Gem-difluoromethylene

The electrogenerated base from pyrrolidone also promotes the introduction of a gem-difluoromethylen unit to aromatic aldehydes to give difluoromethyl carbinols in high yields (Scheme 4.4) [33],... 

R.-W. Wang, X.-L. Qiu, M. Bols, F. Ortega-Caballero, and F.-L. Qing, Synthesis and biological evaluation of glycosidase inhibitors gem-Difluoromethylenated nojirimycin analogues, J. Med. Chem., 49 (2006) 2989-2997. 

The difluoromethylene ylides react with carbonyl derivatives (aldehyde, lactone) to afford gem-difluoromethylene compounds.They are generated starting from halogenodifluoromethane with triphenylphosphine (or trisaminophosphine) or starting from zinc and a phosphonium salt (or a phosphine oxide)." ° ... 

Finally, gem-difluoromethylene analogs, e.g., 315 and 316, designed to mimic artemisinin, have been prepared by the treatment of the trifluoromethyl derivatives 169 and 173 with 2 equiv of MeLi in THF at —78 °C, and their anti-malarial activity investigated (Scheme 53) <2006JFC637>. 

Scheme 2.64 Proposed mechanism for fluorination of carbonyl compounds into the corresponding gem-difluoromethylene derivatives [139].

Many varieties of fluorodesulfuration of protected (or activated) carbonyl compounds are known. Some contain an intermediate reductive step, leading to a wiorto-fluoromethylene instead of a gem-difluoromethylene group [146]. 

Dithianylium salts in combination with oxidative fluorodesulfuration chemistry are also useful reagents for synthesis of gem-difluoromethylene analogs of carboxylic acid derivatives other than esters. If the fluorodesulfuration is conducted in the presence of other O- or M-nucleophiles the corresponding a.a-difluoroalkyl compounds are obtained in reasonable to good yields (Scheme 2.74). 

Scheme 2.170 Synthetic steps towards gem-difluoromethylene analogs of arachidonic acid via bromodifluoromethylation of C-nucleophiles [13].

Nucleophiles therefore attack exclusively at the gem-difluoromethylene carbon of diflu-oroalkenes to form (3-fluorocarbanions (1). The chemical fates of 1 are mostly dependent on the structures of the alkenes and the reaction conditions. The typical reaction pathways of 1 are classified into three as shown in Scheme 2.17. In aprotic solvents, the carbanions (1) undergo defluorination, affording a-substituted monofluoroalkenes (2). Meanwhile, in pro tic solvents or in the presence of electrophiles in aprotic solvents, the carbanions (1) can be trapped with a proton or an electrophile to give addition products (3). The third case is S -type addition where substrates must have a leaving group on the y -carbon of 1 such as an alkoxy or an acyloxy group. 

Wang, R.W. Qing, F.L. Highly stereocontrolled s3mthesis of gem-difluoromethylenated azasugars d- andL-l,4,6-trideoxy-4,4-difluoronojirimycin. Org. Lett. 2005, 7, 2189-2192. 

Urbina-Bianco CA, Skibinski M, O Hagan D, Nolan SP. Accelerating influence of the gem-difluoromethylene group in a ring-closing olefin metathesis reaction. A Thorpe-Ingold effect Chem Commun. 2013 49(65) 7201—7203. 

In the presence of tributyl tin reagents and the radical initiator AIBN, both sulfides and selenides undergo tin hydride-mediated radical cyclizations, providing gem-difluoromethylene products. 

Prakash and co-workers have prepared monofluoro-methyl 3,5-bis(trifluoromethyl)phenyl sulfone and have used it in the fluoroalkenylation of aldehydes and ketones.They employ KOH or CsF as base in DMSO at 20°C. On their side, Hu and co-workers have developed TBTSO2CH2F as a versatile fluoromethylidene synthon. Difluoromethyl 2-pyridyl sulfone has been used for the gem-difluoromethylenation of aldehydes and ketones and was found to be a more efficient difluoromethyfidene synthon than BTSO2CF2H, PTSO2CF2H and TBTS02CF2H. ... 

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