Efficient palladium-catalyzed N-arylation of indoles

Article abstract of DOI:10.1021/ol005728z

(Matrix presented) The N-arylation of indoles, including a variety of substituted ones, has been carried out using bulky, electron-rich phosphines as the supporting ligand in combination with Pd₂(dba)₃. Using this catalyst system, th

Full text of DOI:10.1021/ol005728z

ORGANIC
LETTERS
2000
Vol. 2, No. 10
1403-1406
Efficient Palladium-Catalyzed N-Arylation
of Indoles
David W. Old,† Michele C. Harris, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received February 25, 2000
ABSTRACT
The N-arylation of indoles, including a variety of substituted ones, has been carried out using bulky, electron-rich phosphines as the supporting
ligand in combination with Pd2(dba)3. Using this catalyst system, the efficient coupling of indole and a variety of substituted indoles with aryl
iodides, bromides, chlorides, and triflates can be achieved.
The N-arylindole moiety is a structural element present in
many biologically active and pharmaceutically important
compounds. N-Arylindoles are of interest as angiotensin II-1
antagonists,1 MT1 melatonin receptor partial agonists,2 an-
tipsychotic agents,3 and synthetic intermediates used in the
preparation of other biologically active heterocyclic agents.4
Of the many methods for the synthesis of N-arylindoles,
the Fisher indole synthesis is the best known and most widely
used.5,6 Ullmann-type coupling methodology, involving the
combination of an indole with an aryl halide in the presence
of base and a copper catalyst at high temperatures, is an
important alternative.7 Methods that operate under milder
conditions and utilize aryl bismuth8 and aryl lead9 reagents
have been developed. Finally, the synthesis of N-arylindoles
may also be achieved by nucleophilic aromatic substitution
in instances in which the aryl halides are activated by the
presence of one or more electron-withdrawing groups.10-12
While all of these methods are useful in its own right, each
suffers from one or more limitations including a lack of
generality, the use stoichiometric quantities of toxic reagents,
or the need to employ harsh reaction conditions.
The palladium-catalyzed amination of aryl halides and
sulfonates has been the focus of intense research in recent
years, particularly from our own laboratories13,14 and those
of Hartwig15 who first applied this methodology to the
arylation of indoles using Pd/DPPF and Pd/BINAP catalyst
systems.16 Using these catalysts, Hartwig and co-workers
were able to efficiently combine indole with aryl bromides
that had electron-withdrawing substituents in the para posi-
tion. Electronically neutral aryl bromides required the use
of long reaction times and high temperatures and proceeded
in moderate yield. No examples of the reactions of ortho-
† Present address: Allergan Inc., Irvine, CA 92612.
(1) Stabler, S. R.; Jahangir Synth. Commun. 1994, 24, 123.
(2) Spadoni, G.; Balsamini, C.; Bedini, A.; Diamantini, G.; Giancomo,
B. D.; Tontini, A.; Tarzia, G. J. Med. Chem. 1998, 41, 3624.
(3) Andersen, K.; Liljefors, T.; Hyttel, J.; Perregaard, J. J. Med. Chem.
1996, 39, 3723.
(4) Sarges, R.; Howard, H. R.; Koe, B. K.; Weissman, A. J. Med. Chem.
1989, 32, 437.
(5) Sundberg, R. J. Indoles; Academic Press: San Diego, 1996.
(6) Wagaw, S.; Yang, B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999,
121, 10251.
(7) Pozharskii, A. F.; Martsokha, B. K.; Simonov, A. M. J. Gen. Chem.
USSR 1963, 33, 994.
(8) Barton, D. H. R.; Finet, J.-P.; Khamsi, J. Tetrahedron Lett. 1988,
29, 1115.
(10) Smith, W. J., III; Sawyer, J. S. Tetrahedron Lett. 1996, 37, 299.
(11) Smith, W. J., III; Sawyer, J. S. Heterocycles 1999, 51, 157.
(12) Maiorana, S.; Baldoli, C.; Buttero, P. D.; Ciolo, M. D.; Papagni,
A. Synthesis 1998, 5, 735.
(13) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125.
(14) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(15) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
(16) (a) Mann, G.; Hartwig, J. F.; Driver, M. S.; Ferna´ndez-Rivas, C. J.
Am. Chem. Soc. 1998, 120, 827. (b) Åhman, J.; Buchwald, S. L. Unpublished
results.
(9) Lo´pez-Alvarado, P.; Avendan˜o, C.; Mene´ndez, J. C. J. Org. Chem.
1995, 60, 5678.
10.1021/ol005728z CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/19/2000

substituted aryl bromides were reported. Recently, Hartwig
reported several examples of the use of the Tosoh system
(Pd/P(t-Bu)3) for the N-arylation of indoles. This protocol
shortens the required reaction time for the reactions of
electronically neutral aryl bromides as well as decreasing
the temperature for the process to 100 °C.17 While one
example of the reaction of 3-substituted indole, skatole, with
a simple ortho-substituted aryl bromide (o-bromotoluene) was
described, reactions of similar substrates with “simple
indoles” were reported to give mixtures of three products
via N-arylation, C-arylation, and a combination of the two.
No examples of reactions of polysubstituted indoles or 2-
or 7-substituted indoles were reported. Herein, we describe
our progress in the palladium-catalyzed N-arylation of indoles
which overcome a number of the problems associated with
the techniques described above. Of particular significance
is that through the use of an appropriate set of ligands we
are able to successfully couple indoles which are unsubsti-
tuted in the 3-position with ortho-substituted aryl halide and
triflate substrates, and to utilize a variety of 2-, 7-, and
polysubstituted indoles to provide high yields of the desired
product (Scheme 1).
Table 1. Pd-Catalyzed N-Arylation of Indolea
Scheme 1
We have recently reported that the use of novel biaryl-
(dialkyl)phosphines as supporting ligands provides an active
Pd(0) catalyst which is exceptional in the coupling of
arylboronic acids (Suzuki couplings), ketone enolates, and
amines with aryl bromides and chlorides.18 The wide scope
of these catalysts led us to investigate transformations
involving less-reactive nitrogen nucleophiles, such as indoles
(vide infra).
We were pleased to find that indole was effectively
coupled with a variety of aryl chlorides, bromides, iodides,
and triflates to afford the desired coupling products in good
yields (Table 1). The examples of the latter are the first to
be described. As previously noted above, often a mixture of
three products were produced; C-arylated indoles and N,C-
doubly arylated indoles were formed in addition to the
desired N-arylindole. We found that we were able to
minimize the formation of the side products by choosing an
appropriate ligand (Figure 1).
Our studies showed that NaOt-Bu was the most effective
base, while the use of other bases such as NaH, Et3N, and
Cs2CO3 was less successful. In the instances where the
starting materials were incompatible with NaOt-Bu (including
(17) Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy, K. H.;
Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(18) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722.
triflates), we found K3PO4 to be a useful alternative (Table
1, entries 12-15 and 17). Pd2(dba)3 was found to be the
best source of palladium, while Pd(OAc)2 was ineffective
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Org. Lett., Vol. 2, No. 10, 2000

Table 2. Coupling of Substituted Indoles with Aryl Halides and Triflates
or less efficient in all cases. Toluene was found to be the
optimal solvent, although in a few cases the use of dioxane
was also effective. All of the reactions described herein were
performed in test tubes, under argon, and all reagents were
handled and weighed in the air.19a
Our initial work employed P,N-ligand 1.19b In all of the
reactions involving 1, 2.5-5 mol % Pd is required. This
restriction, combined with our experience that Pd/1 is not
effective in several cases (e.g., ortho-substituted aryl halides),
prompted us to search for more reactive catalytic systems.
Accordingly, several analogues of 1 were prepared and
screened for reactivity in the N-arylation of indoles. Changing
both the alkyl group on phosphorus and the 2′ aryl substituent
proved beneficial. We found that the use of Pd/2, where the
dimethylamino is replaced with an isopropyl group, and the
dicyclohexylphosphine moiety is replaced with a di-tert-
butylphosphine group, was more efficient than the Pd/1
combination for reactions of aryl bromides and chlorides.
These reactions required less catalyst and lower reaction
temperatures than the parent system, while giving comparable
yields. Coupling reactions of ortho-substituted aryl halides
and triflates using the Pd/1 or 2 systems, however, were
(19) (a) The complete experimental details are available in the Supporting
Information. (b) Available from Strem Chemicals, Inc.
Org. Lett., Vol. 2, No. 10, 2000
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After much experimentation, a catalyst employing ligand 4
was found to be most efficient at minimizing, although not
eliminating, the formation of undesired products with
2-arylindoles (Table 2, entries 1-3) and 7-alkylindoles
(Table 2, entries 6 and 7). Unfortunately, conditions employ-
ing milder bases (e.g., K3PO4, Cs2CO3) were inefficient in
reactions of 2-phenylindole with methyl 4-bromobenzoate.
Moreover, an attempt to couple 7-ethylindole with 2-bromo-
p-xylene produced the 3-arylated indole as the exclusive
product in 90% yield.
For the coupling of 2-methylindole, commercially avail-
able 519b is an effective ligand (Table 2, entries 4 and 5).
Even under the best conditions, however, a large amount of
C-arylated and overarylated products were obtained; only
moderate yields of the desired product were obtained. In
many cases when multiple indole products are formed, it
was often difficult to cleanly separate the products by column
chromatography.16a
Figure 1.
For reactions of 2,3-dimethylindole, where competing
arylation at the 3-position is not possible, we found that
ligand 6, also commercially available,19b is an effective ligand
(Table 2, entries 14 and 15). As the substrate’s nitrogen
becomes increasingly hindered, as in the case of 2,3,7-
trimethylindole, the reaction becomes slow; decomposition
of the indole under the reaction conditions led to low yields
of the desired product (average <40%).
In conclusion, the coupling of a wide variety of aryl halides
and triflates with a wide range of indoles is described. With
the proper choice of ligands, a variety of N-arylindoles may
be obtained. Work is underway to ameliorate difficulties
which remain, especially in finding catalysts that efficiently
process hindered substrates.
sluggish. After much experimentation, we found use of 3
gave a more efficient system, although longer reaction times
and more catalyst were required (Table 1, entries 11 and
14).
While the use of 2 provided a more active catalyst in
combining indole with aryl chlorides and bromides, it was
ineffective in the coupling reactions with aryl iodides or
triflates. For aryl iodides and triflates, the use of 1 was most
effective. The reactions of aryl iodides and sulfonates using
the Pd/2 system may be inefficient due to formation of bis-
indolyl Pd (II) complexes.20 A ligand such as 1, which
functions as either a monodentate or bidentate ligand, may
inhibit the formation of such a species.
Given our success in the arylation of indole itself, we
turned our attention to substituted indoles. We found that 3-
and 5-substituted indoles show similar reactivity to indole
itself and that catalysts consisting of Pd and ligands 1-3
were efficient (Table 2, entries 8-12, 16, and 17). In several
instances issues of functional group compatibility necessitated
the use of K3PO4 as the base.
Acknowledgment. We are grateful to the National
Institutes of Health (GM58160) and the National Cancer
Institute (Training Grant NCI CI T32CA09112) for financial
support. We also thank Pfizer, Merck, and Novartis for
additional unrestricted support.
We wished to expand the method to include a wider variety
of substituted indoles. Attempts to employ catalysts based
on 1-3 to N-arylate 2- or 7-substituted indoles produced a
large amount of the 3-arylated and diarylated indole products.
Supporting Information Available: Complete experi-
mental procedures and spectral data for ligands 1-6 and the
compounds listed in Tables 1 and 2. This material is available
free of charge via the Internet at http://pubs.acs.org.
(20) Paul, F.; Patt, J.; Hartwig, J. F. Organometallics 1995, 14, 3030.
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