A new entry of nucleophiles in rhodium-catalyzed asymmetric 1,4-addition reactions: Addition of organozinc reagents for the synthesis of 2-aryl-4-piperidones

Article abstract of DOI:10.1021/ja048825m

A rhodium-catalyzed asymmetric 1,4-addition reaction has been applied to the synthesis of 2-aryl-4-piperidones. While other conventional nucleophiles fail, organozinc reagents have been successfully utilized for the construction of these useful compounds

Full text of DOI:10.1021/ja048825m

Published on Web 04/30/2004
A New Entry of Nucleophiles in Rhodium-Catalyzed Asymmetric 1,4-Addition
Reactions: Addition of Organozinc Reagents for the Synthesis of
2-Aryl-4-piperidones
Ryo Shintani, Norihito Tokunaga, Hidenori Doi, and Tamio Hayashi*
Department of Chemistry, Graduate School of Science, Kyoto UniVersity, Sakyo, Kyoto 606-8502, Japan
Received March 2, 2004; E-mail: thayashi@kuchem.kyoto-u.ac.jp
Table 1. Survey of Nucleophiles in the Rhodium-Catalyzed
1,4-Addition to 1
2-Arylpiperidines are an intensely studied class of compounds
due to their biological activity as well as their synthetic utility.1,2
For example, a subclass of the tachykinin antagonists has a common
structural motif based on a 2-arylpiperidine moiety as shown in
Figure 1 (A and B).3,4 Compound B, developed by Glaxo Group
Ltd., UK, has a strong affinity with the NK1 receptor (one of the
three types of tachykinin receptors identified) and is particularly
useful for the treatment or prevention of depressive states and/or
anxiety.4 As a consequence of the significance of these compounds,
the development of efficient methods for their enantioselective
synthesis is an important objective, but most of the existing methods
rely on the use of a stoichiometric amount of chiral reagents.5 In
contrast, very few catalytic enantioselective routes to the synthesis
of 2-arylpiperidines have been reported.6
entry
Ph−M (equiv)
conditiona
yield (%)b
ee (%)
1
2
3
4
5
PhB(OH)2 (3.0)
PhB(OH)2 (3.0)
Ph-9-BBN (1.1)
PhTi(Oi-Pr)3 (1.6)
PhZnCl (1.5)
A
B
C
D
E
33c
78d
96
98
97
33e
∼70f
>99.5
>99.5
95
a Condition A: Rh(acac)(C2H4)2/(R)-binap, dioxane/H2O (10/1), 100 °C,
2 h. Condition B: [Rh(OH)((R)-binap)]2, dioxane/H2O (10/1), 50 °C, 5 h.
Condition C: [Rh(OMe)(cod)]2/(R)-binap, toluene, 80 °C, 1 h; then MeOH
quench. Condition D: [Rh(OH)((R)-binap)]2, THF, 20 °C, 1 h; then MeOH
quench. Condition E: [RhCl((R)-binap)]2, THF, 20 °C, 2 h; then H2O
quench. b Isolated yield. c 35% conversion of 1 with complete consumption
of PhB(OH)2. d 83% conversion of 1 with complete consumption of
PhB(OH)2. e 33% conversion of 1. f Full conversion of 1 to a ∼3/1 mixture
of 1,4-adduct/1,2-adduct.
Figure 1. Examples of tachykinin antagonists.
We then explored a different type of organometallic reagent as
the nucleophile and employed PhTi(Oi-Pr)3 as we recently described
in the 1,4-addition to R,â-unsaturated ketones.14 Under these condi-
tions, product 2a was obtained in ∼70% yield along with the unde-
sired 1,2-addition product (entry 4; 1,4-adduct/1,2-adduct ∼3/1).
This observation also points out the lack of proper reactivity in
compound 1, because the 1,2-addition of PhTi(Oi-Pr)3 proceeds
smoothly in the absence of a rhodium catalyst. After some
investigations, however, we were able to find that the use of PhZnCl
dramatically improves the reactivity under mild conditions, giving
the desired product 2a in 95% yield with an excellent ee of >99.5%
(R)15 (entry 5).
To remedy this methodological deficiency, we envisioned that
these compounds can be rapidly synthesized by asymmetric 1,4-
addition of organometallic reagents to 2,3-dihydro-4-pyridones (e.g.,
1 in eq 1),7 followed by a reduction of the carbonyl group.8 In this
Communication, we describe the development of a rhodium-cata-
lyzed highly enantioselective synthesis of 2-aryl-4-piperidones (2)
by the use of organozinc reagents (eq 1), which consist of a new type
of nucleophiles in the 1,4-addition reactions by rhodium catalysis.9
It is worth noting that the scope of the catalytic asymmetric 1,4-
addition of organozinc reagents to 1 is fairly broad: the process
Table 2. Scope of Organozinc Reagents in the
Rhodium-Catalyzed Asymmetric 1,4-Addition to 1
In the past few years, we have focused on the development of a
rhodium-catalyzed asymmetric 1,4-addition of organoboron reagents
to a variety of R,â-unsaturated compounds.10 On the basis of these
successes, we initially investigated the reaction of 1 with PhB-
(OH)2 in the presence of 3 mol % Rh(acac)(C2H4)2/(R)-binap at
100 °C (Table 1, entry 1). Unfortunately, these reaction conditions,
which are highly effective for the asymmetric 1,4-addition to
2-cyclohexen-1-one,10a proved only moderately effective for the
formation of 2a (33% yield), suggesting that compound 1 has
relatively low reactivity toward 1,4-addition, although the enanti-
oselectivity was high (96% ee). The use of [Rh(OH)((R)-binap)]2
as the catalyst improved the reactivity to some extent (entry 2; 78%
yield),11,12 while the use of Ph-9-BBN as the nucleophile in an
aprotic solvent did not (entry 3; 33% yield).13
entry
Ar
product
yield (%)
ee (%)
1
Ph
2a
2b
2c
2d
2e
2f
95
97
90
91
87
>99.5
>99.5
99
>99.5
99
2
4-PhC6H4
4-MeOC6H4
4-FC6H4
3,5-Me2C6H3
2-MeC6H4
3a
4
5a
6a
100
99
a 3.0 equiv of ArZnCl was used in the presence of 6 mol % Rh.
9
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10.1021/ja048825m CCC: $27.50 © 2004 American Chemical Society

C O MMU N I C A T I O N S
tolerates a sterically and electronically diverse array of arylzinc
reagents, giving the products uniformly in good yields with excellent
enantioselectivities (Table 2; 2a-2f, 87-100% yield, g99% ee
(R)).16
This 1,4-addition method can also be applied to the preparation
of key intermediate 3 for the synthesis of tachykinin antagonists B
(Figure 1).4 Thus, the reaction of 1 with 4-fluoro-2-methylphenyl-
zinc chloride in the presence of a catalytic amount of [RhCl((R)-
binap)]2, followed by the removal of the benzyloxycarbonyl group,
efficiently affords compound (R)-3 in high yield and ee (eq 2; 73%
yield in two steps, 97% ee).
Acknowledgment. Support has been provided in part by a
Grant-in-Aid for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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Because zinc enolates (e.g., 4) are the primary products in these
1,4-additions of organozinc reagents, they could be further func-
tionalized in one-pot by the addition of electrophiles to the reaction
mixture. For example, the addition of allyl bromide provides
R-allylated product 5 as a single diastereomer in the trans-form
with high yield (eq 3; 83% yield). The use of pivaloyl chloride as
the electrophile, however, affords O-acylated product 6 in excellent
yield (97% yield).
The utility of the asymmetric 1,4-addition of organozinc reagents
catalyzed by Rh(I)/(R)-binap is not limited to the enantioselective
synthesis of 2-aryl-4-piperidones. Thus, both cyclic and acyclic R,â-
enones can be enantioselectively arylated under these conditions,
giving â-chiral ketones (7 and 8) in excellent yield and enantiose-
lectivity as well (eqs 4 and 5; 98-99% yield, 94-99% ee).
(6) There have been some reports on the catalytic asymmetric aza-Diels-
Alder reactions for the construction of 2-aryl-2,3-dihydro-4-pyridones,
see: (a) Kobayashi, S.; Komiyama, S.; Ishitani, H. Angew. Chem., Int.
Ed. 1998, 37, 979. (b) Yao, S.; Johannsen, M.; Hazell, R. G.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 1998, 37, 3121. (c) Josephsohn, N. S.;
Snapper, M. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 4018. (d)
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2004, 126, 456.
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D. H.; Chen, J. S.; Saha, S.; Wang, H.; Roche, D.; Bharathi, S. N.; Chan-
Yu-King, R.; Robinson, P. D.; Iguchi, S. Synlett 1992, 817. (b) Tube´ry,
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Tetrahedron Lett. 1994, 35, 949.
(9) Alkylzinc reagents (e.g., diethyl zinc) have been widely used in the copper-
catalyzed asymmetric 1,4-addition reactions. For an overview, see:
Tomioka, K.; Nagaoka, Y. In ComprehensiVe Asymmetric Catalysis;
Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: New
York, 1999; Chapter 31.1.
(10) (a) Takaya, Y.; Ogasawara, M.; Hayashi, T.; Sakai, M.; Miyaura, N. J.
Am. Chem. Soc. 1998, 120, 5579. (b) For a recent review, see: Hayashi,
T.; Yamasaki, K. Chem. ReV. 2003, 103, 2829.
In summary, we have described that a rhodium-catalyzed 1,4-
addition reaction can be used to prepare synthetically and biologi-
cally important 2-aryl-4-piperidones efficiently with very good
enantioselectivity by employing organozinc reagents as the nucleo-
philic component. This method has then been applied to the
enantioselective synthesis of the key intermediate of tachykinin
antagonists. The utility of this process has been further demonstrated
both by the electrophilic quench and by the employment of other
R,â-unsaturated substrates. Future studies will explore further use
of these versatile nucleophiles, organozinc reagents, in rhodium-
catalyzed 1,4-addition and other related reactions.
(11) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 2002, 124, 5052.
(12) The yield could not be further improved by changing the stoichiometry
of PhB(OH)2, the reaction temperature, or the reaction time.
(13) Yoshida, K.; Ogasawara, M.; Hayashi, T. J. Org. Chem. 2003, 68, 1901.
(14) Hayashi, T.; Tokunaga, N.; Yoshida, K.; Han, J. W. J. Am. Chem. Soc.
2002, 124, 12102.
(15) The absolute configuration of the 1,4-adducts was assigned to be (R),
based on the optical rotation of compound 3 in eq 2 (see Supporting
Information).
(16) Under our standard conditions, alkyl- or alkenylzinc reagents are not
suitable nucleophiles.
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