Alkylation of malonates or schiff base anions with dichlorofluoromethane as a route to α-chlorofluoromethyl or α-fluoromethyl α-amino acids

The preparation of HCF2CdX and HCF2ZnX via direct insertion into the carbon halogen bond of CF2HY (Y=Br, I)

“…The CHF 2 I rapidly inserts cadmium at RT to give a 91% 19 F NMR yield of a mixture of mono-and bis-difluoromethylcadmium. In contrast, bromodifluoromethane requires 5 days at 55 8C (in DMF) to give a 65-75% 19 F NMR yield of the mono-and bis-difluoromethylcadmium reagent (Eq. (7)) with a mono/bis ratio of $3/1.…”

“…The NMR tube was placed in the probe of a 90 MHz JEOL FX90Q NMR spectrometer. The 19 F NMR spectrum was recorded at 25 8C and then recorded every 10-20 min as the temperature was slowly raised (in 10 8C intervals) to 115 8C. The difluoromethylcadmium reagent exhibits excellent stability at RT-with a loss of only 31% activity of the original reagent after 2 months.…”

“…For example, after heating HCF 2 ZnX (in DMF) with cinnamyl bromide for 19 h at 45 8C, followed by 28 h at 55 8C, 18% of HCF 2 ZnX still remained. 19 F NMR analysis of the reaction mixture indicated a 74% ( 19 F NMR yield) of a mixture containing (E)-4,4-difluoro-1-phenyl-1-butene and 4,4-difluoro-3-phenyl-1-butene in a 42:58 ratio. Although the yield was slightly lower due to unreacted zinc reagent and longer reaction times were required, it is noteworthy that the HCF 2 ZnX reagent does react with allyl halides (albeit slower) and provides a less toxic alternative to the cadmium analog.…”

“…(19)). The byproducts of the reaction were CF 2 HCF 2 H and cis-CFH CFH from the decomposition of HCF 2 Cu.…”

“…Bey et al prepared a number of difluoromethyl amino acids using chlorodifluoromethane as the difluoromethyl precursor (Eq. (4)) [16][17][18][19]. Although these reactions with CHF 2 Cl can be rationalized (4) as an S N 2 process, more likely they involve difluorocarbene as a reaction intermediate (Eq.…”