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.

本文报道了一种可获得良好总收率的4-取代氯酞嗪（chlorophthalazines）通用三步合成方法。核心合成步骤中，N,N-二甲基邻苯二甲酰亚胺（N,N-dimethylaminophthalimide，8a）可介导烷基、芳基及杂芳基有机金属试剂发生选择性单加成反应，得到3-取代-3-羟基异吲哚啉酮（3-hydroxyisoindolinones）产物9b、9i~9am。其中多数该类羟基异吲哚啉酮可通过与肼（hydrazine）反应，再经三氯氧磷（POCl3）氯化，转化为氯酞嗪1b~1v。本研究还发现了3-乙烯基-3-羟基异吲哚啉酮与3-炔基-3-羟基异吲哚啉酮的两类新型转化反应：将有机金属乙烯基试剂与N,N-二甲基邻苯二甲酰亚胺（8a）反应，可通过推测的3-乙烯基-3-羟基异吲哚啉酮中间体扩环过程，得到二氢苯并氮杂卓二酮（dihydrobenzoazepinediones）15a~15c；3-炔基-3-羟基异吲哚啉酮可与肼及取代肼反应，生成2-吡唑基苯甲酸（2-pyrazolyl benzoic acids）16a~16d与2-吡唑基苯甲酰肼（2-pyrazolyl benzohydrazides）17a~17g，而非预期的炔基酞嗪酮。