Synthesis of 1-amino-4-( 2 ́-thienyl ) phthalazine derivatives

A synthesis of 1-amino substituted 4-(2 ́-thienyl)-phthalazines is described from haloderivatives of 4-(2 ́-thienyl)-1-(2H)-phthalazinone 3.

Due to the nature of the phthalazine nucleus, synthesis of new derivatives becomes an importante issue.There has been little reported in the literature concerning 4-thienyl substituted phthalazines [17][18], [35][36].It was for that reason that we decide to synthesize new thienylphthalazine derivatives.
In this paper we report the synthesis of new 1-amino-4-(2´-thienyl)phthalazine derivatives 5a-e from halo derivatives 4a-b of the phthalazinone 3. Compound 3 was obtained by cyclization of acylbenzoate 2 using hydrazine hydrate.The latter was made through a Friedel-Crafts reaction between thiophene and phthalic acid monochloride ester 1.

Results and Discussion
The 2-thienyl substituted benzoate 2 was obtained, in good yield (81%), by the standard method of Friedel-Crafts reaction of thiophene with o-phthalic acid monomethylester chloride 1.This compound was subsequently cyclized by condensation with hydrazine hydrate to give phthalazinone 3 in 91% yield from benzoate 2 (Scheme 1, Table 1).
Bromine and chlorine substituted phthalazines play an important role in diazine chemistry since they offer the potential for further funtionalization.By nucleophilic displacement of the halogen group, numerous otherwise inaccessible diazines become available.To this end we have synthesized and characterized chloro-and bromophthalazine derivatives.
From 3, bromo and chloro derivatives were prepared by reaction with phosphoryl halides.The chloride 4a and the bromide 4b, were obtained with respectively 99 and 87% yield.1-Chloro-4-(2´-thienyl)-phthalazine 4a has been already reported in a patent [35], by condensation of 1,4-dichlorophthalzine with thienyllithium.No data about the derivative are given.
Compounds 2-5 were completely characterized by elemental analysis and/or HRMS, 1 H NMR and 13 C NMR spectroscopy and IR spectroscopy.
Starting from the easily available acylbenzoate 2, commercial reagents as well as simple and convenient procedures were used to synthesize new phthalazine derivatives in moderate to excellent yields.
The examination of biological activity of compounds 5a-e are in course.This compound was obtained in a 84% yield as a beige solid, mp 125.