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

• Published in: Journal of organic chemistry 2012-04, Vol.77 (8), p.3887-3906
• Main Authors: Nguyen, Hanh Nho, Cee, Victor J, Deak, Holly L, Du, Bingfan, Faber, Kathleen Panter, Gunaydin, Hakan, Hodous, Brian L, Hollis, Steven L, Krolikowski, Paul H, Olivieri, Philip R, Patel, Vinod F, Romero, Karina, Schenkel, Laurie B, Geuns-Meyer, Stephanie D
• Format: Article
• Language: English
• Subjects: Benzoates - chemical synthesis; Benzoates - chemistry; Catalysis; Chemistry; Exact sciences and technology; Halogenation; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Hydrazines - chemical synthesis; Hydrazines - chemistry; Isoindoles - chemical synthesis; Isoindoles - chemistry; Molecular Structure; Noncondensed benzenic compounds; Organic chemistry; Organometalloidal and organometallic compounds; Phthalazines - chemical synthesis; Phthalazines - chemistry; Phthalimides - chemistry; Preparations and properties; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo3000628

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.