protecting group to reveal the free phenol ( 235 ). Reaction of 235 with
hexamethylene tetramine (HMTA) in acid leads to formylation at the
ortho position to give the substituted hydroxybenzaldehyde ( 236 ). The
phenol is next converted to the corresponding methyl ether ( 237 ), by
alkylation with methyl iodide in the presence of base.
Construction of the second part of the molecule starts with palladium-
catalyzed coupling of the substituted pyridine ( 238 ) with phenylboronic
acid to give 239. Hydrogenation reduces both the nitro group and the sup-
porting pyridine ring to afford 240 as the cis isomer. The enantiomers of
this are then separated by resolution. The desired isomer is then subjected
to reductive amination with aldehyde 237 affording 241.^34
CH 2 ON NCF 3237N O=HCNO 2
ClC 6 H 5 B(OH) 2
Pd
238NNO 2239H 2
NHNH 2240resolveNaB(OAc 3 )HNH241CH 3 ON NN NCF 3NH N NThe renin-angiotensin system plays a profound role in maintaining the
circulatory system. Elevated levels of angiotensin II are closely associated
with hypertension. Angiotensin converting enzyme inhibitors, the
so-called ACE inhibitors, lower blood pressure by preventing generation
of that enzyme from its precursor. These now-widely used drugs were
first introduced starting almost three decades ago. Attention has turned
more recently to drugs that act directly on angiotensin receptors. The prep-
aration of one of these non-peptide agents begins with the formation of an
imidazole. Thus, condensation of the diamine 242 with trimethoxy butyl-
orthoformate affords the heterocycle 243. The nitrile groups are then
hydrolyzed to the corresponding acids; these groups are then esterified
with ethanol ( 244 ). Reaction of intermediate 244 with methylmagnesium
bromide leads to addition of but one of the ester groups. The presence
of the initial charged adduct arguably hinders addition to the second
ester. The free amino group on the imidazole is then allowed to react
- COMPOUNDS WITH TWO HETEROATOMS 111