Halocyclization of substituted 2-(alkenylthio)pyrimidin-6-ones

Article abstract of DOI:10.1023/B:COHC.0000037323.22839.9f

Bromination and iodation of 2-(alkenylthio)pyrimidin-6-ones occur selectively and lead to formation of the corresponding 7-oxo-2,3- dihydrothiazolopyrimidinium or 8-oxo-3,4-dihydro-2H-pyrimidothiazinium salts. The selectivity of the reaction is controlled

Full text of DOI:10.1023/B:COHC.0000037323.22839.9f

Chemistry of Heterocyclic Compounds, Vol. 40, No. 5, 2004
HALOCYCLIZATION OF SUBSTITUTED
2-(ALKENYLTHIO)PYRIMIDIN-6-ONES
N. Yu. Slivka1, Yu. I. Gevaza2, and V. I. Staninets2
Bromination and iodation of 2-(alkenylthio)pyrimidin-6-ones occur selectively and lead to formation of
the corresponding 7-oxo-2,3-dihydrothiazolopyrimidinium or 8-oxo-3,4-dihydro-2H-pyrimido-
thiazinium salts. The selectivity of the reaction is controlled by the nature of the alkenyl substituent on
the sulfur atom and the basicity of the N(1) and N(3) atoms of the pyrimidine ring. The iodation reaction
rate increases as the basicity of the N(3) atom increases.
Keywords: (allylthio)pyrimidines, pyrimidothiazines, thiazolidine pyrimidines, bromination,
heterocyclization, iodation.
Iodation of 2-allylthio-1H-pyrimidin-6-ones leads to formation of 3-iodomethyl-7-oxo-2,3-dihydro-8H-
thiazolo[3,2-a]pyrimidinium iodides and triiodides [1]. An analogous conversion is also observed in the case of
halogenation of 2-(allylthio)thienopyrimidin-6-ones [2, 3].
This work was devoted to determining the selectivity of halocyclization of substituted 2-(alkenylthio)-4-
R-pyrimidin-6-ones 1a-g and studying the effect of the nature of the substituent R on the rate of the indicated
reaction.
The starting compounds 1a-d were synthesized from the sodium salt of 6-methylthiouracil and the
corresponding alkenyl halide by the procedure in [3]. Compounds 1e-g were obtained from 6-amino-4-hydroxy-
2-mercaptopyrimidine and the corresponding alkenyl halide by the procedure in [1].
When compounds 1a-g were reacted with bromine or iodine in chloroform or acetic acid, after treatment
of the initially formed trihalo derivatives (see [1]) with acetone we selectively obtained substituted 7-oxo-2,3-
dihydrothiazolopyrimidinium salts 2a-d, 3a-d or 8-oxo-3,4-dihydropyrimidothiazinium salts 4a-c, 5a-c
(Scheme 1).
Obviously the selectivity of cyclization is determined by the nature and position of the substituents on
the allyl moiety bonded to the sulfur atom. Thus from compounds 1a,b,e,f, which have allyl and methallyl
substituents, only the salts 2a-d, 3a-d are formed, while only the salts 4a-c, 5a-c are formed from compounds
1c,d,g with a thiocinnamyl or thio-2-methylbutenyl group.
The composition and structure of all the synthesized compounds were confirmed by elemental analysis
(Table 1), IR spectra, and 1H NMR (Table 2).
1
The H NMR spectra indicate that the products 2, 3, and 4, 5 belong to different series of compounds.
The signal common to both series, for the SCH2 moiety, in the case of salts 2, 3 has the shape of two doublets of
doublets (for R = Me) or two doublets (for R = NH2) in the 3.44-3.46 ppm and 3.70-3.89 ppm region. The
multiplet signal for the CH2Hal group is typical of the spectra for compounds 2, 3, which is found in the
__________________________________________________________________________________________
1
2
Lesya Ukrainka Volyn State University, Lutsk 43025, Ukraine. Institute of Organic Chemistry,
National Academy of Sciences of Ukraine, Kiev 02094; e-mail: iochkiev@ukrpack.net. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 776-783, May, 2004. Original article submitted
February 15, 2002; revised March 9, 2004.
660
0009-3122/04/4005-0660©2004 Plenum Publishing Corporation

Scheme 1
O
_
O
NH
Hal
O
N
R1
R2
Hal
R3
+
N
Hal2
Hal2
_
Hal
C
R
NH
S
NH
R1
R2
1c,d,g
1a,b,e,f
+
N
R
S
R
S
R3
1a–g
HalH2C
4a–c, 5a–c
2a–d, 3a–d
O
O
N
N
N
AcONa
AcONa
DMSO
2a,b
4a,b
DMSO
N
Me
S
S
Me
R1
R2
R3
BrH2C
Br
6a,b
7a,b
O
N
Me
H2SO4
N
1a
Me
S
8
2, 4 Hal = Br, 3, 5 Hal = I; 1a–d R = Me, e–g R = NH2; a, e R1 = R2 = R3 = H, b, f R1 = R2 = H, R3 = Me,
c, g R1 = R2 = Me, R3 = H, d R1 = R3 = H, R3 = Ph; 2, 3 a, b R = Me, c, d R = NH2;
a, c R3 = H, b, d R3 = Me; 4, 5 a, b R = Me, c R = NH2; a, c R1 = R2 = Me, b R1 = H, R2 = Ph;
6 a R3 = H, b R3 = Me; 7 a R1 = R2 = Me, b R1 = H, R2 = Ph
4.15-4.18 ppm region for R = Me and in the 3.76-3.89 ppm region for R = NH2 (compare compounds 2a, 3a and
2c, 3c, 2b, 3b, and 2d, 3d). This difference, and also the different shapes of the signals for the SCH2 group, may
be connected with the effect of the steric factor (closely surrounded by solvent molecules, the basic NH2 group
creates different steric conditions than the neutral methyl substituent). The appearance of the latter is more likely
when the substituents R and CH2Hal are close to each other, i.e., when cyclization occurs at the N(3) atom. Such a
direction of the reaction is also confirmed by the conversion of the salts 2a,b to the bases 6a,b when treated with
AcONa in DMSO. In the IR spectra of the latter, the absorption band for the carbonyl group is found at 1620 cm-
1, which indicates they have a p-quinoid structure (see [1]).
The spectra of compounds 4, 5 are considerably different from the spectra considered above. The signal
from the SCH2 group of these compounds has the form of two multiplets, which are found 3.56-3.90 ppm and
3.82-3.89 ppm upfield from the signals of the analogous group of compounds 2,3. A typical feature of the
considered spectra is the presence of signals from the CHHal and C(4)R1R2 groups. The multiplet signal from the
CHHal moiety, compared with the signal from the CH2Hal moiety of compounds 2,3, is found downfield in the
narrow interval 4.65-4.70 ppm for all salts 4, 5, which indicates the absence of any appreciable change in its
position when the 6-Me substituent is replaced by 6-NH2. On the other hand, such a replacement causes a
0.19-0.28 ppm upfield shift of the signal from the protons of the methyl group in the 4 position (compare 4a and
4c, 5a and 5c). As in the case of compounds 2,3, this is possibly connected with the effect of the steric factor,
i.e., it is support for the idea that the R and C(4)R1R2 and R groups are close and consequently that cyclization
occurs at the N(3) atom. When the salts 4a,b are treated with AcONa in DMSO, the corresponding bases 7a,b are
formed, and the absorption band for the C=O of those compounds is found at 1630-1620 cm-1, supporting the
idea that they have a p-quinoid structure and that the direction of cyclization is at the N(3) atom.
661

O
+
O
NH
Hal2
_
NH
Hal
Me
N
S
Me
N
S
9
HalHC
10, 11
O
N
AcONa
DMSO
10
Me
BrHC
N
S
12
10 Hal = Br, 11 Hal = I
The structure of compounds 2c-5c is supported by the presence in the IR spectra of a signal from the NH
group in the 10.01-10.60 ppm region, which however is missing in the spectra of the rest of the salts 2-5 (also
see [3]).
Formation of products 2-5 suggests that halocyclization of compounds 1a-g occurs, as we might expect
[4], with participation of the more basic N(3) atom. However, when the pyrimidinone 1a is treated with sulfuric
acid, cyclization occurs at the N(1) atom to form 3,7-dimethyl-5-oxo-2,3-dihydro-8H-thiazolo[3,2-a]pyrimidine
(8), the structure of which is supported by the 1H NMR data (Table 2) and the IR spectrum (the absorption band
for the C=O group is found at 1680 cm-1, which suggests an o-quinoid structure for compound 8 (see [1])). In
this case, the change in the direction of the reaction is probably connected with the high degree of protonation of
the more basic N(3) atom in compound 1a.
TABLE 1. Characteristics of the Synthesized Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield,
%
mp, °С
Rf*
Hal
3
N
4
S
5
1
2
6
146-147
166-167
160-161
Oil
7
8
1b
1c
1d
1e
1f
C9Н12N2OS
C10H14N2OS
C14H14N2OS
C7H9N3OS
14.03
14.28
13.19
13.33
9.97
10.55
22.18
22.96
21.11
21.33
20.14
19.91
16.30
16.34
15.07
15.25
11.65
12.41
17.74
17.50
16.34
16.26
15.29
15.18
9.12
9.37
8.98
9.11
0.84
0.79
0.74
0.89
0.88
0.87
0.46
0.47
0.54
0.53
81
89
86
67
60
64
73
76
63
60
C8H11N3OS
С9H13N3OS
C8H10Br2N2OS
C9H12Br2N2OS
C7H9Br2N3OS
C8H11Br2N3OS
Oil
1g
2а
2b
2c
2d
Oil
47.11
46.70
45.26
44.90
46.83
46.59
45.01
44.77
155-156
161-162 (dec.)
148-149
153-155
9.18
9.34
8.62
8.98
662

TABLE 1 (continued)
1
2
3
4
5
6
7
8
3a
C8H10I2N2OS
C9H12I2N2OS
C7H9I2N3OS
58.50
58.21
56.82
56.41
58.43
58.10
56.61
56.30
7.13
7.35
7.01
7.12
184 (dec.)
189-190 (dec.)
177-178
0.43
0.45
0.56
0.54
0.44
79
63
61
57
78
77
3b
3c
3d
4a
4b
9.31
9.62
9.20
9.32
C8H11I2N3OS
C10H14Br2N2OS
C14H14Br2N2OS
182-183
43.47
43.19
8.34
8.66
182-183 (dec.)
169-176*2
0.44,
0.62
37.98
38.20
7.51
7.67
4c
5a
5b
C9H13Br2N3OS
C10H14I2N2OS
C14H14I2N2OS
43.28
43.08
55.03
54.71
8.34
8.16
6.88
6.90
158-159
0.55
69
61
64
222 (dec.)
0.42
200-209*2 (dec.) 0.43,
0.60
49.83
49.58
5.21
5.47
5c
6a
6b
7a
7b
C9H13I2N3OS
C8H9Br2N2OS
C9H11BrN2OS
C10H13BrN2OS
C14H13BrN2OS
54.78
54.62
30.62
30.59
29.32
29.04
27.51
27.63
9.16
9.04
185-186
139-140
148-149
165-166
148-160*2
0.57
0.81
0.80
0.85
58
80
75
78
79
12.04
12.27
11.83
11.65
9.83
9.69
0.83,
0.92
24.02
23.69
8.56
8.31
8
C8H10N2OS
C8H8N2OS
15.65
15.38
15.65
15.55
17.82
17.60
17.81
17.79
9.28
9.43
101-103
162-163
0.90
0.70
0.48
0.46
0.81
62
81
73
82
72
9
10
11
12
C8H8Br2N2OS
C8H8I2N2OS
C8H7BrN2OS
47.37
47.00
58.83
58.53
31.11
30.84
177-178
6.28
6.46
212-213 (dec.)
157-158
12.58
12.31
_______
* Eluent for TLC: chloroform–acetone–diethylamine, 10:2:1 (compounds
1b-d, 6a,b, 7a,b, 8, 9, and 12), ethyl acetate–methanol–acetone, 15:4:2
(compounds 2a,b-5a,b, 10, 11), methanol–acetone–diethylamine, 10:10:2
(compounds 1e-g, 2c,d, 3c,d, 4c, 5c).
*2 mp of the mixture of diastereomers.
Halocyclization also occurs selectively in the case of 6-methyl-2-(propynylthio)pyrimidin-6-one (9):
when it is halogenated with bromine or iodine in chloroform, only substituted thiazolidinopyrimidinium salts 10,
1
11 are formed (Scheme 2). The structure of the latter is supported by H NMR spectra (the presence of singlet
signals from the SCH2 and CHHal groups in the 4.25-4.34 ppm and 7.07-7.18 ppm respectively), and also by the
conversion of product 10 to base 12 when treated with AcONa in DMSO. In the IR spectrum of compound 12,
the absorption band for the C=O group is found at 1640 cm-1, which indicates that it has a p-quinoid structure.
The starting compound 9 was obtained by the procedure in [3].
In order to determine the effect of the nature of the substituent R on the C(4) atom of
(alkenylthio)pyrimidin-6-ones 1a-g, we estimated the relative rate of iodation of compounds 1a,d,e. We found
that under identical conditions, after 5 h this reaction proceeds to 57.6% (1a), 51.0% d (1d), 81.6% (1e)
663

TABLE 2. 1H NMR and IR Spectra of Synthesized Compounds
Com-
pound
ν (С=О),
сm-1
Chemical shifts, δ, ppm (J, Hz)
1b
1c
1d
1.76 (3Н, s, СH3); 2.12 (3H, s, 4-CH3); 3.81 (2Н, s, SСН2);
5.02 (2Н, m, =СН2); 5.97 (1Н, s, H-5); 12.50 (1Н, s, NН)
1670
1670
1670
1.69 (6Н, s, two CH3); 2.16 (3Н, s, 4-CH3); 3.77 (2Н, d, 3J = 6.9, SСН2);
5.38 (1Н, m, =СН); 5.96 (1Н, s, H-5); 12.46 (1Н, s, NН)
2.21 (3Н, s, 4-CH3); 3.97 (2Н, d, 3J = 7.2, SСН2); 6.39 (1Н, m, =СН);
6.66 (1Н, d, 3J = 10.5, =СНC6H5,); 7.23-7.39 (5Н, m, C6H5);
12.52 (1Н, s, NН)
2.31 (3Н, s, 5-CH3); 3.51 and 3.70 (2Н, two dd, 2J1 = 2J2 = 12.0, 3J = 5.9,
SСН2); 4.12 (2Н, m, СН2Br); 5.18 (1Н, m, H-3); 6.20 (1Н, s, H-6)
2а
2b
2с
2d
3а
3b
3с
3d
4а
4b
4c
5а
5b
5с
6а
8
1680
1700
1690
1695
1685
1700
1700
1700
1700
1690
1685
1680
1700
1690
1620
1680
1670
1700
1700
1.83 (3Н, s, 3-CH3); 2.16 (3Н, s, 5-CH3); 3.58 and 3.75 (2Н, two dd,
2J1 = 2J2 = 12.3, 4J = 2.2, SСН2); 4.15 (2Н, m, СН2Br); 6.22 (1Н, s, H-6)
3.46 and 3.76 (2Н, two d, 2J1 = 2J2 = 12.4, SСН2); 3.81 (2Н, m, СН2Br);
5.17 (1Н, m, H-3); 6.97 (1Н, s, H-6); 9.17 (2Н, br. s, NН2); 10.59 (1Н, s, NН)
1.88 (3Н, s, 3-CH3); 3.46 and 3.72 (2Н, two d, 2J1 = 2J2 = 12.1, SСН2);
3.89 (2Н, m, СН2Br); 6.09 (1Н, s, H-6); 8.73 (2Н, br. s, NН2)
2.31 (3Н, s, 5-CH3); 3.53 and 3.78 (2Н, two dd, 2J1 = 2J2 = 12.3, 3J = 5.8,
SСН2,); 4.13 (2Н, m, СН2I); 5.21 (1Н, m, H-3); 6.23 (1Н, s, H-6)
1.84 (3Н, s, 3-CH3); 2.15 (3Н, s, 5-CH3); 3.66 and 3.76 (2Н, two dd,
2J1 = 2J2 = 12.3, 4J = 1.8, SСН2); 4.18 (2Н, m, СН2І); 6.11 (1Н, s, H-6)
3.48 and 3.77 (2Н, two d, 2J1 = 2J2 = 12.0, SСН2); 3.85 (2Н, m, СН2І);
5.03 (1Н, m, H-3); 6.99 (1Н, s, H-6); 9.14 (2Н, br. s, NН2); 10.60 (1Н, s, NН)
1.83 (3Н, s, 3-CH3); 3.44 and 3.78 (2Н, two d, 2J1 = J2 = 12.3, SСН2);
3.88 (2Н, m, СН2І); 6.16 (1Н, s, H-6); 8.82 (2Н, br. s, NН2)
2.06 (3Н, s, 4-CH3); 2.15 (3Н, s, 4-CH3); 2.65 (3Н, s, 6-CH3);
3.56 and 3.82 (2Н, two m, SСН2); 4.66 (1Н, m, H-3); 6.21 (1Н, s, H-7)
2.34 (3Н, s, 6-CH3); 3.90 and 4.02 (2Н, two m, SСН2); 4.65 (1Н, m, H-3);
5.76 (1Н, d, 3J = 10.2, H-4); 6.21 (1Н, s, H-7); 6.42–7.67 (5Н, m, C6H5)
1.87 (3Н, s, 4-CH3); 1.94 (3Н, s, 4-CH3); 3.67 and 4.09 (2Н, two m, SСН2);
4.65 (1Н, m, H-3); 6.19 (1Н, s, H-7); 9.13 (2Н, br. s, NН2); 10.01 (1Н, s, NН)
2.11 (3Н, s, 4-CH3); 2.23 (3Н, s, 4-CH3); 2.49 (3Н, s, 6-CH3);
3.60 and 3.87 (2Н, two m, SСН2); 4.67 (1Н, m, H-3); 6.15 (1Н, s, H-7)
2.31 (3Н, s, 6-CH3); 3.85 and 4.00 (2Н, two m, SСН2); 4.70 (1Н, m, H-3);
5.79 (1Н, d, 3J = 10.1, H-4); 6.22 (1Н, s, H-7); 7.54–7.72 (5Н, m, C6H5)
1.89 (3Н, s, 4-CH3); 1.95 (3Н, s, 4-CH3); 3.70, 4.12 (2Н, two m, SСН2);
4.67 (1Н, m, H-3); 6.17 (1Н, s, H-7); 9.12 (2Н, br. s, NН2); 10.08 (1Н, s, NН)
2.11 (3Н, s, 5-CH3); 3.48 and 3.66 (2Н, two d, 2J1 = 2J2 = 6.6, SСН2);
3.99 (2Н, m, СН2Br); 5.06 (1Н, m, H-3); 6.01 (1Н, s, H-6)
2.19 (3H, d, 3J = 6.9, 3-CH3); 2.21 (3Н, s, 7-CH3); 3.83 (2H, d, 3J = 6.9,
SСН2); 5.11 (1H, m, H-3); 6.21 (1H, s, H-6)
9
2.11 (3Н, s, 4-CH3); 3.19 (1Н, t, 4J = 2.2, ≡СН,); 3.99 (2Н, d, 4J = 2.2, SCH2);
6.07 (1Н, s, H-5); 12.49 (1Н, s, NН)
10
11
2.31 (3Н, s, 5-CH3); 4.25 (2Н, s, SСН2); 6.26 (1Н, s, H-6);
7.18 (1Н, s, =СНBr)
2.21 (3Н, s, 5-CH3); 4.34 (2Н, s, SСН2); 6.06 (1Н, s, H-6); 7.07 (1Н, s, =СНI)
conversion. The high percentage conversion of compound 1e is probably connected with the presence in that
compound of an NH2 group, the electronic effect of which on the N(3) atom increases the basicity of the latter and
consequently increases the reactivity.
Thus the direction of halocyclization of 2-alkyenylthiopyrimidin-6-ones is substantially affected by the
structure of the S-alkeynyl substituent, which leads to regioselective formation of thiazolidinopyrimidinium or
pyrimidothiazinium derivatives. An electron-donor substituent on the heterocycle (R = NH2) accelerates the
heterocyclization of 2-(alkyenylthio)pyrimidin-6-ones.
664

EXPERIMENTAL
1
The IR spectra were recorded on a UR-20 in KBr disks. The H NMR spectra of solutions of the
substances in DMSO-d6 were obtained on a Varian VXR-300 spectrometer (300 MHz), internal standard TMS.
The course of the reaction was monitored by TLC on Silufol UV-254 plates.
2-Allylthio- (1a), 2-Methallylthio- (1b), and 2-Propargylthio-4-methyl-1H-pyrimidin-6-one (9)
(General Procedure). A solution of allyl bromide, methallyl chloride, or propargyl chloride (45 mmol) in
alcohol (20 ml) was added with heating (~90°C) to sodium salt of 6-methyl-2-thiouracil (5.0 g, 30 mmol) in
water (150 ml). The mixture was vigorously shaken and held for 4-5 h at 18-20°C. The precipitate of product
1a,b or 1c formed was filtered out and washed with alcohol, then crystallized from a 1:2 alcohol–water mixture
and dried at 80-90°C. For compound 1a: mp 134°C (mp 133°C [1]). According to the data in [5], the mp of
compound 9 is 162°C.
4-Methyl-2-(3-methyl-2-butenylthio)- (1c) and 4-Methyl-2-cinnamylthio-1H-pyrimidin-6-one (1d)
(General Procedure). 1-Chloro-3-methyl-2-butene or cinnamyl chloride (45 mmol) was added with stirring to a
solution of sodium salt of 6-methyl-2-thiouracil (5 g, 30 mmol) in DMF (70 ml). The mixture was held for 2 h at
50-60°C and then cooled down and diluted with water (100 ml). The colorless precipitate of product 1c or 1d
formed was filtered out and washed with ether, then crystallized from an alcohol–water mixture and dried at
80-90°C.
2-Allylthio- (1e), 2-Methallylthio- (1f), and 2-(3-Methyl-2-butenylthio)-4-amino-1H-pyrimidin-6-
one (1g) (General Procedure). 6-Amino-4-hydroxy-2-mercaptopyrimidine (5.0 g, 35 mmol) and allyl bromide,
methallyl chloride, or 1-chloro-3-methyl-2-butene (35 mmol) were added to a solution of KOH (1.95 g,
35 mmol) in alcohol (90 ml). The mixture was boiled for 2 h under reflux and then cooled down; the colorless
precipitate was filtered out and then the filtrate was evaporated down. The product 1e,f or 1g was obtained as a
dark yellow oil that dissolved well in water.
3-Bromomethyl-5-methyl-
(2a)
and
3-Bromomethyl-3,5-dimethyl-7-oxo-2,3-dihydro-8H-
thiazolo[3,2-a]pyrimidinium (2b), 3-Bromo-4,4,6-trimethyl- (4a), and 3-Bromo-6-methyl-8-oxo-4-phenyl-
3,4-dihydro-9H-pyrimido[3,2-a]thiazinium (4b), 3-Bromomethylidene-5-methyl-7-oxo-2,3-dihydro-8H-
thiazolo[3,2-a]pyrimidinium (10) Bromides (General Procedure). A solution of bromine (1.44 g, 9.0 mmol)
in glacial acetic acid (15 ml) was added with stirring to a solution of compound 1a-d (4.5 mmol) or 9 in glacial
acetic acid (40 ml). After 2 h, the yellow precipitate of the corresponding tribromide (see [1]) was filtered out
and then washed with hot glacial acetic acid. The tribromide obtained (3.0 mmol) was added in several portions
to acetone (15 ml); the reaction mixture was stirred for 30 min at 25°C. The precipitate was filtered out, washed
with acetone, crystallized from alcohol, and dried at 90-100°C. The product 2a,b, 4a,b, or 10 was obtained
respectively.
3-Iodomethyl-5-methyl- (3a) and 3-Iodomethyl-3,5-dimethyl-7-oxo-2,3-dihydro-8H-thiazolo-
[3,2-a]pyrimidinium (3b), 3-Iodo-4,4,5-trimethyl- (5a), and 3-Iodo-6-methyl-8-oxo-4-phenyl-3,4-dihydro-
9H-pyrimido[3,2-a]thiazinium (5b), and 3-Iodomethylidene-5-methyl-7-oxo-2,3-dihydro-8H-thiazolo-
[3,2-a]pyrimidinium (11) Iodides (General Procedure). A solution of iodine (1.01 g, 4.0 mmol) in alcohol or
chloroform (30 ml) was added to a suspension of compound 1a-d or 9 (0.4 g, 2.0 mmol) in alcohol or
chloroform (30 ml). The mixture was stirred for 3 h, and then it was held at room temperature for 10-12 h. The
brown precipitate of the corresponding triiodide formed (see [1]) was filtered out and washed with alcohol. A
solution of NaI·2H2O (0.74 g, 4.0 mmol) in acetone (10 ml) was added with stirring to a solution of the triiodide
obtained (1.66 g, 2.0 mmol) in acetone (5 ml). After 1 h, the yellow precipitate was filtered out, washed with
acetone, crystallized from alcohol, and dried at 90°C; the product 3a,b, 5a,b, or 11 was obtained respectively.
For compound 3a, the literature mp was 182°C [1].
5-Amino-3-bromomethyl- (2c) and 5-Amino-3-bromomethyl-3-methyl-7-oxo-2,3-dihydro-8H-
thiazolo[3,2-a]pyrimidinium (2d), 6-Amino-3-bromo-4,4-dimethyl-8-oxo-3,4-dihydro-9H-pyrimido[3,2-a]-
thiazinium (4c) Bromides (General Procedure). A solution of bromine (0.79 g, 5.0 mmol) in acetic acid
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(15 ml) was added dropwise with stirring over a 20 min period to a solution of compound 1e-g (2.5 mmol) in
glacial acetic acid (15 ml). The reaction mixture was held for 4 h at 20°C and then held for 4 h at -4°C. The
yellow precipitate of the corresponding tribromide was filtered out and washed with ether. The products 2c,d, 4c
were isolated as for compound 2a.
5-Amino-3-iodomethyl- (3c) and 5-Amino-3-iodomethyl-3-methyl-7-oxo-2,3-dihydro[3,2-a]-
pyrimidinium (3d), 6-Amino-3-iodo-4,4-dimethyl-8-oxo-3,4-dihydro-9H-pyrimido[3,2-a]thiazinium (5c)
Iodides (General Procedure). A solution of iodine (1.01 g, 4.0 mmol) in ethanol (40 ml) was added over a
30 min period to a suspension of compound 1e-g (2.0 mmol) in ethanol (30 ml). The alcoholic solution was
decanted from the oil formed, the oil was dissolved in acetone (10 ml), and a solution of NaI·2H2O (0.74 g,
4.0 mmol) in acetone (10 ml) was added with stirring to the solution obtained. The precipitate was filtered out
and washed with acetone, dried at 100°C and crystallized from alcohol. The product 3c,d or 5c respectively was
obtained.
3-Bromomethyl-5-methyl- (6a) and 3-Bromomethyl-3,5-dimethyl-7-oxo-2,3-dihydrothiazolo-
[3,2-a]pyrimidine (6b), 3-Bromo-4,4,6-trimethyl- (7a), and 3-Bromo-6-methyl-8-oxo-4-phenyl-3,4-
dihydropyrimido[3,2-a]thiazine (7b), 3-Bromomethylidene-5-methyl-7-oxo-2,3-dihydrothiazolo[3,2-a]-
pyrimidine (12) (General Procedure). A 15% solution of AcONa (30 ml) in water was added with stirring to a
solution of bromide 2a,b, 4a,b, or 10 (2.0 mmol) in DMSO (50 ml) and the mixture was held at room
temperature for 2 h. The white precipitate of the corresponding product 6a,b, 7a,b, 12 was filtered out and dried
at 80°C.
3,7-Dimethyl-5-oxo-2,3-dihydrothiazolo[3,2-a]pyrimidine (8). A solution of compound 1a (0.18 g,
1.0 mmol) in conc. H2SO4 (2 ml) was held for 10 min in a water bath at 50°C, and then was held for 25 h at
15-25°C. The reaction mixture was poured into ice water (10 ml) and held for 24 h at 0°C. The precipitate of
product 8 was filtered out and recrystallized from chloroform.
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D. G. Kim and V. I. Shmygarev, Khim. Geterotsikl. Soedin., 211 (1995).
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V. I. Staninets and E. A. Shilov, Usp. Khim., 40, 491 (1971).
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