Abstract
A mild and highly efficient metal-free oxidative α-cyanation of N-acyl/sulfonyl 1,2,3,4-tetrahydroisoquinolines (THIQs) has been accomplished at an ambient temperature via DDQ oxidation and subsequent trapping of N-acyl/sulfonyl iminium ions with (n-Bu)3SnCN. Employing readily removable N-acyl/sulfonyl groups as protecting groups rather than N-aryl ones enables a wide range of applications in natural product synthesis. The synthetic utility of the method was illustrated using a short and efficient formal total synthesis of (±)-calycotomine in three steps.
Highlights
Direct C(sp3 )-H functionalization through oxidative coupling is one of the most efficient strategies for the incorporation of functional groups at a proper position [1,2,3,4,5,6] since it does not need the preactivation of a substrate to generate a reactive key intermediate to form a new bond
It has been known that the formation of N-acyl or N-sulfonyl iminium ions is difficult with commonly used oxidants from N-acyl or N-sulfonyl THIQs, respectively, even in the presence of a transition metal oxidant, the selection of the oxidant is important
Treatment of 5a with DDQ (1.1 equivalent) in the presence of 4 Å molecular sieves (MS) to remove water that might be present in the reaction mixture at room temperature for 30 min, and subsequent addition of a variety of cyanide nucleophiles to trap in situ generated N-Boc iminium ion, afforded the desired product (±)-6a
Summary
Direct C(sp3 )-H functionalization through oxidative coupling is one of the most efficient strategies for the incorporation of functional groups at a proper position [1,2,3,4,5,6] since it does not need the preactivation of a substrate to generate a reactive key intermediate to form a new bond While this process has been most frequently accomplished through employing transition metal catalysts, significant synthetic endeavors were recently devoted to direct C(sp3 )-H functionalization under metal-free conditions [7,8,9]. Most notable methods involve using a transition metal or metal-free oxidants for the α-cyanation of N-aryl THIQs via the direct C(sp3 )-H functionalization (Scheme 1, Equation (1)) [16,17,18,19,20,21,22,23,24,25]
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