Synthesis Of2,4-Disubstituted Pyrrole By Stepwise Iodination And Cross-coupling Reaction

As important intermediates for fine chemicals,2,4-disubstituted pyrroles have many different kinds of biological activity and good photoelectronic properties, which can be widely used as pharmaceuticals, pesticides and photochromic materials. In addition, they can also be used as precursors and building blocks for the synthesis of heterocycles in the field of organic synthesis, especially for the synthesis of natural products. Synthetic methodology for2,4-disubstituted pyrroles mainly includes aromatic electrophilic substitutions, cycloiso-merization catalyzed by transition metals and various coupling reaction. However, synthetic methods of2,4-disubstituted pyrroles are still an challenging research topic in organic synthesis.According to the literatures, we prepared tert-buty12,5-bis(trimethylsilyl)-1H-pyrrole-1-carboxylate starting from simple1H-pyrrole through the pyrrole nitrogen’s protection with Boc group, double a-lithiation and the reaction with TMSC1. We obtained tert-butyl2,5-bis(trimethylsilyl)-1H-pyrrole-l-carboxylate under acidic conditions through TMS βâ†'α migration. We used it as a starting material and synthesized four different2,4-disubstituted pyrrole as target molecules by stepwise iodination, cross-coupling reaction (Suzuki reaction and Sonogashira reaction) and removal of the Boc protection group.Through the optimization of reaction condition for the first iodination, we obtained respectively two different pyrrole iodides with high regioselectivity. When THF was used, the iodination occured mainly at position-4, and however the iodination occured mainly at position-2when the solvent was CH2Cl2, showing obvious solvent effect. Another interesting phenomenon was that, in the second step of the coupling reaction, the Boc group was removed at the same time. The coupling reaction and deprotection takes place concommittedly in one step, eliminating the extra steps to remove protecting group, making the reacton more efficient.We finally obtained14compounds, including12new compounds. Their structures were well characterized by1H NMR,13C NMR and HRMS.