Potassium alkyl fluoride reduction

Reductive removal of fluorine from alkyl fluorides requires a potent reducing agent and so is not normally encountered However, hydrogenolysis of an unactivated carbon-fluorine bond in, for example, 3 p-fluorocholestane has been efficiently accomplished in 88% yield with a solution of potassium and dicyclohexyl 18 crown-6 in toluene at 25 °C [/] Similarly, sodium naphthalene in tetrahydrofuran converts 6 fluorohexene-1 and 1-fluorohexane to hydrocarbons in 50% yield at 25 °C over a 7-h period [2]... 

Reductive cleavage of alkyl fluorides.1 Potassium or Na/K and dicyclohexyl-18-crown-6 in toluene is the most effective of known systems for reductive cleavage of unactivated C—F bonds. Addition of a proton source is not necessary and actually is deleterious. 

ABSTRACT. Toluene radical anion, generated by dissolving potasssium metal in toluene by the assistance of dicyclohexano-18-crown-6, has been proved to be especially effective for reductive removal of fluorine atom from unactivated alkyl fluorides that resist common reduction conditions. Stereochemical and mechanistic aspects of the present method is discussed. In connection with the preparation of substrates the effect of dipolar aprotic solvents on the nucleophilic fluorination with potassium fluoride/dicyclohexano-18-crown-6 system was also examined, and sulfolane or N,N-dimethylformamide was shown to be a solvent of choice. 

Methods reported this year for the reduction of alkyl halides to alkanes include the potassium-dicyclohexyl-18-crown-6 reduction of alkyl fluorides, sodium borohydride reduction of alkyl chlorides, bromides, and iodides (or sulphonate esters) under liquid-liquid phase-transfer conditions, and the selective reduction of tertiary alkyl, benzyl, and allyl halides with the borate (61). Continuing... 

Stereoselective reduction of a-alkyl-3-keto acid derivatives represents an attractive alternative to stereoselective aldol condensation. Complementary methods for pr uction of either diastereoisomer of a-alkyl-3-hydroxy amides from the corresponding a-alkyl-3-keto amides (53) have been developed. Zinc borohydride in ether at -78 C gave the syn isomer (54) with excellent selectivity ( 7 3) in high yield via a chelated transition state. A Felkin transition state with the amide in the perpendicular position accounted for reduction with potassium triethylborohydride in ether at 0 C to give the stereochemi-cally pure anti diastereoisomer (55). The combination of these methods with asymmetric acylation provided an effective solution to the asymmetric aldol problem (Scheme 6). In contrast, the reduction of a-methyl-3-keto esters with zinc borohydride was highly syn selective when the ketone was aromatic or a,3-unsaturated, but less reliable in aliphatic cases. Hydrosilylation also provided complete dia-stereocontrol (Scheme 7). The fluoride-mediated reaction was anti selective ( 8 2) while reduction in trifluoroacetic acid favored production of the syn isomer (>98 2). No loss of optical purity was observed under these mild conditions. 

The starting phenylenediamine (12) was prepared by reaction of a 2-fluoronitro benzene (9) with an aniline (10) in the presence of potassium fluoride and subsequent reduction of the nitro derivative (11). The resulting amine (12) was generally alkylated with an alkyl bromide in the presence of sodium iodide to obtain the intermediate (13). However, when bulky groups had to be introduced, the intermediate (13 ) was conveniently obtained by reductive amination of either aldehydes or ketones. Condensation of (13) with (phenylhydrazono)malonyl dichloride followed by reduction with zinc and acetic acid led to the 3-amino substituted benzodiazepines (15). 

These two milestone syntheses were soon followed by others, and activity in this field continued to be driven by interest in the biologically active esters of cephalotaxine. In 1986, Hanaoka et al. (27) reported the stereoselective synthesis of ( )-cephalotaxine and its analog, as shown in Scheme 4. The amide acid 52, prepared by condensation of ethyl prolinate with 3,4-dimethoxyphenylacetyl chloride, followed by hydrolysis of the ethyl ester, was cyclized to the pyrrolobenzazepine 53 by treatment with polyphos-phoric acid, followed by selective O-alkylation with 2,3-dichloropropene (54) in the presence of sodium hydride. The resulting enol ether 55 underwent Claisen rearrangement on heating to provide C-allylated compound 56, whose reduction with sodium borohydride yielded the alcohol, which on treatment with 90% sulfuric acid underwent cationic cyclization to give the tetracyclic ketone 57. Presumably, this sequence represents the intramolecular version of the Wichterle reaction. On treatment with boron tribromide, ketone 57 afforded the free catechol, which was reacted with dibromometh-ane and potassium fluoride to give methylenedioxy derivative 58, suited for the final transformations to cephalotaxine. Oxidation of ketone 58... 

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