Steroids bearing C12 oxidations are widespread in nature yet only one preparative chemical method addresses this challenge in a low-yielding and not fully understood fashion: Schönecker's Cu-mediated oxidation. This work shines new light onto this powerful C–H oxidation method through mechanistic investigation, optimization, and wider application. Culminating in a scalable, rapid, high-yielding, and operationally simple protocol, this procedure is applied to the first synthesis of several parent polyoxypregnane natural products, representing a gateway to over 100 family members.

The use of copper in directed C−H oxidation has been relatively underexplored. In a seminal example, Schönecker showed that copper and O2 promoted the hydroxylation of steroid-containing ligands. Recently, Baran (J. Am. Chem. Soc. 2015, 137, 13776) improved the reaction conditions to oxidize similar substrates with excellent yields. In both reports, the involvement of Cu2O2 intermediates was suggested. In this collaborative article, we studied the hydroxylation mechanism in great detail, resulting in the overhaul of the previously accepted mechanism and the development of improved reaction conditions. Extensive experimental evidence (spectroscopic characterization, kinetic analysis, intermolecular reactivity, and radical trap experiments) is provided to support each of the elementary steps proposed and the hypothesis that a key mononuclear LCuII(OOR) intermediate undergoes homolytic O−O cleavage to generate reactive RO• species, which are responsible for key C−H hydroxylation within the solvent cage. These key findings allowed the oxidation protocol to be reformulated, leading to improvements of the reaction cost, practicability, and isolated yield.

Conspectus The identification of reliable, general, and high yielding methods for the formation of C­(sp2)–fluorine bonds remains a major challenge for synthetic organic chemists. A very common approach involves nucleophilic aromatic fluorination (SNAr fluorination) reactions of aryl chlorides or nitroarenes. Despite being known for more than a century, traditional SNAr fluorination reactions suffer from significant limitations, particularly on a process scale. These include the high cost of common reagents [e.g., cesium fluoride (CsF)], a requirement for elevated temperatures and long reaction times, poor functional group tolerance, and the need for rigorous exclusion of water. This Account summarizes our collaboration with Corteva Agriscience (previously Dow Agrosciences) to address many of these challenges. This collaboration has provided a platform for fundamental scientific advances involving the development of new methods, reagents, and substrates for mild and high yielding nucleophilic fluorination reactions. Our early studies established that the combination of potassium fluoride (KF) and superstoichiometric tetrabutylammonium chloride (Bu4NCl) serves as a cost-effective alternative to CsF for the SNAr fluorination of chloropicolinate substrates. However, these reactions still require elevated temperatures (>130 °C) and afford moderate yields due to competing decomposition of the substrate and product. The need for high temperature is largely due to slow reaction rates resulting from the low concentration of the active fluorinating reagent [anhydrous tetrabutylammonium fluoride (Bu4NF)] under these conditions. To address this issue, we developed several strategies for generating high concentration solutions of anhydrous tetraalkylammonium fluoride in situ by combining fluorine-containing electrophiles (e.g., hexafluorobenzene, acyl fluorides, sulfonyl fluorides) with tetraalkylammonium nucleophiles (R4NCN or R4NOR). These systems enable SNAr fluorination under unusually mild conditions, affording nearly quantitative yield with chloropicolinate substrates at room temperature. However, the high cost of the electrophiles and the generation of large quantities of byproducts in the R4NF-forming step render this approach unsuitable for process scale applications. As an alternative, we next explored anhydrous tetramethylammonium fluoride (Me4NF) for these transformations. This highly reactive fluoride source can be synthesized directly from inexpensive KF and Me4NCl and then dried by heating under vacuum. Unlike Bu4NF, it is not susceptible to Hofmann elimination. As such, anhydrous Me4NF is stable and isolable, as well as highly effective for the room temperature SNAr fluorination of chloropicolinates and other electron deficient substrates. The studies with anhydrous R4NF drew our attention to another challenge associated with traditional SNAr fluorination reactions: their limitation to substrates bearing resonance electron-withdrawing groups. We hypothesized that this challenge could be addressed by circumven...

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This Letter describes the development of a Ti IIImediated reaction for the C−H amination of arenes with hydroxylamine. This reaction is applied to a variety of electronrich (hetero)arene substrates, including a series of natural products and pharmaceuticals. It offers the advantages of mild conditions (room temperature), fast reaction rates (<30 min), compatibility with ambient moisture and air, scalability, and the use of inexpensive commercial reagents.A niline derivatives (ArNH 2 ) appear in a wide variety of specialty chemicals, materials, natural products, and pharmaceuticals. 1 As such, synthetic methods for the formation of ArNH 2 are highly sought-after in organic synthesis. In general, the most common approaches involve transition-metal catalyzed cross-coupling, 2 arene nitration/reduction, 3 and arene C−H amination protocols. 4−6 However, due to high reagent/catalyst costs as well as reactivity concerns, processscale preparations of ArNH 2 still largely rely on nitration of the corresponding aromatic precursor followed by hydrogenation to yield the aniline products (Figure 1A). 7 We sought to develop a practical alternative to nitration/ reduction that enables the direct conversion of arenes (Ar−H) to ArNH 2 . Recent reports have shown that O-protected hydroxylamine derivatives (e.g., A−D in Figure 1B) are effective reagents for Fe-catalyzed arene C−H amination. 4−6 A key step of these reactions involves Fe-mediated N−O bond cleavage to release an aminyl radical (H 2 N • ). This radical (and/or its conjugate acid H 3 N •+ ) then reacts with the arene substrate, ultimately affording an aniline product. 8 While this is a conceptually attractive approach, in practice current methods are limited by the requirement for an electron-withdrawing substituent on oxygen to facilitate N−O bond scission. 9 These functionalized hydroxylamine derivatives can be expensive and/or require multistep synthesis, thus rendering them less practical for larger scale applications. Herein, we develop a method that accesses an analogous reaction manifold using the commodity chemical hydroxylamine as the aminating reagent (Figure 1C). This transformation is high yielding, inexpensive, and scalable and thus offers a complement to existing C−H amination methods as well as more traditional nitration/ reduction sequences.Pioneering early work by Keller, Kovacic, and Minisci demonstrated the feasibility of the Ti III -mediated amination of electron-rich arenes using hydroxylamine. 10−13 However, these early examples were very limited due to their narrow substrate scope, low yields, formation of side products, and the requirement for large excesses of arene substrate. 14 For

Nucleophilic aromatic fluorination (S N Ar) is among the most common methods for the formation of C(sp 2 )−F bonds. Despite many recent advances, a long-standing limitation of these transformations is the requirement for rigorously dry, aprotic conditions to maintain the nucleophilicity of fluoride and suppress the generation of side products. This report addresses this challenge by leveraging tetramethylammonium fluoride alcohol adducts (Me 4 NF•ROH) as fluoride sources for S N Ar fluorination. Through systematic tuning of the alcohol substituent (R), tetramethylammonium fluoride tert-amyl alcohol (Me 4 NF•t-AmylOH) was identified as an inexpensive, practical, and bench-stable reagent for S N Ar fluorination under mild and convenient conditions (80 °C in DMSO, without the requirement for drying of reagents or solvent). A substrate scope of more than 50 (hetero) aryl halides and nitroarene electrophiles is demonstrated. * sı Supporting InformationThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c01490.Experimental procedures, characterization data, and NMR spectra (PDF) FAIR data, including the primary NMR FID files, for

Marine derived cyclic imine toxins, portimine A and B, have attracted extensive attention owing to their intriguing chemical structure and promising anti-cancer therapeutic potential. However, access to large quantities is currently unfeasible and the molecular mechanism behind their potent activity is unknown. To address this, a scalable 15-step total synthesis of portimines is presented, which benefits from the logic used in two-phase terpenoid synthesis along with unique tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through “self-protection”. Critically, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency. Finally, practical access to the portimines and analogs thereof simplified the development of photoaffinity analogs, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.

An efficient and concise synthesis of vesnarinone and its analogues from readily available starting materials and by using catalytic C–N bond‐forming reactions is reported. In this protocol, a homogeneous Pd‐catalyzed Buchwald–Hartwig amination and a supported Pd nanoparticles catalyzed aminocarbonylation were utilized as the two key reactions to prepare vesnarinone in an overall yield of 73 %. Sixteen analogues were also synthesized in up to 89 % overall yield.