5264
J . Org. Chem. 2001, 66, 5264-5265
Sch em e 1
A Mild P r oced u r e for th e Red u ction of
P yr id in e N-Oxid es to P ip er id in es Usin g
Am m on iu m F or m a te
Boulos Zacharie,* Nancie Moreau, and
Christopher Dockendorff
BioChem Pharma Inc., 275 Armand-Frappier Boulevard,
Laval, Quebec, Canada H7V 4A7
not require special apparatus, hydrogen atmosphere, or
harsh conditions. The workup is easy, requiring only
filtration of catalyst followed by removal of the solvent.
Other reducing systems appear to be inefficient under
this type of reduction conditions, for example, ammonium
formate/Rh on carbon, hydrogen/Pd on carbon, or tin
hydride.
zacharib@biochempharma.com
Received March 26, 2001
Substituted piperidines can be prepared using a variety
of methods.1 The simplest procedure is by reduction of
the corresponding pyridines. This process has generally
required the use of high pressures and temperatures.2
Mild conditions for the reduction of a variety of pyridines,
quinolines, and isoquinolines was achieved by using a
metal alloy.3 This method is not selective, and many
functional groups are reduced under these conditions. For
example, the reduction of 2-phenylpyridine with nickel-
aluminum alloy in dilute base gives 2-cyclohexylpiperi-
dine. Similarly, pyridines are reduced to piperidine with
a lanthanoid metal-hydrochloric acid system.4 This
procedure is limited by the choice of the Ln metal, leads
to a mixture of unsaturated piperidines, and does not
always proceed in good yield. Also, reduction of pyridine-
containing heterocycles with lithium triethylborohydride
(super-hydride) has been reported in the literature.5
Again, this method is limited by the substituents on the
ring. For example, 3,4-lutidine is reduced to a mixture
of tetrahydropyridines and both 2,6-lutidine and 2-(3-
pentenyl)pyridine are totally inert to these conditions.
In this paper, we wish to report a mild procedure for the
reduction of pyridine or substituted pyridine N-oxides to
piperidines. This is accomplished by catalytic transfer
hydrogenation with ammonium formate as the hydrogen
source, in the presence of palladium on carbon.
Our results are summarized in Table 1. A variety of
pyridines, quinolines (entry 1m), and isoquinolines (entry
1n) are converted efficiently to their piperidine deriva-
tives. The method is general, and several reducible
functionalities such as methoxycarbonyl (entry 1f), car-
boxyl (entry 1g), amino (entries 1h-j), hydroxy (entry 1e),
and amide (entries 1k,l) are unaffected with this reagent
system. However, the chlorine atom in the 2 position is
readily eliminated under the standard reaction condi-
tions. In the case of 4-cyano, deoxygenation of the N-oxide
and the reduction of the cyano function to the corre-
sponding alkylamine9b are the only products observed in
the reaction mixture. In the reaction of 2-carboxylpyri-
dine N-oxide with ammonium formate, low yield of the
reduction product was observed by 1H NMR. In contrast,
the corresponding 2-methyl ester pyridine N-oxide gave
a high yield of the expected reduced compound. We
hypothesized that a strong hydrogen bond is formed
between the hydrogen of the carboxyl group and the
oxygen of the N-O. This leads to the deactivation of the
pyridine ring toward the reduction. However, in the case
of the ester, this bond no longer exists and the reduction
readily occurs using this procedure. Heating the reaction
also affects the yield. For example, reduction of 2-hy-
droxypyridine N-oxide (entry 1e) in methanol at room
temperature overnight gave only 50% yield of the ex-
pected product. The yield increases to 98% when the
reaction was carried under reflux.
A number of methods have been described for the
reduction of heteroaromatic N-oxides to the correspond-
ing aromatic derivatives.6 These procedures are efficient
for the reduction of N-oxide and not the aromatic ring.
Our goal, therefore, was to develop a general and mild
procedure for the reduction of pyridine N-oxides7 (Scheme
1). It was observed that ammonium formate/palladium
on carbon is a convenient system for this reduction. The
reaction is carried out in methanolic solution overnight
at room temperature. The procedure is simple and does
In conclusion, we developed an efficient procedure for
the reduction of pyridine N-oxide to piperidine using
ammonium formate9-palladium on carbon. The advan-
tages of this procedure are as follows: simplicity of the
reaction, high yield, mild conditions, and the avoidance
of strong acid and harsh reagents. This approach is
expected to be applicable to synthesize stereoselective
piperidines using chiral catalyst. Investigations toward
the preparation of such compounds are in progress.
(1) Laschat, S.; Dickner, T. Synthesis 2000, 1781.
(2) (a) Freifelder, M.; Stone, G. R. J . Org. Chem. 1961, 26, 3805. (b)
Rylander, P. Catalytic Hydrogenation in Organic Syntheses; Academic
Press: New York, 1979; p214. (c) Chung, J . Y. L.; Hughes, D. L.; Zhao,
D.; Song, Z.; Mathre, D. J .; Ho, G.-J .; McNamara, J . M.; Douglas, A.
W.; Reamer, R. A.; Tsay, F.-R.; Varsolona, R.; McCauley, J .; Grabowski,
E. J . J .; Reider, P. J . J . Org. Chem. 1996, 61, 215-222.
(3) (a) Lunn, G.; Sansone, E. B. J . Org. Chem. 1986, 51, 513. (b)
Lunn, G. J . Org. Chem. 1992, 57, 6317.
(4) Kamochi, Y.; Kudo, T. Chem. Pharm. Bull. 1995, 43, 1422.
(5) Blough, B. E.; Carroll, F. I. Tetrahedron lett. 1993, 34, 7239.
(6) (a) Balicki, R. Synthesis 1989, 645. (b) Ram, S. R.; Chary, K. P.;
Iyengar, D. S. Synth. Commun. 2000, 30, 3511.
Exp er im en ta l Section
Melting points were measured on an Electrothermal melting
point apparatus and are uncorrected.1H NMR spectra were
obtained on a Brucker DRX-400 or on a Varian Inova 400
spectrometer. Mass spectra were recorded on a Micromass
(8) (a) Wenkert, D.; Woodward R. B. J . Org. Chem. 1983, 48, 283.
(b) Younth Rhie, S.; Ryu, E. K. Heterocycles 1995, 41, 323.
(9) For a review on ammonium formate, see: (a) Ranu, B. C.; Sarkar,
A.; Guchhait, S. K.; Ghosh, K. J . Indian Chem. Soc. 1998, 75, 690. (b)
Ram, S. Ehrenkaufer, R. E. Synthesis 1988, 91.
(7) Plaquevent, J .-C.; Chichaoui, I. Bull. Soc. Chim. Fr. 1996, 133,
369. (b) Plaquevent, J .-C.; Chichaoui, I. Tetrahedron lett. 1993, 34,
5287.
10.1021/jo015649g CCC: $20.00 © 2001 American Chemical Society
Published on Web 06/26/2001
Zacharie
