Hydroacylation of 2-vinyl benzaldehyde systems: An efficient method for the synthesis of chiral 3-substituted indanones

Article abstract of DOI:10.1021/ja0564416

Asymmetric rhodium-catalyzed hydroacylation has been utilized in the synthesis of 3-substituted indanones with high conversions and enantioselectivity. The hydroacylation reaction of 2-vinyl benzaldehyde had been previously reported to give a low yield of indanone and an unidentified product. We have identified this compound as a dimer of the starting material. Substitution at the α-position of the 2-vinyl benzaldehyde substrates blocks the competitive dimerization reaction and allows the reaction to proceed with yields generally greater than 90%. Utilization of BINAP as a chiral ligand results in good chemical yields and enantioselectivity greater than 95% in most cases. Copyright

Full text of DOI:10.1021/ja0564416

Published on Web 10/28/2005
Hydroacylation of 2-Vinyl Benzaldehyde Systems: An Efficient Method for the
Synthesis of Chiral 3-Substituted Indanones
Kousik Kundu,‡ James V. McCullagh,† and Andrew T. Morehead, Jr.*
Department of Chemistry, East Carolina UniVersity, GreenVille, North Carolina 27858
Received September 19, 2005; E-mail: moreheada@mail.ecu.edu
Table 1. Hydroacylation of 2-Formyl Styrenesa
Indan ring frameworks are ubiquitous in a large number of
bioactive and pharmaceutically interesting molecules.1 Chiral
3-substituted indanones therefore are very useful molecules as
starting chiral building blocks for the synthesis of biologically active
compounds and thus are of tremendous industrial interest.2 General
approaches toward introducing chirality in the indanone framework
entry
substrate (R
))
yield (%)b
include Friedel-Crafts cyclization of chiral aryl carboxylic acids
synthesized either by resolution or asymmetric synthesis3 and the
kinetic resolution of racemic substrates recently reported by
Buchwald4 and Fu.5 The Friedel-Crafts reaction calls for high
temperature or highly acidic conditions, while the kinetic resolution
approach4 utilizes air-sensitive imines as the substrates. Catalytic
enantioselective Negishi reaction of racemic indanones requires
multistep synthesis of the 3-substituted indanones and suffers from
high catalyst loading.5 Rhodium(I)-catalyzed intramolecular hy-
droacylation6 has emerged as a very efficient method for the
synthesis of various carbocycles mainly via the elegant works of
Bosnich,7a,b Jun,7c,d Fu,7e and Shair.7f However, utilization of this
wonderful methodology in synthesis of chiral indanones has not
been previously reported. Herein, we report our study of the utility
of asymmetric hydroacylation in the synthesis of chiral 3-substituted
indanones and some unexpected mechanistic details.
Our study of rhodium-catalyzed hydroacylation was initiated with
investigation of the results reported for 2-vinyl benzaldehyde (1),8
wherein the authors reported obtaining a 30% yield of the desired
1-indanone product (2) along with unidentified material they
believed was a polymer. When we reproduced the experiment, we
also obtained 30% of the desired product as previously reported.
However, the side product was determined to be a dimer (3) and
not a polymer, as suggested by previous authors. The dimer was
obtained in 70% yield with exclusive selectivity for the trans-isomer.
1
2
3
4
5
6
7
8
Me
Et
Ph
2-Naph
CH2CH2OH
SiMe3
CF3
97
97
98
88
97
93
90
88
COOEt
a [Rh(dppe)(NBD)]ClO4 (1 mol %) was weighed and dissolved in dry
and degassed dichloromethane (1 mL). Hydrogen gas was then passed
through the solution for 5 min, followed by flushing with nitrogen to remove
the hydrogen gas. The substrate (3 mmol in 1 mL of CH2Cl2) was added
dropwise to the above catalyst solution via syringe. The reaction mixture
was stirred for 2 h at ambient temperature under nitrogen. The product
was isolated by flash column chromatography on silica gel using 9:1 hexane
and ethyl acetate. b Isolated yield.
elimination leads to the dimeric product (Scheme 2). Fu has reported
a [4 + 2] cycloaddition of 4-pentynals that likely proceeds via a
similar mechanism.9
In accordance with the proposed mechanism, the concentration
of the substrate should play an important role. As we expected,
95% of the 1-indanone product was obtained when the substrate
was added slowly by a syringe pump over 18 h. (Scheme 2).
We postulated that for steric reasons substitution at the R-position
of the 2-vinyl benzaldehyde might shut down the 2,1-insertion
pathway, leading exclusively to 3-substituted indanone products.
As we hoped, the indanone products were obtained in very high
yields without the formation of any side products. Simple aliphatic
(entries 1, 2, and 5) and aromatic (entries 3 and 4) substituents
were found to be well suited for this reaction. Electron-withdrawing
(entries 7 and 8) as well as electron-donating groups (entry 6) were
also found to be compatible with the reaction conditions. These
additions proceeded efficiently (g90% conversion) using only 1
mol % of the rhodium(I) catalyst (Table 1).
The proposed mechanistic pathway for formation of the dimeric
product is shown in Scheme 1, with the branch point coming after
the initial oxidative addition. The migratory insertion then can occur
in either a 1,2- or 2,1-sense. Migratory 1,2-insertion will lead to
1-indanone as the product after the reductive elimination of the
metallocycle B. Migratory insertion in the 2,1-sense will lead to
the intermediate C, which in the presence of excess 2-vinyl
benzaldehyde can bind with another molecule of the substrate. The
second insertion will form the intermediate D, which upon reductive
â-Substituted 2-vinyl benzaldehydes were found to be extremely
sluggish as hydroacylation substrates. For example, (E)-3-(2-
formylphenyl)ethyl acrylate required 5 days to proceed to 90%
conversion (eq 2).
‡ Department of Chemistry and Biochemistry, University of Maryland, College
Park, MD, 20742.
After the encouraging results from the hydroacylation of
R-substituted 2-formyl styrenes, we concentrated on an asymmetric
† Department of Chemistry, Manhattan College, Riverdale, NY 10471.
9
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J. AM. CHEM. SOC. 2005, 127, 16042-16043
10.1021/ja0564416 CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Mechanistic Rationale for the Formation of the Dimer
Scheme 2. Concentration Dependence of the Hydroacylation of 1
In conclusion, we have utilized our understanding of the
mechanism to successfully carry out the hydroacylation of 2-vinyl
benzaldehydes to synthesize indanones with high conversions and
enantioselectivity. The mechanistic and kinetic details of the dimer
formation and its application toward the development of a novel
formal [4 + 2] cycloaddition are currently under investigation.
Table 2. Asymmetric Hydroacylation of 2-Formyl Styrenesa
Acknowledgment. This work was supported by the University
of Maryland, East Carolina University, and the National Science
Foundation (CHE-0415484).
Supporting Information Available: Experimental details and the
spectral data of all the new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
entry
substrate (R
))
yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
Me
Et
Ph
2-Naph
CH2CH2OH
SiMe3
CF3
97
97
98
88
97
93
90
89
99
99
98
96
96
70
99
96
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