Difluoromethylene ketones

Brigaud and Portella et al. applied Yb(OTf)3 to aldol reaction of a,a-difluoroenol silyl ether (2) affording difluoromethylene ketones, a common structural motif of HlV-1 protease inhibitor [4], (2) was generated from acylsilane and trifluo-romethyltrimethylsilane and directly subjected to the aldol reaction with aldehydes with 10 mol% ofYb(OTf)3 in a one-pot procedure (Scheme 13.1). The same reaction with other Lewis acids such as TiCU or BF3-OEt2 required more than stoichiometric amount. 

Much better known are the fluonnatedphosphoranes, which have been widely used m the Wittig reaction for the preparation of fluoroolefms Difluoromethylena tion reactions have been effected by using a variety of conditions Treatment of dibromodifluoromethane with two equivalents of tns(dimethylammo)phosphine m carefully dried tnglyme yields a solution of bromodifluoromethylphosphonium broomide, which very effectively converts ketones to difluoromethylene derivatives A more sensitive reagent is prepared by the addihon of two equivalents of the phosphine to the reaction mixture of fluorohalomethane and a carbonyl compound [39, 40] (equation 40) (Table 14)... 

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... 

Although the sulfur trifluoride compounds are generally useful as selective agents for conversion of carbonyl and carboxyl groups to difluoromethylene and trifluoromethyl groups, variations in reaction conditions are often necessary.7 Thus the reaction of aromatic ketones requires heating at 150°. Since the reaction with aliphatic aldehydes and ketones is exothermic, it is advan-... 

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... 

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

The mechanism for the cyclization of these perfluoro ketones, proposed by German and coworkers5 and discussed in the review by Krcspan and Petrov.4 involves initial activation of the carbonyl with antimony V) fluoride and a 1.4-fluorine shift from the /1-trifluoromethyl group. The resultant difluoromethylene carbocation then cyclizes with the carbonyl oxygen to give the tetrahydrofuran. 

Difluoroalkenes1 (cf., 11, 180). The anion (LDA) of this reagent effects difluoromethylenation of aldehydes or ketones by a Wittig-Horner type reaction. 

The ylide reacts with the ketone in the sense of the Wittig reaction in that the difluoromethylene group is attached to the carbonyl carbon while the oxygen forms tris(dimethylamino)phosphine oxide. Another mechanism has been suggested by the author of this reaction [/05],... 

Functional groups containing the C = N bond, such as hydrazones, oximes and diazo compounds, can also be used in the synthesis of fluorinated derivatives and these reactions are the subject of this section. The reaction products in these procedures are usually the corresponding g cw-difluoromethylene compounds. Since oximes and hydrazones arc obtained from aldehydes and ketones, these reactions can be considered as an alternative to the direct transformation of a carbonyl group into the difluoromethylene group. As indicated in Section... 

Aminosulphur trifluorides, which are easier to handle than SF4, can also be used for the conversion of most aldehydes and ketones to difluoromethylene derivatives numerous examples have been documented [12] (Table 3.6). A similar reaction mechanism to that for SF4 may be assumed. 

Treatment of certain 1,3-diketones with sulfur tetrafluoride using diethyl ether as solvent leads to the formation of unsaturated /i-fluoro ketones and mixtures of E- and Z-isomers are obtained, e.g. I.8 In this case the monoenolic form of the 1,3-diketone is the substrate for sulfur tetrafluoride. When diethyl ether is not used, the expected conversion of one or two carbonyl groups into difluoromethylene groups occurs. 

Compounds carrying a trifluoroacetyl group, for example trifluoromethyl ketones and esters of trifluoroacetic acid, can be converted into the corresponding trimethylsilyl difluoroenol ethers [27] or into trimethylsilyldifluoroacetic acid esters [28] by reduction with magnesium metal in the presence of Me SiCl (Scheme 2.195). These readily accessible species are synthetically very useful as nucleophilic difluoromethylene equivalents. The same type of chemistry [29] can also be extended to trifluoromethyl imines [30]. 

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. 

Bioactive compounds that contain the difluoromethylene group adjacent to the carbonyl functionality have been the subject of increased research efforts in recent yearsf 59). The most widely utilized methods that have been employed to introduce this group into organic molecules have been (a) Reformatsky reaction of halodifluoroacetates (60-66) (b) elaboration of difluoroketene silyl acetals (67-69) (c) metal catalyzed addition of 3-bromo-3,3-difluoropropene to aldehydes and ketones (70) and (d) alkylation of CuCF2COOR(77). The modest yields associated with these methods prompted us to explore alternative methodology for the preparation of this useful building block. 

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