The Catalytic Synthesis of N-Aryl Indoles Featuring an Alternative Disconnection. Hydroaminoalkylation for a Telescoped Reaction Sequence

Abstract

A tricatalytic telescoped synthesis toward C3methyl-N-aryl indoline and indole products is reported. An in situ generated tantalum(V) ureate catalyst is used for the hydroaminoalkylation of o-chlorostyrene with N-methylaniline to first make a C sp 3 �C sp 3 bond. Subsequent nickel-catalyzed C−N coupling forms N-aryl indolines, and if desired, subsequent oxidation to N-aryl indoles can be achieved using catalytic [Cu(MeCN) 4 ]BF 4 and tert-butylperoxy-2-ethylhexyl carbonate as the terminal oxidant. This strategy highlights an alternative C−C bond disconnection for the synthesis of indoles, which is enabled by the atom-economic hydroaminoalkylation reaction. The method was streamlined using a three-step, two-pot approach to afford up to 73% overall isolated yield of variously substituted C3-methyl-Naryl indoles.

Recent Advances in Saturated N-Heterocycle C–H Bond Functionalization for Alkylated N-Heterocycle Synthesis

“…25,30 Recent efforts in developing group 4 and 5 hydroaminoalkylation catalysts have uncovered excellent reactivity, broad substrate scope, and preliminary efforts toward enantioselectivity. 29,[31][32][33][34][35][36][37][38][39][40][41] Early transition metal hydroaminoalkylation proceeds via a proposed metallaaziridine, generated from amine + early transition metal precatalyst, and subsequent alkene or alkyne insertion to form a new  C-C bond (Scheme 2). Another equivalent of amine is responsible for protonolysis and subsequent product release followed by regeneration of the metallaaziridine.…”

“…For example, Schafer and co-workers applied hydroaminoalkylation as an early stage technique to access Narylated indoles in up to 73% yield over three-steps requiring a single purification (Scheme 3). 31 As N-arylated indoles have known uses as antipsychotic 54 and anticancer 55 drug candidates, the inclusion of ETM catalysis in constructing these privileged scaffolds offers an expansion of the synthetic chemist's toolbox.…”

A General Protocol toward Synthesis of 3-Methylindoles Using Acenaphthoimidazolyidene-Ligated Oxazoline Palladacycle

“…T he indole ring is among the most ubiquitous heterocycles in nature. − Particularly, an indole nucleus featuring a methyl at the 3-position is referred as a “privileged structure”, called 3-methylindole, which enables a high affinity toward binding to many receptors (Scheme a). − For well over a hundred years, efficient synthetic methods − and direct functionalization − via organo-, , electro-, , and photocatalysis − of indoles still remain the core object of focus for chemists. In comparison with Fischer indole synthesis, transition metal catalysis via Pd chemistry is emerging as a powerful synthetic strategy for indoles. ,,, However, a convenient straightforward access to 3-methylindoles has been somewhat neglected to date. − Jørgensen et al first presented a route to synthesize 3-substituted indoles from 2-bromoiodobenzenes and allylamines at 140 °C . Recently Ye et al advanced relevant synthetic methodology via a Pd-mediated nucleomethylation of presynthesized 2-alkynylanilides with methylboronic acid .…”