The
calcium-catalyzed, formal [5 + 2] cycloaddition of indolyl
alkylidene β-ketoesters with mono- and disubstituted aryl olefins
to form cyclohepta[b]indole derivatives has been
established. Unanticipated chemodivergence with phenyl vinyl sulfide/ether
revealed a double [5 + 2] cycloaddition cascade providing ethano-bridged
cyclohepta[b]indoles. Overall, the method’s
highlights include: (1) use of a green, calcium-based catalyst (2.5
mol % loading); (2) reaction times under 1 h; (3) mild reaction conditions;
(4) substrate-derived chemodivergence; (5) functional group tolerance;
and (6) examples of derivatization.
Mounting
concern among forensic examiners regarding the emergence of positional
isomers as technically legal alternatives to scheduled benzodiazepines
has encouraged the preemptive synthesis of analogues as standards.
Recently, flubromazepam was identified by the Drug Enforcement Administration
for future scheduling, and subsequently, 9 of the 12 possible flubromazepam
isomers were synthesized. However, the three (6,X′)-isomers
proved inaccessible via that approach. Herein, through a redesigned
synthetic approach, the remaining three isomers were obtained, thus
completing the set and enabling future forensic analysis.
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