Synthesis of 6-substituted 5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidine-2,4- diones and 2-thioxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-ones

Article abstract of DOI:10.1007/s11172-008-0199-0

Three-component reactions of 6-aminouracils and 6-aminothiouracils with formaldehyde and primary amines gave 6-alkyl-5,6,7,8-tetrahydropyrimido[4,5-d] pyrimidine-2,4-diones and 6-alkyl-2-thioxo-5,6,7,8-tetrahydropyrimido[4,5-d] pyrimidin-4-ones.

Full text of DOI:10.1007/s11172-008-0199-0

Russian Chemical Bulletin, International Edition, Vol. 57, No. 7, pp. 1543—1546, July, 2008
1543
Synthesis of 6ꢀsubstituted
5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidineꢀ2,4ꢀdiones
and 2ꢀthioxoꢀ5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidinꢀ4ꢀones
A. Yu. Aksinenko, V. B. Sokolov, T. V. Goreva, T. A. Epishina, and A. N. Pushin
Institute of Physiologically Active Compounds, Russian Academy of Sciences,
1 Severnyi pr., 142432 Chernogolovka, Moscow Region, Russian Federation.
Fax: +7 (496) 524 9508. Eꢀmail: alaks@ipac.ac.ru
Threeꢀcomponent reactions of 6ꢀaminouracils and 6ꢀaminothiouracils with formaldehyde and
primary amines gave 6ꢀalkylꢀ5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidineꢀ2,4ꢀdiones and 6ꢀalkylꢀ
2ꢀthioxoꢀ5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidinꢀ4ꢀones.
Key words: the Mannich reaction, 5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidineꢀ2,4ꢀdiones,
2ꢀthioxoꢀ5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidinꢀ4ꢀones, 1,2,3,4,8,9ꢀhexahydroꢀ5Hꢀpyrimꢀ
ido[5,4ꢀe][1,3]thiazolo[3,2ꢀa]pyrimidinꢀ5ꢀones, 6ꢀaminouracils, 6ꢀaminothiouracils, primary
amines, formaldehyde, cyclization.
Scheme 1
Tetrahydropyrimidines and their fused analogs conꢀ
stitute an important class of heterocycles. Some of them
(including those of natural origin) are biologically acꢀ
tive.1 One of the routes to tetrahydropyrimidines involves
the Mannich threeꢀcomponent reaction of 1,3ꢀC,Nꢀbiꢀ
nucleophiles, formaldehyde, and primary amines.2 These
transformations are usually performed by heating a mixꢀ
ture of three reagents in an organic solvent at a temperaꢀ
ture above 100 °C. The goal of the present work was to
further develop the Mannich threeꢀcomponent reaction
for 6ꢀaminouracils and 6ꢀaminothiouracils to obtain
6ꢀsubstituted 5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimꢀ
idineꢀ2,4ꢀdiones and 2ꢀthioxoꢀ5,6,7,8ꢀtetrahydropyrimꢀ
ido[4,5ꢀd]pyrimidinꢀ4ꢀones. Previously, the synthesis of
only one representative of such compounds from 6ꢀamiꢀ
noꢀ1,3ꢀdimethyluracil was documented.3,4
We found that reactions of equimolar amounts of
formalin, a primary amine, and 6ꢀaminouracil 1 or
6ꢀaminothiouracil 2 in DMF under mild conditions (stirꢀ
ring, 20—25 °C, 8 h) give 6ꢀsubstituted 5,6,7,8ꢀtetꢀ
rahydropyrimido[4,5ꢀd]pyrimidineꢀ2,4ꢀdiones 3 and
2ꢀthioxoꢀ5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidinꢀ
4ꢀones 4 in 60—90% yields (Scheme 1). With compounds
1a,b and 2c, the completion of the reaction can be easily
inferred from the dissolution of the starting uracil.
It should be noted that this method has some limiꢀ
tations associated with the nature of the primary
amine. With aromatic amines under the same condiꢀ
tions, the expected products were 1,3,5ꢀtriarylperhydꢀ
rotriazines,5 while tetrahydropyrimido[4,5ꢀd]pyrimꢀ
idines 3 and 4 were obtained only from alkyl(arylꢀ
alkyl)amines.
X = O (1a,b, 3a—d), S (2a—c, 4a—e)
1: R = PhCH2 (a), 4ꢀFC6H4 (b); 2: R = All (a), C(Me)=CH2 (b),
2ꢀClC6H4 (c)
3
a
b
c
d
R
R´
4
a
b
c
d
e
R
All
R´
PhCH2
PhCH2 cycloꢀC5H9
4ꢀFC6H4
4ꢀFC6H4
Ph(CH2)2
Ph(CH2)2
Ph(CH2)2
C(Me)=CH2
C(Me)=CH2 cycloꢀC6H11
2ꢀClC6H4
2ꢀClC6H4
PhCH2
Pri
Ph(CH2)2
cycloꢀC5H9
1
In the H NMR spectra of all compounds obtained,
the signals for the methylene groups of the tetrahydropyꢀ
rimidine fragment differ in both chemical shift and shape.
The signals for the C(5)H2 protons appear as a narrow
singlet at δ 3.4—3.7. The signals for the C(7)H2 protons
most often look like a broadened singlet at δ 3.9—4.1.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1512—1515, July, 2008.
1066ꢀ5285/08/5707ꢀ1543 © 2008 Springer Science+Business Media, Inc.

1544
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Aksinenko et al.
In some cases, they appear as doublets with the coupling
constant JNH—CH = 2—3 Hz, which allowed the assignꢀ
ment of these sig2nals. The signal for the N(8)H proton
appears as a broadened singlet (sometimes resolved into
a triplet) at δ 6—7.
The structures of products 4 were confirmed by chemꢀ
ical transformations described earlier6—8 for compounds
containing analogous fragments (allyl and thioxo groups).
For instance, thiones 4d,e were easily alkylated with
Nꢀ(4ꢀfluorophenyl)chloroacetamide to give isothiuroniꢀ
um salts 5. In situ treatment of the latter with triethylꢀ
amine yielded the corresponding sulfides 6a,b (Scheme 2).
group at δ 1.53 (for 7a) and singlets for the CH3 and CH2
protons at δ 1.63 and 4.02 (for 7b), which confirm the
presence of the thiazoline fragment. It should be noted
that the signals for the protons of the tetrahydropyrimidꢀ
ine ring of compounds 7a,b remain virtually unchanged.
Treatment of ethanolic solutions of methallylꢀconꢀ
taining thiones 4b,c with bromine yielded, through inꢀ
tramolecular cyclization, bromomethyl derivatives 8a,b
(Scheme 4). As in the preceding case, the chemical shifts
of the protons of the tetrahydropyrimidine ring remain
the same.
Scheme 4
Scheme 2
8: R = Ph(CH2)2 (a), cycloꢀC6H11 (b)
Cl–
To sum up, we proposed a convenient preparative
method for the synthesis of 6ꢀalkylꢀ5,6,7,8ꢀtetrahydroꢀ
pyrimido[4,5ꢀd]pyrimidineꢀ2,4ꢀdiones and 6ꢀalkylꢀ2ꢀ
thioxoꢀ5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidinꢀ4ꢀ
ones. The method involves threeꢀcomponent reactions of
6ꢀamino(thio)uracils with primary alkylamines and
formaldehyde under mild conditions.
Experimental
1
H and 19F NMR spectra were recorded on a Bruker DPX 200
6: R = 2ꢀClC6H4 (a, b); R´ = Ph(CH2)2 (a), cycloꢀC5H9 (b)
spectrometer (200.13 and 188.29 MHz, respectively) with Me4Si as
the internal standard and with CF3COOH as the external standard.
The starting 6ꢀaminouracils 1a,b and 6ꢀaminothiouracils 2a—c
were prepared as described earlier.9 Alkylamines (Aldrich) were
used as purchased.
Heating of allylꢀ and methallylꢀcontaining thiones
4a,b in HBr at 120 °C for 2 h resulted in intramolecular
cyclization into fused thiazolines 7a,b (Scheme 3).
1ꢀBenzylꢀ6ꢀphenethylꢀ5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]ꢀ
pyrimidineꢀ2,4(1H,3H)ꢀdione (3a), 1ꢀbenzylꢀ6ꢀcyclohexylꢀ
5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidineꢀ2,4(1H,3H)ꢀdione
(3b), 6ꢀbenzylꢀ1ꢀ(4ꢀfluorophenyl)ꢀ5,6,7,8ꢀtetrahydropyrimꢀ
ido[4,5ꢀd]pyrimidineꢀ2,4(1H,3H)ꢀdione (3c), 1ꢀ(4ꢀfluorophenyl)ꢀ
6ꢀisopropylꢀ5,6,7,8ꢀtetrahydropyrimido[4,5ꢀd]pyrimidineꢀ
Scheme 3
2,4(1H,3H)ꢀdione
(3d),
1ꢀallylꢀ6ꢀphenethylꢀ2ꢀthioxoꢀ
2,3,5,6,7,8ꢀhexahydropyrimido[4,5ꢀd]pyrimidinꢀ4(1H)ꢀone (4a),
1ꢀ(2ꢀmethylpropꢀ2ꢀenꢀ1ꢀyl)ꢀ6ꢀphenethylꢀ2ꢀthioxoꢀ2,3,5,6,7,8ꢀ
hexahydropyrimido[4,5ꢀd]pyrimidinꢀ4(1H)ꢀone (4b), 6ꢀcyclohexꢀ
ylꢀ1ꢀ(2ꢀmethylpropꢀ2ꢀenꢀ1ꢀyl)ꢀ2ꢀthioxoꢀ2,3,5,6,7,8ꢀhexahydroꢀ
pyrimido[4,5ꢀd]pyrimidinꢀ4(1H)ꢀone (4c), 1ꢀ(2ꢀchlorophenyl)ꢀ6ꢀ
phenethylꢀ2ꢀthioxoꢀ2,3,5,6,7,8ꢀhexahydropyrimido[4,5ꢀd]pyꢀ
rimidinꢀ4(1H)ꢀone (4d), and 1ꢀ(2ꢀchlorophenyl)ꢀ6ꢀcyclopentylꢀ2ꢀ
thioxoꢀ2,3,5,6,7,8ꢀhexahydropyrimido[4,5ꢀd]pyrimidinꢀ4(1H)ꢀ
one (4e) (general procedure). A primary amine (6 mmol) and 30%
7: R´ = Ph(CH2)2 (a, b); R″ = H (a), Me (b)
As with earlier7 obtained thiazolines, the H NMR
spectra of compounds 7a,b show a doublet for the CH3
1

Tetrahydropyrimido[4,5ꢀd]pyrimidineꢀ2,4ꢀdiones Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Table 1. Yields, melting points, and elemental analysis data for compounds 3a—d, 4a—e, and 6a,b—8a,b
1545
Comꢀ
pound
Yield
(%)
M.p./°C
Found
Calculated
Molecular
formula
(%)
C
H
N
3a
3b
3c
3d
4a
4b
4c
4d
4e
6a
6b
7a
7b
8a
8b
68
74
89
91
65
69
85
77
92
84
88
67
82
63
72
200—202
197—199
221—222
210—212
149—151
172—174
154—156
202—204
200—202
122—124
148—150
175—177
178—180
145—147
156—158
69.47
69.59
66.33
66.24
64.64
64.76
59.12
59.20
62.29
62.17
63.31
63.13
59.81
59.97
60.13
60.22
56.23
56.27
61.30
61.14
58.22
58.42
62.31
62.17
63.38
63.13
51.52
51.31
48.34
48.12
6.03
6.12
6.63
6.79
4.93
4.86
5.62
5.63
6.25
6.14
6.35
6.48
7.73
7.55
4.88
4.80
5.39
5.28
4.52
4.58
4.78
4.90
6.42
6.14
6.31
6.48
5.29
5.02
5.89
5.81
15.61
15.46
17.36
17.16
16.01
15.90
18.49
18.41
17.32
17.06
16.56
16.36
17.38
17.48
14.14
14.04
15.42
15.44
12.81
12.73
13.68
13.62
17.34
17.06
16.48
16.36
13.03
13.30
14.91
14.03
C21H22N4O2
C18H22N4O2
C19H17FN4O2
C15H17FN4O2
C17H20N4OS
C18H22N4OS
C16H24N4OS
C20H19ClN4OS
C17H19ClN4OS
С28H25ClFN5O2S
С16H11ClFN5O2S
С17H20N4OS
С18H22N4OS
C18H21BrN4OS
C16H23BrN4OS
formalin (15 mmol) were added to a solution or suspension of
compound 1 or 2 (5 mmol) in DMF (10 mL). The reaction mixture
was stirred with a magnetic stirring bar for 8 h and then diluted with
water (80 mL). The precipitate that formed was filtered off and
recrystallized from 50% EtOH.
The yields, melting points, elemental analysis data, and 1H NMR
spectra of compounds 3a—d and 4a—e are given in Tables 1 and 2.
Nꢀ(4ꢀFluorophenyl)ꢀ2ꢀ[1ꢀ(2ꢀchlorophenyl)ꢀ4ꢀoxoꢀ6ꢀphenꢀ
ethylꢀ1,4,5,6,7,8ꢀhexahydropyrimido[4,5ꢀd]pyrimidinꢀ2ꢀylsulfꢀ
anyl]acetamide (6a) and Nꢀ(4ꢀfluorophenyl)ꢀ2ꢀ[1ꢀ(2ꢀchloropheꢀ
nyl)ꢀ6ꢀcyclopentylꢀ4ꢀoxoꢀ1,4,5,6,7,8ꢀhexahydropyrimido[4,5ꢀd]ꢀ
pyrimidinꢀ2ꢀylsulfanyl]acetamide (6b) (general procedure). A soluꢀ
tion of thione 4 (2 mmol) and Nꢀ(4ꢀfluorophenyl)chloroacetamide
(2 mmol) was heated in DMF (5 mL) at 80 °C for 1 h. Triethylamine
Table 2. 1H and 19F NMR spectra of compounds 3a—d, 4a—e, and 6a,b—8a,b in DMSOꢀd6
Comꢀ
pound
δH (J/Hz)
δ
F
(m)
3a
3b
3c
2.60—2.89 (m, 4 H, CH2CH2); 2.76 (m, 1 H, CHN); 3.45 (s, 2 H, CH2N); 3.96 (br.s, 2 H, CH2NH);
5.01 (s, 2 H, CH2Ph); 6.95 (br.s, 1 H, CH2NH); 7.17—7.39 (m, 4 H, CHAr); 10.49 (s, 1 H, NH)
—
1.30—1.96 (m, 4 H, CH2); 2.76 (m, 1 Н, CHN); 3.49 (s, 2 H, CH2N); 4.05 (br.s, 2 H, CH2NH);
5.02 (s, 2 H, CH2Ph); 7.03 (br.s, 1 H, CH2NH); 7.10—7.45 (m, 10 H, CHAr); 10.54 (s, 1 H, NH)
—
3.49 (s, 2 H, CH2N); 3.66 (s, 2 H, CH2Ph); 3.88 (d, 2 H, CH2NH, J = 2.5); 5.96 (t, 1 H, CH2NH,
J = 2.5); 7.12—7.48 (m, 9 H, CHAr); 10.52 (s, 1 H, NH)
–34.76
(to be continued)

1546
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Aksinenko et al.
Table 2 (continued)
Comꢀ
pound
δ
H (J/Hz)
δ
(m)
F
3d
4a
4b
4c
4d
4e
6a
1.05 (d, 6 H, Me, J = 6.3); 2.79 (sept, 1 H, CH, J = 6.3); 3.49 (s, 2 H, CH2N); 3.91 (d, 2 H, CH2NH,
J = 2.5); 6.06 (t, 1 H, CH2NH, J = 2.5); 7.39 (m, 4 H, CHAr); 10.63 (s, 1 H, NH)
–36.24
2.60—2.90 (m, 4 H, CH2CH2); 3.49 (s, 2 H, CH2N); 4.05 (s, 2 H, CH2NH); 4.94—5.25 (m, 4 H,
=CH2 + CH2CH=); 5.85 (m, 1 H, CH=); 7.10—7.38 (m, 6 H, CHAr + NH); 12.07 (s, 1 H, NH)
1.80 (s, 3 H, Me); 2.60—2.90 (m, 4 H, CH2CH2); 3.54 (s, 2 H, CH2N); 4.04 (s, 2 H, CH2NH);
4.57, 4.82 (both s, 1 H each, =CH2); 6.84 (s, 1 H, NH); 7.04—7.35 (m, 5 H, CHAr); 11.73 (s, 1 H, NH)
1.22 (m, 5 H, CH2); 1.47—2.00 (m + s, 8 H, CH2 + Me); 2.37 (m, 1 H, CHN); 3.54 (s, 2 H, CH2N);
4.07 (s, 2 H, CH2NH); 4.55, 4.81 (both s, 1 H each, =CH2); 6.77 (s, 1 H, NHCH2); 11.65 (s, 1 H, NH)
—
—
—
2.63—2.90 (m, 4 H, CH2CH2); 3.61 (s, 2 H, CH2N); 3.99 (br.s, 2 H, CH2NH); 6.00 (br.s, 1 H, CH2NH);
7.04—7.32 (m, 5 H, Ph); 7.33—7.68 (m, 4 H, CHAr
—
—
)
1.24—1.96 (m, 4 H, CH2); 2.84 (m, 1 Н, CHN); 3.52 (s, 2 H, CH2N); 3.90 (br.s, 2 H, CH2NH);
5.89 (br.s, 1 H, CH2NH); 7.26—7.64 (m, 4 H, CHAr); 11.76 (s, 1 H, NH)
2.60—2.86 (m, 4 H, CH2CH2); 3.54 (s, 2 H, CH2N); 3.86 (ABꢀsystem, 2 H, CH2S, JAB = 14.9); 3.92
(br.s, 2 H, CH2NH); 6.10 (br.s, 1 H, CH2NH); 6.98 (m, 2 H, CHAr); 7.09—7.26 (m, 5 H, CHAr);
7.50—7.74 (m, 6 H, CHAr); 10.52 (s, 1 H, NH)
–35.04
6b
1.25—1.99 (m, 4 H, CH2); 2.83 (m, 1 Н, CHN); 3.52 (s, 2 H, CH2N); 3.85 (ABꢀsystem, 2 H, CH2S,
JAB = 14.5); 3.88 (br.s, 2 H, CH2NH); 6.04 (br.s, 1 H, CH2NH); 6.93 (m, 2 H, CHAr); 7.43—7.75
(m, 6 H, CHAr); 10.59 (s, 1 H, NH)
–34.88
7a
7b
8a
1.53 (d, 3 H, Me, J = 6.8); 2.80 (m, 4 H, CH2CH2); 3.44 (s, 2 H, CH2N); 3.83—4.14 (s + m, 3 H,
CH2NH + CH2CH); 4.33 (dd, 1 H, CH2CH, J = 10.6, J = 6.8); 6.91 (s, 1 H, NH); 7.23 (m, 5 H, Ph)
1.63 (s, 6 H, Me); 2.80 (m, 4 H, CH2CH2); 3.44 (s, 2 H, CH2N); 3.98 (d, 2 H, CH2NH, J = 3.0);
4.02 (s, 2 H, CH2CS); 7.00 (br.s, 1 H, CH2NH); 7.20 (m, 5 H, Ph)
1.76 (s, 3 H, Me); 2.83 (m, 4 H, CH2CH2); 3.53 (s, 2 H, CH2N); 3.98 (s, 2 H, CH2NH); 4.07 (d, 1 H,
CH2Br, J = 11.9); 4.10 (s, 2 H, CH2CS); 4.40 (d, 1 H, CH2Br, J = 11.9); 7.24 (m, 5 H, Ph);
7.54 (s, 1 H, NH)
—
—
—
8b
1.30 (m, 5 H, CH2); 1.47—2.00 (m + s, 8 H, CH2 + Me); 2.57 (m, 1 H, CHN); 3.53 (s, 2 H, CH2N);
3.93 (s, 2 H, CH2NH); 4.07 (d, 1 H, CH2Br, J = 12.1); 4.11 (s, 2 H, CH2CS); 4.45 (d, 1 H, CH2Br,
J = 12.1); 7.31 (s, 1 H, NH)
—
(2.5 mmol) was added and heating was continued at the same
temperature for an additional 3 h. The reaction mixture was diluted
with water (50 mL). The precipitate that formed was filtered off and
recrystallized from 50% EtOH.
Yields, melting points, elemental analysis data, and 1H NMR
spectra of compounds 8a,b are given in Tables 1 and 2.
References
Yields, melting points, elemental analysis data, and 1H NMR
spectra of compounds 6a,b are given in Tables 1 and 2.
1. R. E. Looper, M. T. C. Runnegar, R. M. Williams, Angew.
Chem., Int. Ed., 2005, 44, 3879.
2. M. Zhang, H. Jiang, H. Liu, Q. Zhu, Org. Lett., 2007, 9, 4111.
3. J. L. Bernier, A. Lefebre, C. Lespagnol, J. Navarro, A. Perio,
Eur. J. Med. Chem., 1977, 12, 341.
8ꢀMethylꢀ3ꢀphenethylꢀ1,2,3,4,8,9ꢀhexahydroꢀ5Hꢀpyrimꢀ
ido[5,4ꢀe][1,3]thiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone (7a) and 8,8ꢀdimeꢀ
thylꢀ3ꢀphenethylꢀ1,2,3,4,8,9ꢀhexahydroꢀ5Hꢀpyrimido[5,4ꢀe]ꢀ
[1,3]thiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone (7b) (general procedure).
A suspension of thione 4 (2 mmol) in 48% HBr (5 mL) was heated
at 120 °C for 2 h to homogenization. On cooling, the reaction
mixture was diluted with water (20 mL) and neutralized with 10%
NaOH. The precipitate that formed was filtered off and recrystalꢀ
lized from EtOH.
4. V. Warin, M. Lobry, F. Baert, J. L. Bernier, J. P. Henichart, Acta
Crystallogr., 1979, 35B, 2165.
5. J. G. Miller, E. C. Wagner, J. Am. Chem. Soc., 1932, 54, 3698.
6. V. B. Sokolov, A. Yu. Aksinenko, Izv. Akad. Nauk, Ser. Khim.,
2005, 1474 [Russ. Chem. Bull., Int. Ed., 2005, 54, 1518].
7. V. B. Sokolov, A. Yu. Aksinenko, A. N. Pushin, I. V. Martynov,
Izv. Akad. Nauk, Ser. Khim., 2005, 1694 [Russ. Chem. Bull.,
Int. Ed., 2005, 54, 1744].
8. V. B. Sokolov, A. Yu. Aksinenko, T. A. Epishina, T. V. Goreva,
I. V. Martynov, Izv. Akad. Nauk, Ser. Khim., 2005, 2755 [Russ.
Chem. Bull., Int. Ed., 2005, 54, 2851].
Yields, melting points, elemental analysis data, and 1H NMR
spectra of compounds 7a,b are given in Tables 1 and 2.
8ꢀ(Bromomethyl)ꢀ8ꢀmethylꢀ3ꢀphenethylꢀ1,2,3,4,8,9ꢀhexahyꢀ
droꢀ5Hꢀpyrimido[5,4ꢀe][1,3]thiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone (8a)
and 8ꢀ(bromomethyl)ꢀ3ꢀcyclohexylꢀ8ꢀmethylꢀ1,2,3,4,8,9ꢀhexahyꢀ
droꢀ5Hꢀpyrimido[5,4ꢀe][1,3]thiazolo[3,2ꢀa]pyrimidinꢀ5ꢀone (8b)
(general procedure). Bromine (4 mmol) was added at 20 °C to
a suspension of thione 4 (2 mmol) in EtOH (10 mL). The reaction
mixture was stirred for 1 h, diluted with water (50 mL), and
neutralized with 10% NaOH. The precipitate that formed was filꢀ
tered off and recrystallized from EtOH.
9. W. Hatzenlaub, W. Pfleiderer, Liebigs Ann. Chem., 1979, 1847.
Received December 13, 2007;
in revised form March 4, 2008