Redox chain reaction - Indole and pyrrole alkylation with unactivated secondary alcohols

Article abstract of DOI:10.1002/anie.201209810

Secondary role: Indole and pyrrole derivatives are alkylated with unactivated secondary aliphatic alcohols by a Bronsted acid-catalyzed redox chain reaction mechanism. Broad functional-group tolerance has been demonstrated and preliminary studies suggest that 1,4-reduction of a putative indolyl carbocation is the dominant mechanistic pathway. Copyright

Full text of DOI:10.1002/anie.201209810

Angewandte
Chemie
DOI: 10.1002/anie.201209810
Synthetic Methods
Redox Chain Reaction—Indole and Pyrrole Alkylation with
Unactivated Secondary Alcohols**
Xinping Han and Jimmy Wu*
The direct alkylation of indoles with alcohols would be of
considerable synthetic utility because of the wide availability
of both starting materials. While this is readily accomplished
with activated substrates such as allylic,[1] benzylic,[2] and
propargylic alcohols,[3] the use of unactivated compounds
such as secondary aliphatic alcohols is exceedingly rare and,
to this day, represents a formidable challenge. Two examples
were reported between 1940 and 1950.[4,5] Despite their
limited scope, the unique mechanism by which they operate
(i.e., disproportionative condensation), piqued our curios-
ity.[6] These transformations yielded C-alkylated products, but
only under harsh reaction conditions (i.e., U.O.P. Ni catalyst,
30–600 mol% Na or K alkoxides, 174–2208C, up to 64 h).
Their synthetic utility, with respect to functional-group
tolerance and product stability, would be considerably
improved if milder reaction conditions could be identified.
We hypothesized that the fundamental mechanistic fea-
tures of the base-promoted disproportionative condensation
could be achieved under milder reaction conditions by
employing an appropriate Brønsted acid catalyst
(Scheme 1). As an illustrative example, indole 1 and alcohol
2 are treated with 5 mol% of the sacrificial ketone 3 and an
appropriate acid catalyst. The reaction is initiated by con-
Scheme 1. Acid-catalyzed redox chain reaction.
densation of 1 with 3 to furnish the indolyl cation 4 which is
converted into the undesired by-product 5 and the new
ketone 6 through a Meerwein–Ponndorf–Verley (MPV)
reduction with 2 (Oppenauer oxidation of iPrOH).[7] Then 6
condenses with 1 to furnish a different indolyl cation 7 which
is similarly reduced to the desired product 8.[8] For every
molecule of product that is formed, a molecule of 6 is
regenerated, thereby propagating the reaction. We suggest
redox chain reaction as an appropriate moniker for this
process because of the similarities it shares with radical chain
reactions,[9] and also to distinguish it from base-promoted
disproportionative condensation.
In line with our ongoing interest in the reactivity of indolyl
cations,[10] we report herein the successful application of the
redox chain reaction to the alkylation of indole and pyrrole
derivatives with unactivated secondary aliphatic alcohols.
While catalytic variants are known,[11,12] Meerwein–Ponn-
dorf–Verley–Oppenauer (MPVO) reactions typically require
stoichiometric amounts of Lewis acids. To the best of our
knowledge, this work is also likely to be the first instance of an
MPVO process catalyzed by a Brønsted acid.[13,14]
At the onset, we set out to identify the most efficient
initiator and Brønsted acid catalyst, as well as their optimal
loadings. After extensive experimentation (see the Support-
ing Information), we determined that 5 mol% of 2-methoxy-
acetophenone (3a) as an initiator and 10 mol% of TfOH in
toluene at 1008C provided the highest yield of 8ad (88%) for
the reaction between N-benzylindole (1a) and iPrOH (2d;
Scheme 2). Cyclohexanone and acetophenone (both
5 mol%) were also effective initiators, but because their by-
products (corresponding to 5) sometimes coeluted with the
desired products on silica gel, we decided to adopt 3a as the
standard initiator. Importantly, control reactions in which
either 3a or TfOH was omitted resulted in no detectable
product.
With the optimized reaction conditions in hand, we
proceeded to explore the scope of the methodology. As is
evident in Scheme 2, the reaction is tolerant to a variety of
functional groups including esters, amides, nitro, nitriles, and
ethers. The aminoalcohol 2g can also be used, but in this case
stoichiometric TfOH was required since up to 1 equivalent of
acid could be consumed by the basic nitrogen center.
[*] X. Han, Prof. Dr. J. Wu
Department of Chemistry, Dartmouth College
6128 Burke Laboratories, Hanover, NH (USA)
E-mail: jimmy.wu@dartmouth.edu
[**] J.W. acknowledges financial support provided by Dartmouth
College. We thank Dr. Richard J. Staples (Michigan State University,
USA) for assistance with X-ray crystallography.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209810.
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alcohols resulted in the formation of only 5 (< 5%). It is likely
that the attenuated reactivity of primary alcohols as hydride
donors, relative to secondary alcohols, precludes efficient
propagation of the redox chain reaction.
Excellent levels of diastereoselectivity can be realized
using alcohols with pre-existing stereocenters. As illustrated
in Scheme 3, when we attempted the late-stage indolylation of
(+)-dihydrocholesterol (2n) with 1a, the expected product
8an was isolated in 81% yield as a single diastereomer
Scheme 3. Diastereoselective alkylation reactions. [a] Standard reaction
conditions as described in Scheme 2. [b] Relative stereochemistry was
confirmed by single-crystal X-ray analysis.[17] [c] Confirmed by compar-
ison of JHH values to 8an.
(stereochemical configuration was confirmed with single-
crystal X-ray analysis). With cis-4-methylcyclohexanol (2o),
high diastereoselectivity (8ao, 10:1 d.r.) was also achieved.
Axial delivery[15] of hydride to the respective indolyl carbo-
cationic intermediates correctly predicts the observed selec-
tivities for 8an and 8ao. Alkylation using 2p (mixture cis/
trans) furnished a 2:1 mixture of 8ap. Curiously, alkylation
with the 2-substituted cyclohexanol 2q (mixture cis/trans)
generated mainly the rearranged product 8aq. By-products
derived from 1,2-hydride shifts were not detected.
Scheme 2. Scope of C3 alkylation of indoles. [a] 1.0 equiv alcohol,
1.1 equiv TfOH. [b] 2.0 equiv alcohol, 1.0 equiv TfOH, 10 mol% 3a.
[c] 2.0 equiv alcohol, 5 mol% TfOH, 10 mol% 3a. Bn=benzyl, Tf=tri-
fluoromethanesulfonyl, TBDPS=tert-butyldiphenylsilyl.
N-methylindole (1e) as well as 2-methyl-N-benzylindole (1d)
are both compatible, thus producing 8dd and 8eb in good
yields. The use of NH indole as the nucleophile resulted in no
reaction.
We wondered whether or not enantioenriched secondary
alcohols would deliver hydride to the prochiral indolyl cation
intermediates in a stereospecific fashion. Unfortunately, the
reaction between 1a and (R)-(À)-2e generated 8ae as
a racemate [Eq. (1)].[16]
As a testament to the improved efficiency of the redox
chain reaction as compared to disproportionative condensa-
tion, we highlight the reaction between 1a and cyclohexanol
(2b) which occurs within only 1 hour at 1008C to provide 8ab
in 93% yield upon isolation. The formation of three other
products 8ac, 8eb, and 8an (see Scheme3) was also complete
within 1 hour. In contrast, the alkylation of indole with
cyclohexanol utilizing base-promoted disproportionative con-
densation requires 64 hours at 174–1858C and furnishes the
desired product in only 54% yield.[4a] The use of primary
This methodology is also compatible with pyrrole nucle-
ophiles (9a–b). Under the optimized reaction conditions, we
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obtained good yields of the anticipated C2-substituted
pyrroles 10a–f (Scheme 4). Importantly, we did not detect
any di- or polysubstituted products. We hypothesize that for
steric reasons, after the first alkylation, the benzyl group is
directed away from the newly installed C2 substituent and
towards C5. Substantial nonbonding interactions experienced
the predominant pathway. These results also provide evidence
in support of the intermediacy of indolyl carbocation 12.
In conclusion, we have developed the Brønsted acid
catalyzed redox chain reaction as it pertains to the alkylation
of indole and pyrrole derivatives with unactivated secondary
alcohols. Broad functional-group tolerance has been demon-
strated. Deuterium-labeling studies support the intermediacy
of an indolyl carbocation which undergoes MPVO conjugate
reduction as a likely reaction mechanism.
We anticipate that it might be possible to apply the
concept of the redox chain reaction to the alkylation of other
nucleophiles such as nonbasic nitrogen atoms, enamines, and
electron-rich benzene derivatives. We are also exploring the
possibility of using chiral Lewis and Brønsted acids to induce
asymmetry.
Received: December 7, 2012
Revised: February 5, 2013
Published online: && &&, &&&&
Keywords: alcohols · alkylation · heterocycles · redox chemistry ·
.
synthetic methods
Scheme 4. Scope of C2 alkylation of pyrroles. [a] Standard reaction
conditions as described in Scheme 2. [b] 1.0 equiv alcohol, 1.1 equiv
TfOH. [c] 2.0 equiv alcohol, 20 mol% TfOH, 10 mol% 3a.
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a second alkylation event. For 9b, we believe that alkylation
takes place proximal to the C3 methyl group because C2 is
more electron rich than C5. Furan and thiophene were not
suitable nucleophiles as they resulted in either decomposition
or no reaction, respectively.
Preliminary mechanistic studies are depicted in Scheme 5.
The alkylation of 1a with deuterated cyclohexanol 11
generated a 92:8 ratio of the isotopic isomers 14 and 15. 1,4-
Reduction would lead exclusively to 14. Alternatively, 1,2-
reduction and subsequent TfOH-promoted tautomerization/
rearomatization would furnish 15. Based on the 92:8 prefer-
ence for the formation of 14, we conclude that 1,4-reduction is
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Scheme 5. Deuterium-labeling studies.
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[7] a) C. F. de Graauw, J. A. Peters, H. van Bekkum, J. Huskens,
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[16] The ee value determination performed by Lotus Separations,
Princeton, NJ, USA.
[17] CCDC 929479 (8an) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
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Synthetic Methods
X. Han, J. Wu*
&&&& — &&&&
Redox Chain Reaction—Indole and
Pyrrole Alkylation with Unactivated
Secondary Alcohols
Secondary role: Indole and pyrrole deriv-
atives are alkylated with unactivated
secondary aliphatic alcohols by
a Brønsted acid-catalyzed redox chain
reaction mechanism. Broad functional-
group tolerance has been demonstrated
and preliminary studies suggest that 1,4-
reduction of a putative indolyl carbocat-
ion is the dominant mechanistic pathway.
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!