Reactions of isatoic anhydride as a masked isocyanate with oxygen and nitrogen nucleophiles—kinetics and mechanism

Abstract

The hydrolysis of isatoic anhydride 1, its 5-nitro 7; (X = NO₂, R = H) and N-methyl derivatives in water at 25 °C occurs mainly via direct HO^– attack on the neutral substrate. At high pH where 1 and 7(X = NO₂, R = H) are ionized, the o-carboxyphenyl isocyanate 8b is formed in equilibrium with the anion 8a, and this undergoes a competing reaction with HO^–(but at a slower rate). Reaction with amines at the anhydride carbonyl (C-4) which occurs at pH < 10 is characterized by a β_nuc value of +1.0 but is highly sensitive to the steric bulk of the attacking amine. In consequence reaction at the isocyanate in the anion 8(X = H) is only important with bulky amines. With the 5-nitro derivative (pK_a 6.7), reaction with the conjugate base can be measured even with non-hindered bases; these yield a β_nuc value of 0.31, providing strong evidence that reaction occurs via the isocyanate 8b(X = NO₂). The implications for heterocyclic synthesis starting from isatoic anhydride are considered.