Platform for Ring-Fluorinated Benzoheterole Derivatives: Palladium-Catalyzed Regioselective 1,1-Difluoroallylation and Heck Cyclization

Abstract

The synthesis of difluoromethylene-containing heterocycles was achieved via the palladium-catalyzed 1,1-difluoroallylation of heteronucleophiles followed by intramolecular Heck reaction. The allylic substitution of 3-bromo-3,3-difluoropropene was regioselectively accomplished by heteronucleophiles without rearrangement to give the corresponding 1,1-difluoroallylated compounds whose Heck cyclization proceeded in a 5-exo manner to afford ring-difluorinated indolines and dihydrobenzofurans. Their defluorinative allylic substitution further provided 2-fluoroindoles and 2-fluorobenzofurans.

Synthesis of Diverse α‐Fluoroalkoxyaryl Derivatives and Their Use for the Generation of Fluorinated Macrocycles

“…As interest into this functionality has grown, there has been much synthetic effort made towards the installation of a variety of CF 2 ‐bearing groups into important scaffolds resulting in numerous innovative and efficient approaches . One such approach was recently reported by Ichikawa and co‐workers and is based on an α‐selective Tsuji–Trost allylation to introduce a difluoropropene chain onto a number of substituted 2‐bromophenols 4 (Scheme ) …”

“…[15] This methodology gives rapid entry to the ArOCF 2 Rfunctionality and therefore was deemed to be ag reat startingp oint for this work. Hyperconjugative p-s* CÀF interaction rationale for the reduced inplanec onformationalp reference of af luoroalkoxyaryl group, as exemplified by PhOCF 2 CF 2 H. [14] Scheme1.1,1-Difluoroallylationofortho bromophenol according to Ichikawa et al [15] [a] Dr. strated only on substituted 2-bromophenols, could be applied to furthere xamples including 3-and 4-bromophenols, which gave 6b and 6c with no loss of yield. The reaction, which had previously been demon- Figure 1.…”

“…With this in mind, the current scope, reported by Ichikawa and co-workers, was examineda nd expanded (Scheme 2). [15] To build on this result and to access more complexd ifluorinated compoundsb yt his approach, it would be desirable to modify the resulting alkene into ar ange of functionalities. Hyperconjugative p-s* CÀF interaction rationale for the reduced inplanec onformationalp reference of af luoroalkoxyaryl group, as exemplified by PhOCF 2 CF 2 H. [14] Scheme1.1,1-Difluoroallylationofortho bromophenol according to Ichikawa et al [15] [a] Dr. strated only on substituted 2-bromophenols, could be applied to furthere xamples including 3-and 4-bromophenols, which gave 6b and 6c with no loss of yield.…”

The role of allyl ammonium salts in palladium-catalyzed cascade reactions towards the synthesis of spiro-fused heterocycles

“…2a , entry 5). It should be noted that related fluorinated heterocycles in general cannot be easily prepared 54 and that to the best of our knowledge no example of such spiro compounds has been reported yet. Apart from 2e , other related ammonium salts 2f – 2i underwent similar coupling processes to provide the desired product 4c in slight lower yield (62–75%) (for details see Supplementary Information, Supplementary Table 2 ).…”

Transition‐Metal‐Mediated and ‐Catalyzed C−F Bond Activation by Fluorine Elimination

“…[14] In contrast, the addition of triethylsilane causes transmetalation of dienylnickel(II) fluorides D to generate nickel(II) hydrides.Subsequent reductive elimination leads to the exclusive formation of 1,1-difluoro-1,4-dienes by single activation of aCÀFbond of the CF 3 group Angewandte Chemie (Scheme 7b). [15] This type of catalytic reaction was also applied successfully to perfluoroalkylalkenes [15] and difluoroallyl compounds [16] to afford the corresponding monofluoroalkenes.T herefore,w es ucceeded in the product-switchable, selective single or double CÀFb ond activation of the CF 3 group in the catalytic coupling of 2-trifluoromethyl-1-alkenes and alkynes. Thegroup of Bi and Liu calculated the energy barriers for two major possible routes for the first C À Fb ond cleavage from nickelacyclopropanes F,w hich we have observed experimentally,t oi ntermediates D (Figure 1).…”