N-(TRIISOPROPYLSILYL)PYRROLE - A PROGENITOR PAR EXCELLENCE OF 3-SUBSTITUTED PYRROLES

A very effective strategy has been devised for the synthesis of 3-substituted pyrroles based on the use of the triisopropylsilyl (TIPS) moiety as a sterically demanding nitrogen substituent to obstruct the attack of electrophilic reagents at the alpha-positions. 1-(Triisopropylsilyl)pyrrole (1) undergoes highly preferential kinetic electrophilic substitution at the beta-position with a variety of electrophiles (Br+, I+, NO2+, RCO+, etc.) and fluoride ion induced desilylation of the products provides the corresponding 3-substituted pyrroles in good overall yields. Competitive trifluoroacetylation experiments demonstrate that substitution of TIPS-pyrrole at the alpha-positions is decelerated by a factor of > 10(4), vs pyrrole at the same sites, without affecting reactivity at the beta-positions. 1-(Triisopropylsilyl)-3-bromopyrrole (2) is readily converted into the 3-lithio compound 44 by bromine-lithium interchange with alkyllithium reagents. This previously unavailable, formal equivalent of 3-lithiopyrrole is itself an excellent source of a wide range of beta-substituted pyrroles, many of which would not be directly preparable from 1. TIPS-pyrrole can be 3,4-dihalogenated and these compounds undergo sequential halogen-metal interchange trapping reactions. This process is exemplified by an efficient, three-step synthesis of the antibiotic verrucarin E (63) from the dibromo compound 5.