DOI: 10.1002/cctc.201600659
Communications
Hydroformylation of 2-Alkynylanilines: Toward an
Alternative Methodology for the Synthesis of
3-Substituted Indoles
Cedric Holzapfel, Etelinda Dasilva, Laetitia Den Drijver, and Tyler Bredenkamp*[a]
A potentially viable route for the synthesis of 3-substituted in-
doles is presented herein. The methodology is based on a re-
gioselective Rh-catalysed hydroformylation of prepared 2-
alkyn-1-ylanilines. The requisite 2-alkynylaniline substrates
were prepared in high yields (>85%) using the Pd-catalysed
mylation have been investigated.[12,15] A particularly attractive
approach is that of Dong and Busacca[15a] that involves
a tandem Heck–hydroformylation process (Scheme 1). Howev-
er, the Heck reaction furnished poor yields if electron-rich sub-
strates were employed, which renders the approach less attrac-
tive. Notwithstanding the elegance displayed by the intrinsical-
ly atom-economic hydroformylation, which allows the func-
tionalisation of unsaturated moieties to valuable aldehydes
that can be further manipulated into the approximately 9 mil-
lion tons of oxo products produced annually,[16] a viable hydro-
formylation approach towards valuable indoles has not yet
been developed.
Sonogashira reaction.
A catalyst complex that comprises
RhI(CO)(PPh3)3 and 1,2-bis(diphenylphosphino)ethane as the
ligand allowed the quantitative conversions of the alkynyl sub-
strates with selectivities >75% for the desired 3-substituted
indoles.
Indoles are ubiquitous in nature and occur in different kinds of
plants, animals and marine organisms.[1] The indole backbone
represents one of the most important structural motifs in drug
discovery, which has been described as a “privileged scaffold”;
a term first introduced by Evans and co-workers[2] to define
scaffolds that bind many receptors.[3] Indole derivatives have
the unique ability to mimic the structure of peptides and to
bind reversibly to enzymes,[4] which provides tremendous op-
portunities to discover new drugs with different modes of
action. Indeed, seven indole-containing commercial drugs are
in the Top-200 Best Selling Drugs by US Retail Sales in 2012.[5]
Given their biological activity and propensity for binding many
receptors, the synthesis of substituted indoles has attracted
the interest of organic chemists for decades.[6] Present in anti-
inflammatory agents,[7] anti-hypersensitive,[8] anti-mural,[9] anti-
HIV[10] and anti-migraine[11] drugs, it is no surprise that a profu-
sion of synthetic methods for the indole motif have been
Previously, Ucciani and Bonfand[15b] transformed o-nitrostyr-
ene to 3-methyl indole using a supported Rh-catalysed hydro-
formylation reaction. However, in addition to the relatively
harsh reaction conditions employed (1608C and 16.0 MPa), no
other substrates were evaluated. More recently, Marchetti
et al.[12] reported the formation of three 3-(2,2-diethoxyethyl)-
1H-indoles from the corresponding (E)-1-(3,3-diethoxyprop-1-
en-1-yl)-2-nitrobenzenes after 168 h at 808C using tris(triphe-
nylphosphine)rhodium(I) carbonyl hydride as the catalyst com-
plex. However, in our hands this approach furnished low yields
of indole because of catalyst decomposition and indole poly-
merisation under the long reaction times.
Coupled with our interest in metal-catalysed carbonylation[17]
and in the synthesis of indoles,[18] we were attracted to the
possibility of a modification of the approach of Dong and Bu-
sacca[15a] to obtain 3-substituted indoles that would avoid the
use of substrates obtained through the Heck reaction. To this
end, a hydroformylation approach based on 2-alkynylanilines,
produced through the well-established Pd-catalysed Sonoga-
shira coupling reaction, was envisaged (Scheme 2).
developed[6] for the demand upward of 20000 tyearÀ1 [12]
.
Despite the vast number of synthetic methods available for
the formation of the indole backbone, most routes furnish 2-
substituted or 2,3-substituted indoles.[6] In contrast, there are
relatively few methodologies for the production of 3-substitut-
ed indoles[6,13,14] (which include serotonin, sumatriptan, melato-
nin and tryptophan), and the Fischer indole synthesis (and
modifications thereof) remains the most important approach
to 3-substituted indoles.[14] However, three potentially viable
routes to 3-substituted indoles that involve catalytic hydrofor-
The implementation of the proposed methodology, amongst
others, required the regioselective hydroformylation of the
alkyne substrate. Although the hydroformylation of alkenes is
well documented,[12,15,19] the hydroformylation of alkynes has
received less attention, despite the atom-economic benefits
for the production of synthetically versatile enals.[19] The rele-
vant literature, particularly with regards to the hydroformyla-
tion of aryl alkynes provides little information on the factors
that determine the outcome of the reaction. Therefore, we ini-
tiated our studies by establishing the parameters (which in-
cluded the RhI source, ligand architecture, temperature, pres-
sure, CO/H2 ratio and Rh/ligand ratio).[20] Optimal branch selec-
tivity (75%) was obtained if the bidentate ligand bis(diphenyl-
phosphino)ethane (dppe; 1) was used as the ligand under the
conditions described in Scheme 3. The only other products of
[a] Prof. C. Holzapfel, E. Dasilva, Dr. L. Den Drijver, Dr. T. Bredenkamp
Research Centre for Synthesis and Catalysis
Department of Chemistry
University of Johannesburg
PO Box 524, Auckland Park, 2006 (South Africa)
Supporting information for this article can be found under http://
ChemCatChem 2016, 8, 1 – 5
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&
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Holzapfel, Cedric
