Synthesis and reactions of 3-acetyl-6-methyl-2-(methylthio)pyridine

Article abstract of DOI:10.1007/s11172-009-0265-2

A reaction of methyllithium with 3-cyano-6-methylpyridine-2(1 H)-thione followed by alkylation of the resulting 3-acetylpyridinethione, or a direct reaction of methyllithium with 3-cyano-6-methyl-2-(methylthio)pyridine, afforded 3-acetyl-6-methyl-2-(methylthio)pyridine. The ketone obtained was examined in bromination reactions under various conditions. Bromi-nation in methanol or chloroform, proceeding through the formation of sulfonium bromides, gave substituted 3-(bromoacetyl)pyridine. A reaction of 3-acetyl-6-methyl-2-(methyl- thio)pyridine with N-bromosuccinimide in CCl₄ afforded N-(pyridinesulfenyl)succinimide. The bromo ketone was used for the synthesis of various heterocyclic compounds.

Full text of DOI:10.1007/s11172-009-0265-2

Russian Chemical Bulletin, International Edition, Vol. 58, No. 9, pp. 1939—1944, September, 2009
1939
Synthesis and reactions of 3ꢀacetylꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine
V. K. Zav´yalova, A. A. Zubarev, and A. M. Shestopalov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: zvk@ioc.ac.ru
A reaction of methyllithium with 3ꢀcyanoꢀ6ꢀmethylpyridineꢀ2(1H)ꢀthione followed by
alkylation of the resulting 3ꢀacetylpyridinethione, or a direct reaction of methyllithium with
3ꢀcyanoꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine, afforded 3ꢀacetylꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine.
The ketone obtained was examined in bromination reactions under various conditions. Bromiꢀ
nation in methanol or chloroform, proceeding through the formation of sulfonium bromides,
gave substituted 3ꢀ(bromoacetyl)pyridine. A reaction of 3ꢀacetylꢀ6ꢀmethylꢀ2ꢀ(methylꢀ
thio)pyridine with Nꢀbromosuccinimide in CCl4 afforded Nꢀ(pyridinesulfenyl)succinimide.
The bromo ketone was used for the synthesis of various heterocyclic compounds.
Key words: 3ꢀcyanoꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine, methyllithium, 3ꢀacetylꢀ6ꢀmethylꢀ
2ꢀ(methylthio)pyridine, Nꢀ(pyridinesulfenyl)succinimide, 3ꢀbromoacetylꢀ6ꢀmethylꢀ2ꢀ(methylthio)ꢀ
pyridine, 4ꢀ(pyridinꢀ3ꢀyl)thiazole, thieno[2,3ꢀb]pyridine, indolizine, imidazo[1,2ꢀa]pyridine.
A fundamental task of preparative organic chemistry
is to obtain new biologically active compounds or strucꢀ
tural units for designing new compounds. In this context,
3ꢀ(bromoacetyl)pyridines are of considerable interest. In
recent years, they have been actively used for the syntheꢀ
sis of novel heterocyclic (including polyfused) systems.
Many of these compounds exhibit pronounced pharmaꢀ
cological (e.g., inotropic1 and antiviral2) activities and are
β3ꢀadrenergic receptor agonists.3 However, in the overꢀ
whelming majority of cases, unsubstituted 3ꢀ(bromoacetyl)ꢀ
pyridine or its halogenated derivatives are employed.
Substituted 5ꢀacylꢀ3ꢀcyanopyridinꢀ2(1H)ꢀones and
2ꢀ(methylthio)pyridines have been reported4—6 to be transꢀ
formed into the corresponding bromo ketones used in the
synthesis of heterocyclic compounds with cardiotropic
and inotropic activities. The starting materials are preꢀ
pared by heterocyclization of cyanothioacetamide with
acetylacetone derivatives. This approach is unsuitable for
the synthesis of substituted 3ꢀacetylꢀ2ꢀ(methylthio)ꢀ
pyridines, which leave them not easily accessible.
Results and Discussion
Earlier,7 a reaction of methyllithium with 3ꢀcyanoꢀ
6ꢀmethylpyridineꢀ2(1H)ꢀthione (1) followed by Sꢀalkylꢀ
ation of the resulting pyridinethione 2 (Scheme 1) afforded
3ꢀacetylꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine (4).
Scheme 1
At the same time, our recent active investigations
have been devoted to modification of the cyano group in
3ꢀcyanopyridineꢀ2(1H)ꢀthiones and 2ꢀalkylthioꢀ3ꢀcyanoꢀ
pyridines. For instance, we have found that substituted
3ꢀcyanopyridineꢀ2(1H)ꢀthiones react with methyllithium7
to give 3ꢀacetylpyridineꢀ2(1H)ꢀthiones.
The resulting substituted 3ꢀacetylꢀ2ꢀ(methylthio)ꢀ
pyridines can serve as convenient starting materials
for the synthesis of bromo ketones, which is the subject
of the present work.
Here we followed an alternative route involving a
direct action of methyllithium on 3ꢀcyanoꢀ6ꢀmethylꢀ
2ꢀ(methylthio)pyridine (3). Earlier,8 compound 3 was
obtained from thione 1 and dimethyl sulfate in aqueous
ethanol in the presence of metallic sodium and characterꢀ
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1878—1883, September, 2009.
1066ꢀ5285/09/5809ꢀ1939 © 2009 Springer Science+Business Media, Inc.

1940
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Zav´yalova et al.
ized by elemental analysis data. In this study, we alkylated
thione 1 with methyl iodide in ethanol in the presence of
KOH. Compound 3 was characterized by spectroscopic
methods. In both cases, acetylpyridine 4 was obtained
from pyridinethione 1 as the starting reagent; the overall
yield was 85—87%. The spectroscopic and physicochemiꢀ
cal characteristics of ketone 4 are identical with the literaꢀ
ture reported.7
We studied the bromination of ketone 4 under various
conditions. Aromatic methyl ketones can be brominated
with molecular bromine in organic solvents,9,10 cupric
bromide,11 ammonium perbromides,12 Nꢀbromosuccinꢀ
imide,13 and some other reagents. Bromination of ketone
4 with molecular bromine in acetic acid and CH2Cl2 was
ineffective. The best results were obtained with chloroꢀ
form as a solvent; the reaction proceeds through the formaꢀ
tion of insoluble bromosulfonium bromide 5a (Scheme 2).
Its structure was confirmed by 1H NMR and mass spectra.
The mass spectrum of compound 5a contains a weak
molecular ion peak and a peak due to its debromination
(MS, m/z (I (%)): 260 [M]+ (0.8), 181 [M – Br]+ (74.0)).
In the 1H NMR spectrum, the signals for the protons are
similar to those for the starting compound 4 but they are
all shifted downfield by 0.1—0.15 ppm for the methyl groups
and by 0.5—0.7 ppm for the pyridine protons. Since such
compounds themselves are brominating (although milder
than Br2) agents,14 the acetyl group is slowly (7 days)
brominated to give bromo ketone 6 in 80% yield. With
methanol instead of chloroform, the reaction seems to
proceed through the formation of methoxysulfonium
tribromide 5b (elemental analysis). Its structure was
confirmed by 1H NMR and mass spectra. The mass specꢀ
trum of compound 5b contains peaks due to the fragmenꢀ
tation of the molecular ion (m/z 212) through sequential
losses of three methyl groups (m/z (I (%)): 197 (31.8), 182
(23.1), 167 (14.7)) and through parallel elimination of the
methoxy group (m/z 166 (71.3)). The 1H NMR spectrum
shows signals similar to those for compound 5a and sigꢀ
nals for the methoxy protons at δ 3.15 (s, 3 H). As in
chloroform, compound 5b is slowly (7 days) brominated
to give bromo ketone 6 in 70% yield. Therefore, methoxyꢀ
sulfonium tribromide 5b is a brominating agent like comꢀ
pound 5a.
In boiling methanol, the reaction is completed in 1 h,
yielding a 1 : 2 mixture of bromo ketone 6 and dimethyl
ketal hydrobromide 7. The structures of bromo ketone 6
1
and dimethyl ketal 7 were proved by IR and H NMR
spectroscopy and mass spectrometry. The IR spectrum of
bromo ketone 6 contains an absorption band at 1668 cm–1
1
(C=O); the H NMR spectrum exhibits a signal for the
methylene protons at δ 4.53 (s, 2 H). The IR spectrum of
ketal 7 does not contain the absorption band of the carboꢀ
Scheme 2
i. Br2, MeOH or CHCl , 20 °C; ii. 7 days, 20 °C
3
5: R = Br, X = Br (a); R = OMe, X = Br3 (b)

3ꢀAcetylꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1941
Scheme 3
13: X = CH (a), N (b)
1
Bromination of ketone 4 with Nꢀbromosuccinimide
in boiling CCl4 gave Nꢀ(pyridinesulfenyl)succinimide 8,
no matter whether a radical initiator was used or not. This
nyl group; its H NMR spectrum shows a signal for the
methylene protons at δ 4.0 and a signal for the protons of
two methoxy groups at δ 3.13 (s, 6 H).
Table 1. Physicochemical characteristics of compounds 3 and 5—13
Comꢀ Molecular
pound weight
Yield
(%)
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
(%)
C
H
N
3
164
93
—
100—101
(hexane)
124—130
(decomp.)
137—139
(EtOH)
142—145
(MeOH)
182—185
(EtOH)
50—52
(AcOEt)
112—116
(AcOEt)
>260
(EtOH)
231—233
(EtOH)
125—129
(AcOEt)
121—123
(AcOEt)
58.72
58.51
27.23
26.57
41.13
41.55
33.42
34.13
53.25
54.53
54.96
55.15
58.16
58.34
59.29
59.45
50.71
51.00
70.52
70.83
65.69
65.86
4.83
4.91
3.00
3.12
3.56
3.87
4.49
4.43
4.76
4.58
4.31
4.24
4.67
4.59
5.11
4.99
4.98
4.85
5.67
5.55
5.02
5.13
17.18
17.06
3.16
3.10
5.36
5.38
3.64
3.62
10.28
10.60
16.13
16.08
12.70
12.76
12.26
12.23
7.76
C8H8N2S
5b
6
452
260
387
264
261
329
343
353
254
255
C10H14Br3NO2S
C9H10BrNOS
C11H17Br2NO2S
C12H12N2O3S
C12H11N3S2
80
57
66
76
83
60
62
66
54
7
8
9
10
11
12
13a
13b
C16H15N3OS2
C17H17N3OS2
C15H17BrN2OS
C15H14N2S
7.93
11.12
11.01
16.51
16.46
C14H13N3S

1942
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Zav´yalova et al.
Table 2. Spectroscopic characteristics of compounds 3 and 5—13
Comꢀ
pound
IR,
ν/cm–1
MS,
m/z (I (%))
1H NMR
(δ, J/Hz)
3
2220 (CN)
164 [M]+ (100), 149 (5.0), 137 (5.8),
131 (15.7), 118 (26.9), 103 (5.6),
93 (20.3), 91 (14.7)
2.56 (s, 3 H, SMe); 2.60 (s, 3 H, Me(6)); 7.15
(d, 1 H, H(5), J = 7.9); 8.02 (d, 1 H, H(4), J = 7.9)
5a
5b
6
—
—
260 [M]+ (0.8), 181 (74.0), 166 (81.8),
147 (83.9), 138 (58.1), 106 (43.4),
92 (100), 82 (80.4), 80 (95.8)
2.59 (s, 3 H, SMe); 2.62 (s, 3 H, Me(6)); 2.72
(s, 3 H, COMe); 7.57 (d, 1 H, H(5), J = 8.0);
8.36 (d, 1 H, H(4), J = 8.0)
197 (31.8), 182 (23.1), 167 (14.7), 166
(71.3), 149 (69.9), 136 (64.3), 106 (52.6), COMe); 3.15 (s, 3 H, OMe); 7.58 (br.s, 1 H,
92 (64.3), 81 (54.5), 79 (100)
2.62 (br.s, 6 H, Me(6) + SMe); 2.73 (s, 3 H,
H(5)); 8.37 (br.s, 1 H, H(4))
1668 (C=O)
1632
259 [М]+ (3.8), 244 (4.7), 180 (68.3),
166 (81.1), 148 (84.3), 138 (72.4),
122 (35.7), 106 (50.3), 92 (100)
305 [М]+ (16.6), 290 (10.4), 274 (15.7),
212 (100), 194 (35.7), 180 (44.8), 166
(32.9), 150 (32.0), 137 (20.6), 120
(30.7), 106 (15.0), 93 (80.8), 81 (87.4)
266 [М]+ (4.5), 250 (3.3), 177 (4.3),
165 (49.7), 137 (48.9), 99 (57.3),
93 (100)
261 [М]+ (50.0), 246 (6.3), 228 (100),
195 (41.3), 149 (42.7), 121 (19.6),
101 (26.8)
329 [М]+ (65.7), 311 (100), 296 (25.7),
282 (72.1), 177 (79), 164 (86.8), 151
(44.5), 137 (24.3), 119 (32.2), 92 (80.9)
2.44 (s, 3 H, SMe); 2.51 (s, 3 H, Me(6)); 4.53
(s, 2 H, COCH2Br); 7.02 (d, 1 H, H(5), J = 7.9);
8.16 (d, 1 H, H(4), J = 7.9)
2.45 (s, 6 H, Me(6) + SMe); 3.13 (s, 6 H, 2 OMe);
4.00 (s, 2 H, CH2Br); 7.02 (d, 1 H, H(5), J = 7.9);
7.71 (d, 1 H, H(4), J = 7.9)
7
8
1652 (C=O)
1732
(N(C=O)2)
2264 (CN)
2.47 (s, 3 H, Me(6)); 2.59 (s, 3 H, COMe); 2.97
(s, 4 H, (N(COCH2)2); 7.02 (d, 1 H, H(5), J = 7.9);
8.01 (d, 1 H, H(4), J = 7.9)
9
2.56 (s, 3 H, SMe); 2.61 (s, 3 H, Me(6)); 4.19
(s, 2 H, CH2); 6.95 (d, 1 H, H(5), J = 7.8); 7.78
(s, 1 H, H(5´)thiazole); 7.89 (d, 1 H, H(4), J = 7.8)
2.45 (s, 3 H, SMe); 2.52 (s, 3 H, Me(6´)); 2.57
(s, 3 H, Me(6)); 7.09 (d, 1 H, H(5´), J = 7.7); 7.35
(d, 1 H, H(5), J = 8.4); 7.73 (d, 1 H, H(4´), J = 7.7);
8.38 (br.s, 2 H, NH2); 8.51 (d, 1 H, H(4), J = 8.4)
2.24 (s, 3 H, Me(4)); 2.30 (s, 3 H, SMe); 2.40
(s, 3 H, Me(6)); 2.55 (s, 3 H, Me(6´)); 4.42 (s, 2 H,
CH2); 7.21 (d, 1 H, H(5´), J = 7.8); 8.47 (d, 1 H,
H(4´), J = 7.8); 13.90 (br.s, 1 H, NH)
2.44 (s, 3 H, SMe); 2.59 (s, 3 H, Me(6)); 2.68 (s, 3 H,
Me(2´)); 6.54 (s, 2 H, CH2); 7.31 (d, 1 H, H(3´),
J = 7.9); 8.09 (t, 1 H, H(5´), J = 6.7); 8.17 (d, 1 H,
H(5), J = 7.8); 8.47 (d, 1 H, H(4), J = 7.8); 8.62
(t, 1 H, H(4´), J = 7.8); 8.95 (d, 1 H, H(6´), J = 5.8)
2.48 (s, 6 H, SMe + Me(6)); 6.56 (t, 1 H, H(6),
J = 6.6); 6.65 (s, 1 H, H(1)); 6.72 (t, 1 H, H(7),
J = 7.7); 7.02 (d, 1 H, H(5´), J = 7.7); 7.41 (d, 1 H,
H(8), J = 9.0); 7.61 (d, 1 H, H(4´), J = 7.7); 7.85
(s, 1 H, H(3)); 8.27 (d, 1 H, H(5), J = 6.9)
10
3580 (NH2)
11
12
1668 (C=O)
2224 (CN)
343 [М]+ (1), 261 (7), 222 (7.7), 180
(14.6), 166 (100), 138 (22), 92 (36.7)
1672 (C=O)
254 (100), 239 (83.6), 221 (18.2),
208 (26.6), 162 (33.2), 109 (10.1),
101 (40.5), 93 (20.3)
13a
13b
1632
254 [М]+ (100), 239 (65.0), 221 (17.5),
208 (28.3), 162 (30.0), 101 (13.3)
1632
255 [М]+ (97.6), 240 (78.3), 222 (100),
209 (82.5), 194 (40.6), 162 (44.8),
128 (14.7)
2.49 (s, 3 H, SMe); 2.55 (s, 3 H, Me(6)); 6.92 (t, 1 H,
H(6), J = 6.6); 7.08 (d, 1 H, H(5´), J = 7.7); 7.28
(t, 1 H, H(7), J = 7.8); 7.58 (d, 1 H, H(8), J = 9.0);
8.16 (d, 1 H, H(4´), J = 7.7); 8.45 (s, 1 H, H(3));
8.62 (d, 1 H, H(5), J = 6.7)
reaction with substituted methylthiobenzenes has been
described in the literature;15 however, its mechanism
remains unclear. Based on the published data,15—17 one
can assume that the reaction proceeds through the formaꢀ
tion of a bromosulfonium derivative, replacement of the
Br atom by the succinimide residue, and elimination
of methyl bromide (see Scheme 2). The structure of
Nꢀ(pyridinesulfenyl)succinimide 8 was confirmed by IR
IR spectrum of imide 8 contains absorption bands at
1652 (C=O, acetyl) and 1732 cm–1 (C=O, imide). The
1H NMR spectrum shows a signal for the protons of
the succinimide ring at δ 2.97 (s, 4 H).
Bromo ketone 6 was used in the synthesis of various
heterocyclic compounds. A reaction with cyanothioacetꢀ
amide gives thiazolylpyridine 9 (Scheme 3). A reaction
with 3ꢀcyanoꢀ6ꢀmethylpyridineꢀ2(1H)ꢀthione (1) in the
presence of excess KOH first involves Sꢀalkylation of
1
and H NMR spectroscopy and mass spectrometry. The

3ꢀAcetylꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009 1943
in methanol (30 mL). The reaction mixture was kept for 10 min,
which resulted in precipitation of methoxysulfonium tribromide
5b. The mixture was homogenized by stirring at 20 °C for seven
days. The solvent was removed and the residue was recrystalꢀ
lized from ethanol. The yield of bromide 6 was 70%, light yellow
crystals.
Bromination in boiling methanol. After Br2 was added (as
described under method B) and a precipitate formed, the mixꢀ
ture was refluxed for 1 h. On cooling, the solvent was removed.
The resulting amorphous mass contained bromide 6 and ketal 7
in a ratio of 1 : 2 (1H NMR). The mixture of the products was
diluted with ethanol (5 mL) and stirred until a white crystalline
precipitate formed. The precipitate was filtered off, the product
was extracted twice with hot hexane, and the combined extracts
were concentrated. The yield of bromide 6 was 31%. The reꢀ
maining white crystalline powder was ketal hydrobromide 7
(57%).
Synthesis of Nꢀ(3ꢀacetylꢀ6ꢀmethylpyridinꢀ2ꢀylthio)succinꢀ
imide (8). NꢀBromosuccinimide (0.37 g, 2 mmol) was added to a
solution of ketone 4 (0.25 g, 1.4 mmol) in CCl4 (6 mL). The
reaction mixture was refluxed for 3 h. The precipitate that formed
was filtered off, washed with CCl4 (5 mL), stirred with water
(10 mL) for 30 min, and filtered off again. The yield of product 8
was 66%, a light yellow powder.
the thione followed by intramolecular cyclization into
thienopyridine 10. A reaction with sodium acetylacetonate
followed by treatment with cyanothioacetamide yields
pyridinethione 11. A reaction with 2ꢀpicoline produces
pyridinium salt 12 and, upon treatment with aqueous
NaHCO3, indolizine 13a. A reaction with 2ꢀaminoꢀ
pyridine immediately gives imidazopyridine 13b (see
Scheme 3). The characteristics of products 9—13 are given
in Tables 1 and 2.
To sum up, we obtained 3ꢀacetylꢀ6ꢀmethylꢀ2ꢀ(methylꢀ
thio)pyridine by a direct action of methyllithium on
3ꢀcyanoꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine. Reactions
of the resulting ketone with bromine in chloroform or
methanol proceed through the formation of bromoꢀ
(methoxy)sulfonium intermediates. Bromination of the
ketone with Nꢀbromosuccinimide in CCl4 gives Nꢀ(pyriꢀ
dinesulfenyl)succinimide as the major product. Brominꢀ
ated ketone was employed in the synthesis of various
heterocyclic compounds.
Experimental
Synthesis of 2ꢀcyanomethylꢀ4ꢀ[6ꢀmethylꢀ2ꢀ(methylthio)ꢀ
pyridinꢀ3ꢀyl]thiazole (9). 2ꢀCyanothioacetamide (0.1 g, 1 mmol)
was added to a solution of bromo ketone 6 (0.25 g, 1 mmol) in
DMF (5 mL). The resulting solution was kept at 20 °C for 12 h
and diluted with water (25 mL). The precipitate that formed was
filtered off and washed with water. The yield of thiazole 9
was 76%, a light yellow powder.
Synthesis of 3ꢀaminoꢀ6ꢀmethylꢀ2ꢀ[6ꢀmethylꢀ2ꢀ(methylthio)ꢀ
pyridinꢀ3ꢀylcarbonyl]thieno[2,3ꢀb]pyridine (10). A 10% aqueous
solution of KOH (0.55 mL, 1 mmol) was added to a suspension
of thione 1 (0.15 g, 1 mmol) in DMF (5 mL). Then bromo
ketone 6 (0.25 g, 1 mmol) was added. The solution was stirred
for 30 min, treated with 10% aqueous KOH (0.55 mL, 1 mmol),
kept for 12 h, and diluted with water (20 mL). The precipitate
that formed was filtered off. The yield of thienopyridine 10 was
83%, a yellow crystalline powder.
Melting points were determined on a Kofler hotꢀstage
microscope. IR spectra were recorded on a Specord Mꢀ80 specꢀ
trophotometer (KBr pellets). 1H NMR spectra were recorded
on a Bruker AM 300 spectrometer (300.13 MHz) in DMSOꢀd6.
A signal of the solvent (δH 2.5) was used as the internal standard.
Mass spectra were measured on a Finnigan MAT INCOSꢀ50
instrument (ionizing energy 70 eV).
Synthesis of 3ꢀcyanoꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine (3).
A 10% aqueous solution of KOH (11.2 mL, 20 mmol) was added
to a suspension of thione 1 (3 g, 20 mmol) in ethanol (20 mL).
Methyl iodide (1.87 mL, 4.26 g, 30 mmol) was added and the
reaction mixture was kept at room temperature for 12 h and
diluted with water (50 mL). The precipitate that formed was
filtered off and recrystallized from hexane. The yield of comꢀ
pound 3 was 93%, white crystals.
Synthesis of 3ꢀacetylꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine (4).
Nitrile 3 (0.5 g, 3 mmol) was added at –3 to –5 °C for 5 min to a
1.6 M solution of MeLi (5.6 mL, 9 mmol) in ether (40 mL). The
solution was stirred at this temperature for 1 h. Then water
(20 mL) and 5% aqueous HCl (10 mL) were added. The resultꢀ
ing twoꢀphase system was vigorously stirred without cooling for
30 min. The organic layer was separated and the aqueous layer
was alkalized with NaOH to pH 12. The product was extracted
with ether (20 mL). The combined organic solution was washed
with water, dried over MgSO4, and concentrated. The yield of
ketone 4 was 94%, yellow crystals.
Synthesis of 3ꢀ(2ꢀbromoacetyl)ꢀ6ꢀmethylꢀ2ꢀ(methylthio)ꢀ
pyridine (6). Method A. Bromine (0.64 g, 4 mmol) was added
dropwise at 20 °C for 15 min to a stirred solution of ketone 4
(0.7 g, 4 mmol) in CHCl3 (30 mL). After one day, bromosulꢀ
fonium bromide 5a formed a precipitate. The mixture was stirred
at 20 °C for six days until the precipitate was reprecipitated. The
final precipitate was filtered off. The yield of bromide 6 was
80%, light yellow crystals.
Synthesis of 3ꢀcyanoꢀ4,6ꢀdimethylꢀ5ꢀ{2ꢀ[6ꢀmethylꢀ2ꢀ
(methylthio)pyridinꢀ3ꢀyl]ꢀ2ꢀoxoethyl}pyridineꢀ2(1H)ꢀthione (11).
Bromo ketone 6 (0.25 g, 1 mmol) was added for 5 min to a
boiling suspension of sodium acetylacetonate (0.12 g, 1 mmol)
in acetone (7 mL). The reaction mixture was refluxed for 20 h.
On cooling, the precipitate that formed was filtered off. The
filtrate was concentrated and the residue was diluted with water
(15 mL). The product was extracted with ether (20 mL). The
organic layer was dried over MgSO4 and concentrated. Crude
3ꢀacetylꢀ1ꢀ[6ꢀmethylꢀ2ꢀ(methylthio)pyridinꢀ3ꢀyl]pentaneꢀ
1,4ꢀdione (0.21 g, 0.75 mmol) was dissolved in ethanol (5 mL);
then cyanothioacetamide (0.07 g, 0.7 mmol) and one drop of
Et3N were added. The resulting solution was heated to boiling
and cooled. The precipitate that formed was filtered off. The
yield of thione 11 was 60%, a yellow powder.
Synthesis of 2ꢀmethylꢀ1ꢀ{2ꢀ[6ꢀmethylꢀ2ꢀ(methylthio)pyridinꢀ
3ꢀyl]ꢀ2ꢀoxoethyl}pyridinium bromide (12). A solution of bromo
ketone 6 (0.25 g, 1 mmol) and 2ꢀpicoline (0.15 g, 1.6 mmol) in
acetone (5 mL) was refluxed for 8 h. On cooling, the precipitate
that formed was filtered off. The yield of bromide 12 was 62%,
a gray powder.
Method B. Bromine (0.64 g, 4 mmol) was added dropwise at
20 °C for 15 min to a stirred solution of ketone 4 (0.7 g, 4 mmol)

1944
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 9, September, 2009
Zav´yalova et al.
Synthesis of 2ꢀ[6ꢀmethylꢀ2ꢀ(methylthio)pyridinꢀ3ꢀyl]indolizine
(13a). A solution of salt 12 (0.21 g, 0.6 mmol) and NaHCO3
(0.2 g, 2.4 mmol) in water (5 mL) was refluxed for 30 min. On
cooling, the product was extracted with ether (2×10 mL).
The organic layer was separated, dried over MgSO4, and conꢀ
centrated. The yield of indolizine 13a was 66%, a light brown
powder.
Synthesis of 2ꢀ[6ꢀmethylꢀ2ꢀ(methylthio)pyridinꢀ3ꢀyl]imidazoꢀ
[1,2ꢀa]pyridine (13b). A solution of bromo ketone 6 (0.25 g,
1 mmol) and 2ꢀaminopyridine (0.15 g, 1.6 mmol) in acetone
(5 mL) was refluxed for 8 h. On cooling, the precipitate that
formed was filtered off and washed with water. The resulting
imidazopyridine hydrobromide dihydrate was stirred with 5%
aqueous NaHCO3 (2 mL), filtered off, and washed with water.
The yield of imidazopyridine 13b was 54%, a light gray powder.
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This work was financially supported in part by
the Russian Foundation for Basic Research (Project
No. 09ꢀ03ꢀ00349a).
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Received February 16, 2009;
in revised form May 20, 2009