C-H activation as a strategic reaction: Enantioselective synthesis of 4-substituted indoles

Article abstract of DOI:10.1021/ja057768+

A method is described for the asymmetric synthesis of 4-substituted indoles from the Rh₂(S-DOSP)₄-catalyzed decomposition of vinyldiazoacetates in the presence of N-Boc-4-acetoxy-6,7-dihydroindole. The reaction proceeds via a combine

Full text of DOI:10.1021/ja057768+

Published on Web 01/05/2006
C-H Activation as a Strategic Reaction: Enantioselective Synthesis of
4-Substituted Indoles
Huw M. L. Davies* and James R. Manning
Department of Chemistry, UniVersity at Buffalo, The State UniVersity of New York, Buffalo, New York 14260-3000
Received November 29, 2005; E-mail: hdavies@buffalo.edu
Table 1. Synthesis of 4-Substituted Indoles
The indole nucleus has long been of great interest to synthetic
chemists owing to its ubiquity in a large number of biologically
active alkaloids1 and pharmaceutical agents.2 Traditional strategies
for the synthesis of functionalized variants of this “privileged”
moiety have relied largely upon cyclization of an appropriately
substituted precursor,3 metalation followed by electrophilic trapping
of the anion,4 and cross-coupling reactions.5 Recently, attention has
been focused on the asymmetric functionalization of the indole
core.6 While these examples take advantage of the relatively
nucleophilic 3-position of the indole nucleus to add electrophiles
via a Friedel-Crafts type reaction, there are comparatively few
methods for selective functionalization of the less reactive 4-posi-
tion. Such methods include a thallation/iodination reaction,7 directed
lithiation of 3-substituted gramines,4a and cross-coupling reactions.8
We herein disclose a novel strategy for the highly enantioselective
synthesis of 4-substituted indoles 2 from a 4-acetoxy-6,7-dihy-
droindole (1) via a rhodium(II)-catalyzed combined C-H activation/
Cope rearrangement-elimination reaction (eq 1).
The development of catalytic methods for C-H activation is of
considerable current interest.9,10 The combined C-H activation/
Cope rearrangement is an impressive example because it proceeds
with excellent stereocontrol.11 The rhodium prolinate catalyst, Rh2-
(S-DOSP)4, is very effective in this chemistry, routinely resulting
in very high enantioselectivity. 1,2-Dihydronaphthalenes have been
versatile substrates for the C-H activation, leading to the synthesis
of formal Michael addition products,11b naphthalene derivatives,11b
double C-H functionalization,11f and the synthesis of the natural
products, (+)-erogorgiaene,11e (-)-colombiasin A,11g and (-)-
elisapterosin B.11g This current study demonstrates that dihydroin-
doles are also effective substrates for this unusual chemistry.
The Rh2(S-DOSP)4-catalyzed reaction with 4-acetoxy-6,7-dihy-
droindole (1) is applicable to a range of terminally substituted
vinyldiazoacetates 3 as illustrated in Table 1. The standard reaction
conditions used 1 mol % of catalyst and 2,2-dimethylbutane (DMB)
as solvent. Electron-rich and electron-deficient aryl substituents are
compatible with this chemistry (entries 1-5), as well as an
indolylvinyldiazoacetate (entry 6). A dienyldiazoacetate is equally
effective (entry 7), and even an alkyl substituent can be accom-
modated (entry 8). In all instances the new stereogenic centers in
the 4-substituted indoles 4 are formed in >97% ee. The absolute
configuration of the bromophenyl derivative 4c (entry 3) was
determined by X-ray crystallography of the reduced analogue,12
while the others are tentatively assigned by assuming an analogous
enantioinduction. The yields in these reactions ranged from 45 to
65% because there was some competing reaction initiated at the
pyrrole ring.13
4-Substituted indoles can also be formed in the reaction of cyclic
vinyldiazoacetates 5 as illustrated in eq 2. In these cases, competing
reactions on the pyrrole ring were not observed and the 4-substituted
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C O M M U N I C A T I O N S
indoles 6 were formed in 90-95% yields. Once again, the
enantioselectivities in these reactions were very high.
from the Rh2(S-DOSP)4-catalyzed decomposition of vinyldiazoac-
etates in the presence of a 4-acetoxy-6,7-dihydroindole precursor.
The reaction proceeds via a combined C-H activation/Cope
rearrangement-elimination mechanism, resulting in good yields and
very high asymmetric induction. The further application of this
chemistry to the synthesis of novel pharmaceutical targets is
currently in progress.
Acknowledgment. This work was supported by the National
Science Foundation (CHE-0350536). We thank Cara L. Nygren
for the X-ray crystallographic analysis.
Supporting Information Available: Full experimental data for the
compounds described in this paper; X-ray crystallographic files in CIF
format.
The C-H activation can be extended to a 4-substituted 6,7-
dihydrobenzothiophene 7 as illustrated in eq 3. Thiophenes are
common reaction partners with rhodium carbenoids,14 but in this
case the C-H activation is the dominant reaction, generating the
4-substituted benzothiophene 8 in 89% yield and 99% ee.
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Scheme 1
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