Chemistry of Heterocyclic Compounds, Vol. 38, No. 5, 2002
FIRST EXAMPLE OF THE SYNTHESIS
OF 2-METHYLTHIO-3-PYRIDINOL
1
2
1
1
N. A. Nedolya , L. Brandsma , N. I. Slyakhtina , and S. V. Fedorov
Keywords: isothiocyanate, 3-(1-ethoxyethoxy)-2-methylthiopyridine, 2-methylthio-3-pyridinol,
-(1-ethoxyethoxy)-2-methoxy-6-methylthio-2,3-dihydropyridine, 1-(1-ethoxyethoxy)allene, aromatization,
hydrolysis, lithiation, sigmatropic rearrangement, electrocyclization.
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2
-Methylthio-3-pyridinol (1) was identified among the most important aromatizing components of
smokehouse smoke, cured meat products, and smoked preparations [1, 2]. However, the synthesis of this
compound has not yet been described.
We have found a simple and original pathway for the synthesis of 2-methylthio-3-pyridinol by the
reaction of α-lithiated 1-(1-ethoxyethoxy)allene (2), which is readily obtained by the deprotonation of allene 3
(
blocked 1-allenol [3]) using butyllithium, with methoxymethyl isothiocyanate (4). The reaction of alkyl and
cycloalkyl isothiocyanates with lithium derivatives of alkoxyallenes under analogous conditions leads to the
formation of mixtures of 3-alkoxypyrroles and 5-alkoxy-2,3-dihydropyridines [3-5].
We have found that the alkylated adduct of intermediate
2
with isothiocyanate
4
(
2,3-butadienimidothioate 5) isomerizes quantitatively under the reaction conditions to give N-(1,3-butadienyl)
iminoformate 6. The electrocyclization of 6 leads selectively to previously unreported 5-(1-ethoxyethoxy)-2,3-
dihydropyridine 7 in high yield. Heating dihydropyridine 7 at 120-130°C for about 1 h leads to the loss of
methanol and quantitative transformation to give 3-(1-ethoxyethoxy)-2-methylthiopyridine (8). Mild hydrolysis
of 8 gives pyridinol 1.
Products 7 and 8 are the first examples of dihydropyridine and pyridine acetals, respectively.
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-(1-Ethoxyethoxy)-2-methoxy-6-methylthio-2,3-dihydropyridine (7). A sample of allene 3 (7.5 g,
0
.06 mol) was added to a solution of n-BuLi (0.06 mol) in hexane (37 ml) and THF (70 ml) cooled to -100°C in
a nitrogen atmosphere. After 10 min stirring at -60°C, the reaction mixture was again cooled to -100°C and
methoxymethyl isothiocyanate (5.3 g, 0.05 mol) was rapidly added. After warming to -65°C and 10 min stirring
at this temperature, MeI (16 g, 0.11 mol) was added. The mixture was stirred for ~20 min at room temperature
and then treated with cold water (~150 ml). The organic layer was separated and the aqueous layer was
extracted with three 50-ml portions of ether and pentane. The combined organic fraction was dried over K
2
CO
3
and the solvent was removed at reduced pressure to give 12 g of methyl-N-[1-methylthio-2-(1-ethoxyethoxy)-
1
1
,3-butadienyl] iminoformate (6) in ~100% purity as indicated by gas-liquid chromatography. H NMR
spectrum (CDCl
3
, 400 MHz), δ, ppm, J (Hz): 7.97 (1H, s, N=CH); 6.88 (1H, dd, J = 17.4 and 11.0, CH=); 5.2
=); 5.23 (1H, q, J = 5.2, OCHO); 5.10 (1H, dd, J = 11.0 and 2.0, cis-CH );
.84 (3H, s, OMe); 3.73 (1H, br. m, OCH ); 3.61 (1H, br. m, OCH ); 2.17 (3H, s, SMe); 1.46 (3H, d, J = 5.2,
(1H, dd., J = 17.4 and 2.0, trans-CH
2
2
3
2
2
Me); 1.17 (3H, t, J = 7.1, Me).
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_________________________________________________________________________________________
A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences,
2
64033 Irkutsk, Russia; e-mail: nina@irioch.irk.ru. Julianalaan 273, 3722 GN Bilthoven, The Netherlands;
e-mail: l.brandsma@wxs.nl. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 707-709, May,
2002. Original article submitted January 30, 2002.
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22 0009-3122/02/3805-0622$27.00©2002 Plenum Publishing Corporation
Nedolya
