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

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journal contribution
posted on 20.04.2012, 00:00 by Hanh Nho Nguyen, Victor J. Cee, Holly L. Deak, Bingfan Du, Kathleen Panter Faber, Hakan Gunaydin, Brian L. Hodous, Steven L. Hollis, Paul H. Krolikowski, Philip R. Olivieri, Vinod F. Patel, Karina Romero, Laurie B. Schenkel, Stephanie D. Geuns-Meyer
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, 9i9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b1v 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 15a15c 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 16a16d and 2-pyrazolyl benzohydrazides 17a17g rather than the expected alkynyl phthalazinones.