Pd-catalyzed tandem C-N/C-C coupling of gem-dihalovinyl systems: A modular synthesis of 2-substituted indoles

Article abstract of DOI:10.1021/ol051286l

(Chemical Equation Presented) 2-Substituted indoles were synthesized via a Pd-catalyzed tandem C-N/Suzuki-Miyaura coupling from readily prepared ortho-gem-dihalovinylanilines. Optimal conditions used a Pd(OAc) ₂/S-Phos catalyst in the presence of K₃PO ₄·H₂O and an organoboron reagent, which included boronic acids, esters, alkyl 9-BBN derivatives, and trialkylboranes. Yields of the desired indoles were good to excellent using low catalyst loadings (typically 1 mol %).

Full text of DOI:10.1021/ol051286l

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3549-3552
Pd-Catalyzed Tandem C−N/C−C
Coupling of gem-Dihalovinyl Systems:
A Modular Synthesis of 2-Substituted
Indoles
Yuan-Qing Fang and Mark Lautens*
DaVenport Chemistry Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario M5S 3H6, Canada
mlautens@chem.utoronto.ca
Received June 1, 2005
ABSTRACT
2-Substituted indoles were synthesized via
a
Pd-catalyzed tandem
C−N/Suzuki
−Miyaura coupling from readily prepared ortho-gem-
dihalovinylanilines. Optimal conditions used a Pd(OAc)2/S-Phos catalyst in the presence of K3PO4‚H2O and an organoboron reagent, which
included boronic acids, esters, alkyl 9-BBN derivatives, and trialkylboranes. Yields of the desired indoles were good to excellent using low
catalyst loadings (typically 1 mol %).
Over the past several decades, palladium has emerged as
one of the most versatile catalysts for the formation of
carbon-carbon, carbon-heteroatom, and carbon-metalloid
bonds.1 A usual protocol involves coupling an sp2 carbon-
halide and various nucleophiles. The reactivity difference
between halides (I > Br . Cl, F usually inert) is significant
to give stepwise couplings of multihalogenated substrates
using different catalyst systems.2 However, regioselective
coupling of the same halogen is usually rather difficult. In
our previous studies, we successfully applied a strategy to
couple a dibromoaryl system selectively using an intramo-
lecular and intermolecular tandem Heck reaction.3 We
therefore decided to extend our method toward the selective
tandem coupling of gem-dihalovinyl systems, which can be
easily obtained via a Ramirez-Corey olefination reaction.4
By tethering a gem-dibromovinyl group ortho to aniline, we
envisaged a modular indole synthesis via a tandem Pd-
catalyzed intramolecular C-N (Buchwald-Hartwig amina-
tion)5 and intermolecular C-C bond (Suzuki-Miyaura
coupling)6 formation (Scheme 1).7 Since the resulting indole
Scheme 1
moiety is a privileged structural motif exhibiting broad
pharmacological properties in numerous therapeutic agents
and natural products,8 a modular synthetic method, which
allows rapid access to a new class of indole derivatives, is
very attractive to synthetic and medicinal chemists.9
(1) For a comprehensive monograph, see: Tsuji, J. Palladium Reagents
and Catalysis; John Wiley & Sons Ltd.: Chichester, U.K., 2004.
(2) Wu, T. Y. H.; Ding, S.; Gray, N. S.; Schultz, P. G. Org. Lett. 2001,
3, 3827.
(3) Lautens, M.; Fang, Y.-Q. Org. Lett. 2003, 5, 3679.
(4) For a review on the preparation of gem-dibromovinyl compounds,
see: Eymery, F.; Iorga, B.; Savignac, P. Synthesis 2000, 185-213.
(5) (a) Muci, A.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (b)
Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York, 2002; Vol. 1,
p 1051.
(6) (a) Suzuki, A. J. Organomet. Chem. 2002, 653, 83. (b) Miyaura, N.;
Suzuki, A. Chem. ReV. 1995, 95, 2457.
10.1021/ol051286l CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/09/2005

Although recent work suggested that activation of the
aniline N-H using an electron-withdrawing Ac group was
essential,7 we found that free anilines afforded the desired
indole product directly and in higher yield. Herein, we report
a highly efficient and modular synthesis of 2-substituted
indoles from ortho-gem-dihalovinylanilines.10
Table 1. Scope of Organoboron Reagents
Initial studies focused on screening the activating groups
on nitrogen, inorganic bases, phosphine ligands, and Pd
sources. Preliminary results gave a yield of 75% using
N-acetyl-2-gem-dibromovinylaniline, Pd2(dba)3/P(o-tol)3, and
K2CO3. However, the range of boronic acids was very limited
and yields did not increase despite further optimization. We
later found that comparable yields for a broader variety of
boronic acids could be obtained by simply using the free
amino group. Gratifyingly, Pd(OAc)2 coupled with Buch-
wald’s S-Phos ligand11 in the presence of K3PO4‚H2O in
toluene at 90 °C gave 2-phenylindole in good yield (84%)
with an attractively low catalyst loading (1 mol % Pd).
Using these optimized reaction conditions, various com-
mercially available aryl and heteroarylboronic acids of
different electronic and steric character were evaluated (Table
1, entries 1-5). For all cases, the expected 2-substituted
indoles were isolated in good yields. Extension to alkenyl
boronic acids and alkenyl catechol boronate esters (Table 1,
entries 6 and 7) also gave the desired products in good yield.
One of the merits of the Suzuki-Miyaura coupling
reaction is its ability to couple sp2 and sp3 carbons.12
Therefore, we decided to examine commercially available
trialkylboron or functionalized alkyl 9-BBN reagents (pre-
pared in situ by premixing a terminal alkene and 9-BBN
overnight at 20 °C). Under mild reaction conditions (60 °C
in THF), the desired indoles were obtained in good yield
(Table 1, entries 8-10).
(7) During our investigation, Bisseret and co-workers disclosed a related
example of this reaction yielding N-acetyl-2-arylindole in moderate yield.
Thielges, S.; Meddah, E.; Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004,
45, 907. The scope of this reaction was not reported.
(8) For recent reviews on indole-containing natural products, see: (a)
Somei, M.; Yamada, F. Nat. Prod. Rep. 2004, 21, 278. (b) Somei, M.;
Yamada, F. Nat. Prod. Rep. 2005, 22, 73. (c) For recent reports on indole-
containing pharmaceuticals, see: Payack, J. F.; Vazquez, E.; Matty, L.;
Kress, M. H.; McNamara, J. J. Org. Chem. 2005, 70, 175.
(9) For reviews see: (a) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1
2000, 1045 and references therein. (b) Indoles; Sundberg, R. J., Ed,;
Academic Press: San Diego, 1996. For recent reports on Pd-catalyzed indole
synthesis, see: (c) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem.,
Int. Ed. 2005, 44, 403. (d) Ackermann, L. Org. Lett. 2005, 7, 439. (e) Nazare,
M.; Schneider, C.; Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed.
2004, 43, 4526. (f) Kamijo, S.; Yamamoto, Y. Angew. Chem., Int. Ed. 2002,
41, 3230. (g) Larock, R. C.; Yum, E. K.; Refvic, M. D. J. Org. Chem.
1998, 63, 7652.
a Isolated yields using Pd(OAc)2 (1%), S-Phos (2%), ArB(OH)2 (1.5
equiv), and K3PO4‚H2O (5 equiv) in PhMe at 90 °C. b Catalyst loading
(3%). c Pd(OAc)2 (3%), S-Phos (6%), R-B (2.5 equiv), and K3PO4‚H2O (5
equiv) in PhMe at 90 °C. d Pd(OAc)2 (2%), S-Phos (5%), R-B (1.5 equiv),
and K3PO4‚H2O (5 equiv) in THF at 60 °C.
(10) ortho-gem-Dibromovinylanilines are readily accessible via Ramirez-
Corey olefination, followed by reduction to the aniline. For example, ortho-
gem-dibromovinylaniline can be easily obtained from 2-nitrobenzaldehyde
by treatment with CBr4/PPh3 (95%), followed by SnCl2‚2H2O (90%) or
Fe/HOAc (85%) reduction. This can also be carried out in a convenient
one-pot preparation on a relatively large scale (>40 g) in 85% overall
isolated yield. For experimental procedures for the preparation of all
substrates in Table 2, please refer to Supporting Information.
(11) (a) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871. (b) Barder, T. E.; Buchwald, S. L.
Org. Lett. 2004, 6, 2649. (c) Barder, T. E.; Walker, S. D.; Martinelli, J. R.;
Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685.
Various substituted ortho-gem-dibromovinylanilines were
also evaluated with phenylboronic acid under the reaction
conditions. This method proved to be very general and
efficient to prepare a variety of benzo-functionalized indoles
(Table 2, entries 1-8). In particular, preparation of 4-sub-
stituted indoles (entries 1-2, 7), which are generally regarded
as challenging targets by traditional Fischer indole methods,
were prepared from their corresponding anilines in good
yield. One of the synthetic advantages of this method is its
compatibility with a broad spectrum of electron-withdrawing
(12) (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2001, 40, 4544. (b) Miyaura, N.; Satoh, M.; Suzuki, A. Tetrahedron
Lett. 1986, 27, 3745.
3550
Org. Lett., Vol. 7, No. 16, 2005

Table 2. Scope of ortho-gem-Dihalovinylaniline Substrates
Table 3. Metal-Controlled Orthogonal Combinatorial Approach
To Synthesize 1,2-Diarylindoles
entry
R
X
Ar1B(OH)2
yield (%)a
Ar2B(OH)2
yield (%)b
1
2
3
4
5
H
H
H
Br PhB(OH)2
Br PhB(OH)2
Br 4-FPhB(OH)2
89
89
69
98
65
PhB(OH)2
4-FPhB(OH)2
PhB(OH)2
4-FPhB(OH)2
PhB(OH)2
90
86c
90
96
94
Me Cl PhB(OH)2
Me Cl 4-FPhB(OH)2
a Isolated yields using ArB(OH)2 (2 equiv), Cu(OAc)2 (1 equiv), myristic
acid (0.4 equiv), 2,6-lutidine (1.07 equiv), and PhMe, 40-60 °C. b Isolated
yields using Pd(OAc)2 (3%), S-Phos (6%), ArB(OH)2 (1.5 equiv), and
K3PO4‚H2O (5 equiv) in PhMe at 100 °C. c Mixed base of KOH (2 equiv)
and K3PO4‚H2O (1 equiv) instead of K3PO4‚H2O (5 equiv).
yields. In particular, we note that use of ortho-gem-
dichlorovinylanilines14 (Table 2, entries 10 and 11) gave near
quantitative yields of the expected indole, suggesting that
these two C-Cl bonds were more selective in the two new
bond formations than their C-Br analogues.15
Substitution on the aniline nitrogen using an N-benzyl-
substituted secondary amine worked almost as well as the
primary amine substrate (Table 2, entry 12). In contrast, we
found that use of an activating acetyl or tosyl protecting
group gave very low yields under the optimized conditions.
We also wanted to explore an orthogonal combinatorial
approach to synthesize 1,2-disubstituted or 1,2,3-trisubstituted
indoles because these compounds generally exhibit a broad
range of application in the pharmaceutical (COX-II inhibi-
tors,16 estrogen agonists and antagonists17) and material
science (electroluminescence18) industries. While initial
attempts to prepare the N-arylated starting material using
Buchwald’s catalytic conditions gave moderate to low yields,
use of stoichiometric Cu(II) and higher reaction temperature
was found to circumvent this problem.19 The N-arylated
substrates were subsequently subjected to the Pd-catalyzed
tandem coupling reaction conditions, affording the indole
a Isolated yields using Pd(OAc)2 (1%), S-Phos (2%), PhB(OH)2 (1.5
equiv), and K3PO4‚H2O (5 equiv) in PhMe at 90 °C. b Catalyst loading
(5%), 90 °C. c Catalyst loading (3%), 100 °C. d Catalyst loading (2%), 90
°C.
(13) (a) Hu, W.; Guo, Z.; Chu, F.; Bai, A.; Yi, X.; Cheng, G.; Li, J.
Bioorg. Med. Chem. 2003, 11, 1153. (b) Guo, Z.; Cheng, G.; Chu, F. U.S.
Patent Appl. US 2004058977; Chem. Abstr. 2004, 140, 270734. (c) Liu,
Y.; Gribble, G. W. Tetrahedron Lett. 2000, 41, 8717.
(14) Olah, G. A.; Yamada, Y. J. Org. Chem. 1975, 40, 1107.
(15) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(16) Gungor, T.; Teulon, J.-M. Patent WO 9,805,639, 1998; Chem. Abstr.
1998, 128, 180330.
(17) (a) Von Angerer, E.; Strohmeier, J. J. Med. Chem. 1987, 30, 131.
(b) Von Angerer, E.; Biberger, C.; Schneider, M. Patent WO 9,603,375,
1996; Chem. Abstr. 1996, 125, 33474.
(18) Lin, T.-s. U.S. Patent 6,790,539, 2004; Chem. Abstr. 2004, 140,
136161.
and electron-donating functionalities, presumably resulting
from the distance from the reaction sites.
We also sought to extend our method toward the prepara-
tion of synthetically important 2,3-disubstituted indoles.13
Using our standard conditions, 3-alkyl-substituted indoles
(Table 2, entries 9 and 11) could be obtained from the
corresponding dihalovinyl substrates in good to excellent
Org. Lett., Vol. 7, No. 16, 2005
3551

products in good to excellent yields (Table 3). Such a
catalyst-controlled combinatorial approach allows the facile
and rapid generation of a diverse and broad library using a
limited number of reagents by simply switching the addition
sequence of the boronic acids in the reactions.20
In conclusion, we have found a very efficient and modular
de novo indole synthesis via a formal intramolecular Buch-
wald-Hartwig C-N/intermolecular Suzuki-Miyaura C-C
coupling reaction. Further study of the mechanism, explora-
tion of scope, application to library synthesis, and synthesis
of biologically active targets are currently under investigation.
Acknowledgment. This work is supported by NSERC
(Canada), Merck Frosst, and the University of Toronto. Y.-
Q.F. thanks the Ontario Government and the University of
Toronto for financial support in the form of postgraduate
scholarships (OGS). We also thank Prof. Steve Buchwald
for correspondence regarding the S-Phos ligand.
Supporting Information Available: Full experimental
1
details and characterization including H and 13C NMR
spectroscopic data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(19) Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077.
(20) Aldrich currently supplies a special catalog of more than 250 boronic
acids and esters. This can be found at http://www.aldrich-sigma.com.
OL051286L
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