Raymond G. Plevey

2-Trifluoromethylimidazole, 2,4,5-tris (trifluoromethyl)imidazole and related compounds

Abstract 2-Trifluoromethylimidazole, prepared by the reaction of imidazole-2-carboxylic acid with sulphur tetrafluoride, afforded a silver salt which reacted with organohalides (bromomethane, ethyl bromoacetate, N,N-dimethyl-2-chloroethylamine, and chloroacetonitrile) to give the corresponding N-alkylated derivatives. 2-Trifluoromethylimidazole-4,5-dicarboxylic acid was obtained by oxidation of 2-trifluoromethylbenzimidazole, and on decarboxylation gave only traces of 2-trifluoromethylimidazole; the major product was 2-trifluoromethylimidazole- 4-carboxylic acid. The di-acid and sulphur tetrafluoride gave 2,4,5-tris (trifluoromethyl) imidazole.

Fluorinations with complex metal fluorides. Part 6 [1] fluorination of yridine and related compounds with caesium tetrafluorocobaltate(III) [2]

Abstract Pyridine has been fluorinated over caesium tetrafluorocobaltate(III) (CsCo III F 4 ) at 300–400°C to give a mixture of undecafluoro-N-methylpyrrolidine, bis(trifluoromethyl)amine, pentafluoropyridine and several polyfluoropyridines; the product composition depended to some extent on the geometry of the reactor. The fluorinations of pentafluoropyridine, piperidine and undecafluoropiperidine were also investigated.

Fluorinations with complex metal fluorides Part 8. Ring rearrangement in the fluorinations of quinoline with caesium tetrafluorocobaltate and with cobalt(III) fluoride

Abstract Fluorination of quinoline by caesium tetrafluorocobaltate at ca. 350° afforded mainly a mixture of pentadecafluoro-2-azabicyclo[4,4,0]dec-1(2)- ene (E), and heptadecafluoro-1-azabicyclo[5,3,0]decane (F), arising by skeletal rearrangement. Minor products were six polyfluorocyclohexa[b]- pyridines (G–L) all with carbocyclic rings having the -(CF 2 )4 - moiety. Compound F was unreactive, but E was highly susceptible to nucleophiles, e.g. water and methanol. Isoquinoline was fluorinated similarly, but the only new product isolated was tridecafluoro-3-azabicyclo[4,4,0]deca- 1(6)-2-diene (R). The rearrangement occurring with quinoline prompted a re-examination of its fluorination by cobalt(III) fluoride. At ca. 350°, compound F was the major product, with very little E: there were some ring-opened materials, the most important being tetradecafluoro-4-pentafluoroethyl- 2-azaoct-2(Z)-ene (N).

Fluorinations with complex metal fluorides. Part 9. Fluorinations of toluene and xylene derivatives by means of caesium tetrafluorocobaltate [III]

Abstract Benzotrifluoride at 320 °C afforded some m-fluorobenzotrifluoride and octafluorotoluene (III), together with perfluoromethylcyclohexane (I), and also traces of 2H-heptafluorotoluene and 1-trifluoromethylnonafluorocyclohex-1-ene. Toluene itself gave (difluoromethyl)benzene, fluoro- and difluoro-methylpentafluorobenzene, difluoromethylundecafluorocyclohexane and (I); also traces of di- and tri-fluoromethylnonafluorocyclohex-1-ene: no benzotrifluoride or (III) were detected. 1,3-Bis(trifluoromethyl)benzene at 420 °C gave 4,5,6-trifluoro-1,3-bis(trifluoromethyl)benzene, decafluoro-1,3-dimethylbenzene, and perfluoro-1,3-dimethylcyclohexane. Para-xylene at 350 °C afforded 1,4-bis(difluoromethyl)tetrafluorobenzene, 1-difluoromethyl -4-trifluoromethyltetrafluorobenzene, decafluoro-1,4-dimethylbenzene (XIX), and perfluoro-1,4-dimethylcyclohexane (XVIII). Defluorination occurred to a significant extent on passage of the saturated cyclic fluorocarbons (I) and (XVIII) over the fully spent fluorinating agent (presumably caesium trifluorocobaltate) at ca. 400 °C; the fluorocarbon arenes, (III) and (XIX) respectively, were obtained.

Fluorinations with complex metal fluorides. Part 7. Fluorinations of the methyl pyridines with caesium tetrafluorocobaltate

Abstract 4-Methylpyridine passed over caesium tetrafluorocobaltate at 330 – 340° gave tridecafluoro(1,3-dimethylpyrrolidine) (1) and its 3-difluoromethyl analogue (2), together with a range of polyfluoro-4-picolines (4 – 10) with −CF 3 , −CHF 2 or −CH 2 F groups in the 4-position. 3-Methylpyridine similarly gave 1 and its 1,2-isomer (11) together with several polyfluoro-3-picolines (14 – 18). 2-Methylpyridine at 270° gave tridecafluoro(1-ethylpyrrolidine) (13), a trace of 11 and 2-trifluoromethyl- (22), 2-difluoromethyl- (23) and 2-fluoromethyl-tetrafluoropyridine (24); there were also products arising by loss of methyl. Other unidentified fluoroalkylpyridines besides those isolated were present in each case.

Synthesis and structure of the first per-substituted anthracene host: Decakis(cyclopentylthio)anthracene

Abstract The title compound, a novel host molecule, has been prepared both from mixtures of unsaturated fluorocarbons related to perfluoro-perhydroanthracene and, in an extension of a remarkable new reaction, perfluoroperhydroanthracene itself. The 1,4-dioxane inclusion compound of this anthracene-based host is triclinic, space group P 1, with a = 11.826(1), b = 15.297(1), c = 20.280(1) A, α = 98.77(1), β = 99.85(1), and γ = 95.83(1)°, with two host, and ca. three 1,4-dioxane guest molecules per unit cell. The host molecule occupies a general position in the unit cell and its anthracene core is markedly non-planar; each of the three crystallographically independent six-membered rings possesses a shallow twist-boat conformation. The hosts side-chain moieties display an asymmetrical conformational distribution of the abbabaabab type (a = above, b = below, mean core plane).

Synthesis of fluorinated derivatives of glutethimide and aminoglutethimide

Abstract Aminoglutethimide (1), used in the treatment of hormone dependent breast cancer, interacts with enzyme complexes desmolase and aromatase. Its action is not specific and its metabolism gives rise to toxic and non-inhibitory metabolites. The work described here explores the impact of fluorine substitution within the glutethimide (2) framework, on the enzyme inhibitory properties of aminoglutethimide. Four new fluorinated derivatives (5), (6), (8) and (9) have been prepared, in which fluorine substituents have been introduced into the phenyl ring and the ethyl side chain. 4-Fluoroglutethimide (5) and 3-trifluoroglutethimide (6) were synthesised from the corresponding fluorophenylacetonitriles (10) and (14) via sequential monoethylation, Michael addition to methyl propenoate and cyclisation. An alternative strategy, devised for the synthesis of (8), involved the monoarylation of ethyl cyanoacetate, and gave rise to the intermediate (29). Incorporation of fluorine was carried out by SF4 fluorination of the cyanoketoester (33), which was subsequently converted to the difluoroaminoglutethimide (8). For the synthesis of trifluoromethyl glutethimide (9), the trifluoromethyl group was introduced by alkylation of phenylcyanoacetate (16) with 2-iodo-1,1,1,-trifluoroethane. Preliminary in vitro enzyme inhibition results have been obtained for compounds (5), (6) and (8).

Polyfluorocycloalkenes. Part XVII. Further preparations of alkoxy-nonafluorocyclohexenes and their pyrolyses to polyfluorocyclohEx-2-enones

Abstract Reactions between decafluorocyclohexene and substituted ethanols (HOCH 2 CH 2 X: X = Cl, Br, I, and OMe) gave, in each case, a mixture of the corresponding 1- and 3-alkoxy-nonafluorocyclohexene (roughly 3:1). Pyrolysis of the 1-(2-methoxyethoxide) over glass or alumina at 520°C gave octafluorocyclohex-2-enone. This was obtained also in good yield by pyrolysis of the known 1-ethoxy- and 1-(2-acetoxyethoxy)- analogues. From the other 1-alkoxides the same enone was formed, but accompanied by other products: from the 1-(2-bromoethoxide), nonafluorocyclohex-1-enyl vinyl ether and 3-bromoheptafluorocyclohex-2-enone; from the 1-(2-iodoethoxide), the vinyl ether and 2-chloroheptafluorocyclohex-2-enone; from the 1-(2-iodoethoxide) at 395°C, 6,6,7,7,8,8,9,9-octafluoro-2-oxabicyclo[4,3,0]nona-1(5),3-diene. Pyrolyses at lower temperatures gave much unreacted 1-alkoxides, but no rearrangement to 3-alkoxides was detected. In contrast, the 3-ethoxy- and 3-(1-bromoethoxy)-isomers decomposed to a greater extent at 390°C, to give the octafluoroenone, but, besides unreacted starting materials, some isomeric 1-alkoxide was present in each case. Reaction of octafluorocyclohex-2-enone with chlorides and bromides gave the respective 3-chloro- and 3-bromo-2-enones, whilst with base, a haloform cleavage took place within the conjugated system to give cis -6H-octafluorohex-5-enoic acid.

The fluorinations of pentafluoronitrobenzene and pentafluorobenzaldehyde by cobalt(III) fluoride

Abstract The nitro-group survived in the fluorination of pentafluoronitrobenzene by cobalt(III) fluoride at 135–150°, the major products being undecafluoronitrocyclohexane and nonafluoro-4-nitrocyclohex-1-ene. 2H- Tetrafluoronitrobenzene similarly afforded cis- and trans -2H-1-nitrodeca- fluorocyclohexane and 5H/4-nitro-octafluorocyclohex-l-ene. Pentafluoro- benzaldehyde was fluorinated to give undecafluorocyclohexanecarbonyl fluoride and nonafluorocyclohex-3-enecarbonyl fluoride. Nonafluoro-4- nitrocyclohex-1-ene was oxidized to 3-nitroheptafluorohexan-1,6-dioic acid, and undecafluoronitrocyclohexane was hydrogenated over a palladium catalyst at low pressure to give decafluorocyclohexanone oxime and 1H-decafluoro- cyclohexanamine, accompanied by 1-aminononafluorocyclohex-1-ene.

Polyfluorocycloalkenes Part XIII [1]. Reactions of perfluorocycloalkenes with 1-ethoxy-1-(2-hydroxyethoxy) ethane in the presence of base

Abstract 1-Ethoxy-1-(2-hydroxyethoxy) ethane and sodium hydride with octafluorocyclopentene, decafluorocyclohexene and dodecafluorocycloheptene produced acid-labile acetals which were hydrolysed to the corresponding 1-(2-hydroxyethoxy) perfluorocycloalkenes. Cyclisation of these compounds under basic conditions gave substituted dioxolans and not 1,4-dioxanes.