Biomedical Engineering Reference
In-Depth Information
SCHEME 2.10 4CR catalyzed by piperidine for the synthesis of complex spirooxindole-
fused heterocycles.
first process, an acyl-Meldrum's acid ( 55 ) cycloreverts to an acyl ketene upon heating
with loss of acetone and CO 2 , which is trapped by the amine. Subsequent addition
of Eschenmoser's salt and a chlorooxime to the flask initiates a three-component
reaction yielding a four-component assembly product, a
-ketoamide isoxazoline. In
the 3CR reaction, Eshenmoser's salt undergoes a Mannich reaction, and the elim-
ination of dimethyl ammonium iodide gives a
-ketoamide. This
dipolarophile then participates in a nitrile oxide (formed in situ from chlorooxime
60 ) 1,3-dipolar cycloaddition.
Another
,
-unsaturated
recent
example
of
an
“isonitrile-free”
MCR
involved
reaction
of
hydrazine,
-keto ester, isatin, and malononitrile (or ethyl cyanoacetate) under ultra-
sound irradiation to form spirooxindole-fused heterocycles [35]. The spirooxindole
system is at the core of many pharmacological agents and natural products; thus, a
number of methods have been reported for the preparation of spirooxindole-fused
heterocycles [36-38]. This particular MCR is noteworthy due to the ease of purifi-
cation, as simply washing the crude solid products with ethanol avoids the need for
chromatography or recrystallization (Scheme 2.10).
Recently, an efficient enantioselective inverse electron-demand aza-Diels-Alder
(IEDDA) reaction with isoeugenol derivatives as the dienophile catalyzed by chiral
phosphoric acid ( 68 ) has been developed by He et al. [39]. This cycloaddition pro-
ceeds with a wide range of aldehydes and anilines, providing a highly diastereo-
and
enantioselective
method
to
2,3,4-trisubstituted
4-aryl-tetrahydroquinolines
(Scheme 2.11).
2.3 MCRs AS STARTING POINTS FOR DOS
MCRs can serve as key transformations in versatile approaches to DOS. One common
strategy involves the application of inputs having functional groups that are orthogonal
to the MCR but will participate in subsequent bond-forming events. In early examples,
these processes were often spontaneous under MCR conditions or induced thermally
by warming the reaction mixture. In later DOS approaches, functional groups that
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