Palladium-catalyzed dearomative 1,4-hydroamination

Abstract

A dearomative 1,4-hydroamination of nonactivated arenes has been developed, using a key arene-arenophile photocycloaddition strategy to disrupt aromaticity. Palladium catalysis with K-Selectride^® as a hydride source uniquely enables selective reactivity and provides access to a range of substituted 1,4-cyclohexadienes from aromatic starting materials. We demonstrate a few synthetic applications of this scalable procedure by preparing highly-functionalized small molecules in three to four steps from naphthalene.

Keywords: Arenophiles; Catalysis; Dearomatization; Hydroamination; Palladium.

Fig. 1.

(a) Previous work in arenophile-mediated dearomative aminofunctionalization. (b) Precedented examples of dearomative 1,4-hydroamination. (c) Biologically active natural products that could be accessed via a dearomative 1,4-hydroamination. (d) This work.

Fig. 2.

Derivatization of naphthalene-derived product 7i. Reagents and conditions: (a) OsO₄ (cat.), NMO, citric acid, 48 %, >20:1 dr. (b) NaOCl, 22 %. (c) 2,2-DMP, TsOH, 83 %. (d) ^tBuOCl, AcOH, 18 %. (e) Et₂Zn, ICH₂Cl, 36 %, >20:1 dr. (f) α-bromoacetophenone, K₂CO₃, 76 %. (g) KOH, 41 %.