Asymmetric Intramolecular C-H Insertions of Aryldiazoacetates

Article abstract of DOI:10.1021/ol0157858

matrix presented The enantioselectivity of Rh₂(S-DOSP)₄ catalyzed C-H insertion of aryldiazoacetates is very dependent on the site of the C-H insertion. The highest enantioselectivity is obtained for insertion into methine C-H bonds.

Full text of DOI:10.1021/ol0157858

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1475-1477
Asymmetric Intramolecular C−H
Insertions of Aryldiazoacetates
Huw M. L. Davies,* Moˆnica V. A. Grazini,‡ and Emmanuel Aouad
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York,
Bufalo, New York 14260-3000
hdaVies@acsu.buffalo.edu
Received March 2, 2001
ABSTRACT
The enantioselectivity of Rh2(S-DOSP)4 catalyzed C−H insertion of aryldiazoacetates is very dependent on the site of the C−H insertion. The
highest enantioselectivity is obtained for insertion into methine C−H bonds.
Recently, it has been shown that the intermolecular C-H
insertion of aryldiazoacetates is a very effective method for
asymmetric C-H activation.1,2 For example, the reaction of
methyl phenyldiazoacetate (2) with N-BOC pyrrolidine,
catalyzed by Rh2(S-DOSP)4 (1a), generates the C-H inser-
tion product 3 in 92% de and 94% ee (eq 1).1d Excellent
regio-, diastereo-, and enantiocontrol are possible in this
chemistry.
intrigued with the very low enantioselectivity that Sulikowski
reported3 for Rh2(S-TBSP)4 (1b) catalyzed intramolecular
C-H insertion of aryldiazoacetate 4 to form the C-H
insertion products 5a-d that were ultimately converted to
the fused indole 6 (Scheme 1). Rh2(S-TBSP)4 (1b) usually
performs very well as a chiral catalyst when aryldiazoacetates
are used as substrates,4 but the results in Scheme 1 are far
inferior to the intermolecular example shown in eq 1.
Prompted by the apparent dichotomy between the inter- and
intramolecular C-H insertions of aryl diazoacetates,5 we
decided to carry out a systematic study on intramolecular
(1) (a) Davies, H. M. L.; Hansen, T. J. Am. Chem. Soc. 1997, 119, 9075.
(b) Davies, H. M. L.; Stafford, D. G.; Hansen, T. Org. Lett. 1999, 1, 233.
(c) Davies, H. M. L.; Antoulinakis, E. G.; Hansen, T. Org. Lett. 1999, 1,
383. (d) Davies, H. M. L.; Hansen, T.; Hopper, D.; Panaro, S. A. J. Am.
Chem. Soc. 1999, 121, 6509. (e) Axten, J. M.; Ivy, R.; Krim, L.; Winkler,
J. D. J. Am. Chem. Soc. 1999, 121, 6511. (f) Davies, H. M. L.; Stafford, D.
G.; Hansen, T.; Churchill, M. R.; Keil, K. M. Tetrahedron Lett. 2000, 41,
2035. (g) Muller, P.; Tohill, S. Tetrahedron 2000, 56, 1725. (h) Davies, H.
M. L.; Hansen, T.; Churchill, M. R. J. Am. Chem. Soc. 2000, 122, 3063. (i)
Davies, H. M. L.; Antoulinakis, E. G. Org. Lett. 2000, 2, 4153. (j) Davies,
H. M. L.; Ren, P. J. Am. Chem. Soc. 2001, in press.
(2) For a general review, see: Davies, H. M. L.; Antoulinakis, E. G. J.
Organomet. Chem. 2001, 617-618, 45.
(3) Lim, H.-J.; Sulikowski, G. A. J. Org. Chem. 1995, 60, 2326.
(4) (a) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459. (b) Davies, H.
M. L. Aldrichimica Acta 1997, 30, 105.
(5) Dirhodium tertaprolinates have been successfully used for intermo-
lecular C-H insertions of other classes of diazoacetates; see: (a) Ye, T.;
Garc´ıa, C. F.; McKervey, M. A. J. Chem. Soc., Perkin Trans. 1 1995, 1373.
(b) Garc´ıa, C. F.; McKervey, M. A.; Ye, T. Chem. Commun. 1996, 1465.
Considering the efficiency of rhodium prolinate catalyzed
intermolecular C-H insertions of aryldiazoacetates, we were
‡ Visiting professor from Centro de Cieˆncias Exatas e de Tecnologia da
Universidade de Mogi das Cruzes, Mogi das Cruzes, SP, Brazil 0870-911.
10.1021/ol0157858 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/21/2001

Scheme 1
C-H insertions in order to reconcile the differences between
the two modes of reaction.
prolinate catalysts Rh2(S-biTISP)2 (8)7 and 98 are described
in this paper.
A complicating feature associated with Sulikowski’s
system is that four diastereomeric products, 5a-d, are
formed in the C-H insertion step. These compounds were
not individually analyzed. Instead, pairs of diastereomers
were oxidized to the indole 6. Thus, the overall enantio-
selectivity that was reported is not directly related to the
carbenoid face selectivity during the reaction. Furthermore,
the reaction conditions that were used (CH2Cl2, reflux) are
far from the ideal conditions established for asymmetric
catalysis by rhodium prolinates (hydrocarbon solvent,
temperatures as low as -78 °C).6 Consequently, we decided
to study the intramolecular C-H insertions of aryldiazo-
acetates by using a simpler system, 7 (eq 2). This system
Our intermolecular studies have established that the
carbenoid from aryldiazoacetates displays subtle chemo-
selectivity for insertion at secondary or tertiary sites.
Electronically, attack at a tertiary site is preferred, but this
is balanced by steric factors that favor attack at a secondary
site. On the basis of this reactivity pattern, the intramolecular
substrates 7 that were used were chosen to explore the effect
of substitution at the C-H insertion site on the outcome of
the reaction. The aryldiazoacetates were readily prepared by
a diazotransfer reaction using p-acetamidobenzenesulfonyl
azide (p-ABSA) and DBU as base (eq 3).9
The first system that was examined, 7a, would only be
able to undergo a C-H insertion into a methyl group
(Scheme 2). So far, no effective C-H insertion into a methyl
Scheme 2
group has been reported for the intermolecular reactions. Rh2-
(S-DOSP)4 catalyzed decomposition of 7a at -50 °C failed
would enable the differences in asymmetric induction
between inter- and intramolecular C-H insertions of aryl-
diazoacetates to be determined. The results of these studies
using Rh2(S-DOSP)4 (1a) and the second generation bridged
(6) Davies, H. M. L.; Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M.
J. J. Am. Chem. Soc. 1996, 118, 6897.
1476
Org. Lett., Vol. 3, No. 10, 2001

to generate any C-H insertion product. Carbene dimer was
the major product. In contrast, repeating the reaction at room
temperature resulted in a 98% yield of C-H insertion product
10a. The enantioselectivity, however, for the formation of
10a was very low (<5% ee). As a result of the rigid nature
of the bridged catalysts 8 and 9, CH2Cl2 can be used as
solvent with these catalysts without a detrimental effect on
asymmetric induction.7,8 Decomposition of 7a at -50 °C with
either 8 or 9 generated 10a in 43% and 68% ee, respectively.
The next substrates that were examined, 7b and 7c, would
be expected to undergo C-H insertion into a methylene
group. Rh2(S-DOSP)4 (1a) catalyzed decomposition of 7b
at -50 °C resulted in the formation of the dihydrobenzo-
furans 11b and 12b in 85% yield as a 4:1 mixture of cis and
trans isomers (Scheme 3).10 Furthermore, the major cis
lyzed decomposition of the isopropyl derivative 7d at -50
°C resulted in a very efficient transformation (Scheme 4).
Scheme 4
Scheme 3
The C-H insertion product 13d was formed in 98% yield
and 94% ee. The reaction of 7d catalyzed by either 8 and 9
was considerably less enantioselective than the reaction
catalyzed by Rh2(S-DOSP)4. The Rh2(S-DOSP)4 catalyzed
reaction with the cyclopentyl derivative 7e generated the
C-H insertion product 13e in 93% yield and 90% ee.
Reaction of the cyclohexyl derivative 13f, however, resulted
in a very low yield of the C-H insertion product. Carbene
dimer formation predominates in this case. This may be an
indication that an axial C-H bond in cyclohexane does not
react well in these C-H insertions of carebenoids derived
from aryldiazoacetates.
These studies demonstrate that effective asymmetric intra-
molecular C-H insertion is possible with aryldiazoacetate
derivatives but the extent of asymmetric induction is very
dependent on the site of C-H insertion and the catalyst. With
the bridged prolinate catalysts, 8 and 9, the highest enantio-
selectivity is obtained for insertion into a methyl group. The
highest enantioselectivity using Rh2(S-DOSP)4 is obtained
for insertion into methine C-H bonds. This trend is different
from that observed in the intermolecular C-H insertions,
where reasonably high enantioselectivity generally occurs
for insertion into methylene C-H bonds.2
isomer was formed in 60% ee. An even more highly
diastereoselective reaction occurred with 7c, in which the
size of the methylene substituent was increased from methyl
to cyclohexyl. The cis-dihydrobenzofuran 11c was formed
in 95% de and 63% ee. The reaction of 7b with the bridged
prolinate catalysts 8 and 9 occurred with enantioselectivity
similar but opposite to that of the reaction catalyzed by
Rh2(S-DOSP)4. Opposite asymmetric induction between
Rh2(S-DOSP)4 and the bridged prolinate catalysts has been
observed previously in cyclopropanation reactions.7,8 The
reaction of 7c catalyzed by either 8 and 9 was considerably
less diastereoselective and enantioselective than the reaction
catalyzed by Rh2(S-DOSP)4.
Acknowledgment. Financial support of this work by the
National Science Foundation (CHE-0092490) is gratefully
acknowledged. We also thank the State of Sa˜o Paulo
Research Foundation for a postdoctoral fellowship to
M.V.A.G. We thank Dr. Tadamichi Nagashima and Stephen
A. Panaro for the preparation of catalysts 8 and 9.
Supporting Information Available: Experimental condi-
tions and spectral data for 7 and 10-13. This material is
available free of charge via the Internet at http://pubs.acs.org.
The final substrates, 7d-f, would be expected to undergo
insertion into a methine position. Rh2(S-DOSP)4 (1a) cata-
OL0157858
(7) Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett. 1999, 40, 5287.
(8) Davies, H. M. L.; Kong, N. Tetrahedron Lett. 1997, 40, 4203.
(9) Davies, H. M. L.; Cantrell, W. R.; Romines, K. R.; Baum, J. S. Org.
Synth. 1991, 70, 93.
(10) The absolute stereochemistry for the C-H insertions products has
not been unamabiguously determined, but the configuration that is drawn
is that expected from the predictive model for Rh2(S-DOSP)4 catalyzed C-H
insertions (see ref 2).
Org. Lett., Vol. 3, No. 10, 2001
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