Intramolecular cyclization of 1-allyl- and 1-methallyl-6-amino-2- thiouracils

Article abstract of DOI:10.1007/s11172-006-0032-6

Intramolecular cyclization of 1-allyl- and 1-methallyl-6-amino-2- thiouracils afforded 5-amino-2,3-dihydrothiazolo[3,2-a]pyrimidin-4-ones, whose structures were proved by chemical transformations.

Full text of DOI:10.1007/s11172-006-0032-6

1744
Russian Chemical Bulletin, International Edition, Vol. 54, No. 7, pp. 1744—1746, July, 2005
Brief Communications
Intramolecular cyclization of 1ꢀallylꢀ and 1ꢀmethallylꢀ6ꢀaminoꢀ2ꢀthiouracils
V. B. Sokolov,ꢀ A. Yu. Aksinenko, A. N. Pushin, and I. V. Martynov
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
1
42432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (095) 785 7024. Eꢀmail: alaks@ipac.ac.ru
Intramolecular cyclization of 1ꢀallylꢀ and 1ꢀmethallylꢀ6ꢀaminoꢀ2ꢀthiouracils afforded
5
ꢀaminoꢀ2,3ꢀdihydrothiazolo[3,2ꢀa]pyrimidinꢀ4ꢀones, whose structures were proved by chemiꢀ
cal transformations.
Key words: allylthioureas, acylimines, hexafluoroacetone, methyl trifluoropyruvate,
6
ꢀaminoꢀ2ꢀthiouracils, 5ꢀaminoꢀ2,3ꢀdihydrothiazolo[3,2ꢀa]pyrimidinꢀ4ꢀones, cyclization,
cyclocondensation, bromination.
Combination of two and more pharmacophoric moiꢀ
Scheme 1
eties in one molecule is an approach of chemical design of
biologically active substances. In this report, we consider
the data on introduction of a thiazoline moiety, which is a
1
,2
component of various biologically active substances,
into a molecule of 6ꢀaminoꢀ2ꢀthiouracils by intramolecuꢀ
lar cyclization of 1ꢀallylꢀ and 1ꢀmethallylꢀ6ꢀaminoꢀ2ꢀ
thiouracils 1a,b. This study is based on the known data on
cyclization of Nꢀallylthioureas to 2ꢀaminothiazolines by
the action of inorganic acids, halogens, and halophilic
reagents.3 The presence of an Nꢀallylthiourea moiety
in molecules 1a,b allows one to suggest similar reactions.
In fact, when heating compounds 1a,b in 48% HBr at
—6
1
20 °С for 2 h, 5ꢀaminothiazolopyrimidinones 2a,b were
formed in 69 and 73% yields, respectively. The brominaꢀ
tion of alcohol solutions of 1a,b gave unambiguous results
when two equivalents of molecular bromine were used,
because bromination to position 5 of the pyrimidine ring
occurs in parallel with the formation of the bromoꢀ
methylthiazoline fragment: 5ꢀaminoꢀ6ꢀbromothiazoloꢀ
R = H (a), Me (b)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1694—1696, July, 2005.
066ꢀ5285/05/5407ꢀ1744 © 2005 Springer Science+Business Media, Inc.
1

Cyclization of 1ꢀallylꢀ6ꢀaminoꢀ2ꢀthiouracils
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 7, July, 2005
1745
Scheme 2
8
pyrimidinones 3a,b are formed in 70 and 59% yields,
uracils using refluxing of methyl cyanoacetate with allylꢀ
and methallylthioureas in a methanolic solution of soꢀ
dium methoxide.
respectively (Scheme 1).
5
ꢀAminothiazolopyrimidinones 2a,b and 3a,b are solid
crystalline substances, whose compositions and structures
were proved by the data of elemental analysis, NMR specꢀ
troscopy, and chemical transformations. For instance,
pyrimidinone 2b undergoes reactions characteristic of
enamines (Scheme 2), namely, it is brominated to posiꢀ
tion 5 to form pyrimidinone 4 and interacts with 1,2ꢀbisꢀ
electrophilic reagents: indacenedione 7 and indacenylꢀ
benzamide 8 are formed as a result of cyclocondensation
of 2b with methyl trifluoropyruvate 5 and methyl triꢀ
fluoropyruvate Nꢀbenzoylimine (6).
Thus, 1ꢀallylꢀ and 1ꢀmethallylꢀ6ꢀaminoꢀ2ꢀthiouracils
undergo cyclization to 5ꢀaminotriazolopyrimidinones unꢀ
der the action of HBr and bromine, similarly to other
compounds containing the Nꢀallylthioamide moiety.
A similar reaction can be extended to the products of
transformations of 1ꢀallylꢀ and 1ꢀmethallylꢀ6ꢀaminoꢀ2ꢀ
thiouracils.
Experimental
Pyrimidinone 4 and pyrrolothiazolopyrimidines 7
and 8 are crystalline solids, whose compositions and strucꢀ
tures were proved by the data of elemental analysis
and NMR spectroscopy. Pyrrolothiazolopyrimidine 8
was prepared by an unambiguous synthesis. Thus, thioꢀ
uracil 1b on heating in DMF undergoes the earlier deꢀ
scribed cyclocondensation with imine 6 to form pyrroꢀ
lo[2,3ꢀd]pyrimidinedione 9, which is transformed into
compound 8 being heated in 48% HBr at 120 °С for 2 h
1H and 19F NMR spectra were recorded on a Bruker
DXP 200 spectrometer. Melting points were determined in a
glass capillary. Methyl trifluoropyruvate Nꢀbenzoylimine (6) was
synthesized according to a previously published procedure.
Allylthiourea, methallylthiourea, methyl cyanoacetate, and meꢀ
thyl trifluoropyruvate (Aldrich) were used as received.
1ꢀAllylꢀ6ꢀaminoꢀ2ꢀthioxoꢀ2,3ꢀdihydroꢀ1Нꢀpyrimidinꢀ4ꢀone
(1a). Sodium (6.9 g, 0.3 mol) was dissolved in MeOH (100 mL),
and allylthiourea (11.6 g, 0.1 mol) and methyl cyanoacetate
9
7
(
9.9 g, 0.1 mol) were added. The reaction mixture was refluxed
(
Scheme 3).
for 6 h, cooled, diluted with Н О (300 mL), and neutralized
2
with AcOH. A precipitate formed was filtered off and recrysꢀ
tallized from EtOH to obtain thiouracil 1a (13.2 g, 72%),
m.p. 218—220 °С. Found (%): C, 45.41; H, 4.78; N, 22.81.
C H N OS. Calculated (%): C, 45.59; H, 4.95; N, 22.93.
Scheme 3
7
9
3
1
Н NMR (DMSOꢀd ), δ: 4.87 (s, 1 H, —CH=); 5.09—5.21 (m,
6
4
2
H, —CH N + CH =); 5.78—5.96 (m, 1 H, —CH=); 6.97 (s,
2 2
H, NH ); 11.7 (s, 1 H, NH).
2
6
ꢀAminoꢀ1ꢀ(2ꢀmethylallyl)ꢀ2ꢀthioxoꢀ2,3ꢀdihydroꢀ1Нꢀpyriꢀ
midinꢀ4ꢀone (1b) was synthesized similarly to 1а from methallylꢀ
thiourea (13.0 g, 0.1 mol) and methyl cyanoacetate (9.9 g,
0
.1 mol). The yield was 13.5 g (69%). M.p. 231—233 °С.
Found (%): C, 48.52; H, 5.77; N, 21.12. C H N OS. Calcuꢀ
8
11
3
1
lated (%): C, 48.71; H, 5.62; N, 21.30. Н NMR (DMSOꢀd ), δ:
6
1
ꢀAllylꢀ and 1ꢀmethallylꢀ6ꢀaminoꢀ2ꢀthiouracils were
1.79 (s, 3 H, Me); 4.55 (s, 2 H, CH =); 4.86 (s, 1 H, —CH=);
2
synthesized by a procedure known for synthesis of aminoꢀ
5.01 (s, 2 H, NH ); 6.97 (s, 2 H, CH N); 11.65 (s, 1 H, NH).
2
2

1
746
Russ.Chem.Bull., Int.Ed., Vol. 54, No. 7, July, 2005
Sokolov et al.
5
ꢀAminoꢀ2ꢀmethylꢀ2,3ꢀdihydrothiazolo[3,2ꢀa]pyrimidinꢀ
3ꢀBenzoylaminoꢀ7,7ꢀdimethylꢀ3ꢀtrifluoromethylꢀ1,3,7,8ꢀ
tetrahydropyrrolo[3,2ꢀe][1,3]thiazolo[3.2ꢀa]pyrimidineꢀ2,4ꢀ
dione (8). A. Methyl trifluoropyruvate Nꢀbenzoylimine (6)
(2.59 g, 0.01 mol) was added to a solution of pyrimidinone 2b
(1.97 g, 0.01 mol) in DMF (10 mL). The reaction mixture was
7
(7H )ꢀone (2a). A suspension of thiouracyl 1a (9.15 g, 0.05 mol)
in 48% HBr (50 mL) was heated for 2 h at 120 °С. Then the
reaction mixture was cooled, diluted with Н О (200 mL), and
neutralized with 10% NaOH. A precipitate formed was filtered
2
off and recrystallized from EtOH to obtain pyrimidinone 2a
heated for 1 h at 100 °С and diluted with Н О (100 mL).
2
(
6.3 g, 69%). M.p. 271—273 °С. Found (%): C, 45.47; H, 4.81;
A precipitate formed was filtered off and recrystallized from
EtOH to obtain benzamide 8 (3.1 g, 73%). M.p. 317—319 °С.
B. A suspension of benzamide 9 (2.12 g, 0.005 mol) in 48%
HBr (10 mL) was heated for 2 h at 120 °С. Then the reaction
N, 22.78. C H N OS. Calculated (%): C, 45.59; H, 4.95;
N, 22.93. Н NMR (DMSOꢀd ), δ: 1.55 (d, 3 H, Me, J =
6
6
7
9
3
1
6
.3 Hz); 4.34 (m, 2 H, CH N + CHS); 4.63 (m, 1 H, CH N);
2
2
.02 (s, 1 H, —CH=); 8.87 (s, 2 H, NH ).
mixture was cooled, diluted with Н О (50 mL), and neutralized
2
2
5
ꢀAminoꢀ2,2ꢀdimethylꢀ2,3ꢀdihydrothiazolo[3,2ꢀa]pyrimidinꢀ
with 10% NaOH. A precipitate formed was filtered off and reꢀ
crystallized from EtOH to obtain benzamide 8 (1.6 g, 75%).
M.p. 317—319 °С. Found (%): C, 50.77; H, 3.71; N, 13.32.
C H F N O S. Calculated (%): C, 50.94; H, 3.56; N, 13.20.
7
(7H )ꢀone (2b) was synthesized similarly to 2а from 1b (9.85 g).
The yield was 7.2 g (73%). M.p. 284—286 °С. Found (%):
C, 48.53; H, 5.79; N, 21.19. C H N OS. Calculated (%):
C, 48.71; H, 5.62; N, 21.30. 1Н NMR (DMSOꢀd ), δ: 1.62
8
11
3
18 15
3
4
3
1
Н NMR (DMSOꢀd ), δ: 1.74 (s, 6 H, Me); 4.21, 4.35 (both d,
6
6
(
(
s, 6 H, Me); 4.11 (s, 2 H, CH ); 4.85 (s, 1 H, —CH=); 6.57
1 H each, CH , J = 11.4 Hz); 7.46 (m, 3 H, CH ); 7.94 (m,
2 Ar
2
19
s, 2 H, NH ).
2 H, CH ); 9.88 (s, 1 Н, NH); 12.04 (s, 1 Н, NH). F NMR
2
Ar
5
ꢀAminoꢀ6ꢀbromoꢀ2ꢀbromomethylꢀ2,3ꢀdihydrothiazoꢀ
(DMSOꢀd ), δ: 5.82 s.
6
lo[3,2ꢀa]pyrimidinꢀ7(7H )ꢀone (3a). Molecular bromine (3.2 g,
5ꢀBenzoylaminoꢀ1ꢀ(2ꢀmethylallyl)ꢀ2ꢀthioxoꢀ5ꢀtrifluoroꢀ
methylꢀ2,3,5,7ꢀtetrahydroꢀ1Нꢀpyrrolo[2,3ꢀd]pyrimidineꢀ4,6ꢀ
dione (9). Methyl trifluoropyruvate Nꢀbenzoylimine (6) (2.59 g,
0.01 mol) was added to a solution of thiouracil 1b (1.97 g,
0.01 mol) in DMF (10 mL). The reaction mixture was heated
0
0
.02 mol) was added to a suspension of thiouracil 1а (1.83 g,
.01 mol) in EtOH (20 mL) at 20 °С. The reaction mixture was
stirred for 1 h, diluted with Н О (100 mL), and neutralized with
2
1
0% NaOH. A precipitate formed was filtered off and recrystalꢀ
lized from EtOH to obtain pyrimidinone 3a (2.4 g, 70%).
M.p. 227—229 °С. Found (%): C, 24.49; H, 1.91; N, 12.18.
C H Br N OS. Calculated (%): C, 24.65; H, 2.07; N, 12.32.
for 1 h at 100 °С and diluted with Н О (100 mL). A precipitate
2
formed was filtered off and recrystallized from EtOH to obtain
benzamide 9 (3.3 g, 78%). M.p. 301—303 °С. Found (%):
C, 50.78; H, 3.43; N, 13.37. C H F N O S. Calculated (%):
7
7
2
3
1
Н NMR (DMSOꢀd ), δ: 3.95 (d, 2 H, CH Br, J = 5.8 Hz);
6
2
18 15
3
4
3
1
4
.33—4.48 (m, 3 H, —CH= + CH ); 7.04 (s, 2 H, NH ).
C, 50.94; H, 3.56; N, 13.20. Н NMR (DMSOꢀd ), δ: 1.86 (s,
2
2
6
5
ꢀAminoꢀ6ꢀbromoꢀ2ꢀbromomethylꢀ2ꢀmethylꢀ2,3ꢀdihydroꢀ
3 H, Me); 4.63 (m, 1 H, =CH ); 4.92 (m, 1 H, CH N + =CH );
2
2
2
thiazolo[3,2ꢀa]pyrimidinꢀ7(7H )ꢀone (3b) was synthesized
similarly to 3а from 1b (1.97 g). The yield was 2.1 g (59%).
M.p. 238—240 °С. Found (%): C, 27.21; H, 2.73; N, 11.72.
C H Br N OS. Calculated (%): C, 27.06; H, 2.55; N, 11.87.
7.47 (m, 3 H, CH ); 7.93 (m, 2 H, CHAr); 9.91, 12.10, 12.42
Ar
19
(all s, 1 H each, NH). F NMR (DMSOꢀd ), δ: 4.90 s.
6
8
9
2
3
References
1
Н NMR (DMSOꢀd ), δ: 1.75 (s, 3 H, Me); 3.96 (d, 1 H,
6
CH Br, J = 10.5 Hz); 4.01 (d, 1 H, CH Br, J = 10.5 Hz); 4.14,
2
2
1
. R. S. Roy, A. M. Gehring, J. C. Milne, P. J. Belshaw, and
C. T. Walsh, Nat. Prod. Rep., 1999, 16, 249.
. P. Wipf, Chem. Rev., 1995, 95, 2115.
. T. S. Jagodzin´ski, Chem. Rev., 2003, 103, 197.
. N. I. Korotkikh, G. F. Raenko, A. F. Aslanov, and O. P.
Shvaika, Khim. Geterotsikl. Soedin., 1994, 706 [Chem.
Heterocycl. Compd., 1994 (Engl. Transl.)].
4
.55 (both d, 1 H each, CH N, J = 11.9 Hz); 6.89 (s, 2 H, NH ).
2
2
5
ꢀAminoꢀ6ꢀbromoꢀ2,2ꢀdimethylꢀ2,3ꢀdihydrothiazoꢀ
2
3
4
lo[3,2ꢀa]pyrimidinꢀ7(7H )ꢀone (4). Molecular bromine (3.2 g,
0
0
.02 mol) was added to a suspension of pyrimidinone 2b (1.97 g,
.01 mol) in EtOH (20 mL) at 20 °С. The reaction mixture was
stirred for 1 h, diluted with Н О (100 mL), and neutralized with
2
1
0% NaOH. A precipitate formed was filtered off and recrystalꢀ
5
6
. V. I. Shmygarev and D. G. Kim, Khim. Geterotsikl. Soedin.,
lized from EtOH to obtain pyrimidinone 4 (1.8 g, 69%).
M.p. 240—242 °С. Found (%): C, 34.62; H, 3.52; N, 15.41.
C H BrN OS. Calculated (%): C, 34.79; H, 3.65; N, 15.22.
2
004, 1241 [Chem. Heterocycl. Compd., 2004 (Engl. Transl.)].
. S. E. Tkachenko, A. N. Pushin, V. B. Sokolov, V. M.
Fedoseev, and I. V. Martynov, Khim. Geterotsikl. Soedin.,
8
10
3
1
Н NMR (DMSOꢀd ), δ: 1.59 (s, 6 H, Me); 4.24 (s, 2 H, NH );
6
2
1
998, 381 [Chem. Heterocycl. Compd., 1998 (Engl. Transl.)].
6
.91 (s, 1 H, NH).
ꢀHydroxyꢀ7,7ꢀdimethylꢀ3ꢀtrifluoromethylꢀ1,3,7,8ꢀtetraꢀ
hydropyrrolo[3,2ꢀe][1,3]thiazolo[3,2ꢀa]pyrimidineꢀ2,4ꢀdione
7). Methyl trifluoropyruvate 5 (1.56 g, 0.01 mol) was added to a
7
. V. B. Sokolov, A. Yu. Aksinenko, and I. V. Martynov, Izv.
Akad. Nauk, Ser. Khim., 2001, 1064 [Russ. Chem. Bull., Int.
Ed., 2001, 50, 1113].
3
(
8
9
. W. Hatzenlaub and W. Pfleiderer, Lieb. Ann. Chem.,
solution of pyrimidinone 2b (1.97 g, 0.01 mol) in DMF (10 mL).
The reaction mixture was heated for 1 h at 100 °С and diluted
1
979, 1847.
. S. N. Osipov, V. B. Sokolov, A. F. Kolomiets, I. V. Martynov,
and A. V. Fokin, Izv. Akad. Nauk SSSR, Ser. Khim., 1987,
with Н О (100 mL). A precipitate formed was filtered off and
2
recrystallized from EtOH to obtain indacenedione 7 (2.6 g, 81%).
M.p. 293—295 °С. Found (%): C, 41.29; H, 3.31; N, 13.22.
C H F N O S. Calculated (%): C, 41.12; H, 3.14; N, 13.08.
1
185 [Bull. Acad. Sci., Div. Chem. Sci., 1987, 26, 1098 (Engl.
Transl.)].
1
1
10
3
3
3
1
Н NMR (DMSOꢀd ), δ: 1.69 (s, 6 H, Me); 4.21 (AB system,
6
2
H, CH , J = 11.6 Hz); 7.26 (br.s, 1 Н, ОН); 11.87 (s, 1 Н,
Received April 21, 2005;
in revised form, June 6, 2005
2
19
NH). F NMR (DMSOꢀd ), δ: 1.61 s.
6