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

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• 作者：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
• 刊名：The Journal of Organic Chemistry
• 出版年：2012
• 出版时间：April 20, 2012
• 年：2012
• 卷：77
• 期：8
• 页码：3887-3906
• 全文大小：682K
• 年卷期：v.77,no.8(April 20, 2012)
• ISSN：1520-6904

文摘

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鈥?b>9am. Many of these hydroxyisoindolinones are converted to chlorophthalazines 1b鈥?b>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鈥?b>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鈥?b>16d and 2-pyrazolyl benzohydrazides 17a鈥?b>17g rather than the expected alkynyl phthalazinones.