K. Gnanasekaran, M. Rivera, R. Bunce
May 4, 2018
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Organic Preparations and Procedures International
Abstract
A recent synthesis in our drug discovery program required access to 4,7-diaminoisoindoline-1,3-dione (1, also 3,6-diaminophthalimide) in 250–500 mg quantities. This compound has been previously reported from the known 4,7-dichloroisobenzofuran-1,3-dione (also 3,6-dichlorophthalic anhydride). The preparation of this anhydride involved zinc promoted hydrodechlorination of 3,4,5,6-tetrachlorophthalic anhydride under basic conditions to initially give 3,4,6-trichlorophthalic acid. Further dechlorination with zinc generated 3,6-dichlorophthalic acid, and boiling in toluene with azeotropic removal of water gave 3,6-dichlorophthalic anhydride. We repeated this sequence on a small scale to get all of these compounds with physical and spectral properties identical to those reported. Subsequent reaction of 3,6-dichlorophthalic anhydride with excess aq NH3 and CuI (sealed tube, 120–130 C, 8 h) according to the literature procedure, however, gave a product that melted at 273–275 C, which did not match the reported value. Spectral analysis of this material suggested that it was 4-amino-7-chloroisoindoline-1,3dione rather than the diamino compound. The H NMR spectrum displayed a singlet at d 11.1 (1H) for the imide proton, two doublets at d 7.38 and d 7.02 (1H each) for the coupled protons at C6 and C7, and a broad singlet at d 6.53 (2H) for the amino protons. Additionally, the C NMR showed eight carbons rather than four carbons expected for the symmetrically substituted phthalimide, and the mass spectrum gave parent ion peaks at 196 and 198 in an approximate 3:1 ratio. Though the original work apparently did yield the correct product from 3,6-dichlorophthalimide, problems were documented when 3,6-dichlorophthalic anhydride was used as the starting material. Since the 4-amino-7chloro derivative did not meet our needs and the procedure was rather labor intensive, this approach was not repeated, but instead, we opted to develop our own route to the 4,7diamino compound. Our findings are reported below. The successful synthesis required two steps and was more straightforward than the