Indole synthesis via palladium-catalyzed intramolecular cyclization of alkynes and imines [14]

Full text of DOI:10.1021/ja000390p

5662
J. Am. Chem. Soc. 2000, 122, 5662-5663
Scheme 1. Palladium-Catalyzed Indole Syntheses
Indole Synthesis via Palladium-Catalyzed
Intramolecular Cyclization of Alkynes and Imines
Akira Takeda, Shin Kamijo, and Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science
Tohoku UniVersity, Sendai 980-8578, Japan
ReceiVed February 2, 2000
Indole is one of the most basic units among a wide variety of
naturally occurring alkaloids, and much attention has been paid
to developing a new methodology for the construction of this
structural framework.1 Among the approaches employing transi-
tion metal catalysts,2 the palladium-catalyzed ring construction
of indole has been investigated widely.3 The previous methods
are categorized under the following three types: the intramolecular
cyclization of 2-alkynylanilines (a in Scheme 1),3a-d Heck-type
cyclization of 2-halo-N-allyl-3e or vinylanilines (b),3f,g and inter-
molecular cycloaddition of 2-haloanilines and internal alkynes
(c).3h-j Therefore, the indole ring is formed between N and C-2
(a), between C-3 and C-aryl (b), and between N and C-2 and
between C-3 and C-aryl (c). We report an entirely new palladium-
catalyzed indole synthesis in which 2-(1-alkynyl)-N-alkylidene-
anilines 1 give 2-substituted-3-(1-alkenyl)indoles 2 in good yields
(eq 1). Here the bond formation takes place between C-2
Table 1. Palladium-Catalyzed Cyclization of Alkynylimines 1a
and C-3 (d).4
The results are summarized in Table 1. When N-benzylidene-
2-(1-pentynyl)aniline (1a) was heated at 100 °C for 25 h in the
presence of 5 mol % palladium acetate and 20 mol % tri-n-
butylphosphine in 1,4-dioxane, 3-((E)-1-butenyl)-2-phenylindole
(2a) was formed in 88% NMR yield (entry 1). It is known that
2- or 3-alkenylindoles are unstable,5 and actually at the beginning
we had difficulty isolating 2a in a pure form. However, we found
that pure 2a could be isolated with Al2O3 column chromatography
(hexane-AcOEt 50-20/1) in 58% yield (entry 1). The hydro-
a Pd(OAc)2 (5 mol%), nBu3P (20 mol%), 1,4-dioxane (0.5 M), 100
°C in the sealed vial. b Isolated yield. Yield in parentheses was
1
determined by H NMR. c Reaction was carried out at 80 °C. d THP,
f
tetrahydropyranyl. e Trans:cis ) 4:1 as determined by 1H NMR. MOM,
methoxymethyl.
genation of 2a with H2/Pd-C gave 3-butyl-2-phenylindole in 60%
yield, confirming the structure of 2a unambiguously. The p-
nitrophenyl-substituted substrate 1b reacted smoothly within 7 h
to give 2b in 70% yield. 4-Pyridyl 1c, 2-thienyl 1d, and 2-(5-
methylfuryl) derivatives 1e afforded the corresponding indoles
2c-e, respectively, in good yields (entries 3-5). Cyclohexyl
derivative 1f afforded the â,â-disubstituted vinylindole 2f in a
good yield. Not only ethyl-substituted derivatives but also the
functional group-substituted 1g-i gave the corresponding indoles
2g-i in moderate isolated yields. An attempt to prepare alkyl-
substituted imines failed because of lack of stability of the
resulting imines.6 Accordingly, we attempted the in situ formation
of the imine from the 2-alkynylaniline 3 and cyclohexanecar-
boxaldehyde followed by subsequent cyclization. This trial
proceeded well and 2j was obtained in 52% yield (eq 2). The in
(1) For a recent review, see: Toyota, M.; Ihara, M. Nat. Prod. Rep. 1998,
15, 327.
(2) (a) For reviews, see: Hegedus, L. S. Angew. Chem., Int. Ed. Engl. 1988,
27, 1113. (b) Colquhoun, H. M.; Holston, J.; Thompson, D. J.; Twigg, M. V.
New Pathway for Organic Synthesis: Practical Applications of Transition
Metals; Plenum Press: New York, 1984; p 148. (c) Sakamoto, T.; Kondo,
Y.; Hiroshi, Y. Heterocycles 1988, 27, 2225.
(3) 2-Alkynylanilines: (a) Taylor, E. C.; Katz, A. H.; Salgado-Zamora,
H.; McKillop, A. Tetrahedron Lett. 1985, 26, 5963. (b) Iritani, K.; Matsubara,
S. Utimoto, K. Tetrahedron Lett. 1988, 29, 1799. (c) Arcadi, A.; Cacchi, S.;
Marinelli, F. Tetrahedron Lett. 1992, 33, 3915. (d) Kondo, Y.; N, Shiga.;
Murata, N.; Sakamoto, T.; Yamanaka, H. Tetrahedron 1994, 50, 11803.
N-Allyl-2-haloanilines: (e) Larock, R. C.; Basu, S. Tetrahedron Lett. 1987,
28, 5291. N-Vinyl-2-haloanilines: (f) Kasahara, A.; Szumi, T.; Murakami,
S.; Yanai, H.; Takatori, M.; Bull. Chem. Soc. Jpn. 1986, 59, 927. (g) Sakamoto,
T.; Nagano, T.; Kondo, Y.; Yamanaka, H. Synthesis 1990, 215. Intermolecular
cycloaddition of 2-haloanilines and alkynes: (h) Larock, R. C.; Yum, E. K.
J. Am. Chem. Soc. 1991, 113, 6689. (i) Larock, R. C.; Yum, E. K.; Refvik,
M. D. J. Org. Chem. 1998, 63, 7652. (j) Roesch, K. R.; Larock, R. C. Org.
Lett. 1999, 1, 1551.
(4) For the C-2-C-3 bond formation via radical cyclization: (a) Fukuyama,
T.; Chen, X.; Peng, G. J. Am. Chem. Soc. 1994, 116, 3127. (b) Tokuyama,
H.; Yamashita, T.; Reding, M. T.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem.
Soc. 1999, 121, 3791. (c) Rainier, J. D.; Kennedy, A. R.; Chase, E. Tetrahedron
Lett. 1999, 40, 6325.
(5) (a) Bergamasco, R.; Porter, Q. N.; Yap, C. Aust. J. Chem. 1977, 30,
1531. (b) Lambert, J. D.; Porter, Q. N. Aust. J. Chem. 1981, 34, 1483. (c)
ComprehensiVe Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon: Oxford, U.K., 1984; Vol. 4, p 282.
10.1021/ja000390p CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/27/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 23, 2000 5663
Scheme 2. Plausible Mechanism
situ reaction of 3 with the other secondary aliphatic aldehydes,
such as 2,2-diphenylethanal, 2-phenylpropanal, and 2-methylpro-
panal, proceeded without problem to give the corresponding
indoles 2k, 2l, and 2m, respectively, in good to acceptable yields.
The in situ reaction of 3 with benzaldehyde gave 2a in 74% NMR
yield.
To clarify the mechanism of this unprecedented palladium-
catalyzed cyclization, the reaction of the deuterated substrate 4
was examined (eq 3). Nondeuterated 2a was produced in 76%
NMR yield. If the oxidative addition of the C-D bond of imine
4 to palladium followed by the carbopalladation or hydropalla-
dation to alkyne takes place, the product deuterated at the C-1
position of the alkenyl substituent should be obtained.7 On the
other hand, when the reaction of nondeuterated 1a was carried
out in the presence of deuterium oxide (1.0 equiv), the deuterated
product 5 was obtained in 80% NMR yield in which D content
Scheme 3
(Scheme 3).10 As previously reported,11 a palladium-hydride
species would be formed by the reaction of Pd(0) with AcOH,
which is generated in situ by the hydrolysis of Ac2O with H2O.12
Actually the reaction of 1a in the presence of 2.5 mol % Pd2-
dba3‚CHCl3, 10 mol % n-Bu3P, and 1.1 equiv of AcOD gave 5
in 42% NMR yield in which D content at C-1 position of alkenyl
substituent was 21%. Furthermore, the above reaction did not
occur in the absence of AcOD.
The palladium-catalyzed intramolecular cyclization of the
alkyne and imine functional groups of 1 gives functionalized
3-alkenylindoles 2, which are not easily available via the
traditional synthetic methods, in good yields. Especially, the three-
component coupling reaction (amine, aldehyde, alkyne) for the
indole synthesis (as shown in eq 2) is attractive. Further studies
are in progress in our laboratories.
at the C-1 position of the alkenyl substituent was 29%.8
Accordingly, the reaction proceeds most probably through the
regioselective insertion of a palladium-hydride species to the
alkyne of 1 (Scheme 2). The resulting vinylpalladium 6 would
give 9 either through the carbopalladation (leading to 7)-â-
hydride elimination pathway or through the oxidative addition
(leading to 8)-reductive elimination route.9 The bond rearrange-
ment of the indolenine 9 would give 2. It is known that the
reaction of Pd(OAc)2 with Bu3P gives Pd(0), Bu3PdO, and Ac2O
Supporting Information Available: Experimental procedures and
spectroscopic and analytical data for relevant compounds (PDF). This
material is available free of charge via the Internet at http://pubs.acs.org.
(6) The reaction of 3 with the corresponding aromatic aldehydes with Na2-
SO4, MgSO4, and Dean-Stark dehydrator was very sluggish and not completed
even after a prolonged reaction time. However, the use of molecular sieves
gave 1a-i in high yields with shorter reaction times. In the case of aliphatic
aldehydes, there was no need to use molecular sieves: (a) Sandler, S. R.;
Karo, W. Organic Functional Group Preparations; Academic Press: Orlando,
FL, 1986; Chapter 12. (b) Layer, R. B. Chem. ReV. 1963, 63, 489.
(7) For a recent review for C-H bond activation, see: (a) Gerald, D. Angew.
Chem., Int. Ed. 1999, 38, 1698. Oxidative addition of aldehyde’s C-H bond
to a transition metal complexes: (b) Barnhart, R. W.; McMorran, D. A.;
Bosnich, B. Chem. Commun. 1997, 589. (c) Kokubo, K.; Matsubara, K.; Miura,
M.; Nomura, M. J. Org. Chem. 1997, 62, 4564. (d) Lenges, C. P.; Brookhart,
M. J. Am. Chem. Soc. 1997, 119, 3165. (e) Kondo, T.; Akazome, M.; Tsuji,
Y.; Watanabe, Y. J. Org. Chem. 1990, 55, 1286.
JA000390P
(9) The intramolecular cyclization of vinylpalladium and aldehydes or
ketones, see: (a) Quan, L. G.; Gevorgyan, V.; Yamamoto, Y. J. Am. Chem.
Soc. 1999, 121, 3545. (b) Gevorgyan, V.; Quan, L. G.; Yamamoto, Y.
Tetrahedron Lett. 1999, 40, 4089. (c) Tao, W.; Silverberg, L. J.; Rheingold,
A. L.; Heck, R. F. Organometallics 1989, 8, 2550. (d) Larock, R. C.; Doty,
M. J.; Cacchi, S. J. Org.Chem. 1993, 58, 4579. For the intramolecular
cyclization of vinylpalladium and imines, see ref 3j.
(10) Mandai, T.; Matsumoto, T.; Tsuji, J.; Saito, S. Tetrahedron Lett. 1993,
34, 2513.
(11) (a) For a review, see: Trost, B. M. Acc. Chem. Res. 1990, 23, 34. (b)
Trost, B. M.; Lee, D. C.; Rise, F. Tetrahedron Lett. 1989, 30, 651.
(12) It is thought that trace amounts of H2O exist in the reaction media,
although a dry solvent was used.
(8) No deuterium was found in the other carbons of the indole product.