A self-assembled supramolecular complex is reported to catalyze alkyl-alkyl reductive elimination from high-valent transition metal complexes such as gold(III) and platinum(IV), the central ...bond-forming elementary step in many catalytic processes. The catalytic microenvironment of the supramolecular assembly acts as a functional enzyme mimic, applying the concepts of enzymatic catalysis to a reactivity manifold not represented in biology. Kinetic experiments delineate a Michaelis-Menten-type mechanism, with measured rate accelerations (Kcat/Kuncat)up to 1.9 × 10⁷ (here Kcat and Kuncat are the Michaelis-Menten enzymatic rate constant and observed uncatalyzed rate constant, respectively). This modality has further been incorporated into a dual catalytic cross-coupling reaction, which requires both the supramolecular microenvironment catalyst and the transition metal catalyst operating in concert to achieve efficient turnover.
Discovery chemists routinely identify purpose-tailored molecules through an iterative structural optimization approach, but the preparation of each successive candidate in a compound series can ...rarely be conducted in a manner matching their thought process. This is because many of the necessary chemical transformations required to modify compound cores in a straightforward fashion are not applicable in complex contexts. We report a method that addresses one facet of this problem by allowing chemists to hop directly between chemically distinct heteroaromatic scaffolds. Specifically, we show that selective photolysis of quinoline
-oxides with 390-nanometer light followed by acid-promoted rearrangement affords
-acylindoles while showing broad compatibility with medicinally relevant functionality. Applications to late-stage skeletal modification of compounds of pharmaceutical interest and more complex transformations involving serial single-atom changes are demonstrated.
While primary aliphatic amines are ubiquitous in natural products, they are traditionally considered inert to substitution chemistry. This review highlights historical and recent advances in the ...field of aliphatic deamination chemistry which demonstrate these moieties can be harnessed as valuable C(sp
3
) synthons. Cross-coupling and photocatalyzed transformations proceeding through polar and radical mechanisms are compared with oxidative deamination and other transition metal catalyzed reactions.
This review covers recent and historical aliphatic deaminative functionalization reactions to encourage the use of primary amines as aliphatic building blocks.
Strained hydrocarbons have recently regained interest as potential drug candidates. However, the study of their heteroatom analogs has remained limited, despite differing by only a single atom. The ...first synthesis of 1-azahomocubane by Williams, Eaton and co-workers (T. Fahrenhorst-Jones
et al.
,
Chem. Sci.
, 2023,
14
, 2821-2825,
https://doi.org/10.1039/D3SC00001J
) is discussed within the context of nitrogen scanning of strained hydrocarbons.
A highlight of the first synthesis of 1-azahomocubane and initial studies of this molecule (
https://doi.org/10.1039/D3SC00001J
), presenting opportunities for nitrogen scanning of strained hydrocarbon molecules.
Given the ubiquity of heterocycles in biologically active molecules, transformations with the capacity to modify such molecular skeletons with modularity remain highly desirable. Ring expansions that ...enable interconversion of privileged heterocyclic motifs are especially interesting in this regard. As such, the known mechanisms for ring expansion and contraction determine the classes of heterocycle amenable to skeletal editing. Herein, we report a reaction that selectively cleaves the N–N bond of pyrazole and indazole cores to afford pyrimidines and quinazolines, respectively. This chlorodiazirine-mediated reaction provides a unified route to a related pair of heterocycles that are otherwise typically prepared by divergent approaches. Mechanistic experiments and DFT calculations support a pathway involving pyrazolium ylide fragmentation followed by cyclization of the ring-opened diazahexatriene intermediate to yield the new diazine core. Beyond enabling access to valuable heteroarenes from easily prepared starting materials, we demonstrate the synthetic utility of skeletal editing in the synthesis of a Rosuvastatin analog as well as in an aryl vector-adjusting direct scaffold hop.
A sp3–sp2 CC cross‐coupling reaction catalyzed by gold in the absence of a sacrificial oxidant is described. Vital to the success of this method is the implementation of a bimetallic catalyst ...bearing a bis(phosphino)amine ligand. A mechanistic hypothesis is presented, and observable transmetalation, CBr oxidative addition, and CC reductive elimination in a model gold complex are shown. We expect that this method will serve as a platform for the development of novel transformations involving redox‐active gold catalysts.
Teaching Au new tricks: A novel manifold for reactivity in gold catalysis has been realized, allowing the cross‐coupling of arylboronic acids and allylic bromides without a sacrificial oxidant. A bimetallic catalyst is employed, providing allylbenzene products with unique scope and chemoselectivity. A mechanistic proposal is put forward based on stoichiometric experiments, including the isolation of an AuIII allyl complex.
Herein, we report a reaction that selectively generates 3-arylpyridine and quinoline motifs by inserting aryl carbynyl cation equivalents into pyrrole and indole cores, respectively. By employing ...α-chlorodiazirines as thermal precursors to the corresponding chlorocarbenes, the traditional haloform-based protocol central to the parent Ciamician-Dennstedt rearrangement can be modified to directly afford 3-(hetero)arylpyridines and quinolines. Chlorodiazirines are conveniently prepared in a single step by oxidation of commercially available amidinium salts. Selectivity as a function of pyrrole substitution pattern was examined, and a predictive model based on steric effects is put forward, with DFT calculations supporting a selectivity-determining cyclopropanation step. Computations surprisingly indicate that the stereochemistry of cyclopropanation is of little consequence to the subsequent electrocyclic ring opening that forges the pyridine core, due to a compensatory homoaromatic stabilization that counterbalances orbital-controlled torquoselectivity effects. The utility of this skeletal transform is further demonstrated through the preparation of quinolinophanes and the skeletal editing of pharmaceutically relevant pyrroles.
Since initial reports, cross-coupling technologies employing photoredox catalysts to access novel reactivity have developed with increasing pace. In this Outlook, prominent examples from the recent ...literature are organized on the basis of the elementary transformation enabled by photoredox catalysis and are discussed in the context of relevant historical precedent in stoichiometric organometallic chemistry. This treatment allows mechanistic similarities inherent to odd-electron transition metal reactivity to be generalized to a set of lessons for future reaction development.
Recent interest in skeletal editing necessitates the continued development of reagent classes with the ability to transfer single atoms. Terminal transition metal nitrides hold immense promise for ...single‐atom transfer, though their use in organic synthesis has so far been limited. Here we demonstrate a synthetic cycle with associated detailed mechanistic studies that primes the development of terminal transition metal nitrides as valuable single‐atom transfer reagents. Specifically, we show cis‐terpyOsNCl2PF6 inserts nitrogen into indenes to afford isoquinolines. Mechanistic studies for each step (insertion, aromatization, product release, and nitride regeneration) are reported, including crystallographic characterization of diverted intermediates, kinetics, and computational studies. The mechanistic foundation set by this synthetic cycle opens the door to the further development of nitrogen insertion heteroarene syntheses promoted by late transition metal nitrides.
An osmium nitride is shown to insert nitrogen into indenes to afford isoquinolines. A synthetic cycle to regenerate the starting nitride is presented alongside mechanistic studies of each step.
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