CHAPTER 8
SIX-MEMBERED HETEROCYCLES
FUSED TO ONE BENZENE RING
1. COMPOUNDS WITH ONE HETEROATOM
A. Benzopyrans
A prominent feature in the majority of estrogen antagonists consists of a
pair of aromatic rings disposed on adjacent positions on either an acyclic
ethylene or a fused bicyclic ring system; in the latter case, one of those
rings is positioned next to the ring fusion. Those two moieties are
present in the antagonist acolbifene ( 9 ); the structure of this agent,
however, departs from previous examples by the fact they occupy the
2,3- rather than 1,2-position of the bicylic system. This finding may
account for the report that this agent is a pure antagonist that, unlike its
predecessors, shows no partial agonist activity at estrogen receptors. The
synthesis of this agent begins with Fiedel–Crafts acylation of resorcinol
( 1 ) with 4-hydroxyphenylacetic acid ( 2 ) to afford the desoxybenzoin ( 3 ).
Reaction with dihydropyran (DHP) leads to formation of the bis(tetrahydro
pyrranyl) ether ( 4 ); the phenolic group adjacent to the ketone does not react
as a result of its chelation with that carbonyl group. Condensation of that
intermediate withp-hydroxybenzaldehyde in the presence of piperidine
initially leads to the chalcone ( 5 ). The phenol then adds to the double
bond conjugated with the carbonyl group to afford the benzopyranone
The Organic Chemistry of Drug Synthesis, Volume 7. By Daniel Lednicer
Copyright#2008 John Wiley & Sons, Inc.
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