Palladium‐Catalyzed Cross‐Coupling Reactions of Amines with Alkenyl Bromides: A New Method for the Synthesis of Enamines and Imines

Abstract

The palladium-catalyzed cross-coupling reaction of alkenyl bromides with secondary and primary amines gives rise to enamines and imines, respectively. This new transformation expands the applicability of palladium-catalyzed C-N bond forming reactions (the Buchwald-Hartwig amination), which have mostly been applied to aryl halides. After screening of different ligands, bases, and solvents, the catalytic combination [Pd(2)(dba)(3)]/BINAP in the presence of NaOtBu in toluene gave the best results in the cross-coupling of secondary amines with 1-bromostyrene (dba=dibenzylideneacetone, BINAP=2,2'-bis(diphenylphosphino)-1,1'-binaphthyl). The corresponding enamines are obtained cleanly and in nearly quantitative yields. However, steric hindrance seems to be a limitation of the reaction, as amines carrying large substituents are not well converted. The same methodology can be applied to the coupling of secondary amines with 2-bromostyrene. Moreover, the reaction with substituted 2-bromopropenes allows regioselective synthesis of isomerizable terminal enamines without isomerization of the double bond. The best catalytic conditions for the cross-coupling of 1-bromostyrene with primary amines include again the use of the Pd(0)/BINAP/NaOtBu system. The reaction gives rise to the expected imines in very short times and with low catalyst loadings. A set of structurally diverse imines can be prepared by this methodology through variations in the structure of both coupling partners. However, 2-bromostyrene failed to give good results in this coupling reaction, probably due to product inhibition of the catalytic cycle. Competition experiments of vinyl versus aryl amination reveal that the reaction occurs preferentially on vinyl bromides.

The Buchwald–Hartwig Amination After 25 Years

“…In this context, the arylation of benzophenone hydrazones was coupled to hydrolysis and trapping with an excess of either aldehydes or ketones, which led to a novel entry into the Fischer indole synthesis . Furthermore, alkenyl bromides and triflates could also be used as coupling partners to form enamines and imines upon Pd‐catalyzed amination using BINAP as ligand.…”

“…In addition, RuPhos ( 10 ) turned out to be a superior ligand for the coupling of secondary amines with aryl chlorides . This series of dialkylbiaryl phosphane ligands was not only suitable for the amination and amidation of arenes, but also alkenyl halides and triflates could be converted into imines, enamines, and enamides by Pd‐catalyzed coupling with the corresponding nitrogen‐based nucleophile.…”

Biaryl Phosphane Ligands in Palladium‐Catalyzed Amination

“…[137] For the amination of vinyl bromides with alkyl and aromatic amines Barluenga showed that BINAP was a highly effective ligand. [138,139] In order to utilize vinyl chlorides as substrates, however, DavePhos was required (Scheme 5). [140] Similarly for 1-halo-1,3-butadienes the same workers found that XPhos provided the most useful results (Scheme 6).…”

Synthesis of Substituted 4-, 5-, 6-, and 7-Azaindoles from Aminopyridines via a Cascade C–N Cross-Coupling/Heck Reaction

“…Consequently, metal-catalyzed approaches toward imines and enamines have been developed. 25,26 Simultaneously to our work, Nolan and co-workers reported the α-arylation of stable preformed imines from 3-amino-o-chloropyridines to achieve the corresponding 4-and 6-azaindoles, yet for 5-and 7-azaindoles the method proved to be unsuitable. 22 Our group has been employing metal-catalyzed crosscoupling reactions for the preparation of bioactive heterocycles such as indole and benzimidazole.…”