Stereoselectivity in the rhodium(II) acetate catalysed cyclopropanations of 2-diazo-1-indanone with styrenes

Article abstract of DOI:10.1016/S0040-4039(00)00002-2

The rhodium(II) acetate catalysed cyclopropanation reactions of 2- diazo-1-indanone 4 with various substituted styrenes 5 have been investigated. The cyclopropane diastereomer 6a bearing a trans relationship between the carbonyl and the aryl ring was in all cases the predominant isomer and the ratio of stereoisomers almost constant over a range of styrene substituents. Styrenes bearing electron-donating substituents gave slightly better stereoselectivity in favour of the trans isomer. These results are substantiated by a mechanistic proposal. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00002-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1491–1494
Stereoselectivity in the rhodium(II) acetate catalysed
cyclopropanations of 2-diazo-1-indanone with styrenes
William Bauta,a,∗ John Dodd,a James Bullington,a Diane Gauthier,b Gregory Leo b and
Patricia McDonnell b
aDrug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Route 202, Raritan, New Jersey 08869, USA
bChemical Support, The R. W. Johnson Pharmaceutical Research Institute, Spring House, Pennsylvania 19477, USA
Received 24 November 1999; revised 17 December 1999; accepted 19 December 1999
Abstract
The rhodium(II) acetate catalysed cyclopropanation reactions of 2-diazo-1-indanone 4 with various substituted
styrenes 5 have been investigated. The cyclopropane diastereomer 6a bearing a trans relationship between the
carbonyl and the aryl ring was in all cases the predominant isomer and the ratio of stereosiomers almost
constant over a range of styrene substituents. Styrenes bearing electron-donating substituents gave slightly better
stereoselectivity in favour of the trans isomer. These results are substantiated by a mechanistic proposal. © 2000
Published by Elsevier Science Ltd. All rights reserved.
The rhodium(II) catalysed cyclopropanation of olefins by α-diazocarbonyl compounds is a well-
established synthetic method. The diastereoselectivity and enantioselectivity in the intermolecular cyclo-
propanation reactions of diazoacetates has been a subject of continuing interest.1 Generally, the sterically
larger olefin substituent (R0 in 2) is trans (anti) to the carboxylate group in the product cyclopropanes 3.
This selectivity can be increased by choosing the right catalyst2 or by adding sterically larger R and R0
groups on the diazoacetate 1 and the olefin 2, respectively.1a
In contrast to diazoacetates, there is considerably less data on the intermolecular cyclopropanation
stereoselectivity of diazoketones under rhodium catalysis. In connection with an SAR development
∗
Corresponding author. Current address: Ilex Oncology, Inc., 14785 Omicron Drive, Suite 201, San Antonio, TX 78245,
USA.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00002-2
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program, we required access to cyclopropanes of type 6. We report here our results on the stereoselectivity
of the rhodium(II) acetate catalysed cyclopropanation of various styrenes 5 with 2-diazo-1-indanone 4 to
give cyclopropanes 6 (Table 1).3
Table 1
Reactions of diazoketone 4 with olefins to give cyclopropanes 6a
Diazoketone 4 was prepared from the corresponding oxime by a Forester reaction.4 Cyclopropanations
were conducted by dropwise addition of 4 (1 equiv.) in CH2Cl2 over 20 min to a well-stirred CH2Cl2
solution of the styrene 5 (10 equiv.) and Rh2(OAc)4 (0.01 equiv.) at room temperature. Solvent was
removed after 2 h. The resulting product mixtures consisted of two cyclopropane isomers (6a and 6b),
unreacted styrene 5, and polar baseline materials, which were not, characterised (Table 1). Product ratios
were determined by proton NMR analysis of the crude reaction mixtures and the isomers separated by
chromatography on silica gel. Product stereochemistries were assigned according to the NOESY spectra
of the purified isomers.
Diazoketone 4 presents a conformationally rigid framework with only a small steric difference
between substituents on the carbene carbon. Over a range of electron-donating (entries 2,3,4), electron-
withdrawing (entries 5–8) and hydrogen (entry 1) substituents on the styrene ring, the stereoselectivity
of the reaction was between 2:1 and 3:1. The trans (anti) relationship between the aromatic ring and
carbonyl was in all cases predominant. Likewise, the sterically more demanding 2,4,6-trimethylstyrene
(entry 9) and α-methyl styrene (entry 10) did not significantly affect the stereoselectivity. Interestingly,

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the more electron-poor styrenes (entries 5–8) gave rise to slightly worse stereoselectivity (2:1 vs 3:1)
3-nitrostyrene failed to give cyclopropane product as did β-methylstyrene and t-butylstyrene (entries
15–17). Good reactivity was observed with 1,1-diphenylstyrene which gave only 1 isomer (entry 14).
Doyle has proposed a mechanistic model to account for the predominance of trans stereoisomers
in the cyclopropanations of diazoacetates and related diazo compounds.5 Applying this idea to the
case of diazoketone 4 suggests that stereoisomeric pi-complexes 7a and 7b are reversibly formed,
the aryl group favouring an orientation away from the bulky metal, leading, respectively, to transition
states 9a and 9b. The preference for trans stereochemistry presumably arises due to stabilisation of the
developing positive charge at the benzylic carbon by the carbonyl group as the transition state geometry is
approached (8a vs 8b). This stabilisation can occur in 8a but not in the case of 8b. The slight decrease in
stereoselectivity observed in the case of halogen and acetoxy-substituted styrenes would imply a decrease
in positive charge at the benzylic carbon (greater double bond character) as the transition state geometry

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is approached, making the stabilising effect of the carbonyl in 8a less pronounced. The opposite is true
for substituents, which stabilise the benzylic cation. The fact that the stereoselectivities for 4 are greater
than is observed for styrene and ethyl diazoacetate with rhodium(II) acetate (cis/trans=1.6)2a may be
accounted for by the greater electron density of the ketone carbonyl in 8a compared to the ester. The
present results are thus generally consistent with the Doyle interpretation.
References
1. (a) Doyle, M. P. Chem. Rev. 1986, 86, 919. (b) Doyle, M. P.; Protopopova, M. N. Tetrahedron 1998, 54, 7919. (c) Loffler,
F.; Hagen, M.; Luning, U. Synlett 1999, 1826. (d) Kolotuchin, S. V.; Meyers, A. I. J. Org. Chem. 1999, 64, 7921. (e) Ye, T.;
McKervey, M. A. Chem. Rev. 1994, 94, 1091. (f) Doyle, M. P. In Comprehensive Organometallic Chemistry II; Hegedus, L.
S., Ed.; Pergamon Press: New York, 1995; Vol. 12, Chapter 5.1. Reissig, H.-U. In Stereoselective Synthesis of Houben–Weyl
Methods of Organic Chemistry; Helmchen, G.; Hoffmann, R. W.; Mulzer, J.; Schaumann, E., Eds.; Georg Thieme Verlag:
New York, 1995; Vol. E21c. (g) Doyle, M. P.; McKervey, M. A. Chem. Commun. 1997, 11, 983.
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P. Chin. Chem. Lett. 1998, 9, 607. (c) Endres, A.; Maas, G. Tetrahedron Lett. 1999, 40, 6365.
3. Shechter and co-workers have reported the rhodium acetate catalysed reaction of 4 with styrene in toluene from which
they isolated a single cyclopropane of undetermined stereochemistry in 59% yield. Rosenfeld, M. J.; Ravi Shankar, B. K.;
Schechter, H. J. Org. Chem. 1988, 53, 2699.
4. Horner, L.; Kirmse, W.; Muth, K. Chem. Ber. 1958, 91, 430.
5. Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L. Organometallics 1984, 3, 53.