Direct C−H Carbamoylation of Nitrogen‐Containing Heterocycles

Jouffroy, Matthieu; Kong, Jongrock

doi:10.1002/chem.201806159

Cited by 44 publications

(22 citation statements)

References 46 publications

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“…Not only are these energy barriers rather large for a reaction that occurs at room temperature, but more importantly, the incorrect regioisomer ( C2-adduct ), relative to the experimentally observed outcome, was favored, with an associated Gibbs free energy barrier (Δ G ⧧ ) of 26.3 kcal/mol versus the C4 barrier of 29.4 kcal/mol. We note that oxidation of the C2-adduct followed by loss of H + (or the combined process of losing H • ) would lead to a Minisci-type product ( C2-product ), which was not observed experimentally under the optimized conditions. On the other hand, reduction of the C4-adduct , which is quite facile ( E red = −0.13 V vs SCE; electron affinity of 94.0 kcal/mol), followed by loss of cyanide would afford the experimentally observed product 5 .…”

Section: Resultsmentioning

confidence: 74%

Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer

et al. 2019

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Accessing hindered amines, particularly primary amines α to a fully substituted carbon center, is synthetically challenging. We report an electrochemical method to access such hindered amines starting from benchtop-stable iminium salts and cyanoheteroarenes. A wide variety of substituted heterocycles (pyridine, pyrimidine, pyrazine, purine, azaindole) can be utilized in the cross-coupling reaction, including those substituted with a halide, trifluoromethyl, ester, amide, or ether group, a heterocycle, or an unprotected alcohol or alkyne. Mechanistic insight based on DFT data, as well as cyclic voltammetry and NMR spectroscopy, suggests that a proton-coupled electron-transfer mechanism is operational as part of a hetero-biradical cross-coupling of α-amino radicals and radicals derived from cyanoheteroarenes.

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Section: Resultsmentioning

confidence: 74%

Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer

et al. 2019

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“…Jouffroy and Kong soon after developed apersulfatepromoted method that uses only one equivalent of oxamic acid under photocatalytic conditions. [51]…”

Section: Direct Decarboxylation Of Carboxylic Acidsmentioning

confidence: 99%

“…They propose that the DMSO plays a key role in allowing the persulfate decomposition under mild conditions (40 °C). Jouffroy and Kong soon after developed a persulfate‐promoted method that uses only one equivalent of oxamic acid under photocatalytic conditions …”

Section: Advances In Radical Generation Via Decarboxylationmentioning

confidence: 99%

Recent Advances in Minisci‐Type Reactions

2019

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Reactions that involve the addition of carbon‐centered radicals to basic heteroarenes, followed by formal hydrogen atom loss, have become widely known as Minisci‐type reactions. First developed into a useful synthetic tool in the late 1960s by Minisci, this reaction type has been in constant use over the last half century by chemists seeking to functionalize heterocycles in a rapid and direct manner, avoiding the need for de novo heterocycle synthesis. Whilst the originally developed protocols for radical generation remain in active use today, they have been joined in recent years by a new array of radical generation strategies that allow use of a wider variety of radical precursors that often operate under milder and more benign conditions. The recent surge of interest in new transformations based on free radical reactivity has meant that numerous choices are now available to a synthetic chemist looking to utilize a Minisci‐type reaction. Radical‐generation methods based on photoredox catalysis and electrochemistry have joined approaches which utilize thermal cleavage or the in situ generation of reactive radical precursors. This review will cover the remarkably large body of literature that has appeared on this topic over the last decade in an attempt to provide guidance to the synthetic chemist, as well as a perspective on both the challenges that have been overcome and those that still remain. As well as the logical classification of advances based on the nature of the radical precursor, with which most advances have been concerned, recent advances in control of various selectivity aspects associated with Minisci‐type reactions will also be discussed.

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“…Our initial success with the decarboxylative alkylation of lepidine prompted us to investigate its decarboxylative carbamoylation with oxamic acids (Table ) . Unfortunately, the same electrophotochemical conditions that we used above failed to promote the reaction of lepidine with 5 .…”

Section: Resultsmentioning

confidence: 99%

Electrophotocatalytic Decarboxylative C−H Functionalization of Heteroarenes

et al. 2020

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Decarboxylative C−H functionalization reactions are highly attractive methods for forging carbon–carbon bonds considering their inherent step‐ and atom‐economical features and the pervasiveness of carboxylic acids and C−H bonds. An ideal approach to achieve these dehydrogenative transformations is through hydrogen evolution without using any chemical oxidants. However, effective couplings by decarboxylative carbon–carbon bond formation with proton reduction remain an unsolved challenge. Herein, we report an electrophotocatalytic approach that merges organic electrochemistry with photocatalysis to achieve the efficient direct decarboxylative C−H alkylation and carbamoylation of heteroaromatic compounds through hydrogen evolution. This electrophotocatalytic method, which combines the high efficiency and selectivity of photocatalysis in promoting decarboxylation with the superiority of electrochemistry in effecting proton reduction, enables the efficient coupling of a wide range of heteroaromatic bases with a variety of carboxylic acids and oxamic acids. Advantageously, this method is scalable to decagram amounts, and applicable to the late‐stage functionalization of drug molecules.

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Direct C−H Carbamoylation of Nitrogen‐Containing Heterocycles

Cited by 44 publications

References 46 publications

Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer

Electrochemical Synthesis of Hindered Primary and Secondary Amines via Proton-Coupled Electron Transfer

Recent Advances in Minisci‐Type Reactions

Electrophotocatalytic Decarboxylative C−H Functionalization of Heteroarenes

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