General and efficient indole syntheses based on catalytic amination reactions

Article abstract of DOI:10.1021/ol047649j

(Chemical Equation Presented) Highly flexible and efficient syntheses of the indole backbone are presented starting from o-alkynylhaloarenes. These transformations proceed via a palladium- or a copper-catalyzed amination reaction and a subsequent cyclization reaction in good to excellent yields. Furthermore, a multicatalytic one-pot indole synthesis starting from o-chloroiodobenzene is viable using a single catalyst consisting of an N-heterocyclic carbene palladium complex and Cul.

Full text of DOI:10.1021/ol047649j

ORGANIC
LETTERS
2005
Vol. 7, No. 3
439-442
General and Efficient Indole Syntheses
Based on Catalytic Amination Reactions
Lutz Ackermann*
Department of Chemistry, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstrasse 5-13, D-81377 Mu¨nchen, Germany
lutz.ackermann@cup.uni-muenchen.de
Received November 14, 2004
ABSTRACT
Highly flexible and efficient syntheses of the indole backbone are presented starting from o-alkynylhaloarenes. These transformations proceed
via a palladium- or a copper-catalyzed amination reaction and a subsequent cyclization reaction in good to excellent yields. Furthermore, a
multicatalytic one-pot indole synthesis starting from o-chloroiodobenzene is viable using a single catalyst consisting of an N-heterocyclic
carbene palladium complex and CuI.
The prevalence of indoles in natural products and biologically
active compounds results in a continued strong demand for
the development of general, flexible, and especially regio-
selective synthetic methods of this structural moiety.1 In this
context, palladium-catalyzed transformations for the synthesis
of the indole backbone, starting from o-alkynylanilines or
derivatives thereof2 as well as o-haloanilines,3 have been
studied intensively. However, much less attention has been
paid to the use of o-dihaloarenes 1 or o-alkynylhaloarenes
2,4 although they are easily accessible from inexpensive
starting materials. Transition metal-catalyzed C-N bond
forming reactions using aryl halides have proved to be a
versatile method for the synthesis of a variety of amines.5
Additionally, cyclization reactions of o-alkynylanilines 3
have been mediated by strong bases6 or catalyzed inter alia
by palladium complexes2 and Lewis acids,7 such as CuI.8
Herein, highly efficient, regioselective indole syntheses are
reported, that are based on amination reactions of o-
alkynylhaloarenes 2 (Scheme 1). Furthermore, a multicata-
lytic one-pot indole synthesis consisting of a Sonogashira
reaction and an amination reaction with subsequent cycliza-
tion is presented. This multicatalytic reaction is accomplished
by a single catalytic system.
Scheme 1. Indole Synthesis Using o-Dihaloarenes
(1) (a) Gilchrist, T. L. Heterocyclic Chemistry; Addison-Wesley
Longman Limited: Singapore, 1997. (b) Joule, J. A.; Mills K.; Smith, G.
F. Heterocyclic Chemistry; Stanley Thornes Ltd.: Cheltenham, 1995.
(2) (a) Utimoto, K.; Miwa, H.; Nozaki, H. Tetrahedron Lett. 1981, 22,
4277-4278. (b) Irtani, K.; Matsubara, S.; Utimoto, K. Tetrahedron Lett.
1988, 29, 1799-1802. (c) Arcadi, A.; Cacchi, S.; Marinelli, F. Tetrahedron
Lett. 1989, 30, 2581-2584. (d) Cacchi, S.; Carnicelli, V.; Marinelli, F. J.
Organomet. Chem. 1994, 475, 289-296. (e) Tsuji, J. Palladium Reagents
and Catalysts, 2nd ed.; Wiley: Chichester, 2004; pp 211-216. (f) Leni,
G.; Larock, R. C. Chem. ReV. 2004, 104, 2285-2309.
(3) (a) For a review, see: Larock, R. C. J. Organomet. Chem. 1999,
576, 111-124. Selected recent examples: (b) Chen, C.; Lieberman, D. R.;
Larsen, R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1997, 62,
2676-2677. (c) Nazare´, M.; Schneider, C.; Lindenschmidt, A.; Will, D.
W. Angew. Chem., Int. Ed. 2004, 43, 4526-4528. (d) Ackermann, L.;
Kaspar, L. T.; Gschrei, C. J. Chem. Commun. 2004, 2824-2825.
10.1021/ol047649j CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/07/2005

Preliminary studies showed that a palladium complex
generated from the sterically hindered N-heterocyclic carbene
precursor 5 (Figure 1), in combination with KO-t-Bu,9 was
Table 1. Palladium-Catalyzed Indole Synthesisa
Figure 1. Imidazolium salt 5.
an efficient catalyst for the direct conversion of alkynes 210
to the corresponding indoles 4 in 2 h with excellent isolated
yields (Table 1).11 In contrast to the previously described
method,4 the protocol was not only applicable to sterically
hindered amines (entry 3), but to simple less sterically
demanding alkyl-substituted amines (entries 4 and 5).
Furthermore, it was not limited to simple alkyl-substituted
alkynes, but was used for the conversion of aryl- and t-Bu-
substituted derivatives with excellent yields. Different N-
protecting groups, such as benzyl- (entries 2, 8, and 9) or
p-methoxybenzyl (PMB) (entry 6), could be introduced via
the corresponding amine, allowing for further elaboration
of the resulting indoles. Additionally, mild bases, such as
12
Cs2CO3 or less expensive and less toxic K3PO4 could be
(4) For a two-step, one-pot approach consisting of a hydroamination and
a subsequent intramolecular palladium-catalyzed amination reaction, see:
Siebenreicher, H.; Bytschkov, I.; Doye, S. Angew. Chem., Int. Ed. 2003,
42, 3042-3044.
(5) (a) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576,
125-146. (b) Hartwig, J. F. In Modern Amination Methods; Ricci, A., Ed.;
Wiley-VCH: Weinheim, 2000; pp 195-262. (c) Tsuji, J. Palladium
Reagents and Catalysts, 2nd ed.; Wiley: Chichester, 2004; pp 373-391.
(6) (a) Rodriguez, A. L.; Koradin, C.; Dohle, W.; Knochel, P. Angew.
Chem., Int. Ed. 2000, 39, 2488-2490. (b) For a review, see: Seayad, J.;
Tillack, A.; Hartung, C. G.; Beller, M. AdV. Synth. Catal. 2002, 344, 795-
813.
(7) (a) For a recent example, see: Hiroya, K.; Itoh, S.; Sakamoto, T. J.
Org. Chem. 2004, 69, 1126-1136. (b) See also: Barluenga, J.; Trincado,
M.; Gonza´lez, J. Angew. Chem., Int. Ed. 2003, 42, 2406-2409 and
references therein.
(8) Early examples: (a) Castro, C. E.; Stephens, R. D. J. Org. Chem.
1963, 28, 2163. (b) Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org.
Chem. 1966, 31, 4071-4078.
(9) For the use of heterocyclic carbene ligands in C-N bond-forming
processes, see: (a) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1,
1307-1309. (b) Stauffer, S. R.; Lee, S.; Stambuli, J. P.; Hauck, S. I.;
Hartwig, J. F. Org. Lett. 2000, 2, 1423-1426.
(10) Alkynes 2 were obtained from o-dihaloarenes 1 with excellent
selectivity in 73-96% isolated yields by Sonogashira coupling reactions
using Pd(PPh3)2Cl2 and CuI. For a review, see: Marsden, J. A.; Haley, M.
M. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; pp 317-394.
(11) Representative Procedure for Palladium-Catalyzed Indole
Synthesis: 2-Phenyl-1-p-tolyl-1H-indole (4a). To a solution of Pd(OAc)2
(11 mg, 0.05 mmol, 5 mol %), HIPrCl (5) (21 mg, 0.05 mmol, 5 mol %),
and KOt-Bu (336 mg, 3.0 mmol) in PhMe (3 mL) were added 1-chloro-
2-phenylethynylbenzene (212 mg, 1.0 mmol) and 4-methylaniline (129 mg,
1.2 mmol) at room temperature. The resulting red mixture was stirred at
105 °C for 2 h, after which GC/MS analysis indicated complete conversion
of the starting material. CH2Cl2 (50 mL) and aq HCl (2 N, 50 mL) were
added to the cooled reaction mixture. The separated aqueous phase was
extracted with CH2Cl2 (2 × 50 mL). The combined organic layers were
dried over MgSO4 and concentrated in vacuo. The remaining residue was
purified by column chromatography on silica gel (n-pentane/Et2O, 200/1)
to yield 4a as a white solid (282 mg, 99%).
a Alkyne (1.0 mmol), amine (1.2 mmol), Pd(OAc)2 (5 mol %), HIPrCl
(5) (5 mol %) in PhMe (3 mL), 105 °C. b A: KO-t-Bu (3 mmol); B: K3PO4
(3 mmol), 16 h; C: CuI (5 mol %), K3PO4 (3 mmol), 5-18 h.
employed (entry 9), thereby expanding the functional group
tolerance significantly.13 Longer reaction times, and in some
cases, incomplete cyclization of the amination product 3 were
observed using these bases,14 suggesting an acceleration of
the ring closing reaction by KO-t-Bu.6 Because copper salts
were frequently used for the cyclization of o-alkynylanilines
440
Org. Lett., Vol. 7, No. 3, 2005

3,8 such problems could be circumvented by addition of 5
mol % CuI to the catalytic system, leading to quantitative
conversion to the corresponding indoles 4j, 4k, and 4a, when
using K3PO4 (entries 10-12).
Recently, renewed interest has focused on the copper-
catalyzed Ullman-Goldberg amination reaction.15 “Ligand-
free” CuI-catalyzed amination reactions employing KO-t-
Bu as base have also been described.16 Consequently, the
possibility of accomplishing a copper-catalyzed indole
synthesis was explored (Table 2).
these reaction conditions gave mainly rise to the correspond-
ing hydroamination product. This suggests that here a
sequence consisting of an intermolecular hydroamination and
a subsequent intramolecular amination18,19 is predominantly
operative.
As the palladium amination catalyst was found com-
patible with the addition of substoichiometric amounts of
CuI, a multicatalytic20 one-pot indole synthesis consisting
of a Sonogashira coupling reaction, an amination and
an intramolecular hydroamination sequence was probed
(Scheme 2).21 A combination of commercially available
imidazolium salt 5, Pd(OAc)2, CuI, and Cs2CO3 enabled
quantitative conversion to 4a, which was isolated in 64%
yield.
Table 2. CuI-Catalyzed Indole Synthesisa
Scheme 2. Multicatalytic One-Pot Indole Synthesis
In conclusion, general and efficient approaches to the
indole framework starting from o-alkynylhaloarenes 2 are
presented. These transformations proceed via either a pal-
ladium- or a copper-catalyzed amination reaction, and are
applicable to alkyl- and aryl-substituted alkynes and amines.
Furthermore, they allow for the use of mild bases, such as
K3PO4, and the introduction of different protecting groups
at nitrogen of the indole moiety. Remarkably, a one-pot
indole synthesis starting from ortho-chloroiodobenzene is
viable using a single catalytic system consisting of Pd(OAc)2,
CuI, HIPrCl (5), and Cs2CO3.
(14) The use of K3PO4 instead of KO-t-Bu under otherwise identical
conditions to the one outlined in Table 1, entry 8, yielded exclusively the
corresponding amine 3, supporting the sequence outlined in Scheme 1.
(15) (a) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400-5449. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428-
2439.
(16) Kelkar, A. A.; Patil, N. M.; Chaudhari, R. V. Tetrahedron Lett.
2002, 43, 7143-7146.
a Isolated yields; alkyne (1.0 mmol), amine (1.2 mmol), KO-t-Bu (3.0
mmol), and CuI (10 mol %) in PhMe (3 mL), 105 °C. b Conversion of 2
by GC analysis, 48 h.
(17) Representative Procedure for CuI-Catalyzed Indole Synthe-
sis: 2-n-Hexyl-1-p-tolyl-1H-indole (4n). To a solution of CuI (18 mg, 0.10
mmol, 10 mol %) and KO-t-Bu (336 mg, 3.0 mmol) in PhMe (3 mL) were
added 1-bromo-2-oct-1-ynylbenzene (265 mg, 1.0 mmol) and 4-methyl-
aniline (129 mg, 1.2 mmol) at room temperature. The resulting mixture
was stirred at 105 °C for 2 h, after which GC/MS analysis indicated complete
conversion of the starting material. CH2Cl2 (50 mL) and aq HCl (2 N, 50
mL) were added to the cooled reaction mixture. The separated aqueous
phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic layers
were dried over MgSO4 and concentrated in vacuo. The remaining residue
was purified by column chromatography on silica gel (n-pentane/Et2O, 200/1
f 50/1) to yield 4n as a yellow oil (195 mg, 67%).
Aryl chlorides reacted sluggishly and low isolated yields
were obtained due to the formation of byproducts (entries 1
and 2). However, complete conversion was obtained for the
corresponding aryl bromides, allowing isolation of the indoles
in high yields after only 2 h (entries 3-7).17
Subjecting the o-alkynylbromoarene 2 employed in Table
2, entries 3-6, and the secondary amine N-methylaniline to
(18) For copper-catalyzed intramolecular amination reactions of aryl
chlorides under mild conditions, see: Kwong, F. Y.; Buchwald, S. L. Org.
Lett. 2003, 5, 793-796.
(19) KO-t-Bu can assist similar cyclization reactions via formation of
an aryne intermediate. See, for example: Beller, M.; Breindl, C.; Riermeier,
T. H.; Tillack, A. J. Org. Chem. 2001, 66, 1403-1412.
(12) Under otherwise identical reaction conditions to the ones outlined
in Table 1, entry 9, the use of Cs2CO3 or KOAc instead of K3PO4 led to
complete conversion (4j: 40% isolated yield) and no conversion of the
corresponding alkyne, respectively.
(13) Wolfe, J. P.; Buchwald, S. L. Tetrahedron Lett. 1997, 38, 6359-
6362.
(20) Lee, J. M.; Na, Y.; Han, H.; Chang, S. Chem. Soc. ReV. 2004, 33,
302-312.
(21) For the use of N-heterocyclic carbene palladium complexes for
Sonogashira coupling reactions, see: Yang, C.; Nolan, S. P. Organometallics
2002, 21, 1020-1022.
Org. Lett., Vol. 7, No. 3, 2005
441

Acknowledgment. Support by Professor Paul Knochel
and the Ludwig-Maximilians-Universita¨t, as well as the
DFG through an Emmy Noether fellowship, is gratefully
acknowledged. The author thanks Sebastian Barfu¨sser for
the synthesis of starting materials.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
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