ANALOGS OF THE CYCLIC HYDROXAMIC ACID 2,4-DIHYDROXY-7-METHOXY-2H-1,4-BENZOXAZIN-3-ONE - DECOMPOSITION TO BENZOXAZOLINONES AND REACTION WITH BETA-MERCAPTOETHANOL

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 alpha-(o-nitrophenoxy)-alpha-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), CO2Me (11a)]. The pK(a) values for the hydroxamic acid and the phenol moieties were determined for each member of the C-7 series. They correlated well with sigma in a linear free energy relationship (LFER) yielding values of rho = 0.71 (with sigma-p) for pK(a1) (the hydroxamic acid) and rho = 1.6 (with sigma-m) for pK(a2) (the phenol). A LFER also existed between the rate constants for the unimolecular decomposition of these hydroxamic acids to benzoxazolinones and sigma+ (rho = 1.1). The rates of hydroxamic acid reduction to lactams by beta-mercaptoethanol were also investigated. It was found that only compounds with electron-rich aromatic rings and specifically an oxa functionality para to the hydroxamic acid nitrogen atom (compounds 1 and 3-5) had measurable rates of reduction. H-1 NMR spectra recorded during this reaction in D2O buffers (pD9), however, showed that compounds 1, 2, 6-9 (the only ones investigated) formed a hemithioacetal at C-2 even though only 1 has a measurable rate of reduction by the same thiol. The remarkable rate enhancement provided by an oxa functionality suggests that reduction occurs by direct attack of thiolate on the hydroxamic nitrogen of a resonance-stabilized ion pair.