methylene–propargyl group. Alkylation of the enolate from dimethylho-
motetrephthalate ( 197 ) with propargyl bromide attaches that group to the
benzylic carbon to yield 198. Reaction of the enolate from that com-
pound with the bromomethylpteridine ( 199 ) yields the alkylation
product 200. Saponification of the esters in that product that leads to
the free acid. The carboxyl group on the tertiary benzylic carbon decar-
boxylates on heating to yield the key intermediate 201. This compound is
then converted to a folate-like compound by reaction of the acid chloride
with diethylglutamine. Saponification of diethylglutamine yields the free
acid and thus 202.^29
A more recent example omits one of the nitrogen atoms in the pteridine
ring and replaces the linking benzene ring of the side chain by thiophene.
The convergent synthesis begins with the palladium-catalyzed coupling of
the brominated pyridopyrimidone ( 203 ) with trimethylsilyl acetylene to
afford the ethynyl derivative 203. The silyl protecting group is then
removed to afford 204. In the second arm of the scheme, thiophene-
carboxylic acid ( 205 ) is treated with bromine to afford the brominated
derivative 206. The carboxylic acid is then esterified with ethanol to
yield 207. Palladium-catalyzed coupling of the thiophene derivative
( 207 ) with the ethynyl derivative 204 then affords 208. Catalytic hydrogen-
ation reduces both the acetylene bond and the heterocyclic ring to which it
is attached to afford 209 as a mixture of enatiomers.^30
212 BICYCLIC FUSED HETEROCYCLES