Benzopiperazinone

Benzopiperazinones 200 were prepared by Erb et al. via the Ugi four-component reaction followed by palladium-catalyzed intramolecular Al-arylation [61]. XPhos was used as a supporting ligand to afford the 3,4-dihydroquinoxalin-3-ones 200 (Scheme 36). Microwave irradiation was found to be determinant on the reaction efficiency. 

The use of diamine derivatives in the three-component process leads to peptidomimetic heterocycles, such as 2-oxopiperazines (piperazinones) [58], benzopiperazi-nones [58] and benzodiazepines. In fact, the 2-oxopiperazines 89 can be obtained directly in one step via the reaction of a diamine 85 with glyoxylic acid 86 and a boronic acid 87 (Scheme 7.12) [58]. Presumably, the intermediate amino acids 88 can undergo a subsequent boronic acid-catalyzed lactamization [29] to afford 89. A two-step approach was used for the synthesis of benzopiperazinones (e.g. 96) [58]. 

Although benzopiperazinones (l,2,3,4-tetrahydroquinoxalin-2-ones) are structurally related to benzodiazepines, their use in drug discovery is less well established. Examples of biological activity of benzopiperazinones include their action as inhibitors of aldose reductase [208], as partial agonists of the y-aminobutyric acid (GABA)/benzodiazepine receptor complex [209, 210], and as angiotensin II receptor antagonists [211]. In addition, derivatives with antiviral acti vity associated vfith HIV have been reported [212, 213]. 

A similar approach has been outlined by Petasis and Patel for the formation of piperazinones and benzopiperazinones, using either stepwise or one-pot" protocols (Scheme 7.5) [41], A sequential protocol was used for reactions of mono-Boc protected ethylenediamines, 1,2-cyclohexanediamines or 1,2-phenylenediamines 19. Standard conditions were used for the Petasis borono-Mannich reaction, followed by Boc... 

Scheme 7.5 Synthesis of benzopiperazinones and 2-piperazinones using the Petasis borono-Mannich reaction.

Synthesis of Benzopiperazinone Derivatives. Employing ortho-Quoio nitrobenzene derivatives as the main scaffold, the fluoro group is substituted by amino acids or amines. Subsequent reduction of the nitro group on the benzene ring triggers the cyclization. The key step in obtaining benzopiperazinones is the intramolecular formation of an amide bond. 

In order to demonstrate the versatility of the immobilized 4-fluoro-3-nitro benzoic acid scaffold 10, we also synthesized benzopiperazinones derivatives. The building block used for the synthesis of benzopiperazinones is shown in Fig. 14. Complete acylation of 12 at the secondary aniline site was achieved by a reaction with chloroacetyl chloride in the presence of triethyl amine. Finally, one pot intramolecular cyclization of 25 and cleavage was done with NaOMe/ MeOH at room temperature. According to the thin layer chromatography analy-... 

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