Multicomponent assembly of highly substituted indoles by dual palladium-catalyzed coupling reactions

Full text of DOI:10.1002/anie.201204633

Angewandte
Chemie
DOI: 10.1002/anie.201204633
Indole Synthesis
Multicomponent Assembly of Highly Substituted Indoles by Dual
Palladium-Catalyzed Coupling Reactions**
John M. Knapp, Jie S. Zhu, Dean J. Tantillo, and Mark J. Kurth*
The development of new methods for the synthesis of
heterocycles[1] continues to be an important area of chemical
research, and new organometallic catalytic methods[2] are
providing synthetic routes to important targets previously
unavailable to the synthetic chemist. As indoles are ubiqui-
tous in pharmaceuticals and in natural products,[3]dozens of
methods for their construction have been developed.[4] The
Scheme 2. Ligands.
search for straightforward, diversity-oriented routes to
indoles is of importance to both synthetic and biological
researchers.[5] Some of these synthetic strategies have
involved the use of palladium catalysis and there are reports
Table 1: Optimization of one-pot reaction conditions.
of indole syntheses using Heck and Buchwald–Hartwig
assemblies.[6] There are also reports of multicomponent
reactions to form indoles.[7] We report herein a general
palladium-catalyzed multicomponent assemblies for indole
synthesis that incorporates both a Buchwald–Hartwig[8]
Entry
Ligand
Base
Solvent
Yield [%]
reaction and an arene–alkene coupling[9] reaction and
requires a single catalyst/ligand system. This method involves
three components and allows for easy diversification from
readily available starting materials. Multicomponent reac-
tions are advantageous in that they provide expedient
methods for the construction of complex structures, minimize
synthetic steps, and use relatively simple starting materials.[10]
The overall one-pot three-step multicomponent assembly
reported herein is illustrated in Scheme 1.
Reaction optimization established that the use of the dppf
ligand (1,1’-bis(diphenylphosphanyl)ferrocene; Scheme 2)
and Cs2CO3 as base (Table 1, entry 4) gave the best yields.
When Xphos, tBuXphos, and Xantphos (entries 1, 2, and 3,
1
2
3
4
5
6
7
8
Xphos
tBuXphos
Xantphos
dppf
PPh3
PtBu3
dppf
dppf
dppf
dppf
dppf
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOtBu
K3PO4
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
DMF
55
49
61
68
0
0
51
0
9
Cs2CO3
Cs2CO3
Cs2CO3
trace
14
0
10
11[a]
toluene
[a] Pd(OAc)2 was used in place of [Pd2dba3]. DMF=N,N-dimethylform-
amide.
respectively) were used the product was obtained, albeit in
lower yields, whereas PPh3 (entry 5) and PtBu3 (entry 6) did
not promote the reaction. When KOtBu was used the yields
were lower (entry 7), possibly because of enolate formation
from the ketone or aldehyde, thus reducing the likelihood of
an amine–carbonyl condensation. No product was obtained
when K3PO4 was used (entry 8). The addition of MgSO4
favors enamine formation by effectively excluding water
from the carbonyl + amine Q enamine + H2O equilibrium.
Attempts at using a palladium(II) catalyst as a source of
palladium(0) resulted in no product (entry 11); this result may
indicate that reduction of PdII to Pd0 is too slow for the PdII
species to be an effective precatalyst for this process.
Our optimized reaction conditions work effectively with
an array of substrates (Scheme 3) and proceed with a catalyst
loading of 2 mol% of [Pd2(dba)3] (4% Pd).[11] Awide range of
carbonyl compounds are suitable as substrates for this
process. Cyclic and acyclic ketones were used and both gave
the indole products (cyclic: 8, 14, 17, 18, 21; acyclic: 15, 20, 22)
Scheme 1. A one-pot, three-reactant palladium-catalyzed indole syn-
thesis. dba=dibenzylideneacetone.
[*] J. M. Knapp, J. S. Zhu, Prof. D. J. Tantillo, Prof. M. J. Kurth
Department of Chemistry, University of California Davis
1 Shields Ave., Davis, CA 95616 (USA)
E-mail: mjkurth@ucdavis.edu
[**] We thank the National Institute of Health (GM089153), the National
Science Foundation (CHE-0910870 and CHE-030089 with the
Pittsburgh Supercomputer Center) for their generous financial
support. We also thank Prof. Annaliese Franz (UC Davis) and Prof.
Tomislav Rovis (Colorado State) for helpful discussions.
Supporting information (including experimental, spectral and
computational data) for this article is available on the WWW under
http://dx.doi.org/10.1002/anie.201204633.
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Scheme 4. Examination of the order of events for the reported indole
synthesis. NaHMDS=sodium hexamethyldisilazide.
our reaction. Experiments 1–3 involve the intermediacy of
enolates.[13] In experiment 1, the use of a strong base
(NaHMDS) favors enolate formation; although Buchwald–
Hartwig coupling occurred (to form 9), subsequent enolate
coupling (to form 10) failed. In experiment 2, initial enolate
generation and coupling occurred but subsequent amine
addition did not give the Buchwald–Hartwig product (10). For
experiment 3 the attempted enolate coupling using optimized
reaction conditions (that is, with a weaker base) gave only
a trace amount of desired product; the major product (12)
formed arose from dimerization of cyclopentanone. On the
basis of these results, we conclude that enolates do not play
a significant role in the transformation described herein.
Preformation of the enamine (13) yielded only small amounts
of product using the optimized conditions, thus indicating that
such a process likely does not initiate the catalytic cycle
(Scheme 4, experiment 4). Initial Buchwald–Hartwig cou-
pling, followed by addition of the ketone, did produce the
indole product in 68% yield (Scheme 4, experiment 5). In
light of the results of experiments 1–5, we propose the
catalytic cycle shown in Scheme 5.
Several mechanisms for indole ring formation from an N-
arylenamine were examined using density functional theory
calculations (at the B3LYP/6-31G(d)[C,H,N],LANL2DZ
[Pd] levels with the simplified model system shown in
Scheme 6).[14] No transition-state structures corresponding
to the alkene insertion step of a traditional Heck reaction
were found. Instead, a two-step alkene insertion process via
an intermediate metallacycle (A!B!C) was located. Simple
insertion (that is, A!C, as in the Heck reaction) is likely
disfavored owing to the strain associated with endo cycliza-
tion and the fact that intermediate cation B is stabilized by
imine resonance. Formation of B can be formulated as the
attack of an enamine on an electrophilic metal center (with or
without prior Brꢀ loss). Intermediate C, which displays
a significant agostic interaction (Pd—H distance of 2.0 ꢀ
Scheme 3. Three-component indole products and yields. Reaction con-
ditions: o-bromoiodoarene (1 mmol), primary amine (1 mmol),
ketone/aldehyde (3 mmol), [Pd2dba3] (2 mol%), dppf (5 mol%),
Cs2CO3 (2.2 mmol), MgSO4 (10 mmol), toluene (0.5m), 1308C. Yields
are of the isolated product after purification by column chromatogra-
phy.
in similar yields. Aldehydes also successfully form indoles (16
and 19) under our optimized reaction conditions. A variety of
primary amines can be used and the aryl component can be
a carbocycle, an anisole, or a pyridine. For all of the indoles
prepared, the appropriate o-bromoiodo arene was used. A
larger scale reaction (5 mmol rather than the typical 1 mmol)
was also conducted for the synthesis of 14. A substantial
change in yield was not observed for this larger scale reaction
(that is, the yield for the 5 mmol reaction was only a 2% more
than that of the 1mmol reaction). The optimized yield for the
synthesis of 8 is 68%, which equates to each of the three steps
in our one-pot reaction sequence (Buchwald–Hartwig cou-
pling, condensation, and arene–alkene coupling) proceeding
in 88% average yield. Indeed, the yield of our one-pot
transformation is comparable to the overall yield recently
reported by Urabe and co-workers for their three-step three-
pot indole synthesis.[12]
Three bonds are formed in this transformation: an N–aryl
bond by a Buchwald-Hartwig coupling, an N–vinyl bond by
condensation of a nitrogen nucleophile onto an aldehyde or
ꢀ
ketone giving an enamine, and a C C bond by an arene–
alkene coupling. We envisioned that several possible reaction
sequences could be used to construct the indole core from
these three transformations. As shown in Scheme 4, several
experiments were carried out to probe the order of events in
2
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An alternative to this “interrupted Heck” reaction was
also examined. Deprotonation of one of the acidic methylene
protons of B would lead to E, which can undergo reductive
elimination to form indole D with a low predicted barrier
( ꢁ 5 kcalmolꢀ1). Although both mechanisms (A!B/B’!C/
C’!D/D’ and A!B!E!D) are consistent with our exper-
imental results, we favor the latter on energetic grounds,
assuming the reaction conditions allow for rapid deprotona-
tion of B.[14] This mechanistic proposal differs from the
traditional Heck mechanism proposed (or implied) in pre-
vious studies on N-arylenamine cyclizations of this type.[6c,d,15]
In conclusion, we have developed a versatile one-pot
three-step multicomponent assembly route to highly substi-
tuted indoles using a palladium-catalyzed reaction involving
three independent components. Indole formation can be
accomplished using suitable reaction conditions that favor
in situ generation of an aniline, condensation to an arylen-
amine, and a subsequent arene–alkene coupling reaction to
close the ring. A single palladium catalyst/ligand system
mediates both coupling reactions. We have also presented
a detailed mechanism for the palladium-catalyzed ring-
closing step. The mechanism described herein is supported
by quantum chemical calculations and offers an alternative to
direct Heck coupling as previously suggested. This work
significantly extends indole construction and diversification
strategies.
Scheme 5. Proposed catalytic multicomponent-assembly mechanism.
The dppf ligand is omitted for clarity.
Received: August 21, 2012
Published online: && &&, &&&&
Keywords: homogeneous catalysis · nitrogen heterocycles ·
.
multicomponent reactions · palladium · synthetic methods
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ꢀ
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)
relative to that of A: + 5.6 (A!B), ꢀ17.2 (B), + 14.7 (B!C).
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Communications
Indole Synthesis
J. M. Knapp, J. S. Zhu, D. J. Tantillo,
M. J. Kurth*
&&&& — &&&&
Highly substituted indoles were synthe-
sized by a palladium-catalyzed reaction
involving three independent components
in a one-pot reaction. Two distinct palla-
dium-catalyzed coupling reactions occur
with a single catalytic system: a Buch-
Multicomponent Assembly of Highly
Substituted Indoles by Dual Palladium-
Catalyzed Coupling Reactions
wald-Hartwig reaction and an arene-
alkene coupling. Quantum chemical
computations provide insight into the
mechanism of the latter coupling step.
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