Tandem C/N-Difunctionalization of Nitroarenes: Reductive Amination and Annulation by a Ring Expansion/Contraction Sequence

Li, Gen; Lavagnino, Marissa N.; Ali, Siraj Z.; Hu, Shicheng; Radosevich, Alexander T.

doi:10.1021/jacs.2c12450

Cited by 37 publications

(14 citation statements)

References 82 publications

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“…Both of these approaches are problematic in that the nitrogen insertion and carbon deletions are conducted with differing selectivity, leading to an overall sequence that produces multiple products (in the case of nonsymmetric starting aryl azides), removes distal functional groups, retains the incoming amine nucleophile, and thereby promotes rearrangement of the arene skeleton. Indeed, such rearrangements are the norm in the handful of other ring-contraction reactions of azepines that have been reported (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34). Whereas in certain instances this may be desirable, such skeletal rotation precludes straightforward structure-activity interrogation and complicates retrosynthetic analysis.…”

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confidence: 99%

Aromatic nitrogen scanning by ipso -selective nitrene internalization

Pearson,

Shimazumi,

Driscoll

et al. 2023

Science

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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 3 H -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.

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confidence: 99%

Aromatic nitrogen scanning by ipso -selective nitrene internalization

Pearson,

Shimazumi,

Driscoll

et al. 2023

Science

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“…[19][20] At this point, in order to restore the aromatic ring with the appropriate distribution of N-and O-groups, we envisaged that simple treatment with a competent electrophile, such as TFAA, would generate the azepine VII (step f). [21] We proposed that the instability provided by its anti-aromatic character, combined with the lack of opportunity for isomerization, would trigger a 6π electrocyclic ring closure to reform the CÀ C bond, giving rise to aziridine VIII (step g). Finally, the push-pull nature of this hemi-acetal & aziridine intermediate should lead to fast re-aromatization to afford product 3 (step h), whereby the N-functionality has been shifted to its ortho position by formal displacement of alcohol and further converted into an amide.…”

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confidence: 99%

A Photochemical Strategy for ortho‐Aminophenol Synthesis via Dearomative‐Rearomative Coupling Between Aryl Azides and Alcohols

Li,

Ruffoni,

Leonori

2023

Angew Chem Int Ed

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Abstractortho‐Aminophenols are aromatic derivatives featuring vicinal N‐ and O‐based functionalities commonly found in the structures of many high‐value materials. These molecules are generally prepared using multistep strategies that follow the rules of electrophilic aromatic substitution (SEAr) chemistry. Despite their high fidelity, such approaches cannot target substrates featuring a “contra‐SEAr” arrangement of N‐ and O‐groups. Here we report an alternative strategy for the preparation of such ortho‐aminophenols using aryl azides as the precursors. The process utilizes low‐energy photoexcitation to trigger the decomposition of aryl azides into singlet nitrenes that undergo a dearomative‐rearomative sequence. This allows the incorporation of alcoholic nucleophiles into a seven‐membered ring azepine intermediate via temporary disruption of aromaticity, followed by electrophile‐induced re‐aromatization. The net retrosynthetic logic is that the alcohol displaces the azide, which, in turn, moves to its ortho position and furthermore is converted into an amide. The synthetic value and complementarity of this strategy has been demonstrated by the coupling of aryl azides with complex, drug‐like alcohols and phenols as well as amines, thiols and thiophenols, which provides a general platform for the fast and selective heterofunctionalization of aromatics.

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“…13 In recent years, ring expansions emerged as some of the most attractive chemical conversions from an atom-and step-economic perspective to synthesize a versatile range of heterocyclic cores. 14,15 To date, many remarkable advancements using transition metals (e.g., Ir, Rh, and Pd) have been achieved in this field, 16,17 and the most recent work has been concentrated on strained-ring systems such as three-and four-membered rings (e.g. cyclopropanes, cyclobutanes, aziridines, and oxiranes).…”

Section: Introductionmentioning

confidence: 99%