Synthesis of 2-vinylic indoles and derivatives via a Pd-catalyzed tandem coupling reaction

Article abstract of DOI:10.1021/ol061374l

(Chemical Equation Presented) A novel one-step synthesis of valuable 2-vinylic indoles and their tricycle derivatives is described. This reaction, which utilizes a gemdibromovinyl unit as a readily available starting material, occurs via an efficient Pd-c

Full text of DOI:10.1021/ol061374l

ORGANIC
LETTERS
2006
Vol. 8, No. 19
4203-4206
Synthesis of 2-Vinylic Indoles and
Derivatives via a Pd-Catalyzed Tandem
Coupling Reaction
Aude Fayol, 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 5, 2006
ABSTRACT
A novel one-step synthesis of valuable 2-vinylic indoles and their tricycle derivatives is described. This reaction, which utilizes a gem-
dibromovinyl unit as a readily available starting material, occurs via an efficient Pd-catalyzed tandem Buchwald Hartwig/Heck reaction.
−
gem-Dihalovinyl systems are important, versatile synthons
in organopalladium chemistry, and they have been used in
many different cross-coupling reactions with organostan-
nane,1 organomagnesium,2 organoborane,3 organozinc,4 and
also organocopper5 reagents as coupling partners.
2-substituted indoles8 or Cu-catalyzed tandem intramolecular
amidation to provide imidazoindolones.9 Herein, we describe
an extension to this concept where a tandem Pd-catalyzed
C-N10/Heck reaction11 is involved to provide a novel, highly
efficient, and modular synthesis of 2-vinylic indoles12 and
their tricyclic derivatives (Scheme 1).13,14
The gem-dihalovinyl moiety also represents a very attrac-
tive key unit for the syntheses of various heterocycles and
carbocycles by judicious selection of the coupling partners
and well-designed starting materials. Despite this great
potential, relatively few reports utilizing palladium-catalyzed
chemistry have been published in this area.6
Scheme 1
In the context of developing a selective tandem coupling
of gem-dihalovinyl systems,7 our previous studies showed
that ortho-gem-dibromovinylanilines can undergo a Pd-
catalyzed tandem C-N/Suzuki-Miyaura coupling to provide
Vinylic indoles are valuable building blocks and are used
in the synthesis of biologically significant compounds such
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Dong, G.; Venkataiah, B. Tetrahedron Lett. 2005, 46, 763. (d) Molander,
G. A.; Yokoyama, Y. J. Org. Chem. 2006, 71, 2493.
(6) Indole and benzofuran syntheses: (a) Thielges, S.; Meddah, E.;
Bisseret, P.; Eustache, J. Tetrahedron Lett. 2004, 45, 907. Isocoumarin
syntheses: (b) Wang, L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625. Six-
membered carbocycle syntheses: (c) Soderquist, J. A.; Le´on, G.; Colberg,
J. C.; Mart´ınez, I. Tetrahedron Lett. 1995, 36, 3119. Fused bicycle
syntheses: (d) Ma, S.; Xu, B.; Ni, B. J. Org. Chem. 2000, 65, 8532. (e)
Ma, S.; Xu, B. J. Org. Chem. 1998, 63, 9156. (f) McAlonan, H.;
Montgomery, D.; Stevenson, P. J. Tetrahedron Lett. 1996, 37, 7151.
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Chem. 1999, 64, 8770.
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Tan, Z.; Negishi, E. Angew. Chem., Int. Ed. 2006, 45, 762.
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10.1021/ol061374l CCC: $33.50
© 2006 American Chemical Society
Published on Web 08/25/2006

as indole alkaloids, carbazoles, and carbolines.15 They are
also present in medicinally important compounds such as
fluvastatin16 (cholesterol-lowering drug) or SB-24278217
(treatment for osteoporosis; Figure 1).
PCy3, P(o-tolyl)3, PPh3, P(o-tolyl-p-OMe)3, X-Phos, Dav-
ePhos, S-Phos), and additives have been tested.
Three catalyst systems were discovered to give good
results depending on the substituent on the nitrogen. The
use of Pd(OAc)2 (4 mol %) and P(o-tolyl)3 (8 mol %) with
N-benzyl-vinylaniline 2a gave a 71% yield of 2-vinylic
indole 1a (Scheme 2). The use of Jeffery’s conditions (4
mol % of Pd(OAc)2, Me4NCl)20 which avoid the use of
expensive phosphines is even better as 1a is obtained in 79%
yield. Although longer reaction times are usually required
under Jeffery’s conditions, yields are generally much better
than those obtained with P(o-tolyl)3. Using Pd(OAc)2/P(o-
tolyl)3 with N-aryl-vinylaniline 2b gave 50% of vinylic indole
1b and 40% of an interesting byproduct 3 (Scheme 2). This
product (3) is probably the result of a 1,4-migration palladium
species, followed by a Heck reaction, as shown by Larock
and Gallagher with a biaryl system.21 Additional screening
showed that the use of Pd2dba3 (3 mol %) and S-Phos22 (12
mol %) with 2b avoids the formation of the indole 3 and
provides 1b in 78% yield. Toluene was found to be the best
solvent, and reflux was the optimum temperature for a
complete and rapid conversion. Screening a range of bases
revealed that a combination of organic and inorganic bases
(Et3N and K3PO4‚H2O) provided the best yields.
Figure 1. Biologically active 2-vinylic indoles.
The existing synthetic methods present some limitations,
such as the necessity of introducing a functional group on
the heterocycle prior to the vinylation step resulting in longer
linear syntheses and limited ability to introduce significant
molecular diversity.18
This novel tandem Pd-catalyzed C-N/Heck reaction was
first investigated using 2a and 2b19 with tert-butyl acrylate
to screen different Pd sources, ligands, organic and inorganic
bases, additives, and temperatures (Scheme 2). Catalyst
The optimized conditions were then applied to various
commercially available alkenes of different electronic char-
acter using N-benzyl-ortho-gem-dibromovinylaniline (2a). In
all cases, the expected 2-vinylic indoles were isolated in good
yields (Table 1, entries 1-8). The reaction tolerates a wide
Scheme 2
Table 1. Scope of Alkene Reagents
systems comprising different palladium sources (Pd(OAc)2,
Pd2dba3, Pd(PPh3)4, Pd/C), ligands (HP(tBu)3‚BF4, P(tBu)3,
(7) (a) Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am. Chem. Soc. 1962,
84, 1745. (b) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13, 3769.
For a review on the preparation of gem-dibromovinyl compounds, see: (c)
Eymery, F.; Iorga, B.; Savignac, P. Synthesis 2000, 185.
(8) Fang, Y.-Q.; Lautens, M. Org. Lett. 2005, 7, 3549.
(9) Yuen, J.; Fang, Y.-Q.; Lautens, M. Org. Lett. 2006, 8, 653.
(10) For a review on Pd-catalyzed C-N couplings, see: (a) Jiang, L.;
Buchwald, S. L. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
de Meijere, A., Diederich, F., Eds.; John Wiley & Sons: Weinheim, 2004.
(b) Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., de Meijere, A., Eds.; Wiley-Interscience: Wein-
heim, 2002. (c) Prim, D.; Campagne, J. M.; Joseph, D.; Andrioletti, B.
Tetrahedron 2002, 58, 2041.
a Isolated yields. b Alkene (2.0 equiv), Pd(OAc)2 (4 mol %), Me4NCl
(1.0 equiv), K3PO4‚H2O (2.0 equiv), NEt3 (2.0 equiv), reflux, toluene. c P(o-
tolyl)3 (8 mol %) instead of Me4NCl. d Mixture of ketone/allylic alcohol:
3:1. e 80% conversion.
(11) For a review on Heck reactions, see: (a) Beletskaya, I. P.;
Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (b) de Meijere, A.; Meyer,
F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379.
(12) For reviews on indoles, see: (a) Gribble, G. W. In ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., Ress, C. W., Servien, E. F.
V., Eds.; Pergamon: Oxford, 1996; Vol.2, p 207. (b) Sundberg, R. J. Indoles;
Academic Press: San Diego, 1996. (c) For a review on Pd-catalyzed indole
syntheses, see: Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873.
variety of alkene reagents containing ester, amide, nitrile,
sulfone, and alcohol moieties (Table 1, entries 1 and 4-8)
4204
Org. Lett., Vol. 8, No. 19, 2006

and also phenyl moieties with different electronic properties
(Table 1, entries 2-4).
Various dibromovinylanilines substituted on the phenyl
ring were also evaluated with tert-butyl acrylate (Table 3,
The effect of substitution on the aniline nitrogen of the
gem-dibromovinylaniline has also been studied using tert-
butyl acrylate under the standard reaction conditions (Table
2, entries 1-6). The coupling with both the electron-rich
Table 3. Scope of ortho-gem-Dibromovinylaniline Substrates
Table 2. Scope of ortho-gem-Dibromovinylaniline Substrates
a Isolated yields. b tert-Butyl acrylate (2.0 equiv), Pd(OAc)2 (4 mol %),
Me4NCl (1.0 equiv), K3PO4‚H2O (2.0 equiv), NEt3 (2.0 equiv), reflux,
toluene. c Pd(OAc)2 (4 mol %), P(o-tolyl)3 (8 mol %).
a Isolated yields. b tert-Butyl acrylate (2.0 equiv), Pd(OAc)2 (4 mol %),
Me4NCl (1.0 equiv), K3PO4‚H2O (2.0 equiv), NEt3 (2.0 equiv), reflux,
toluene. c Pd2dba3 (3 mol %), S-Phos (12 mol %). d Pd(OAc)2 (4 mol %),
P(o-tolyl)3 (8 mol %).
entries 1-6). This methodology proved to be a very general
and efficient method to prepare functionalized indoles.
Electronic factors and steric hindrance had little effect on
the yield. A broad spectrum of electron-donating and
electron-withdrawing functionalities in different positions
around the phenyl ring is tolerated. The only limitation of
this reaction is in the formation of 3-substituted indoles, as
yields were poor when attempts were made with the
corresponding substituted dibromovinylanilines.
and the electron-deficient N-aryl substrate and N-benzyl
derivative proceeded smoothly to afford the desired product
in good yields (Table 2, entries 1-3). In addition, N-alkyl-
substituted anilines with different steric hindrance (entries
4 and 5) also reacted efficiently. The use of the unsubstituted
aniline (2h), which allows flexibility, gave the expected
product, but in lower yield (Table 2, entry 6).
(18) Synthesis of 2-vinyl indole via C-H functionalization: (a) Grimster,
N. P.; Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int.
Ed. 2005, 44, 3125. (b) Capito, E.; Brown, J. M.; Ricci, A. Chem. Commun.
2005, 1854. Via a Stille cross-coupling reaction: (c) Hudkins, R. L.;
Diebold, J. L.; Marsh, F. D. J. Org. Chem. 1995, 60, 6218. (d) Beccalli, E.
M.; Marchesini, A. Tetrahedron 1995, 51, 2353. Via Wittig reaction: (e)
Eitel, M.; Pindur, U. Synthesis 1989, 364. (f) Nagarathnam, D. Synthesis
1992, 743. Via a hetero-Cope rearrangement: (g) Wilkens, J.; Ku¨hling,
A.; Blechert, S. Tetrahedron 1987 43, 3237. (h) Macor, J. E.; Newman, M.
E.; Ryan, K. Tetrahedron Lett. 1989, 30, 2509.
(19) For the preparation of the gem-dibromovinylaniline system, see
Supporting Information and also the Supporting Information of ref 8.
(20) Jeffery, T. Tetrahedron 1996, 52, 10113.
(21) (a) Campo, M. A.; Larock, R. C. J. Am. Chem. Soc. 2002, 124,
14326. (b) Karig, G.; Moon, M.-T.; Thasana, N.; Gallagher, T. Org. Lett.
2002, 4, 3115. For a review on 1,4-migration on biaryl systems, see: (c)
Ma, S.; Gu, Z. Angew. Chem., Int. Ed. 2005, 44, 7512.
(13) For a synthesis of indoles occurring via a tandem Pd-catalyzed Heck
reaction/amination, see: Barluenga, J.; Ferna´ndez, A. M.; Aznar, F.; Valde´s,
C. Chem.-Eur. J. 2005, 11, 2276.
(14) For Heck reaction involving 2-iodo-indole, see: Tokuyama, H.;
Kaburagi, Y.; Chen, X.; Fukuyama, T. Synthesis 2000, 429.
(15) For some recent applications, see: (a) Laronze, M.; Sapi, J.
Tetrahedron Lett. 2002, 43, 7925. (b) Wiest, O.; Steckhan, E. Angew. Chem.,
Int. Ed. 1993, 32, 901. (c) Noland, W. E.; Xia, G. M.; Gee, K. R.; Konkel,
M. J.; Wahlstrom, M. J.; Condoluci, J. J.; Rieger, D. L. Tetrahedron 1996,
52, 4555. (d) Ishikura, M.; Hino, A.; Yaginuma, T.; Agata, I.; Katagiri, N.
Tetrahedron 2000, 56, 193. (e) Padwa, A.; Lynch, S. M.; Mejia-Oneta, J.
M.; Zhang, H. J. Org. Chem. 2005, 70, 2206. (f) Rawat, M.; Wulff, W. D.
Org. Lett. 2004, 6, 329. (g) Grieco, P. A.; Kaufman, M. D. J. Org. Chem.
1999, 64, 7586.
(16) Repic, O.; Prasad, K.; Lee, G. T. Org. Process Res. DeV. 2001, 5,
519.
(17) Conde, J. J.; McGuire, M.; Wallace, M. Tetrahedron Lett. 2003,
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Angew. Chem., Int. Ed. 2004, 43, 1871.
Org. Lett., Vol. 8, No. 19, 2006
4205

An intramolecular version of this methodology was
developed to provide more elaborate heterocycles using
substrates where the alkene moiety is tethered to the nitrogen
of the ortho-gem-dibromovinylaniline. The enoate 4a23 was
used for this study, and different palladium sources and
ligands were screened. Pd2dba3 (4 mol %) with nBu4NCl (1
equiv) in the presence of NEt3/K3PO4‚H2O in toluene at 120
°C gave the desired tricyclic adduct in good yield (76%) as
a mixture of two easily separable isomers (5a and 5a′;
Scheme 3).
stereoselective syntheses of indole alkaloids, carbazoles, and
nonnatural annulated indole derivatives of pharmological
interest.25 The reactivity of 2-vinylic indoles 1a was briefly
examined using N-phenylmaleiimide and dimethyl acety-
lenedicarboxylate as a dienophile in toluene at reflux. The
interesting carbazole derivatives 6 and 7 were obtained in
good yields (Scheme 4).26
Scheme 4. Utility of a 2-Vinylic Indole Building Block
Scheme 3
The generality of the intramolecular process was explored
as shown in Figure 2. Substituents on the aromatic ring with
In conclusion, we have developed an efficient and modular
one-pot procedure giving rapid access to a wide range of
substituted 2-vinylic indoles from readily accessible gem-
dibromovinylaniline substrates via a palladium-catalyzed
tandem Buchwald-Hartwig amination/Heck reaction. The
intramolecular variant of this reaction leads to the formation
of interesting cyclic compounds including pyrido and azepino
indole derivatives.
Acknowledgment. We thank NSERC (Canada), ORDCF,
and the University of Toronto for the funding of this research.
A.F. thanks the French “Ministe`re des Affaires Etrange`res”
for financial support in the form of a post-doctorate fellow-
ship (Bourse Lavoisier). Y.-Q.F thanks the Ontario Govern-
ment and the University of Toronto for financial support
(OGS, OGSST).
Figure 2. Scope of the intramolecular version. (Isolated yields.
Conditions: Pd2dba3 (4 mol %), nBu4NCl (1 equiv), K3PO4‚H2O
a
(2 equiv), NEt3 (2 equiv), toluene, reflux. Pd(OAc)2 (4 mol %),
P(o-tolyl)3 (8 mol %).)
Supporting Information Available: Full experimental
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.
1
different electronic properties have been used successfully
(examples 5a-c), and it is also possible to use a nonactivated
alkene (5e). Moreover, a compound with a seven-membered
ring attached to the indole unit has been readily obtained
using the amination-Heck sequence. It is worth noting that
these interesting pyrido and azepino-indole skeletons are
simultaneously constructed from the corresponding acyclic
precursors in just one step, which is distinctive from the
traditional ring-by-ring approach.24
OL061374L
(24) For some examples, see: (a) Germain, A. L.; Gilchrist, T. L.;
Kemmitt, P. D. Heterocycles 1994, 37, 697. Gilchrist, T. L.; Kemmitt, P.
D.; Germain, A. L. Tetrahedron 1997, 53, 4447. (b) Conza´lez-Pe´rez, P.;
Pe´rez-Serrano, L.; Casarrubios, L.; Dom´ınguez, G.; Pe´rez-Castells, J.
Tetrahedron Lett. 2002, 43, 4765. (c) Siebeneicher, H.; Bytschkov, I.; Doye,
S. Angew. Chem., Int. Ed. 2003, 42, 3042. (d) Bit, R. A.; Davis, P. D.;
Hill, C. H.; Keech, E.; Vesey, D. R. Tetrahedron 1991, 47, 4645.
(25) For reviews of Diels-Alder reactions of vinyl indoles, see: (a)
Pindur, U. Heterocycles 1988, 27, 1253. (b) Pindur, U. Chimia 1990, 44,
406.
2-Vinyl indole moieties have been shown to be versatile
dienes in Diels-Alder reactions for the regioselective and
(23) For syntheses of 4, see the Supporting Information.
(26) Eitel, M.; Pindur, U. J. Org. Chem. 1990, 55, 5368.
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Org. Lett., Vol. 8, No. 19, 2006