Yoshio Arakawa

Synthesis of perfluorochemicals for use as blood substitutes, part II: electrochemical fluorination of partly fluorinated compounds

Abstract Electrochemical fluorination of 2-methoxy-1,1,1-trifluoro-2-(F-methyl) octane gave the corresponding perfluorinated ether in 27% yield, along with cyclic by-products in 9%. A mixture of partly fluorinated tertiary amines, consisting of 1-dipropylamino-F-1-propene and 1-dipropylamino-2-hydryl-F-propane, did not afford a superior yield of tri(F-propyl)amine compared to the unfluorinated tripropylamine. 1-Diethylamino-2-(F-methyl)-F-1-pentene was fluorinated to give the corresponding F-tertiary amine in fairly good yields, together with 1-di(F-ethyl)amino-2-hydryl-2-(F-methyl)-F-pentane and their fragmented products. The study indicates that blocking of the α-carbon atom of an ether with F-methyl groups seems to reduce fragmentation, resulting in good yields of an unrearranged product. However, partial fluorination of a tertiary amine prior to electrochemical fluorination rather allows high yields of undesired by-products, as far as our experiments were concerned.

Synthesis of perfluorochemicals for use as blood substitutes, Part I. Electrochemical fluorination of N-methyldecahydroquinoline and N-methyldecahydroisoquinoline

Abstract Electrochemical fluorination of N-methyldecahydroquinoline afforded mainly a mixture of cis and trans N-(F-methyl)-F-decahydroquinoline, their rearranged isomers and F-propyl-F-cyclohexane arising from the cleavage at carbon-nitrogen bonds, in a ratio of approximately 2:4:6:3. N-Methyldecahydroisoquinoline was also fluorinated electrochemically to give a mixture of cis and trans N-(F-methyl)-F-decahydroisoquinoline, their rearranged isomers and 1-(F-ethyl)-2-(F-methyl)-F-cyclohexane in a ratio of approximately 4:4:6:1. No correlation was found between the cis and trans ratio of starting materials and that of the corresponding perfluorinated amines. Fluorination of N-methyl-1,2,3,4-tetrahydroquinoline gave much lower yields.

Synthesis of perfluorochemicals for use as blood substitutes. Part IV. Electrochemical fluorination of N-cycloalkyl-pyrrolidines and -piperidines

Abstract Electrochemical fluorination of N-cyclopentylpyrrolidine gave the corresponding F-amine together with a ring-opened compound N-(F-pentyI)-F-pyrrolidine in the ratio of 1 to 1, in 55% yield. N-cyclohexylpyrrolidine, N-cyclopentylpiperidine, and N-cyclohexylpiperidine were also eletrochemically fluorinated in the same manner to give the corresponding F-amines, their isomers with rearranged structures, and ring-opened ones, in the ratio of ca - 4:2:1, and 2:1:1, respectively in 51 to 53% yields. Supporting spectral data are presented.

Synthesis of perfluorochemicals for use as blood substitutes. Part III. [1] electrochemical fluorination of quinolozidine, 4-methylquinolizidines and 4-trifluoromethylquinolizidines [2]

Abstract Electrochemical fluorination of quinolizidine gave F-quinolizidine in 16-23% isolated yields. 4-Methylquinolizidine was also fluorinated electrochemically to give the corresponding amine stereoisomers along with their fragmented and rearranged products in isolated yields of 28-34% and 2-3%, respectively. Introduction of an F-methyl group into the quinolizidine in place of the methyl group prior to electrochemical fluorination did not stabilize the 4-methyl quinolizidine structure and rather allowed the formation of F-quinolizidine to a greater extent. Oxidation of 4-(F-methyl)-F-quinolizidine with fuming sulfuric acid in the presence of a catalytic amount of HgSO 4 gave 6-oxo-4-(F-methyl)-F-quinolizidine in 60% yield, the F-nmr spectra of which gave further support to the structure of the starting material. The physical and spectral properties of these F-chemicals are described.

Electrochemical fluorination of cyclic amines useful as blood substitute components

Abstract Fluosol-DA, a PFC emulsion has been developed by The Green Cross Corp. of Japan as the first practical artificial blood substitute. From basic and clinical studies, this preparation has been proven to be safe and effective. In many cases with massive hemorrhage, this preparation significantly improved hemodynamics and blood gas state. A major inconvenience of this preparation, however, is that it must be kept under frozen state for long-term storage due to its instability at room temperature. To improve this point, we have continued to study new PFCs from the aspects of toxicity and emulsion stability. As a main part of this project, a number of compounds were synthesized by electrochemical fluorination, purified, characterized, and used for screening test. Among these are: F-N-alkylperhydroisoindoles, F-octahydroquinolidines, F-N-methylperhydroquinoline, and F-N-cycloalkylpyrrolidines. There has been a little known about electrochemical fluorination on cyclic amines. Our findings concerning the effects of molecular structure, reaction conditions on the fluorination of these cyclic amines will be reported in detail.