Bromodifluoromethylation

Double dehydrobromination of cis- and tranj-l-(bromodifluoromethyl)-2-bromocyclohexane with potassium hydroxide gives, as the final product, 1 -cyclohexene-1-carboxylic acid as a result of the hydrolysis of the intermediate, 1-cyclohexenecarbonyl fluoride 4 (equation 4)... 

Hydroxy group of 8-hyd oxy-2-cycloalkyl-2,3,4,6,ll,lla-hexahydro-l//-pyrazino[l,2-i]isoquinoline-l,4-diones was alkylated with allyl bromide, 2-(bromodifluoromethyl)pyridines, l-(bromodifluoromethyl)- and l-(bro-momethyl)benzenes, halomethyl derivatives of different heterocycles (pyridine, pyrazine, pyrazole, pyrrole, thiazole, thiophene) in the presence of CS2CO3 or K2CO3 (98MIP7). Hydroxy group of 8-hydroxy-2-cyclopentyl-... 

Electrochemical reduction of the 5-(bromodifluoromethyl)-l,2,4-oxadiazole 168 in the presence of tetrakis (dimethylamino)ethylene (TDAE) generates the 5-(difluoromethyl) anion which reacts with aldehydes to give the 5-g. 

Difluorocarbene cannot be generated (<1%) under liquiddiquid phase-transfer catalytic conditions [29] owing to the rapid hydrolysis of the carbene at the interface [30], although it has been indicated that it is possible to obtain low yields of 1,1-difluorocyclopropanes under soliddiquid conditions [1]. More successful is the reaction of dibromomethane and dibromodifluoromethane under basic conditions. It is assumed that the initially formed dibromomethyl anion is transported into the organic phase where an equilibrium reaction with dibromodifluoromethane produces the bromodifluoromethyl anion and, subsequently, the difluorocarbene [31]. 

Radical addition of dibromodifluoromethane to alkenes followed by sodium borohydride reduction is a convenient two-step method for the introduction of the difluoromethyl group.5 Either one or both carbon-bromine bonds in the intermediate dibromides may be reduced, depending on the reaction conditions. In the case of acyclic dibromodifluoromethane-alkene adducts, the reduction occurs regioselectively to yield the relatively inaccessible bromodifluoromethyl-substituted alkanes. The latter are potential building blocks for other fluorinated compounds. For example, they may be dehydrohalogenated to 1,1-difluoroalkenes an example of this methodology is illustrated in this synthesis of (3,3-difluoroallyl)trimethylsilane. 

Phenyl-5-bromodifluoromethyl-l,2,4-oxadiazole was obtained in the system PhC(=NOH)NH2/BrCF2COOEt/Et3N/toluene ". 1,2,4-Oxadiazoles can be also successfully obtained from amidoximes linked to solid resin and (C1CH2C0)20 in 2-methoxyethyl ether (MeOCH2CH2)203 ... 

Most of these reactions have been extended to ethyl bromodifluoromethyl phos-phonate (Figure 2.15). ° However, conversely to the anions of difluoroacetate, lithiated anions of diethyl difluoromethylphosphonate are easily generated through the deprotonation of ethyl difluoromethyl phosphonate. They are frequently used for the synthesis of difluorophosphonates (cf. Chapter 7)." ° ... 

Recently, Zhu and coworkers have investigated the reaction of the zinc reagent from ethyl 3-bromodifluoromethyl-3-benzyloxyacrylate. The exclusive zinc reagent formed in DMF was the -carbon metallated product (equation 88)82. These workers utilized this reaction to prepare -dilluorovinyl substituted / -hydroxyesters in high yields and high regioselectivity via the reactions of aldehydes mediated by zinc (equation 89)82. 

However, difluoromethylation occurs when nucleophiles intercept difluoro-carbene generated under basic conditions, providing a route to difluoromethyl-ethers of phenols [33] and thiophenols [34]. The reaction with phosphite anion leads to the corresponding difluoromethyl phosphonate (see Sect. 2.3.2) while nucleophilic carbanions such as alkynes [35] also undergo formal alkylation, as do malonates [36,37]. An -difluoromethylaziridine was reported in a reaction with a glycine imine [38]. The scope of the established chemistry is summarised in Fig. 1. Bromodifluoromethylation occurs with a similar range of nucleophiles [39,40], and also with carbonyl-stabilised carbanions such as malonates [41,42]. 

Figure 2 represents both alkylation reactions mechanistically. More recently, reactive enolates were bromodifluoromethylated successfully via difluoro-carbene formed in situ. [43, 44]. The reaction solvent was critical for the outcome of the reaction (Eq. 11). 

Bromine trifluoride, neat or dissolved in liquid bromine, has found application for the selective substitution of fluorine for bromine (Table 3).108,109 The reactions are carried out at temperatures of no more than 60 C. Under these conditions no hydrogen substitution is observed. As established for bromofluoroethanes. the relative ease of replacement of bromine in various groups decreases in the order tribromomethyl > dibromofluoromethyl > dibromomethyl > bromofluoromethyl > bromomethyl. The presence of fluorine at either the same or an adjacent carbon tends to retard the substitution. Bromine trifluoride is more effeetive than antimony fluorides as it replaces bromine in bromodifluoromethyl and bromomethyl groups. 

The reaction of 5-bromo-2-furoic acid with the sulfur tetrafluoridc/hydrogen fluoride system proceeds under mild conditions and results not only in conversion of the carboxylic acid group but also in addition of two fluorines and replacement or migration of bromine a 1 3.5 mixture of 2,2,5-trifluoro-5-(trifluoromethyl)-2.5-dihydrofuran (10) and 2-(bromodifluoromethyl)-2,5.5-trifluoro-2,5-dihydrofuran (11) is obtained.153... 

Decarboxylation of (bromodifluoromethyl)malonates (9) reminiscent of Krapcho s deal-koxycarbonylation process, is observed on treatment with potassium fluoride in dimethyl sulfoxide at 170 °C to give 2-(trifluoromethyl)-substituted esters 10.43 The precursors are prepared by reacting diethyl malonates 8 with dibromodifluoromethane in the presence of sodium hydride. The exchange of bromine for fluorine in 9 followed by decarboxylation is an excellent method of introducing a trifluoromethyl group a- to an ester group. 

The conversion of the bromodifluoromethyl group to a trifluoromethyl group is only possible after cleavage of one ester group. The direct SN2 displacement of bromide ion by fluoride ion is prevented by electronic and steric factors. 

Trifluoromethyl) Esters 10 from (Bromodifluoromethyl)malonates 9 General Procedure 43... 

Dehydrobromination of m-and tra/w-l-bromo-2-(bromodifluoromethyl)cyclohexane(44) with potassium hydroxide gives products 45, 46, and the hydrolysis product cyclohex-l-ene-l-car-bonyl fluoride (47).83... 

Similarly, trihalo-substituted methyl groups, e. g. bromodifluoromethyl, can be converted into the corresponding nitriles.50... 

Hydrolysis of bromodifluoromethyl tnphenylphosphonium bromide, yielding bromodifluoromethane and triphenylphosphine oxide, proceeds via difluorocar-bene rather than by the bromodifluoromethyl carbanion [46 (equation 46). Bromodifluoromethane is a candidate for the replacement of Halon 1301 (CFjBr), a fire extinguishant presumed to cause damage to the stratospheric ozone layer... 

Compounds with Two Different Heteroatom Groups Attached to CF2 Including Chloro- and Bromodifluoromethyl Ethers... 

Dibromodifluoromethane (134g, 0.64 mol) was added to a magnetically stirred, cold (ice bath) solution of (EtO)jP (i lOOg, 0.6 mol) in anhyd EtjO (300 mL). The colorless solution under a Nj atmosphere was warmed to rt and then refluxed for 24 h. After concentration of the mixture, vacuum distillation afforded diethyl bromodifluoromethyl phosphonate (4b) yield 152g (95%) bp 99-102 C/16 Torn... 

Interestingly, the bromomethyl group and not the bromodifluoromethyl moiety of the allylic compound 6 reacts when treated with triethyl phosphite. Obviously steric factors play an important part in this reaction. 

Alkylation of the Schiff base of glycine with 2-hydroxy-3-pinanone proceeds in an extremely diastereoselective manner. Thus, fluoro-functionalization on the a-carbon of the Schiff base followed by hydrolysis provides fluorinated a-amino acids in a highly enantiomerically enriched form. 2-Fluoroethylation and 2-fluoroallylation of 157 (see Scheme 9.35) and bromodifluoromethylation of 161 (see Scheme 9.36) give the desired adducts 158 and 162, respectively, with excellent diastereoselectivities. Lithium enolate dimer 160 has been proposed as a reactive intermediate for the stereocontrolled alkylation [61]. The adducts 158 and 162 were transformed to 4-fluoro-2-amino acids (>96% ee) 159 [61] and 3,3-difluoroglutamine 164 [62], respectively. 

Bromodifluoromethyl(triphenyl)phosphonium bromide, preformed from dibromodifluoromethane and triphenylphosphane in triglyme, reacted with potassium fluoride and alkenes (20°C, 24 h) to give 1,1-difluorocyclopropanes (Houben-Weyl, Vol. El9b, pp 1474-1475 and Table 1). 

Partial attack at the central double bond took place when bromine was reacted with 1,1-difluorobenzocyclopropene. The products were 2,7-dibromotropone (3a, 21%), 2,4,7-tri-bromotropone (3b, 7%) and l-bromo-2-(bromodifluoromethyl)benzene (25%). The tropones are the hydrolysis products of the intermediate l,l-difluorocyclohepta-l,3,5-trienes which originate from attack at the bridging double bond. 

Stable gem-difluoroallenylindiurri(l) is prepared from bromodifluoromethyl silyl acetylene, which couples with aldehydes to give homopropargylic gem-difluoro alcohols with aqueous formaldehyde allenyl alcohols are obtained (Scheme 8.3) [17]. 

Kawamoto, A.M., and Campbell, M.M., A new method for the synthesis of a phosphonic acid analogue of phosphoserine via a novel 1,1-difluorophosphonate intermediate, J. Fluorine Chem.. 81, 181, 1997. Burton, D.J., Naae. D.G., Flynn, R.M., Smart, B.E., and Brittelli, D.R.. Phosphine- and phosphite-mediated difluorocarbene exchange reactions of (bromodifluoromethyl)phosphonium salts. Evidence for facile dissociation of (difluoromethylene)triphenylphosphorane. J. Org. Chem.. 48. 3616, 1983. Li, A.-R., and Chen. Q.-Y., Diethyl iododifluoromethylphosphonate. A new synthetic method and its reaction with alkynes. Synthesis, 606, 1996. 

Bromodifluoromethylation of C-nucleophiles which are not resonance stabilized is supposed to proceed via the carbene mechanism (Scheme 2.170). A typical by-product of this reaction is the brominated nucleophile [13]. 

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