of a halomethyl carbonyl group with an amide. Thus, condensation of the
cinnamic amide ( 219 ) with 1,3-dichloroacetone leads to formation of
oxazole 220 , which retains a leaving group for a displacement reaction.
Treatment of 220 with the alkoxide from treatment of 218 with base
leads to the corresponding ether ( 221 ).^32
F 3 CF 3 CONH 2
219Cl Cl
O220NOO OSO 2 CH 3HNN N- H 2
HO N NN217 218O N NNF 3 CNO
Cl221C 6 H 5 CH 2E. Tetrazoles
Though the exact cause of Alzheimer’s disease is still unclear, evidence
points to the utility of increasing acetylcholine (AcCh) levels for treating
that condition. Most approaches are aimed at devising inhibitors of cholin-
esterase, the enzyme that destroys AcCh. A quite different tack involves
developing compounds that have cholinergic activity in their own right.
The tetrazolealvameline( 230 ), for example, was developed as a bio-
isostere of the muscarinic cholinergic compound arecoline ( 222 ). The
design devolves on the fact that the proton on a free tetrazole shows a
pKacomparable to that of a carboxylic acid. Fully substituted tetrazoles
as in 230 , may thus in some ways may be viewed as surrogate esters.
Alkylation of nicotinonitrile ( 223 ) with methyl iodide affords methiodide
224. Treatment of this intermediate with borohydride reduces it to tertrahy-
dropyridine ( 225 ) in which the position of the double bond mimics
that in arecoline. Reaction of 225 with ethyl chloroformate results
in N-demethylation and consequent formation of the corresponding
- COMPOUNDS WITH TWO HETEROATOMS 109