A regioselective
Pd-mediated C–H bond arylation methodology
for tryptophans, utilizing stable aryldiazonium salts, affords C2-arylated
tryptophan derivatives, in several cases quantitatively. The reactions
proceed in air, without base, and at room temperature in EtOAc. The
synthetic methodology has been evaluated and compared against other
tryptophan derivative arylation methods using the CHEM21 green chemistry
toolkit. The behavior of the Pd catalyst species has been probed in
preliminary mechanistic studies, which indicate that the reaction
is operating homogeneously, although Pd nanoparticles are formed during
substrate turnover. The effects of these higher order Pd species on
catalysis, under the reaction conditions examined, appear to be minimal:
e.g., acting as a Pd reservoir in the latter stages of substrate turnover
or as a moribund form (derived from catalyst deactivation). We have
determined that TsOH shortens the induction period observed when [ArN2]BF4 salts are employed with Pd(OAc)2. Pd(OTs)2(MeCN)2 was found to be a superior
precatalyst (confirmed by kinetic studies) in comparison to Pd(OAc)2.
C–F functionalization of arenes with a range of alcohol and pyrazole nucleophiles has been achieved without the need for metal catalysts or highly electron‐poor substrates. Treatment of fluoroarenes with alcohols or pyrazoles and DDQ under irradiation by blue LED light provides the corresponding substituted products. The procedure is complementary to classical SNAr chemistry which generally requires basic reaction conditions and high temperatures, and provides products under non‐basic conditions at ≈ 40 °C.
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