Difluorocarbene chlorodifluoroacetates

The pyrolysis of sodium chlorodinuoroacetate is still a widely used, classical method for generating difluorocarbene, especially with enol and allyl acetates [48, 49, 50, 51] (equation 21) A convenient alternative that avoids the hygroscopic salt uses methyl chlorodifluoroacetate with 2 equivalents of a lithium chlonde-hexa-methylphosphoric triamide complex at 75-80 °C in triglyme [52], Yields are excellent with electron-rich olefins but are less satisfactory with moderately nucleophilic alkenes (4-5% yields for 2-bulenes)... 

Simultaneous elimination of chloride ion and carbon dioxide occurs dunng heating of methyl chlorodifluoroacetate with lithium chloride in hexamethyl-phosphoric tnamide (HMPA) The difluorocarbene generated in this way is trapped by electron-rich alkenes to form 1,1-difluorocyclopropanes [26] (equation 24)... 

The generation of difluorocarbene has been the subject of intense investigation. Difluorocarbene has been successfully formed from a wide range of fluorinated precursors, including metal salts of chlorodifluoroacetic acid, methyl chlorodifluoroacetate, ethyl chlorodi-fluoroacetate, difluorodiiodomethane, " chlorodifluoromethane." " difiuorotris(trifluoro-methyl)-A -phosphane hexafluoropropylene oxide,tetrafluoroethylene... 

Heating a mixture of methyl chlorodifluoroacetate, lithium chloride and hexamelhylphosphoric triamidc in dichloromethane at reflux, or in diglyme at 80 C. results in the generation of difluorocarbene under relatively mild nonbasic conditions. Alternatively, difluorocarbene can... 

Alkali metal salts of chlorodifluoroacetic acid decarboxylate generating difluorocarbene (carbenoid) which undergoes addition to alkenes to give 1,1-difluorocyclopropanes (Houben-Weyl, Vol. E19b, pp 1476-1478). 

The sodium salt is generally used, but lithium chlorodifluoroacetate is more effective, particularly in diglyme (see Houben-Weyl, Vol. E19b, p 1478). Added alkali metal fluoride salts usually greatly accelerate the decomposition of the difluorocarbene source, but this has not applied to the preparation of 1,1-difluorocyclopropanes. 

The difluorocarbene thus generated does not undergo addition to alkenes of low reactivity. The highly hygroscopic salts of chlorodifluoroacetic acid must also be thoroughly dried before use. Finally, a very large excess of the carbene source is often required to achieve good yields of the products. 

The Palo Alto Syntex Research group8 effected addition of difluorocarbene to th double bond of 17/3-hydroxy-5a-A -androstene-3-one acetate (1) by drop wise addition of a saturated solution of 20-50 equivalents of sodium chlorodifluoroacetate in diglyme or triglyme to a 10% solution of the enone in the same solvent at 165-... 

Precursor of difluorocarbene [before references]. In a study of the behavior of cholesterol to dihalocarbenes, a Syntex group6 found that dichlorocarbene does not add to the somewhat unreactive double bond of cholesterol but that the less bulky difluorocarbene, generated from sodium chlorodifluoroacetate, does add to give a difluorocyclopropane which was assigned the 5/3,6/3-orientation mainly on the basis... 

Slagel12 reports that the lithium salt of chlorodifluoroacetic acid is superior to the sodium salt for generation of difluorocarbene and difluoromethylenetriphenylphos-phorane. Thus the yield of 4,5-dicarbethoxy-l,l-difluoronorcarane from the lithium salt was 50.6% and from the sodium salt was 25.7%. 

S. A. Fuqua, W. G. Duncan, and R. M. Silverstein, Org. Syn., 47,49 (1967) definitive paper F. E. Elerkes and D. J. Burton, J. Org., 32, 1311 (1967). In the early work it was assumed that the reaction of sodium chlorodifluoroacetate in the presence of triphenyl-phosphinc involved formation of difluorocarbene, which then reacts with triphenylphosphine to form difluoromethylenetriphenylphosphorane, (C2H,i.,P—CF,. However, addition of tetra-methylethylene to the reaction in the presence of a ketone failed to yield any cyclopropane derivative. Herkes and Burton (loc. cit.) suggest that a phosphobetaine salt (a) is the intermediate which loses carbon dioxide to form the active reagent (b). 

Methyl chlorodifluoroacetate decomposes to difluorocarbene on reaction with lithium chloride complexed with hexamethylphosphoric triamide or potassium fluoride with 18-crown-657 (Houben-Weyl, Vol. El 9b, p 1478), for example, formation of 13.21,57... 

Generation of difluorocarbene. In an early study1 of the reaction of difluoro-carbene with steroidal double bonds, the methylenation was conducted by portion wise addition of an excess of dry sodium chlorodifluoroacetate to a diglyme solution of the substrate at temperatures of 120-150°. The same laboratory (Syntex)2 now reports that the reaction is improved by addition of a solution of the salt in diglyme to a refluxing diglyme solution of the substrate. The reaction with A4-6- and AI 4 a-3-ketosteroids results mainly in addition to the Afi-double bond to give 6a,7a-difluoromethylene-A4- and A -4-3-ketones, respectively. 

Metal, Metalloidal, and Non-metal Fluoroacetates.— Fluorine Magnetic Resonance Studies.I.para-Substituted P-DifluorostyTeae [thepP-difluorostyrenesp-XC,H(-CH CFs (X — NMe OMe, Me, H, F, Cl, or CN) were obtained via the CF,Cl-CO,Na-Ph,P-aldehyde route]. Reaction of Difluorocarbene with 2-Benzylidenecyclohexanones to afford Phenylfluorofurans (CF2 generated via thermal decomposition of CF CI-COjNa). Cyclodecapentaene Derivatives (reaction of CF, from CFjCI-COjNa with 1,4,5,8-tetrahydronaphthalenes). Action of Sodimn and Lithium Chlorodifluoroacetates on... 

The reaction of difluorocarbene, generated by thermal decomposition of sodium chlorodifluoroacetate, with 2-benzylidene-5a-cholestan-3-one 57 and related substrates afforded 3-fluoro-2-phenylfuran fused to steroid fragment via C4-C5 bond 58. 2-Benzylidenecyclohexanone reacted similarly with difluorocarbene yielding 3-fluoro-2-phenyl-4,5,6,7-tetrahydrobenzofuran in low yield [42]. 

A novel use for the pyrolysis (at 385 °C) of sodium chlorodifluoroacetate has been described, viz. the modification of flifi surfaces of common commercial polymers. The critical surface tension values of the polymers decrease with increasing exposure to difluorocarbene vapours and ultimately approach the critical surface tension values of poly(fluoroethylenes). ... 

Steroid chemists continue to use the thermal decarboxylation of sodium chlorodifluoroacetate in boiling diglyme as a source of difluorocarbene and in connection with cyclopropane formation via addition of halogeno-carbenes to ri W-steroid olefins, the stereochemistry of addition to 10-methyl-... 

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