Direct Access to Isotopically Labeled Aliphatic Ketones Mediated by Nickel(I) Activation

Donslund, Aske S.; Pedersen, Simon S.; Gaardbo, Cecilie; Neumann, Karoline T.; Kingston, Lee P.; Elmore, Charles S.; Skrydstrup, Troels

doi:10.1002/anie.201916391

Cited by 42 publications

(27 citation statements)

References 47 publications

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“…Much to our delight, the yields of 3a could be further improved to 87% and 83%, respectively, when amide-type pincer ligand (e.g. N -(pyridin-2-ylmethyl)picolinamide ( L1 ) or N -(quinolin-8-yl)picolinamide ( L2 )) was used (entries 3–4), though they were seldom used as ligands in transition metal-catalyzed cross-coupling reactions 70 – 73 . This discovery encouraged us to synthesize two sterically more hindered methylated derivatives L3 and L4 as ligands.…”

Section: Resultsmentioning

confidence: 99%

Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand

Zhang

Jiao

et al. 2021

Nat Commun

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Alkynes are amongst the most valuable functional groups in organic chemistry and widely used in chemical biology, pharmacy, and materials science. However, the preparation of alkyl-substituted alkynes still remains elusive. Here, we show a nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts. Key to the success of this coupling is the development of an easily accessible and bench-stable amide-type pincer ligand. This ligand allows naturally abundant alkyl amines as alkylating agents in Sonogashira reactions, and produces diverse alkynes in excellent yields under mild conditions. Salient merits of this chemistry include broad substrate scope and functional group tolerance, gram-scale synthesis, one-pot transformation, versatile late-stage derivatizations as well as the use of inexpensive pre-catalyst and readily available substrates. The high efficiency and strong practicability bode well for the widespread applications of this strategy in constructing functional molecules, materials, and fine chemicals.

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Section: Resultsmentioning

confidence: 99%

Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand

Zhang

Jiao

et al. 2021

Nat Commun

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“…Reductive elimination of the nickel(III) intermediate subsequently leads to the desired thioester and a Ni I ‐complex. The latter is a strong reductant, [24] and undoubtedly capable of reducing the disulfide as well, or combining with a thiyl radical, which in both cases will yield a Ni II ‐SPy end‐product. By analyzing the precipitation formed from the reaction with disulfide by 1 H NMR spectroscopy, we observed the signals corresponding to a Ni II ‐SPy compound (see Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

A Nickel(II)‐Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides

Pedersen

Donslund

Mikkelsen

et al. 2021

Chemistry A European J

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As eries of pharmaceutically relevant small molecules and biopharmaceuticals bearing aliphatic carboxamides have been successfully labeled with carbon-13. Key to the successo ft his novel carbon isotopel abeling technique is the observation that 13 C-labeled Ni II -acyl complexes, formed from a 13 CO insertion step with Ni II -alkyl intermediates, rapidly react in less than one minute with 2,2'-dipyridyl disulfide to quantitatively form the corresponding 2-pyridyl thioesters.E ither the use of 13 C-SilaCOgen or 13 C-COgen allows for the stoichiometric additiono fi sotopically labeled carbon monoxide. Subsequento ne-pot acylation of as eries of structurally diverse amines provides the desired 13 C-la-beled carboxamides in good yields. Asingle electron transfer pathway is proposedb etween the Ni II -acyl complexes and the disulfide providing ar eactive Ni III -acyl sulfide intermediate, which rapidly undergoes reductivee limination to the desired thioester.B yf urthero ptimization of the reactionp arameters, reaction times down to only 11 min were identified, opening up the possibility of exploring this chemistry for carbon-11i sotope labeling. Finally,t his isotope labeling strategyc ould be adapted to the synthesis of 13 C-labeled liraglutide and insulind egludec, representing two antidiabetic drugs.

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“…An alternative pathway for the formation of the carbon‐centered radical may be considered under the catalytic conditions as well, as illustrated by the catalytic cycle in Scheme 9 b. We have previously proposed an inner sphere electron transfer pathway involving the Ni I NNN pincer complex D and the alkyl halide in our work on the carbonylative coupling of alkyl iodides with organozinc reagents [39] . Subsequently, combining the carbon‐centered radical with the Ni complex B formed from the hydrometalation step leads to the high‐valent Ni species C .…”

Section: Resultsmentioning

confidence: 99%

Regioselective Hydroalkylation of Vinylarenes by Cooperative Cu and Ni Catalysis

2021

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Disclosed here is a dual copper and nickel catalytic system with a silyl hydride source for promoting the linear selective hydroalkylation of vinylarenes. This carbon–carbon bond‐forming protocol is applied to couple a variety of functionalized vinylarenes with alkyl halides applying a nickel(II) NNN pincer complex in the presence of an NHC‐ligated copper catalyst. This combination allows for a 1 mol % loading of the nickel catalyst leading to turnover numbers of up to 72. Over 40 examples are presented, including applications for pharmaceutical diversification. Labeling experiments demonstrated the regioselectivity of the reaction and revealed that the copper catalyst plays a crucial role in enhancing the rate for formation of the reactive linear alkyl nickel complex. Overall, the presented work provides a complimentary approach for hydroalkylation reactions, whilst providing a preliminary mechanistic understanding of the cooperativity between the copper and nickel complexes.

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Direct Access to Isotopically Labeled Aliphatic Ketones Mediated by Nickel(I) Activation

Cited by 42 publications

References 47 publications

Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand

Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand

A Nickel(II)‐Mediated Thiocarbonylation Strategy for Carbon Isotope Labeling of Aliphatic Carboxamides

Regioselective Hydroalkylation of Vinylarenes by Cooperative Cu and Ni Catalysis

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