ORGANIC
LETTERS
2010
Vol. 12, No. 24
5740-5743
Friedel-Crafts Acylation of Pyrroles
and Indoles using
1,5-Diazabicyclo[4.3.0]non-5-ene (DBN)
as a Nucleophilic Catalyst
James E. Taylor, Matthew D. Jones, Jonathan M. J. Williams, and Steven D. Bull*
Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath,
BA2 7AY, United Kingdom
Received October 21, 2010
ABSTRACT
1,5-Diazabicyclo[4.3.0]non-5-ene (DBN) has been shown to be an effective catalyst for the regioselective Friedel-Crafts C-acylation of pyrroles
and indoles in high yields. A detailed mechanistic study implies that DBN is acting as a nucleophilic organocatalyst, with the X-ray crystal
structure of a key N-acyl-amidine intermediate having been determined for the first time.
Substituted pyrroles and indoles are found in many natural
products and biologically active compounds.1 However, their
synthesis remains challenging, with syntheses often suffering
from poor regioselectivity and/or low yields due to oxidative
degradation.2 Traditionally, stoichiometric amounts of Lewis
acids have been used for the Friedel-Crafts acylation of
pyrroles and other heteroaromatic compounds,3,4 while recently
metal-based catalytic methods have also proven successful.5
Organocatalysts have been used previously for the O-
acylation of alcohols and amines, with a few examples of
intramolecular organocatalytic C-acylations having been re-
ported.6,7 However, to the best of our knowledge, organocata-
lysts have never been used for the direct intermolecular
C-acylation of aromatic substrates. We now report the develop-
ment of a high yielding and regioselective organocatalytic
methodology for the C2-acylation of N-protected pyrroles and
C3-acylation of N-protected indoles.
Initially, we screened a range of organocatalysts for the
acylation of commercially available N-methylpyrrole (1) with
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10.1021/ol1025348 2010 American Chemical Society
Published on Web 11/15/2010