The copper(I) catalyzed alkyne-azide cycloaddition (CuAAC), a click reaction, is one of the most powerful catalytic reactions developed during the last two decades. Conducting CuAAC enantioselectively would add a third dimension to this reaction and would enable the direct synthesis of α-chiral triazoles. Doing so is demanding because the two precursors have linear geometries, and the triazole product is a flat heterocycle. Designing a chiral catalyst is further complicated by the complex mechanism of CuAAC. We report an enantio-selective CuAAC (E-CuAAC), enabled by dynamic kinetic resolution (DKR). The E-CuAAC is high yielding and affords up to 99:1 er. The E-CuAAC can directly generate α-chiral triazoles in a complex molecular environment.
The cross-coupling of sodium (hetero)aryl carboxylates with (hetero)aryl chlorides proceeds with 1 mol % palladium catalyst and does not require inorganic base, silver salts, or copper salts. This coupling uses two low energy partners, and the only stoichiometric byproducts are carbon dioxide and sodium chloride. The substrate scope includes less activated aryl chlorides and carboxylates (>25 examples). The palladium loading could be reduced to 0.1 mol %, and Buchwald-style precatalysts could be used.
An enantioselective copper-catalyzed azide− alkyne cycloaddition (E-CuAAC) is reported by kinetic resolution. Chiral triazoles were isolated in high yield with limiting alkyne (up to 97:3 enantiomeric ratio (er)). A range of substrates were tolerated (>30 examples), and the reaction was scaled to >1 g. The er of a triazole product could be enhanced by recrystallization and the recovered scalemic azide could be racemized and recycled. Recycling the azide allows efficient use of the undesired azide enantiomer.
Developing reactions to generate complex and modular building blocks in a concise and direct fashion remains a contemporary synthetic challenge. This work describes a stereoselective cascade reaction between allylic azides and acrylates that directly generates tetrahydro-pyrrolo-pyrazole ring systems. These products contain up to four contiguous stereocenters, two of which may be tetrasubstituted carbon atoms attached to a nitrogen atom.Over 30 examples are provided with an average isolated yield of 71% (ranging from 40% to 94%). The reaction was easily scaled to use more than one gram of starting material, and the products can be readily diversified.
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