1
196
Russ.Chem.Bull., Int.Ed., Vol. 52, No. 5, May, 2003
Prokhorov et al.
from the spinꢀspin coupling between the protons in posiꢀ
tions 5 and 6 of the pyrimidine ring in their H NMR
the case of cyanamide, the suggested addition of its nuꢀ
cleophilic amino group at position 2 of a pyrimidine
1ꢀoxide is followed by cyclization and subsequent openꢀ
ing of the oxadiazole ring. The aforesaid reactions can be
considered to be a convenient approach to the synthesis
of aminopyrimidines.
1
spectra (J = 4.9—5.3 Hz).
1
Previous results allowed one to suggest that in this
case, nucleophilic substitution of the cyanamide residue
for a hydrogen atom in a pyrimidine Nꢀoxide is followed
by the hydrolysis of the cyano group. However, the same
reaction products were obtained in the absence of traces
of water. In addition, 2ꢀcyanoaminopyrimidines are
Experimental
2
1H NMR spectra were recorded on a Bruker WMꢀ250 specꢀ
trometer (250.13 MHz) in DMSOꢀd with Me Si as the internal
known to be resistant to hydrolysis both under acidic and
basic conditions. Apparently, the O atom in the urea resiꢀ
due of compounds 2a—c comes from the Nꢀoxide group
of the substrate.
6
4
standard. Mass spectra were recorded on a Varian MATꢀ311A
instrument. The starting 4ꢀarylpyrimidine 1ꢀoxides 1 were preꢀ
1
0
pared according to the known procedure.
On the one hand, this can be due to dipolar cycloaddiꢀ
tion with pyrimidine 1ꢀoxides 1a—c as dipoles and cyanaꢀ
mide as a dipolarophile. This process seemed to be quite
possible because cyanamide can react with, e.g., 1,2,4ꢀtriꢀ
Synthesis of 2ꢀureidopyrimidines 2a—c (general procedure).
Gaseous dry HCl (0.1 mol) was passed through a mixture of
cyanamide (0.19 g, 4.5 mmol) and a corresponding 4ꢀarylꢀ
pyrimidine 1ꢀoxide 1 (3 mmol) in 40 mL of CHCl . Then the
3
3
,4
azines to give [4+2]ꢀcycloadducts. It is also known that
dipolar 1,3ꢀcycloaddition of pyrimidine 1ꢀoxides (through
the Nꢀoxide group) to such dipolarophiles as phenyl isoꢀ
cyanate and dimethyl acetylenedicarboxylate6 yields
reaction mixture was refluxed for 15 min. The precipitate that
formed was filtered off, washed with CHCl , and recrystallized
3
from EtOH.
5
4
ꢀPhenylꢀ2ꢀureidopyrimidine (2a). Yield 365 mg (57%),
m.p. 221—223 °C. Found (%): C, 61.48; H, 4.89; N, 25.95.
2
ꢀanilineꢀ and 2ꢀmethoxycarbonylmethylpyridines, reꢀ
spectively.
On the other hand, the in situ protonation of pyrimiꢀ
C H N O. Calculated (%): C, 61.67; H, 4.71; N, 26.15.
1
1
10
4
1
H NMR, δ: 7.06, 8.55 (both br.s, 1 H each, NH ); 7.51 (m,
2
4
5
H, Ph, H(5)); 8.07 (m, 2 H, Ph); 8.59 (d, 1 H, H(6), J =
.2 Hz); 9.42 (s, 1 H, NH). MS, m/z: 214 [M] .
dine 1ꢀoxides 1a—c makes the substrate significantly more
electrophilic, which facilitates, to a large extent, the addiꢀ
tion of a nucleophile to give intermediate σꢀadducts A.
A subsequent intramolecular nucleophilic attack of the
Nꢀhydroxy group on the C atom of the nitrile group afꢀ
fords cyclic intermediate B (see Scheme 1). This step can
also be facilitated in the presence of HCl by analogy with
the wellꢀknown formation of imino esters in reactions of
nitriles with alcohols. A similar route was proposed for
reactions of 1,2,4ꢀtriazine 4ꢀoxides with benzoylacetone.7
It is worth noting that both pathways proposed should
proceed via formation of the same intermediate cycloꢀ
adduct B, which undergoes the opening of its 1,2,4ꢀoxaꢀ
diazole ring to give products 2 (see Scheme 1). This proꢀ
cess is analogous to aromatization of σꢀadducts in reacꢀ
tions of azine Nꢀoxides with nucleophiles as a result of
elimination of a carboxylic acid molecule following the
+
4
ꢀ(4ꢀChlorophenyl)ꢀ2ꢀureidopyrimidine (2b). Yield 485 mg
65%), m.p. 255—257 °C. Found (%): C, 53.08; H, 3.59;
N, 22.49. C H ClN O. Calculated (%): C, 53.13; H, 3.65;
(
1
1
9
4
1
N, 22.53. H NMR, δ: 7.18, 8.48 (both br.s, 1 H each, NH );
2
7
1
.65 (m, 3 H, H arom., H(5)); 8.13 (m, 2 H, H arom.); 8.65 (d,
H, H(6), J = 5.2 Hz); 9.72 (s, 1 H, NH).
4
ꢀTolylꢀ2ꢀureidopyrimidine (2c). Yield 405 mg (59%),
m.p. 252—253 °C. Found (%): C, 63.10; H, 5.43, N, 24.41.
C H N O. Calculated (%): C, 63.15; H, 5.30; N, 24.55.
12
12
4
1
H NMR, δ: 2.39 (s, 3 H, Me); 7.18, 8.47 (both br.s, 1 H each,
NH ); 7.39 (d, 2 H, H arom.); 7.62 (d, 1 H, H(5), J = 5.3 Hz);
2
8
.04 (d, 2 H, H arom.); 8.60 (d, 1 H, H(6), J = 5.3 Hz); 9.75
(s, 1 H, NH).
Reaction of pyrimidine 1ꢀoxide 1a with trichloroacetonitrile.
A suspension of pyrimidine 1ꢀoxide 1a (850 mg, 5 mmol) in
0 mL of trichloroacetonitrile was refluxed for 24 h. Every two
1
hours, the suspension was bubbled with dry HCl through a 1ꢀmm
capillary at a rate of 1 bubble per second for 10 min. The solvent
was evaporated in vacuo, and the residue was chromatographed
on Merck 100 silica gel in AcOEt to give products 3 and 4.
8
Oꢀacylation of the Nꢀoxide fragment.
For comparison, we studied the reaction of pyrimiꢀ
dine oxide 1a with trichloroacetonitrile, which exhibit no
nucleophilic properties, but is a typical dipolarophile.9
This reaction yielded 4ꢀphenylꢀ2ꢀ(trichloroacetylamiꢀ
no)pyrimidine 3, which can be formed only through diꢀ
polar cycloaddition, and its hydrolysis product, namely,
4
ꢀPhenylꢀ2ꢀ(trichloroacetylamino)pyrimidine (3). Yield
100 mg (6%), m.p. 125—127 °C (from hexane). Found (%):
C, 45.72; H, 2.50; N, 13.07. C H Cl N O. Calculated (%):
12
8
3
3
1
C, 45.53; H, 2.55; N, 13.27. H NMR, δ: 7.70 (m, 3 H, Ph); 7.86
d, 1 H, H(5), J = 4.9 Hz); 8.23 (m, 2 H, Ph); 8.79 (d, 1 H,
H(6), J = 4.9 Hz); 11.38 (br.s, 1 H, NH). MS, m/z: 316, 318,
(
2
ꢀaminoꢀ4ꢀphenylpyrimidine 4. The same compound 4
+
3
20 [M] (1 : 0.98 : 0.31).
ꢀAminoꢀ4ꢀphenylpyrimidine (4). Yield 70 mg (6%), m.p.
61 °C (from EtOH) (cf. Ref. 11: m.p. 161 °C). Found (%):
was obtained by hydrolysis of ureidopyrimidine 2a in boilꢀ
ing formic acid.
Hence, the low yield of products and the drastic conꢀ
ditions in the reactions of pyrimidine 1ꢀoxides 1 with
trichloroacetonitrile (compared to those with cyanamide)
suggest the mechanism of dipolar 1,3ꢀcycloaddition. In
2
1
C, 70.01; H, 5.27; N, 24.68. C H N . Calculated (%): C, 70.16;
1
0
9
3
1
H, 5.30; N, 24.54. H NMR, δ: 6.42 (br.s, 2 H, NH ); 7.01 (d,
2
1 H, H(5), J = 5.2 Hz); 7.46 (m, 3 H, Ph); 8.01 (m, 2 H, Ph);
8.25 (d, 1 H, H(6), J = 5.2 Hz).