gem‐Difluoroolefination of Diaryl Ketones and Enolizable Aldehydes with Difluoromethyl 2‐Pyridyl Sulfone: New Insights into the Julia–Kocienski Reaction

Abstract

The direct conversion of diaryl ketones and enolizable aliphatic aldehydes into gem-difluoroalkenes has been a long-standing challenge in organofluorine chemistry. Herein, we report efficient strategies to tackle this problem by using difluoromethyl 2-pyridyl sulfone as a general gem-difluoroolefination reagent. The gem-difluoroolefination of diaryl ketones proceeds by acid-promoted Smiles rearrangement of the carbinol intermediate; the gem-difluoroolefination is otherwise difficult to achieve through a conventional Julia-Kocienski olefination protocol under basic conditions due to the retro-aldol type decomposition of the key intermediate. Efficient gem-difluoroolefination of aliphatic aldehydes was achieved by the use of an amide base generated in situ (from CsF and tris(trimethylsilyl)amine), which diminishes the undesired enolization of aliphatic aldehydes and provides a powerful synthetic method for chemoselective gem-difluoroolefination of multi-carbonyl compounds. Our results provide new insights into the mechanistic understanding of the classical Julia-Kocienski reaction.

Copper-Catalyzed Asymmetric Defluoroborylation of 1-(Trifluoromethyl)Alkenes

“…[2][3][4][5][6] Although impressive progress has been made in the synthesis of gem-difluoroalkenes in recent years, for example, the classical Wittig olefination and Julia-Kocienski reaction, some issues remain unresolved. [7][8][9][10][11][12][13][14][15][16][17][18] First, most traditional approaches require strong bases, which leads to a limited substrate scope and low efficiency; second, the a position of a gem-difluorovinyl group in a drug candidate is usually a chiral carbon center, and the induction of enantioselectivity at this position is still challenging 19 ; third, the rapid and efficient installation of a range of functional groups such as hydroxyl, amino, and alkyl substituents to a position of a difluorovinyl group is in high demand. On the other hand, a-chiral boronate-substituted compounds are an important family of target molecules, because the C-B linkage provides an extremely useful stereogenic center.…”

One‐Pot Generation of Benzynes from Phenols: Formation of Primary Anilines by the Deoxyamination of Phenols

“…[9] The use of 5.0 equiv KHMDS insteado f 3.0 equiv led to the formation of 3a in al ower yield (31%), and ag reater amounto f2a (54 %) was recovered (entry 2). We then explored the use of severala dditives, such as 18-crown-6, Me 3 SiCl, and (Me 3 Si) 3 N, [10] to enhancet he formation of 1a.T he addition of 18-crown-6 or Me 3 SiCl resultedi ns ignificantly inferior yields of 3a;i .e.,2 1and 1%,r espectively (entries 3a nd 4). In sharp contrast, the addition of (Me 3 Si) 3 Ni mprovedt he yield of 3a to 77 and 65 %( entries 5a nd 6).…”

“…At the same time, the strongly nucleophilic KNHSiMe 3 ,g enerated by the reaction between KF and HMDS, can attack the sulfonyl group of 4 to form 2 (see Scheme 3). The addition of (Me 3 Si) 3 Nisexpected to quench KNHSiMe 3 and/or KF to regenerate KHMDS and suppress the regenerationo f2, [10] leading to an increase in the yields of 3 and 5 (see Ta ble 1a nd Scheme 3).…”

Iminoiodane- and Brønsted Base-Mediated Cross Dehydrogenative Coupling of Cyclic Ethers with 1,3-Dicarbonyl Compounds

“…1). This test gave 4n along with a 1:1 mixture of 2a and 3n in 35% and 43% yield, respectively, with the latter two adducts being obtained, presumably, from a competitive retro-Mannich-type pathway [113,114,115,116,117,118]. The role of DBU in mediating the cyclization of the 1,4 amino aldol was also supported by our findings showing the recovery of the substrate on treating it to the standard conditions in the absence of the Schiff base (Scheme 3, Equation (2)).…”