title: Synthesis of 4-substituted chlorophthalazines, dihydrobenzoazepinediones, 2-pyrazolylbenzoic acid, and 2-pyrazolylbenzohydrazide via 3-substituted 3-hydroxyisoindolin-1-ones.
abstract: 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 POCl(3). 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.
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., 360 Binney St., Cambridge, Massachusetts 02142, USA. hanhn@amgen.com
authors.forename: Hanh Nho
authors.initials: HN
authors.lastname: Nguyen
authors.forename: Victor J
authors.initials: VJ
authors.lastname: Cee
authors.forename: Holly L
authors.initials: HL
authors.lastname: Deak
authors.forename: Bingfan
authors.initials: B
authors.lastname: Du
authors.forename: Kathleen Panter
authors.initials: KP
authors.lastname: Faber
authors.forename: Hakan
authors.initials: H
authors.lastname: Gunaydin
authors.forename: Brian L
authors.initials: BL
authors.lastname: Hodous
authors.forename: Steven L
authors.initials: SL
authors.lastname: Hollis
authors.forename: Paul H
authors.initials: PH
authors.lastname: Krolikowski
authors.forename: Philip R
authors.initials: PR
authors.lastname: Olivieri
authors.forename: Vinod F
authors.initials: VF
authors.lastname: Patel
authors.forename: Karina
authors.initials: K
authors.lastname: Romero
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Schenkel
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Geuns-Meyer
mesh_terms: D001565:Benzoates / Q000138:chemical synthesis* / Q000737:chemistry*; D002384:Catalysis; D054879:Halogenation; D006834:Hydrazines / Q000138:chemical synthesis* / Q000737:chemistry*; D054833:Isoindoles / Q000138:chemical synthesis* / Q000737:chemistry*; D015394:Molecular Structure; D010793:Phthalazines / Q000138:chemical synthesis* / Q000737:chemistry*; D010797:Phthalimides / Q000737:chemistry*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry*; D013237:Stereoisomerism
chemical_list: C573962:2-pyrazolylbenzohydrazide; C573961:2-pyrazolylbenzoic acid; D001565:Benzoates; D006834:Hydrazines; D054833:Isoindoles; C573964:N,N-dimethylaminophthalimide; D010793:Phthalazines; D010797:Phthalimides; D011720:Pyrazoles