Difluoromethylene group

The transformation of an ester carbonyl group to a difluoromethylene group, which IS usually difficult to perform, can be accomplished by conversion to the thiaesier followed by treatment with diethylaminosulfur trifluoride (DAST). A vanety of ester types react efficiently, although the reaction fails with lactones. Remarkably, trimethylsilylmethyl esters carry through the proeedure with the silyl group intact [13] (equation 17). 

Trifluoromethyl groups are very resistant to hydrolysis, unless they are allylic or benzylic, or vicinal to a carbon linked to hydrogen. In the last case, elimination of hydrogen fluonde leads to the formation of a difluoromethylene group which is key to additional reactions... 

Initial C-perfluoroalkylation of p diketonesoccurs dunng thenUV irradiation in the presence of perfluoroalkyl iodides in liquid ammonia Pluorinated enami-noketones are obtained by subsequent ammonolysis of a difluoromethylene group and removal of the acetyl group [131] C-alkylation of dimethyl malonate takes... 

An older procedure based upon the thermally induced decarboxylation of sodium chlorodifluoroacetate in the presence of triphenylphosphine was used to introduce the difluoromethylene group into a substituted benzo[h]fluoranthene [48] (equation 46)... 

Miller et al. [9] hypothesized rules on the regioselectivity of addition from the study of the base-catalyzed addition of alcohols to chlorotnfluoroethylene. Attack occurs at the vinylic carbon with most fluorines. Thus, isomers of dichloro-hexafl uorobutene react with methanol and phenol to give the corresponding saturated and vinylic ethers The nucleophiles exclusively attack position 3 of 1,1-dichloro-l,2,3,4,4,4-hexafluoro-2-butene and position I of 4,4-dichloro-l,l,2,3,3,4-hexafluoro-1-butene [10]. In I, l-dichloro-2,3,3,4,4,4-hexafluoro-l-butene, attack on position 2 is favored [J/] (equation 5) Terminal fluoroolefms are almost invariably attacked at tbe difluoromethylene group, as illustrated by the reaction of sodium methoxide with perfluoro-1-heptene in methanol [/2J (equation 6). 

The strength of the carbon-carbon bond adjacent to a difluoromethylene group IS hardly affected by the presence of fluorine on the cyclopropyl ring When heated, 2,2 difluoromethylenecyclopropane undergoes methylene-cyclopropane rearrangement [/2 ] Under kinetic control, 2,2 difluoro 1 methylenecyclopropane and (difluoromethylene)cyclopropane are formed in a 2 1 ratio, although the latter IS slightly more stable [129] (equation 27)... 

Sugars having a difluoromethylene group were prepared by reaction of an aldehyde group in sugars with difluoromethylene tris(dimethyl-amino)phosphorane some of these were 554- 559. Similarly, (Z)- 560) and f ))-. tw-bromofluoroalkene 561 were prepared from l,2 3,4-di-0-iso-propylidene-a-D-gfl/ac/o-hexodialdo-l,5-pyranose (395) by treatment with Ph3P=CFBr. 

This method can also be utilized as a general method for the preparation of olefins with terminal difluoromethylene groups from aldehydes.8 Also, by the substitution of tributylphosphine for triphenylphosphine in this procedure, ketones other than those containing an a-perfluoroalkyl group can be converted to terminal difluoromethylene compounds.9... 

The N-pyrrolylzinc chloride 53 undergoes Pd-catalyzed coupling with perfluoroalkyl iodides to afford the 2-substituted pyrroles 54 in good yield [52], Smaller amounts (15-20%) of 2-perfluoroalkanoyl pyrroles, which presumably arise by hydrolysis of the benzylic difluoromethylene group, are also formed. This reaction, which is performed in one pot, also affords 2-phenylpyrrole (75%) and 3-phenylpyrrole (5%) with iodobenzene. Some biphenyl (15%) is also formed. 

Dexivacaine, 95 DBxnorgBstrel acetime, 152 Diabetes, 116 Diamocaine, 336 Diapamide, 93 Diaveridine, 302 Diazepam, 452 Diazoxide, 395 Dibenzepin, 424, 471 DichloroisopTTOterenol, 106 Diclofenac, 70 Dicyanamide, 21 Dieckmann cyclization, 72 Difenoximide, 331 Difenoxin, 331 Diflucortolone, 192 Diflumidone, 98 Diflunisal, 85, 86 Difluoromethylene groups, from ketones, 196 Difluprednate, 191 Dihydrocodeinone, 318 Dihydropyridine synthesis, 283... 

Starting from Difluorovinyl Glycosides Saccharidic derivatives that have a difluoromethylene group in the pseudo-anomeric position are important synthetic intermediates for preparation of difluoro-C-glycosides, difluoro-C-phos-phonates, and difluoro-C-disaccharides. ° ... 

Carbonyl difluoride (2) has been used to convert the carbonyl group in ketones, aldehydes and amides to the corresponding difluoromethylene group. 

A difluoromethylene group adjacent to an aromatic ring is readily hydrolyzed to a carbonyl group in an acidic medium. l-C.hloro-3-(pentafluoroethyl)benzene is converted, on treatment with sulfuric acid, into l-(3-chlorophenyl)-2,2,2-trifluoroethanone (14).144... 

Difluoromethylene groups in fluorinated cyclopentenes and cyclohexenes are hydrolyzed to oxo groups on heating with oleum and sulfur trioxide. 1,2-Dichlorohexafluorocyclopentene (17) is converted into cyclopentenone 18 and cyclopentenedione 19.146... 

Octafluorocyclohepta-1,3,5-triene is hydrolyzed to hexafluorotropone even in moist air, so activated is its difluoromethylene group.125... 

The difluoromethylene group in 2,2,4-trichloro-3,5,5-trifluoro-2,5-dihydrofuran (30) is activated towards acidic hydrolysis to give chlorofluoromaleic acid.152... 

Sulfur also facilitates the hydrolysis of a difluoromethylene group. Treatment of dodecafluoro-l,6-bis(methylsulfanyl)hexane with sulfuric acid affords octafluorohexanedioic acid (33).156... 

Oligomerisation of tetrafluoroethene [55-57] leads to the interesting internal perfluoroalkene (37), a tetramer [58] which, together with the pentamer (66) are the principal products (Scheme 29). Remarkably, the hexamer (67), i.e. with a terminal difluoromethylene group, is also formed rather than an internal isomer and this is probably attributable to the destabilising influence of steric effects on the alternative structures. 

Prolinates (33) containing a,a-difluoromethylene group can be also prepared via N-protected a-methyl difluoroalaninyl radicals (eq. 3.11c). 

The chemical change of diadds is carried out in the classic manner and yet the high degree of activity brought about by the difluoromethylene groups modify their reactivity. 

In another example, 2-methoxyperfluoro-3,4-dimethyl-4-ethylhex-2-ene reacts with pyridine or CsF, or with water in the presence of triethylamine, forming perfhioro-2,5-dihydro-2,3,4,5-tetramethylfurans (79USP983009). The reaction occurs via the intermediate formation of the O-anion, involved in intramolecular nucleophilic attack of the O-nucleophilic center at the difluoromethylene group. Perfluoro-3,4-dimethylhex-2-ene behaves analogously with methanol in the presence of pyridine (or triethylamine, or trimethylamine). 

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