a readily available ketosulfone 2, a 1,5-diazapentadienium
salt 3 (vinamidinium salt) as a three-carbon electrophile, and
ammonia.
Table 1. Annulation of Ketones and Aldehydes with
N,N-Dimethyl-2-chlorotrimethinium Hexafluorophosphate (3)a
Vinamidinium species, mainly as their perchlorate salts,
have been used in synthesis since the mid-1960s for the
preparation of nitrogen-containing heterocycles such as
pyrroles and pyrimidines.4 Although pyridines have been
prepared by the reaction of â-aminocrotononitriles or â-amino-
crotonates with vinyloguous iminium salts,5 the direct
transformation of ketones to pyridines using vinamidinium
salts as annulating reagents has not been reported. Carbonyl
enolates are known to add to vinamidinium salts to produce
dienaminones,6 and enolates of substituted aryl methyl
ketones are alkylated by vinamidinium salts.7 In the latter
case the formation of pyridine rings was achieved in a three-
step process in 36-46% yield via the formation of the
corresponding pyrylium salts and reaction with ammonium
acetate.7 We recently reported the preparation of several
â-substituted vinamidinium hexafluorophosphate salts in
good yields by reacting the corresponding acetic acids or
acetyl chlorides with phosphorus oxychloride in DMF at 70
°C followed by quenching in aqueous HPF6.8 The use of
hexafluorophosphate as the counterion resulted in thermally
stable salts that were not prone to hydrolysis upon exposure
to air. We now report that these salts are suitable three-carbon
synthons that react with R-aryl ketone enolates to form 2,5-
disubstituted-3-arylpyridines in fair to excellent yields.
The 2-chloro-N,N-dimethylamino trimethinium hexafluo-
rophosphate salt (3)8 was reacted with ketone 2 in the
presence of an equimolar amount of t-BuOK in THF and
the resulting adduct was quenched in a mixture of acetic
acid and TFA. Ring closure of the pyridine ring occurred
upon heating at reflux in the presence of an excess of aqueous
ammonium hydroxide. The desired COX-2 specific inhibitor
5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridi-
nyl)pyridine (1) was obtained as a single regioisomer with
an excellent isolated yield of 94% (Table 1, entry 1).9
Replacement of the potassium base by sodium tert-
butoxide or LDA decreased the yields significantly and
resulted in the recovery of large quantities of unreacted
ketosulfone. This reaction is general and was applied to the
preparation of analogues of 1 in excellent yields (entries 2
and 3). R-Aryl acetophenones such as deoxybenzoin, des-
a Unless otherwise noted, all reactions were conducted in THF using
1.05 equiv of 20 wt % t-BuOK/THF and 1.05 equiv of vinamidinium salt.
For a typical experimental procedure, see footnote 10. b Yields refer to the
average of at least two isolated yields. Only one regioisomer has been
observed by NMR analysis of the crude reaction mixture. c A solution of
the aldehyde in THF was added dropwise to a suspension of KHMDS at
-78 °C and was warmed to rt before the addition of salt 3.
oxyanisoin, and bis(p-methylsulfonyl) deoxybenzoin give
access to the corresponding 2,3-diaryl-5-chloropyridines,
albeit in lower yields than the corresponding pyridyl ketones.
These substrates were highly dependent upon the aromatic
substitution (entries 4-6). â-tetralone and p-fluorophenyl
acetone give access to the corresponding cyclized product
in good yields (entries 7 and 8) without formation of the
other possible regioisomers as determined by NMR analysis
of the crude reaction mixture.
(4) (a) Gupton, J. T.; Petrich, S. A.; Hicks, F. A.; Wilkinson, D. R.;
Vargas, M.; Hosein, K. N.; Sikorski, J. A. Heterocycles 1998, 47, 689 and
references therein. (b) Kase, K.; Katayama, M.; Ishihara, T.; Yamanaka,
H.; Gupton, J. T. J. Fluor. Chem. 1998, 90, 29. (c) Gompper, R.; Harfmann,
C.; Polborn, K. J. Prakt. Chem., 1998, 340, 381. (d) Gupton, J. T.;
Krolikowski, D. A.; Yu, R. H.; Riesinger, S. W. Sikorski, J. A. J. Org.
Chem. 1990, 55, 4735. (e) Lloyd, D.; McNab, H. Angew. Chem., Int. Ed.
Engl. 1976, 15, 459.
(5) (a) Petrich, S. A.; Hicks, F. A.; Wilkinson, D. R.; Tarrant, J. G.;
Bruno, S. M.; Vargas, M.; Hosein, K. N.; Gupton, J. T. Tetrahedron 1995,
51, 1575. (b) Jutz, C.; Lobering, H.-G.; Trinkl, K.-H. Synthesis 1977, 326.
(6) Nair, V.; Cooper, C. S. J. Org. Chem. 1981, 46, 4759.
(7) Pavlyuchenko, A. I.; Smirnova, N. I.; Kovshev, E. I. Khim.
Geterotsikl. Soedin. 1985, 10, 1392.
(8) Davies, I. W.; Marcoux, J.-F.; Wu, J.; Corley, E. G.; Robbins, M.
A.; Palucki, M.; Tsou, N.; Ball, R. G.; Dormer, P.; Larsen, R. D.; Reider,
P. J. J. Org. Chem. 2000, in press.
The reaction is not limited to ketones since phenylacet-
aldehyde reacted in good yield to give 3-phenyl-5-chloro-
pyridine (entry 9).10
(10) General Experimental Procedure for the Annulation of Ketones.
To a suspension of ketosulfone (25 mmol) in dry THF (50 mL) at 0 °C
was added dropwise a 20 wt % solution of t-BuOK in THF (26.3 mmol).
The yellow slurry was stirred at room temperature for 45 min and the
vinamidinium hexafluorophosphate salt (26.3 mmol) was added in one
portion. The resulting mixture was stirred at room temperature for 45 min
and transferred dropwise with a cannula under nitrogen to a solution of
acetic acid (175 mmol) and TFA (20 mmol) in THF (25 mL) at 25-30 °C.
The mixture was stirred 45 min and concentrated ammonium hydroxide
(15 mL, 250 mmol NH3) was added in one portion. The resulting dark
(9) The structure of compound 1 was unambiguously assigned by NMR
analysis (COSY, HMBC, HMQC) and by comparison with an authentic
sample obtained by a different route (see ref 3a).
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Org. Lett., Vol. 2, No. 15, 2000