
74.08
4.09
10.23
7
74.17
4.03
10.18
70.04
69.75
4.78
4.68
15.93
16.27
8а
8b
8c
8d
8e
9
71.42
5.61
14.01
71.48
5.74
14.49
73.61
73.88
4.84
4.46
13.90
13.79
72.12
5.64
13.94
72.34
5.57
14.06
68.96
68.99
4.96
5.03
14.03
13.99
68.09
3.70
9.25
16.10
16.06
68.20
3.70
9.36
TABLE 2. Parameters of 1H NMR Spectra of Compounds 4-9
Chemical shifts, δ, ppm (J, Hz)
Com-
pound
5-Н (d, J, Hz)
6-H (d, J, Hz)
C6H5 (m)
Other signals
6.25 (8.3)
8.18 (8.3)
7.57-7.92 (20Н,
9.96 (1H, d, NH–CH,
J = 10.2); 10.13 (1H, d,
NH–CN, J = 10.2)
4
4С6Н5 + 2 CH–NH)
5.85 (8.3)
5.86 (8.3)
6.25 (8.3)
6.14 (8.3)
7.86 (8.3)
7.83 (8.3)
8.22 (8.3)
7.89 (8.3)
7.47-8.12 (10H, 2C6H5)
7.45-8.12 (10H, 2C6H5)
7.60-8.12 (20H, 4C6H5)
7.47-8.10 (10H, 2C6H5)
11.80 (1H, NH-uracil)
5
6
7
3.14 (3Н, d, CH3–NH,
J = 7.0); 8.00 (1H, m,
NH–CH3)
8a
6.21 (8.3)
7.81 (8.3)
7.46-8.08 (10H, 2C6H5)
1.15 (6H, t, CH3–CH2);
8b
3.49 (4H, m, CH2–CH3)
6.21 (8.3)
6.41 (8.2)
7.93 (8.3)
7.56 (8.2)
7.33-8.26 (15H, 3C6H5)
7.46-7.91 (10H, 2C6H5)
10.12 (1H, s, NH–Ph)
8c
8d
1.75 (6Н, m, C(CH2)3C);
3.60 (4Н, m, CH2NCH2)
6.43 (8.2)
6.40 (8.3)
7.95 (8.2)
8.32 (8.3)
7.60-8.11 (10H, 2C6H5)
7.47-7.98 (20H, 4C6H5)
3.68 (4Н, m, CH2NCH2);
3.83 (4Н, m, CH2OCH2)
8e
9
1,3-Di[(benzoylamino)phenacyl]uracil (4). Uracil (1.12 g, 10 mmol) was added to a solution of
sodium hydroxide (0.8 g, 20 mmol) in water (10 ml). Then after the uracil had dissolved, a solution of reagent 2
(5.48 g, 20 mmol) in dioxane (20 ml) was added at 20°C. The mixture was stirred for 2 h. The precipitate of
uracil 4 was washed with water (50 ml), dried in air, and recrystallized from acetonitrile (Table 1).
1-(2,5-Diphenyloxazol-4-yl)-4-chloropyrimidin-2(1H)-one (5). DMF (3 ml) was added dropwise at
10°C with stirring to POCl3 (10 ml). The mixture was stirred at that temperature for 0.5 h, and then compound 3
(3.5 g, 10 mmol) was added in small portions. The reaction mass was refluxed for 7 h; the solution was
662

evaporated down under a vacuum created by a water-jet pump, and absolute acetonitrile (3 ml) was added to the
oily residue. The precipitate of compound 5 was washed with absolute acetonitrile, dried in a vacuum desiccator
over P2O5, and recrystallized from absolute acetonitrile.
1-(2,5-Diphenyloxazol-4-yl)uracil (6). The reaction was carried out according to the procedure
described above. After refluxing for 7 h, the solution was cooled and poured over ice. The precipitate of uracil 6
was washed with water, dried in air, and recrystallized from dioxane.
1,3-Bis(2,5-diphenyloxazol-4-yl)uracil (7). A mixture of compound 4 (3 g, 5 mmol) and thionyl
chloride (20 ml, 250 mmol) was refluxed for 2 h. The solution was evaporated under a vacuum created by a
water-jet pump, the residue was triturated with acetonitrile (10 ml), the precipitate of uracil 7 formed was
washed with water, dried in air, and recrystallized from dioxane.
1-(2,5-Diphenyloxazol-4-yl)-4-RR'N-pyrimidin-2(1H)-ones (8a-e). A solution of the corresponding
amine (3.6 mmol) in absolute benzene (2 ml) was added dropwise to a solution of compound 5 (0.5 g, 1.2 mmol)
in absolute benzene (5 ml). The reaction mixture was stirred for 48 h at 20°C; the precipitate was filtered out,
washed with water, and dried in air. Compounds 8a,b were recrystallized from acetone; compound 8c was
recrystallized from dioxane; and compounds 8d,e were recrystallized from benzene.
1,3-Bis(2,5-diphenylthiazol-4-yl)-4-thiouracil (9). A mixture of compound 4 (3 g, 5 mmol), P2S5
(4.5 g, 20 mmol), and absolute dioxane (25 ml) was refluxed for 3 h. The hot solution was decanted from the
precipitate, the dioxane was evaporated under a vacuum created by a water-jet pump down to a volume of
2-3 ml, and 2-propanol (2-3 ml) was added. The mixture was heated to boiling, and after cooling a bright yellow
precipitate of thiouracil 9 was obtained which was filtered off, dried, and recrystallized from benzene.
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3.
B. M. Khutova, S. V. Klyuchko, and L. P. Prikazchikova, Khim. Geterotsikl. Soedin., 512 (1991).
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R. C. Elderfield, ed., Heterocyclic Compounds [Russian translation], Izdat. Inostr. Lit., Moscow (1961),
Vol. 5, p. 243.
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