Transformation of sterically hindered tertiary alkyl electrophiles under nickel-catalyzed conditions to forge C(sp3)-C bonds and simultaneously create challenging all-carbon quaternary centers has received growing attention in the recent years. The unique nature of nickel featuring flexible oxidation states ranging from Ni0 to NiIV, allows the effective activation of tertiary alkyl electrophiles through ionic (2e) or radical pathways. In nickel-catalyzed coupling of tertiary alkyl electrophiles, the competitive β-H elimination upon the resulting alkyl-Ni intermediate is relatively slow, thus benefiting the C-C bond forming process. Meanwhile, nickel-catalyzed radical addition of tertiary alkyl electrophiles to unsaturated C-C bonds has also advanced rapidly due to the successful incorporation of carboxylic acid and alcohol derivatives as radical precursors, and more importantly due to further interception of the intermediate radical adducts with nucleophiles and electrophiles to accomplish three-component cascade reactions. This review highlights these state-of-the-art nickel-catalyzed transformations of tertiary electrophiles, organized by reaction types with emphasis on the reaction mechanisms.

Nickel-catalyzed formation of quaternary carbon centers using tertiary alkyl electrophiles.

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.

Carbon Atom Insertion into Pyrroles and Indoles Promoted by Chlorodiazirines.

Alcohols and carboxylic acids are among the most commercially abundant, synthetically versatile, and operationally convenient functional groups in organic chemistry. Under visible light photoredox catalysis, these native synthetic handles readily undergo radical activation, and the resulting open-shell intermediates can subsequently participate in transition metal catalysis. In this report, we describe the C(sp3)-C(sp3) cross-coupling of alcohols and carboxylic acids through the dual combination of N-heterocyclic carbene (NHC)-mediated deoxygenation and hypervalent iodine-mediated decarboxylation. This mild and practical Ni-catalyzed radical-coupling protocol was employed to prepare a wide array of alkyl-alkyl cross-coupled products, including highly congested quaternary carbon centers from the corresponding tertiary alcohols or tertiary carboxylic acids. We demonstrate the synthetic applications of this methodology to alcohol C1-alkylation and formal homologation, as well as to the late-stage functionalization of drugs, natural products, and biomolecules.

Nontraditional Fragment Couplings of Alcohols and Carboxylic Acids: C(sp3)-C(sp3) Cross-Coupling via Radical Sorting.

C -aryl glycosyl compounds offer better in vivo stability relative to O- and N- glycoside analogues. C -aryl glycosides are extensively investigated as drug candidates and applied to chemical biology studies. Previously, C -aryl glycosides are derived from lactones, glycals, glycosyl stannanes, and halides, via methods displaying various limitations with respect to the scope, functional group compatibility, and practicality. Challenges remain in the synthesis of C -aryl nucleosides and 2-deoxysugars from easily accessible carbohydrate precursors. Herein, we report a cross-coupling method to prepare C -aryl and heteroaryl glycosides, including nucleosides and 2-deoxysugars, from glycosyl esters and bromoarenes. Activation of the carbohydrate substrates leverages dihydropyridine (DHP) as an activating group followed by decarboxylation to generate a glycosyl radical via C-O bond homolysis. This strategy represents a new means to activate alcohols as a cross-coupling partner. The convenient preparation of glycosyl esters and their stability exemplifies the potential of this method in medicinal chemistry.

Diastereoselective Synthesis of Aryl C-Glycosides from Glycosyl Esters via C−O Bond Homolysis

Given their ubiquity in natural products and pharmaceuticals, alcohols represent one of the most attractive starting materials for the construction of C-C bonds. We report herein the first catalytic strategy to harness the reactivity of aryl radicals for the activation of C-O bonds in alcohol-derived xanthate esters, allowing for the discovery of the first catalytic deoxygenative difluoromethylation reaction. Under copper-catalyzed conditions, a wide variety of alkyl xanthate esters, readily synthesized from alcohol feedstocks, were activated by catalytically generated aryl radicals and were converted to the alkyl-difluoromethane products via alkyl radical intermediates. This scalable protocol exhibits a broad substrate scope and functional group tolerance, enabling late-stage modification of complex pharmaceutical agents. A one-pot protocol has been developed that allows for the direct use of free alcohols without purification of the xanthate esters. Mechanistic studies are consistent with the hypothesis of aryl radicals being formed and initiating the cleavage of the C-O bonds of xanthate esters, to generate alkyl radicals as the key intermediates. This aryl radical activation approach represents a new strategy for the activation of alcohols as cross-coupling partners.

Aryl Radical Activation of C-O Bonds: Copper-Catalyzed Deoxygenative Difluoromethylation of Alcohols.

The
ability to understand and predict reactivity is essential for
the development of new reactions. In the context of Ni-catalyzed C­(sp3)–O functionalization, we have developed a unique strategy
employing activated cyclopropanols to aid the design and optimization
of a redox-active leaving group for C­(sp3)–O arylation.
In this chemistry, the cyclopropane ring acts as a reporter of leaving-group
reactivity, since the ring-opened product is obtained under polar
(2e) conditions, and the ring-closed product is obtained under radical
(1e) conditions. Mechanistic studies demonstrate that the optimal
leaving group is redox-active and are consistent with a Ni­(I)/Ni­(III)
catalytic cycle. The optimized reaction conditions are also used to
synthesize a number of arylcyclopropanes, which are valuable pharmaceutical
motifs.

/pdf/the-cyclopropane-ring-as-a-reporter-of-radical-leaving-group-3bsg9vybdi.pdf

The Cyclopropane Ring as a Reporter of Radical Leaving-Group Reactivity for Ni-Catalyzed C(sp3)-O Arylation.

https://pubs.acs.org/doi/pdf/10.1021/acs.orglett.1c03674

Ni-Catalyzed C(sp3)-O Arylation of α-Hydroxy Esters.

https://pubs.rsc.org/en/content/articlepdf/2020/cc/d0cc05895e

Boronic acid-mediated ring-opening and Ni-catalyzed arylation of 1-arylcyclopropyl tosylates

Despite the importance of heteroatom-substituted cyclopropane derivatives in drug design and organic synthesis, cyclopropanethiols remain critically underexplored. Inspired by the wide use of the Newman-Kwart rearrangement to access valuable thiophenols from phenol feedstocks, we report the development of a photocatalytic approach for efficient ambient temperature aliphatic O- to S-rearrangement on tertiary cyclopropanol derivatives. After demonstrating that a range of cyclopropanethiols - that are difficult to access by other methods - can be obtained with this strategy, we show that these rearranged products can be easily hydrolyzed and further derivatized. We conclude this study with mechanistic findings that enabled an initial extension of this approach toward other classes of aliphatic alcohols.

Photocatalytic O- to S-Rearrangement of Tertiary Cyclopropanols.

Mandelic acid derivatives represent a valuable class of compounds due to their wide use in synthetic organic chemistry and the pharmaceutical sector. Herein, we report a novel reductive Ni/photoredox cross-coupling of readily accessible, bench stable N-alkoxyphthalimides and aryl halides to prepare unprotected mandelic acid ester derivatives. Mechanistic experiments suggest that this cross-coupling likely proceeds via a pathway that is distinct from previous reports using similar redox-active alkoxy radical precursors.

A Dual Ni/Photoredox Cross-Coupling Approach toward Mandelic Acids.

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

John J. Monteith

Author Tools

Chat about Author