Synthesis of new pyrimido[4,5-d]pyrimidine derivatives from 5-acetyl-6-methyl-4-methylsulfanylpyrimidine-2(1H)-thiones and guanidine

Article abstract of DOI:10.1007/s11172-014-0454-5

Reactions of 5-acetyl-1-aryl(alkyl)-6-methyl-4-methylsulfanylpyrimidine-2(1H)-thiones (prepared from diacetylketene N,S-acetal) with guanidine afforded 3-alkyl- and 3-aryl-7-amino-5-methyl-4-methylidene-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thiones.

Full text of DOI:10.1007/s11172-014-0454-5

Russian Chemical Bulletin, International Edition, Vol. 63, No. 2, pp. 469—474, February, 2014
469
Synthesis of new pyrimido[4,5ꢀd]pyrimidine derivatives
from 5ꢀacetylꢀ6ꢀmethylꢀ4ꢀmethylsulfanylpyrimidineꢀ2(1H)ꢀthiones
and guanidine*
A. V. Komkov, S. V. Baranin, and V. A. Dorokhov†
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: svbar@ioc.ac.ru
Reactions of 5ꢀacetylꢀ1ꢀaryl(alkyl)ꢀ6ꢀmethylꢀ4ꢀmethylsulfanylpyrimidineꢀ2(1H)ꢀthiones
(prepared from diacetylketene N,Sꢀacetal) with guanidine afforded 3ꢀalkylꢀ and 3ꢀarylꢀ7ꢀ
aminoꢀ5ꢀmethylꢀ4ꢀmethylideneꢀ3,4ꢀdihydropyrimido[4,5ꢀd]pyrimidineꢀ2(1H)ꢀthiones. Byꢀ
products of these reactions (5ꢀacetylꢀ1ꢀalkyl(aryl)ꢀ6ꢀmethylꢀ2ꢀthiouracils) can also be obꢀ
tained from the starting pyrimidinethiones and EtONa in EtOH. Pyrimidopyrimidinethiones
can react with MeOH at the methylidene group in the presence of MeONa.
Key words: diacetylketene N,Sꢀacetal, isothiocyanates, 5ꢀacetylꢀ6ꢀmethylꢀ4ꢀmethylꢀ
sulfanylpyrimidineꢀ2(1H)ꢀthiones, guanidine, condensation, 7ꢀaminoꢀ5ꢀmethylꢀ4ꢀmethꢀ
ylideneꢀ3,4ꢀdihydropyrimido[4,5ꢀd]pyrimidineꢀ2(1H)ꢀthiones, 4ꢀalkoxyꢀ7ꢀaminoꢀ4,5ꢀdimethꢀ
ylꢀ3,4ꢀdihydropyrimido[4,5ꢀd]pyrimidineꢀ2(1H)ꢀthiones, 5ꢀacetylꢀ1ꢀaryl(alkyl)ꢀ6ꢀmethylꢀ2ꢀ
thiouracils.
Pyrimido[4,5ꢀd]pyrimidines, which are structurally reꢀ
lated to pteridines and purines, are of biological interest
because of a variety of their pharmacological activity inꢀ
cluding bronchodilating,1 antimicrobial,2,3 antiallergic,4
antihypertensive effects.5 In addition, they are phosphodꢀ
iesterase1 and dihydrofolate reductase6 inhibitors.
study the possibility of employing bifunctional nucleoꢀ
philes for a singleꢀstep synthesis of fused heterocycles from
such pyrimidinethiones.
In the present work, we studied reactions of pyrꢀ
imidinethione 2a and similarly prepared thiones 2b,c with
guanidine.
As a next step in our searching for synthetic routes to
pyrimido[4,5ꢀd]pyrimidines,7—12 here we obtained new deꢀ
rivatives of this heterocyclic system, viz., 3ꢀalkylꢀ and
3ꢀarylꢀ7ꢀaminoꢀ5ꢀmethylꢀ4ꢀmethylideneꢀ3,4ꢀdihydropꢀ
yrimido[4,5ꢀd]pyrimidineꢀ2(1H)ꢀthiones and 4ꢀalkoxyꢀ7ꢀ
aminoꢀ4,5ꢀdimethylꢀ3,4ꢀdihydropyrimido[4,5ꢀd]pyrimidꢀ
ineꢀ2(1H)ꢀthiones.
Earlier,10 we have demonstrated that diacetylketene
N,Sꢀacetal 1 prepared from acetylacetone and methyl thioꢀ
cyanate in the presence of Ni(acac)213 reacts with phenyl
isothiocyanate to give 5ꢀacetylꢀ4ꢀmethylsulfanylpyrimidꢀ
ineꢀ2ꢀthione 2a (Scheme 1). When the MeS group is reꢀ
placed by an amino group, compound 2a can be used in
reactions with dimethylformamide dimethyl acetal (or diꢀ
ethyl oxalate) and isocyanates to obtain the bicyclic sysꢀ
tems pyrimido[4,5ꢀd]pyrimidine and pyrido[2,3ꢀd]pyrꢀ
imidine, respectively. However, we found it interesting to
We found that reactions of pyrimidinethiones 2a,b with
guanidine acetate in boiling nꢀbutanol in the presence of
MeONa give pyrimidopyrimidinethiones 3a,b in 46 and
36% yields, respectively, and 5ꢀacetylthiouracils 4a,b as
byꢀproducts (see Scheme 1). It should be noted that the
pyrimidine ring undergoes reconstruction during the reacꢀ
tion, and compounds 3a,b containing the exocyclic methꢀ
ylidene group, instead of the expected products 5a,b, were
obtained.
Under similar conditions, pyrimidinethione 2c reacts
with guanidine to produce compounds 3c and 4c and,
unexpectedly, pyrimidopyrimidinethione 6c. Note that the
yield of the latter is higher than that of 3c. Obviously,
compound 6c is formed by addition of BunOH to the exoꢀ
cyclic methylidene group of heterocycle 3c. The absence
of such products in the reactions with pyrimidinethiones
2a,b is probably due to the steric hindrances presented by
the 3ꢀaryl substituent, making the exocyclic methylidene
group in compounds 3a,b less accessible to a sufficiently
bulky butanol molecule.
* On the occasion of the 80th anniversary of the N. D. Zelinsky
Institute of Organic Chemistry of the Russian Academy of
To verify this assumption, we carried out a reaction of
pyrimidinethione 2c with guanidine in tertꢀbutanol instead
Sciences.
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 0469—0474, February, 2014.
1066ꢀ5285/14/6302ꢀ0469 © 2014 Springer Science+Business Media, Inc.

470
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Komkov et al.
Scheme 1
R = Ph (a), 2,5ꢀMe2C6H3 (b), Et (c)
Reagents and conditions: i. RNCS, toluene, ; ii. 1) (NH2)2C=NH•AcOH, MeONa, BunOH, ; 2) AcOH, 20 C;
iii. 1) NH2C(=NH)NH2•AcOH, MeONa, ButOH, ; 2) AcOH, 20 C.
of nꢀbutanol. Indeed, only compounds 3c and 4c were
obtained; tertꢀbutanol formed no adduct at the exocyclic
methylidene group.
We tried to add methanol to the exocyclic methylidene
group of pyrimidopyrimidinethione 3a. It turned out that
no reaction occurs even when compound 3a is refluxed in
MeOH. Nevertheless, in the presence of MeONa, we obꢀ
tained pyrimidopyrimidinethione 7 structurally related to
compound 6c (Scheme 2).
dine), to both opening of the pyrimidinethione ring folꢀ
lowed by formation of methylidenepyrimidinethiones
(compounds 3) and substitution of the methylsulfanyl
group in pyrimidinethiones 2 leading to thiouracils 4.
Heterocyclic compounds 3, 4, 6, and 7 are nearly colꢀ
orless solids. Pyrimidopyrimidinethiones 3a—c are well
soluble in DMSO but poorly soluble in other organic solꢀ
vents. Adducts 6c and 7 are well soluble in chloroform and
acetone; in addition, compound 6c is soluble in benzene.
Acetylthiouracils 4a—c are well soluble in chloroform,
acetonitrile, and acetone. Note that adducts 6c and 7, in
contrast to compounds 3a—c and 4a—c, are not acidic,
yielding no salts in reactions with MeONa. The structures
of all the heterocycles obtained were determined by mass
Scheme 2
1
spectrometry and IR and H NMR spectroscopy. Strucꢀ
tures 3a and 7 were additionally confirmed by 13C NMR
spectroscopy and 2D correlation experiments (1H—13C
HSQC and HMBC). The mass spectra of all the comꢀ
pounds contain molecular ion peaks; their main fragmenꢀ
tation pathways are given in Table 1. The 1H NMR spectra
of pyrimidopyrimidinethiones 3a—c in DMSOꢀd6 show
signals at  6.5—6.8 (NH2), sufficiently narrow singlets at
 11.2—11.6 (NH), and two doublets for the protons of
the exocyclic methylidene group (AB system). The 1H—13C
HSQC spectrum of compound 3a in DMSOꢀd6 reveals
couplings between the protons resonating at  3.80 and
4.58 and the C atom resonating at  95.9, which provides
evidence for the presence of the exocyclic methylidene
Reagents and conditions: MeONa, MeOH, .
Therefore, the addition of an alcohol to the exocyclic
methylidene group of compounds 3 is facilitated by the
formation of a thiolate anion under the action of bases
(MeONa, guanidine) with subsequent polarization of
the double bond of the methylidene fragment. In conꢀ
trast, MeOH in the presence of MeONa does not react
with 1ꢀbenzylꢀ5ꢀmethylꢀ4ꢀmethylideneꢀ3,6ꢀdiphenylꢀ7ꢀthiꢀ
oxoꢀ3,4,6,7ꢀtetrahydropyrimido[4,5ꢀd]pyrimidinꢀ2(1H)ꢀ
one.10 It is worth noting that heterocycle 3a in the presence
of bases reacts with MeOH, remaining inert to nꢀbutanol.
A probable mechanism of the reactions of pyrimidꢀ
inethiones 2 with guanidine is shown in Scheme 3.
1
group. The H NMR spectra of adducts 6c and 7 in
DMSOꢀd6 also show signals at  6.5—6.6 (NH2) and sufꢀ
ficiently narrow singlets at  10.7—11.3 (NH). Instead of
the doublets for the methylidene protons, the spectra conꢀ
tain a singlet at  1.5—1.7 (4ꢀMe) and signals for the
OMe (7) or OBu group (6) (Table 2). In addition, the CH2
protons of the ethyl substituent in compound 6c are nonꢀ
The water released during the intramolecular cycloꢀ
condensation leads, in the presence of a strong base (guaniꢀ

New pyrimido[4,5ꢀd]pyrimidine derivatives
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
471
Scheme 3
equivalent and so are the orthoꢀprotons of the Ph substituꢀ
ent in compound 7 (1H NMR data). All the six C atoms of
the Ph substituent in compound 7 are also nonequivalent
The IR spectra of acetylthiouracils 4a—c in KBr pelꢀ
lets contain absorption bands at 1692—1708 (COMe) and
1648—1672 cm–1 (CON) (in CHCl3, both the CO groups
1
1
(13C NMR data). The H—13C HMBC spectrum of hetꢀ
absorb at ~1688 cm–1). The H NMR spectra of comꢀ
erocycle 7 in DMSOꢀd6 shows two cross peaks for the
protons resonating at  1.55 (4ꢀMe) and 3.08 (OMe) and
the C atom resonating at  91.2 (C(4)) as well as two cross
peaks for the proton resonating at  11.25 (NH) and the
C(4a) and C(2) atoms ( 99.7 and 178.0, respectively).
pounds 4a—c in DMSOꢀd6 show a sufficiently narrow
singlet at  12.8—13.0 (NH) (see Table 2).
We found that, like pyrimidinethiones 2a—c, 5ꢀacetylꢀ
4ꢀethylsulfanylpyrimidinꢀ2ꢀone 8 (see Ref. 8) reacts with
guanidine acetate in BunOH in the presence of MeONa to
Table 1. Elemental analysis data and mass spectra of compounds 3a—c, 4a—c, 6c, 7, 9, and 10
Comꢀ
pound
Found
Calculated
Molecular
formula
MS, m/z (Irel (%))
(%)
C
H
N
S
3a
3b
3c
4a
4b
4c
6c
7
59.39
59.34
4.81
4.62
24.57
24.72
11.50
11.32
C14H13N5S
C16H17N5S
283 [M]+ (100), 282 [M – H]+ (95),
268 [M – Me]+ (18)
311 [M]+ (57), 296 [M – Me]+ (100),
278 [M – HS]+ (19)
235 [M]+ (100), 220 [M – Me]+ (20),
207 [M – C2H4]+ (58), 202 [M – HS]+ (30)
260 [M]+ (100), 245 [M – Me]+ (69),
218 [M – COCH2 – OH]+ (37)
288 [M]+ (100), 273 [M – Me]+ (39),
255 [M – HS]+ (51)
212 [M]+ (100), 197 [M – Me]+ (12),
169 [M – COMe]+ (44)
309 [M]+ (8), 252 [M – Bu]+ (19),
236 [M – OBu]+ (100), 235 [M – BuOH]+ (95)
315 [M]+ (3), 284 [M – OMe]+ (33),
283 [M – MeOH]+ (100), 282 [M – MeOH – H]+
(92), 268 [M – MeOH – Me]+ (27)
61.35
61.71
5.65
5.50
22.17
22.49
19.95
10.30
51.07
51.04
5.54
5.57
29.62
29.76
13.59
13.63
C10H13N5S
59.86
59.98
4.61
4.65
10.69
10.76
11.99
12.32
C13H12N2O2S
C15H16N2O2S
C9H12N2O2S
C14H23N5OS
C15H17N5OS
62.36
62.48
5.40
5.59
9.60
9.71
10.81
11.12
51.09
50.92
5.85
5.70
13.29
13.20
14.81
15.11
54.45
54.34
7.45
7.49
22.57
22.63
10.28
10.36
57.04
57.12
5.55
5.43
22.32
22.20
19.69
10.17
9
62.86
62.91
5.01
4.90
26.17
26.20
—
—
C14H13N5O
C13H12N2O3
267 [M]+ (51), 266 [M – H]+ (100),
252 [M – Me]+ (8)
244 [M]+ (23), 243 [M – H]+ (39), 229 [M – Me]+
(27), 76 (100)
10
64.07
63.93
5.11
4.95
11.52
11.47

472
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Komkov et al.
Table 2. 1H NMR (DMSOꢀd6) and IR spectra (KBr) of compounds 3a—c, 4a—c, 6c, 7, 9, and 10
Comꢀ
pound
1H NMR (, J/Hz)
IR,/cm–1
3a
2.38 (s, 3 Н, Ме); 3.80, 4.58 (both d, each 1 Н, СН2=, J = 2.0); 6.81 (br.s, 2 Н, NH2);
7.23 (d, 2 Н, оꢀНPh, J = 7.5); 7.42 (t, 1 Н, рꢀНPh, J = 7.5); 7.51 (t, 2 Н, mꢀНPh, J = 7.5);
11.62 (s, 1 H, NH)
3316, 3152, 1660,
1608, 1544, 1520
3b
2.05 (s, 3 Н, Ме); 2.31 (s, 3 Н, Ме); 2.42 (s, 3 Н, 5ꢀМе); 3.83, 4.58 (both d, each 1 Н,
3332, 3180, 1648,
СН2=, J = 2.0); 6.61 (br.s, 2 Н, NH2); 6.97 (s, 1 Н, оꢀНС Н ); 7.14, 7.24 (both d, each 1 Н, 1624, 1608, 1552, 1508
6
3
mꢀНС Н , рꢀНС Н , J = 8.0); 11.25 (s, 1 H, NH)
6
3
6
3
3c
4a
1.28 (t, 3 Н, МеСН2, J = 8.0); 2.38 (s, 3 Н, Ме); 4.30 (q, 2 Н, СН2N, J = 8.0);
4.68, 4.92 (both d, each 1 Н, СН2=, J = 2.0); 6.67 (br.s, 2 Н, NH2); 11.20 (s, 1 H, NH)
3324, 3148, 1656, 1624,
1600, 1548, 1516
1.82 (s, 3 Н, 6ꢀМе); 2.48 (s, 3 Н, COМе); 7.32—7.62 (m, 5 H, Ph); 12.93 (s, 1 H, NH)
3164, 1692 (C=O); 1652
(C=O), 1580 3364* (NH),
1688 (C=O), 1580
4b
1.78 (s, 3 Н, 6ꢀМе); 2.05 (s, 3 Н, Ме); 2.31 (s, 3 Н, Ме); 2.48 (s, 3 Н, COМе);
3164, 1700 (C=O);
1672 (C=O);
1600, 1508
7.09 (s, 1 Н, оꢀНС Н ); 7.17, 7.25 (both d, each 1 Н, mꢀНС Н , рꢀНС Н , J = 8.0);
6
3
6
3
6
3
13.03 (s, 1 H, NH)
4c
6c
1.27 (t, 3 Н, МеСН2, J = 8.0); 2.32 (s, 3 Н, Ме); 2.38 (s, 3 Н, Ме); 4.42 (q, 2 Н,
СН2, J = 8.0); 12.83 (s, 1 H, NH)
3172, 1708 (C=O);
1648 (C=O)
0.84 (t, 3 Н, МеBu, J = 8.0); 1.20—1.58 (m, 7 Н, МеEt, 2 CH2 Bu); 1.74 (s, 3 Н, 4ꢀМе);
2.32 (s, 3 Н, 5ꢀМе); 2.85 (m, 2 Н, СН2О); 3.77, 4.02 (both m, each 1 Н, СН2N);
6.48 (br.s, 2 Н, NH2); 10.73 (s, 1 H, NH)
3324, 3150, 1652,
1612, 1560, 1524
0.88** (t, 3 Н, МеBu, J = 8.0); 1.20—1.68 (m, 7 Н, МеEt, 2 CH2 Bu); 1.45 (s, 3 Н, 4ꢀМе);
2.50 (s, 3 Н, 5ꢀМе); 2.82 (m, 2 Н, СН2О); 3.88, 4.35 (both m, each 1 Н, СН2N);
6.62 (br.s, 2 Н, NH2); 11.20 (s, 1 H, NH)
7
1.55 (s, 3 Н, 4ꢀМе); 2.35 (s, 3 Н, 5ꢀМе); 3.08 (s, 3 Н, ОМе); 6.64 (br.s, 2 Н, NH2);
7.14, 7.29 (both d, each 1 Н, оꢀНPh, J = 8.0); 7.32—7.46 (m, 3 Н, mꢀНPh, рꢀНPh);
11.25 (s, 1 H, NH)
3468, 3312, 3148,
1636, 1608, 1560,
1532
9
2.41 (s, 3 Н, Ме); 3.78, 4.47 (both d, each 1 Н, СН2=, J = 2.0); 6.61 (br.s, 2 Н, NH2);
7.25 (d, 2 Н, оꢀНPh, J = 8.0); 7.42 (t, 1 Н, рꢀНPh, J = 8.0); 7.51 (t, 2 Н, mꢀНPh, J = 8.0)
10.44 (s, 1 H, NH)
3356, 3196, 1684 (C=O),
1660, 1644, 1620, 1600,
1548
10
1.83 (s, 3 Н, 6ꢀМе); 2.46 (s, 3 Н, COМе); 7.32—7.62 (m, 5 H, Ph); 11.71 (s, 1 H, NH)
3176, 1728 (C=O); 1700
(C=O), 1652 (C=O), 1596
3380* (NH), 1724 (C=O),
1688 (C=O), 1576
* In CHCl3.
** In C6D6.
give pyrimidopyrimidinone 9 and acetyluracil 10, which
are structurally related to compounds 3a and 4a (Scheme 4).
The lower yields of compounds 9 and 10 are consistent
with our previous observations: the alkylsulfanyl group in
position 4 of pyrimidineꢀ2ꢀthiones is much more suscepꢀ
tible to nucleophilic substitution than that in related pyrꢀ
imidinꢀ2ꢀones. For instance, a reaction of compound 2a
with Nꢀmethylpiperazine in boiling toluene results in disꢀ
placement of the methylsulfanyl group by this nucleoꢀ
philic agent, while pyrimidinꢀ2ꢀone remains intact under
the same conditions.
In contrast to the exocyclic methylidene group in
thione 3a, that in compound 9 proved to be very inꢀ
ert: even its prolonged (12 h) reflux with a twofold
amount of MeONa in MeOH yields no adduct like comꢀ
pound 11.
Unlike its analog 3a, pyrimidopyrimidinone 9 is sparꢀ
ingly soluble in DMSO; in contrast, acetyluracil 10 is
soluble in organic solvents better than acetylthiouracil 4a.
Structures 9 and 10 were confirmed by spectroscopic methꢀ
ods (see Tables 1 and 2).
Since 5ꢀacetylꢀ2ꢀthiouracils 4 and 5ꢀacetyluracil 10
were synthesized from 4ꢀalkylsulfanylpyrimidin(ethi)ones 2
and 8 in the presence of the strong base guanidine, we
assumed that the use of another base instead of guanidine
could make this reaction pathway predominant.
Indeed, it turned out that reactions of compounds 2a,c
and 8 with EtONa in boiling 96% EtOH afford acetylthioꢀ
uracils 4a,c in 81 and 86% yields and acetyluracil 10 in
39% yield (Scheme 5).
Earlier, the synthesis of 5ꢀacetyluracils from diketene and
urethan followed by treatment of intermediate Nꢀacetoacetꢀ

New pyrimido[4,5ꢀd]pyrimidine derivatives
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
473
Scheme 4
5ꢀAcetylꢀ1ꢀ(2,5ꢀdimethylphenyl)ꢀ6ꢀmethylꢀ4ꢀmethylsulfanꢀ
ylpyrimidineꢀ2(1H)ꢀthione (2b). A mixture of diacetylketene
N,Sꢀacetal 1 (1.0 g, 5.78 mmol) and 2,5ꢀdimethylphenyl isothioꢀ
cyanate (1.88 g, 11.56 mmol) in toluene (10 mL) was refluxed for
7 h and cooled to 20 C. Then light petroleum (6 mL) was added,
and the precipitate that formed was filtered off and recrystallized
from EtOH (5 mL). Yield 0.61 g (33%), m.p. 169—170 C.
Found (%): C, 60.39; H, 6.00; N, 8.68; S, 19.98. C16H18N2OS2.
Calculated (%): C, 60.35; H, 5.70; N, 8.80; S, 20.14. IR (KBr),
/cm–1: 1700 (C=O); 1584, 1572, 1560, 1508. 1H NMR (DMSOꢀd6),
: 1.85 (s, 3 H, 6ꢀMe); 2.01, 2.32 (both s, 3 H each, 2 Me); 2.57
(s, 6 H, COMe, SMe); 7.06 (s, 1 H, oꢀHC H ); 7.20, 7.30 (both d,
6
1 H each, mꢀHC H , pꢀHC H , J = 8.0 Hz). 3
6
3
6
3
5ꢀAcetylꢀ1ꢀethylꢀ6ꢀmethylꢀ4ꢀmethylsulfanylpyrimidineꢀ2(1H)ꢀ
thione (2c). A mixture of diacetylketene N,Sꢀacetal 1 (1.6 g,
9.2 mmol) and ethyl isothiocyanate (1.6 mL, 18.4 mmol) in
toluene (10 mL) was refluxed for 6 h and cooled to 20 C. The
precipitate that formed was filtered off and washed with light
petroleum. Yield 1.28 g (57%), m.p. 176—177 C. Found (%): C,
49.58; H, 6.03; N, 11.49; S, 26.44. C10H14N2OS2. Calculated (%):
C, 49.56; H, 5.82; N, 11.56; S, 26.46. IR (KBr), /cm–1: 1700
Reagents and conditions: i. 1) (NH2)2C=NH•AcOH, MeONa,
BunOH, ; 2) AcOH, 20 C; ii. MeONa, MeOH, .
1
(C=O); 1580. H NMR (DMSOꢀd6), : 1.32 (t, 3 H, MeCH2,
J = 8.0 Hz); 2.41 (s, 3 H, Me); 2.50 (s, 3 H, Me); 2.53 (s, 3 H,
Me); 4.58 (q, 2 H, CH2, J = 8.0 Hz).
Scheme 5
7ꢀAminoꢀ5ꢀmethylꢀ4ꢀmethylideneꢀ3ꢀphenylꢀ3,4ꢀdihydropyrꢀ
imido[4,5ꢀd]pyrimidineꢀ2(1H)ꢀthione (3a). nꢀButanol (5 mL),
guanidine acetate (0.185 g, 1.55 mmol), and pyrimidinethione
2a (0.3 g, 1.03 mmol) were added to MeONa (1.7 mmol) subseꢀ
quent to removal of MeOH in vacuo. The reaction mixture was
refluxed for 2 h. The solvent was removed in vacuo. Acetonitrile
(3 mL), water (10 mL), and AcOH (0.5 mL) were added to the
residue. The resulting mixture was stirred for 10 min. The preꢀ
cipitate that formed was filtered off, washed with water (20 mL),
dried, and heated to boiling in MeCN (10 mL). On cooling to 20 C,
the precipitate of compound 3a was filtered off. Yield 0.134 g
(46%), m.p. 303—305 C. The elemental analysis data and mass
R = Ph (2a, 4a, 8, 10), Et (2c, 4c); R´ = Me (2), Et (8);
X = S (2, 4), O (8, 10)
Reagents and conditions: EtONa, 96% EtOH, .
1
spectrum of compound 3a are given in Table 1. The H NMR
and IR spectra are given in Table 2. 13C NMR (DMSOꢀd6),
: 24.7 (Me); 95.9 (CH2=); 100.4 (C(4a)); 128.0, 129.3, 129.5,
141.5 (Ph); 140.0 (C(4)); 153.4, 161.6 (C(7), C(8a)); 164.6 (C(5));
176.0 (C(2)). The acetonitrile filtrate was concentrated. Reꢀ
crystallization of the residue from benzene (6 mL) gave 5ꢀacetꢀ
ylꢀ6ꢀmethylꢀ1ꢀphenylꢀ2ꢀthiouracil (4a) (0.042 g, 16%), m.p.
264—265 C. Its elemental analysis data and spectral characterꢀ
istics are given in Tables 1 and 2.
ylurethan with ethyl orthoformate and amines has been
reported.14 5ꢀAcetylꢀ2ꢀthiouracils have been obtained from
amines and 5ꢀacetylꢀ2ꢀethylsulfanylꢀ1,3ꢀthiazinꢀ4ꢀone.15 Here
we proposed a simple alternative route to such compounds.
Experimental
7ꢀAminoꢀ3ꢀ(2,5ꢀdimethylphenyl)ꢀ5ꢀmethylꢀ4ꢀmethylideneꢀ
3,4ꢀdihydropyrimido[4,5ꢀd]pyrimidineꢀ2(1H)ꢀthione (3b) was
obtained from pyrimidinethione 2b (0.182 g, 0.57 mmol), guaniꢀ
dine acetate (0.088 g, 0.74 mmol), and MeONa in BunOH as
described for compound 3a. Compound 3b was separated from
thiouracil 4b by treatment with boiling benzene (10 mL). Yield
0.064 g (36%), m.p. 303—305 C (see Tables 1 and 2). 5ꢀAcetylꢀ
1ꢀ(2,5ꢀdimethylphenyl)ꢀ6ꢀmethylꢀ2ꢀthiouracil (4b) was isolatꢀ
ed from the benzene filtrate by column chromatography on SiO2
with CHCl3—EtOH (100 : 1) as an eluent. Yield 0.020 g (12%),
m.p. 214—215 C (see Tables 1 and 2).
7ꢀAminoꢀ3ꢀethylꢀ5ꢀmethylꢀ4ꢀmethylideneꢀ3,4ꢀdihydropyrimꢀ
ido[4,5ꢀd]pyrimidineꢀ2(1H)ꢀthione (3c). tertꢀButanol (5 mL),
guanidine acetate (0.295 g, 2.47 mmol), and pyrimidinethione 2c
(0.3 g, 1.23 mmol) were added to MeONa (2.7 mmol) subseꢀ
quent to removal of MeOH in vacuo. The reaction mixture was
refluxed for 1 h. The solvent was removed in vacuo. Acetonitrile
1
H NMR spectra were recorded on a Bruker AMꢀ300 instruꢀ
ment (300 MHz) in DMSOꢀd6 and C6D6. The residual proton
signals of these deuterated solvents ( 2.50 and 7.32, respectively)
served as internal standards. 13C NMR and 2D correlation spectra
(1H—13C HSQC and HMBC) were recorded on a Bruker Avance
600 instrument (600 (1H) and 150 MHz (13C)) with reference to
multiplet signals of DMSOꢀd6 ( 39.50). The signals in the 1H
C
and 13C NMR spectra were assigned using 2D correlation experꢀ
iments (1H—13C HSQC and HMBC). IR spectra were recorded
on a SpecordꢀM 82 instrument. Mass spectra were measured on
a Kratos MSꢀ30 instrument (EI, 70 eV, ion source temperature
250 C, direct inlet probe).
Commercial isothiocyanates (Acros) were used. 5ꢀAcetylꢀ6ꢀ
methylꢀ4ꢀmethylsulfanylꢀ1ꢀphenylpyrimidineꢀ2(1H)ꢀthione (2a)10
and 5ꢀacetylꢀ4ꢀethylsulfanylꢀ6ꢀmethylꢀ1ꢀphenylpyrimidinꢀ2(1H)ꢀ
one (8)8 were prepared according to known procedures.

474
Russ.Chem.Bull., Int.Ed., Vol. 63, No. 2, February, 2014
Komkov et al.
(4 mL), water (10 mL), and AcOH (0.4 mL) were added to the
residue. The resulting mixture was stirred for 10 min. The precipꢀ
itate that formed was filtered off, washed with water, dried, and
heated to boiling in MeCN (5 mL). On cooling to 20 C, the precꢀ
ipitate of compound 3c was filtered off. Yield 0.086 g (33%), m.p.
272—273 C (see Tables 1 and 2). Organic matter from the comꢀ
bined filtrates was extracted with CHCl3 (2×30 mL). The extracts
were concentrated in vacuo. The residue was washed with light
petroleum. The yield of 5ꢀacetylꢀ1ꢀethylꢀ6ꢀmethylꢀ2ꢀthiouracil
(4c) was 0.13 g (50%), m.p. 214—215 C (see Tables 1 and 2).
7ꢀAminoꢀ4ꢀbutoxyꢀ3ꢀethylꢀ4,5ꢀdimethylꢀ3,4ꢀdihydropyrimiꢀ
do[4,5ꢀd]pyrimidineꢀ2(1H)ꢀthione (6c). nꢀButanol (5 mL), guanꢀ
idine acetate (0.19 g, 1.6 mmol), and pyrimidinethione 2c (0.3 g,
1.2 mmol) were added to MeONa (1.76 mmol) subsequent to
removal of MeOH in vacuo. The reaction mixture was refluxed
for 1 h. The solvent was removed in vacuo. Acetonitrile (3 mL),
water (20 mL), and AcOH (0.4 mL) were added to the residue.
The resulting mixture was stirred at 20 C for 10 min. The preꢀ
cipitate that formed was filtered off, washed with water, dried,
and heated to boiling in benzene (10 mL). On cooling to 20 C,
the precipitate that formed was filtered off and heated to boiling
in MeCN (5 mL). On cooling to 20 C, the precipitate of pyrimꢀ
idopyrimidinethione 3c was filtered off. Yield 0.062 g (21%),
m.p. 272—273 C. The elemental analysis data and mass specꢀ
and washed with water. The yield of compound 4a was 0.145 g
(81%), m.p. 264—265 C (from benzene). The product is identiꢀ
cal in spectral characteristics with compound 4a obtained from
pyrimidinethione 2a and guanidine.
5ꢀAcetylꢀ1ꢀethylꢀ6ꢀmethylꢀ2ꢀthiouracil (4c) was obtained
from pyrimidinethione 2c and EtONa in EtOH as described
above for compound 4a. Yield 86%, m.p. 214—215 C.
5ꢀAcetylꢀ6ꢀmethylꢀ1ꢀphenyluracil (10). A mixture of pyrimidꢀ
inone 8 (0.2 g, 0.69 mmol) and EtONa (0.83 mmol) in 96%
EtOH (10 mL) was refluxed for 2 h and cooled to 20 C. Acetic
acid (0.4 mL) was added, and the mixture was concentrated
in vacuo. The residue was diluted with water (10 mL), and the
product was extracted with CHCl3 (2×10 mL). The combined
organic extracts were concentrated in vacuo. The residue was
dissolved in benzene (2 mL), whereupon light petroleum (4 mL)
was added. The precipitate that formed was filtered off. The
yield of compound 10 was 0.066 g (39%), m.p. 193—194 C. The
product is identical in spectral characteristics with compound 10
obtained from pyrimidinone 8 and guanidine.
We are grateful to A. S. Shashkov for recording and
analyzing 2D NMR spectra.
References
1
trum of compound 3c are given in Table 1. The H NMR and
IR spectra are given in Table 2. The benzene filtrate was conꢀ
centrated in vacuo. The residue was washed with light petroleum
(5 mL). The yield of compound 6c was 0.113 g (30%), m.p.
186—187 C (see Tables 1 and 2). The acetonitrile filtrate was
concentrated in vacuo. The residue was washed with light petroꢀ
leum to give thiouracil 4c (0.070 g, 27%).
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Baranin, L. S. Vasil´ev, Russ. Chem. Bull. (Int. Ed.), 2010,
59, 1035 [Izv. Akad. Nauk, Ser. Khim., 2010, 1012].
13. V. A. Dorokhov, M. F. Gordeev, E. M. Shashkova, A. V.
Komkov, V. S. Bogdanov, Bull. Acad. Sci. USSR, Div. Chem.
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14. J. H. Dewar, G. Shaw, J. Chem. Soc., 1961, 3254.
15. R. Lofthouse, G. Mackenzie, G. Shaw, N. J. Cusack,
J. Chem. Res., Synop., 1978, 56.
7ꢀAminoꢀ4ꢀmethoxyꢀ4,5ꢀdimethylꢀ3ꢀphenylꢀ3,4ꢀdihydropyrꢀ
imido[4,5ꢀd]pyrimidineꢀ2(1H)ꢀthione (7). A mixture of pyrimidoꢀ
pyrimidinethione 3a (0.057 g, 0.2 mmol) and MeONa (0.4 mmol)
in MeOH (6 mL) was refluxed for 6 h. On cooling to 20 C, the
precipitate that formed was filtered off. Yield 0.043 g (68%),
m.p. 300—303 C. 13C NMR (DMSOꢀd6), : 22.9 (5ꢀMe); 29.8
(4ꢀMe); 50.8 (OMe); 91.2 (C(4)); 99.8 (C(4a)); 127.6, 127.8,
128.2, 129.5, 132.3, 140.5 (Ph); 153.2, 162.6 (C(7), C(8a)); 167.0
(C(5)); 178.0 (C(2)). The elemental analysis data and other specꢀ
tral characteristics of compound 7 are given in Tables 1 and 2.
7ꢀAminoꢀ5ꢀmethylꢀ4ꢀmethylideneꢀ3ꢀphenylꢀ3,4ꢀdihydropyrꢀ
imido[4,5ꢀd]pyrimidinꢀ2(1H)ꢀone (9). nꢀButanol (5 mL), guanidꢀ
ine acetate (0.248 g, 2.08 mmol), and pyrimidinone 8 (0.3 g,
1.04 mmol) were added to MeONa (2.3 mmol) subsequent to
removal of MeOH in vacuo. The reaction mixture was refluxed
for 2 h. The solvent was removed in vacuo. Acetonitrile (3 mL),
water (10 mL), and AcOH (0.4 mL) were added to the residue.
The resulting mixture was stirred for 10 min. The precipitate of
compound 9 was filtered off, washed with water, and dried. Yield
0.043 g (15%), m.p. 338—340 C (see Tables 1 and 2). Organic
matter from the filtrate was extracted with CHCl3 (2×20 mL).
The combined extracts were concentrated in vacuo. The residue
was triturated with light petroleum and recrystallized from benzꢀ
ene (4 mL) to give 5ꢀacetylꢀ6ꢀmethylꢀ1ꢀphenyluracil 10. Yield
0.067 g (26%), m.p. 192—193 C (see Tables 1 and 2).
5ꢀAcetylꢀ6ꢀmethylꢀ1ꢀphenylꢀ2ꢀthiouracil (4a). A mixture of
pyrimidinethione 2a (0.2 g, 0.69 mmol) and EtONa (0.76 mmol)
in 96% EtOH (10 mL) was refluxed for 1 h. The solvent was
removed in vacuo. Water (10 mL) and AcOH (0.4 mL) were
added to the residue. The precipitate that formed was filtered off
Received October 22, 2013;
in revised form January 13, 2014