Vilsmeier-Haack reactions of α-hydroxyketenedithioacetals: A facile synthesis of substituted pyridines

Article abstract of DOI:10.1016/S0040-4039(02)00174-0

The reaction of α-hydroxyketenedithioacetals, generated by the 1,2-addition of methyl Grignard reagent to α-oxoketenedithioacetals, with the Vilsmeier reagent was investigated. The reaction proceeds with acid-catalysed dehydration to afford sulphur substituted 1,3-butadienes, which undergo subsequent iminoalkylations. The intermediate iminium salts formed were successfully transformed into 2-methylsulfanyl substituted 4-aryl pyridines, in the presence of ammonium acetate

Full text of DOI:10.1016/S0040-4039(02)00174-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 2273–2275
Vilsmeier–Haack reactions of a-hydroxyketenedithioacetals:
a facile synthesis of substituted pyridines
Ajith Dain Thomas and C. V. Asokan*
School of Chemical Sciences, Mahatma Gandhi University, Kottayam, Kerala, India 686 650
Received 2 November 2001; revised 16 January 2002; accepted 24 January 2002
Abstract—The reaction of a-hydroxyketenedithioacetals, generated by the 1,2-addition of methyl Grignard reagent to a-
oxoketenedithioacetals, with the Vilsmeier reagent was investigated. The reaction proceeds with acid-catalysed dehydration to
afford sulphur substituted 1,3-butadienes, which undergo subsequent iminoalkylations. The intermediate iminium salts formed
were successfully transformed into 2-methylsulfanyl substituted 4-aryl pyridines, in the presence of ammonium acetate © 2002
Elsevier Science Ltd. All rights reserved.
The Vilsmeier–Haack reaction is one of the useful
general methods employed for the formylation of vari-
ous electron rich aromatic, aliphatic and heteroaro-
matic substrates1 and the halomethyleneiminium salt
intermediates are highly versatile for the synthesis of
heterocycles.2 For instance, by the condensation of
enamines with iminium salts, Risch and co-workers
developed a simple method for the synthesis of substi-
tuted pyridines.3 Boruah and co-workers have reported
the reactions of conjugated steroidal oximes with the
the synthesis of substituted pyridines. Potts and co-
workers have studied the conjugate addition of active
methylene ketones to a-oxoketenedithioacetals in the
presence of potassium t-butoxide in THF. The 1,5-ene-
diones formed in these reactions have been subse-
quently exploited for the synthesis of substituted
pyridines and annulated pyridines in moderate yields.8,9
The same protocol was applied for the synthesis of
oligopyridines and quinquepyridines as well.10 1,2-
Addition of lithioacetonitrile or lithiopropionitrile to
a-oxoketenedithioacetals afforded enol acetals which
underwent intramolecular Ritter reactions accompanied
by a 1,3-methylthio shift in the presence of H3PO4 to
give a variety of substituted and annulated 2,6-bis-
(methylthio)pyridines in good yields.11 Transformations
of a-hydroxyketenedithioacetals, readily available by
the chemoselective reduction or 1,2-nucleophilic addi-
tion reactions of a-oxoketenedithioacetals, have also
been well studied. Their reaction with the
chloromethylene iminium salt proceeds with dehydra-
tion followed by iminoalkylation to afford conjugated
Vilsmeier reagent resulting in
a
pyrido-steroidal
product.4 Jutz et al. have demonstrated that the cyclisa-
tion of the intermediate iminium salts formed by the
multiple iminoalkylations of certain alkenes, in the
presence of ammonium acetate leads to the formation
of substituted pyridines and naphthyridines.5 We have
recently generalised this protocol, starting from appro-
priate tertiary alcohols, rather than alkenes.6 We envis-
aged that
a similar ammonium acetate induced
cyclisation of the intermediates formed by the treatment
of a-hydroxyketenedithioacetals would afford a useful
method for the synthesis of substituted pyridines.
OH SMe
O
SMe
SMe
i
The chemistry of a-oxoketenedithioacetals leading to
the formation of heterocycles, aromatic compounds,
and various valuable reactive intermediates has been
studied extensively.7 Potts et al.8–10 and Junjappa et
al.11 have used a-oxoketene dithioacetals extensively for
Ar
SMe
Ar
CH3
2
1
ii, iii
N
i. MeMgI / Et2O
ii. POCl3 / DMF(2 equiv.) rt. 24h,
iii. NH4OAc, 80 οC, 2h
Keywords: pyridines; ketenedithioacetals; Vilsmeier reagent; imino-
alkylations; sulphur compounds.
* Corresponding author. Tel.: +91 481 598015; fax: +91 481 594432;
e-mail: asokancv@yahoo.com
Ar
SMe
3
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00174-0

2274
A. D. Thomas, C. V. Asokan / Tetrahedron Letters 43 (2002) 2273–2275
pentadiene–aldehydes, on aqueous alkaline workup.
This protocol has been established as a useful proce-
dure for the synthesis of conjugated polyene aldehydes
of the diene with chloromethylene iminium salt leads to
the iminoalkylated intermediate 8, which on cyclisation
in the presence of ammonium acetate affords 4-aryl-2-
(methylsulfanyl)pyridines 3. It is interesting to note that
products derived from further iminoalkylations have
not been isolated from these reactions. This could be
attributed to the relatively lower electron rich character
of bis(methylthio)substituted 1,3-butadienes compared
to the N,N-dimethylamino substituted 1,3-butadienes
which are intermediates in the multiple iminoalkylation
reactions of aliphatic tertiary alcohols.
and
polyene
esters
by
1,n-carbonyl
group
transpositions.12
In the present work we studied the reactions of a-
hydroxy-ketenedithioacetal13 2a, generated by the 1,2-
addition of the methyl Grignard reagent to a-oxo-
ketenedithioacetal 1a, with the Vilsmeier reagent. The
intermediate iminium salt formed was successfully
transformed into 2-methylsulfanyl-4-phenylpyridine14,15
3a in 51% yield, in the presence of ammonium acetate
(Scheme 1).
Alkyl and arylthio substituents a or g to a ring nitrogen
are reactive leaving groups in nucleophilic substitution
reactions16 and their oxidised forms, the sulfoxides and
sulfones are even more readily displaced. Thus, the
alkylthiopyridines 3 could serve as precursors for fur-
ther synthetic transformations. In short our studies,
directed towards the exploitation of the synthetic utility
of functionalised ketenedithioacetals has led to the
development of an expedient method for the synthesis
of 2-methylsulfanyl substituted 4-arylpyridines.
The reactions of other aryl substituted a-hydroxy-
ketenedithioacetals 2b–f with chloromethylene–iminium
salt also proceeded in a similar fashion, to afford the
4-aryl-2-(methylsulfanyl)pyridines14 3b–f in 41–56%
overall yields (Table 1). Our attempts to synthesise
pyridines from acyl ketene dithioacetal 4 and other
systems such as ketenedithioacetals of a-tetralone 5,
propiophenone 6 etc. afforded complex reaction mix-
tures. All the substituted pyridines prepared were fully
characterised with the help of spectral and analytical
data.
Acknowledgements
We thank CDRI, Lucknow for providing spectral and
analytical data. A.D.T. thanks the Mahatma Gandhi
O
O
SMe
SMe
H3C
MeS
University for the award of
Fellowship.
a Junior Research
SMe
4
5
References
O
CH3
C6H5
1. (a) Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355;
(b) Marson, C. M. Tetrahedron 1992, 48, 3659; (c) Jutz,
C. In Advances in Organic Chemistry; Taylor, E. C., Ed.;
John Wiley & Sons: New York, 1976; Vol. 9, p. 225; (d)
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Chem. Soc., Chem. Commun. 1995, 1463; (c) Jackson, A.;
Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1995,
1319.
MeS
SMe
6
Me
Me
N
OPOCl2
SMe
SMe
SMe
Ar
Ar
SMe
3. Risch, N.; Esser, A. Synthesis 1988, 337.
4. Ahmed, S.; Boruah, R. C. Tetrahedron Lett. 1996, 37,
8231.
5. Jutz, C.; Muller, W.; Muller, E. Chem. Ber. 1966, 99,
2479.
6. Thomas, A. D; Asokan, C. V. J. Chem. Soc., Perkin
Trans. 1 2001, 2583.
7
8
A probable mechanistic pathway leading to the forma-
tion of 4-aryl-2-(methylsulfanyl)pyridines 3 involves the
dehydration of a-hydroxy ketenedithioacetals induced
by the presence of Vilsmeier reagent to afford 1,1-bis-
(methylthio)-3-aryl-1,3-butadienes 7. Further reaction
7. (a) Dieter, R. K. Tetrahedron 1986, 42, 3029; (b) Jun-
jappa, H.; Ila, H.; Asokan, C. V. Tetrahedron 1990, 46,
5423; (c) Kolbe, M. Synthesis 1990, 171.
Table 1. 4-Aryl-2-(methylsulfanyl)pyridines 3 prepared
Entry
Substrate
Product
Yield (%)
8. Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J.
Org. Chem. 1982, 47, 3027.
1
2
3
4
5
6
(1a), Ar=C6H5
3a
3b
3c
3d
3e
3f
51
55
53
51
56
41
9. (a) Potts, K. T.; Ralli, P.; Theodoridis, G.; Winslow, P.
A. Org. Synth. 1985, 64, 189; (b) Potts, K. T.; Winslow,
P. A. Synthesis 1987, 839; (c) Potts, K. T.; Winslow, P. A.
J. Org. Chem. 1985, 50, 5405.
(1b), Ar=4-ClC6H4
(1c), Ar=4-MeOC6H4
(1d), Ar=4-MeC6H4
(1e), Ar=4-BrC6H4
(1f), Ar=2-Naphthyl
10. Potts, K. T.; Cipullo, M. J.; Ralli, P.; Theodoridis, G. J.
Am. Chem. Soc. 1981, 103, 3585.

A. D. Thomas, C. V. Asokan / Tetrahedron Letters 43 (2002) 2273–2275
2275
11. (a) Gupta, A. K.; Ila, H.; Junjappa, H. Tetrahedron 1990,
46, 2561; (b) Junjappa, H.; Ila, H.; Patro, B.; Rao, C. S.
Indian J. Chem. 1994, 71, 501.
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reaction mixture was stirred for 24 h at room tempera-
ture. Solid ammonium acetate was added to the reaction
mixture in excess (15 equiv., 5.8 g) and the mixture was
again stirred for a further 2 h. The mixture was then
added to cold saturated K2CO3 solution (300 mL) and
extracted with diethyl ether (3×50 mL). The organic layer
was washed with water, dried over anhydrous Na2SO4
and evaporated to give the crude product which was
chromatographed over silica gel using hexane: ethyl acet-
ate, (98:2) as eluent to give the 4-aryl-2-(methylsulfanyl)
pyridines 3a–f.
13. General procedure for the preparation of a-hydroxy-
ketenedithioacetals from a-oxoketenedithioacetals: The
methyl Grignard reagent was prepared from 1.06 g (7.5
mmol) methyl iodide, 0.21 g (8.75 mmol) magnesium and
a pinch of iodine crystals (0.10 g) in ether. The methyl
magnesium iodide was cooled to 0–5°C and the
ketenedithioacetal (5 mmol) in ether was added slowly
over 15 min. The mixture was stirred at this temperature
for half an hour and was poured over cold saturated
ammonium chloride solution. It was then extracted with
ether (3×50 mL). The combined organic layer was washed
with water and dried over anhydrous sodium sulphate.
Ether was removed and the a-hydroxyketenedithioacetal
formed was used for the next step without further purifi-
cation.
14. General procedure for the synthesis of 4-aryl-2-(methyl-
sulfanyl)pyridines froma-hydroxyketenedithioacetals: The
Vilsmeier reagent was prepared by mixing ice cold dry
DMF (50 mL) and POCl3 (1.24 mL, 10 mmol). The
mixture was then stirred for 15 min at room temperature.
The a-hydroxyketenedithioacetals 2a–f (5 mmol)
obtained from the Grignard reaction were dissolved in
dry DMF and added in about 15 min at 0–5°C. The
15. All compounds gave satisfactory spectroscopic data and
elemental analyses. Spectral data of representative com-
pound 2-(methylsulfanyl)-4-phenylpyridine 3a was
obtained from the reaction of 4,4-bis(methylsulfanyl)-2-
phenyl-3-buten-2-ol 2a (1.35 g, 5 mmol) as a brown oil,
yield: 0.51 g (51%); IR (neat, wmax) 1580, 1530, 1445,
1
1360, 1120 cm−1. H NMR (200 MHz, CDCl3): l 2.59 (s,
3H, SCH3); 7.16 (d, J=6 Hz, 1H, Py 5-H); 7.37 (s, 1H,
Py 3-H); 7.40–7.60 (m, 5H, aromatic); 8.46 (d, J=6 Hz,
1H, Py 6-H) ppm. 13C NMR (50.33 MHz, CDCl3): l
13.78 (SCH3), 118.01, 119.63, 127.39, 128.44, 128.76,
129.07, 129.47, 138.41, 148.76, 150.12, 160.94 ppm (aro-
matic); EIMS m/z (%): 201 (100, M+), 200 (88.7), 128
(39.4). Anal. calcd for C12H11NS: C, 71.61; H, 5.51; N,
6.96; S, 15.93. Found: C, 71.57; H, 5.48; N, 6.82; S,
15.86%
16. Comprehensive Heterocyclic Chemistry; Vol. 2, Katritzky,
A. R.; Rees, C. W. Eds.; Pergamon Press, 1984.