Ring‐Closing Metathesis of Vinyl Fluorides towards α‐Fluorinated α,β‐Unsaturated Lactams and Lactones

Abstract

Ring‐closing olefin metathesis reactions (RCM) using Grubbs II or Hoveyda's catalysts have been applied to a series of N‐alkenyl‐N‐benzyl‐α‐fluoroacrylamides. α‐Fluoro‐α,β‐unsaturated γ‐ or δ‐lactams incorporating a fluorinated double bond were obtained in moderate to good yields, depending on the nature of substituents on the benzyl ring. The corresponding seven‐ and eight‐membered lactams were not formed under similar conditions. When the N‐benzyl group was replaced by an N‐tosyl group, the corresponding ϵ‐lactam was also formed in 38 % yield. When N‐(2‐fluoroallyl) derivatives were used instead of fluoroacryloyl derivatives, six‐, seven‐, and eight‐membered N‐heterocycles were obtained in low yields. This method was also used to synthesize fluorinated α,β‐unsaturated analogues of pyrrolizidine and indolizidine alkaloids from prolinol, and also to synthesize N‐benzyl‐3‐fluoroquinolone in three steps from commercially available 2‐vinylaniline in 44 % overall yield. Also 3‐fluorocoumarin and 3‐fluorochromene were prepared from o‐vinylphenol, and 3‐fluoro‐benzoxepine was available from o‐allylphenol.

Computational study of productive and non-productive cycles in fluoroalkene metathesis

“…In contrast to common alkenes, the metathesis of fluoroalkenes has attracted far less attention [ 23 ]. Fluorinated modifications have mostly concentrated on the side chain of the vinyl group [ 24 – 27 ] or applications of 2-fluoroalkenes [ 28 – 30 ]. As an exception, the reaction of the Grubbs 2 nd generation catalyst with 1,1-difluoroethene gave an isolable difluoromethylene-containing ruthenium complex with very poor catalytic activity [ 31 ] and the analogous reaction of 1-fluoroalkene formed a fluoromethylene-containing complex with low catalytic activity [ 32 – 33 ].…”

Metal-Catalyzed Metathesis of Fluorinated Alkenes: Still a Current Major Challenge

“…Further, in 2014 Haufe and co-workers described the synthesis of several α-fluorinated α,βunsaturated lactams, and lactones via an RCM of vinyl fluorides. 21…”

Synthesis of Monofluoroalkenes: A Leap Forward

“…In 2014, the Haufe group developed the ring-closing metathesis of N-alk-ω-enyl-2-fluoroacrylamides to access α-fluorinated α,β-unsaturated lactams and lactones. 162 Various starting materials were studied (Scheme 156) and fluorinated derivatives of pyrrolizinone, indolizinone, and quinolinone were also synthesized.…”