Reduction of N-acyl-2,3-dihydro-4-pyridones to N-acyl-4-piperidones using zinc/acetic acid

Full text of DOI:10.1021/jo001609l

J . Org. Chem. 2001, 66, 2181-2182
2181
Sch em e 1
Red u ction of
N-Acyl-2,3-d ih yd r o-4-p yr id on es to
N-Acyl-4-p ip er id on es Usin g Zin c/Acetic
Acid
Daniel L. Comins,* Clinton A. Brooks, and
Charles L. Ingalls
Department of Chemistry, North Carolina State University,
Raleigh, North Carolina 27695-8204
Ta ble 1. Red u ction of 1 to 2 Usin g Zn /AcOH
entrya
R1
R2 product conditions yieldd(%)
daniel_comins@ncsu.edu
Received November 13, 2000
1
2
3
4
5
6
vinyl
Me
Ph
Bn
Ph
Ph
Bn
Bn
2a
2b
2c
2d
2e
2f
ab
94
a, bc
a, b
a, b
a,b
b
95, 93
95, 95
94, 95
92, 92
91
Ph
PhCH2CH2
EtO2CCHdCH(CH2)3 Ph
Substituted 4-piperidones are important synthetic
intermediates for the preparation of various alkaloids
and pharmaceuticals.1 Derivatives of 4-piperidones have
been found to exhibit antidepressant,2 antiarrhythmic,3
antithrombogenic,4 spasmolytic,5 tranquilizing,6 and blood
cholesterol lowering6 activities. Due to their medicinal
potential, syntheses of substituted 4-piperidones have
been of current interest.1 As part of a program directed
at studying the synthesis and synthetic utility of 1-acyl-
2,3-dihydropyridones (1), we examined various reduc-
tions of 1 to provide the corresponding 4-piperidones
2 (Scheme 1). Conjugate reduction of dihydropyridones
of the type 1 have generally been carried out using L-
or K-Selectrides,7 as catalytic hydrogenation often
leads to over reduction.8 Although the Selectride reduc-
tion is effective in most cases, the reagent is expensive,
competing 1,2-reduction can occur,9 and purification of
large scale reaction products can be tedious. Since
dissolving metal reductions, i.e., lithium/ammonia, of
related enaminones have been reported to give â-amino
ketones in good yield,10 we decided to investigate a
mild reduction of dihydropyridones 1 using zinc in acetic
acid.
a
The reactions were performed on a 0.1 to 1.0-mmol scale.
bExperimental method A. c Experimental method B. dYield of
purified product obtained from radial preparative-layer chroma-
tography.
Sch em e 2
using literature procedures.11 In most cases, the reduction
could be carried out using inexpensive zinc dust (-325
mesh) at room temperature to provide excellent yields
of the corresponding piperidones 2 (see Table 1). Trace
impurities present in the metal do not influence the
reaction since ultrapure zinc powder (99.999%) gives
identical results.12 The reduction of dihydropyridone 1f
to give piperidone 2f demonstrates the chemoselectivity
and mildness of this procedure. The bicyclic carbamate
313 was also reduced in excellent yield to give indolizidi-
none 4 (Scheme 2).
In contrast, when reduction of 3 was carried out using
catalytic hydrogenation over palladium on carbon, over-
reduction to alcohol 5 could not be prevented.
This simple, inexpensive, and mild procedure should
be amenable to the large scale preparation of various
The N-acyldihydropyridones 1 were prepared by the
addition of Grignard reagents to 1-acylpyridinium salts
(1) (a) Wang, C.-L.; Wuorola, M. A. Org. Prep. Proceed. Int. 1992,
24, 585-621. (b) Grishina, G. V.; Gaidarova, E. L.; Zefirov, N. S. Chem.
Heterocycl. Compd. 1994, 30, 1401-1426. (c) Angle, S. R.; Breiten-
bucher, J . G. In Studies in Natural Products Chemistry; Stereoselective
Synthesis, Atta-ur-Rahman, Ed.; Elsevier: New York, 1995; vol. 16,
Part J , pp 453-502.
(2) Champseix, A. A.; Lefur, G. R. Eur. Pat. 12,643; Chem. Abstr.
1981, 94, 15175.
(3) Samczuk, S.; Hermans, H. K. F. Ger. Pat. 2,642,856; Chem.
Abstr. 1977, 87, 53094.
(4) Ciba-Geigy, Fr. Pat. 2,437,405; Chem. Abstr. 1981, 94, 83739.
(5) Abignente, E.; Biniecka-Picazio, M. Acta Pol. Pharm. 1977, 34,
241.
(6) Nalanishi, M.; Shiraki, M.; Kobayakawa, T.; Kobayashi, R. J pn.
Pat. 74-03987; Chem. Abstr. 1974, 81, 12085.
(7) (a) Comins, D. L.; Williams, A. L. Tetrahedron Lett. 2000, 41,
2839. (b) Huang, S.; Comins, D. L. Chem. Commun. 2000, 569. (c)
Comins, D. L.; Hong, H. J . Org. Chem. 1993, 58, 5035 and references
therein.
(8) (a) Ma, D.; Sun, H. Org. Lett. 2000, 2, 2503. (b) Ban, Y.; Sato,
Y.; Inoue, I.; Nagai, M.; Oishi, T.; Terashima, M.; Yonemitsu, O.;
Kanaoka, Y. Tetrahedron Lett. 1965, 2261.
(11) (a) Comins, D. L.; Brown, J . D. Tetrahedron Lett. 1986, 27, 4549.
(b) Comins, D. L.; J oseph, S. P.; Zhang, Y. Tetrahedron Lett. 1996, 37,
793.
(12) A trace amount of lead in zinc powder has been demonstrated
to promote certain reductions; see: (a) Takai, K.; Kakiuchi, T.; Kataoka,
Y.; Utimoto, K. J . Org. Chem. 1994, 59, 2668. (b) Hansen, M. M.;
Grutsch, J . L. Org. Process Res. Dev. 1997, 1, 168.
(13) (a) Comins, D. L.; Stolze, D. A.; Thakker, P.; McArdle, C. L.
Tetrahedron Lett. 1998, 39, 5693. (b) Al-awar, R. S.; J oseph, S. P.;
Comins, D. L. J . Org. Chem. 1993, 58, 7732.
(9) (a) Comins, D. L.; Libby, A. H.; Al-awar, R. S.; Foti, C. J . J . Org.
Chem. 1999, 64, 2184 and references therein. (b) Waldmann, H.; Braun,
M. J . Org. Chem. 1992, 57, 4444.
(10) (a) Ramesh, N. G. Klunder, A. J . H.; Zwanenburg, B. J . Org.
Chem. 1999, 64, 3635 and references therein.
10.1021/jo001609l CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/23/2001

2182 J . Org. Chem., Vol. 66, No. 6, 2001
Notes
racemic or enantiopure14 4-piperidones of the type 2, or
indolizidinones such as 4.
mL of glacial acetic acid was added zinc dust (1.049 g, 16 mmol).
The suspension was brought to reflux and stirred for 15 h. The
mixture was cooled to room temperature and filtered through a
silica plug with CH2Cl2. The solution was concentrated to give
a white solid which was purified by column chromatography
(100% EtOAc) to give 165.5 mg (93%) of 4 as a white solid: mp
Exp er im en ta l Section
Typ ica l Exp er im en ta l P r oced u r e for th e Red u ction of
Dih yd r op yr id on es 1. Meth od A. A solution of dihydropyridone
1 (1 mmol) in 10 mL of glacial acetic acid was stirred vigorously
as zinc dust (15 mmol) was added in one portion. The mixture
was stirred at room temperature for 36 h, filtered through Celite,
and concentrated under reduced pressure. Purification using
radial PLC (10% EtOAc/hexane) gave the desired piperidone in
91-95% yield as a clear oil.
115-116 °C; [R]23 -19.8 (c 0.45, MeOH; 1H NMR (300 MHz,
D
CDCl3) δ 4.47 (ddd, 1 H, J ) 13.3 Hz, 6.8 Hz, 2.1 Hz), 3.42 (m,
1 H), 3.02 (td, 1 H, J ) 12.3 Hz, 4.6 Hz), 2.65-2.22 (m, 6 H),
1.85 (m, 1 H), 1.10 (d, 3 H, J ) 6.5 Hz); 13C NMR (75 MHz,
CDCl3) δ 208.2, 173.8, 63.0, 51.9, 40.1, 38.9, 30.1, 24.5, 9.8; IR
(thin film, NaCl) 2970, 2930, 2873, 1685, 1448, 1416, 1360, 1267
cm-1; HRMS calcd for C9H13NO2 167.0946 (M+), found 167.0952.
Meth od B. A solution of the dihydropyridone (1 mmol) in 10
mL of acetic acid is stirred vigorously as zinc dust (15 mmol) is
added in one portion. The mixture is refluxed from 12 to 20 h
until the reaction is complete by TLC (10% EtOAc/hexane). The
reaction mixture was filtered through Celite and concentrated
under reduced pressure. Purification of the residue by radial
PLC (10% EtOAc/hexane) gave the resulting piperidone in 91-
95% yield as a clear oil.
Ack n ow led gm en t. We gratefully acknowledge the
support of this work by the National Institutes of Health
(Grant GM 34442). NMR and mass spectra were ob-
tained at NCSU instrumentation laboratories, which
were established by grants from the North Carolina
Biotechnology Center and the National Science Founda-
tion (Grants CHE-9121380 and CHE-9509532).
(8R,9S)-8-Meth yl-5,6-h exah ydr oin dolizidin e-3,7-dion e (4).
To a stirred solution of 3 (176.7 mg, 1.07 mmol) dissolved in 53
Su p p or tin g In for m a tion Ava ila ble: Spectroscopic data
for 2a -f, 13C NMR spectra of 2a -f and 4. This material is
available free of charge via the Internet at http://pubs.acs.org.
(14) For the asymmetric synthesis of N-acyldihydropyridones 2, see
(a) Comins, D. L.; J oseph, S. P.; Goehring, R. R. J . Am. Chem. Soc.
1994, 116, 4719. (b) Comins, D. L.; LaMunyon, D. H. Tetrahedron Lett.
1994, 35, 7343. (c) Comins, D. L.; Guerra-Weltzien, L. Tetrahedron
Lett. 1996, 37, 3807.
J O001609L