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N. A. Nedolya et al. / Tetrahedron Letters 43 (2002) 9679–9681
tion of water and extraction with ether, the organic
solution was dried over potassium carbonate and the
solvents removed on the rotary evaporator. In the
last stage of this operation exothermic reactions
occurred resulting in the ring closure of the interme-
diary iminoformates 6 to the dihydropyridines 7. The
products (purity>95%) were obtained in good to
excellent yields. Their structures were corroborated by
NMR and mass spectroscopy and microanalytical
results were in agreement with the calculated values.
We here report that the use of the readily available
methoxymethyl isothiocyanate6 in this synthesis
affords 2,3-dihydropyridines
7
that readily lose
methanol with formation of 2-(methylthio)-substituted
pyridines 8. The first step in this novel approach to
pyridine derivatives involves the reaction of this isoth-
iocyanate with the lithiated allenic ether or acetylene
3 and subsequent alkylation of adducts 4 with methyl
iodide. The resulting intermediates 5 isomerise under
mild reaction conditions quantitatively to 1,3-butadi-
enyliminoformates 6. Electrocyclisation of 6 affords
exclusively the hitherto unknown 2,3-dihydropyridines
7 in good yields (Scheme 1).
3-Methoxy-2-(methylthio)pyridine (8, R=OMe) was
obtained in 72% yield by heating a mixture of 7 (1.75
g), diethyl ether (25 mL) and concentrated aqueous
hydrochloric acid (2.5 g of a 33% solution) for 1.5 h
under reflux, followed by treatment with excess of an
aqueous solution of potassium hydroxide, extraction
with ether and distillation. B.p. ꢀ80°C/1.5 mmHg.
1H NMR (250 MHz, CDCl3): l=8.07 (dd, J=3.8
and 2.3 Hz, 1H, Hꢁ6); 6.96 (m, 1H, Hꢁ4); 6.95 (m,
1H, Hꢁ5); 3.88 (OMe); 2.53 (3H, SMe) ppm.
After storage of 7, R=OCH(Me)OEt or OMe for
some period in the refrigerator the NMR spectrum
showed signals of the corresponding pyridine 8, obvi-
ously as the result of an elimination of methanol.
Suspecting that the elimination of methanol had been
catalysed by traces of acid on the glass wall we
heated a solution of 7, R=OMe or SMe in diethyl
ether containing a small amount of concentrated
aqueous hydrochloric acid under reflux for 1–2 hours.
This procedure indeed resulted in complete conversion
to 8. The elimination of methanol could also be
achieved by heating the neat compounds 7 at 120–
130°C for about 1 h (R=OCH(Me)OEt, SMe or Me)
or about 4 h (R=OMe). In all cases 8 could be
isolated in good to excellent yields.
3-(1-Ethoxyethoxy)-2-(methylthio)pyridine (8, R=
OCH(Me)OEt), was prepared (89% yield) by heating
4.2 g of the corresponding dihydropyridine 7 for
1
about 1 h at 120–130°C. B.p. ꢀ95°C/1 mm Hg. H
NMR spectrum (400 MHz, CDCl3): l=8.12 (dd, J=
6.8 and 1.3 Hz, 1H, Hꢁ6); 7.21 (dd, J=8.0 and 1.3
Hz, 1H, Hꢁ4); 6.92 (dd, J=8.0 and 4.8 Hz, 1H,
Hꢁ5); 5.40 (q, J=5.4 Hz, 1H, OCHO); 3.80 (m, 1H,
OCH2); 3.56 (m, 1H, OCH2); 2.50 (3H, SMe); 1.51
(d, 3H, J=5.4 Hz, OCMe); 1.18 (t, J=7.1 Hz, 3H,
OCMe) ppm.
It is interesting to mention the conversion, in a high
yield, of 3-(1-ethoxyethoxy)-2-(methylthio)pyridine (8,
R=OCH(Me)OEt) into 2-(methylthio)-3-pyridinol (9)
by treatment with concentrated aqueous hydrochloric
acid followed by addition of a potassium hydroxide
solution (Scheme 2). This pyridine derivative has been
found and identified as the most important aroma
component of smoked meat products.7
The 13C NMR and mass spectra of the products 8
were in agreement with the assumed structures, while
the microanalytical results were satisfactory.
2-(Methylthio)-3-pyridinol (9) was obtained in 84%
yield by stirring a mixture of 0.34 g of 8, R=
OCH(Me)OEt, 3 mL of water and 0.38 g of 33%
aqueous hydrochloric acid at room temperature for
10 min followed by treatment with potassium hydrox-
ide solution, extraction with ether and crystallisation
(m.p. 149–154°C). 1H NMR spectrum (400 MHz,
CDCl3): l=8.13 (d, J=4.3 Hz, 1H, Hꢁ6); 7.13 (d,
J=7.7 Hz, 1H, Hꢁ4); 7.02 (dd, J=4.5 and 8.1 Hz,
1H, H-5); 4.60 (1H, OH); 2.59 (s, 3H, SMe) ppm.
400 MHz 1H spectra in THF-d8, DMSO-d6 and
CD3OD as well as 13C NMR spectra in CDCl3, THF-
d8, DMSO-d6 and CD3OD were in agreement with
the structure of 9, while the mass spectrum showed
the expected fragments and microanalytical results
were satisfactory.
Our approach to the substituted pyridines 8 may be
illustrated by the following procedures.
Methoxyallene or 1-ethoxyethoxyallene (1, R=OMe
or OCH(Me)OEt) (0.11 mol) was added over a few
seconds to a solution of 0.10 mol of n-BuLi in 62
mL of hexane and 70 mL of THF cooled at −90°C.
The temperature was allowed to rise to −40°C, then
the solution was cooled again to −100°C after which
0.10 mol of methoxymethyl isothiocyanate was added
in one portion with vigorous stirring and cooling,
allowing the temperature of the reaction mixture to
rise to −60°C. Methyl iodide (0.15 mol) was then
added in one portion and the reaction mixture was
stirred for 15 min at room temperature. After addi-
Acknowledgements
This investigation was financially supported in part
by the Russian Foundation for Basic Research (Grant
NR. 01-03-32698).
Scheme 2.
Nedolya, Nina A.
