Hydroamination/Heck reaction sequence for a highly regioselective one-pot synthesis of indoles using 2-chloroaniline

Abstract

A one-pot indole synthesis consisting of a highly regioselective TiCl(4)-catalyzed hydroamination and a 5-endo Heck cyclization starting from 2-chloroaniline is described, using an in-situ generated, sterically hindered imidazol-2-ylidene palladium complex.

Modular N,O‐Chelating Ligands: Group‐4 Amidate Complexes for Catalytic Hydroamination

“…There are no side products in this reaction, thus hydroamination can be used in a tandem reaction sequence, utilizing the imine as an in situ intermediate. [65][66][67][68] Following an initial report of titanium catalyzed hydroamination by Rothwell and coworkers, [69] research into hydroamination catalysis has also followed the trend of focusing on Cp-based ligand systems and then moving onto non-Cp-based catalysts. A variety of systems have been developed for hydroamination reactions including work from the groups of Bergman, [15,64,[70][71][72][73] Livinghouse, [74,75] Odom, [67,[76][77][78][79][80][81] Beller, [65,[82][83][84][85][86] Doye, [87][88][89][90][91][92][93][94] ourselves, [59,61,62,95,96] and others.…”

Transition‐Metal‐Catalyzed Hydroamination Reactions

“…Approaches for indole synthesis using hydroamination as a key step in their syntheses has been an ongoing area of investigation over the past several years [329,330]. Early examples focused on one-pot intermolecular hydrohydrazination followed by the Lewis-acid-catalyzed Fischer indole synthesis [331,332] (Scheme 15.102) or one-pot intermolecular hydroamination followed by cross-coupling to either form a C-N bond (via the Buchwald-Hartwig amination) [333] (Scheme 15.103) or a C-C bond (via a Heck reaction) [334,335] (Scheme 15.104). Alternatively, σ-alkynylanilines can be used directly as substrates for intramolecular hydroamination (Scheme 15.105) [198,200,[336][337][338][339][340].…”

The Palladium‐Catalyzed Synthesis of Aromatic Heterocycles

“…This latter approach can provide a very effective method to selectively incorporate a range of alkyl, aryl or functionalized units into the 3-indole position, many of which are not easily accessible via other routes. A variant of this reaction involves the formation of the enamine precursors for Heck cyclization via the hydroamination of alkynes [76]. Examples of this transformation are shown in Scheme 6.55.…”