Room temperature and phosphine free palladium catalyzed direct C-2 arylation of indoles

Article abstract of DOI:10.1021/ja710731a

We report the first room-temperature direct C-2 arylation of indoles with iodoarenes by using a highly electrophilic palladium catalyst generated in situ from Pd(OAc)2 and a silver carboxylate. These mild conditions permit a broad set of functionalities both in the indole and in the aryl iodide units such as free alcohols, phenols, aldehydes, bromides, or nitriles, thus allowing the synthesis of a variety of novel compounds in excellent yields. Copyright

Full text of DOI:10.1021/ja710731a

Published on Web 02/16/2008
Room Temperature and Phosphine Free Palladium Catalyzed Direct C-2
Arylation of Indoles
Nathalie Lebrasseur and Igor Larrosa*
School of Biological and Chemical Sciences, Queen Mary, UniVersity of London, Mile End Road,
London E1 4NS, United Kingdom
Received November 30, 2007; E-mail: i.larrosa@qmul.ac.uk
Scheme 1. Working Hypothesis: Highly Activated Palladium(II)
Direct C-H functionalization has emerged over the past few
Species for C-H Arylation
years as an attractive strategy to enhance molecular complexity.1
However, in spite of major advances in this field, the important
aryl-aryl bond formation is still almost exclusively carried out by
traditional cross-coupling reactions, which require a differential
prefunctionalization of both aryl coupling partners.2 Indeed, the few
currently available methods for direct C-H arylation suffer
from the need for drastic conditions, elevated temperatures (125 to
150 °C), and long reaction times (24 to 48 h) which significantly
limit their scope and functional group tolerance. Recently an elegant
methodology for the C-2 arylation of indoles based on a PdII/IV
cycle that allows the use of lower temperatures (room temperature
Table 1. Optimization of the Room Temperature Coupling
between N-Methylindole (1) and PhI (2)a
to 80 °C) has been reported.3 However, this oxidative approach
suffers the limitation of requiring noneasily accessible iodine(III)
arylating reagents. Therefore, a milder methodology able to carry
out the direct arylation at room temperature with the extensive pool
entry
base
acid
conv (%)b
of commercially available aryl iodides would be highly desirable.
Since indoles are ubiquitous among biologically active natural
products and pharmaceutical compounds, their arylation reactions
are of considerable importance.3-5 The limiting step in the arylation
of indoles in a Pd0/II catalytic cycle is believed to be the electrophilic
palladation of the electron-rich palladium(II) species I (path a,
Scheme 1).4g Silver(I) salts are commonly employed to abstract
halide anions from transition metal complexes thus rendering them
more electrophilic.6 Therefore, we reasoned that by using an
appropriate silver(I) salt to remove the iodide from the palladium-
(II) complex I, a cationic palladium species (IV), which would be
more electrophilic toward the indole unit (Ar′-H), could be
generated, thus increasing the rate of the palladation step (path b).
Initially, silver-mediated ligand metathesis of I would afford
complex III. The crucial choice of a relatively poorly coordinating
carboxylate as the counterion should allow the dissociation to the
cationic species IV in catalytically useful amounts.7 At the same
time, the carboxylate would act as a base in the electrophilic
palladation step.8 We report here a methodology based on this
reasoning which allows the direct arylation of indoles at room
temperature under very mild conditions.
As a starting point, we analyzed the coupling between N-
methylindole (1) and iodobenzene (2, Table 1). In order to easily
test several silver(I) carboxylates, a procedure to generate them in
situ from Ag2O (0.75 equiv) and the corresponding carboxylic acid
(1.5 equiv) was employed (compare entries 2 and 4). The substitu-
tion on the carboxylic acid had a dramatic effect on the efficiency
of the reaction, showing an inverse correlation with its pKa (entries
5-9). ortho-Nitrobenzoic acid was found to be the best carboxylic
acid, affording the C-2 arylation adduct 3 with complete conversion
and a remarkable 92% isolated yield after 7 h at room temperature
(entry 9).
1
2
3
4
5
6
7
8
9c
K2CO3
AgOAc
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
Ag2O
none
none
none
<5
53
12
49
13
51
95
81
>99
CH3CO2H
o-MeO-C6H4-CO2H
o-Me-C6H4-CO2H
o-Ph-C6H4-CO2H
p-O2N-C6H4-CO2H
o-O2N-C6H4-CO2H
a
Unless otherwise noted, all reactions were carried out using 5 mol %
Pd(OAc)2, 1.5 equiv (entries 1-2) or 0.75 equiv (entries 3-9) of base, 1.5
equiv of acid, 1.0 equiv of 1 and 2.0 equiv of 2 in a 0.5 M solution, for 18
h at 25 °C. b Conversion measured by GC using an internal standard. c The
reaction was carried for 7 h.
yields are obtained in the reaction of N-methylindole with several
aryl iodides. Both, electron-withdrawing (entries 2 and 3) and
electron-donating substitutents (entries 4-9) are suitable. The
reaction conditions are compatible with nitriles, ethers and, remark-
ably, even with bromides and unprotected benzylic alcohols (entries
2 and 7) that could be easily substituted or oxidized under harsher
conditions. Even the more acidic phenol group (entry 4) was also
found to be compatible with the reaction conditions. It is noteworthy
that most of the substrates afford quantitative conversion to products
greatly facilitating the purification process. In addition, no C-3
arylation was observed in any of the examples.9 As expected, the
more hindered ortho- substituted aryl iodides react considerably
more slowly than the meta- and para- counterparts and afford
slightly lower yields (entries 8-10). Notably, the highly reactive
2-(o-methoxyphenyl)-N-methylindole is obtained in moderate yields
under these mild conditions (entry 9).
We next examined the substitution in the heteroarene moiety
(see Table 3). Gratifyingly, the methyl group in the nitrogen of the
indole can be replaced for a benzyl group without affecting the
yield (entry 1). Interestingly, free N-H-indoles are less reactive
We next examined the scope of the reaction with a variety of
differently substituted aryl iodides. As shown in Table 2, excellent
9
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C O M M U N I C A T I O N S
was found.12 This would be explained in terms of an easier
formation of cationic species IV.13
Table 2. Scope of C-2 Arylation of N-Methylindole
In conclusion, we have developed a new methodology that allows
for the first time the direct C-2 arylation of indoles with aryl iodides
at room temperature without the presence of phosphines or other
ligands. These mild conditions permit a broad set of functionalities
both in the indole and in the aryl iodide units, and a variety of
novel compounds have been prepared in excellent yields. Mecha-
nistic studies toward the understanding of the catalytic cycle are
under way.
Acknowledgment. We are grateful to Prof. Anthony G. M.
Barrett for his support. We also gratefully acknowledge the EPSRC
National Mass Spectrometry Service, University of Wales Swansea.
Supporting Information Available: Detailed experimental pro-
cedures and characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
a
b
The reaction was carried out for 7 h. The reaction was carried out
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c
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38 h.
Table 3. C-2 Arylation of Functionalized Indoles
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a
b
The reaction was carried out at 50 °C for 38 h. The reaction was
carried out using 10 mol % Pd(OAc)2.
under this system (entry 2) requiring 38 h at 50 °C to afford 62%
of the C-2 arylated product. As for the substitution on the benzene
ring of the indole unit, it can incorporate a wide array of functional
groups such as nitrile, bromide, aldehyde, and benzylic alcohol
(entries 3-6).
Mechanistically both a Pd0/II and a PdII/IV catalytic cycle are
conceivable. A PdII/IV cycle has been suggested in a related C-H
arylation system using silver acetate in acetic or trifluoroacetic acid
as the solvent but at much higher temperatures (120 to 140 °C).10
Otherwise, removal of iodide from a palladium(II) species by Ag2O
has also been suggested in other cross-coupling processes.11 In our
system, the mechanistic rationale must account for the important
role of the base. Indeed, the counterintuitive inverse correlation
between the pKa of the conjugated acid and catalytic activity is
consistent with the hypothesis suggested in Scheme 1. Furthermore,
an important solvent specificity for the highly coordinating DMF
JA710731A
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