Angewandte
Chemie
DOI: 10.1002/anie.201106927
ꢀ
C H Bond Functionalization
Aerobic Palladium(II)-Catalyzed 5-endo-trig Cyclization: An Entry
into the Diastereoselective C-2 Alkenylation of Indoles with Tri- and
Tetrasubstituted Double Bonds**
Sandeep R. Kandukuri, Julia A. Schiffner, and Martin Oestreich*
The Mizoroki–Heck reaction, that is the palladium(0)-cata-
lyzed alkenylation of prefunctionalized arenes (or alkenes),[1]
is now rivaled by oxidative palladium(II)-catalyzed processes
(also referred to as Fujiwara–Moritani reactions) that involve
[2]
ꢀ
C H bond activation. These related palladium catalyses
ꢀ
proceed through the same C C bond-forming step, the
migratory insertion of a C C double bond into the inter-
ꢀ
2
II
ꢀ
mediate C(sp ) Pd bond. Intermolecular coupling reactions
are, however, limited to unhindered alkenes. If not function-
alized with a directing group,[3] di- or even trisubstituted
alkenes are usually not sufficiently reactive,[4,5] and the few
successful oxidative coupling reactions are associated with
selectivity problems[5] (I)II and III, Scheme 1, upper). This
situation changes in the intramolecular variant, in which those
alkenes participate indeed in C C couplings.[1,6] We therefore
ꢀ
had the idea to temporarily tether a trisubstituted alkene III
with a synthetically useful functional group to an arene II
(V)II and III, Scheme 1, upper). Intramolecular coupling
(IV)V, Scheme 1, upper) would then be followed by the
cleavage of the tether (I)IV, Scheme 1, upper). The net
Scheme 1. Strategy for the diastereocontrolled formation of tetrasubsti-
ꢀ
tuted double bonds by “indirect” C H bond alkenylation of trisubsti-
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outcome of this three-step sequence is a C H bond alkeny-
tuted alkenes: Application to the C-2 alkenylation of indoles (FG and
FG’=functional groups).
lation with complete control of the double bond geometry in
the fully substituted alkene. For this, the planned ring closure
onto the trigonal carbon atom would have to occur with endo
selectivity, which is still the exception in oxidative palladi-
um(II) catalysis.[7–9]
a diastereocontrolled access to C-2 alkenylated indoles, which
ꢀ
are hitherto not accessible by direct C H coupling with the
With our experience in intramolecular alkenylation (exo
requisite trisubstituted a,b-unsaturated acceptors (VII)VI,
Scheme 1, lower).[5c,d,14] Herein, we show the realization of
this strategy for several alkene substitution patterns and also
for functionalized indole building blocks, for example,
tryptophan und tryptamine.
mode)[10,11] of indole C H bonds and exo cyclization of a,b-
ꢀ
unsaturated amides,[12] we designed indole VIII with an
alkene tethered to the indole nitrogen atom by an amide
group (Scheme 1, lower). Its unprecedented endo ring
closure[9] would give the rare motif of 3H-pyrrolo[1,2-
a]indole-3-ones[13] (VII)VIII, Scheme 1, lower). Subsequent
ring-opening by cleavage of the amide linkage would provide
Our investigation began with the identification of suitable
reaction conditions for the endo cyclization of a representa-
tive precursor (1!2, Table 1). Our previously elaborated
aerobic oxidative setup[12] in the presence of pivalic acid[15]
using Stoltzꢀs Pd(OAc)2–L1 combination[11a,c,12,16] afforded
fully substituted 2 in reasonable yield[17] (Table 1, entry 1).
Variation of acid and solvent was only detrimental (Table 1,
entries 2–4), and control experiments showed that all compo-
nents of the Pd(OAc)2–L1–acid system are necessary for the
reaction (Table 1, entries 5–7). It is worth mentioning that no
exocyclic alkene regioisomer is formed because competing b-
hydride elimination pathways (b-H versus b’-H) are an issue
in intermolecular coupling reactions of a-methyl-substituted
a,b-unsaturated acceptors.[5c,d]
[*] S. R. Kandukuri, Dr. J. A. Schiffner, Prof. Dr. M. Oestreich
Institut fꢀr Chemie, Technische Universitꢁt Berlin
Strasse des 17. Juni 115, 10623 Berlin (Germany)
E-mail: martin.oestreich@tu-berlin.de
S. R. Kandukuri
NRW Graduate School of Chemistry, Organisch-Chemisches
Institut, Westfꢁlische Wilhelms-Universitꢁt Mꢀnster
Corrensstrasse 40, 48149 Mꢀnster (Germany)
[**] S.R.K. thanks the NRW Graduate School of Chemistry for a
predoctoral fellowship (2009–2012). Benedikt Kappelt (Universitꢁt
Mꢀnster) is acknowledged for his experimental contributions.
In analogy to the seminal work of Stoltz and co-work-
ers,[11a,c,16a] we also tested several electronically modified
pyridines (L2–L7, Figure 1). It emerged from this screening
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2012, 51, 1265 –1269
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1265