hydrolysis opens the ring to afford the intermediate mercapto aniline, the
sequence in effect having delivered sulfur to the ortho position. In the con-
vergent arm treatment of the anion from sodium hydride and indole ( 42 )
with ethyl bromoacetate gives the alkylated product ( 43 ). Condensation
of the mercaptoaniline ( 44 ) with the indole ( 43 ) in the presence of
strong acid couples the two moieties via a new thiazole ring ( 45 ). The reac-
tion can be rationalized by assuming addition of sulfur to the nitrile as the
initial step. Addition–elimination of the aniline nitrogen to the resulting
imine then closes the ring. Saponification of the ester on the pendant
acetate then affordslidorestat( 46 ).^7
Receptors for the estrogens, estrone and estradiol, are characteristically
indiscriminate in terms of the structures of the compounds that they will
bind. The estrogen antagonists show similarly loose structural require-
ments for binding (see, e.g., fluvestant in Chapter 2, ospemifene in
Chapter 3, lasoxifene in Chapter 4 acolbifene in Chapter 8, and arzoxifene
( 141 ). An indole provides the nucleus for the estrogen antagonistbazedox-
ifene( 55 ); not only the ring system, but also the connectivity of the
benzene ring that carries the basic ether differs from earlier compounds.
The convergent scheme starts with an unusual method for building an
indole. Thus, reaction of the aniline ( 47 ) with the bromo acetophenone
( 48 ) in the presence of triethylamine leads to the benzo heterocycle ( 49 )
in a single step. The aromatic alkylation step required to close the five-
membered ring is likely made possible by the high electron density in
C 6 H 5 CH 2 O
NH 2
47+
OBr48OCH 2 C 6 HEt^3 NC^6 H^5 CH^2 O
NHOCH 2 C 6 H
49
HOOH
50BrCH 2 CO 2 C 2 H 5HOO51CO 2 C 2 H 5ClO
52 CO^2 C^2 H^5SO 2 ClC 6 H 5 CH 2 O
OCH 2 C 6 H
NO(^53) CO 2 C 2 H 5
- LiAlH 4
2. CBr 4 /Ph 3 P
C 6 H 5 CH 2 O
OCH 2 C 6 H
NO541.- H 2
HO
OH
N
O(^55) N Br
N
- COMPOUNDS WITH ONE HETEROATOM 145