Palladium-catalyzed direct 2-alkylation of indoles by norbornene-mediated regioselective cascade C-H activation

Article abstract of DOI:10.1021/ja2055066

A palladium-catalyzed direct 2-alkylation reaction of free N-H indoles has been developed. This reaction relies on a norbornene-mediated cascade C-H activation process at the indole ring, which features high regioselectivity and excellent functional group tolerance. The reaction represents the first example for a generally applicable, direct C-H alkylation of indole at the 2-position.

Full text of DOI:10.1021/ja2055066

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Palladium-Catalyzed Direct 2-Alkylation of Indoles by
Norbornene-Mediated Regioselective Cascade CꢀH Activation
Lei Jiao and Thorsten Bach*
Lehrstuhl f€ur Organische Chemie I and Catalysis Research Center (CRC), Technische Universit€at M€unchen, Lichtenbergstrasse 4,
85747 Garching, Germany
S Supporting Information
b
Scheme 1. Pd(0)-Catalyzed Tandem Alkylation/Alkenylation
Reaction Mediated by Norbornene
ABSTRACT: A palladium-catalyzed direct 2-alkylation
reaction of free N-H indoles has been developed. This
reaction relies on a norbornene-mediated cascade CꢀH activ-
ation process at the indole ring, which features high regio-
selectivity and excellent functional group tolerance. The
reaction represents the first example for a generally applic-
able, direct CꢀH alkylation of indole at the 2-position.
ndole derivatives are important compounds that occur wide-
I
spread in nature and exhibit significant biological activity.1
Consequently, there is continuing interest in reactions that allow
for a regioselective indole functionalization.2 Among them, transi-
tion metal-catalyzed direct CꢀH functionalization reactions3 of
indole derivatives are very attractive. To date, the regioselective
direct CꢀH arylation4,5 and alkenylation6,7 at either the C2- or
C3-position of indole have been successfully achieved by using
palladium, rhodium, or copper catalysis. However, attempts to
perform direct CꢀH alkylation reactions of indoles have been
less successful so far. Although the 3-alkylation of indole can be
achieved by catalytic methods such as FriedelꢀCrafts alkylation,
allylic alkylation, and conjugate addition,2 a general protocol for
the regioselective direct CꢀH alkylation at the C2-position of free
N-H indoles has not yet been established.8 Given the limited
availability of synthetic routes toward 2-alkylindoles,9 a straight-
forward approach is highly demanded. Herein, we report in
preliminary form on the first direct 2-alkylation reaction of free
N-H indole derivatives by a norbornene-mediated cascade CꢀH
activation process under palladium catalysis.
Scheme 2. Postulated Catalytic Cycle for a Direct 2-Alkylation
of Indole by a Norbornene-Mediated Cascade CꢀH Activation
Our design was inspired by the alkylation/alkenylation reaction of
aryl halides via a Pd-catalyzed norbornene-mediated tandem
CꢀH activation (the Catellani reaction, Scheme 1).10,11 It was
reported that, in this reaction, reactive norbornene can insert into the
ArꢀPd bond of the previously formed ArPdX species to generate
intermediate Ithat then undergoes an intramolecular CꢀH activation
at the proximate aromatic position to form palladacycle II.10
Oxidative addition of an alkyl halide to the Pd(II) center of II
forms Pd(IV) intermediate III, which after reductive elimination
(formation of IV) and expulsion of norbornene generates an
alkylated ArPdX species V. Finally, a Heck-type reaction between
intermediate V and an acrylate generates the alkylation/alkenyla-
tion product.10 This norbornene-mediated process provides an
opportunity to activate the CꢀH bond at the neighboring
position of the initially generated ArꢀPd bond and thus enables
an arylꢀalkyl linkage at this position.
We envisioned that a similar mechanism might also operate in
a designed palladium-catalyzed cascade CꢀH activation process
to achieve the 2-alkylation of indole (Scheme 2): direct pallada-
tion of indole with a Pd(II) complex should occur preferentially
at the C3-position7 (the first CꢀH activation, step a), and the
generated 3-palladated indole may interact with norbornene to
undergo insertion and the second intramolecular CꢀH activ-
ation at the C2-position to form an indole-fused palladacycle
(step b); after oxidative addition with an alkyl halide RꢀX (step c),
reductive elimination (step d), and a norbornene expulsion step
(step e), a 2-alkyl-indol-3-yl palladium species may form, which
Received: June 14, 2011
Published: August 02, 2011
r
2011 American Chemical Society
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|

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can release the 2-alkyl indole product and regenerate the Pd(II)
species for the next catalytic cycle (step f). Different from the
previous oxidative-addition-triggered norbornene-mediated cascade
reactions,10,11 we hoped to initiate the catalytic cycle by a CꢀH
activation reaction and to complete it by a proto-depalladation. If
these postulated steps proceeded smoothly, a direct 2-alkylation
reaction of indole could be achieved by combining indole, an
alkyl halide, norbornene, and a base in one flask.
Table 1. Optimization Studies for the 2-Butylation of Indole
To test the described hypothesis, the reaction of indole with
butyl bromide was attempted in the presence of norbornene and
Pd(OAc)2 under different conditions (Table 1). The first runs
were conducted at room temperature to 50 °C employing
KOAc as a mild base11a in acetonitrile, N,N-dimethylformamide
(DMF), or N,N-dimethylacetamide (DMA) as the solvents
(entries 1ꢀ3). In all solvents tested the desired 2-butylindole
(1) could be detected, and the possible uncatalyzed alkylation
byproducts, N- and 3-butylindole, were not formed. Although
the desired 2-butylindole was only generated in low yields, these
results indicated that the postulated catalytic cycle could indeed
operate. Since DMA proved to be better suited than the other
two solvents, it was selected as the solvent in the following tests.
A screen of base showed that Cs2CO3 resulted in the formation
of N-butylindole (entry 4) as the major product, while K2CO3
turned out to be optimal (entry 5). Raising the reaction
temperature from rt to 50 °C promoted the reaction to afford
a reasonable yield after 14 h (entry 6). However, the use of freshly
distilled DMA instead of the previous reagent grade DMA
resulted in a decreased reaction rate (entry 7). Therefore, we
probed the effect of residual water on this reaction.
yielda (%)
entry solvent
base
T (°C) t (h) conv.a (%)
1
2
3
4
1
MeCN KOAc
DMF KOAc
DMAc KOAc
DMAc Cs2CO3
DMAc K2CO3
DMAc K2CO3
DMAd K2CO3
DMAe K2CO3
DMAf K2CO3
DMAg K2CO3
DMAh K2CO3
DMAg K2CO3
rtꢀ50 64b
rtꢀ50 64b
rtꢀ50 64b
29
38
37
47
46
90
56
83
88
84
47
93
97
90
>99
ꢀ
3
ꢀ
ꢀ
ꢀ
3
ꢀ
ꢀ
ꢀ
5
ꢀ
ꢀ
ꢀ
20
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
2
9
11
4
3
4
rt
rt
48
48
14
14
14
14
14
14
8
5
19
8
5
6
50
50
50
50
50
50
70
70
70
70
70
58 17
36
ꢀ
ꢀ
5
7
7
8
46 17
54 18
55 17
9
3
10
11
12
2
29
6
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
56 19
62 14
60 12
61 13
67l 11l
13i DMAg K2CO3
14j DMAg K2CO3
15k DMAg K2CO3
16k DMAg K2CO3
14
14
14
14
It was found that the presence of water accelerates the reaction,12
and a water concentration of [H2O] = 0.5 M was ideal in a range
of 0.1ꢀ1 M (entries 8ꢀ11). Elevated temperature (70 °C)
resulted in a faster reaction (entry 12). Finally, a brief screen of
Pd(II) sources showed that commonly used Pd(II) salts exhibit
no obvious difference in promoting this reaction (entries 13ꢀ15).
PdCl2(MeCN)2 was chosen as the preferred catalyst because
it provided higher conversion than the other catalysts and could
avoid undesired nucleophilic attack of the catalyst anion at an
alkyl bromide. Thus, DMA with H2O (0.5 M) as the solvent,
K2CO3 as the base, a reaction temperature of 70 °C, and a reac-
tion time of 14 h were selected as the optimal conditions. A
synthetic-scale run (1 mmol) under these conditions afforded
isolated product 1 in 67% yield (entry 16). It is noteworthy that
in most of the reactions, 2,3-dibutylindole (2) was observed as
the byproduct due to overalkylation. Control experiments
showed that no trace of 2-butylindole or 2,3-dibutylindole could
be detected in a reaction without either norbornene or a Pd(II)
source, supporting the catalytic cycle proposed in Scheme 2.
Having achieved the desired direct 2-alkylation of indole, we
started to explore the substrate scope (Table 2). It was found that
the present reaction is compatible with a variety of simple and
functionalized alkyl bromides as the alkylation reagent. Gener-
ally, the reactions proceeded smoothly at 70 °C, and the yield of
2-alkylated indole varied from 40% to 82% according to the nature
of the alkyl bromide employed. In many cases 2,3-dialkylindole
was generated as the byproduct (in ca. 10% yield, entries 1, 3, 9,
10 and 11), but for more sterically hindered alkyl bromides, little
or no 2,3-dialkylindole was observed (e.g., entries 2, 4, and 7).
The reaction delivered an array of 2-substituted indoles with
various functional groups, such as tetrahydropyran (entry 5), silyl
ether (entries 4 and 6), acetal (entries 7 and 8), carboxylic ester
(entries 9 and 10), nitrile (entry 11), and tosylamide (entry 12).
a Determined by 1H NMR using an internal standard. b Reaction was run
c
under rt for 13 h, and then at 50 °C for 51 h. Reagent grade DMA
without purification. d Freshly distilled DMA. Freshly distilled DMA
e
with 0.1 M H2O. Freshly distilled DMA with 0.2 M H2O. g Freshly
f
distilled DMA with 0.5 M H2O. h Freshly distilled DMA with 1 M H2O.
i Use of 2 equiv BuBr. Pd(OCOCF3)2 (10 mol %) as the catalyst,
j
2 equiv BuBr. k PdCl2(MeCN)2 (10 mol %) as the catalyst, 2 equiv BuBr.
l Yield of isolated product after column chromatography.
The reaction was sensitive to steric hindrance of the alkyl group;
for the reaction employing an alkyl bromide with a secondary
carbon atom adjacent to the bromide methylene group, higher
temperature and prolonged reaction times were required (entries 2
and 7); secondary alkyl halides did not react with indole under
the optimized conditions.13
The scope of the indole component was explored with different
alkyl bromides (Scheme 3). Indoles with electron-donating and -
withdrawing substituents at the C5, C6, or C7 position partici-
pated in the C2-alkylation reaction smoothly. Interestingly, electron-
deficient indoles reacted well to give good yields of 2-alkylindole
products when a weaker base, KHCO3 or K2HPO4, was employed
(8eꢀi), while they reacted poorly under the standard conditions
using K2CO3 as the base (due to the generation of undesired
N-alkylated indole as byproduct). Halogen-substituted indoles
were proved to be suitable substrates, and the successful synth-
esis of halogen-substituted 2-alkylindoles 8dꢀf enabled further
access to more complex compounds by cross-coupling reactions.
It is noteworthy that when 5-iodoindole (7j) was employed as
the substrate, a 2,50-bisindole byproduct 8j0 was obtained in
8% yield in addition to the expected 2-alkylation product 8j
(Scheme 4a). This observation indicates that an arylꢀiodine
bond is reactive toward the palladacycle intermediate,10 which is
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Table 2. Alkylation of Indole at the C2-Position with
Scheme 3. C2-Alkylation of Substituted Indole Derivativesa
Different Alkyl Bromides
a Yield of isolated product after column chromatography. In parentheses
the yield of the corresponding 2,3-dialkylated indole derivative (80) is
given if formed in significant amounts. b 23% of indole 7b was recovered.
The yield based on recovered starting material was 78%. c KHCO3 (3equiv)
was used as the base instead of K2CO3. d K2HPO4 (3 equiv) was used as
the base instead of K2CO3.
Scheme 4. Reactions of Substrates with an ArylꢀIodine Bond
a Method A: 1 equiv indole and 2 equiv alkyl bromide; method B: 2 equiv
indole and 1 equiv alkyl bromide. b Yield of isolated product after column
chromatography. In parentheses the yield of the corresponding 2,3-
dialkylated indole derivative (60) is given if formed in significant amounts.
c Pd(OCOCF3)2 (10 mol %) was used as the catalyst. d Intramolecular
cyclization byproduct of 6i, 8,9-dihydropyrido[1,2-a]indol-6(7H)-one
(6i00), was obtained in 10% yield. e 50% of indole was recovered.
The yield based on recovered starting material was 85%. TBS = tert-
butyldimethylsilyl, THP = tetrahydropyran-2-yl, Ts = 4-toluenesulfonyl.
alkyl bromide 5m bearing a trisubstituted olefin moiety could
participate in the 2-alkylation reaction (Scheme 5), albeit with
diminished reactivity. However, the 2-alkylation reaction was
completely inhibited when terminal-olefin-containing bromides
were used.15 We suppose that a terminal olefin reacts in com-
petition with norbornene with the indole-palladium species to
block the norbornene-mediated catalytic cycle, while a more
hindered trisubstituted olefin does not, and thus the 2-alkylation
reaction proceeded in the normal way.
In summary, we have developed a straightforward and synthe-
tically useful method for the regioselective alkylation of free N-H
indoles at the C2-position. This reaction is compatible with a
wide range of simple and functionalized primary alkyl bromides,
as well as various substituents on indole with different electronic
natures. The present method highlights a facile one-step
further supported by the generation of 2-phenylindole (9) from
indole and iodobenzene under the standard C2-alkylation con-
ditions (Scheme 4b). Therefore, the scope of the electrophilic
component in the present reaction can be extended to an aryl
iodide,14 which serves as a complement to the well-established
Pd(0)-catalyzed indole C2-arylation reaction.4,5
Since the 2-alkylation reaction relies on the interaction of the
palladated indole species and norbornene, it was interesting to
investigate whether the reaction could proceed normally when an
olefin-containing alkyl bromide is employed. It was found that
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Scheme 5. Reaction of Indole 7f with Olefin-Containing
Alkyl Bromide 5m
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transformation from easily available indole and alkyl components
to structurally diverse 2-alkylindole derivatives, which are not readily
available by conventional synthetic methods. Further studies of
this reaction (mechanism and synthetic application) are underway.
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S
Supporting Information. Experimental procedures, ana-
b
lytical data for all new compounds, and NMR spectra for the
products. This material is available free of charge via the Internet
at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
thorsten.bach@ch.tum.de
’ ACKNOWLEDGMENT
L.J. acknowledges support by the Alexander von Humboldt
foundation.
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norbornene-mediated cascade CꢀH activation reactions, see refs 11b
and 11h.
(13) The reaction between indole and 2-iodopropane was also
attempted under the optimized conditions (50ꢀ90 °C), but no 2-alky-
lation product was observed.
(14) A control experiment showed that without norbornene, the
reaction between indole and iodobenzene did not occur under otherwise
identical conditions, which excludes the Pd(0)-catalyzed C2-arylation
mechanism in this reaction.
(15) The reactions of indole with 5-bromo-1-pentene and 11-bromo-
1-undecene were conducted under the optimized conditions. However,
no 2-alkylation product was observed.
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