Oxidation of indoles is a fundamental organic transformation to deliver a variety of synthetically and pharmaceutically valuable nitrogen-containing compounds. Prior methods require the use of either organic oxidants (meta-chloroperoxybenzoic acid, N-bromosuccinimide, t-BuOCl) or stoichiometric toxic transition metals [Pb(OAc)4, OsO4, CrO3], which produced oxidant-derived by-products that are harmful to human health, pollute the environment and entail immediate purification. A general catalysis protocol using safer oxidants (H2O2, oxone, O2) is highly desirable. Herein, we report a unified, efficient halide catalysis for three oxidation reactions of indoles using oxone as the terminal oxidant, namely oxidative rearrangement of tetrahydro-β-carbolines, indole oxidation to 2-oxindoles, and Witkop oxidation. This halide catalysis protocol represents a general, green oxidation method and is expected to be used widely due to several advantageous aspects including waste prevention, less hazardous chemical synthesis, and sustainable halide catalysis.

Reported is a new green protocol for the efficient in situ generation of nitrile oxides through NaCl/ Oxone oxidation of aldoximes and their dipolar cycloaddition.The key feature is the use of a green chemistry approach to address the substrate scope of aldoximes: broad scope (aliphatic, aromatic, and alkenyl aldoximes) without production of organic byproducts derived from oxidant and/or catalyst. Importantly, NaCl/Oxone-promoted three-component cycloaddition of aldehyde, hydroxylamine hydrochloride, and alkene was demonstrated to be competent (63−81%).

The discovery of iron(ii) bromide and cerium(iii) bromide as a bifunctional catalyst enables the oxidative rearrangement of indoles with hydrogen peroxide as the terminal oxidant.

Achmatowicz rearrangement (AchR) is a very important transformation for the synthesis of various heterocyclic building blocks and natural products. Here, the discovery of Fenton chemistry for AchR using a bifunctional catalyst (FeBr2 or CeBr3), which has environmental friendliness and a broad substrate scope at the same time has been reported. This method addresses the major limitation of conventional chemical (hazardous) and enzymatic (limited scope) methods. Mechanistic studies suggested that reactive brominating species (RBS) is the true catalyst for AchR and that Fenton chemistry [Fe/Ce (cat.) + H2O2 → HO•/HOO• + H2O] is responsible for the oxidation of bromide into RBS. Importantly, this in situ RBS generation from M-Br x –H2O2 under neutral conditions addresses the long-lasting problem of many haloperoxidase mimics that require a strong acidic additive/medium for bromide oxidation with H2O2, which creates opportunities for many other brominium-mediated organic reactions.

Metrics & MoreArticle Recommendations CONSPECTUS:The six-membered heterocycles containing oxygen and nitrogen (tetrahydropyrans, pyrans, piperidines) are among the most common heterocyclic structures ubiquitously present in bioactive molecules such as carbohydrates, smallmolecule drugs, and natural products. Chemical synthesis of fully functionalized pyrans and piperidines is a research theme of practical importance and scientific significance and, thus, has attracted continuous interest from synthetic chemists. Among the numerous synthetic approaches, Achmatowicz rearrangement (AchR) represents a general and unique strategy that uses biomass-derived furfuryl alcohols as the renewable starting material to obtain fully functionalized six-membered oxygen/nitrogen heterocycles, which provides golden opportunities for organic chemists to address various synthetic challenges. This Account summarizes our 10 years of work on exploiting AchR to address some challenges in organic synthesis ranging from green chemistry and organic methodology to the total synthesis of natural products. We enabled the sustainable and safe use of AchR in a small (academia) or large (industrial) scale by developing two generations of green approaches for AchR (oxone-halide and Fenton-halide), which largely eliminate the use of the most popular, but more toxic and expansive, NBS and m-CPBA. This triggered our intensive interest in developing new green chemistry for important organic reactions, in particular, halogenation/oxidation reactions involving reactive halogenating species with the aim of eliminating the use of commonly used toxic halogen agents such as elemental bromine, chlorine gas, and various N-haloamide reagents (NBS, NCS, and NIS). We successfully employed oxone-halide and Fenton-halide as green alternatives to several mechanistically related organic reactions including arene/alkene halogenation, oxidation or oxidative rearrangement of indoles, oxidation of alcohols/thioacetals, and oxidative halogenation of aldoximes for the in situ generation of nitrile oxide. These green reactions are expected to have a solid impact on the future of organic synthesis in academia and industries. We expanded the synthetic utility of AchR by exploring several new transformations of AchR products and developed a cascade reductive ring expansion, reductive deoxygenation/Heck−Matsuda arylation, palladium-catalyzed C-arylation, and regiodivergent [3 + 2] cycloaddition with 1,3-dicarbonyls. These methodologies offer a new avenue to fully functionalized six-membered heterocycles.The synthetic utility of AchR was demonstrated in our total synthesis of 28 natural products with a pyran/piperidine moiety. The AchR-based strategy endows the total synthesis with scalability, sustainability, and flexibility. The green and scalable approaches developed in our lab for AchR allow us to easily obtain decagrams of synthetically valuable pyrans and/or piperidines with low risk and low cost from biomass-derived furfuryl alcohol/aldehyde.

A zero-gap flow cell was designed for the first electro-oxidative rearrangement of tetrahydro-β-carbolines to spirooxindoles with high yield, faradaic efficiency and productivity when LiBr was discovered as a bi-functional mediator and catalyst.

Chiral tetrahydro-b-carboline (THbC) is not only ap revailing structural feature of many natural alkaloids but also av ersatile synthetic precursor for av ast arrayo f monoterpenoid indole alkaloids.Asymmetric synthesis of C1alkynyl THbCs remains rarely explored and challenging. Herein, we describe the development of two complementary approaches for the catalytic asymmetric alkynylation of 3,4dihydro-b-carbolinium ions with up to 96 %yield and 99 %ee. The utility of chiral C1-alkynyl THbCs was demonstrated by the collective total syntheses of seven indole alkaloids: harmicine,eburnamonine,desethyleburnamonine,larutensine, geissoschizol, geissochizine,and akuammicine.

Chiral tetrahydro-b-carboline (THbC) is not only ap revailing structural feature of many natural alkaloids but also av ersatile synthetic precursor for av ast arrayo f monoterpenoid indole alkaloids.Asymmetric synthesis of C1alkynyl THbCs remains rarely explored and challenging. Herein, we describe the development of two complementary approaches for the catalytic asymmetric alkynylation of 3,4dihydro-b-carbolinium ions with up to 96 %yield and 99 %ee. The utility of chiral C1-alkynyl THbCs was demonstrated by the collective total syntheses of seven indole alkaloids: harmicine,eburnamonine,desethyleburnamonine,larutensine, geissoschizol, geissochizine,and akuammicine.