Angewandte
Chemie
DOI: 10.1002/anie.200800823
Multicomponent Synthesis
Palladium(0)-Catalyzed Alkynyl and Allenyl Iminium Ion Cyclizations
Leading to 1,4-Disubstituted 1,2,3,6-Tetrahydropyridines**
Hirokazu Tsukamoto* and Yoshinori Kondo
Piperidines, aliphatic six-membered nitrogen-con-
taining heterocycles, are among the most promis-
ing therapeutic agents for a wide variety of
diseases, including Alzheimerꢀs disease and Par-
kinsonꢀs disease.[1] The development of new and
efficient methods for the preparation of structur-
ally diverse piperidine derivatives is desired for the
drug-discovery process.[2] The introduction of a
variety of substituent groups into preformed
piperidine scaffolds is the conventional approach.
This method has been applied to the synthesis of
1,4-disubstituted 1,2,3,6-tetrahydropyridines 1,
which are biologically important unsaturated
piperidine derivatives[3] and useful synthetic inter-
mediates for the preparation of saturated deriva-
tives (Scheme 1). Synthetic routes to piperidines
can be divided into the following two classes:
1) the condensation of a 4-piperidinone 2 with an
Scheme 1. Retrosynthetic analysis of the 1,2,3,6-tetrahydropyridine structure 1.
Tf =trifluoromethanesulfonyl.
organometallic reagent 3 (route A);[4] 2) the cross-
coupling of a halogen- or triflate-containing piper-
idine
4 with an organometallic reagent 5
(route B).[5,6] Although the latter route is superior to the
former in terms of its compatibility with a variety of func-
tional groups, the preparation of the starting triflate 4 for
route B requires regioselective deprotonation of a piperidi-
none 2 with a strong base,[5] a transformation that is not
appropriate for unsymmetrical or base-labile piperidinones.
Alternatively, the starting halide 4 can be prepared by a
6-endo-trig cyclization reaction of an alkynyl iminium ion 6
generated in situ from the parent secondary amine and
formaldehyde.[7,8] However, a single-step procedure for the
transformation of structurally simple acyclic precursors 6 into
tetrahydropyridines 1 with diverse substituents has never
been developed. Such a procedure would avoid the prepara-
tion of the cyclic intermediate 4 and make the overall process
atom economical. Herein, we describe two newly developed
three-component syntheses[9] of 1 based on a Pd0-catalyzed
“anti-Wacker”-type cyclization[10] of an alkynyl or allenyl
iminium ion 6 or 7 generated in situ with an organoboron
reagent 8. These single-step routes C and D involving carbon–
carbon bond formation at C4 and concomitant C5–C6–N1
and C3–C2–N1bond formation, respectively, complement
each other.[11]
We first developed reaction conditions for the cyclization
of the terminal-alkyne-containing amine 9a[12] with the
concomitant introduction of a p-methoxyphenyl group at C4
(Table 1) on the basis of those for the related 6-exo-trig
cyclization of a 5-alkynal[10a] (Scheme 2). Upon heating at
508C in the presence of a slight excess of p-methoxyphenyl-
boronic acid (8A), aqueous formaldehyde,[13] and a catalytic
amount of [Pd(PPh3)4], 9a underwent arylative cyclization to
afford a single cyclized product 1aA. The yield of the product
is affected dramatically by the solvent; 1aAwas formed in the
highest yield in THF (Table 1, entries 1–5 versus entry 6). The
reaction conditions are applicable to cyclizations of 9a with
the electron-rich and neutral aryl boronic acids 8B–E
(Table 1, entries 7–10). The heteroaryl boronic acids 8F,G
also served as nucleophiles in this process, with the formation
of the cyclized products 1aF and 1aG in high yields (Table 1,
entries 11 and 12). Importantly, no reaction takes place in the
absence of the palladium catalyst.
[*] Dr. H. Tsukamoto, Prof. Dr. Y. Kondo
Graduate School of Pharmaceutical Sciences
Tohoku University
Aramaki-aza aoba 6-3, Aoba-ku, Sendai 980-8578 (Japan)
Fax: (+81)22-795-3906
E-mail: hirokazu@mail.pharm.tohoku.ac.jp
The electron-deficient aryl boronic acid 8H was found to
be much less effective in the [Pd(PPh3)4]-catalyzed cyclization
than electron-rich derivatives under the same reaction con-
ditions (Table 2, entry 1). Ligand screening revealed that
palladium ligated with PPh(c-C6H11)2 catalyzed effectively the
cyclization reaction of 9a with 8H (Table 2, entry 4). Fur-
[**] This research was partly supported by a Grant-in-Aid from the Japan
Society for the Promotion of Science (No. 18790003) and a Banyu
Pharmaceutical Co. Ltd. Award in Synthetic Organic Chemistry
(Japan).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2008, 47, 4851 –4854
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
4851