A general
γ-C(sp2)–H iodination method directed by an
aliphatic keto group has been developed under transition-metal-free
conditions for the first time, generating iodoarenes in good to excellent
yields with excellent site selectivity. This protocol features a wide
range of aryl-substituted ketones, short reaction times, mild reaction
conditions, and scalable synthetic procedures. A possible reaction
mechanism was also proposed based on several control experiments.
Abstractα‐Halogenated ketones are both unique structure moieties existing in biologically natural products and valuable synthetic intermediates for the preparation of functional molecules. An efficient and scalable method for the preparation of α‐halogenated ketone using iron (III) chloride and iron (III) bromide as halogen sources with phenyliodonium diacetate as oxidant has been developed, featuring mild reaction conditions, environmentally friendly reagents, and wide substrate scope. Notably, the three‐step synthesis of drug prasugrel was achieved using this developed method as a key step with 30% yield on gram‐scale. Additionally, the reaction mechanism involving chloride cation was proposed based on some preliminary control experiments.magnified image
Although the classical Ritter reaction has been widely applied to prepare sterically hindered amides since 1948, it has intrinsic problems, such as harsh reaction conditions, the multistep preparation of synthetic precursors, and the use of solvent quantities of nitrile. In particular, only a few examples of the total syntheses of natural products using the Ritter reaction as a key step have been reported to date. In this article, an oxidative Ritter-type reaction of α-arylketones was developed to efficiently construct a sterically hindered N-acyl aza-quaternary carbon moiety. The current transformation features the use of 10 equivalents of nitriles, a broad substrate scope (81 examples), a short reaction time, and mild reaction conditions; notably, both of the use of a limited amount of nitriles and the producing carbocation intermediates via the C-H bond oxidation strategy address two intractable problems of the classical Ritter reaction. Furthermore, based on an unprecedented synthetic strategy using this oxidative Ritter reaction to construct a C-5 aza-quaternary carbon center, the collective total syntheses of erythrina alkaloids, including erysotramidine, 11-α-methoxyerysotramidine, 11-β-hydroxyerysotramidine, erytharbine, the proposed 11-βmethoxyerysotramidine and 10,11-dioxoerysotramidine, and the unnatural 11-α-hydroxyerysotramidine, have been completed using a common precursor through a one-step chemical transformation.
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