Palladium‐Catalyzed Carbonylative Coupling of Aryl Iodides with Alkyl Bromides: Efficient Synthesis of Alkyl Aryl Ketones

Abstract

Alkyl aryl ketones are important structures with applications in many areas of chemistry. Hence, efficient procedures for their production are particularly attractive. In this communication, a general and efficient carbonylative cross-coupling of aryl iodides and unactivated alkyl bromides is presented. By using a simple palladium catalyst, a series of alkyl aryl ketones were synthesized in moderate to excellent yields from readily available alkyl and aryl halides in an In-Ex tube with formic acid as the CO source. In this study both primary and secondary alkyl bromides/iodides were suitable coupling partners. Additionally, this method can also be employed for the late-stage functionalization of complex natural products and polyfunctionalized molecules.

Carbonylative Negishi‐Type Coupling of 2‐Iodoglycals with Alkyl and Aryl Halides

“…Tri‐ O ‐benzyl‐2‐iodoglucal ( 2a ) was then selected for the optimization of the reaction conditions for the Negishi‐type carbonylative coupling with 1‐bromobutane (Table ). Initial conditions based on a previous report by Wu and co‐workers[14a] gave 3a in encouraging 56% (Entry 1). Changing the catalyst to a NHC‐based Pd complex, PEPPSI, led to a poor conversion of 2a and the formation of significant amounts of 1a , resulting from de dehalogenation of the starting material (Entry 2).…”

“…While carbonylative reactions to obtain amides, esters, aryl‐ketones and alkynones are widespread, those aiming alkyl‐ketones are much more limited, due to the challenges associated with making C(sp 2 )–C(sp 3 ) bonds.…”

Palladium‐Catalyzed Carbonylative Cross‐Coupling of Aryl Iodides and Alkenyl Bromides with Benzyl Halides under Reductive Conditions

“…A relatively high CO pressure was necessary for this transformation, and the scope was limited to primary benzyl halides. To build on the scope of this method, Wu's group reported a Pd 2 (dba) 3 catalyzed carbonylative cross‐coupling reaction with aliphatic alkyl bromides, providing a series of aliphatic alkyl aryl ketones with formic acid as the CO source [14] (Scheme 3b). Despite the impressive advances in this work, no benzylic halides were employed.…”

Carbonylative Cross-Electrophile Coupling between Aryl Bromides and Aryl Triflates Enabled by Palladium and Rhodium Cooperative Catalysis and CO as Reductant

“…Furthermore, they are part of the core skeleton in many natural products and pharmaceuticals . The tremendous progress in transition-metal-catalyzed carbonylative cross-coupling reactions has made it a powerful strategy for accessing the ketone functionality (Scheme a) . These transition-metal-catalyzed reactions require the combination of an electrophilic coupling partner, typically aryl halides or pseudohalides, with a nucleophilic coupling partner, typically a metal-based reagent .…”

“…The tremendous progress in transition-metal-catalyzed carbonylative cross-coupling reactions has made it a powerful strategy for accessing the ketone functionality (Scheme a) . These transition-metal-catalyzed reactions require the combination of an electrophilic coupling partner, typically aryl halides or pseudohalides, with a nucleophilic coupling partner, typically a metal-based reagent . Unfortunately, many of these metal-based nucleophiles have limited accessibility and stability, which can place restrictions on the substrate scope and affect the functional group tolerance for these normal cross-coupling reactions.…”