Direct Indole/Pyrrole Coupling to Carbonyl Compounds
A R T I C L E S
without a prohibitive excess of one of the coupling partners
remained a far more daunting task. In fact, the technology was
so limited in scope that it had been scarcely utilized in total
syntheses,18d,23b,d,26d,37 mainly in the construction of various
symmetrical lignans.
methodology could be rendered more synthetically useful.
Indeed, when a mixture of carvone enolate and indole anion
were treated with FeCl3 as oxidant, a minor amount (8%) of
the desired coupled product (12) was obtained as a single
diastereomer (Table 1, entry 15).
In order to address the selectivity problem (homocoupling
vs heterocoupling) in intermolecular couplings, a few potential
solutions have been put forth. In these reports, selective homo-
or heterocouplings are performed by first converting one or both
coupling partners into either the enol ethers or silyl enol ethers
and reacting those with either ketones or other silyl enol ethers
to give coupled products in reasonable yields. A similar reaction
manifold has been observed for the coupling of enamines with
various nucleophilic π-systems.38 A variety of oxidants have
been utilized in such couplings including Mn(OAc)3,39 Ag2O,40
TiCl4,41 Cu(OTf)2,22f CAN,42 direct electrochemical oxidation,43
(EtO)VOCl2,44 and Fe(phen)3(PF6)3.45 Using vanadium oxidants,
it was discovered that selective heterocouplings could be
performed by exploiting the differing rates of oxidation of
sterically dissimilar enol silanes.44 Silicon or titanium tethers
can be employed to ensure that a heterocoupling will occur
between two distinct carbonyl compounds.45 Similarly, it was
shown that two different esters could be heterocoupled by
constructing the mixed diester of BINOL.28e The selective
reaction of silyl enol ethers with furans has also been reported.46
Unfortunately, these studies stopped short of achieving a
selective heterocoupling of two free carbonyl compounds
without resorting to prefunctionalization of one or more of the
substrates. It is likely that enolate-type couplings would find
more widespread use if this were possible.
Optimization
Given the initial success, a more detailed study and optimiza-
tion of the direct indole coupling reaction was undertaken. It
was initially reasoned that the oxidant played a major role in
the efficiency of the reaction, so a variety of oxidants were
screened that were known (Vide supra), or predicted, to promote
the direct coupling reaction (Table 1). It was quickly discovered
that FeCl3 did not have to be used as a DMF solution (as is
commonly reported in enolate oxidation)23a but could simply
be added to the reaction as a solid, a finding that facilitated the
screening of the remaining oxidants. In addition to the technical
simplicity, the reactions were much cleaner in the absence of
DMF. While many common oxidants [I2, K3Fe(CN)6, Mn-
(OAc)3] failed to furnish any of the desired coupled product,
success was realized when copper-based oxidants were explored.
A screen of several readily available soluble copper salts led to
the selection of copper(II) 2-ethylhexanoate as the optimum
oxidant for the desired coupling reaction, in part due to its high
solubility in organic solvents. It should also be noted that these
reactions were extremely “clean” as monitored by TLC; only
12, indole, and two diastereomeric carvone dimers were
observed.
In addition to the “standard” oxidants precedented in the
literature for these coupling reactions, several other oxidants
should be mentioned, since they unexpectedly provided product.
For example, ceric ammonium nitrate (CAN) cleanly provided
the desired product in 16% yield, even though it was not soluble
in THF and had never before been used in an oxidative enolate
coupling (however, it has been used in enol silane couplings,
Vide supra). Interestingly, if CAN was added as a solution in
DMF, no product was observed. Surprisingly, Pb(OAc)4 also
gave a 17% yield of the product when used as a solution in
DMF, even though it too had never been employed in an
oxidative enolate coupling. It was also discovered that by
changing the ligand environment (and therefore tuning the
oxidation potential of the metal center), the outcome of the
coupling could be modulated [i.e., Mn(acac)3 versus Mn(OAc)3].
Also worthy of note is that stoichiometric palladium(II) provided
no detectable product.47
Given the aforementioned considerations and the somewhat
daunting precedent, success of an oxidative coupling to forge
the key bond in the hapalindoles seemed unlikely. Experimental
studies were therefore initiated in the hope that a greater
understanding of the process could be realized and perhaps the
(31) (a) Kofron, W. G.; Hauser, C. R. J. Org. Chem. 1970, 35, 2085-2086. (b)
Enders, D.; Mu¨ller, P.; Klein, D. Synlett 1998, 43-44.
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1847.
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Once the proper oxidant was selected, a systematic screen of
the other reaction parameters was undertaken, beginning with
a search for the optimum solvent (Table 1). A screen of common
solvents revealed that DCM and THF provided identical results,
so THF was selected for its ease of use with various bases. A
study of an assortment of bases showed that LHMDS was
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