Ruthenium‐Catalyzed meta‐C_Ar–H Bond Difluoroalkylation of 2‐Phenoxypyridines

Abstract

A ruthenium‐catalyzed meta‐selective CAr–H bond difluoroalkylation of 2‐phenoxypyridine using 2‐bromo‐2,2‐difluoroacetate has been developed. Mechanistic studies indicated that this difluoroalkylation might involve a radical process. Furthermore, a new method is reported for the synthesis of 2‐(meta‐difluoroalkylphenoxy)pyridine derivatives, which are present in many pharmaceuticals and other functional compounds.

Recent Developments in Remote Meta‐C−H Bond Functionalizations

“…Therefore, the introduction of dilfuoromethylene group, in particular, is very effective for biologically active compounds and also employed as bioisostere for oxygen atom [133,134] . To this context, Cui and teammates have used the inspiring from Ru‐catalyzed C−H bonds activation/functionalization and revealed a novel protocol for difluoroalkylation at meta‐ position of phenol derivatives (e. g. 2‐phenoxypyridine) as depicted in the Scheme 31 [135] . Although in their experimentations, they have attempted different Ru‐catalyst viz RuCl 3 , Ru 3 (CO) 12 , Ru(PPh 3 ) 3 Cl 2 , and [Ru(p‐cymene)Cl 2 ] 2 as well as solvents but RuCl 3 in dichloroethane (DCE) provided the better results.…”

“…[133,134] To this context, Cui and teammates have used the inspiring from Ru-catalyzed CÀ H bonds activation/functionalization and revealed a novel protocol for difluoroalkylation at meta-position of phenol derivatives (e. g. 2-phenoxypyridine) as depicted in the Scheme 31. [135] Although in their experimentations, they have attempted different Ru-catalyst viz RuCl 3 , Ru 3 (CO) 12 , Ru(PPh 3 ) 3 Cl 2 , and [Ru(p-cymene)Cl 2 ] 2 as well as solvents but RuCl 3 in dichloroethane (DCE) provided the better results. With optimized conditions in hands, they examined the scope of the reaction with diverse substituted phenol derivatives and difluoroalkylating reagents to diverse meta-functionalized phenol derivatives.…”

Promising reagents for difluoroalkylation

“…Recently, the Ru-catalyzed meta-C-H bond difluoroalkylation of 2-phenoxypyridines was realized by the Cui group (Scheme 82b). 165 The ruthenium(II)-catalyzed para-and meta-selective C-H difluoroalkylation of aniline derivatives with BrCF 2 CO 2 Et was reported by the Liang group (Scheme 83). 166 Mechanistic investigation implied that the key factor of the para-selective difluoroacetylation derived from the cycloruthenation that occurred at N-H and C-H simultaneously.…”

Regiodivergent C−H and Decarboxylative C−C Alkylation by Ruthenium Catalysis: ortho versus meta Position‐Selectivity

“…[4] Especially,s ite-selective ortho-, [5] meta- [6] as well as para-alkylations [7] of arenes were devised by ruthenium catalysis,w ith major contributions by the groups of Frost, [8] and Ackermann, [9] among others. [10] Ty pically,s econdary and tertiary alkyl halides result in C À H alkylations at the meta-orpara-position with excellent levels of selectivity.Incontrast, ortho-alkylated arenes were thus far predominantly obtained with primary alkyl halides (Scheme 1a).…”