Indole Synthesis via Palladium-Catalyzed Intramolecular Cyclization of Alkynes and Imines

Abstract

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 transition 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 intermolecular 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 palladiumcatalyzed indole synthesis in which 2-(1-alkynyl)-N-alkylideneanilines 1 give 2-substituted-3-(1-alkenyl)indoles 2 in good yields (eq 1). Here the bond formation takes place between C-2 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-nbutylphosphine 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 Al 2 O 3 column chromatography (hexane-AcOEt 50-20/1) in 58% yield (entry 1). The hydrogenation of 2a with H 2 /Pd-C gave 3-butyl-2-phenylindole in 60% yield, confirming the structure of 2a unambiguously. The pnitrophenyl-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 , -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 alkylsubstituted 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 cyclohexanecarboxaldehyde 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. 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.

Heterogeneous Palladium Catalysts Applied to the Synthesis of 2- and 2,3-Functionalised Indoles

“…[13,14] These methods include the palladium-induced cycloadditions of 2-haloanilines with terminal or internal alkynes (route 1, retrosynthetic disconnections a & e), [15 -18] and the intra-or intermolecular reactions of 2-alkynylanilides with aryl or alkyl halides to give either 2-, or 2,3-functionalised indoles (route 4, disconnections b & e). [19 -22] Other approaches are based on Heck-type cyclization reactions (route 2, disconnection a), [23,24] on reactions of alkynes with imines (route 5, disconnection c) [25] or on heteroannulation sequences achieved through palladium-catalysed arylamination reactions (disconnection f, not represented). [26 -29] Some of these methods have proven to be most powerful and are currently applied in the target-or the diversityoriented synthesis of indoles.…”

A practical Cu(I)-catalyzed domino approach to 1,2-disubstituted indoles and its application for the assembly of indolophenanthridines

“…Toluene, o-xylene and dioxane were distilled from Na; DCE and DMF were distilled from CaH 2 . 2-alkynylanilines 47 and aryl halides 48 were synthesized according to the known literature. All other reagents were obtained from commercial sources and used without further purification, unless stated otherwise.…”

π-Conjugated carbocycles and heterocycles via annulation through C-H and X-Y activation across CC triple bonds

“…-substituted indoles 9, in which the alkenyl group originated from R of alkyne. [77][78][79] Gold(III) or In(III)-catalyzed reaction of ortho-alkynyl-N-sulfonylanilines 10 produced 3-sulfonylindoles 11; [80][81] under certain conditions accompanied by the formation of 6-sulfonylindoles. Platinum(II)-olefin-catalyzed reaction of ortho-alkynylphenyl acetals 12 gave 3-(1-alkoxyethyl)-2-alkylbenzofurans 13 in high yields (Scheme 4).…”