3-Fluoro-1-hydroxypropan-2-one (Fluorohydroxyacetone) and Some Esters. Syntheses and Effects in BDF₁ mice

1-(Benzoyloxy), 1-(4-nitrobenzoyloxy), and 1-(3,5-dinitrobenzoyloxy) derivatives of 3-fluoro-, 3-chloro-, and 3-bromopropan-2-one were prepared by oxidation of the 1-benzoyloxy-3-halopropan-2-ols in turn prepared from the appropriate benzoyl chloride and 3-halo-1,2-propanediols. l-Benzoyloxy-3-fluoropropan-2-one was allowed to react with acidic trimethyl orthoformate to yield 1-benzoyloxy-2,2-dimethoxy-3-fluoropropane which upon basic hydrolysis afforded 2,2-dimethoxy-3-fluoropropan-1-ol (fluorohydroxyacetone dimethyl ketal). This was deketalized with aqueous HC1 to afford 3-fluoro-1-hydroxypropan-2-one (fluorohydroxyacetone), the title compound. By reacting 1-chloro-3-fluoropropan-2-one and 1,3-dichloropropan-2-one with potassium acetate, 1-acetoxy-3-fluoropropan-2-one and l-acetoxy-3-chloropropan-2-one (fluoro-and chlorohydroxyacetone acetate, respectively) were obtained. Similarly, sodium benzoate and 1-chloropropan-2-one produced l-benzoyloxypropan-2-one. Structure-activity relationships are discussed which relate chemical structure, alkylating ability, toxicity, and antitumor effects. Comparative toxicities in mice showed decreasing toxicity, on a molar basis, in the 1-benzoyloxy-3-halopropan-2-one series of bromo > fluoro > chloro. Ketones were much more toxic than the corresponding alcohols. In general the phosphate and benzoyloxy derivatives are more toxic than acetoxy compounds, with nitro-substituted benzoyloxy derivatives being much less toxic.