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A new concept of highly chemo- and regioselective formation of the benzene ring by a palladium-catalyzed formal [2 + 2 + 2] sequential intermolecular trimerization of alkynes is proposed. Homodimerization of terminal alkynes and subsequent [4 + 2] benzannulation with diynes gives tetrasubstituted benzenes in moderate to good yields. The introduction of two different alkynes (terminal and internal) in the first step of the sequence allows for construction of pentasubstituted benzenes from three different acyclic acetylenic units. In all cases the tetra- and pentasubstituted benzenes are formed as a single reaction product without being accompanied by any of regio- or chemoisomers. A significant acceleration of the sequential trimerization reaction in the presence of Lewis acid/phosphine combined system was observed. Mechanistic studies reveal that the Lewis acid assisted isomerization of the E-enyne formed in the first step of the sequence to the more reactive Z-isomer is responsible for the observed acceleration effect. The proposed methodology provides a conceptually new and synthetically useful route to multifunctional aromatic compounds.

The enyne-diyne [4+2] cross-benzannulation proceeded smoothly in the presence of Pd(0) catalyst to give 1,2,4-trisubstituted benzenes 8a-j, 1,2,3-trisubstituted benzenes 9a-i, 1,2,3,5-tetrasubstituted benzenes 11a-k, 1,2,3,4-tetrasubstituted benzenes 11l,m, and 1,2,3,4,5-pentasubstituted benzenes 11n-p in moderate to quantitative yields. In all cases the reaction was found to be regiospecific with regard to substitution at the benzene ring. The palladium-catalyzed [4+2] cycloaddition of monosubstituted conjugated enynes 3a-c and 5a with unsymmetrical diynes 13a-j and triynes 16a-g also proceeded with perfect regiochemistry with regard to substitution at the benzene ring. However, since two differently substituted triple bonds are present in the enynophiles 13 and 16, the enyne preference toward either triple bond in the enynophiles became an issue, and in most cases, two regioisomeric products were obtained. The detailed deuterium-labeling studies were performed, and the mechanism of this regiospecific [4+2] cycloaddition between enynes and diynes was proposed.

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.