A general and practical method of alkynyl indole and benzofuran synthesis via tandem Cu- And Pd-catalyzed cross-couplings

Article abstract of DOI:10.1021/ol071370w

A new tandem coupling approach to synthesize 2-alkynyl indoles and benzofurans is described. This reaction utilizes easily accessible gemdibromovinyl substrates and terminal alkynes and proceeds via Pd/C- and Cul-catalyzed tandem Ullman/Sonogashira coupli

Full text of DOI:10.1021/ol071370w

ORGANIC
LETTERS
2007
Vol. 9, No. 15
2955-2958
A General and Practical Method of
Alkynyl Indole and Benzofuran
Synthesis via Tandem Cu- and
Pd-Catalyzed Cross-Couplings
Masatoshi Nagamochi, Yuan-Qing Fang, and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario M5S 3H6, Canada
mlautens@chem.utronto.ca
Received June 11, 2007
ABSTRACT
A new tandem coupling approach to synthesize 2-alkynyl indoles and benzofurans is described. This reaction utilizes easily accessible gem-
dibromovinyl substrates and terminal alkynes and proceeds via Pd/C- and CuI-catalyzed tandem Ullman/Sonogashira couplings.
Transition-metal-catalyzed reactions have increasingly
attracted attention in the pharmaceutical and fine chemical
industries. Palladium is clearly one of the most versatile
metals for numerous transformations in construction of
carbon-carbon and carbon-heteroatom bonds.1 In order to
develop and apply new methods to industrial processes,
addressing practical issues including reaction generality,
robustness, catalyst loadings as well as type of precatalyst
and ligand, and metal residue in the product is extremely
important but often overlooked.2
We now report a simple method to prepare both benzo-
furan and indole scaffolds bearing an alkyne at the 2-position
and show that choice of catalyst is extremely important in
achieving high yields.
Recently, we developed a number of new methods for the
synthesis of indoles, azaindoles, and thienopyrroles, all very
useful subunits found in biologically relevant structures,3 via
Pd-catalyzed tandem cross-coupling strategies using easily
accessible gem-dihalovinyl substrates.4 In these processes,
homogeneous palladium precatalysts, such as Pd(OAc)2 or
Pd2(dba)3, and a specialized phosphine ligand (e.g., S-Phos)
were used which can lead to a high residual metal content
in the product. In addition, boronic acids were used as the
coupling partner, and while they are among the best of the
organometallic reagents, they are not as attractive as feed-
stock materials such as alkenes or alkynes. Here we report
a new general and practical catalyst system using CuI and
Pd/C to synthesize 2-alkynyl indoles from gem-dibromo-
vinylanilines and terminal alkynes via a tandem Ullman
(3) For reviews on indole synthesis, see: (a) Indoles; Sundberg, R. J.,
Ed.; Academic Press: San Diego, CA, 1996. (b) Gribble, G. W. J. Chem.
Soc., Perkin Trans. 1 2000, 1045. (c) Cacchi, S.; Fabrizi, G. Chem. ReV.
2005, 105, 2873. (d) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006,
106, 2875 and references therein.
(1) Tsuji, J. Palladium Reagents and Catalysis, New PerspectiVe for the
21st Century; Wiley-VCH: Weinheim, Germany, 2004.
(4) Indole, azaindole, and thienopyrrole synthesis via Pd-catalyzed tandem
C-N/Suzuki-Miyaura couplings: (a) Fang, Y.-Q.; Lautens, M. Org. Lett.
2005, 7, 3549. (b) Fang, Y.-Q.; Karisch, R.; Lautens, M. J. Org. Chem.
2007, 72, 1341. (c) Fang, Y.-Q.; Yuen, J.; Lautens, M. J. Org. Chem.
Published online June 9, 2007 http://dx.doi.org/10.1021/jo07046b. Indole
synthesis via tandem C-N/Heck couplings: (d) Fayol, A.; Fang, Y.-Q.;
Lautens, M. Org. Lett. 2006, 8, 4203. Imidazoindolone synthesis via Cu-
catalyzed double intramolecular amidation: (e) Yuen, J.; Fang, Y.-Q.;
Lautens, M. Org. Lett. 2006, 8, 653.
(2) For excellent reviews on Pd-catalyzed reactions from industrial
laboratories, see: (a) Schlummer, B.; Scholz, U. AdV. Synth. Catal. 2004,
346, 1599. (b) Farina, V. AdV. Synth. Catal. 2004, 346, 1553. (c) Buchwald,
S. L.; Mauger, C.; Mignani, G.; Scholz, U. AdV. Synth. Catal. 2006, 348,
23. For general information on process chemistry, see: (d) Anderson, N.
G. Practical Process Research & DeVelopment; Academic Press: San
Diego, CA, 2000.
10.1021/ol071370w CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/27/2007

C-N/Sonogashira reaction under relatively mild conditions.
We also show that this catalyst system is equally effective
for the formation of benzofuran analogues, another family
of biologically important heterocycles.5
Our preliminary efforts were carried out using gem-
dibromovinylaniline 1a with phenylacetylene in the presence
of Pd(PPh3)4 (5 mol %), CuI (5 mol %), and Et3N in toluene,
affording the desired product 2a in 65% yield (Scheme 1).
Further fine-tuning of the reaction conditions using 1a and
the more challenging substrate 1-octyne was achieved by
varying the phosphine ligand. In general, monodentate
triarylphosphines were more effective than electron-rich and
sterically hindered phosphines, such as S-Phos or P(tBu)3,
or bidentate ligands, such as DPPF. Moderately electron-
rich P(p-MeOPh)3 proved to be the ligand of choice. The
ligand to CuI ratio of 2:1 was the most effective to use,
affording the product 2b in 83% yield. Catalyst loading could
be reduced to 0.3 mol % of Pd and 2 mol % of CuI; however,
a longer reaction time was necessary to obtain full conversion
(36 h). The optimal solvent is toluene, and simple degassing
is sufficient treatment for solvent-grade toluene.
Scheme 1
The optimized conditions were then applied to various
aromatic and aliphatic terminal alkynes with different
electronic properties using 1a. In all cases, the expected
2-alkynyl indoles 2 were isolated in moderate to good yields
(Table 1, entries 1-9). The reaction tolerated many func-
To our surprise, no double-alkynylated product was observed,
despite literature precedent demonstrating that Sonogashira
coupling of gem-dibromoolefins is a rather unselective
process, which would prevent ring formation.6
Table 1. Scope of Alkyne Reagents
Changing the base (K2CO3, K3PO4, Cs2CO3, DABCO,
iPr2NH, and iPr2NEt) revealed that organic amine bases were
i
more effective than inorganic bases, and that Pr2NH (2.5
equiv) was optimal. Screening a range of palladium cata-
lysts (Pd2(dba)3, Pd(OAc)2, Pd(MeCN)2Cl2, Pd(PhCN)2Cl2,
Na2PdCl4, Pd(acac)2, [Pd(allyl)Cl]2, Pd/C) showed that
Pd/C7 gave the cleanest reaction, affording 2a in 85% isolated
yield.8 Comparing to the homogeneous complexes, Pd/C is
an ideal Pd source due to its low cost, easy recovery through
simple filtration, and low level of Pd contamination in
the product.9 Other heterogeneous Pd catalysts such as
Pd-Al2O3, Pd-BaSO4, and Lindlar’s catalyst worked equally
well. Since the solid support did not affect the efficacy of
the catalyst system, it is most likely that the reaction itself
occurs in a homogeneous organic phase with trace amounts
of leached Pd(0).
(5) For reviews on benzo[b]furan-containing natural products, see: (a)
Donelly, D. M. X.; Meegan, M. J. Furans and Their Benzo Derivatives. In
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon:
New York, 1984; Vol. 4, pp 657-712. (b) Cagniant, P.; Cagniant, D. AdV.
Heterocycl. Chem. 1975, 18, 337. (c) Bird, C. W.; Cheeseman, G. W. H.
Synthesis of Five-membered Rings with One Heteroatom. In ComprehensiVe
Heterocyclic Chemistry; Katritzky, A. R., Ed.; Pergamon: New York, 1984;
Vol. 4, pp 89-153. For a recent report on benzo[b]furan-containing
pharmaceuticals, see: (d) Chen, C; Dormer, P. G. J. Org. Chem. 2005, 70,
6964.
(6) (a) Uenishi, J.; Kawahama, R.; Yonemitsu, O.; Tsuji, J. J. Org. Chem.
1998, 63, 8965. (b) Uenishi, J.; Matsui, K.; Ohmiya, H. J. Organomet. Chem.
2002, 653, 141. (c) Ogasawara, M.; Ikeda, H.; Ohtsuki, K.; Hayashi, T.
Chem. Lett. 2000, 776.
a Isolated yields using alkyne (1.5 equiv), Pd/C (2 mol %), CuI (4 mol
%), P(p-MeOPh)3 (8 mol %), and iPr2NH (2.5 equiv) in toluene at 100 °C
for 1.5-48 h. b Reaction performed using Pd/C (5 mol %), CuI (5 mol %),
i
PPh3 (11 mol %), and Pr2NH (2.5 equiv) in toluene at 100 °C for 1 h.
tional groups including hydroxyl, nitrile, chloro, acetal, and
trimethylsilyl, although longer reaction times were required
for some cases (entries 8 and 9). Altering the electron-
donating and electron-withdrawing groups on the gem-
dibromovinyl substrate did not affect the efficacy of the
tandem reaction, giving the products 2j-2m in 55-84%
yields (Table 2, entries 1-4).
In contrast to our previous observations on the Pd-
catalyzed tandem C-N/Heck and C-N/Suzuki reaction,4a,d
alkyl or aryl substituents on the aniline nitrogen of the gem-
(7) 10% Pd/C (Pearlman) provided by Degussa is marginally better than
common 10% Pd/C.
(8) Pd/C-catalyzed Sonogashira coupling reactions: (a) De la Rosa, M.
A.; Velarde, E.; Guzma`n, A. Synth. Commun. 1990, 20, 2059. (b) Bleicher,
L; Cosford, N. D. Synlett 1995, 1115. (c) Cosford, N. D.; Bleicher, L.;
Herbaut, A.; McCallum, J. S.; Vernier, J.-M.; Dawson, H.; Whitten, J. P.;
Adams, P.; Chavez-Noriega, L.; Correa, L. D.; Crona, J. H.; Mahaffy, L.
S.; Menzaghi, F.; Rao, T. S.; Reid, R.; Sacaan, A. I.; Santori, E.; Stauderman,
K. A.; Whelan, K.; Lloyd, G. K.; McDonald, I. A. J. Med. Chem. 1996,
39, 3235. (d) Breicher, L. S.; Cosford, N. D.; Herhaut, A.; MacCallum, J.
S.; MacDonald, I. A. J. Org. Chem. 1998, 63, 1109.
(9) For reviews, see: (a) Felpin, F.-X.; Ayad, T.; Mitra, S. Eur. J. Org.
Chem. 2006, 2679. (b) Seki, M. Synthesis 2006, 2975.
2956
Org. Lett., Vol. 9, No. 15, 2007

nylbenzofurans directly from easily accessible phenol deriva-
tives. A general, practical, and modular method has not been
reported.
Table 2. Scope of ortho-gem-Dihalovinylaniline Substrates
Our initial studies using gem-dibromovinylphenol 3a10 and
1-octyne found that the same catalytic system employed for
the indole examples afforded the desired benzofuran 4a in
69% yield (Table 4, entry 1). Interestingly, use of biphasic
Table 4. Scope of Alkyne Reagents
a Isolated yields using 1-octyne (1.5 equiv), Pd/C (2 mol %), CuI (2
mol %), P(p-MeOPh)3 (4 mol %), and iPr2NH (2.5 equiv) in toluene at 100
°C for 12-24 h. b Pd/C (5 mol %), CuI (4 mol %), P(p-MeOPh)3 (8 mol
i
%), and Pr2NH (2.5 equiv) for 24 h.
dibromovinylaniline in general lowers the yield, although
longer reaction times and higher catalyst loadings can be
used to force the reaction to completion (Table 3).
a Isolated yields using alkyne (1.5 equiv), Pd/C (1 mol %), CuI (2 mol
%), iPr2NH (2.5 equiv), and P(p-MeOPh)3 (4 mol %) in toluene/H2O (2:1)
at 100 °C for 12 h. b Toluene was used as solvent instead of a mixture of
toluene/H2O.
Table 3. Scope of Nitrogen Substituents
toluene/H2O (2:1) instead of toluene alone was found to
improve the yield to 80%. The intriguing beneficial effect
of water is presumably due to its ability to remove bromide
from the organic phase. A control experiment, in which an
external source of bromide (Bu4NBr) was found to inhibit
the reaction progress, lends support to this proposal.
The scope of the reaction regarding terminal alkynes is
very broad, as shown in Table 4. Substrates containing aryl,
heteroaryl, and nitrile groups (entries 6-8) were tolerated,
as were alcohols (entries 3 and 5). Even a relatively
complicated steroid derivative bearing two acidic hydroxyl
groups (entry 9) proceeded in good yield. Similarly, various
substitution on the gem-dibromovinylphenol was tolerated
(Table 5, entries 1-3). Higher catalyst loading and longer
reaction time for substrate 3d was needed to overcome the
entry
substrate R
product 2/yielda (%)
1
2
3
4
1g Me
1h iPr
1i Bn
1j Ph
2n 61
2o 60
2p 51
2q 65
a Isolated yields using alkyne (1.5 equiv), Pd/C (1-7 mol %), CuI
i
(2-10 mol %), Pr2NH (2.5 equiv), and P(p-MeOPh)3 (4-10 mol %) in
toluene at 100 °C.
Having developed a novel procedure for the synthesis of
2-alkynyl indoles, we next sought to extend this methodology
to the synthesis of 2-alkynylbenzofurans. There have been
reports on preparation of this class of compounds using
Sonogashira coupling with 2-halobenzofurans and terminal
alkynes, but little is known about the synthesis of 2-alky-
(10) For the preparation of 3a, see: Thilges, S.; Meddah, E.; Bisseret,
P; Eustache, J. Tetrahedron Lett. 2004, 45, 907.
Org. Lett., Vol. 9, No. 15, 2007
2957

Scheme 2
Table 5. Scope of ortho-gem-Dihalovinylphenol Substrates
Cu-catalyzed C-N coupling process occurs prior to the Pd-
and Cu-catalyzed Sonogashira coupling in this sequence.
In conclusion, we have established a general and practical
CuI and Pd/C catalyst system that provides rapid access to
a variety of 2-alkynyl indoles and benzofurans via tandem
cross-couplings. This is the first reliable method to stereo-
selectively functionalize gem-dibromoolefins using the
Sonogashira reaction. These alkynyl-substituted heterocycles
are difficult to obtain using existing indole-forming (e.g.,
Fischer or Larock’s indole synthesis) and benzofuran-forming
methods. While the triple bond provides a unique structure
motif for biological systems, it can also undergo a rich array
of chemical transformations to form other functional groups.
Preliminary study shows that both Cu and Pd participate in
the C-C bond formation, while Cu is responsible for Ullman
C-N bond formation.
a Isolated yield using alkyne (1.5 equiv), Pd/C (2 mol %), CuI (4 mol
i
%), P(p-MeOPh)3 (8 mol %), and Pr2NH (2.5 equiv) in toluene/H2O, at
100 °C for 12 h. b Pd/C (1 mol %), CuI (2 mol %), P(p-MeOPh)3 (4 mol
%) for 12 h. c Pd/C (7 mol %), CuI (5 mol %), P(p-MeOPh)3 (10 mol %).
coordination of two adjacent oxygens, which may retard the
catalytic cycle. We also showed that 2,3-disubstituted ben-
zofuran 4m could be obtained from substrate 3e in 82% yield.
Acknowledgment. We thank NSERC (Canada), Merck
Frosst, Daiichi Pharmaceutical (Tokyo), and the University
of Toronto for the funding of this research. Y.-Q.F. thanks
the Ontario Government and University of Toronto for
financial support (OGS, OGSST).
A plausible mechanism, which accounts for the formation
of the 2-alkynyl heteroaryl compounds from the dibromo-
vinyl precursors, is shown in Scheme 2. When the tandem
C-N/Sonogashira reaction was performed using 1a in the
absence of Pd/C under the optimized conditions, no desired
product was observed. However, a significant amount of
2-bromoindole was obtained, presumably formed via an
intramolecular Ullman reaction. On the other hand, when
the reaction was performed in the presence of Pd/C and
PPh3 without CuI, only the starting material 1a was
recovered. On the basis of this evidence, we believe that the
Supporting Information Available: Full experimental
1
details and characterization including H and 13C spectro-
scopic data for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL071370W
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Org. Lett., Vol. 9, No. 15, 2007