Regioselective oxidative arylation of indoles bearing N-alkyl protecting groups: Dual c-h functionalization via a concerted metalation-deprotonation mechanism

Article abstract of DOI:10.1021/ja107159b

The most direct method for synthesizing 2-arylindoles is oxidative coupling of an arene with an indole. We have shown that both the activity and regioselectivity of this cross-coupling reaction are correlated with the acidity of the medium. This insight has been applied to predict the best conditions for the oxidative cross-coupling of N-alkylindoles, an important class of substrates that has heretofore been incompatible with the harsh conditions required for oxidative cross-coupling. Both experimental and computational data indicate that the mechanism for C-H palladation of both the indoles and simple arenes is best described as concerted metalation-deprotonation, regardless of the substitution on the arene.

Full text of DOI:10.1021/ja107159b

Published on Web 09/23/2010
Regioselective Oxidative Arylation of Indoles Bearing N-Alkyl
Protecting Groups: Dual C-H Functionalization via a
Concerted Metalation-Deprotonation Mechanism
Shathaverdhan Potavathri,† Kyle C. Pereira,† Serge I. Gorelsky,‡ Andrew Pike,†
Alexis P. LeBris,† and Brenton DeBoef*,†
Department of Chemistry, UniVersity of Rhode Island, 51 Lower College Road,
Kingston, Rhode Island 02881, and Centre for Catalysis Research and InnoVation, Department
of Chemistry, UniVersity of Ottawa, 10 Marie Curie PVt., Ottawa, Ontario, Canada K1N 6N5
Received August 9, 2010; E-mail: bdeboef@chm.uri.edu
Abstract: The most direct method for synthesizing 2-arylindoles is oxidative coupling of an arene with an
indole. We have shown that both the activity and regioselectivity of this cross-coupling reaction are correlated
with the acidity of the medium. This insight has been applied to predict the best conditions for the oxidative
cross-coupling of N-alkylindoles, an important class of substrates that has heretofore been incompatible
with the harsh conditions required for oxidative cross-coupling. Both experimental and computational data
indicate that the mechanism for C-H palladation of both the indoles and simple arenes is best described
as concerted metalation-deprotonation, regardless of the substitution on the arene.
Introduction
Palladium-catalyzed oxidative cross-coupling of arenes is a
desirable process because prefunctionalization of either substrate
prior to the coupling reaction is not required, thus allowing for
a rapid and green synthesis of biaryls.1-9 A consortium of
leading pharmaceutical companies have described such pro-
cesses as some of the most “aspirational” reactions that remain
undeveloped in the “key green chemistry research areas”.10
Arylated indoles represent a privileged class of heterocycles that
have diverse applications in pharmaceuticals, fragrances, dyes,
and agrochemicals.11,12 Ideally, the biaryl bond in these com-
pounds could be synthesized by oxidative cross-coupling, but
such reactions, involving double C-H bond functionalization,
are difficult because the oxidative conditions often decompose
electron-rich N-alkylindole substrates. Herein, we disclose that
tuning the acidity of the reaction medium enables the synthesis
of arylated indoles via oxidative cross-coupling and prevents the
Figure 1. Limits of current oxidative coupling technology. SEM )
2-(trimethylsilyl)ethoxymethyl; MOM ) methoxymethyl; Bn ) benzyl.
oxidative decomposition of the important but sensitive indole sub-
strates and products.
We have previously shown that benzofuran (1) can be
oxidatively cross-coupled with benzene (used as a cosolvent)
to regioselectively form 2-phenylbenzofuran (2) (Figure 1,
reaction a).13 The reaction is notable because of its high yield,
short reaction time, and use of molecular oxygen as the terminal
oxidant. However, our initial efforts to apply these optimized
conditions to indoles were unfruitful. The acidic, oxidizing
conditions that were ideal for benzofurans rapidly decomposed
N-alkylindole substrates (reaction b).14
Subsequently, both we and the Fagnou group achieved intra-
and intermolecular oxidative arylation of N-acetylindoles by
replacing the acidic medium with a neutral cosolvent15 or
buffering it with either AgOAc or Cu(OAc)2, which can act as
† University of Rhode Island.
‡ University of Ottawa.
(1) McGlacken, G. P.; Bateman, L. M. Chem. Soc. ReV. 2009, 38, 2447.
(2) Chen, X.; Engle, K.; Wang, D.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094.
(3) Joucla, L.; Djakovitch, L. AdV. Synth. Catal. 2009, 351, 673.
(4) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(5) Li, B.; Yang, S.; Shi, Z. Synlett 2008, 949.
(6) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174.
(7) Rong, Y.; Li, R.; Lu, W. Organometallics 2007, 26, 4376.
(8) Brasche, G.; Garc´ıa-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008,
10, 2207.
(9) Zhao, X.; Yeung, C. S.; Dong, V. M. J. Am. Chem. Soc. 2010, 132,
5837.
(10) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. L., Jr.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman,
B. A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411.
(11) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed. 2009, 48, 9608.
(12) Sundberg, R. J. The Chemistry of Indoles; Academic Press: New York,
1970.
(13) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B. Org.
Lett. 2007, 9, 3137.
(14) Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc. 1951,
73, 2641.
(15) Potavathri, S.; Dumas, A. S.; Dwight, T. A.; Naumiec, G. R.;
Hammann, J. M.; DeBoef, B. Tetrahedron Lett. 2008, 49, 4050.
9
14676 J. AM. CHEM. SOC. 2010, 132, 14676–14681
10.1021/ja107159b  2010 American Chemical Society

Regioselective Oxidative Arylation of Indoles
A R T I C L E S
Table 1. Discovery and Optimization of Regioselective Oxidative
Arylation with Electron-Rich Indoles
entry
R
equiv of PivOH
conv. (%)a
yield (%)a
ratiob
1
2
3
4
5
6
H
H
H
H
0
1
2.5
5
2.5
2.5
62
81
96
98
100
100
43
58
69
65
97
56
2.1:1
2.2:1
2.6:1
2.5:1
8.7:1
2.7:1
CO2Me
OMe
a Unreacted starting material and products were isolated by flash
chromatography. b 5/6 (entries 1-4), 8/9 (entry 5), or 11/12 (entry 6), as
determined by GC.
tions containing nearly equal amounts of PivOH and AgOAc,
but we were cognizant of the regioselectivity issues that could
be observed. Gratifyingly, when the “buffered” conditions were
applied to the oxidative cross-coupling of N-SEM-indole 4, the
reaction proceeded with modest yield and regioselectivity (Table
1, entries 2-4). Reactions containing no PivOH failed to com-
pletely convert the starting material (entry 1). The optimal
conditions contained a slight excess of AgOAc relative to
PivOH, which likely prevented the acid-promoted oxidative
decomposition of the indole substrate and products.
The regioselectivities of the indole reactions were not
dramatically affected by the acidity of the reaction medium;
rather, they were modulated by substitution on the indole
substrate. The electron-withdrawing ester functionality (7) tripled
the regioselectivity of the oxidative arylation, favoring the
2-phenylindole product (8), and significantly increased the
overall yield (entry 5). Substitution with an electron-donating
methyl ether (10) had a minimal effect on the regioselectivity
and a slight deleterious effect on the yield (entry 6).
Scope of the Oxidative Cross-Coupling Reaction. The opti-
mized oxidative coupling conditions were amenable to N-
alkylindoles decorated with a wide variety of functional groups
(Table 2). Indoles substituted with an N-protecting group such
as SEM, benzyl, or MOM were all amenable to the oxidative
coupling reaction (5, 13, 14). Protection of the indole with the
electron-withdrawing tosyl group did not prevent the oxidative
coupling (16). N-Methylindole provided a diminished yield
despite rapid conversion, which implies that oxidative decom-
position of the starting material, the product, or both may be a
competitive process for this substrate.
Indoles bearing electron-withdrawing groups (8, 18-21)
provided higher yields and regioselectivities than those contain-
ing electron-donating groups (10, 23, 24). Notably, N-SEM-7-
azaindole, which could potentially deactivate the catalyst via
ligation, underwent the coupling with good regioselectivity and
yield (22).
Figure 2. Oxidative coupling of benzofuran (1) and benzene as a function
of acid concentration.
both an oxidant and a weak base.15-17 Additionally, both groups
found that the selectivity for arylation at either the 2- or
3-position of the indole was influenced by the choice of oxidant,
with AgOAc favoring the 2-aryl product and Cu(OAc)2 favoring
arylation at the 3-position.15,16 However, none of these condi-
tions were compatible with N-alkylindoles, as they provided
negligible yields and a loss of regiochemical control, regardless
of the oxidant.
In light of this precedent, we hypothesized that the reactivity
of the oxidative cross-coupling could be modulated as a function
of the medium’s acidity. This was verified by studying the
oxidative coupling of 1 with benzene as the concentration of
organic acid in the reaction mixture was modulated (Figure 2).
1 was an ideal substrate for these studies because of its reactivity
under all of the conditions and because it was not prone to
oxidative decomposition. PivOH was used as the acidic additive
because it minimized the formation of acetoxylated byproduct.18
The most active conditions for the oxidative arylation of 1
were the most acidic. As the concentration of organic acid was
lowered relative to the concentration of AgOAc, which served
as both a stoichiometric oxidant and a weak base, the rate of
the reaction was retarded. All of the reactions containing PivOH
and AgOAc produced nearly a 1:1 mixture of the two regiomeric
products (2 and 3), but when PivOH was removed from the
reaction, the 2-aryl product was preferentially formed (2/3 )
4:1). Consequently, we concluded that both the activity and
regioselectivity of the oxidative cross-coupling are correlated
with the acidity of the reaction medium.
Results and Discussion
Reaction Discovery. In light of these trends, we hypothesized
that sensitive indole substrates might be amenable to oxidative
cross-coupling with arene solvents using the “buffered” condi-
A variety of functional groups on the benzene substrate were
also tolerated. Ortho-, meta-, and para-disubstituted benzenes
provided only one regiomeric product (25-28). However, the
steric interaction associated with the coupling of p-xylene
diminished its yield (28). Additionally, there appears to be a
limit to the electron density of the arene that can be coupled to
(16) Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007,
129, 12072.
(17) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.
(18) Lie´gault, B.; Lee, D.; Huestis, M. P.; Stuart, D. R.; Fagnou, K. J.
Org. Chem. 2008, 73, 5022.
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A R T I C L E S
Potavathri et al.
Table 2. Scope of the Oxidative Arylation Reactiona
Figure 3. Probing the mechanism of indole palladation: (a) deuteration
study; (b) competition experiment. In (b), the reaction time was ∼15 min,
and the conversion was computed from GC data. The competing reactions
displayed pseudo-zeroth-order kinetics, so the relative rates could be
calculated directly from the conversions (the data were normalized to the
rate for unsubstituted indole).
substrates bearing halogens, which are generally considered to
be deactivated for electrophilic aromatic substitutions, could also
be oxidatively cross-coupled with indoles, albeit in slightly
diminished yields (30, 31).
Mechanism of Indole Palladation. In general, two C-H bond
activation mechanisms are commonly used to describe the
substitution of arenes by electrophilic metals such as Pd(II).
The first involves electrophilic palladation via an SEAr process.
For indoles, this proposed mechanism involves the initial
palladation at the nucleophilic 3-position, after which a 1,2-
migration of the metal to the 2-position of the substrate can
follow.19 Alternatively, palladation via a concerted metalation-
deprotonation (CMD) process with a six-membered transition
state has been described as a possible mechanism in the
metalation of many heterocyclic arenes, and the regioselectivity
of such a process for N-methylindole substrates has been
reported recently.20
To probe these two mechanistic possibilities, we conducted
a series of experiments (Figure 3). We first used a simple
deuteration study (reaction a) to confirm that N-SEM-indoles
containing both electron-donating and electron-withdrawing
groups are nucleophilic at the 3-position. This showed that
regardless of the substitution on the indole’s benzenoid ring,
palladation of the indole substrate does not occur via direct
electrophilic substitution at the 2-position (i.e., by a pyrrole-
like mechanism). However, the longer reaction times required
for deuterium incorporation into 33 confirmed the well-known
fact that the electrophilic aromatic substitution of electron-poor
indoles at the 3-position (e.g., 33-d) is less favorable than that
of electron-rich substrates (e.g., 32-d).
a Conditions: 0.15 mmol of indole, 4 mL of arene, 10 mol % Pd(OAc)2,
3 equiv of AgOAc, 2.5 equiv of PivOH, 120 °C (microwave). b Only the
major isomer is shown. The minor isomer is the 3-arylindole. Yields and
regioselectivities were obtained by isolation of both isomers following flash
chromatography. c N-MOM-indoles behaved similarly to N-SEM indoles in
that the 5-NO2 derivative of 14 was phenylated exclusively at the 2-position
with a better yield (17, 68%; see the Supporting Information for details).
(19) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem. Soc. 2005, 127,
8050.
the indole, as the yield for coupling of o-xylene (26) was 5
times greater than that of veratrole (29). Interestingly, benzene
(20) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. J. Am. Chem. Soc. 2008,
130, 10848.
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Regioselective Oxidative Arylation of Indoles
A R T I C L E S
Figure 5. Occupied frontier orbitals for the indoles that contribute to the
interaction with the Pd(II) catalyst in the CMD transition state. The C2
atomic contribution (%) and the energy (eV) for each orbital are shown.
Figure 4. Potential mechanisms for palladation of indole.
Table 3. Distortion/Interaction Analysis (kcal mol-1) for the
Lowest-Free-Energy CMD Transition States at the C2 sites of
N-Methylindoles Bearing an Electron-Donating or -Withdrawing
Group at the 6-Position
tions to ∆Gq were calculated using a distortion/interaction
analysis of the corresponding transition states. In this approach,
the distortion energies Edist associated with distortions of the
arene (ArH) and the catalyst [Pd(OAc)2] from their ground-
state geometries to the geometries in the transition state as well
as the electronic interaction energy Eint between Pd(OAc)2 and
ArH in the CMD transition state were evaluated (Table 3). The
OMe group on the indole increased Edist(ArH) by 3.0 kcal mol-1
(entry 1 vs 2). On the other hand, the NO2 group on the indole
decreased Edist(ArH) by 4.7 kcal mol-1 (entry 3 vs 2). The value
of Edist(Pd) (between 23.7 and 25.7 kcal mol-1) showed little
variation for reactions of different indoles. The presence of an
electron-donating or -withdrawing substituent was also found
to influence the interaction energy Eint (Table 3). Eint became
more negative for the indole bearing an OMe substituent and
less negative for the indole bearing a NO2 substituent. The
analysis of the covalent interactions in the CMD transition states
also indicated that the Pd-C bond order decreases in order OMe
> H > NO2. Since the influence of the substituents on Edist(ArH)
is weaker than their influence on Eint, the observed reactivity
trend (OMe > H > NO2) for these indole substrates is caused
by the change in Eint between the indole and the Pd(II) catalyst.
The changes in Eint can be traced to how these electron-donating
and -withdrawing groups tune the energy and electron distribu-
tion of the two highest occupied molecular orbitals of the indole
(the HOMO and HOMO-1) upon substitution (Figure 5).
b
entry
R
∆Gq
∆Eq
Edist(ArH)
Edist(Pd)a
-Eint
BPd-C2
1
2
3
OMe
H
NO2
15.7
17.7
20.2
5.5
7.6
10.1
39.1
36.1
31.4
25.7
24.8
23.7
59.2
53.3
45.0
0.813
0.794
0.742
a Pd(OAc)2. b Mayer bond order for the Pd-CAr interaction in the tran-
sition state.
A competition experiment between N-SEM-6-methoxyindole
(10) and N-SEM-indole (4) (Figure 3, reaction b) found that
the indole bearing an electron-donating group (10 f 11) reacted
1.34 times faster than its unsubstituted counterpart. Additionally,
N-SEM-6-nitroindole (34) reacted 3 times slower than its
unsubstituted counterpart. These data seem to indicate that
during the course of the oxidative coupling reaction, palladation
of the indole substrate proceeds via an electrophilic substitution
process. As described previously, the electrophilic palladium
should attack at the aromatic heterocycle’s nucleophilic 3-posi-
tion, after which a 1,2-migration of the metal to the indole’s
2-position can occur (Figure 4, mechanism b). However, such
a mechanism is not in line with the observations shown in Table
2, where the attachment of electron-withdrawing groups to the
indole’s 6-position, which should destabilize the product of such
a migration (37), actually enhanced the formation of the
2-arylated indole products (compare 11 with 18 in Table 2).
Consequently, we hypothesized that indole substrates bearing
both electron-donating and electron-withdrawing groups are
palladated by the aforementioned CMD mechanism (Figure 4,
mechanism a).
Computational analysis of the palladation of substituted
N-methylindoles corroborated the CMD mechanism. The reac-
tion barriers (Gibbs free energies of activation, ∆Gq) were eval-
uated using indoles bearing electron-donating and electron-
withdrawing groups (Table 3). In accord with the experimental
outcomes, the ∆Gq value for the CMD pathway was found to
be 2.0 kcal mol-1 lower for the indole bearing the 6-methoxy
group (entry 1) and 2.5 kcal mol-1 higher for the indole bearing
the 6-nitro group (entry 3) relative to the nonsubstituted indole
(entry 2).
According to the analysis of fragment orbital interactions in
the CMD transition state, significant contributions to indole-
to-metal charge transfer interactions involve only two donor
orbitals (the HOMO and HOMO-1) of the indole. When the
CMD transition state is formed, the electron populations of these
two orbitals change by 13.0 and 10.0%, respectively. The OMe
substituent increases the energy of the HOMO to -5.35 eV
and increases the HOMO density at the C2 site (20%). As a
result, for OMe-indole, the HOMO becomes the only donor
orbital that participates in indole-to-metal charge transfer, and
upon the formation of the CMD transition state, the population
of this orbital changes by 21.1%. On the other hand, the NO2
substituent lowers the energies of the occupied orbitals of indole.
As a result, the electronic interaction between NO2-indole and
Pd(II) is weakened, and Eint is only -45.0 kcal mol-1 (Table 3,
entry 3), which can be compared with the Eint value of -59.2
kcal mol-1 in OMe-indole.
To explain the impact of electron-donating and -withdrawing
groups on the direct arylation reactivity of indoles, the contribu-
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A R T I C L E S
Potavathri et al.
Mechanism of Palladation of the Simple Arene Substrate.
The ability to couple both electron-rich and electron-poor arenes
to indole substrates is incongruent with our previous work (Table
2, 25-31), in which acidic conditions could not couple het-
eroaromatic substrates with pentafluorobenzene13 and basic
conditions could not couple N-acetylindoles with anisole.15 To
explain these phenomena, we hypothesized that the optimized,
buffered reaction conditions allowed for mechanistic promiscuity
whereby the simple arene, like the indole substrate, could be
palladated by either an electrophilic substitution or proton
abstraction process. Alternatively, the palladation of the simple
arene could proceed via a CMD mechanism.20
To test these two hypothetical reaction pathways, we per-
formed a competition experiment in which indole 34 was mixed
with equimolar amounts of o-dichlorobenzene (40) and o-xylene
(41) (Figure 6, reaction a). Our optimal conditions for oxidative
cross-coupling resulted in a nearly equal mixture of products
(26/30 ) 1.1:1). This product ratio did not change significantly
as the acidity of the medium was modulated.
This unpredicted lack of chemoselectivity was further ex-
emplified by the regioselective competition reaction that occurs
in the oxidative coupling of o-trifluoromethyltoluene (42)
(Figure 6, reaction b). Interestingly, a 1.4:1 ratio of products
43 and 44 was observed, with the major product arising from
palladation para to the methyl group. The results of these
competition studies, in which there was no marked chemose-
lectivity, are not consistent with either an electrophilic palla-
dation mechanism or a proton abstraction mechanism involving
the buildup of charged intermediates.
Computational analysis of arene 42 provided insight into the
mechanism by which it is palladated (see the Supporting
Information for details). The carbon atom para to the methyl
group contains the largest partial negative charge, so it should
be most amenable to palladation via an SEAr mechanism. The
anion formed by abstraction at the position para to the tri-
fluoromethyl group is more stable than that formed by abstrac-
tion para to the methyl group, indicating that the former proton
would be more easily abstracted by a traditional acid-base
reaction. Interestingly, the lengths of these two C-H bonds were
computed to be identical (1.075 Å). Previous computational and
experimental work has shown the CMD mechanism is favored
by longer C-H bonds.20 Thus, the CMD mechanism predicts
the minimal selectivity that was observed in the oxidative
coupling of 42. Importantly, these computations can be per-
formed using readily available, user-friendly software (such as
Spartan21) and a desktop/laptop computer, indicating that
predictions about the reactivity of a given substrate in palladation
reactions involving CMD mechanisms can easily be obtained
by a conventional synthetic organic chemist.
Figure 6. Probing the mechanism of palladation of the simple arene
substrate.
proton abstraction process, where considerable C-H bond
breaking can be observed in the transition state (KIE > 3).22,23
As predicted, large KIE values were observed in a competition
reaction using equimolar amounts of benzene and benzene-d6,
indicating that cleavage of the solvent arene’s C-H bond is
rate-determining. Furthermore, the data show that the KIE for
the oxidative coupling did not vary dramatically as a function
of the acidity of the medium, which indicates that the palladation
of the simple arene occurs via a single CMD mechanism as
Finally, to differentiate between the possibility of two
competing mechanisms and the action of a single, unique
mechanism, we performed kinetic isotope effect (KIE) studies
of the oxidative coupling reaction and varied the concentration
of the PivOH (Figure 6, reaction c). It has been previously
suggested that electrophilic palladation processes in which
minimal C-H bond breaking is involved in the transition state
(KIE < 3) should be favored by higher concentrations of acid
(usually AcOH but in our case PivOH). Conversely, reactions
containing less acid should be more basic and should favor a
(22) Campeau, L.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc.
2006, 128, 581.
(23) Pascual, S.; de Mendoza, P.; Echavarren, A. M. Org. Biomol. Chem.
2007, 5, 2727.
(21) Spartan ’08; Wavefunction, Inc.: Irvine, CA, 2008.
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Regioselective Oxidative Arylation of Indoles
A R T I C L E S
opposed to competing electrophilic palladation and proton
abstraction mechanisms.
indole-derived arenes in oxidative cross-coupling reactions.
Future work in our laboratory will seek to develop oxidative
cross-coupling reactions for new classes of high-value substrates
and will be guided by the mechanistic investigations that have
been disclosed in this article.
Conclusions
This work is one of a small number of studies involving
complementary experimental and computational evidence sup-
porting a C-H palladation mechanism involving a concerted
metalation-deprotonation (CMD) mechanism.20 Other research-
ers have described similar metalation processes, which have been
called proton abstraction24-26 or σ-bond metathesis,27 and
numerous palladium-catalyzed C-H functionalization reactions
have been characterized as having both the ability to react with
both electron-rich and electron-poor heterocycles and KIEs in
the 3-5 range. Consequently, we hypothesize that the CMD
mechanism demonstrated herein may not be limited to a select
set of reactions but rather may operate in a variety of C-H
functionalizations. Our work further validates the idea that the
CMD mechanism, though often called proton abstraction, is not
traditional acid-base chemistry, as it is not affected by the
acidity of the reaction medium. Rather, a given C-H bond’s
propensity to participate in a CMD process is better predicted
by the length of the bond as opposed to its relative acidity.
In summary, we have discovered a mild and efficient method
for oxidative cross-coupling of indoles with benzene substrates
via double C-H functionalization. Both the indole and simple
arene substrates are palladated by CMD processes. This work
represents the first example of the operation of a CMD
mechanism in an acidic reaction medium, as is common for
oxidative cross-coupling reactions. However, we have shown
that the acidity of the medium does not significantly affect the
CMD process for the palladation of simple, benzene-derived
arenes but does affect the regioselectivity of the palladation of
Methods
Representative Procedure. A magnetically stirred solution of
1-[2-(trimethylsilyl)ethoxymethyl]indole-6-carboxylate (64 mg, 0.21
mmol), palladium acetate (4.7 mg, 0.021 mmol), silver acetate (104
mg, 0.63 mmol), and 2,2-dimethylpropanoic acid (53 mg, 0.52
mmol) in 5 mL of benzene was microwave-heated at 120 °C for
3 h. After evaporation of the solvent, the mixture was then diluted
with 40 mL of water and extracted with three 50 mL portions of
ethyl acetate. The combined organic extracts were washed with
two 40 mL portions of brine followed by two portions of 40 mL
of water and then dried with anhydrous magnesium sulfate. After
filtration, the solvent was removed at reduced pressure, and the
crude product was purified by column chromatography to give pure
8 (70 mg, 87% yield) and the corresponding 3-phenyl product (8
mg, 10% yield). Both compounds were analytically pure, as
determined by 1H and 13C NMR spectroscopy and mass spectrom-
etry (see the Supporting Information for complete characterization).
Acknowledgment. In memory of Keith Fagnou. The authors
thank CEM Corp. for use of a Discover microwave synthesizer;
William Euler, Ben Reukberg, and Melanie Sanford for helpful
discussions; and Christopher Latendresse for computational as-
sistance. This work was supported by the National Science Foun-
dation (CAREER 0847222), the Petroleum Research Fund (47019-
G1), and a Pilot/Feasibility Grant from the Rhode Island INBRE
Program (NIH-NCRR P20RR016457). S.G. thanks the Centre for
Catalysis Research and Innovation (CCRI), University of Ottawa,
for funding.
Supporting Information Available: Complete experimental
and computational details, compound characterization data, and
analysis of product purity. This material is available free of
charge via the Internet at http://pubs.acs.org.
(24) Garc´ıa-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M.
J. Am. Chem. Soc. 2006, 128, 1066.
(25) Garc´ıa-Cuadrado, D.; de Mendoza, P.; Braga, A. A. C.; Maseras, F.;
Echavarren, A. M. J. Am. Chem. Soc. 2007, 129, 6880.
(26) Lafrance, M.; Rowley, C. N.; Woo, T. K.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 8754.
(27) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 9651.
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