Rh-catalyzed intermolecular cyclopropanation with α-alkyl-α- diazoesters: Catalyst-dependent chemo- and diastereoselectivity

Article abstract of DOI:10.1021/ol800983y

(Chemical Equation Presented) A Rh-catalyzed procedure for the cyclopropanation of alkenes with α-alkyl-α-diazoesters is described. With dirhodium tetraoctanoate, the predominant pathway is β-hydride elimination. While a number of sterically demanding carboxylate ligands serve to avoid β-hydride elimination, it was found that triphenylacetate (TPA) also imparts high diastereoselectivity.

Full text of DOI:10.1021/ol800983y

ORGANIC
LETTERS
2008
Vol. 10, No. 14
2987-2989
Rh-Catalyzed Intermolecular
Cyclopropanation with
r-Alkyl-r-diazoesters:
Catalyst-Dependent Chemo- and
Diastereoselectivity
Patricia Panne, Andrew DeAngelis, and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry, UniVersity of
Delaware, Newark, Delaware 19716
jmfox@udel.edu
Received April 29, 2008
ABSTRACT
A Rh-catalyzed procedure for the cyclopropanation of alkenes with r-alkyl-r-diazoesters is described. With dirhodium tetraoctanoate, the
predominant pathway is ꢀ-hydride elimination. While a number of sterically demanding carboxylate ligands serve to avoid ꢀ-hydride elimination,
it was found that triphenylacetate (TPA) also imparts high diastereoselectivity.
Rhodium carbenoids are reactive intermediates that effect
a range of transformations, and both the nature of the
Scheme 1
.
Intermolecular Reactions without ꢀ-Hydride
carbenoid and the auxiliary ligands on rhodium have a
dramatic impact on the selectivity of these reactions.1
While R-alkyl-R-diazoesters (1) are readily available and
attractive precursors to Rh-carbenoids, such carbenoids
had only limited applicability in intermolecular reactions
due to their propensity to undergo ꢀ-hydride elimination.2
Recently, our group described several intermolecular Rh-
catalyzed transformations of R-alkyl diazoesters that
tolerate ꢀ-hydrogens, including reactions that produce
Elimination
cyclopropenes (2)3 and dioxolanes via putative carbonyl
ylides of structure 3 (Scheme 1).4 Low reaction temper-
atures (-78 °C)5 and the use of sterically demanding
carboxylate ligands6 [e.g., dirhodium tetrapivalate
(Rh2Piv4)] were key to the success of these reactions and
(1) (a) Catalytic Methods for Organic Synthesis with Diazo Compounds;
John Wiley: NewYork, 1998. (b) Davies, H. M. L.; Walji, A. M. In Modern
Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-VCH:
Weinheim, Germany, 2005; pp 301-340. (c) Davies, H. M. L.; Bechwith,
R. Chem. ReV. 2003, 103, 2861. (d) Doyle, M. P.; Ren, T. In Progress in
Inorganic Chemistry; Karlin, K. A., Ed. Wiley: New York, 2001; Vol. 49,
pp 113-168. (e) Padwa, A.; Austin, D. J. Angew. Chem., Int. Ed. Engl.
1994, 33, 1797. (f) Merlic, C. A.; Zechman, A. L. Synthesis 2003, 8, 1137.
(2) Taber, D. F.; Herr, R. J.; Pack, S. K.; Geremia, J. M. J. Org. Chem.
1996, 61, 2908.
(3) Panne, P.; Fox, J. M. J. Am. Chem. Soc. 2007, 129, 22.
(4) DeAngelis, A.; Panne, P.; Yap, G. P. A.; Fox, J. M. J. Org. Chem.
2008, 73, 1435.
10.1021/ol800983y CCC: $40.75
Published on Web 06/12/2008
2008 American Chemical Society

to the dramatic suppression of ꢀ-hydride elimination. In
prior studies on the effects of ligand structure6 and
temperature5 on suppressing ꢀ-hydride elimination, only
modest effects had been noted.
Table 1. The Effect of Ligand Choice on Rh-Catalyzed
Cyclopropanation
The rhodium-catalyzed cyclopropanation of alkenes has
broad applicability in organic syntheses.1,7 However, ex-
amples of intermolecular cyclopropanation by diazoalkanes
are rare.8–10 With Rh catalysis, we are aware of only three
reports that describe intermolecular cyclopropanation in
preference to ꢀ-hydride elimination.8 These transformations
involved
a
limited range of alkenes (diketene,8a
methylenespiropentane,8b or furans8c) with ethyl R-diazo-
propionate. Rh-catalyzed cyclopropanation of R-alkyldiazo
compounds with more reactive ꢀ-hydrogens has not been
described previously.
Unlike the reactions displayed in Scheme 1, cyclopropa-
nation reactions have the additional challenge of diastereo-
control. Diastereocontrol in cyclopropanation chemistry can
be highly dependent on the structure of the carbenoid,1 and
it was unclear if the reactions of R-alkyl diazoesters would
be selective. As shown in Table 1, a range of catalysts were
surveyed for their effectiveness in the reaction of ethyl
R-diazobutanoate with styrene. These reactions were screened
with use of the diazoalkane as the limiting reagent, so that
the relative amounts of cyclopropanation and ꢀ-hydride
elimination could be measured.
Consistent with earlier observations on the reactions of
alkynes with R-alkyl-R-diazoesters,3 dirhodium tetraoctanoate
(Rh2Oct4) gave only small amounts of cyclopropane products:
cis-ethyl crotonate 6 and azine 74 dominated. While dirhod-
ium tetrapivalate (Rh2Piv4) is the most useful catalyst for
cyclopropenation and dioxolane formation,3,4 this catalyst
gave rise to cyclopropane products 4 and 5 only in modest
a Yields were determined by analyzing the crude 1H NMR spectrum
with mesitylene as a standard. “Cyclopropane yield” represents the combined
yield of 4 and 5. b Impurities in the 1H NMR made it difficult to determine
the ratio of 4:5. c The dr was determined by GC analysis. d The yield of 4
as determined by 1H NMR analysis (this table) was slightly higher than the
e
1
isolated yield (Scheme 2). The dr was determined by H NMR.
yields and with poor diastereoselectivity (42:58), with a slight
preference for 5. The use of Rh2esp211 provided no significant
advantage (Table 1, entry 9). However, increasingly higher
selectivities were observed along a series of catalysts with
increasingly larger carboxylate ligands. Thus, 4 and 5 were
obtained in a 76:24 ratio with Rh2(O2CCMe2Ph)4 (8), in a
89:11 ratio with Rh2(O2CCMePh2)4 (9), and in a 98:2 ratio
with Rh2TPA4. In line with previous observations, the use
of low temperature was critical: ꢀ-hydride elimination
predominated in experiments that were carried out at room
temperature (Table 1, entries 2, 4, and 8).
Rh2TPA4 had previously been shown to be uniquely
effective in a number of catalytic tranformations.12,13 With
the discovery that Rh2TPA4 is also an effective catalyst for
diastereoselective cyclopropanation, the substrate scope of
the reaction was determined (Scheme 2).14 Successful
cyclopropanations were observed with R-methyl and R-n-
(5) Lowering temperature had been shown to have an effect on selectivity
over ꢀ-hydride elimination in Rh2(S-PTTL)4-catalyzed, intramolecular C-H
insertions: 99:1 selectivity was observed at -78 °C vs 82:18 selectivity at
0 °C. Minami, K.; Saito, H.; Tsutsui, H.; Nambu, H.; Anada, M.; Hashimoto,
S. AdV. Synth. Catal. 2005, 347, 1483.
(6) Modest improvements in selectivity over ꢀ-hydride elimination had
been previously observed in intermolecular O-H insertions and intramo-
lecular C-H insertions when sterically demanding ligands were used in
room temperature. For an intermolecular O-H insertion reaction, 88:12
selectivity was observed with Rh2(1-adamantoate)4 vs 82:18 selectivity with
Rh2(OAc)4: (a) Cox, G. G.; Haigh, D.; Hindley, R. M.; Miller, D. J.; Moody,
C. J. Tetrahedron Lett. 1994, 35, 3139. For an intramolecular C-H insertion
reaction, 85:15 selectivity was observed with Rh2(Piv)4 vs 78:22 selectivity
with Rh2(OAc)4: (b) Taber, D. F.; Joshi, P. V. J. Org. Chem. 2004, 69,
4276. (c) Taber, D. F.; Hennessy, M. J.; Louey, J. P. J. Org. Chem. 1992,
57, 436.
(7) (a) Davies, H. M. L.; Antoulinakis, E. G. Org React. (N.Y.) 2001,
57, 8. (b) Doyle, M. P. In Modern Rhodium-Catalyzed Organic Reactions;
Evans, P. A., Ed.; Wiley-VCH: Weinheim, Germany, 2005; pp 341-356.
(c) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV.
(10) Intramolecular cyclopropanation reactions in the presence of
ꢀ-hydrogens with Rh-catalysts, see ref 2 and: (a) Doyle, M. P.; Zhou, Q.-
L. Tetrahedron: Asymmetry 1995, 6, 2157. (b) Nicolaou, K. C.; Postema,
M. H. D.; Miller, N. D.; Yang, G. Angew. Chem., Int. Ed. Engl. 1997, 36,
2821. (c) Taber, D. F.; Hoerrner, R. S. J. Org. Chem. 1992, 57, 441. (d)
Ikota, N.; Takamura, N.; Young, S. D.; Ganem, B. Tetrahedron Lett. 1981,
22, 4163. (e) Baird, M. S.; Hussain, H. H. Tetrahedron 1987, 43, 215. (f)
Bonnaud, B.; Funes, P.; Jubault, N.; Vacher, B. Eur. J. Org. Chem. 2005,
3360. (g) Dudones, J. D.; Sampson, P. Tetrahedron 2000, 56, 9555. With
Cu catalysts: (h) Dauben, W. G.; Hendricks, R. T.; Luzzio, M. J.; Ng, H. P.
Tetrahedron Lett. 1990, 31, 6969. (i) Molander, G. A.; Alonso-Alija, C.
Tetrahedron 1997, 53, 8067. (j) Hudlicky, T.; Koszyk, F. J.; Dochwat,
D. M.; Cantrell, G. L. J. Org. Chem. 1981, 46, 2911.
2003, 103, 977
.
(8) (a) Murphy, P. V.; O’Sullivan, T. J.; Geraghty, N. W. A. J. Chem.
Soc., Perkin Trans. 1 2000, 2109. (b) Eaton, P. E.; Lukin, K. A. J. Am.
Chem. Soc. 1993, 115, 11370. (c) Wenkert, E.; Guo, M.; Lavilla, R.; Porter,
B.; Ramachandran, K.; Sheu, J.-H. J. Org. Chem. 1990, 55, 6203
.
(9) Cu-catalyzed, intermolecular cyclopropanation reactions of alkenes
with ethyl R-diazopropionate: (a) Gottschling, S. E.; Grant, T. N.; Milnes,
K. K.; Jennings, M. C.; Baines, K. M. J. Org. Chem. 2005, 70, 2686. (b)
Wenkert, E.; Alonso, M. E.; Buckwalter, B. L.; Chou, K. J. J. Am. Chem.
Soc. 1977, 99, 4778. (c) Creary, X. J. Org. Chem. 1976, 41, 3734. For
cyclopropanation reactions with ethyl R-diazopropionate via 1-pyrazolines,
see: (d) Doyle, M. P.; Dorow, R. L.; Tamblyn, W. H. J. Org. Chem. 1982,
(11) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem.
Soc. 2004, 126, 15378.
47, 4059
.
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Org. Lett., Vol. 10, No. 14, 2008

conditions, all of the products in Scheme 2 were obtained
in 80-100% yield with the exception of 2g, which was
obtained in 54% yield. Good yields were also obtained when
the stoichiometry of the reactions in Table 1 was inverted,
and the diazo compound was used as the limiting reagent
with a 3-fold excess of the alkene (Scheme 2). In an
experiment with 1:1 stoichiometry of alkene and diazo
compound, 4a was obtained in 48% yield.
Scheme 2. Rh2TPA4-Catalyzed Cyclopropanationd
Recently, Davies and co-workers provided evidence that
the high diastereoselectivity in cyclopropanations of styrene
derivatives with R-aryl or R-styryl diazo compounds is partly
due to an attracting π-interaction between the substituents
on the carbenoid and the alkene15 in a mechanism involving
a concerted, nonsynchronous transition state.16 Our observa-
tions are consistent with Davies’ hypothesis, as the Rh2Piv4-
catalyzed reaction of styrene with ethyl R-diazopropionate
proceeds with low diastereoselectivity relative to the analo-
gous reactions of styrene with R-aryl or R-styryl diazoesters.13
In conclusion, a chemoselective and diastereoselective Rh-
catalyzed protocol for cyclopropanation of alkenes with
R-alkyl-R-diazoesters has been described. While a number
of sterically demanding carboxylate ligands serve to avoid
ꢀ-hydride elimination, it was found that triphenylacetate
(TPA) is uniquely effective in terms of diastereoselectivity.
It is likely that the high diastereoselectivity observed in
cyclopropanation reactions with Rh2TPA4 is a consequence
of the very high steric demands of the TPA ligand. Ongoing
experiments and calculations in our laboratories aim to
understand the catalyst effect.
Acknowledgment. This work was supported by NIH grant
GM068640-01. PP thanks the Deutsche Forschungsgemein-
schaft (DFG) for postdoctoral fellowship support.
aThe alkene was the limiting reagent, and the diazo compound was
used in 3-fold excess. bThe diazo compound was the limiting reagent, and
the alkene was used in 3-fold excess. cThe alkene was the limiting reagent,
and the diazo compound was used in 4-fold excess. dAll yields refer to the
average isolated yield from two experiments. Hexane was the solvent for
the preparation of 9a-c; other compounds were prepared in CH2Cl2.
Supporting Information Available: Experimental details,
stereochemical assignments, and 1H, 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800983Y
alkyldiazoesters. Successful alkene substrates include sub-
stituted styrenes, R-vinylnapthalene R-methylstyrene, 1,1-
diphenylethylene, butyl vinyl ether, and 3,4-dihydro-2H-
pyran. The highest yields for cyclopropanation were obtained
when the alkene was the limiting reagent; the diazo
compound was typically used in 3-fold excess. Under these
(13) Davies, H. M. L.; Coleman, M. G.; Ventura, D. L. Org. Lett. 2007,
9, 4971.
(14) We know of several limitations of the Rh2TPA4-catalyzed cyclo-
propanation reaction. Unlike the analogous reactions of ethyl R-diazopro-
pionate to give 8f and 8g, the reactions of ethyl R-diazobutanoate (1 equiv)
with either 1,1-diphenylethylene (3 equiv) or 1-vinylmesitylene (3 equiv)
were both unsuccessful, and led predominantly to ꢀ-hydride elimination.
Cyclopropane products were not observed in the reactions of ethyl
R-diazobutanoate with 1-vinylcyclohexane, trans-ꢀ-methylstyrene, cis-
diphenylethylene, or 1-octene. The reaction of ethyl R-diazohydrocinnamate
(3 equiv) with styrene proceeded with poor efficiency: in hexane, the
cyclopropanation product was formed in 28% yield (NMR analysis) along
with uncharacterized products and unreacted styrene.
(12) See refs 3, 6b, and: (a) Hashimoto, S.-i.; Watanabe, N.; Ikegami,
S. Tetrahedron Lett. 1992, 33, 2709. (b) Davies, H. M. L.; Hodges, L. M.;
Thornley, C. T. Tetrahedron Lett. 1998, 39, 2707. (c) Fiori, K. W.; Fleming,
J. J.; Du Bois, J. Angew. Chem., Int. Ed. 2004, 43, 4349. (d) Sugimura, T.;
Ohuchi, M.; Kagawa, M.; Hagiya, K.; Okuyama, T. Chem. Lett. 2004, 33,
404. (e) Marmsa¨ter, F. P.; Vanecko, J. A.; West, F. G. Org. Lett. 2004, 6,
1657. (f) Marmsa¨ter, F. P.; Vanecko, J. A.; West, F. G. Tetrahedron 2002,
58, 2027.
(15) Denton, J. R.; Cheng, K.; Davies, H. M. L. Chem. Commun. 2008,
1238.
(16) Nowlan, D.; Gregg, T.; Davies, H. M. L.; Singleton, D. J. Am.
Chem. Soc. 2003, 125, 15902.
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