Acetophenone → Phenacyl bromide

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반응 단계

The optically pure epoxide (FAE) is prepared from commercially available 4-benzyloxy-3-nitroacetophenone. Thus, the acetophenone may be brominated with bromine or pyridinium tribromide in an inert organic solvent such as CH3CN, MeOH or chloroform to give the α-bromoacetophenone. The bromoacetophenone is then reduced with a borane reducing agent, such as BH3.THF, BH3.diethylaniline or BH3Me2S, in the presence of a chiral oxazaborolidine catalyst, such as cis-(1R,2S)-aminoindanol-B-Me catalyst, to give the optically active bromohydrin after isolation by crystallization in >96% ee. The bromohydrin can be further enriched to >98% ee by recrystallization. The absolute configuration of the bromohydrin is determined by the chirality of the oxazaborolidine catalyst. The nitro group in the bromohydrin is selectively reduced to the amine group using a reducing agent known for selective nitro reduction, such as Sn, Fe with acid, SnCl2 or by heterogeneous catalytic hydrogenation in the presence of a noble metal catalyst such as PtO2 or Pt/C. Catalytic hydrogenation is cleaner if a noble metal catalyst such as platinum on carbon poisoned with dimethyl sulfide is used. The amine group is then formylated with a mixture of formic acid and acetic anhydride without racemization, and the resulting compound is converted to optically pure 4-benzyloxy-3-formamidostyrene oxide with a base such as aq. NaOH or K2CO3 in an alcohol solvent or solvent mixture such as MeOH/THF. The epoxide obtained can be purified by recrystallization from an inert organic solvent or solvent mixture, preferably from EtOAc/heptane or toluene/heptane.

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