Synthesis of 4-Substituted Chlorophthalazines, Dihydrobenzoazepinediones, 2-Pyrazolylbenzoic Acid, and 2-Pyrazolylbenzohydrazide via 3-Substituted 3-Hydroxyisoindolin-1-ones

Herein we describe a general three-step synthesis of
4-substituted chlorophthalazines in good overall yields. In the key
step, N,N-dimethylaminophthalimide
(8a) directs the selective monoaddition of alkyl, aryl,
and heteroaryl organometallic reagents to afford 3-substituted 3-hydroxyisoindolinones 9b, 9i–9am. Many of these
hydroxyisoindolinones are converted to chlorophthalazines 1b–1v via reaction with hydrazine, followed by
chlorination with POCl3. We have also discovered two novel
transformations of 3-vinyl- and 3-alkynyl-3-hydroxyisoindolinones.
Addition of vinyl organometallic reagents to N,N-dimethylaminophthalimide (8a) provided dihydrobenzoazepinediones 15a–15c via the proposed ring expansion
of 3-vinyl-3-hydroxyisoindolinone intermediates. 3-Alkynyl-3-hydroxyisoindolinones
react with hydrazine and substituted hydrazines to afford 2-pyrazolyl
benzoic acids 16a–16d and 2-pyrazolyl
benzohydrazides 17a–17g rather than
the expected alkynyl phthalazinones.