Heck Arylation of Maleic Anhydrides Using Arenediazonium Tetrafluoro­borates: Synthesis of Mono- and Diarylated Maleic Anhydrides and of the ­Marine Alkaloids Prepolycitrin A and Polycitrin A

Abstract

The Heck arylation of maleic anhydrides using arenediazonium tetrafluoroborates was investigated. Symmetrical and unsymmetrical 3,4-diarylmaleic anhydrides, some of them showing interesting fluorescent properties, were prepared in one or two steps from cheap and commercially available maleic anhydride. This Heck arylation methodology constitutes a new and direct entry to the synthesis of arylated maleic anhydride materials, natural products and their derivatives, as demonstrated with the total syntheses of the marine alkaloids prepolycitrin A and polycitrin A and with the synthesis of a N-protected fluorescent phenylalanine.

arenediazonium tetrafluoroborates - Heck arylation - 3,4-diarylmaleic anhydrides - polycitrin A - fluorescent materials

References and Notes

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<A NAME="RS07306ST-11">11</A>

Reactions using Pd₂(dba)₃ as catalyst generate a number of colored side products, probably due to the Heck arylation of the ligand dba. A better Pd(0) source was obtained by in situ reduction of Pd(OAc)₂ using dihydrofuran, and anisole as additive. This procedure provided a finely dispersed Pd(0) in MeCN (see ref. 17). Arylation failed with other bases, such as: 2,6-di(tert-butyl)-4-methylpyridine, Et₃N, imidazole, K₂CO₃ and BaCO₃.

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Superstoichiometric amount of the arenediazonium salts (2 or 4 equiv) is not strictly required for the synthesis of the diarylated adducts. However, the use of excess of this reagent leads to shorter reaction times and higher yields.

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Typical Experimental Procedure.
To a solution of 4.5 mg of Pd(OAc)₂ in 3 mL of MeCN was added anisole (0.8 mL of a 0.1 M solution in MeCN) and 2,3-dihydrofuran (0.2 mL of a 0.1 M solution in MeCN). After 5 min, 49 mg of maleic anhydride (0.5 mmol), 123 mg of NaOAc (1.5 mmol) and 443 mg of 4-methoxybenzene-diazonium tetrafluoroborate (2 mmol) were added and the reaction mixture refluxed for 1 h. After cooling, the reaction mixture was diluted with 15 mL of EtOAc and filtered through a short pad of Celite^®. The solvent was then evaporated in vacuo and the residue flash chromatographed (SiO₂, hexane-EtOAc = 8:2) to provide 93 mg (60% yield) of the Heck adduct 3 as homogeneous material by TLC.