Synthesis of vinylsulfonyl(halo)pyridines and their reactions with binucleophilic reagents

Article abstract of DOI:10.1007/s11178-005-0075-4

Oxidation of vinylthio(halo)pyridines with 30-33% hydrogen peroxide solution in acetic anhydride at 20-25°C furnished vinylsulfonyl(halo) pyridines. Nucleophilic addition reactions of 2-amino-1-ethanethio hydrochloride and thiosemicarbazide to the multiple bonds of vinylsulfonyl(halo)pyridines were performed. 2004 MAIK "Nauka/Interperiodica".

Full text of DOI:10.1007/s11178-005-0075-4

Russian Journal of Organic Chemistry, Vol. 40, No. 11, 2004, pp. 1657 -1661. Translated from Zhurnal Organicheskoi Khimii, Vol. 40, No. 11,
2004, pp. 1705-1708.
Original Russian Text Copyright Ó 2004 by Amosova, Gavrilova.
Synthesis of Vinylsulfonyl(halo)pyridines and Their Reactions
with Binucleophilic Reagents
S.V.Amosova and G.M. Gavrilova
Faworsky Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences,
Irkutsk, 664033 Russia
e-mail: amosova@irioch.irk.ru
Received April 13, 2004
Abstract-- Oxidation of vinylthio(halo)pyridines with 30–33% hydrogen peroxide solution in acetic anhydride at
20–25°C furnished vinylsulfonyl(halo)pyridines. Nucleophilic addition reactions of 2-amino-1-ethanethio
hydrochloride and thiosemicarbazide to the multiple bonds of vinylsulfonyl(halo)pyridines were performed.
Preparation procedures for unsaturated sulfur-
containing pyridines underlain by the use of divinyl sulfide
for introduction of vinylthio- and 3-butenylthio groups [1]
provided an opportunity to obtain a series of vinylthio-
(halo)- and 3-butenylthio(halo)pyridines possessing a
significant synthetic potential.
evaluation of their reactivity toward binucleophilic
reagents.
Preparation conditions were developed for 2,6-di-
(vinylthio)pyridine (I) affording a 55% yield by reaction
of 2,6-dibromopyridine with an ethenethiolate anion
generated by divinyl sulfide cleavage with sodium in liquid
ammonia. The reaction occurred in DMF at 20–25°C.
Under similar conditions the 2,5-dibromopyridine gave rise
to 5-bromo-2-(vinylthio)pyridine (II) in 62% yield.
This study is an extension of our research in the field
of the synthesis of new vinylthio(halo)pyridines and
preparing thereof vinylsulfonyl(halo)pyridines aiming at
+
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Inasmuch as the synthesis of the pyridine vinylthio
derivatives by procedure [1] alongside the vinylthio-
(halo)pyridines furnished also 3-butenylthio(halo)pyridines
(in a ratio from 3:1 to 5:1), and we failed to separate the
latter, the oxidation was performed with the mixture of
compounds at the minimum content of 3-butenylthio
derivatives. Therewith we failed to isolate the oxidation
products of 3-butenyl-thio(halo)pyridines.
anhydride at 20–25°C within 48 h afforded 2-(vinyl-
sulfonyl)-6-chloro- (IV), 5-bromo-2-(vinylsulfonyl)- (V),
and 2,6-di(vinylsulfonyl)pyridines (VI) in 52, 50, and 32%
yields respectively (Scheme 1).
The nucleophilic addition to vinylsulfonyl(halo)pyridines
IV–VI of 2-amino-1-ethanethiol hydrochloride occur-
ring in the presence of Triton B catalyst at the expense
of the free SH (DMF, 20°C) provided water-soluble
adducts, hydrochlorides of 2-(5-amino-3-sulfa-
pentylsulfonyl)-6-chloro- (VII), 2-(5-amino-3-sulfapentyl-
sulfonyl)-5-bromo- (VIII), and 2,6-bis(5-amino-3-sulfa-
The oxidation of 2-(vinylthio)-6-chloro- (III), 5-bromo-
2-(vinylthio)- (II), and 2,6-di(vinyl-thio)pyridines (I) by
excess 30–33% hydrogen peroxide solution in acetic
1070-4280/04/4011-1657Ó2004 MAIK “Nauka/Interperiodica”

AMOSOVA, GAVRILOVA
1658
Scheme 1.
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Scheme 2.
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Scheme 3.
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1+1+&ꢀ6ꢁ1+
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;,
pentylsulfonyl)pyridines (IX) in 64, 42, and 72% yields
respectively (Scheme 2).
biologically active substances among compounds
containing SCH2CH2NH2 moiety.
The 2-amino-1-ethanethiol hydrochloride has been
selected as nucleophilic reagent for there are many
By an example of thiosemicarbazide nucleophilic
addition to vinylsulfonyl(halo)pyridines IV and V we
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

SYNTHESIS OFVINYLSULFONYL(HALO)PYRIDINESANDTHEIR REACTIONS
1659
4
demonstrated the possibility to obtain pyridine derivatives
containing a 2-thiosemicarbazidoethylsulfonyl fragment.
2-(2- Thiosemicarbazidoethylsulfonyl)-6-chloro- (X) and
5-bromo-2-(2- thiosemicarbazidoethylsulfonyl)pyridines
(XI) were obtained in 23% yield in ethanol (70–75°C) or
DMF (25°C) (Scheme 3).
(HBHX) 17.1, J (CH2HX) 1.6 Hz; 6.88 d (1H, H3 of
pyridine), 7.07 d (1H, H5 of pyridine), 7.26 t (1H, H4 of
pyridine). Mass spectrum, m/z: [M]+ 195 (compound I),
[M]+· 245 (compound XII).
Likewise a mixture of 5-bromo-2-(vinylthio)-
pyridine (II) and 5-bromo-2-(3-butenylthio)pyridine
(XIII) was obtained in 3:1 ratio according to NMR and
GC-MS data.
The presence in the pyridine ring of a thiosemicarbazide
or thiosemicarbazone moiety is known to endow these
compounds with biological activity. Among these
substances some possess high tuberculocidal activity [2,
3], also in this series herbicides and plant growth
stimulators have been found [4]. Therefore the
vinylsulfonyl(halo)pyridines we obtained are promising
synthons for preparation of potentially biologically active
compounds via nucleophilic addition reactions.
Compound II, 1H NMR spectrum (CDCl3), d, ppm:
5.53 d (1H, HA), 5.58 d (1H, HB), 7.04 d.d (1H, HX), 3J
(HAHX) 9.9, J (HB HX) 17.1 Hz; 7.08 d (1H, H3 of
3
pyridine), 7.63 d (1H, H4 of pyridine), 8.50 s (1H, H6 of
pyridine). 13C NMR spectrum, d, ppm: 117.19 (Cb),
127.32 (Ca), 116.71 (C5 of pyridine), 122.85 (C3 of
pyridine), 138.72 (C4 of pyridine), 150.34 (C6 of pyridine),
156.12 (C2 of pyridine), 1J(CbHA) 162.0, 1J (CbHB) 159.9,
1J (CaHX) 179.2 Hz.
The structure of compounds I–XIII was confirmed
by IR, 1H and 13C spectroscopy [5].
Compound XIII, 1H NMR spectrum (CDCl3), d, ppm:
2.35 m (2H, CH2=CHCH2CH2S), 3.15 t (2H, SCH2);
4.45 d.q (1H, HA), 5.12 d.q (1H, HB), 5.85 m (1H, HX), 2J
EXPERIMENTAL
IR spectra were recorded on spectrophotometer
Bruker IFS-25 from samples prepared as thin films or
KBr pellets. H and 13C NMR spectra were registered
on spectrometer Bruker DPX-400, internal reference
HMDS. GC-MS measurements were carried out on HP
5971 A instrument at the energy of ionizing electrons
70 eV.
3
3
4
(HAHB) 1.6, J (HAHX) 10.2, J (HBHX) 17.1, J (CH2,
HX) 1.6 Hz; 7.15 d (1H, H3 of pyridine), 7.55 d (1H, H4
of pyridine), 8.43 s (1H, H6 of pyridine). Mass spectrum,
m/z: [M]+· 216 (compound II), [M]+ 244 (compound
XIII).
1
2-(Vinylsulfonyl)-6-chloropyridine (IV). To a
solution of 2.8 g of 2-(vinylthio)-6-chloropyridine and 2-
(3-butenylthio)-6-chloropyridine (in a 5:1 ratio) prepared
by method [1] in 20 ml of acetic anhydride was added
dropwise at 10°C 20 ml of 32% hydrogen peroxide. The
reaction mixture was left standing at room temperature
for 48 h. The reaction products were extracted into
chloroform, the extract was washed with water and dried
with MgSO4. On removing chloroform at reduced
pressure we obtained 2.3 g of crystalline compound IV.
2,6-Di(vinylthio)pyridine (I). To a solution of 9.3 g
of divinyl sulfide in 200 ml of liquid ammonia was added
at stirring by small portions 5.5 g of sodium metal. After
evaporation of ammonia 140 ml of DMF was added. To
the solution obtained was added dropwise at 20–25°C
7.1 g of 2,6-dibromopyridine in 30 ml of DMF, the mixture
was stirred for 48 h at 20–25°C. The reaction mixture
was treated with water, the reaction products were
extracted into ethyl ether, the extract was washed with
water and dried on MgSO4. On removing the ether we
obtained 4.6 g of viscous liquid of amber color containing
according to NMR and GC-MS data 2,6-di(vinylthio)-
pyridine (I) and 2-(3-butenylthio)-6-bromo-pyridine (XII)
in 5:1 ratio. Compound I, 1H NMR spectrum (CDCl3), d,
ppm: 5.50 d (1H, HA), 5.56 d (1H, HB), 7.18 d.d [1H, HX,
3J (HAHX) 9.9, 3J (HBHX) 16.6 Hz], 6.91 d (2H, H3 and
H5 of pyridine), 7.36 t (1H, H4 of pyridine); 13C NMR
spectrum, d, ppm: 116.33 (Cb), 127.41 (Ca), 117.86 (C3
and C5 of pyridine), 136.51 (C4 of pyridine), 157.22 (C2
and C6 of pyridine), 1J (CbHA) 162.2, 1J (CbHB) 159.5, 1J
(Ca HX ) 179.0 Hz. 1H NMR spectrum of compound
XII (CDCl3), d, ppm: 2.44 m (2H, CH2=CHCH2CH2S),
3.18 t (2H, SCH2), 5.04 d.q (1H, HA), 5.10 d.q (1H, HB),
–1
Yield 52%, mp 76–77°C (ethanol). IR spectrum, n, cm :
1155 and 1311 (SO2), 1571, 1551 and 1420 (pyridine ring),
1
1610 (C=C), 3028, 3058, 3111 (=CH). H NMR spectrum
(CDCl3), d, ppm: 6.27 d (1H, HA), 6.61 d (1H, HB),
3
3
6.93 d.d (1H, HX), J (HAHX) 9.8, J (HBHX) 16.6 Hz;
7.56 d (1H, H3 of pyridine), 7.97 d (1H, H5 of pyridine),
8.00 t (1H, H4 of pyridine). 13C NMR spectrum, d, ppm:
120.60 (C5 of pyridine), 128.67 (C3 of pyridine), 140.80
(C4 of pyridine); 131.71 (Cb), 135.3 (Ca). Mass spectrum,
m/z: [M]+· 203. Found, %: C 41.08; H 2.94; Cl 17.21;
N 6.56; S 15.94. C7H6Cl NO2S. Calculated, %: C 41.29;
H 2.97; Cl 17.41; N 6.88; S 15.74.
5-Bromo-2-(vinylsulfonyl)pyridine (V) was
prepared by oxidation of a mixture of compounds II and
2
3
3
5.84 m (1H, HX), J (HAHB) 1.6, J (HAHX) 10.2, J
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

AMOSOVA, GAVRILOVA
1660
XIII, 3:1, under similar conditions. Yield 50%, mp 88°C
(ethanol). IR spectrum, n, cm : 1158 and 1309 (SO2),
pyridine). Found, %: C 33.88; H 4.20 ; Cl 22.48; N 8.71;
S 19.92. C9H14Cl2N2O2S2. Calculated, %: C 34.07; H
4.45; Cl 22.35; N 8.83; S 20.21.
–1
1562, 1547 and 1443 (pyridine ring), 1606 (C=C), 3052,
3090 and 3114 (=CH). 1H NMR spectrum, d, ppm:
6.50 d (1H, HA), 6.60 d (1H, HB), 6.79 d.d (1H, HX), 3J
(HAHX) 9.9, 3J (HBHX) 16.8 Hz; 7.89 d (H3 of pyridine),
8.19 d (H4 of pyridine), 8.84 C (H6 of pyridine). Mass
spectrum, m/z: [M]+· 248. Found, %: C 33.98; H 2.70; Br
32.65; N 5.34; S 12.70. C7H6BrNO2S. Calculated, %:
C 33.89; H 2.44; Br 32.21; N 5.65; S 12.92.
2,6-Bis(5-amino-3-sulfapentylsulfonyl)pyridine
dihydrochloride (IX) was prepared in the same manner
in a 72% yield, mp 145°C (decomp.). IR spectrum, n,
–1
+
1
cm : 1147 and 1322 (SO2), 2960 br.s (NH3 ). H NMR
spectrum (DMF-d7), d, ppm: 3.21 t (2H, SCH2CH2NH2 ·
HCl), 3.37 t (2H, SCH2CH2SO2), 3.75 t (2H, CH2SO2),
4.00 t (2H, H2NH2·HCl), 8.47 d (1H, H3 and 1H, H5 of
pyridine), 8.67 s (1H, H4 of pyridine). Found, %: C 32.20;
H 5.32; Cl 14.30; N 8.48; S 26.22. C13H25Cl2N3O4S4.
Calculated, %: C 32.09; H 5.18; Cl 14.57; N 8.64; S 26.36.
2,6-Di(vinylsulfonyl)pyridine (VI) was prepared
under similar conditions in a 36% yield, mp 92–93°C
–1
(ethanol). IR spectrum, n, cm : 1149 and 1321 (SO2),
1568, 1550 and 1419 (pyridineObOe ring), 1625 (C=C),
2-(2-Thiosemicarbazidoethylsulfonyl)-6-chloro-
pyridine (X). To a solution of 1.8 g of 2-(vinylsulfonyl)-
6-chloropyridine in 20 ml of ethanol was added at stirring
a solution of 0.8 g of thiosemicarbazide in 10 ml of ethanol.
The reaction proceeded for 12 h at 75°C. The reaction
mixture was evacuated to get 1.1 g of thick resinous
product that on recrystallization from ethanol afforded
0.6 g (23%) of compound X, mp 154–155°C. IR spectrum,
1
3020, 3057, 3104 (=CH). H NMR spectrum (CDCl3),
d, ppm: 6.32 d (1H, HA), 6.60 d (1H, HB), 6.96 d.d (1H,
HX), 3J (HAHX) 9.9, 3J (HBHX) 16.6 Hz; 8.29 m (3H, H3,
H4, H5 of pyridine). 13C NMR spectrum, d, ppm: 132.14
(Cb), 134.80 (Ca), 124.83 (C3 and C5 of pyridine), 141.17
(C4 of pyridine). Mass spectrum, m/z: [M]+· 259. Found,
%: C 41.88; H 3.65; N 5.65; S 24.58. C9H9NO4S2.
Calculated, %: C 41.69; H 3.50; N 5.40; S 24.73.
–1
n, cm : 1153 and 1314 (SO2), 3166, 3259, 3369 (NH),
2-(5-Amino-3-sulfapentylsulfonyl)-5-bromo-
pyridine hydrochloride (VIII). To a solution of 0.32 g
of 2-amino-1-ethanethiol hydrochloride in 5 ml of DMF
was added two drops of Triton B, then dropwise while
stirring at 20–25°C was added a solution of 0.7 g of
5-bromo-2-(vinylsulfonyl)pyridine in 10 ml of DMF. The
reaction proceeded for 12 h. DMF was removed at
reduced pressure, the residue was washed with acetone
and dried in a vacuum to obtain 0.5 g (42%) of compound
1
3407 (NH2). H NMR spectrum (DMSO-d6), d, ppm:
3.06 br.q (2H, CH2NH), 3.59 br.t (2H, CH2SO2),
7.31 br.s (2H, NH2C=S), 7.73 s (1H, CH2NH), 7.91 d
and 8.07 d (1H, H3 and 1H, H5 of pyridine), 8.24 t (1H,
H4 of pyridine), 8.83 s (1H, NHC=S). 13C NMR
spectrum, d, ppm: 43.94 (CH2N), 50.32 (CH2SO2), 121.34
(C3 of pyridine), 129.29 (C5 of pyridine), 142.58 (C4 of
pyridine), 150.88 and 156.53 (Ci and Ci of pyridine),
181.34 [NH–C(S)NH2]. Found, %: C 32.40; H 3.80; Cl
11.90; N 19.40; S 21.60. C8H11ClN4O2S2. Calculated,
%: C 32.60; H 3.76; Cl 12.03; N 19.01; S 21.75.
–1
VIII, mp 125°C (decomp.). IR spectrum, n, cm : 1159
+
1
and 1323 (SO2), 3000 br.s (NH3 ). H NMR spectrum
(DMF-d7), d, ppm: 2.98 t (2H, SCH2CH2NH2·HCl),
3.04 t (2H, SCH2CH2SO2), 3.18 t (2H, CH2SO2), 3.86 t
(2H, CH2NH2), 8.08 d (1H, H3 of pyridine), 8.49 d (1H,
H4 of pyridine), 9.00 s (1H, H6 of pyridine). Found, %:
C 29.53; H 4.48; Br 22.57; Cl 10.10; N 7.40; S 18.04.
C9H14BrClN2O2S2. Calculated, %: C 29.88; H 3.90;
Br 22.11; Cl 9.80; N 7.74; S 17.72.
5-Bromo-2-(2-thiosemicarbazidoethylsulfonyl)-
pyridine (XI) was prepared in the same way in a 23%
–1
yield, mp 165°C (decomp.). IR spectrum, n, cm : 1146
and 1317 (SO2), 3173–3430 (NH, NH2). 1H NMR
spectrum (DMCO-d6), d, ppm: 3.15 br.q (2H, CH2NH),
3.68 br.t (2H, SO2), 7.52 br.s (2H, NH2C=S), 8.40 s (1H,
CH2NH), 7.98 d (1H, H3 of pyridine), 8.54 d (1H, H4 of
pyridine), 8.83 C (1H, H6 of pyridine). Found, %: C 27.98;
H 3.05; Br 23.70; N 16.65; S 19.02. C8H11BrN4O2S2.
Calculated, %: C 28.32; H 3.27; Br 23.55; N 16.51; S
18.90.
2-(5-Amino-3-sulfapentylsulfonyl)-6-chloro-
pyridine hydrochloride (VII) was prepared in the same
way in a 64% yield, mp 112–114°C (decomp.). IR spec-
–1
+
trum, n, cm : 1156 and 1322 (SO2), 2962 br.s (NH3 ).
1H NMR spectrum (DMF-d7), d, ppm: 2.96 t (2H,
SCH2CH2NH2·HCl), 3.06 t (2H, SCH2CH2SO2), 3.15 t
(2H, CH2SO2), 3.88 t (2H, CH2NH2), 7.98 d (1H, H3 of
pyridine), 8.16 d (1H, H5 of pyridine), 8.37 t (1H, H4 of
The study was carried out under financial support of
the Russian Foundation for Basic Research (grant no.
02-03 –32844).
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004

SYNTHESIS OFVINYLSULFONYL(HALO)PYRIDINESANDTHEIR REACTIONS
1661
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RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 40 No. 11 2004