Conrad R. Burkholder

Synthesis and reactivity of halogeno-difluoromethyl aromatics and heterocycles: Application to the synthesis of gem-difluorinated bioactive compounds

Abstract In an effort to prepare new fluorine-containing compounds which are active against HIV, and based on the electrochemical reduction of a series of bromodifluoromethyl compounds, the tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reductant of the 2-(bromodifluoromethyl)benzoxazole 1 and of the 5-(bromodifluoromethyl)-3-phenyl-1,2,4-oxadiazole 3 . A stepwise electron transfer with a difluoromethyl radical as intermediate is assumed to take place in this reaction. Under mild conditions, the generated difluoromethyl heterocyclic anion was efficiently trapped with aromatic and heterocyclic aldehydes 7 – 14 and ketones 15 – 16 . In this way the corresponding β,β-difluoro-α-heteroarylated alcohols 17 – 32 were obtained in moderate to good yields. The same methodology was successfully applied to the reduction of chlorodifluoromethylated ketones 4 – 6 and the generated α,α-difluoroacetyl anion was trapped with several aldehydes 7 , 8 , 10 , 11 , under mild conditions, to give the corresponding 2,2-difluoro-3-hydroxy ketone derivatives 33 – 38 , in moderate yields. The S RN 1 reactions of 2-(bromodifluoromethyl)benzoxazole ( 1 ) with the anions of heterocyclic thiols and phenolic compounds were also carried out. The products 39 – 54 , which all have a CF 2 group, were tested for activity against HIV, and several were found to be active, including 44 which was very active.

Fluorinated allenes: the syntheses of 1-fluoropropadiene, 1,1-difluoropropadiene and 1,1-difluoro-3-methyl-1,2-butadiene

Abstract Improved syntheses of 1-fluoropropadiene and 1,1-difluoropropadiene are presented as is the synthesis of a third reactive allene, 1,1-difluoro-3- methyl-1,2-butadiene. Gram quantities of these highly reactive fluorinated allenes may be prepared conveniently in high yield and purity. All three are reactive dienophiles and cycloadd regiospecifically using their non- fluorine-substituted double bonds.

Syntheses of 2-(bromodifluoromethyl)benzoxazole and 5-(bromodifluoromethyl)-1,2,4-oxadiazoles

Abstract Facile syntheses of CF 2 Br-substituted heterocycles are reported. Preparation of 2-(bromodifluoromethyl)benzoxazole ( 2 ) was achieved in two steps by reaction of 2-aminophenol ( 3 ) with CF 2 BrCO 2 Et to give amide ( 4 ), followed by cyclization of 4 with PPA to give 2 . The 5-(bromodifluoromethyl)-1,2,4-oxadiazoles ( 6a–c ) were prepared by one step reaction of amidoximes ( 5a–c ) with CF 2 BrCO 2 Et. These CF 2 Br-substituted heterocycles are intermediates in an ongoing investigation of the synthesis of inhibitors of HIV reverse transcriptase having a CF 2 substitution.

Tetrakis(dimethylamino)ethylene (TDAE) as a useful reductant of some chlorodifluoromethylated ketones. A new approach for the synthesis of α,α-difluoroketone derivatives

Abstract Tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reductant of chlorodifluoromethylated ketones 1–3 . The generated α,α-difluoroacetyl anion was trapped with several aldehydes 4–7 , under mild conditions, to give the corresponding 2,2-difluoro-3-hydroxy ketone derivatives 8–13 , in moderate yields.

Synthesis and electron-transfer reactions of some 3-difluoroacetylated imidazo[1,2-a]pyridine derivatives

Abstract The synthesis of new 3-chlorodifluoroacetylated imidazo[1,2- a ]pyridines 1 – 6 and their difluoroacetyl derivatives is presented. The reductive cleavage of the halogenated ketones was investigated by cyclic voltammetry, and tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reductant for the generation of the corresponding α,α-difluoroacetyl anions and for the synthesis of new gem -difluoromethylated imidazo[1,2- a ]pyridine derivatives 7 – 12 .

Reaction of the 2-(bromodifluoromethyl)benzoxazole with tetrakis(dimethylamino)ethylene (TDAE) in the presence of aldehydes. A convenient synthesis of 2-(difluoromethyl)benzoxazole alcohols

Abstract Tetrakis(dimethylamino)ethylene (TDAE) was found to be an effective reductant of the 2-(bromodifluoromethyl)benzoxazole 1 . The generated 2-(difluoromethyl) benzoxazole anion was trapped with several aldehydes 2 – 9 , under mild conditions, to give the corresponding 2-(difluoromethyl)benzoxazole alcohols 10 – 17 , in moderate to good yields.

Synthesis of α-(heteroarylthio)-α,α-difluoroacetophenone derivatives via the SRN1 methodology

Abstract New α-(heteroarylthio)-α,α-difluoroacetophenone Ar 1 -COCF 2 S-Ar 2 derivatives 8 – 15 were synthesized in moderate to good yields via the S RN 1 methodology, from the reaction of a series of chlorodifluoromethylated ketones 1 – 4 with aromatic and heterocyclic thiols 5 – 7 . The corresponding Ar 1 -CHOHCF 2 S-Ar 2 16 – 23 were also prepared in moderate yields, using sodium borohydride in absolute ethanol. The compounds may find some biological applications as potent anti-HIV-1 as well as useful synthons for agrochemicals.

The thermal conversions of 6,6-difluorobicyclo[3.1.0]hex-2-enes to fluorobenzenes. An interesting dichotomy of mechanisms

Abstract A kinetic study of the thermal, dehydrofluorinative aromatization reactions of two ostensibly-similar 6,6-difluorobicyclo[3.1.0]hex-2-ene systems led to the conclusion that drastically different mechanisms operate for the two reactions. Activation parameters, solvent effects, kinetic isotope effects, isotope labelling experiments and observation of reactive intermediates all contributed to the conclusion that the reaction of 6,6-difluorobicyclo[3.1.0]hex-2-ene, 1 , proceeds via a homolytic hydrogen-shift rearrangement, while the reaction of 2,3-benzo-6,6-difluorobicyclo[3.1.0]hex-2-ene, 6 , proceeds via a solvolytic mechanism involving rate-determining carbocation formation.

The regiochemistry and stereochemistry of 1,3-dipolar cycloadditions of 1-fluoro- and 1,1-difluoroallene

Abstract 1,3-Dipolar cycloadditions of diazoalkanes, nitrones and nitrileoxides occur with high regioselectivity to 1,1-difluoroallene and fluoroallene, and with variable syn or anti π-facial diastereoselectivity with regard to additions to the latter. The roles of steric effects, frontier molecular orbital effects, electrostatic interactions and other factors which may be involved in determining the observed regioselectivity and π-facial diastereoselectivity are discussed.

The reactions of n-benzoylperoxycarbamic acid with azines and imines

Abstract N-Benzoylperoxycarbamic acid (BPC) was found to react generally with imines and azines to form oxaziridines rather than N-oxides. The imine products were stable, but those found from azines apparently were unstable and converted to ketones or aldehydes plus diazo compounds.