A convenient synthesis to N-aryl-substituted 4-piperidones

Article abstract of DOI:10.1021/ol990930r

(matrix presented) A general and efficient procedure for the synthesis of N-aryl-substituted 4-piperidones was developed. The general methodology was applied to the synthesis of several different N-aryl-4-piperidones utilizing an expedient two-step proces

Full text of DOI:10.1021/ol990930r

ORGANIC
LETTERS
1
999
Vol. 1, No. 8
261-1262
A Convenient Synthesis to
N-Aryl-Substituted 4-Piperidones
1
David R. Tortolani* and Michael A. Poss
Combinatorial Drug DiscoVery, Bristol-Myers Squibb Pharmaceutical Research
Institute, P.O. Box 4000, Princeton, New Jersey 08543
tortolad@bms.com
Received August 10, 1999
ABSTRACT
A general and efficient procedure for the synthesis of N-aryl-substituted 4-piperidones was developed. The general methodology was applied
to the synthesis of several different N-aryl-4-piperidones utilizing an expedient two-step process.
The synthesis of N-aryl-substituted 4-piperidones has been
a subject of continuing research because of its importance
as a synthetic building block in medicinal chemistry. These
heterocycles have been used as synthetic intermediates en
route to a considerable number of pharmacologically active
al.1b In this method, the piperidone was made in a two-step
synthesis where the N substituent was introduced in the final
step. Therein, the authors demonstrated that 1,5-dichloro-3-
pentanone was capable of directly reacting with various
anilines to yield N-aryl-4-piperidones. The drawback to this
approach is the tedious synthesis of the 1,5-dichloro-3-
1
agents. Most notably, this pharmacophore is predominant
5
in many CNS agents such as antidepressants, anxiolytics,
pentanone. Kuehne and co-workers have reported a conve-
2
and antipsychotics. The synthetic methodology leading to
nient synthesis of N-alkyl-substituted 4-piperidones by the
reaction of N-methyl-4-piperidone methiodide with tryptamine
for the synthesis of complex alkaloids. Although the synthesis
of N-alkyl piperidones has been reported using this meth-
odology, the preparation of N-aryl-substituted 4-piperidones
has not been addressed.
3
the preparation of aryl-4-piperidones is well documented.
All of these methods, however, have their shortcomings.
The most convenient approach has been reported by
4
Bowden and Green and then later optimized by Scherer et
(1) (a) Dyakov, M. Y.; Sokolova, T. D.; Peretokin, A. S.; Moskovkin,
Herein we report a general and efficient method for the
synthesis of N-aryl-substituted 4-piperidones. The aryl pip-
eridones were synthesized in two steps utilizing a modified
A. S.; Unkovskii, B. V. Chem. Heterocycl. Comp. 1991, 26, 183. (b) Scherer,
T.; Hielkema, W.; Krijnen, B.; Hermant, R. M.; Eijckelhoff, C.; Kerkhof,
F.; Ng, A. K. F.; Verleg, R.; van der Tol, E. B.; et al. Recl. TraV. Chim.
Pays-Bas 1993, 112, 535.
6
method of Kuehne. In this process, the N-aryl-piperidones
(2) (a) Maryanoff, C. A.; Reitz, A. B.; Scott, M. K. U.S. Pat., 8 pp,
Continuation-in-part of U.S. Pat. 5,314,885. (b) Kerrigan, F.; Heal, D. J.;
Martin, K. F. PCT Int. Appl., 103 pp.
were prepared directly from the easily accessible N-methyl-
N-benzyl-4-oxopiperidinium iodide (2). Construction of the
N-aryl-substituted 4-piperidones was conveniently achieved
(3) (a) Krijnen, B.; Beverloo, H. B.; Verhoeven, J. W.; Reiss, C. A.;
Goubitz, K.; Heijdenrijk, D. J. Am. Chem. Soc. 1989, 111, 4433. (b)
Rubiralta, M.; Giralt, E.; Diez, A. Piperidine, Structure, Preparation,
ReactiVity and Synthetic Applications of Piperidine and its DeriVatiVes,
Studies in Organic Chemistry 43; Elsevier: Amsterdam, 1991; p 313. (c)
Baliah, V.; Jeyaraman, R.; Chandrasekaran, L. Chem. ReV. 1983, 83, 379.
(4) Bowden, K.; Green, P. N. J. Chem. Soc. 1952, 1164.
(5) (a) Kuehne, M. E.; Muth, R. S. J. Org. Chem. 1991, 56, 2701. (b)
Kuehne, M. E.; Matson, P. A.; Bornmann, W. G. J. Org. Chem. 1991, 56,
513.
(6) Tschaen, D. M.; Abramson, L.; Cai, D.; Desmond, R.; Dolling, U.-
H.; Frey, L.; Karady, S.; Shi, Y.-J.; Verhoeven, T. R. J. Org. Chem. 1995,
60, 4324.
(
d) Prostakov, N. S.; Gaivoronskaya, L. A. Usp. Khim. 1978, 47, 859. (e)
McElvain, S. M.; Stork G. J. Am. Chem. Soc. 1946, 68, 1053. (f) Gallagher,
M. J.; Mann, F. G. J. Chem. Soc. 1962, 5110. (g) Baty, J. D.; Jones, G.;
Moore, C. J. Chem. Soc. C 1967, 24, 2645. (h) Reese, C. B.; Thompson,
E. A. J. Chem. Soc., Perkin Trans. 1 1988, 10, 2881.
1
0.1021/ol990930r CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/24/1999

by the exchange reaction between N-methyl-N-benzyl-4-
oxopiperidinium iodide (2) with the desired aniline. This
iodide salt 2 was prepared by exposure of commercially
available N-benzyl-4-piperidone (1) to methyl iodide in
Table 1: Examples of N-Aryl-Substituted 4-Piperidones
Prepared
entry
R
% yield of 3
% yield of 4
7
acetone (Scheme 1). The aniline was then treated with
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
3,4-OCH2CH2O
2-CH3-5-OCH3
3,4,5-OCH3
3-Cl-4-OCH3
3,4-NdCHS
3-CN
2,4-OCH3-5-Cl
3-CN-4-F
3-Cl
2,4-F-3-CN
3-CN-4-Cl
2,3-NSNd
2,6-OCH3-4-CH3
2,6-OCH2CH3
2-OPh
99
71
80
73
51
28
63
23
29
0
8
0
34
30
20
0
0
0
0
0
0
0
0
0
49
44
42
0
0
30
Scheme 1
0
1
2
3
4
5
N-methyl-N-benzyl-4-oxopiperidinium iodide (2) in the pres-
8
ence of K
2
CO
3
in aqueous ethanol at 100 °C (Scheme 2).
studied with this methodology varied in electronic and steric
properties. As one might expect, reactions of the electron
rich anilines gave the highest yields of product, while reaction
of anilines which were electron deficient or sterically
hindered gave lower yields.
Scheme 2
We believe that the mechanism of the reaction presumably
follows the process previously described by Rubiralta et al.9
This process may be a â-elimination/intramolecular cycliza-
tion to form the N-aryl-substituted piperidones. In particular,
N-methyl-N-benzyl-4-oxopiperidinium iodide (2) undergoes
a base-catalyzed Hofmann elimination to form the transient
Michael acceptor. The aniline nucleophile then adds in a
Michael type fashion, and the resulting secondary amine may
displace benzylmethylamine to give the desired product. We
also observed that when the aniline is of an electron deficient
nature or sterically hindered, cross-coupled side product 4
is observed along with the desired product (entries 11 and
Utilizing this methodology, N-aryl-substituted 4-piperidones
Table 1) were obtained conveniently and rapidly in fair to
excellent yields from a wide variety of anilines. The anilines
(
1
5, Table 1). In some cases, this side product is all that is
(
7) Preparation of N-methyl-N-benzyl-4-oxopiperidinium iodide
isolated (entries 10 and 12, Table 1). This cross-coupled side
product may be obtained from the intermolecular displace-
ment of benzylmethylamine by aniline.
In summary, we have demonstrated that N-aryl-4-piperi-
dones can be conveniently prepared utilizing a simple two-
step procedure. In most cases, the key cyclization step
proceeds with a large variety of anilines, including those
having electron-withdrawing and electron-donating groups.
Overall yields are typically good, allowing for the easy and
rapid synthesis of N-aryl-substituted 4-piperidones.
(
2): Methyl iodide (11.3 mL, 181.5 mmol) was slowly added to a solution
of N-benzylpiperidone (27.3 mL, 147.3 mmol) in acetone (150 mL) at room
temperature. The mixture was stirred at room temperature for 3 h, and the
product was collected by filtration and washed with acetone (4 × 50 mL).
The product was dried in vacuo for 16 h to provide 47 g (96% yield): 1
H
NMR (270 MHz, CDCl3) δ 2.55 (m, 4H), 3.12 (s, 3H), 3.70 (m, 4H), 4.72
s, 2H), 7.54 (m, 5H).
8) General Procedure for N-Aryl-Substituted 4-Piperidone: A slurry
(
(
of iodide salt 2 (1.8 g, 5.4 mmol) in water (2.8 mL) was added over 30
min to a refluxing solution of 3,4,5-trimethoxyaniline (650 mg, 3.55 mmol)
and potassium carbonate (70 mg, 0.50 mmol) in ethanol (6.5 mL). The
reaction mixture was heated to reflux for an additional 45 min. Water (20
mL) was then added, and the product was extracted with dichloromethane
(
2 × 30 mL). The combined extracts were evaporated in vacuo, and the
residue was chromatographed on silica gel (hexane:ethyl acetate ) 4:2) to
OL990930R
1
give 750 mg (80% yield) of the desired N-aryl-piperidone: H NMR (270
MHz, CDCl3) δ 2.56 (t, J ) 6 Hz, 4H), 3.50 (t, J ) 6 Hz, 4H), 3.78 (s,
(9) Rubiralta, M.; Diez, A.; Vila, C.; Castells, J.; Lopez, I. Heterocycles
1992, 34, 643 .
+
1
3
H), 3.86 (s, 6H), 6.19 (s, 2H). MS (E+) m/z: 266 (MH ).
1262
Org. Lett., Vol. 1, No. 8, 1999