Reactive intermediates that can promote nonintuitive bond disconnections underpin advancements in skeletal editing methodologies. Accordingly, a detailed understanding of their reactivity and its underlying mechanisms is central to progress in this space. Herein, we catalog and study the reactivity of nonstabilized cyclic isodiazene intermediates generated via the reaction of cyclic secondary amines with an anomeric amide reagent. Depending on the amine structure, distinct and predictable product classes can be accessed: cyclic hydrazones are formed from pyrrolidines, N-amino indoles from indolines, orthoquinodimethane intermediates from isoindolines, cyclopropanes from azetidines, and cyclic tetrazines from piperidines. Mechanistic experiments and density functional theory calculations suggest that many of these transformations proceed through an azomethine imine intermediate. In most cases, this reactive species subsequently rearranges to a cyclic hydrazone by an unusual self-catalysis mechanism proceeding through a dimeric tetrazine. This oxidative nitrogen insertion was leveraged in several subsequent synthetic applications. Redox diversification of the cyclic hydrazones enables access to pyridazines and cyclic hydrazines, including the synthesis of an orthogonally protected l-piperazic acid from the readily available chiral pool l-prolinol.

Pairs of heterocycles differing by a single constitutive ring atom can exhibit stark differences in the retrosynthetic disconnections available for their preparation. Such a synthesis gap is exemplified by pyridine and pyridazine. Pyridine (a six-membered C5N ring) has risen to prominence in discovery chemistry, its ease of assembly spurring further synthetic development. Despite a host of favorable properties, pyridazine (an analogous C4N2 ring) has comparatively lagged behind-a discrepancy attributable to its often-challenging preparation, which arises from an electronically dissonant heteroatom arrangement. In this work, we achieve a single-atom skeletal edit that produces pyridazines from pyridines by direct carbon-to-nitrogen atom replacement: Azide introduction at the ortho position enables a photoinitiated rearrangement of N-amino-2-azidopyridinium cations. This transformation links the two heterocycles such that the richness of pyridine retrosynthesis becomes available to pyridazines.

Pyrazoles are heterocycles commonly found as key substructures in agrochemicals and medicinally active compounds alike1,2. Despite their pervasiveness, established methods fall notably short in delivering complex pyrazoles selectively due to issues of differentiation during either assembly or N-functionalization3. This is a direct consequence of a dominant synthetic strategy that attempts to control selectivity-determining bonds between poorly differentiated starting materials. To overcome this longstanding challenge, we here describe a prototypical example of an alternative conceptual approach, 'strategic atom replacement', in which we synthesize N-alkyl pyrazoles from isothiazoles. The net forward transformation is a 'swap' of the isothiazole sulfur atom with a nitrogen atom and its associated alkyl fragment to deliver the alkylated pyrazole4,5. Linking the two azoles is an orphaned heterocycle class, 1,2,3-thiadiazine-S-oxides, whose synthetic potential has yet to be tapped6. By proceeding through these unusual heterocycles, the typical selectivity and separation challenges associated with exclusively bond-based pyrazole preparations are circumvented, and even minimally differentiated peripheral substituents can be discriminated to afford isomerically pure products.

Selectivity in organic chemistry is generally presumed to arise from energy differences between competing selectivity-determining transition states. However, in cases where static DFT fails to reproduce experimental product distributions, dynamic effects can be examined to understand the behavior of more complex reaction systems. Previously, we reported a method for nitrogen deletion of secondary amines which relies of the formation of isodiazene intermediates that subsequently extrude dinitrogen with concomitant C-C bond formation via a caged diradical. Herein, a detailed mechanistic analysis of the nitrogen deletion of 1-aryl-tetrahydroisoquinolines is presented, suggesting that in this system the previously determined diradical mechanism undergoes dynamically controlled partitioning to both the normal 1,5-coupling product and an unexpected spirocyclic dearomatized intermediate, which converges to the expected indane by an unusually facile 1,3-sigmatropic rearrangement. This mechanism is not reproduced by static DFT but is supported by quasi-classical molecular dynamics calculations and unifies several unusual observations in this system, including partial chirality transfer, non-statistical isotopic scrambling at the ethylene bridge, the isolation of spirocyclic dearomatized species in a related heterocyclic series, and the observation that introduction of an 8-substituent dramatically improves enantiospecificity.

Divergent synthesis is a powerful strategy that provides simultaneous access to multiple derivatives of a given substrate. However, the emerging developments in skeletal editing have largely delivered methods that lack this potential for diversification. Herein, we report the serendipitous discovery of reagent-controlled selective deletion of C3 or C2 carbon atoms of quinolines, affording indoles. An initial observation that an impurity in commercial samples of DBU promoted cyclization of a benzoxazepine-derived imidate led to the identification of indoline and aminoethanol as C3- and C2-selective carbon-atom scavengers, respectively. These two methods successfully convert a broad scope of quinolines and related azaarenes to the corresponding indoles and azaindoles, enabling divergent carbon deletion. In-depth mechanistic studies support the HFIP-promoted ring opening of 3,1-benzoxazepines to amidine intermediates as a rate-determining step, while providing insights into the selectivity afforded by indoline. These methods and their associated mechanisms offer a blueprint for the rational design of reagent-controlled, divergent skeletal edits.

Atom insertion reactions into ring systems may occur via one of two pathways, proceeding either through initial cyclization to form a 3-membered ring intermediate followed by cleavage of the ring-fusion bond, or through initial ring-scission followed by recyclization onto the inserting atom. Herein, we demonstrate the use of regioretention probes, substrates with latent symmetry that is unveiled only in the case of ring scission and are thus able to distinguish between possible mechanisms for atom insertion. We apply these probes to three previously reported nitrogen insertion methods and in each case unambiguously establish whether the reaction proceeds through aziridination or CC cleavage. In particular, we show that recently reported cobalt- or manganese-catalyzed nitrogen insertion protocols, postulated to proceed via an aziridinyl radical intermediate, instead proceed through a ring-opened ketone-containing intermediate.

Functional group interconversions are particularly sought after by medicinal chemists as a means to enable both lead optimization and library diversification. Here we report SO2 insertion into the C–N bond of primary amines, enabling the direct synthesis of primary sulfonamides without preactivation and effectively inverting the nitrogen’s properties (acidity, hydrogen bonding and so on). The key to this transformation is the implementation of an anomeric amide as a dual-function reagent that both serves to cleave the initial C–N bond and delivers a nitrogen atom to the product after SO2 incorporation. The process tolerates a wide array of functionalities and can be run in an automated fashion, thus allowing libraries of amines to be viable progenitors to highly desirable sulfonamides. Mechanistic studies support an isodiazene radical chain mechanism that generates an intermediate sulfinate that reacts with the anomeric amide to forge the S–N bond. Our protocol was used to conduct a high-throughput library diversification campaign, was applied to the synthesis and modification of approved active pharmaceutical ingredients and was used to enable a net CO-to-SO2 isosteric replacement approach. Despite recent advances in primary sulfonamide synthesis, approaches using primary amines as starting points for direct sulfonamide construction remain elusive. Now a formal SO2 insertion into the C–N bond of primary amines has been developed, using an anomeric amide reagent for both C–N cleavage and S–N bond formation.

Selectivity in organic chemistry is generally presumed to arise from energy differences between competing selectivity-determining transition states. However, in cases where static density functional theory (DFT) fails to reproduce experimental product distributions, dynamic effects can be examined to understand the behavior of more complex reaction systems. Previously, we reported a method for nitrogen deletion of secondary amines which relies on the formation of isodiazene intermediates that subsequently extrude dinitrogen with concomitant C-C bond formation via a caged diradical. Herein, a detailed mechanistic analysis of the nitrogen deletion of 1-aryl-tetrahydroisoquinolines is presented, suggesting that in this system the previously determined diradical mechanism undergoes dynamically controlled partitioning to both the normal 1,5-coupling product and an unexpected spirocyclic dearomatized intermediate, which converges to the expected indane by an unusually facile 1,3-sigmatropic rearrangement. This mechanism is not reproduced by static DFT but is supported by quasi-classical molecular dynamics calculations and unifies several unusual observations in this system, including partial chirality transfer, nonstatistical isotopic scrambling at the ethylene bridge, the isolation of spirocyclic dearomatized species in a related heterocyclic series, and the observation that introduction of an 8-substituent dramatically improves enantiospecificity.

Retrosynthetic simplicity is introduced as a metric by which methods can be evaluated. An argument in favor of reactions which are retrosynthetically simple is put forward, and recent examples in the context of skeletal editing from my own laboratory as well as contributions from others are analyzed critically through this lens.

Controllable installation of a single nitrogen atom is central to many major goals in skeletal editing, with progress often gated by the availability of an appropriate N-atom source. Here we introduce a novel reagent, termed DNIBX, based on dibenzoazabicycloheptadiene (dbabh), which allows the electrophilic installation of dbabh to organic substrates. When indanone β-ketoesters are aminated by DNIBX, the resulting products undergo divergent ring expansions depending on the mode of activation, producing heterocycles in differing oxidation states under thermal and photochemical conditions. The mechanism of each transformation is discussed, and the different reactivity modes of the indanone-dbabh adducts are compared to other nitrogenous precursors.

This chapter presents the procedure for the N‐(Benzyloxy)‐N‐(pivaloyloxy)‐4‐(trifluoromethyl)‐benzamide which belongs to the N‐(alkoxy)‐N‐(acyloxy)benzamide class of anomeric amides. In this class of compounds, in order to satisfy the electron demand of the two oxygen substituents, the resonance of the nitrogen lone pair with the amide carbonyl is largely diminished. This results in an sp 3 configuration and pyramidalization at nitrogen. The authors have used N‐(Benzyloxy)‐N‐(pivaloyloxy)‐4‐(trifluoromethyl)‐benzamide to selectively edit secondary amines containing a range of functional groups and heterocycles. Nitrogen deletion of cyclic secondary amines results in a ring contraction, which has been applied to give substituted cyclobutene products from pyrrolidine precursors. This methodology also enabled a new synthetic route to the chemotherapeutic Pemetrexed and enabled the late‐stage editing of the kinase inhibitor Lapatinib.

Skeletal editing allows chemists to insert, delete or exchange atoms in molecules. The focus of this webcheminar was on transformations that modify the heavy-atom skeleton of organic compounds, especially those amenable to late-stage synthesis. Transformations agnostic of the underlying chemical modality (e.g., transition metal catalysis, photochemistry, reagent development, etc.).

When searching for the ideal molecule to fill a particular functional role (for example, a medicine), the difference between success and failure can often come down to a single atom 1 . Replacing an aromatic carbon atom with a nitrogen atom would be enabling in the discovery of potential medicines 2 , but only indirect means exist to make such C-to-N transmutations, typically by parallel synthesis 3 . Here, we report a transformation that enables the direct conversion of a heteroaromatic carbon atom into a nitrogen atom, turning quinolines into quinazolines. Oxidative restructuring of the parent azaarene gives a ring-opened intermediate bearing electrophilic sites primed for ring reclosure and expulsion of a carbon-based leaving group. Such a ‘sticky end’ approach subverts existing atom insertion–deletion approaches and as a result avoids skeleton-rotation and substituent-perturbation pitfalls common in stepwise skeletal editing. We show a broad scope of quinolines and related azaarenes, all of which can be converted into the corresponding quinazolines by replacement of the C3 carbon with a nitrogen atom. Mechanistic experiments support the critical role of the activated intermediate and indicate a more general strategy for the development of C-to-N transmutation reactions.

Nitrogen scanning in aryl fragments is a valuable aspect of the drug discovery process, but current strategies require time-intensive, parallel, bottom-up synthesis of each pyridyl isomer because of a lack of direct carbon-to-nitrogen (C-to-N) replacement reactions. We report a site-directable aryl C-to-N replacement reaction allowing unified access to various pyridine isomers through a nitrene-internalization process. In a two-step, one-pot procedure, aryl azides are first photochemically converted to 3H-azepines, which then undergo an oxidatively triggered C2-selective cheletropic carbon extrusion through a spirocyclic azanorcaradiene intermediate to afford the pyridine products. Because the ipso carbon of the aryl nitrene is excised from the molecule, the reaction proceeds regioselectively without perturbation of the remainder of the substrate. Applications are demonstrated in the abbreviated synthesis of a pyridyl derivative of estrone, as well as in a prototypical nitrogen scan.

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 detailed mechanistic analysis of the nitrogen deletion of 1-aryl-tetrahydroisoquinolines is presented, suggesting that the anticipated diradical mechanism undergoes dynamically controlled partitioning to both the normal 1,5-coupling product and an unexpected spirocyclic dearomatized intermediate, which converges to the expected indane by an unusually facile 1,3-sigmatropic rearrangement. This mechanism is not reproduced by static DFT but is supported by quasi-classical molecular dynamics calculations and unifies several unusual observations in this system, including partial chirality transfer, non-statistical isotopic scrambling at the ethylene bridge, and the isolation of spirocyclic dearomatized species in a related heterocyclic series. This latter family of compounds exhibit sterically controlled E/Z selectivity ranging from >20:1 to <1:20, prompting the consideration of an analogous cis isomer in the parent transformation. However, despite the observation that an 8-methyl substituent dramatically increases enantiospecificity, calculations indicate that this effect is best explained by dynamic torsional locking of the intermediate diradical.

Good chemistry, like great music, sometimes needs a good collaboration. The Cover Picture shows a combination of nitrogen-deleting anomeric amide power (discovered by Levin's group from the University of Chicago) and parallel synthesis capabilities of Ukrainian chemists, which resulted in a combinatorial library obtained through formal C(sp3)–C(sp3) coupling and a unique synthetically accessible chemical space of nearly 600 K representatives. Background photo by Kristina Krynytska. More information can be found in the Research Article by O. O. Grygorenko and co-workers. (DOI: 10.1002/chem.202203470).

We report a method that enables the fast incorporation of carbon isotopes into the ipso carbon of phenols. Our approach relies on the synthesis of a 1,5-dibromo-1,4-pentadiene precursor, which upon lithium–halogen exchange followed by treatment with carbonate esters results in a formal [5 + 1] cyclization to form the phenol product. Using this strategy, we have prepared 12 1-13C-labeled phenols, show proof-of-concept for the labeling of phenols with carbon-14, and demonstrate phenol synthesis directly from cyclotron-produced [11C]CO2.

A protocol for parallel C(sp(3))-C(sp(3)) coupling of (hetero)aromatic aldehydes and (hetero)arylmethyl amines based on a reductive amination - "nitrogen deletion" reaction sequence has been developed. After preliminary validation experiments, an illustrative compound library of 25 members was prepared with 76 % synthetic efficiency. The estimated chemical space accessible by the proposed approach covers almost 600 000 representatives that are scarcely represented in current compound databases.