Highly diastereoselective and enantioselective C-H functionalization of 1,2-dihydronaphthalenes: A combined C-H activation/cope rearrangement followed by a retro-cope rearrangement

Article abstract of DOI:10.1021/ja047185k

The Rh₂(S-DOSP)₄-catalyzed reaction of vinyldiazoacetates with dihydronaphthalenes results in a highly enantioselective (91-99.6% ee) and diastereoselective (>98% de) C-H functionalization. The apparent intermolecular C-H insertion w

Full text of DOI:10.1021/ja047185k

Published on Web 08/17/2004
Highly Diastereoselective and Enantioselective C-H Functionalization of
1,2-Dihydronaphthalenes: A Combined C-H Activation/Cope Rearrangement
Followed by a Retro-Cope Rearrangement
Huw M. L. Davies* and Qihui Jin
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York, Buffalo, New York 14260-3000
Received May 13, 2004; E-mail: hdavies@buffalo.edu
Over the past few years, the intermolecular C-H insertion
chemistry of donor/acceptor-substituted rhodium carbenoid inter-
mediates has become a very effective method for catalytic enan-
tioselective C-H activation.1 Two stereocenters are generated when
the C-H activation occurs at methylene sites,2 and in systems with
good size differentiation between the methylene substituents, highly
diastereoselective and enantioselective reactions can be achieved.
In this paper we describe the reaction between vinylcarbenoids and
1,2-dihydronaphthalenes and related systems (eq 1), which results
in the formation of formal C-H activation products with very high
diastereoselectivity (>98% de) and enantioselectivity (91-99.6%
ee).
activation, the reaction of 2 with the ethyl-substituted vinyldiazo-
acetate 4 was examined (eq 3). This resulted in the formation of
the combined C-H activation/Cope rearrangement product 5 in
57% yield and very high diastereoselectivity (>98% de) and
enantioselectivity (98.4% ee). In this case, the reverse Cope
rearrangement is not as favored because the product 6 is not as
fully conjugated as 3. However, on heating in toluene for 6 h, 5
does rearrange to 6 in 92% yield (eq 4).
The exceptional reactivity between vinylcarbenoids and 1,2-
dihydronaphthalene was discovered while studying the Rh2(S-
DOSP)4-catalyzed decomposition of the vinyldiazoacetate 1 in the
presence of 4-methyl-1,2-dihydronaphthalene (2). Under the stan-
dard reaction conditions of 1 mol % of catalyst and 2 equiv of 2 at
23 °C with 2,2-dimethylbutane (DMB) as solvent, a very clean
transformation was observed (eq 2). The formal C-H activation
product 3 was formed in 92% yield, >98% de, and 98.9% ee. When
only 1.2 equiv of 2 and 0.1 mol % of catalyst were used, the yield
of 3 was still 82% and virtually no loss in stereoselectivity was
observed. The optimum conditions were using 1.1 equiv of diazo
compound 1 at 0 °C.
Further evidence for the more elaborate reaction mechanism was
observed in the reaction with 1,2-dihydronaphthalene (7). When
the reaction was conducted at 0 °C, the crude NMR indicated the
predominant formation of the combined C-H activation/Cope
rearrangement product 8 and the cyclopropane 9. Products 8 and 9
can be isolated as a mixture in 77% yield. On heating in toluene
for 48 h at 60 °C, 8 underwent rearrangement to the formal C-H
activation product 10, which was isolated in 60% overall yield,
>98% de, and 99.4% ee (eq 5). The selective introduction of the
two stereocenters in 8 could be of general utility for the rapid
construction of diterpene natural products such as erogorgianene.4
The highly stereoselective nature of the reaction to form 3 was
unexpected because earlier studies on the reaction of aryldiazoac-
etates with cycloalkenes displayed only moderate diastereoselec-
tivity.2d,f A possible explanation for the high diastereoselectivity is
the involvement of a more elaborate reaction mechanism than a
direct C-H activation. It is conceivable that the reaction could occur
by a combined C-H activation/Cope rearrangement3 followed by
a retro-Cope rearrangement. To explore the mechanism of the C-H
The intermediacy of the combined C-H activation/Cope rear-
rangement product can be used in a very advantageous manner as
illustrated in the reaction of 1 with 4-acetoxy-1,2-dihydronaphtha-
lene 11 (eq 6). A very clean transformation was observed, but the
product is the naphthalene derivative 13 formed in 85% yield and
99.6% ee. In this case aromatization of the intermediate 12 by
elimination of acetic acid occurs faster than the retro-Cope
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J. AM. CHEM. SOC. 2004, 126, 10862-10863
10.1021/ja047185k CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Predictive Model
rearrangement. This scheme has the potential to be a very effective
method for the enantioselective synthesis of 1,1-diarylalkyl deriva-
tives, units which have been incorporated into various pharmaceuti-
cal agents.5
The formal C-H activation can be applied to a range of
substrates. Both 7-methoxy- and 6-methoxy-4-methyl-1,2-dihy-
dronaphthalene 14 are suitable substrates to form 15, but the reaction
is more efficient with 14a because with 14b competing benzylic
C-H activation occurs to a minor extent (eq 7).
front side and over the vinyl portion of the carbenoid,3a which is
necessary for occurrence of the combined C-H activation/Cope
rearrangement to form 22. A retro-Cope rearrangement of 22
through a chair transition state would generate a formal C-H
insertion product 23 of defined stereochemistry. The assigned
stereochemistry for the other products is assumed on the basis of
this predictive model. The high diastereoselectivity is an indication
that very little direct C-H activation is occurring,2d in contrast to
our previous diastereoselective examples of the combined C-H
activation/Cope rearrangement.3c
In summary, we have described herein a highly diastereoselective
and enantioselective method for the C-H functionalization of
dihydronaphthalenes. The actual mechanism of the reaction is
complicated and involves a combined C-H activation/Cope rear-
rangement followed by a retro-Cope rearrangement. Dihydronaph-
thalenes such as 8 and naphthylaryl derivatives such as 13 are very
useful chirons, whose application in organic synthesis is currently
under investigation. These studies further demonstrate the broad
synthetic utility of donor/acceptor-substituted rhodium carbenoid
intermediates.
The reactions with 4-siloxy-1,2-dihydronaphthalenes 16 are very
interesting transformations because the products 17 can be formally
considered to be equivalent to the Michael addition products with
the keto tautomer of 1-naphthol, clearly an impossible transforma-
tion (eq 8). Interestingly, the increase size of the silyl group does
not affect the diastereoselectivity, but only slightly drops the ee.
The silyl enol ethers can be easily deprotected by using HCl (for
17a) or HF (for 17b and 17c) to form 18 in a range of 84-99%
yield.
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0350536). We thank Oksana O. Gerlits
for the X-ray crystallographic analysis.
Supporting Information Available: Full experimental data for the
compounds described in this paper, 1H and 13C spectra of selected
compounds, and X-ray structure of p-bromophenyl derivative of 18
(PDF). This material is available free of charge via the Internet at http://
pubs.acs.org.
The reaction can also be extended to 2H-chromene derivative
19 (eq 9). Once again, a very selective reaction occurs to form the
C-H activation product 20 in 75% yield, 95% ee, and >98% de
(eq 9).
References
(1) Davies, H. M. L.; Beckwith, R. E. J. Chem. ReV. 2003, 103, 2861-2903.
(2) (a) Davies, H. M. L.; Venkataramani, C.; Hansen, T.; Hopper, D. W. J.
Am. Chem. Soc. 2003, 125, 6462-6468. (b) Davies, H. M. L.; Beckwith,
R. E. J.; Antoulinakis, E. G.; Jin, Q. J. Org. Chem. 2003, 68, 6126-
6132. (c) Davies, H. M. L.; Jin, Q.; Ren, P.; Kovalevsky, A. Y. J. Org.
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The relative and absolute configuration of the p-bromo derivative
of 18 was determined by X-ray crystallography,6 while the
configuration of 10 was confirmed by its conversion to 18. The
observed configuration is consistent with the previously demon-
strated stereochemistry of the combined C-H activation/Cope
rearrangement,3a,c followed by the retro-Cope rearrangement oc-
curring through the expected chair transition state (Scheme 1).7 In
this model, the catalyst is considered to exist in a D2-symmetric
arrangement and can be simply viewed as having two blocking
groups as indicated in 21.8 The substrate is approaching from the
(7) (a) Nubbemeyer, U. Synthesis 2003, 961-1008. (b) Lutz, R. P. Chem.
ReV. 1984, 84, 205-247.
(8) Nowlan, D. T., III; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A. J.
Am. Chem. Soc. 2003, 125, 15902-15911.
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