Synthesis of (Difluoromethyl)cycloalkenes from 2‐Cycloalkenones by Utilizing Phospha‐Brook Rearrangement

Abstract

Difluoromethyl‐substituted allylic phosphates were synthesized from 2‐cycloalkenones through the addition of a (difluoromethyl)phosphonate and subsequent phospha‐Brook rearrangement. The obtained allylic phosphates were converted to the corresponding difluoromethyl‐substituted cycloalkenes using the Cu‐mediated SN2’ reaction of Grignard or organolithium reagents.magnified image

Synthesis of 1-(Difluoromethyl)alk-1-enes via Palladium-Catalyzed SN2′-Type Substitution Reaction of Difluoromethylated Allylic Phosphates with 1,3-Dicarbonyl Compounds and Imides

“…The scope of the Pd-catalyzed allylic substitution was then investigated, and the results are shown in Figure . Cyclopentenyl phosphate 4b readily undergoes dephosphorylation during column chromatography . Consequently, 4b was prepared via a phospha-Brook rearrangement of the isolated phosphonate adduct generated from cyclopentenone and LiCF 2 PO­(OEt) 2 and then directly subjected to the Pd-catalyzed allylic substitution reaction with 5a .…”

“…CF 2 HPO­(OEt) 2 , 1,3-dicarbonyl compounds, and dry solvents were purchased and used as received. Allylic phosphates 4a–4d , trans - 4e , cis - 4f , and 4j were synthesized in our previous study …”

“…Nevertheless, the synthesis of 1-(difluoromethyl)­alkenes has been underdeveloped because the pregeneration of special reagents and/or the use of expensive difluoromethylating agents are still necessary in previously reported methods . We have previously developed an efficient strategy to synthesize 3-aryl-1-(difluoromethyl)­cycloalk-1-enes utilizing a phospha-Brook rearrangement and S N 2′ substitution reaction using organocuprate reagents (Scheme a) . Although this method provides a short-step route to 3-aryl-1-(difluoromethyl)­cycloalk-1-enes from readily available 2-cycloalkenones and commercial HCF 2 PO­(OEt) 2 , acyclic phosphates are incompatible in the reaction and the substituents introduced at the 3-position are limited to simple (hetero)­aryl groups.…”

Re-evaluation of P-Chiral, N-Phosphoryl Sulfonamide Brønsted Acids in the Asymmetric Synthesis of 1,2,3,4-Tetrahydroquinoline-2-carboxylate Esters via Biomimetic Transfer Hydrogenation

“…Examples include the preparation of optically active phosphoric esters, 27 Brønsted base catalyzed [2,3]-­Witting rearrangements of 2-allyloxy-2-phosphonoacetates, 28 intramolecular cyclization of alkynyl α-ketoanilide, 29 asymmetric organocatalytic reductive coupling of benzylidene pyruvates and aldehydes, 30 the synthesis of 3-aryloxindoles, 31 preparation of 2,3-allenylamides, 32 Brønsted base catalyzed three-component coupling reactions of α-ketoesters, imines and diethyl phosphite, 33 intramolecular addition of benzyl anion to alkyne, 34 the generation of homoenolate equivalent compounds, 35 preparation of tetrasubstituted furans, 36 transformation of α,β-epoxyketones to allylic alcohols, 37 and the fluorinative ring expansion of 2-benzoylpyrrolidines. 38 Most recently, the use of this rearrangement has also been reported in the preparation of (difluoromethyl)cycloalkenes, 39 the Passerini–Smiles reaction of α-ketophosphonates, 40 and the asymmetric synthesis of enantioenriched axial chiral allenes. 41 All of the above mentioned reactions proceed under basic conditions, and examples of a Lewis acid catalyzed reaction are extremely rare.…”

Stereoselective Synthesis of Dihydrocoumarins via [1,2]-Phospha-Brook Rearrangement in Three-Component Coupling Reaction of α-Ketoesters, o-Quinone Methides, and Dialkyl Phosphites

“…Over the years, the applicability of umpolung approach that involves the reversal of the inherent polarity of functional groups for new synthetic reactions, including C–C bond forming reactions, has tremendously increased . The [1,2]-phospha-Brook rearrangement that is based on umpolung of carbonyl groups entails the migration of the dialkoxyphosphoryl moiety of the alkoxides of α-hydroxyphosphonates from carbon to oxygen to furnish α-oxygenated carbanions (Figure a), also known as α-phosphonyloxy enolates, which can be trapped intermolecularly, by electrophiles such as protons, imines/aldehydes, or Michael acceptors . Interestingly, substrates having an electron stabilizing group adjacent to the carbonyl moiety have proven to be better candidates for such polarity inversion sequences, rendering such methodologies as a valuable tool for developing new C–C bond forming reactions.…”