Progress of Difluoromethyl Heteroaryl Sulfones as Difluoroalkylation Reagents

Abstract

Due to the uniqueness of fluorine atom and C-F bond, difluoromethylene has special properties. As a bioisostere of an oxygen or a carbonyl group, it plays an important role in medicines, pesticides and materials. Difluoromethyl heteroaryl sulfones, represented by 2-PySO 2 CF 2 H (Hu reagent), have been developed recently as difluoromethylation reagents, and widely recognized by synthetic chemists for their ease of preparation, good functional group tolerance and universal applicability to a wide range of carbonyl compounds. Through different types of reactions such as nucleophilic substitution, nucleophilic addition, Julia-Kocienski olefination reaction, and radical-mediated difunctionalization, they introduced difluoromethyl, difluoromethylene, gem-difluoroalkene and other fluorine-containing groups into aldehydes, ketones, and heterocyclic compounds. For the first time, the synthesis of fluorine-containing organic compounds involved in various difluoromethyl heteroaryl sulfones in the past decade is reviewed from the perspective of reaction types and their application studies.

Copper-Catalyzed Difluoroalkylation Reaction

“…Various catalysts (Pd, [ 7 ] Ir, [ 8 , 9 ] Cu [ 10 ], Ni [ 11 ], etc. [ 12 , 13 ]) have been successfully applied in difluoroalkylation reactions [ 14 , 15 , 16 , 17 , 18 , 19 ]. However, it is still a great challenge to selectively control the catalytic cycle and obtain the desired fluorinated compounds by directly using classical transition-metal-catalyzed cross-coupling reactions, as some difluoroalkyl metal species have significantly different properties from their nonfluorinated analogues.…”

Synthesis of Enantiopure Benzo Fused Cyclic Sulfoximines Through Stereoselective [3+2] Cycloaddition between N‐tert‐Butanesulfinyl [(2‐Pyridyl)sulfonyl]‐difluoromethyl Ketimines and Arynes

“…Moreover, the so‐obtained PhSO 2 CF 2 ‐substituted cyclic sulfoximines can be easily transformed into the HCF 2 ‐substituted cyclic sulfoximines through reductive desulfonylation or into the cyclic sulfinamides through stereoselective de‐ tert ‐butylation and formal nucleophilic substitution of the PhSO 2 CF 2 group [21] . Considering that fluorinated heteroaryl sulfones, as represented by difluoromethyl 2‐pyridyl sulfone, have been developed into more versatile fluoroalkylation reagents than the fluorinated phenyl sulfones and widely used for the incorporation of various fluorinated moieties into organic molecules, [31,32] we envisioned that the use of a (heteroarylsulfonyl)difluoromethyl group instead of PhSO 2 CF 2 could provide new opportunities for the transformation of the fluorinated benzo fused cyclic sulfoximines, thus expanding the synthetic application of our previously developed [3+2] cycloaddition reaction between N ‐sulfinimines and arynes. Herein, we report our results using [(2‐pyridyl)sulfonyl]difluoro methyl group (2‐PySO 2 CF 2 ) as a facilitating group ( Scheme 1 ,b ) [33]…”

Promising reagents for difluoroalkylation

“…[1][2][3] Therefore, the development of efficient and simple methods for the introduction of difluoroalkyl groups has received more and more attention in recent years. [4][5][6][7][8] At present, various reagents such as HCF 2 Cl, 9 BrCF 2 P(O)(OEt) 2 , 10 TMSCF 2 Br, 11,12 HFPO, 13 CF 3 ZnBr 2 •CH 3 CN, 5 FSO 2 CF 2 CO 2 H 14 and so on 4,[15][16][17][18] are used for difluoroalkylation reactions. But some side reactions such as dimerization, protonation and other unknown byproducts accompany the difluoroalkylation reaction when some of these reagents especially metal species are employed.…”

“…4 According to the pathways by which the difluoroalkyl halides react, they classified these reactions into four categories: nucleophilic difluoroalkylation, electrophilic difluoroalkylation, radical difluoroalkylation and difluoromethylation by metal-difluorocarbene coupling. There have been some other reviews about difluoroalkylation (CF 2 R) reactions, 4,6,[19][20][21][22] and these reactions will not be described in this review. Besides metal-catalyzed difluoroalkylation reactions, difluor-oalkylation reactions which are conducted under metal-free conditions also have made much progress in recent years, and these reactions will be described in this review.…”