Alkyne-tethered indoles

An intramolecular iminoannulation reaction of alkyne-tethered indole 169 gave y-carboline 170. Employing this methodology, a wide variety of y-carbolines and related fused systems were obtained <03JOC5132>. 

A synthesis of 2-acyl and 2-alkoxycarbonyl-indoles was carried out by Tamariz and coworkers via an intramolecular Friedel-Crafts heteroannulation of enaminone precursors <06SL749>. A lac type palladium-catalyzed intramolecular indolization of alkyne-tethered 2-chloroanilines has been reported by Lu and co-workers <06OL3573>. 

We have recently reported an intramolecular variant of this annulation process using an alkyne tethered to an indole (Eq. 81) [117,118]. 

In 2014, Rh(III)-catalyzed intramolecular annulation of alkyne-tethered acetanilides for the synthesis of fused tricyclic indoles 3 via C-H activation was developed by the groups of Liu, Jia, and Li [6a-c]. The reactions have a good substrate scope, utilize molecular oxygen as the cooxidant, and proceed with complete regioselectivity. It is interesting to note that only the sterically hindered ortho-C-H bond of the arene moiety participated in C-C bond formation (Eq. (5.3)). Similarly, the cyclization of anilides with allyl carbonates also proceeded to form 2-substituted indoles 4 (Eq. (5.4)) [6d]. 

This methodology has been used to showcase new methodology for catalyst and reaction optimization employing nonaqueous capillary-array electrophoresis coupled with microreaction technology [ 116]. By tethering the alkyne to the nitrogen of the indole ring, one can readily prepare polycyclic substrates (Eq.57) [117,118]. 

The indole 2-3 double bond can participate in a cobalt-mediated combination with two alkyne units. In particular, when one of the alkynes is tethered to the indole nitrogen atom by an acyl group, cyclization occurs to give an unusual dihydrocarbazole such as compound (286), which can be demetallated either to the dihydrocarbazole (287) or to the carbazole (288) (Scheme 84) <86JA2091>. 

Larock heteroannulation reaction was further extended and an intramolecular Larock indole synthesis of 2-chloroanilines bearing tethered acetylenes 106 was developed for the elaboration of a variety of polycyclic indole skeletons 107, for example, in 108-112. This intramolecular indolization method unveiled an unusual >sy -anidopalladation pathway of a tethered alkyne. The major side product is the dechlorinated starting material as a result of a reductive process. 

Recently, palladium(II)-catalyzed arylation/carboxylation reactions were reported for the synthesis of carbazoles starting from 2-alkenyl indoles. These reactions employ the electron-rich C-3 carbon atom of the indole nucleus as carbon nucleophile in cyclization/carboalkoxylation reactions. The conditions that proved effective for 2-(2,3 or 5-alkenyl)-3-unsubstituted indoles are similar to those reported for the cyclization ofalkenes and alkynes bearing tethered heteronucleophiles. In particular, the best results has been obtained using PdCl2(CH3CN)2, CuCl2 in methanol under CO (latm). Under these conditions methyl (9-methyl-2,3,4,9-tetrahydro-4-carbazolyl)acetate 86 was isolated in 94% yield (Scheme 13.53) (100,101]. 

A Rh(III)-catalyzed intramolecular redox-neutral or oxidative cyclization strategy for the rapid synthesis of 3,4-fused indole skeletons from tethered alkynes was... 

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