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.

Key words

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

References and Notes

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11

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.

12

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.

17

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.