Alcohols difluoromethyl

Difluoroethanol is prepared by the mercuric oxide cataly2ed hydrolysis of 2-bromo-l,l-difluoroethane with carboxyHc acid esters and alkaH metal hydroxides ia water (27). Its chemical reactions are similar to those of most alcohols. It can be oxidi2ed to difluoroacetic acid [381-73-7] (28) it forms alkoxides with alkaH and alkaline-earth metals (29) with alkoxides of other alcohols it forms mixed ethers such as 2,2-difluoroethyl methyl ether [461-57-4], bp 47°C, or 2,2-difluoroethyl ethyl ether [82907-09-3], bp 66°C (29). 2,2-Difluoroethyl difluoromethyl ether [32778-16-8], made from the alcohol and chlorodifluoromethane ia aqueous base, has been iavestigated as an inhalation anesthetic (30,31) as have several ethers made by addition of the alcohol to various fluoroalkenes (32,33). Methacrylate esters of the alcohol are useful as a sheathing material for polymers ia optical appHcations (34). The alcohol has also been reported to be useful as a working fluid ia heat pumps (35). The alcohol is available ia research quantities for ca 6/g (1992). 

The one-pot reaction of the a-(difluoromethyl)-p-sulfinylenamine 70 with trifluoroacetic anhydride in CHCI3, followed by treatment with silica gel affords 4-(difluoromethyl)-5-p-tolylthio-2(3//)-oxazolone 74 (Fig. 5.18). This reaction proceeds via a Pummerer-type rearrangement, followed by [l,3]-proton shift and the simultaneous elimination of trifluoroacetic acid and benzyl alcohol. ... 

A shift from allenes to acetylenic products formed from acetylenic alcohols in which trifluoro-methyl groups are replaced by difluoromethyl groups can be explained in terms of lowering the positive character of the terminal acetylenic carbon atom, thus retarding the nucleophilic attack of fluorine at this position.56... 

A novel method for the convenient synthesis of alkenyl fluorides 15, as well as diflu-oromethyl-substituted alcohols 16 and amides 17, via electrophilic fluorination with one equivalent of F-Teda BF4 (6) of alkenyl boronic acids and trifluoroborates, has been reported.87 The alkenyl fluorides 15 are obtained as Z/E mixtures when the reaction is carried out with one equivalent of F-Teda BF4 in acetonitrile at room temperature. When the reaction is performed with two equivalents of F-Teda BF4 in water or a nitrile solvent the difluoromethyl-substituted alcohols 16 or amides 17, respectively, are obtained. 

A well-established feature of nucleophilic reactions of fluoroalkenes is that attack occurs exclusively at a difluoromethyl group.61 The order of increasing reactivity is F2C = CF2 < F,C = CFCFj < < F2C = C(CF, )2.61 The primary products of base-catalyzed additions of alcohols to fluoroethenes are saturated ethers 87 however, with higher concentrations of base, unsaturated ethers are formed. Tetrafiuoroethene with sodium methoxide yields a product of substitution, trifluoromethoxyethene (4), and the addition product 1,1,2,2-tetrafluoro-l-methoxyethane (5).62... 

Difluoromelhyl)dimethylphenylsilane, in the presence of a catalytic source of fluoride, reacts eificiently with aryl and alkyl aldehydes to produce difluoromethyl alcohols, e.g. 12.On the other hand, it has been reported - that (difluoromethyl)dimcthylphenylsilane reacts with some carbonyl compounds under these conditions to give only silyl enol ethers. The authors suggested that destabilization of the negative charge at the a-carbon by the difluoromethyl fragment induces enolization. 

Asymmetric hydrogenation of either a carbonyl or an imino group to a hydroxyl group or an amino group has frequently been employed for the introduction of chirality in amino acid syntheses. Corey s catecolborane-oxazaborolidine protocol enables transformation of difluoromethyl ketone 1 into alcohol 2 with excellent enantioselectivity. The reaction of diastereoselective amination of a-hydroxyaldehyde 3 with A,A-diallylamine and 2-furyl-boronic acid provides furyl amino alcohol 4 in good chemical yield along with excellent diastereoselectivity. This protocol is applicable for the preparation of amino acids and amino alcohols with a trifluoromethyl group by the combination of /V,/V-diallyl or N,N-dibenzyl amine and aromatic, heteroaromatic and alkenyl boronic acids [7]. The usual chemical transformations as shown in steps 5 to 8 in Scheme 9.1 lead to (2S,3R) difluorothreonine 5 [8]. 

Prakash, G. K. S., Mandal, M., Schweizer, S., et al. (2002) Stereoselective synthesis of anti-CX-(difluoromethyl)-P-amino alcohols by boronic acid based three-component condensation. Stereoselective preparation of (2.V, 3 W) -d i (1norothreonine. J. Org. Chem., 67, 3718-3723. 

Methods involving electrophilic fluorination have been used to prepare a number of fluorophosphonates. Examples include benzylic a,a-difluoromethyl-phosphonates, e.g. 157, by the reaction of the carbanion of 156 with N-fluorobenzenesulfonimide (NFBS) (Scheme 10), which is claimed to be superior to DAST, and (a,a-difluoroprop-2-ynyl)phosphonates 159 by the direct di-fluorination of the a-ketophosphonate 158 (Scheme ll). Compound 158 is prepared by Pfitzner-Moffatt oxidation of the corresponding alcohol and it is worth noting that few such oxidations of a-hydroxyalkylphosphonates have been reported. 

The difluoromethylation of aliphatic alcohols is also possible, in principle, but the resulting difluoroethers often tend to undergo acid-catalyzed hydrolysis to the corresponding formates. They are only stable if the corresponding alcohol is sufficiently acidic, i. e. if it carries electron-withdrawing substituents. O-Difluoro-methylated carbohydrates have been reported [7]. In contrast, some highly fluorinated alkyl difluoromethyl ethers can be synthesized under quite drastic conditions (Scheme 2.168), and because of their extreme stability they can be used as inhalation anesthetics [3, 8]. 

Difluoromethyl phenyl sulfone is lithiated by LiHMDS at -78°, and the lithio species attacks cyclic sulfates of 1,2-diols and 1,2-amino alcohols to afford a,a-difluoroalkyl sulfones. The benzenesulfonyl group can be reductively removed (Mg, HOAc, NaOAc) or eliminated to provide 1,1-difluoroalkenes with an allylic OH or NH2 group. 

Chloro-3-(difluoromethyl)-3.4,4-trifluorobut-1-yne (7g) is claimed to be a pesticidal fumigant.26 An analogous reaction occurs with allylic tertiary alcohols, e.g. formation of 8.27... 

Fluorinated methyl aryl ethers. The facile rearrangement of oxygenated benzyl derivatives effected by XeFa to give fluorinated methyl ethers, i.e., benzyl alcohols to fluoromethyl aryl ethers and benzaldehydes to difluoromethyl aryl ethers, may involve the formation of fluoroxy intermediates and thence oxaspirobenzenium ions. 

Difluoromethyl ethers Primary and secondary alcohols are transformed into difluoromethyl ethers on reaction with CFjZnBr in MeCN/CHjClj at room temperature. 

Solid-support-bound 1-aminoimidazolium chlorochromate 82 proved to be a selective oxidant for benzylic and cinnamylic alcohols <01S382>. Imidazolyl-A -difluoromethyltrimethylsilanes 83 are versatile sources of heteroaryl-A -difluoromethyl anions in reactions with carbonyl compounds <01SL374>. 

Similar results are obtained with fluorine-substituted aUylic esters as reported by Kitazume et al. [21]. Ireland-Claisen rearrangement of the difluoromethylated esters 29 and 31 provided the desired syn- or anti-configured unsaturated acids, which were directly reduced to the corresponding alcohols in overall high yield. 

Bromodifluoromethyl phenyl sulfone can be transformed to [difluoro(phenylsulfonyl)methyl]trimethylsilane which was employed for fluoride-induced (phenylsulfonyl)difluoromethylation (eq 4). Alternatively, the reaction of bromodifluoromethyl phenyl sulfone with aldehydes mediated by electron-transfer reagent, tetrakis(dimethylamino)ethylene (TDAE), yields (phenyl-sulfonyl)-difluoromethylated alcohols in good yields which can be further transformed to difluoromethyl alcohols and e/B-difluoroalkenes via reductive desulfonylation and Julia olefination, respectively (eq 5). ... 

Another interesting discovery is that the diesters of the 2-(difluoromethyl)-6-(trifluoromethyl)- and the 2-(fluoromethyl)-6-(trifluoromethyl)pyridines can be selectively hydrolyzed on the ester group adjacent to either the difluoromethyl or the fluoromethyl group by using one equivalent of an alkaline base in a refluxing aqueous alcoholic solvent or by using excess alkaline base at room temperature. However, refluxing the diesters in an excess amounts of alkaline solution does produce the diacids (Scheme VII). 

Prakash, Petasis and Olah used this approach to synthesize anti-a-(trifluo-romethyl)-P-amino alcohols (R = CFj) [50], and awti-o-(difluoromethyl)-P-amino alcohols (R = CF2H) (Scheme 7.9) [51, 52). An example application is the single enantiomer synthesis of anti-dif luorothreonine, which was readily obtained following N-deallylation and ozonolytic cleavage of the furan ring in the adduct 37 (R = 2-furyl,... 

Aldehydes were converted into gcm-difluoroalkenes using difluoromethyl 2-pyildyl sulfone as a difluoroolefination agent (Schane 7.104) [167]. The chanistry was carried out at low temperatures and afforded moderate to excellent yields of the difluoroalkenes. A range of substrates were screened, and ethers, halides, and even a secondary alcohol were tolerated by the halogenation reaction. In contrast with previous reports, this approach is operationally straightforward. 

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