A Palladium Iodide-Catalyzed Carbonylative Approach to Functionalized Pyrrole Derivatives

A novel and convenient approach to functionalized pyrroles
is presented,
based on Pd-catalyzed oxidative heterocyclization–alkoxycarbonylation
of readily available N-Boc-1-amino-3-yn-2-ols. Reactions
were carried out in alcoholic solvents at 80–100 °C and
under 20 atm (at 25 °C) of a 4:1 mixture of CO–air, in
the presence of the PdI2–KI catalytic system (2–5
mol % of PdI2, KI/PdI2 molar ratio = 10). In
the case of N-Boc-1-amino-3-yn-2-ols 3, bearing alkyl or aryl substituents, the carbonylation reaction
led to a mixture of Boc-protected and N-unsubstituted
pyrrole-3-carboxylic esters 4 and 5, respectively.
This mixture could be conveniently and quantitatively converted into
deprotected pyrrole-3-carboxylic esters 5 by a simple
basic treatment. In the case of diastereomeric (3RS,4RS)- and (3RS,4SR)-N-Boc-3-amino-2-methyldec-5-yn-4-ol (syn-3f and anti-3f, respectively,
whose relative configuration was determined by X-ray crystallographic
analysis), no particular difference was observed in the reactivity
of the two diastereomers between them and with respect to the diastereomeric
mixture (3S,4S) + (3S,4R). Interestingly, N-Boc-2-alkynyl-1-amino-3-yn-2-ols 6, bearing an additional alkynyl substituent α to the
hydroxyl group, spontaneously underwent N-deprotection
under the reaction conditions and regioselective water addition to
the alkynyl group at C-3 of the corresponding pyrrole-3-carboxylic
ester derivative, thus directly affording highly functionalized pyrrole
derivatives 7 in one step. In a similar manner, a novel
functionalized dihydropyrrolizine derivative 9 was directly
synthesized starting from (S)-7-(pyrrolidin-2-yl)­trideca-5,8-diyn-7-ol 8.