Difluorocarbenes

Thermal Reactions. Those perfluoroepoxides that contain a CF2 group in the epoxide ring undergo a smooth decomposition at relatively mild, neutral conditions (140—220°C) to give a perfluorocarbonyl compound and difluorocarbene (16,17) (eq. 1). 

Perfluoroepoxides have also been prepared by anodic oxidation of fluoroalkenes (39), the low temperature oxidation of fluoroalkenes with potassium permanganate (40), by addition of difluorocarbene to perfluoroacetyl fluoride (41) or hexafluoroacetone (42), epoxidation of fluoroalkenes with oxygen difluoride (43) or peracids (44), the photolysis of substituted l,3-dioxolan-4-ones (45), and the thermal rearrangement of perfluorodioxoles (46). 

Pubhcations have described the use of HFPO to prepare acyl fluorides (53), fluoroketones (54), fluorinated heterocycles (55), as well as serving as a source of difluorocarbene for the synthesis of numerous cycHc and acycHc compounds (56). The isomerization of HFPO to hexafluoroacetone by hydrogen fluoride has been used as part of a one-pot synthesis of bisphenol AF (57). HFPO has been used as the starting material for the preparation of optically active perfluorinated acids (58). The nmr spectmm of HFPO is given in Reference 59. The molecular stmcture of HFPO has been deterrnined by gas-phase electron diffraction (13). 

Perfluoroisobutylene Oxide PIBO has been prepared primarily by the addition of difluorocarbene to hexafluoroacetone or by the reaction... 

The thermally formed difluorocarbene adds stereospecifically to either (Z)- or ( )-butene to form the corresponding dimethyldifluorocyclopropanes, which points to a singlet difluorocarbene. With butadiene mono- (220) and bis-cyclopropanated product (221) are formed, and with perfluorobutadiene the mono-adduct (222) results 65JA758). 

Difluoroaminofluorodiazirine (225) extrudes nitrogen at only 75 °C. Intramolecular stabilization gives trifluoromethylenimine (226) added tetrafluoroethylene is cyclopropa-nated. This type of dichotomy is not often found in carbene chemistry alkylcarbenes undergo intramolecular stabilization as a rule, whereas intermolecular stabilization is observed exclusively with alkoxycarbonylcarbenes and with difluorocarbene. In the latter case CF2 attacks its precursor when no other reaction partner is present. 

Difluorocarbene reacts with A -steroids (19) bearing a 10 -methyl group affording both the 3a,4a- (20) and 5, 6 -adducts (21), an exception being 17a-acetoxypregna-3,5-dien-20-one, which gives only the 3a,4a-product... 

The reaction of the ethynylestradiol derivative (50) with difluorocarbene represents an equally fascinating series of reactions. The major product obtained in 48% yield is the difluorocyclopropene (51). The latter is hydrolyzed to the cyclopropenone (53), and is readily alkylated at C-21 to (54), which is also obtained by difluoromethylation of the propynyl derivative (57). The cyclopropenone (53) loses carbon monoxide at elevated temperature to... 

Condensatron between lithium acetylides and dibromodifluoromethane [124] or dichlorofluoromethane [125] leads to fluorohaloacetylenes (equation 107) Sodium alkyl malonates are also alkylated by dihalogenodifluoromethanes [124] (equation 108) These reactions involve difluorocarbene as intermediate (for the mechanism of the Cp2Br2 condensation, see equation 15)... 

Copyrolysis of 1,1-diehloroperfluoroindane and chlorodifluoromethane or tetrafluoroethylene gives 1-perfluoromethyleneindane as the major product and three minor products [3] (equation 2) Insertion of difluorocatbene into the benzylic carbon-chlorine bond and subsequent loss of a chlonne molecule is observed in the copyrolysis of chlorodifluoromethane and pentafluorobenzotnchlonde to give a-chloroperfluorostyrene as the major product. Aromatic carbon-chlorine bonds are unreactive to the difluorocarbene in this reaction [4] (equation 3). 

Difluorocarbene generated by the thermolysis of trimethyltnfluoromethylsilane reacts with disilanes by insertion into the silicon-silicon bond [S] (equation 9) Thermolysis of pentafluoroethyltnfluorosilane at 200 °C gives tetrafluoro ethylidene carbene, which reacts with phosphorus trifluonde to give trifluoro vinyltetrafluorophosphorane [9] (equation 10) and with perfluorotnmethylphos-phine to give perfluorodimethyhsopropylphosphine and perfluoro-2-butene [9] (equation 10)... 

Tnmethyl(trifluororaethyl)tin can also be prepared via in situ formation and capture of tnfluorometbide by trimethyltin chlonde [13, 14] (equation 9) This tin analogue has been used as a precursor for difluorocarbene either by thermal decomposition or by reaction with sodium iodide m 1,2-dimethoxyethane This carbene generation procedure has been used to study difluorocarbene selectivity with steroidal olefins [75] (equation 10). 

Trifluoromethylzinc compounds can be prepared via the direct reaction of dihaloditluoromethane with zinc powder in DMF [J5] (equation 24) In this reaction, the DMF functions both as solvent and reactant Mechanistic experiments support a difluorocarbene reaction intermediate Indeed, a mixture of zinc and difluorodibromomethane in THF has been used for the synthesis of gewi-difluo-ro-cyclopropane derivatives [34 (equaUon 25)... 

Dialkylcadmium reagents are often useful alternatives to the more reactive Gngnard reagents in the preparation of ketones from acyl halides However, bis(trifluotomethyl)cadmium glyme is decomposed by acyl halides and does not give trifluoromethyl ketones [, 124] Nevertheless, this reaction can be used as a low-temperature source of difluorocarbene [S, 124] (equation 102)... 

Among the many methods of generating difluorocarbene, the treatment of bromodifluoromethylphosphonium bromides with potassium or cesium fluoride is particularly useful at room temperature or below [II, 12 13] The sodium iodide promoted decomposition of phenyl(trifluoromethyl)mercury is very effective at moderate temperatures [S, 14] Hexafluoropropylene oxide [/5] and chlorodifluo-roacetate salts [7] are excellent higher temperature sources of difluorocarbene... 

The phosphonium salt method works best with nucleophilic olefins [//, 12, 16, 17, 18, 19] (Table 1 and equations 1-3) and has been used m mechanistically important studies of difluorocarbene additions to norbornadienes [20 21, 22, 23] that provided the first example of a concerted homo-l,4-addition (equation 4) A recent modification uses catalytic 1,4,7,10,13,16 hexaoxacyclooctadecane (18-crown-6) to shorten reaction times and increase yields with less nucleophilic olefins [12] (Table 1) Neither procedure, however, compares with the use of phenyl(tri-f1uoromethyl)mercury or (trifluoromethyl)trimethyltin reagents [efficient reactions with less nucleophilic olefins (equations 3 and 5) and cyclic dienes [24, 25] (equations 6 and 7)... 

The use of dibromodifluoromethane with zinc [26] or lead metal [27] is a simple, economical method for generating difluorocarbene under mild conditions, but the reaction is limited to highly nucleophilic olefins (equation 8)... 

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)... 

Phase-transfer systems for generating fluorohalocarbenes from the corre spending haloforms are simple and effective with nucleophilic olefins [5J, 54 55, 56, 57, 58, 59] (Table 3 and equations 23 and 24), and the process was extended recently to difluorocarbene [60] Chlorofluorocarbene also can be generated from fluorotrichloromethane and utanium(O) produced in situ (T1CI4 + L1AIH4) Yields of gem-chlorofluorocyclopropanes range from excellent (85% for a. meth ylstyrene) to poor (12% for 1-hexene) [61]... 

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)... 

Similarly, fluorosulfonyldifluoroacetic acid can be decarboxylated easily to give difluoromethanesulfonic acid by using catalytic amounts of sodium chloride, but the reaction can proceed readily to the next step, resulting in loss of sulfur dioxide and formation of difluorocarbene [101, 102] (equations 68 and 69)... 

Strong acids or superacid systems generate stable fluorinated carbocations [40, 42] Treatment of tetrafluorobenzbarrelene with arenesulfonyl chlorides in nitro-methane-lithium perchlorate yields a crystalline salt with a rearranged benzo barrelene skeleton [43] Ionization of polycyclic adducts of difluorocarbene and derivatives of bornadiene with antimony pentafluonde in fluorosulfonyl chloride yields stable cations [44, 45]... 

The common side reaction in most thermal studies of fluorine-substituted cyclopropanes is difluorocarbene extrusion Increasing the number of fluonne substituents on the cyclopropane ring significantly increases the rate of difluorocarbene extrusion [135, 136, 137]... 

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