Palladium-catalyzed C3-benzylation of indoles

Article abstract of DOI:10.1021/ja2095393

A general method for regioselective C3-benzylation of indoles has been developed. Various 3-substituted indoles and benzyl methyl carbonates with different electronic properties react under mild conditions to afford a diverse range of 3-benzylindolenine products in good yields.

Full text of DOI:10.1021/ja2095393

Communication
pubs.acs.org/JACS
Palladium-Catalyzed C3-Benzylation of Indoles
Ye Zhu and Viresh H. Rawal*
Department of Chemistry, University of Chicago, 5735 South Ellis Avenue, Chicago, Illinois 60637, United States
S
* Supporting Information
a
Table 1. Ligand Screening
ABSTRACT: A general method for regioselective C3-
benzylation of indoles has been developed. Various 3-
substituted indoles and benzyl methyl carbonates with
different electronic properties react under mild conditions
to afford a diverse range of 3-benzylindolenine products in
good yields.
he prevalence of the indole nucleus in natural products,
pharmaceutical ingredients, and organic materials has
T
spurred considerable effort on the development of efficient and
selective functionalizations of this primary heterocycle.1 In the
past few decades, Pd-catalyzed reactions of indoles have
become powerful tools in the arsenal of synthetic chemists.1a
While much attention has been focused on Pd-catalyzed indole
allylation reactions,2 the corresponding benzylation reaction of
3-substituted indoles3 has not been reported. Such a
fundamental transformation would allow access to 3-
benzylindolenines bearing a newly formed quaternary center,4
which constitute the core structures of many biologically active
natural products and synthetic compounds.5 In view of the
centrality of the benzyl unit, there have been several recent
reports on synthetic methods6−8 involving π-benzyl-Pd
intermediates,9 although the Pd-catalyzed benzylation of
nonstabilized nucleophiles using simple benzyl alcohol
derivatives remains undeveloped. We report here a general,
mild method for the Pd-catalyzed C3-benzylation of 3-
substituted and 2,3-disubstituted indoles using benzyl carbo-
nates (Scheme 1).
a
Reactions were carried out using 1.5 equiv of 2a, 10 mol %
[Pd(allyl)(cod)]BF4, 11 mol % ligand, and 1.2 equiv of N,O-
b
c
bis(trimethylsilyl)acetamide (BSA). Isolated yields. 22 mol % ligand.
d
e
f
1
Yield was determined by H NMR analysis. 3a was not detected. 5
g
mol % catalyst, 4.5 h reaction time. 1.5 h reaction time.
revealed that the yield diminished when either electron-rich
(entries 9 and 10) or electron-deficient (entries 11 and 12)
phosphine ligands were utilized. DPEphos was found to be
optimal in providing the right balance between the rates of
different steps in the catalytic cycle, resulting in the highest
overall reaction rate.
Scheme 1. Pd-Catalyzed Indole Benzylation
Further optimization of the reaction conditions was aimed at
lowering the catalyst loading and the reaction temperature
(Table 2). Benzyl acetate and benzyl alcohol afford the product
in low yields (entries 1 and 2), and lowering the catalyst
loading to 5 mol % slows the reaction considerably (entry 3).
Examination of additives led to the observation that
triethylborane (BEt3) significantly promotes the reaction
(entries 4 and 5).2b Indeed, in the presence of BEt3, a 2.5
mmol scale reaction proceeds at 40 °C, giving the product in
83% yield (entry 6). To the best of our knowledge, this result
represents the first example of a Pd-catalyzed benzylation
reaction using a benzyl carbonate carried out below 60 °C. The
As anticipated, the benzylation of indoles proved more
challenging than the corresponding allylation. Reaction
conditions that are effective for allylation of 2,3-dimethylindole
(1a) gave little or no benzylation product when benzyl methyl
carbonate (2a) was used, even at 80 °C (Table 1, entries 1−5).
It was observed that ligands bearing large bite angles10 such as
DPPF, Xantphos, and in particular DPEphos, are quite effective
for the benzylation reaction (entries 6−8). Importantly, the
reaction is completely C3-selective, with no N-benzyl product
being formed. Evidently, the highly polarizable π-benzyl-Pd
intermediate preferentially reacts at the carbon of the ambident
indole. Evaluation of a series of synthetic DPEphos-type ligands
Received: October 10, 2011
Published: December 1, 2011
© 2011 American Chemical Society
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Journal of the American Chemical Society
Communication
a
a
Table 2. Reaction Optimization
Table 3. Benzylation of 2,3-Disubstituted Indoles
a
Reactions were carried out using 0.50 mmol of 1a, 1.5 equiv of 2, 5
mol % [Pd(allyl)(cod)]BF4, 5.5 mol % DPEphos, and 1.2 equiv of
b
c
d
BSA. Isolated yields. 10 mol % catalyst. Yield was determined by 1H
e
NMR analysis. Reaction was carried out using 10 mol % Pd(PPh3)4 in
f
g
h
THF. 3a was not detected. COD = 1,5-cyclooctadiene. 2.5 mmol
i
scale reaction. 24 h reaction time.
benzylation reaction also proceeds with substoichiometric BEt3,
albeit in lower yield (entry 7).11
The optimized conditions (1.2 equiv of 2, 5 mol % catalyst,
1.2 equiv of BSA, 1.1 equiv of BEt3, 50 °C) were found to be
applicable to a diverse range of 2,3-disubstituted indoles and
substituted benzyl methyl carbonates (Table 3). Both electron-
rich and electron-deficient substituted benzyl carbonates were
well-tolerated (entries 1−4). Substitutions on the indole
modulated the reactivity, with the indole nucleophilicity being
enhanced by a methoxy group and diminished by a chloro
substituent (entries 5 and 6). Moreover, both carba- and
heterocycle-fused indoles proved to be excellent substrates. The
reactions between 1,2,3,4-tetrahydrocarbazole and various
benzyl carbonates with different electronic properties afforded
high yields (entries 7−11), with naphthylmethyl carbonate
reacting faster than 2a (entry 12). Notably, both tetrahydro-β-
carboline and tetrahydro-γ-carboline derivatives were trans-
formed to the respective heterocycle-fused benzylindolenines
(entries 13 and 14).
The benzylation reactions of 3-substituted indoles are more
challenging because the 3-alkyl-3-benzylindolenine products are
prone to rearrangement to 3-alkyl-2-benzylindoles as a result of
the high migratory aptitude of the benzyl group. Jackson
synthesized 3o in only 4% yield via 3-methylindolylmagnesium
iodide, and the preparation of 3-(p-methoxybenzyl)-3-methyl-
indolenine failed completely.12 In contrast, 3-methylindole (1b)
nicely underwent the Pd-catalyzed benzylation reaction,
furnishing the desired product 3o in 88% yield. The unwanted
rearrangement was completely avoided under these reaction
conditions (Table 4, entry 1). In addition, 1b reacted smoothly
with substituted benzyl carbonates 2b and 2c. Although the 3-
benzyl-3-methylindolenine products were in equilibrium with
the corresponding cyclic trimers (1,3,5-triazinanes),13 they
could be transformed cleanly to indoline derivative 3p by
reduction and 2-benzylindole derivative 3q via acid-catalyzed
rearrangement, respectively (entries 2 and 3). The intra-
molecular trapping of the indolenine CN bond by a pendant
nucleophile is of particular interest since the resulting
a
Reactions were carried out using 0.50 mmol of 1, 1.2 equiv of 2, 5
mol % [Pd(allyl)(cod)]BF4, 5.5 mol % DPEphos, 1.2 equiv of BSA,
b
c
and 1.1 equiv of BEt3 at 50 °C for 18 h. Isolated yields. 8 h reaction
time. Np = naphthyl. Tr = triphenylmethyl.
d
heterocycle-fused indoline is found as a core structure of
many natural products. N-tosyltryptamine (1c) and tryptophol
(1d) participated nicely in the reaction, giving the correspond-
ing cis-fused pyrrolo- and furanoindolines in high yields
(entries 4 and 5). The fact that a sulfonamide and an alcohol
were tolerated reflects the high chemoselectivity of the reaction.
The reaction between indole (1e) and 1.0 equiv of 2a afforded
3-benzylindole (3t) in 69% yield along with a small amount of
3,3-dibenzylindolenine (3u) (entry 6). The use of excess 2a
afforded 3u as the sole product in high yield (entry 7). Finally,
in contrast to 1-phenylethyl methyl carbonate (2d) (entry 8),
1-(naphthalen-2-yl)ethyl methyl carbonate (2e) showed
excellent reactivity (entries 9 and 10).
To probe the reactivity differences between allyl, naph-
thylmethyl, and benzyl carbonates, a series of competition
studies was carried out (Scheme 2). The Pd-catalyzed reactions
of 1f with mixtures of 4 and 2a or 4 and 2f produced allylation
product 5 exclusively (eqs 1 and 2). When 1f was subjected to a
mixture of equal amounts of 2a and 2f, product 3l was isolated
predominantly, together with a <2% yield of 3g (eq 3). The
dramatic decrease in reactivity for Pd-catalyzed indole
alkylation reactions in going from 4 to 2f to 2a correlates
with the increased disruption of π-conjugation or aromaticity in
the formation of the corresponding η3-palladium complexes. In
comparison with many reports of Pd-catalyzed benzylation
reactions employing extended π-systems, the indole benzylation
reaction described above represents a rare example of Pd-
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Journal of the American Chemical Society
Communication
a
a
Table 4. Benzylation of Indole and 3-Substituted Indoles
Scheme 3. Proposed Reaction Mechanism
a
L = ligand; TMS = trimethylsilyl.
cation, and the resulting amide anion (B) subsequently
deprotonates indole 1 to generate the indolyl anion (C).
In conclusion, we have developed the first general method
for the regioselective C3-benzylation of 3-substituted indoles.
This Pd-catalyzed transformation is effective for indoles and
benzyl carbonates possessing sterically and electronically
diverse substituents and affords the C3-benzyl indolenine
products in high yields. The mild reaction conditions provide
future opportunities to apply this methodology to complex
molecules and develop an enantioselective variant of this
reaction.6g,17
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and characterization data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
a
b
The reaction conditions were the same as in Table 3. Isolated yields.
c
Reduction of the indolenine product using NaBH4 in AcOH yielded
d
3p. Treatment of the indolenine product with CF3COOH yielded 3q.
e
f
g
Ts = p-toluenesulfonyl. 2.2 equiv of BSA was used. The reaction was
h
i
AUTHOR INFORMATION
quenched with K2CO3 in MeOH. 1.0 equiv of 2 was used. The
product was isolated as a 5:1 mixture of 3t and 1e. The yield of 3t was
determined by 1H NMR analysis. 3u was isolated in 15% yield as a side
■
Corresponding Author
vrawal@uchicago.edu
j
k
product. 2.2 equiv of 2a was used. 3v was not detected.
a
ACKNOWLEDGMENTS
■
Scheme 2. Competition Studies
This work was funded by the National Institutes of Health
(P50-GM086145).
REFERENCES
■
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The reaction conditions were the same as in Table 3.
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Journal of the American Chemical Society
Communication
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