presence of mild base would then lead to the antiarrythmic agent dronedar-
one ( 9 ).^1
O 2 NOH
1PPh 3 O^2 NO^2 NO 2 NOH
2OH
3OBr P+Ph 3 P+Ph 3O4OCH 3 OCH^3COCl
O AlCl 3CH R^2 N
3 SO 2 Cl
OCH 3 SO 2 HNCH 3 SO 2 HNOCH 3OOHOCH 3 SO 2 HNO5 ; R = O
6 ; R = H
BBr 3Cl N(C^4 H^9 )^2N(C 4 H 9 ) 278 9O OO OC 4 H 9 COClA benzoisofuran illustrates the breadth of the structures that demonstrate
SSRI antidepressant activity. Condensation of the phthalide ( 10 ) with the
Gignard reagent ( 11 ) from 4-bromofluorobenzene leads to addition to the
carbonyl group to afford the ring-opened hydroxyketone ( 12 ). Addition of
a single organometallic group to the phtalide may be attributable to the
stability of the first-formed addition complex. The benzylic hydroxyl
group is next converted to itst-BOC derivative 13. Condensation of that
intermediate with the Grignard reagent from 3-chloropropyl dimethyla-
mine 14 leads to the addition product ( 15 ). The reason for specificity for
the ketone over the carbonate may be due to the sterically crowded con-
dition about the latter. Treatment with acid then removes that protecting
group. Reaction of the free alcohol with methanesulfonyl chloride forms
the mesylate of the primary alcohol. Exposure to triethylamine leads to
displacement of that function by the adjacent tertiary hydroxyl group
and thus closure to the isobenzofuran ring ( 16 ). The phenolic hydroxyl
is then converted into a leaving group, in this case a triflate, by acylation
with trifluoromethyl sulfonyl chloride. Reaction of this last with sodium
cyanide, in the presence of triphenylphosphine : palladium and cuprous
iodide, replaces the triflate by cyanide. Thus, the antidepressant compound
citalopramis obtained ( 17 ).^2
140 FIVE-MEMBERED HETEROCYCLES FUSED TO ONE BENZENE RING