Synthesis of Fluoropyrrolidines and (Fluoroalkyl)pyrrolidines

Abstract

Pyrrolidines and their derivatives are of great interest in medicinal chemistry and organic synthesis. Fluoropyrrolidines and (fluoroalkyl)pyrrolidines have been utilized in the preparation of medicinal drugs and also as organocatalysts. The synthesis of such compounds is achieved through the fluorination of pyrrolidine derivatives or by multistep synthesis from already containing fluoroalkyl precursors.1 Introduction1.1 General Interest of Fluorine-Containing Pyrrolidines1.2 Fluoroalkylpyrrolidines and the Gauche Effect2 Fluoropyrrolidines2.1 3-Fluoropyrrolidines2.2 3,3- and 3,4-Difluoropyrrolidines2.3 3,3,4-Trifluoropyrrolidines2.4 3,3,4,4-Tetrafluoropyrrolidines3 (Difluoromethyl)- and (Trifluoromethyl)pyrrolidines3.1 2-(Trifluoromethyl)pyrrolidines3.2 3- and 4-(Trifluoromethyl)pyrrolidines3.3 2-(Difluoromethyl)pyrrolidines3.4 3- and 4-(Difluoromethyl)pyrrolidines4 (Monofluoroalkyl)pyrrolidines4.1 2-(Monofluoromethyl)pyrrolidines4.2 2-(Monofluoroalkyl)pyrrolidines4.3 2-(Monofluoroalkenyl)pyrrolidines5 Conclusion

Photoinduced Nonstabilized Azomethine Ylide Formation for the Preparation of Fluorine Containing Pyrrolidines

“…Pyrrolidines and in particular 3-fluoro- and 3-fluoroalkylpyrrolidines play an important role in drug discovery, as illustrated by the development of new important classes of antibiotics, modified amino acids, and nucleoside phosphorylase inhibitors . The preparation of these derivatives was achieved by 1,3-dipolar cycloaddition reaction from alkenes and nonstabilized azomethine ylide precursor 1 (Scheme ).…”

Horner–Wadsworth–Emmons reaction as an excellent tool in the synthesis of fluoro-containing biologically important compounds

“…Such compounds are used as peptide isosteres in the design of enzyme inhibitors or as organocatalysts. 116…”

“…Such compounds are used as peptide isosteres in the design of enzyme inhibitors or as organocatalysts. 116 Lequeux, in his latest publication, employed the HWE reaction to yield a series of fluorovinylsulfones 174 (Table 10), which may be used as precursors of fluoropeptidomimetics. For this purpose, sulfone 9 was reacted with aldehydes 173 under LiCl and NEt 3 in THF.…”

The Asymmetric Construction α‐CF2H Pyrrolidine via 1,3‐Dipolar Cycloaddition of N‐2,2‐Difluoroethylthioisatin Ketoimines with Meldrum's Acid Derived Electron‐Deficient Olefins

“…As a consequence, the asymmetric synthesis of difluoromethyl substituted pyrrolidine derivatives has become an area of intense research activity. While significant progress has been made in the construction of optically pure monofluoromethyl or trifluoromethyl containing compounds in the past few decades, the asymmetric synthesis of α ‐ or β ‐(difluoromethyl) pyrrolidines and their derivatives remain an area of limited success [8] . Until now, the synthesis of optically pure difluoromethylated pyrrolidine mostly was through the functional group conversion of optically pure pyrrolidine derivatives, and there are very few effective asymmetric synthesis strategies for the enantioselective construction of pyrrolidines [9–15] …”

“…While significant progress has been made in the construction of optically pure monofluoromethyl or trifluoromethyl containing compounds in the past few decades, the asymmetric synthesis of αor β-(difluoromethyl) pyrrolidines and their derivatives remain an area of limited success. [8] Until now, the synthesis of optically pure difluoromethylated pyrrolidine mostly was through the functional group conversion of optically pure pyrrolidine derivatives, and there are very few effective asymmetric synthesis strategies for the enantioselective construction of pyrrolidines. [9][10][11][12][13][14][15] In this context, the 1,3-dipolar cycloaddition reaction of azomethine ylides with alkenes is arguably one of the most straightforward and most efficient strategy to access chiral pyrrolidine derivatives.…”