Palladium‐Catalyzed C(sp²)−H Alkylation of Aldehyde‐Derived Hydrazones with Functionalized Difluoromethyl Bromides

Abstract

A palladium-catalyzed C(sp(2))-H difluoromethylation of aldehyde-derived hydrazones using bromodifluoromethylated compounds to afford the corresponding functionalized difluoromethylketone hydrazones has been established. It is proposed that a radical/SET mechanism proceeding via a difluoroalkyl radical may be involved in the catalytic cycle. Applications of the methodology to the synthesis of α,α-difluoro-β-ketoesters and α,α-difluoroketones (RCOCF2 H) have been illustrated.

Direct Access to α,α‐Difluoroacylated Arenes by Palladium‐Catalyzed Carbonylation of (Hetero)Aryl Boronic Acid Derivatives

“…The mechanism for the transition metal catalyzed coupling of fluoroalkyl halides has been proposed in several cases. In the presence of either copper, palladium, or nickel, experimental data supports the formation of radicals on the fluorinated carbon by a single‐electron transfer (SET) pathway . To evaluate the possibility for such a pathway under our reaction conditions, the coupling of 2 a and 3 a was performed in the presence of 1,4‐dinitrobenzene as a SET scavenger.…”

Radical‐Mediated Formal C(sp2)–H Functionalization of Aldehyde‐Derived N,N‐Dialkylhydrazones

“…Notably, various functionalized halodifluoromethylated compounds [Hal‐CF 2 ‐FG, with FG = CO 2 Et, CONR 2 , PO(OEt) 2 , SO 2 Ph] have recently been shown to be convenient reagents for accessing difluoromethylated compounds through transition‐metal‐catalyzed radical processes . In 2016, our group reported the synthesis of ( E )‐α,α‐difluoro‐β‐ketohydrazones 25 through Pd‐catalyzed (or Cu‐catalyzed) difluoromethylation of aldehyde‐derived N , N ‐dialkylhydrazones by use of functionalized difluoromethyl bromides as difluoromethyl radical precursors, with a particular focus on ethyl bromodifluoroacetate (BrCF 2 CO 2 Et, 24a ) , . Indeed, this reagent has become particularly popular, because it is practical and inexpensive and provides a convenient functional handle for further elaboration or increasing molecular complexity (Scheme ).…”

“…The Pd‐catalyzed coupling reaction proceeded at 80 °C in dioxane in the presence of AcOK as a base and catalytic Pd 2 (dba) 3 as a source of Pd 0 . Of the several phosphorus ligands that were screened, the bidentate ligand t BuXantphos ( 26 ) was shown to be by far the most effective . However, the use of such an expensive palladium/ligand catalyst system was not really attractive when considering upscaling of reactions for practical, large‐scale applications.…”

“…It is also conceivable that the Pd‐catalyzed process might instead follow a Heck‐type pathway in which the terminating step that restores the hydrazone functional group would be β‐H elimination from a [hydrazinylPd II Br] complex D , resulting from trapping of the hydrazinyl radical by Pd I . It is also of note that carbopalladation of the hydrazones by the regular oxidative addition adduct, [EtO 2 CCF 2 Pd II Br], is also considered as a possible alternative pathway (not shown), which avoids the radical addition step …”

Recent advances in the synthesis of fluorinated hydrazones

“…[25][26][27] Monteiro and co-workers reported a palladium-catalysed C-H diuoromethylation of aldehyde-derived hydrazones (Scheme 5). 28 This method proceeded with low catalyst loading, high regioselectivity, and excellent functional group compatibility. However, the presence of a vinyl substituent on the aryl moiety led to decomposition of the substrate.…”