CHAPTER 7
FIVE-MEMBERED HETEROCYCLES
FUSED TO ONE BENZENE RING
1. COMPOUNDS WITH ONE HETEROATOM
A. Benzofurans
The presence of two iodine atoms on one of the aromatic rings on
venerable antiarhythmic agent amiodarone may indicate that it was orig-
inally conceived as an agent for treating various thyroid anomalies. A
recent halogen-free benzofuran that shares many structural features with
its predecessor shows equal or even superior activity in controlling arryth-
mias. The synthesis starts with an unusual scheme for building the furan
ring. Reaction of the benzyl bromide ( 1 ) with triphenylphosphine leads
to the phosphonium salt ( 2 ). Treatment of the salt with valeryl chloride
in the presence of pyridine results in acylation on the now highly activated
benzylic carbon. That product ( 3 ) cyclizes to the benzofuran ( 4 ) on heating
with expulsion of triphenylphosphine. Friedel–Crafts acylation of 4 with
anisoyl chloride in the presence of stannic chloride proceeds on the elec-
tron-rich furan ring to afford 5. The nitro group is next reduced with stan-
nous chloride to give amine 6. That newly formed amine is converted to
the corresponding sulfonamide ( 7 ) by means of methanesulfonyl chloride.
Reaction of 7 with boron tribromide cleaves the methyl ether leading to
the free phenol ( 8 ). Alkylation of 8 with chloroethyldibutylamine in the
The Organic Chemistry of Drug Synthesis, Volume 7. By Daniel Lednicer
Copyright#2008 John Wiley & Sons, Inc.
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