Novel Synthesis of Pyridine-2(1H)-thiones: Reaction of Imino Esters with Cyanothioacetamide

Article abstract of DOI:10.1039/a608114b

A novel synthesis of pyridine-2(1H)-thiones via the reaction of imino esters with cyanothioacetamide is reported and the synthetic potential of the method is demonstrated.

Full text of DOI:10.1039/a608114b

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260 J. CHEM. RESEARCH (S), 1997
J. Chem. Research (S),
1997, 260–261†
Novel Synthesis of Pyridine-2(1H)-thiones: Reaction of
Imino Esters with Cyanothioacetamide†
Galal E. H. Elgemeie,*a Ahmed H. Elghandour,b Hosny A. Alib and
Ahmed A. Hussainb
aChemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt
bChemistry Department, Faculty of Science, Cairo University (Bani Suef Branch), Bani Suef,
Egypt
A novel synthesis of pyridine-2(1H)-thiones via the reaction of imino esters with cyanothioacetamide is reported and the
synthetic potential of the method is demonstrated.
NH2
Imino esters are highly reactive compounds and are exten-
sively utilized as reactants or reaction intermediates since
CN
their imino and ester functions are suitably situated to enable
reactions with common bidentate reagents to form a variety
Y
N
H
S
of heterocyclic compounds.1,2 Moreover, the active hydrogen
atom on C-2 of these compounds can also take part in a
variety of condensation and substitution reactions. As part of
a medicinal chemistry program in our laboratories, the syn-
theses of several substituted pyridine-2(1H)-thiones were
required. The importance of the synthesized compounds as
intermediates for the synthesis of the biologically active
deazafolic acid and deazapyrimidine nucleoside ring systems
prompted our interest in the synthesis and chemistry of this
class of compounds.3–10 We now report the novel reaction of
imino esters 2 with cyanothioacetamide.
3
3
Y
a
b
c
Ph
OH
SH
CN
S
NH2
OEt
CN
+
EtOH–HCl
0 °C
NH2 Cl–
EtOH–MeCO2–NH4
+
X
X
It was found that treating the cyano compounds 1a–c with
hydrogen chloride in absolute ethanol at 0 °C gave the imino
esters 2 in good yield. Compounds 2 reacted with cyanothio-
acetamide in refluxing ethanol containing ammonium acetate
to yield 1:1 adducts, for which two possible structures, 3 and
4, were considered. The structure of 4 was established and
confirmed on the basis of elemental analysis and spectral
data. The IR spectrum of compound 4a showed the absence
of a cyano group and the presence of a carbonyl group at
1650 cmꢀ1. The formation of 4 from the reaction of 2 with
cyanothioacetamide is assumed to proceed via the initial
Michael addition of the active methylene in 2 to the cyano
group in cyanothioacetamide to yield intermediates, which
cyclize via ethanol elimination to give the stable pyridine-
2(1H)-thione derivatives 4.
Compounds 4 bearing latent functional substituents were
found to be useful for the synthesis of pyridine derivatives.
Thus, compounds 4 reacted with methyl iodide and phenacyl
bromide in sodium ethoxide to afford the corresponding
S-substituted derivatives 5. When compound 5b was treated
with hydrazine, the 2-hydrazino derivative 6 was obtained.
Compounds 4 were also coupled with aryldiazonium chlor-
ides in ethanol containing sodium acetate to yield the corre-
sponding hydrazones 7. The structures of 7 were established
on basis of their elemental analysis and spectral data.
1
2
1,2,4
X
a
b
c
COPh
CO2Et
C(S)NH2
NH2
NH2
N
NH2
EtO2C
H2N
X
X
NH2NH2
RI
EtO–Na+
in the case
of 5b
N
NHNH2
H2N
S
R
H2N
N
H
S
6
5
4
5
X
R
a
b
c
d
COPh
CO2Et Me
COPh CH2COPh
Me
CO2Et CH2COPh
NH2
+
N
Ar
NCl–
X
N
S
N
Ar
H2N
N
H
7
Experimental
All melting points are uncorrected. The IR spectra were
obtained (KBr disk) on a Perkin Elmer/1650 FT-IR instrument. 1H
NMR spectra were measured on a Varian 400 MHz spectrometer
for solutions in (CD3)2SO using SiMe4 as internal standard. Mass
spectra were recorded on a Varian MAT 112 spectrometer. Ana-
lytical data were obtained from the Microanalytical Data Center at
Cairo University. Compounds 2a,b were prepared following the
literature procedures.11
7
X
Ar
4-MeC6H4
a
b
c
d
COPh
CO2Et 4-MeC6H4
C(S)NH2 4-MeC6H4
COPh
4-OMeC6H4
Scheme 1
b-Imino-b-ethoxythioacetamide Hydrochloride 2c.sHydrogen
chloride gas was passed through a mixture of cyanothioacetamide
(0.1 mol) and absolute ethanol (0.1 mol) in dry 1,4-dioxane for 3 h
at 0 °C. The resultant precipitate was isolated by filtration and
recrystallized from 1,4-dioxane–ethanol (2:1) to give 2c, mp
154 °C, yield 96%; vmax (KBr)/cmꢀ1 3590–3124 (NH2, NH).
5-Substituted 4,6-Diaminopyridine-2(1H)-thiones 4. General Pro-
cedure.sA mixture of cyanothioacetamide (0.1 mol) and com-
pounds 2a–c (0.1 mol) was treated with sodium acetate (0.15 mol)
*To receive any correspondence.
†This is a Short Paper as defined in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1997, Issue 1]; there is there-
fore no corresponding material in J. Chem. Research (M).

View Article Online
J. CHEM. RESEARCH (S), 1997 261
and dry ethanol (100 ml) and then heated for 12 h. The solution
was then poured into iced water and the resultant precipitate was
collected and recrystallized from the appropriate solvent. 4a: mp
190 °C, yield 67%; vmax (KBr)/cmꢀ1 3637–3443, 3302 (NH2), 1650
(CO); dH [(CD3)2SO] 6.18 (brs, 2 H, NH2), 6.83 (s, 1 H, CH),
7.22–7.58 (m, 5 H, Ph), 7.62 (brs, 2 H, NH2), 13.86 (brs, 1 H, NH);
m/z 245 (Mǹ) (Found: C, 60.0; H, 4.8; N, 17.6. C12H11N3SO
requires C, 58.8; H, 4.5; N, 17.1%). 4b: mp ꢁ300 °C, yield 53%;
ethanol containing sodium acetate (2.0 g) was cooled to 0 °C and
then treated gradually with a cold solution of aryldiazonium chlor-
ide [prepared from arylamine (0.01 mol) and the appropriate quan-
tities of HCl and NaNO2]. The solid product formed was collected
and recrystallized from the appropriate solvent. 7a: mp 210 °C,
yield 80%; vmax (KBr)/cmꢀ1 3443, 3304, 3198 (NH2, NH),
1640–1620 (CO); dH [(CD3)2SO] 2.52 (s, 3 H, CH3), 7.13 (brs, 2 H,
NH2), 7.20–7.50 (m, 9 H, Ph and C6H4), 7.97 (brs, 2 H, NH2), 9.60
(brs, 1 H, NH); m/z 363 (Found: C, 62.3; H, 4.5; N, 19.0.
C19H17N5SO requires C, 62.8; H, 4.7; N, 19.3%). 7b: mp 280 °C,
yield 75%; vmax (KBr)/cmꢀ1 3550–3367 (NH2, NH), 1677–1614
(CO); m/z 331 (Mǹ) (Found: C, 54.8; H, 4.98; N, 21.4. C15H17N5SO2
requires C, 54.4; H, 5.14; N, 21.15%). 7c: mp ꢁ300 °C, yield 86%;
v
max (KBr)/cmꢀ1 3400–3132 (NH2, NH), 1747 (CO); m/z 213 (Mǹ)
(Found: C, 45.6; H, 5.0; N, 19.9. C8H11N3SO2 requires C, 45.1; H,
5.2; N, 19.7%). 4c: mp ꢁ300 °C, yield 53%; vmax (KBr)/cmꢀ1
3404–3200 (NH2, NH); m/z 200 (Mǹ) (Found: C, 35.8; H, 4.3; N,
28.5. C6H8N4S2 requires C, 36.0; H, 4.0; N, 28.0%).
5-Substituted 4,6-Diamino-2-methylsulfanylpyridines 5a,b. General
Procedure.sTo a solution of sodium ethoxide [prepared by dis-
solving sodium metal (0.01 mol) in anhydrous ethanol (10 ml)], the
equivalent amounts of 4a,b dissolved in 6 ml DMF were added.
The reaction mixture was refluxed for 15 min, cooled, and then
methyl iodide (0.012 mol) was added. The solution was stirred for
1 h at room temperature and allowed to stand overnight. The
product was isolated by neutralizing the reaction mixture with dil.
HCl and recrystallizing from the appropriate solvent. 5a: mp
165 °C, yield 62%; vmax (KBr)/cmꢀ1 3227, 3112 (NH2), 1707 (CO);
m/z 259 (Mǹ) (Found: C, 60.5; H, 4.8; N, 16.0. C13H13N3SO
requires C, 60.2; H, 5.0; N, 16.2%). 5b: mp ꢁ300 °C, yield 79%;
v
max (KBr)/cmꢀ1 3400–3122 (NH2, NH); m/z 318 (Mǹ) (Found: C,
49.2; H, 4.6; N, 27.0. C13H14N6S2 requires C, 49.0; H, 4.4; N, 26.4%).
7d: mp 222 °C, yield 67%; vmax (KBr)/cmꢀ1 3450, 3368–3275 (NH2,
NH), 1680–1619 (CO); dH [(CD3)2SO] 3.88 (s, 3 H, OCH3), 7.06
(brs, 2 H, NH2), 7.11–7.55 (M, 9 H, Ph and C6H4), 7.78 (brs, 2 H,
NH2), 9.99 (brs, 1 H, NH); m/z 379 (Mǹ) (Found: C, 59.8; H, 4.7;
N, 18.3. C19H17N5SO2 requires C, 60.2; H, 4.5; N, 18.5%).
Received, 2nd December 1996; Accepted, 25th March 1997
Paper E/6/08114B
v
max (KBr)/cmꢀ1 3350–3186 (NH2), 1750–1730 (CO); m/z 227 (Mǹ)
(Found: C, 47.8; H, 5.4; N, 18.4. C9H13N3SO2 requires C, 47.5; H,
5.7; N, 18.4%).
References
5-Substituted 4,6-Diamino-2-phenacylsulfanylpyridines 5c,d.
General Procedure.sTo a solution of sodium ethoxide (0.01 mol),
the equivalent amounts of 4a,b and phenacyl bromide were added.
The mixture was then heated for 3 h and the product isolated by
neutralization of the reaction mixture with dil. HCl and recrystalli-
zation from ethanol. 5c: mp 175 °C, yield 70%; vmax (KBr)/cmꢀ1
3650, 3334 (NH2), 1706, 1633 (2CO); dH [(CD3)2SO] 4.49 (s, 2 H,
CH2), 6.77 (brs, 2 H, NH2), 6.92 (s, 1 H, CH), 7.18–7.76 (m, 10 H,
2Ph), 7.89 (brs, 2 H, NH2); m/z 363 (Mǹ) (Found: C, 66.5; H, 4.5;
N, 11.9. C20H17N3SO2 requires C, 66.1; H, 4.7; N, 11.6%). 5d: mp
221 °C, yield 56%; vmax (KBr)/cmꢀ1 3327 (NH2), 1795–1647 (2 CO);
m/z 331 (Mǹ) (Found: C, 57.7; H, 5.4; N, 12.8. C16H17N3SO3
requires C, 58.0; H, 5.1; N, 12.7%).
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7
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equivalent mixture of 5b and hydrazine hydrate (0.01 mol) was
stirred in ethanol (20 ml) for 1 h. The product that separated on
cooling was filtered and recrystallized from DMF–EtOH. 6: mp
ꢁ300 °C, yield 54%; vmax (KBr)/cmꢀ1 3748, 3450–3175 (NH2, NH),
1735–1688 (CO); m/z 211 (Mǹ) (Found: C, 45.0; H, 5.8; N, 33.5.
C8H13N5O2 requires C, 45.5; H, 6.2; N, 33.17%.
3345.
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5-Substituted 3-Arylazo-4,6-diaminopyridine-2(1H)-thiones 7a–d.
General Procedure.sA solution of compounds 4 (0.01 mol) in
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C 07C67 122) (Chem. Abstr., 1977, 86, 16305 q).