Synthesis and transformations of 3-acetylpyridine-2(1H)-thiones

Article abstract of DOI:10.1007/s11172-008-0197-2

Reactions of substituted 3-cyanopyridine-2(1H)-thiones with methyllithium gave 3-acetylpyridine-2(1H)-thiones. The best results were achieved by adding a solid-state thione to a solution of methyllithium in ether (thione: MeLi = 1: 3). The compounds obtained and their 3-pentanoyl analogs were used to synthesize a number of fused heterocyclic systems.

Full text of DOI:10.1007/s11172-008-0197-2

Russian Chemical Bulletin, International Edition, Vol. 57, No. 7, pp. 1534—1538, July, 2008
1534
Synthesis and transformations of 3ꢀacetylpyridineꢀ2(1H)ꢀthiones
V. K. Zav´yalova, A. A. Zubarev, and V. P. Litvinov†
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
Reactions of substituted 3ꢀcyanopyridineꢀ2(1H)ꢀthiones with methyllithium gave 3ꢀacetylpyriꢀ
dineꢀ2(1H)ꢀthiones. The best results were achieved by adding a solidꢀstate thione to a solution of
methyllithium in ether (thione : MeLi = 1 : 3). The compounds obtained and their 3ꢀpentanoyl
analogs were used to synthesize a number of fused heterocyclic systems.
Key words: 3ꢀcyanopyridineꢀ2(1H)ꢀthiones, 3ꢀacetylpyridineꢀ2(1H)ꢀthiones, 3ꢀpentanoylpyriꢀ
dineꢀ2(1H)ꢀthiones, methyllithium, thieno[2,3ꢀb]pyridines, 3ꢀcyanopyrido[2,3ꢀb]thiopyrans,
4,8ꢀdialkylꢀ2ꢀcyanomethylidenepyrido[2,3ꢀb][1,3]thiazines.
Scheme 1
3ꢀCyanopyridineꢀ2(1H)ꢀthiones are widely employed
in the synthesis of various pyridine derivatives and fused
heterocyclic systems exhibiting a variety of biological
activity.1 In recent years, with the aim of extending
the synthetic scope of 3ꢀcyanopyridineꢀ2(1H)ꢀthiones
as building blocks in heterocyclic chemistry, we activeꢀ
ly studied modification of the cyano group in these
compounds2—5 through the use of various reducing
agents and butyllithium.6 In the present work, we studꢀ
ied reactions of substituted 3ꢀcyanopyridineꢀ2(1H)ꢀ
thiones with methyllithium and transformations of the
resulting acetyl derivatives that are of interest as building
blocks. 3ꢀAcetylꢀ and 3ꢀpentanoylpyridineꢀ2ꢀthiones
were used to obtain a number of fused heterocyclic
systems.
Results and Discussion
Reactions of 3ꢀcyanopyridineꢀ2(1H)ꢀthiones 1a—c
with methyllithium (3 equiv.) in ether at –3 to –5 °C
followed by dilution of the reaction mixture with water
and acidification gave 3ꢀacetylpyridineꢀ2(1H)ꢀthiones
2a—c in good yields (Scheme 1).
1, 2
a
b
R1
Me
Me
Pr
R2
H
Me
H
3
a
b
c
d
R1
Me
Me
Pr
R2
H
Me
H
R3
COC6H4ꢀ4ꢀBr
COC6H4ꢀ4ꢀBr
COC6H4ꢀ4ꢀBr
CN
c
Me
H
Compounds 2a—c are yellow crystalline solids with
distinct melting points; their structures were confirmed
by IR and 1H NMR spectroscopy and mass spectrometry.
The IR spectra of compounds 2a—c show an absorption
band at 1692—1696 cm–1 (C=O). Their 1H NMR spectra
exhibit, apart from the signals for the protons of the
pyridine ring and the alkyl substituents, a singlet for the
acetyl group at δ 2.62—2.81.
of a double excess of KOH afforded substituted thienoꢀ
[2,3ꢀb]pyridines 3a—d. A reaction with methyl iodide
gave 2ꢀmethylthiopyridine 4 (see Scheme 1).
The structures of compounds 3a—d were proved by
IR and 1H NMR spectroscopy and mass spectrometry.
The IR spectra of compounds 3a—c contain absorption
bands at 1644—1648 cm–1 (conjugated carbonyl group).
The spectrum of compound 3d shows a band at 2216 cm–1
Reactions of thiones 2a—c with chloroacetonitrile
and pꢀbromophenacyl bromide in ethanol in the presence
1
(C≡N). The H NMR spectra of compounds 3a—c conꢀ
tain a system of two doublets for the 4ꢀbromophenyl
substituent (δ 7.65 and 7.77, 2 H each). In addition,
† Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1504—1507, July, 2008.
1066ꢀ5285/08/5707ꢀ1534 © 2008 Springer Science+Business Media, Inc.

3ꢀAcetylpyridineꢀ2(1H)ꢀthiones
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1535
the signals for the protons of the pyridine ring are shifted
downfield for all compounds 3.
The physicochemical and spectroscopic characterisꢀ
tics of the compounds obtained are given in Tables 1 and 2.
To sum up, we demonstrated that reactions of 3ꢀcyanoꢀ
pyridineꢀ2(1H)ꢀthiones with methyllithium give 3ꢀaceꢀ
tylpyridineꢀ2(1H)ꢀthiones. The compounds obtained
are regioselectively alkylated at the S atom and, with
alkylating reagents containing an active methylene
group, undergo further cyclization into thienopyridines.
Reactions of 3ꢀacetylꢀ and 3ꢀpentanoylpyridineꢀ2(1H)ꢀ
thiones with malononitrile afford either pyridothiopyrꢀ
ans (ethanol, base) or pyrido[1,3]thiazines (benzene, aceꢀ
tic acid).
Reactions of 3ꢀacetylꢀ and 3ꢀpentanoylpyridineꢀ
2(1H)ꢀthiones 2a,c—e with malononitrile gave differꢀ
ent products, depending on the reaction conditions
(Scheme 2). In boiling ethanol in the presence of an
equimolar amount of Et3N, iminothiopyrans 5a—d were
obtained. The reactions in benzene in the presence of
acetic acid afforded pyrido[3,2ꢀe][1,3]thiazines 6a,b.
Apparently, thiopyrans 5 are formed by condensation
of malononitrile at the carbonyl group with subsequent
cyclization of dinitrile 7. Another possible pathway inꢀ
volves intramolecular cyclization of intermediate 8,
which agrees with the literature data.7 The formation of
thiazines 6 probably also involves intermediate 8, which
isomerizes in the presence of an acid into more stable
enamine 9. This rearrangement favors subsequent cyꢀ
clization through the N atom.
Compounds 5a—d and 6a,b are yellow crystalline solꢀ
ids with distinct melting points. Their structures were
confirmed by IR and 1H NMR spectroscopy and mass
spectrometry. The IR spectra of pyridothiopyrans 5a—d
contain an absorption band at 2220 cm–1 (conjugatꢀ
ed C≡N group). Their 1H NMR spectra show a characterꢀ
istic broadened singlet at δ 9.30—9.40 (imino group).
The IR spectra of pyridothiazines 6a,b also exhibit
a band at 2216—2220 cm–1 (conjugated C≡N group);
their 1H NMR spectra show a singlet at δ 5.40—5.70
(NC=CH—).
Experimental
Melting points were determined on a Kofler hot stage. IR spectra
were recorded on a Specord Mꢀ80 spectrophotometer (KBr pelꢀ
lets). 1H NMR spectra were recorded on a Bruker WM250 specꢀ
trometer (250.13 MHz) in CDCl3. The signal for the residual
protons of the solvent was used as the internal standard. Mass
spectra were recorded on a Finnigan MAT INCOSꢀ50 instrument
(EI, 70 eV). 3ꢀPentanoylpyridineꢀ2(1H)ꢀthiones were prepared
according to a known procedure.6 The characteristics of the comꢀ
pounds obtained are given in Tables 1 and 2.
3ꢀAcetylpyridineꢀ2(1H)ꢀthiones 2a,c (general procedure). Solꢀ
idꢀstate thione 1a,c (6.5 mmol) was added in portions under argon
at –3 to –5 °C in 10 min to a solution of MeLi (40 mL, 0.45 g,
20 mmol) in ether. The reaction mixture was stirred at the
same temperature for 1.5 h. Then, water (40 mL) was added dropꢀ
wise and the aqueous layer was separated, washed with ether,
Scheme 2
Compound
R1
Me
Pr
Me
Bui
Me
R2
H
H
H
H
R3
Me
Me
Bu
Bu
Me
Compound
R1
Pr
Me
Bui
Me
Me
R2
H
H
H
H
R3
Me
Bu
Bu
Me
Bu
2a
2c
2d
2e
5a
5b
5c
5d
6a
6b
H
H

1536
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
Zav´yalova et al.
Table 1. Selected physicochemical characteristics of the comꢀ
pounds obtained
and acidified with dilute HCl. The product was extracted from
the resulting suspension with chloroform (2×20 mL) and, after
removal of the solvent, crystallized from aqueous 50% ethanol into
yellow crystals. The yields of compounds 2a,c were 91 and 95%,
respectively.
3ꢀAcetylꢀ4,6ꢀdimethylpyridineꢀ2(1H)ꢀthione (2b) was obtained
analogously with the exceptions that a different amount of water
(8 mL) was added to the reaction mixture after stirring and that the
aqueous layer was acidified with conc. HCl. The crystals that formed
after three days were separated and recrystallized from methanol.
The yield of thione 2b was 40%, yellow crystals.
Thieno[2,3ꢀb]pyridines 3a—d (general procedure). Aqueous 10%
KOH (1.1 mL, 2 mmol) and 4ꢀbromophenacyl bromide (3a—c) or
chloroacetonitrile (3d) (2 mmol) were added successively to
a suspension of thione (2a—c) (2 mmol) in EtOH (10 mL). The
resulting solution was stirred at room temperature for 5 min. Aqueꢀ
ous 10% KOH (1.1 mL, 2 mmol) was added and stirring was
continued at 45 °C for 15 min. On cooling, the crystals that formed
were filtered off and washed with water. The product was recrystalꢀ
lized from aqueous 50% ethanol. The yields were 73—93%, light
yellow crystals.
3ꢀAcetylꢀ6ꢀmethylꢀ2ꢀ(methylthio)pyridine (4). Aqueous 10%
KOH (0.7 mL) and MeI (0.1 mL, 1.55 mmol) were added succesꢀ
sively to a suspension of thione 2a (0.2 g, 1.2 mmol) in EtOH
(3 mL). The resulting solution was stirred at room temperature
for 4 h and diluted with water (10 mL). The product was extracted
with CHCl3 (2×5 mL). The extract was concentrated and the
residue was recrystallized twice from hexane. The yield of comꢀ
pound 4 was 74%, light yellow crystals.
Comꢀ Yield
pound (%)
M.p./°C
(solvent)
Found
Calculated
Molecular
formula
(%)
N
C
H
2a
2b
2c
3a
3b
3c
3d
4
91
189—191
(EtOH—H2O) 57.46 5.42 8.38
156—157.5 59.49 6.19 7.60 C9H11NOS
(MeOH)
104—107
(EtOH—H2O) 61.51 6.71 7.17
117—119
(EtOH—H2O) 55.50 3.49 4.05
146—148
(EtOH—H2O) 56.68 3.92 3.89
108.5—111 57.58 4.40 3.62 C18H16BrNOS
(EtOH—H2O) 57.76 4.31 3.74
122—124
(EtOH—H2O) 63.80 4.28 14.88
61—63
(hexane)
191—193
57.31 5.49 8.26 C8H9NOS
40
59.64 6.12 7.73
61.28 6.83 6.98 C10H13NOS
95
93.5
89
55.38 3.43 4.17 C16H12BrNOS
56.42 3.99 3.80 C17H14BrNOS
82.5
73.5
92
63.57 4.34 14.98 C10H8N2S
59.51 6.16 7.60 C9H11NOS
59.64 6.12 7.73
61.24 4.26 19.39 C11H9N3S
61.37 4.21 19.52
63.97 5.47 17.14 C13H13N3S
64.17 5.39 17.27
65.18 6.11 15.58 C14H15N3S
65.37 5.84 16.34
68.01 7.23 13.85 C17H21N3S
68.23 7.02 14.05
61.19 4.37 19.30 C11H9N3S
61.40 4.19 19.53
65.33 6.34 16.50 C14H15N3S
65.37 5.94 16.34
5a
5b
5c
5d
6a
6b
81
63
100—102
94
115—117
(MeOH)
69—71
(MeOH)
188—191
(EtOH)
97—99
3ꢀCyanopyrido[2,3ꢀb]thiopyrans 5a—d (general procedure).
Malononitrile (0.15 g, 2.3 mmol) was dissolved in ethanol (15 mL).
Thione 2a,c—e (2.3 mmol) and triethylamine (0.25 mL, 2.3 mmol)
were added successively. The resulting solution was brought
to boiling, cooled, and diluted with a threefold volume of water.
The precipitate that formed was crystallized from aqueous 50%
methanol.
62
77
72
(EtOH)
Table 2. Spectroscopic characteristics of the compounds obtained
Comꢀ
pound
IR,
ν/cm–1
MS,
m/z (Irel (%))
1H NMR,
δ (J/Hz)
2a
1692 (C=O)
167 [М]+ (77.8), 166 (100),
152 (31.6), 138 (11.8), 124
(34.7), 97 (37.5), 81 (66)
2.50 (s, 3 H, C(6)Me); 2.81 (s, 3 H,
COMe); 6.60 (d, 1 H, H(5), J = 7.5);
7.70 (d, 1 H, H(4), J = 7.5); 13.02
(br.s, 1 H, NH)
2b
2c
1696 (C=O)
1692 (C=O)
181 [М]+ (87.5), 180 (100),
166 (51.4), 138 (36.1), 111
(12.4), 95 (27.1)
195 [М]+ (100), 180 (88.7),
149 (9.8), 106 (8.1),
77 (12.8)
2.12 (s, 3 H, C(6)Me); 2.41 (s, 3 H,
C(4)Me); 2.62 (s, 3 H, COMe); 6.40
(s, 1 H, H(5)); 13.33 (br.s, 1 H, NH)
0.98 (t, 3 H, Meγ, J = 7.5); 1.74 (m, 2 H,
C(2)H2); 2.72 (t, 2 H, C(1)H2, J = 7.3);
2.81 (s, 3 H, COMe); 6.58 (d, 1 H, H(5),
J = 7.5); 7.68 (d, 1 H, H(4), J = 7.5);
13.05 (br.s, 1 H, NH)
3a
1644 (C=O)
346 [М]+ (11.1), 266 (100),
249 (22.4), 236 (16.7), 190
(18.6), 157 (33.6), 118
(12.6), 83 (19.4)
2.55 (s, 3 H, C(6)Me); 2.72 (s, 3 H, C(3)Me);
7.28 (d, 1 H, H(5), J = 8.3); 7.64 (d, 2 H,
H(2´) + Н(6´), J = 8.7); 7.77 (d, 2 H, H(3´) +
Н(5´), J = 8.7); 8.03 (d, 1 H, H(4), J = 8.3)
(to be continued)

3ꢀAcetylpyridineꢀ2(1H)ꢀthiones
Table 2 (continued)
Russ.Chem.Bull., Int.Ed., Vol. 57, No. 7, July, 2008
1537
Comꢀ
pound
IR,
ν/cm–1
MS,
m/z (Irel (%))
1H NMR,
δ (J/Hz)
3b
1644 (C=O)
359 [М]+ (27.1), 280 (100),
265 (37), 204 (43), 155 (33.9),
132 (32.3), 117 (69.9), 91 (53.8)
2.62 (s, 3 H, C(6)Me); 2.71 (s, 3 H, C(3)Me);
2.77 (s, 3 H, C(4)Me); 6.99 (s, 1 H, H(5));
7.64 (d, 2 H, H(2´) + H(6´), J = 8.7); 7.78
(d, 2 H, H(3´) + H(5´), J = 8.7)
3c
1648 (C=O)
374 [М]+ (26.8), 347 (97.2),
1.01 (t, 3 H, Meγ, J = 7.5); 1.84 (m, 2 H,
294 (88.9), 265 (100), 252 (28.1), C(2)H2); 2.55 (s, 3 H, Me); 2.93 (t, 2 H,
236 (27.9), 183 (31), 162 (20)
C(1)H2, J = 7.3); 7.28 (d, 1 H, H(5), J = 8.3);
7.65 (d, 2 H, H(2´) + H(6´), J = 8.7);
7.78 (d, 2 H, H(3´) + H(5´), J = 8.7);
8.04 (d, 1 H, H(4), J = 8.3)
3d
4
2216 (CN)
188 [М]+ (100), 173 (29.4),
160 (15.4), 146 (13.3),
116 (6.4), 89 (10.8)
2.62 (s, 3 H, C(6)Me); 2.72 (s, 3 H, C(3)Me);
7.29 (d, 1 H, H(5), J = 8.3); 7.96 (d, 1 H, H(4),
J = 8.3)
1672 (C=O)
181 [М]+ (63.8), 166 (100),
148 (97.3), 138 (33.2),
107 (20.8)
2.50 (s, 3 H, C(6)Me); 2.56 (s, 3 H, SMe); 2.57
(s, 3 H, COMe); 6.91 (d, 1 H, H(5), J = 7.4);
7.95 (d, 1 H, H(4), J = 7.4)
5a
5b
2220 (CN),
3260 (NH)
215 [М]+ (100), 188 (65.7),
101 (14), 57 (34.3), 43 (41.3)
2.58 (s, 3 H, C(4)Me); 2.70 (s, 3 H, C(7)Me);
7.12 (d, 1 H, H(6), J = 8.1); 7.85 (d, 1 H, H(5),
J = 8.1); 9.42 (br.s, 1 H, NH)
2220 (CN),
3268 (NH)
243 [М]+ (16.1), 215 (31.8),
188 (30.8), 178 (100),
101 (13.3)
0.97 (t, 3 H, Meγ, J = 7.5); 1.75 (m, 2 H,
C(2)H2); 2.70 (s, 3 H, C(4)Me); 2.76 (t, 2 H,
C(1)H2, J = 7.3); 7.11 (d, 1 H, H(6), J = 8.1);
7.87 (d, 1 H, H(5), J = 8.1); 9.40 (br.s, 1 H, NH)
5c
5d
2220 (CN),
3264 (NH)
257 [М]+ (96.8), 228 (63.7),
226 (86.2), 215 (43.56),
188 (100)
0.99 (t, 3 H, Meδ, J = 7.5); 1.59 (m, 4 H,
C(2)H2 + C(3)H2); 2.59 (s, 3 H, C(4)Me); 3.08
(t, 2 H, C(1)H2, J = 7.3); 7.11 (d, 1 H, H(6),
J = 8.1); 7.83 (d, 1 H, H(5), J = 8.1); 9.35
(br.s, 1 H, NH)
2220 (CN),
3260 (NH)
299 [М]+ (38.8), 284 (40.2),
271 (38.1), 258 (100), 256
(62.9), 231 (75.2), 227 (24.4),
189 (33.8),188 (34.9)
0.90 (d, 6 H, Me2CHCH2, J = 6.5); 1.00
(t, 3 H, Meδ, J = 7.5); 1.60 (m, 4 H,
C(2)H2 + C(3)H2); 2.12 (m, 1 H, Me2CHCH2);
2.65 (d, 2 H, Me2CHCH2, J = 6.1); 3.08 (t, 2 H,
C(1)H2, J = 7.3); 7.08 (d, 1 H, H(6), J = 8.1);
7.85 (d, 1 H, H(5), J = 8.1); 9.31 (br.s, 1 H, NH)
6a
6b
2220 (CN),
1640 (C=C)
215 [М]+ (100), 150 (88.9),
134 (24.8), 116 (27.8),
106 (42.5)
2.50 (s, 6 H, C(4)Me, C(7)Me); 5.40 (s, 1 H,
CH); 7.08 (d, 1 H, H(6), J = 8.1); 7.84 (d, 1 H,
H(5), J = 8.1)
2216 (CN),
1640 (C=C)
257 [М]+ (14.8), 242 (12.6),
228 (14.3), 215 (100), 150
(24.8), 149 (42.7)
0.89 (t, 3 H, Meδ, J = 7.5); 1.60 (m, 4 H,
C(2)H2 + C(3)H2); 2.50 (s, 3 H, C(7)Me);
2.90 (t, 2 H, C(1)H2, J = 7.3); 5.71 (s, 1 H,
CH); 7.28 (d, 1 H, H(6), J = 8.1); 8.19
(d, 1 H, H(5), J = 8.1)
4,7ꢀDialkylꢀ2ꢀcyanomethylideneꢀ2Hꢀpyrido[3,2ꢀe][1,3]thiꢀ
azines 6a,b (general procedure). A mixture of malononitrile
(0.15 g, 2.3 mmol) and thione 2a,d (2.3 mmol) was refluxed
with a Dean—Stark trap in benzene (15 mL) in the presence
of glacial acetic acid (0.05 mL) and ammonium acetate (0.02 g) for
2 h. The solution was washed with water (2×30 mL), dried
over MgSO4, and concentrated. The product was crystallized from
ethanol.
This work was financially supported in part by the Preꢀ
sidium of the Russian Academy of Sciences (Program Pꢀ8).
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Received November 13, 2007;
in revised form March 13, 2008