Alcohols difluoromethylene

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 addition of nucleophiles to cyclic fluoroolefins has been reviewed by Park et al. [2 ]. The reaction with alcohols proceeds by addition-elimination to yield the cyclic vinylic ether, as illustrated by tlie reaction of l,2-dichloro-3,3-di-fluorocyclopropene Further reaction results in cyclopropane ring opening at the bond opposite the difluoromethylene carbon to give preferentially the methyl and ortho esters of (Z)-3-chloro-2-fluoroacrylic acid and a small amount of dimethyl malonate [29] (equation 8). 

The HF-pyridine reagent is an effective complement to di-methylaminosulfur trifluoride (DAST) reagent6 in the preparation of alkyl fluorides from alcohols. DAST is also useful for the conversion of carbonyl groups to difluoromethylene functions. The... 

The clue to the reaction is the polarity of the double bond. The lowest electron density is at the carbon linked to hydrogen, and is due to the strong inductive effect of the difluoromethylene groups and a slight effect of the vinylic chlorine. The attacking species, ethoxide anion, which is in an equilibrium with hydroxide ion in alcoholic potassium hydroxide, reacts in an SN2 reaction by joining the carbon bonded to hydrogen. The subsequent shift of the double bond facilitates ejection of fluorine as an anion and leads to an ether, compound O [77]. 

The third reaction pattern in nucleophilic reaction to difluoroalkenes is addition. Protic nucleophiles such as amines and alcohols add sometimes to the difluoroalkenes in a manner of 1,2-addition to the double bond where both nucleophilic moiety and proton are incorporated into the double bond (Scheme 2.27). A difluoromethylene moiety is potentially a carbonyl synthon and a difluoroalkylidene moiety is a synthon of an amide [17] and an ester (53) [18]. l,l-Difluoro-2-aminoalkenes (52) (R1 = amino moiety) would be transformed to dipeptides (53) (RX = amino ester, R1 = amino moiety) on reacting with amino esters. This idea was realized by the reaction of 60 with a variety of amino esters, leading to a practical synthesis of trifluoroalanine dipeptides (62) as shown in Scheme 2.27 [ 19]. 

An alternate route to fluoroolefins relies upon the ease of reduction of difluoroolefins(18). Reduction of 114 with sodium bis(2-methoxyethoxy)aluminum hydride (Scheme 35) afforded the fluoroolefins 115 and 116 considerably enriched with the (E)-isomer 116. In a complementary reaction, reduction of the allylic alcohol 117 with LiAlH4 afforded selectively the (Z)-isomer 118. The difluoromethacrylic acid (121) was prepared in similar manner from 120 (Scheme 36) (53 for related examples see references 75 and 76). Under more forcing conditions, further reduction afforded 3-fluoromethacrylic acid 122. Of more general use is the reaction of 120 with Grignard reagents whereupon the 1,4-addition elimination mechanism offers an entry into a-difluoromethylene substituted aliphatic and aromatic carboxylic acids 123. Ester enolates (125) have been shown to add to trifluoropropene (124) forming the difluoroolefins (126) (Scheme 37) (54). 

Prior hydrolysis of the difluoromethylene group in either the 3- or 17-cycIo-propenyl alcohols (13Sa and b) affords the corresponding cyclopropenones, which on treatment with the fluoramine reagent are converted cleanly into analogous 3 - and 17/9-allenic carbonyl fluorides (142) and (143) in this case a-isomers were not detected (Scheme 38). 

Ema, T, Kadoya, T, Akihara, K., and Sakai, T. (2010) Chemoenzymatic synthesis of optically active alcohol and p-amino-acid derivative containing the difluoromethylene group. J. Mol. Catal. B Enzym., 66 (1-2), 198-202. 

In the following Figures 8 and 9 was described the preparation of the CF3-containing substances. As was already discussed, DAST plays a pivotal role in converting an exo-difluoromethylene group into the corresponding n /o-trifluoro-methylated olefin via 8 2 type attack of fluoride (38). Because 6a includes two latent terminally difluorinated lylic alcohol structures two different types of saturated... 

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