Analogues of the Cyclic Hydroxamic Acid 2,4-Dihydroxy-7-methoxy-2H-1,4-benzoxazin-3-one: Decomposition to Benzoxazolinones and Reaction with β-Mercaptoethanol

Abstract

Analogues of the aglucones of naturally occurring cyclic hydroxamic acids (2,4-dihydroxy-1,4-benzoxazin-3-ones) from Gramineae (Poaceae) have been synthesized by the reductive cyclization of the ring-substituted methyl α-(o-nitrophenoxy)-α-methoxyacetates, followed by demethylation of the C-2 methoxy group with BBr3 or BCl3 to reveal the 2-hydroxy group. A structure-activity series was produced by varying the substituent at C-7 on the aromatic ring [R = MeO (1), t-Bu (6), Me (7), H (8), Cl (9), F (10), C02Me (11a)]. The pKa, values for the hydroxamic acid and the phenol moieties were determined for each member of the C-7 series. They correlated well with σ in a linear free energy relationship (LFER) yielding values of p = 0.71 (with σp) for pKa1 (the hydroxamic acid) and ρ = 1.6 (with σm) for pKa2 (the phenol). A LFER also existed between the rate constants for the unimolecular decomposition of these hydroxamic acids to benzoxazolinones and σ+ (ρ=-1.1). The rates of hydroxamic acid red