Synthetic Study Of Pyrrolnitrin Analogues

Pyrrolnitrin analogues belong to 3,4-disubstituted pyrroles, on which a chloride and a substituted aryl group are attached to its β-positions. Although the synthetic methodology of 3 4-disubstituted pyrrole have been much developed, how to introduce a substituent to its β-position to prepare 3,4-disubstituted pyrrole is still a great challenge.Trimethylsilyl (TMS) in an organic aromatic molecule can be replaced by an electrophile on the ipso position of the aromatic rings. This means that a substituent can be introduced to the position of TMS. In addition, we also found in previous studies that a TMS group on a pyrrole ring can be substituted with a chroride, followed by the TMS migration in the presence of NCS. We use these two properties of TMS to designe two new routes for the synthesis of pyrrolnitrin analogues.These two synthetic routes all take 3,4-bis(trimetylsilyl)-1-tert-butoxycarbonyl-1H-pyrrole (7) as a starting material. The first one achieves the chlorination through TMS migration, giving an 2,4-bis(trimethylsilyl)-3-chloro-1-tert-butoxycarbonyl-1H-pyrrole (8). This compound can be iodinated with NIS to afford mono-iodination product. After removing the remaining TMS and coupling with aryl boronic acids, we obtained 3-chloro-4-substituted phenyl-1H-pyrroles. The second route includes the iodination of 3,4-bis(trimethylsilyl)-1-tert-butoxycarbonyl-1H-pyrrole (7), Suzuki coupling reaction, and ipso-chlorination, to produce the target pyrrolnitrin analogues. Compared with the first route, the second has obvious advantages, with shorter reaction steps and slightly higher yield.In the course of the study, we obtained three pyrrolnitrin analogues as well as eight intermediates, which have not recorded in the literatures. There structures have been confirmed by 1H NMR,13C NMR and HRMS.