Methyl Radical Initiated Kharasch and Related Reactions

10.26434/chemrxiv.12834125 ◽

2020 ◽

Author(s):

Nicholas Tappin ◽

Philippe Renaud

Keyword(s):

Halogen Atom ◽

Functional Group ◽

Chain Process ◽

Methyl Radicals ◽

Methyl Radical ◽

Reaction Conditions ◽

Alternative Source ◽

Group Transfer ◽

Radical Trap ◽

Flash Column Chromatography

An improved procedure to run halogen atom and related chalcogen group transfer radical additions is reported. The procedure relies on the thermal decomposition of di-tert-butylhyponitrite (DTBHN), a safer alternative to the explosive diacetyl peroxide, to produce highly reactive methyl radicals that can initiate the chain process. This mode of initiation generates byproducts that are either gaseous (N2) or volatile (acetone and methyl halide) thereby facilitating greatly product purification by either flash column chromatography or distillation. In addition, remarkably simple and mild reaction conditions (refluxing EtOAc during 30 minutes under normal atmosphere) and a low excess of the radical precursor reagent (2.0 equivalents) make this protocol particularly attractive for preparative synthetic applications. This initiation procedure has been demonstrated with a broad scope since it works efficiently to add a range of electrophilic radicals generated from iodides, bromides, selenides and xanthates over a range of unactivated terminal alkenes. A diverse set of radical trap substrates exemplifies a broad functional group tolerance. Finally, di-tert-butyl peroxyoxalate (DTBPO) is also demonstrated as alternative source of tert-butoxyl radicals to initiate these reactions under identical conditions which gives gaseous byproducts (CO2).

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C(sp3)–H methylation enabled by peroxide photosensitization and Ni-mediated radical coupling

Science ◽

10.1126/science.abh2623 ◽

2021 ◽

Vol 372 (6540) ◽

pp. 398-403

Author(s):

Aristidis Vasilopoulos ◽

Shane W. Krska ◽

Shannon S. Stahl

Keyword(s):

Building Blocks ◽

Hydrogen Atom Transfer ◽

Drug Candidate ◽

Methyl Radicals ◽

Methyl Radical ◽

Triplet Energy ◽

Reaction Conditions ◽

Radical Coupling ◽

Triplet Energy Transfer ◽

Methyl Effect

The “magic methyl” effect describes the change in potency, selectivity, and/or metabolic stability of a drug candidate associated with addition of a single methyl group. We report a synthetic method that enables direct methylation of C(sp3)–H bonds in diverse drug-like molecules and pharmaceutical building blocks. Visible light–initiated triplet energy transfer promotes homolysis of the O–O bond in di-tert-butyl or dicumyl peroxide under mild conditions. The resulting alkoxyl radicals undergo divergent reactivity, either hydrogen-atom transfer from a substrate C–H bond or generation of a methyl radical via β-methyl scission. The relative rates of these steps may be tuned by varying the reaction conditions or peroxide substituents to optimize the yield of methylated product arising from nickel-mediated cross-coupling of substrate and methyl radicals.

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Modern Organic Synthesis in the Laboratory

10.1093/oso/9780195187984.001.0001 ◽

2008 ◽

Cited By ~ 1

Author(s):

Jie Jack Li ◽

Chris Limberakis ◽

Derek A. Pflum

Keyword(s):

Organic Chemistry ◽

Graduate Students ◽

Organic Synthesis ◽

Functional Group ◽

Bond Formation ◽

Reaction Conditions ◽

Carbon Bond ◽

Oxidation Reduction ◽

Carbon Carbon Bond ◽

Daunting Task

Searching for reaction in organic synthesis has been made much easier in the current age of computer databases. However, the dilemma now is which procedure one selects among the ocean of choices. Especially for novices in the laboratory, it becomes a daunting task to decide what reaction conditions to experiment with first in order to have the best chance of success. This collection intends to serve as an "older and wiser lab-mate" one could have by compiling many of the most commonly used experimental procedures in organic synthesis. With chapters that cover such topics as functional group manipulations, oxidation, reduction, and carbon-carbon bond formation, Modern Organic Synthesis in the Laboratory will be useful for both graduate students and professors in organic chemistry and medicinal chemists in the pharmaceutical and agrochemical industries.

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Nickel-Catalyzed Multicomponent Coupling Reaction of Alkyl Halides, Isocyanides and H2O: An Expedient Way to Access Alkyl Amides

Synthesis ◽

10.1055/s-0040-1707229 ◽

2020 ◽

Vol 52 (22) ◽

pp. 3466-3472

Author(s):

Yunkui Liu ◽

Bingwei Zhou ◽

Qiao Li ◽

Hongwei Jin

Keyword(s):

Functional Group ◽

Coupling Reaction ◽

Alkyl Halides ◽

Previous Literature ◽

Catalytic Cycle ◽

Reaction Conditions ◽

Multicomponent Coupling ◽

Easy Operation

We herein describe a Ni-catalyzed multicomponent coupling reaction of alkyl halides, isocyanides, and H2O to access alkyl amides. Bench-stable NiCl2(dppp) is competent to initiate this transformation under mild reaction conditions, thus allowing easy operation and adding practical value. Substrate scope studies revealed a broad functional group tolerance and generality of primary and secondary alkyl halides in this protocol. A plausible catalytic cycle via a SET process is proposed based on preliminary experiments and previous literature.

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Rh(III)-Catalyzed Olefination and Alkylation of Arenes with Maleimides: A Tunable Strategy for C(sp2)–H Functionalization

Synthesis ◽

10.1055/s-0037-1610765 ◽

2021 ◽

Author(s):

Hongji Li ◽

Wenjie Zhang ◽

Xueyan Liu ◽

Zhenfeng Tian

Keyword(s):

Room Temperature ◽

Functional Group ◽

Reaction Conditions ◽

Bond Functionalization ◽

Alkylation Process ◽

Coupling Partner

AbstractWe herein report a new nitrogen-directed Rh(III)-catalyzed C(sp2)–H bond functionalization of N-nitrosoanilines and azoxybenzenes with maleimides as a coupling partner, in which the olefination/alkylation process can be finely controlled at room temperature by variation of the reaction conditions. This method shows excellent functional group tolerance, and presents a mild access to the resulting olefination/alkylation products in moderate to good yields.

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Sulfonyl Radical Triggered Selective Iodosulfonylation and Bicycli-zations of 1,6-Dienes

Chemical Communications ◽

10.1039/d1cc03252f ◽

2021 ◽

Author(s):

Shi-Ping Wu ◽

Dong-Kai Wang ◽

Qing-Qing Kang ◽

Guo-Ping Ge ◽

Hongxing Zheng ◽

...

Keyword(s):

Functional Group ◽

High Selectivity ◽

Reaction Conditions ◽

First Time

A novel sulfonyl radical triggered selective iodosulfonylation and bicyclizations of 1,6-dienes has been described for the first time. High selectivity and efficiency, mild reaction conditions, excellent functional group compatibility, and...

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Ligand-Driven Advances in Iridium Catalyzed sp3 C-H Borylation: 2,2’-Dipyridylarylmethane

Synlett ◽

10.1055/a-1344-1904 ◽

2020 ◽

Author(s):

Margaret R Jones ◽

Nathan D. Schley

Keyword(s):

Recent Work ◽

Organic Synthesis ◽

Functional Group ◽

Reaction Conditions ◽

Recent Advances ◽

Additional Ligand ◽

Limited Application ◽

Hydrocarbon Substrates ◽

Phenanthroline Ligands

The field of catalytic C-H borylation has grown considerably since its founding, providing a means for the preparation of synthetically versatile organoborane products. While sp2 C-H borylation methods have found widespread and practical use in organic synthesis, the analogous sp3 C-H borylation reaction remains challenging and has seen limited application. Existing catalysts are often hindered by incomplete consumption of the diboron reagent, poor functional group tolerance, harsh reaction conditions, and the need for excess or neat substrate. These challenges acutely affect C-H borylation chemistry of unactivated hydrocarbon substrates, which has lagged in comparison to methods for the C-H borylation of activated compounds. Herein we discuss recent advances in sp3 C-H borylation of undirected substrates in the context of two particular challenges: (1) utilization of the diboron reagent and (2) the need for excess or neat substrate. Our recent work on the application of dipyridylarylmethane ligands in sp3 C-H borylation has allowed us to make contributions in this space and has presented an additional ligand scaffold to supplement traditional phenanthroline ligands.

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Mercury-photosensitized decomposition of dimethyl ether. Part I. Mechanism

Canadian Journal of Chemistry ◽

10.1139/v67-448 ◽

1967 ◽

Vol 45 (22) ◽

pp. 2763-2766 ◽

Cited By ~ 16

Author(s):

L. F Loucks ◽

K. J Laidler

Keyword(s):

Mass Balance ◽

Dimethyl Ether ◽

Pressure Range ◽

Reaction Vessel ◽

No Decomposition ◽

Methyl Radical ◽

Reaction Conditions ◽

Products Of Reaction

The mercury-photosensitized decomposition of dimethyl ether was investigated from 200 to 300 °C and over the pressure range 3 to 600 mm Hg. Measurements were made of the initial rates of formation of the products of reaction, which are CO, H2, C2H6, CH4, CH3OC2H5, and CH3OCH2CH2OCH3. It is concluded that the primary step involves a C—H split; there is no evidence for a primary C—O split. Over the range 200 to 300 °C the methoxymethyl radical, CH3OCH2, decomposed to give formaldehyde and a methyl radical, whereas at 30 °C no decomposition of the CH3OCH2 radical was detected. The mass balance is consistent with the mechanism proposed. The homogeneity of the reaction conditions was examined by varying the concentration of mercury in the reaction vessel.

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Intermolecular 3+3 Ring Expansion of Aziridines to Dehydropiperidines through the Intermediacy of Aziridinium Ylides

10.26434/chemrxiv.9961937.v1 ◽

2019 ◽

Author(s):

Jennifer Schomaker ◽

Josephine Eshon ◽

Kate A. Nicastri ◽

Steven C. Schmid ◽

William T. Raskopf ◽

...

Keyword(s):

Natural Product ◽

Functional Group ◽

Ring Expansion ◽

Sigmatropic Rearrangement ◽

Reactive Intermediate ◽

Mechanistic Studies ◽

Reaction Conditions ◽

Complex Molecules ◽

Form Complex ◽

Reaction Proceeds

Bicyclic aziridines undergo formal [3+3] ring expansion reactions when exposed to rhodium-bound vinyl carbenes to form complex dehydropiperidines in a highly stereocontrolled rearrangement. Mechanistic studies and DFT computations indicate the reaction proceeds through the formation of a vinyl aziridinium ylide; this reactive intermediate undergoes a concerted, asynchronous, pseudo-[1,4]- sigmatropic rearrangement to directly furnish the heterocyclic products with net retention at the new C-C bond. In combination with an asymmetric silver-catalyzed aziridination developed in our group, this method quickly delivers enantioenriched scaffolds with up to three contiguous stereocenters. The mild reaction conditions, functional group tolerance, and high stereochemical retention of this method are especially well-suited for appending piperidine motifs to natural product and complex molecules. Ultimately, our work establishes the value of underutilized aziridinium ylides as key intermediates in strategies to convert small, strained rings to larger N-heterocycles.

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