Ni-Catalyzed Reductive Cross-Coupling of Cyclopropylamines and Other Strained Ring NHP Esters with (Hetero)Aryl Halides

West, Michael S.; Gabbey, Alexis L.; Huestis, Malcolm P.; Rousseaux, Sophie

doi:10.26434/chemrxiv-2022-853zt

Cited by 3 publications

(3 citation statements)

References 9 publications

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“…Producing carbon–carbon bonds from readily available feedstocks is particularly impactful. The C(sp 3 )–C(sp 2 ) substructure is often synthesized from an organometallic reagent and an alkyl or aryl (pseudo)halide via cross-coupling with palladium, − nickel, − copper, − iron, − cobalt, − or other metal catalysts. − Recently, nickel catalysis has found complementary utility in reductive C(sp 3 )–C(sp 2 ) couplings. − …”

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confidence: 99%

Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp³–sp² Carbon–Carbon Bonds

et al. 2023

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Amines and carboxylic acids are abundant synthetic building blocks that are classically united to form an amide bond. To access new pockets of chemical space, we are interested in the development of amine–acid coupling reactions that complement the amide coupling. In particular, the formation of carbon–carbon bonds by formal deamination and decarboxylation would be an impactful addition to the synthesis toolbox. Here, we report a formal cross-coupling of alkyl amines and aryl carboxylic acids to form C(sp3)–C(sp2) bonds following preactivation of the amine–acid building blocks as a pyridinium salt and N-acyl-glutarimide, respectively. Under nickel-catalyzed reductive cross-coupling conditions, a diversity of simple and complex substrates are united in good to excellent yield, and numerous pharmaceuticals are successfully diversified. High-throughput experimentation was leveraged in the development of the reaction and the discovery of performance-enhancing additives such as phthalimide, RuCl3, and GaCl3. Mechanistic investigations suggest phthalimide may play a role in stabilizing productive Ni complexes rather than being involved in oxidative addition of the N-acyl-imide and that RuCl3 supports the decarbonylation event, thereby improving reaction selectivity.

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confidence: 99%

Formal Cross-Coupling of Amines and Carboxylic Acids to Form sp³–sp² Carbon–Carbon Bonds

et al. 2023

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“…Shortened syntheses to medicinal chemistry intermediates a,b a Cross-coupling using standard conditions with 4CzIPN or Ir-1; b Literature yields provided where reported. carbamates (55), a cyclopropane substrate (56), 29 -hydroxy acids (57), and acids with increased steric bulk (58); aryl halide limitations include ortho-substitution (59), monocyclic heteroarenes (60), and electron-rich aryl bromides (61). 30 To further demonstrate the utility of this method, we synthesized a series of published intermediates from medicinal chemistry campaigns that previously required multi-step sequences (Scheme 3).…”

Section: Scheme 2 Scope Amentioning

confidence: 99%

Unlocking Tertiary Acids for Metallaphotoredox C(sp2)-C(sp3) Decarboxylative Cross-Couplings

Guo

Norris

Ramı́rez

et al. 2023

Preprint

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Dual nickel photoredox catalysis conditions have been developed for the decarboxylative cross-coupling of aryl halides and carboxylic acids containing fully substituted alpha carbons, a valuable but challenging substrate class for C(sp2)–C(sp3) bond-forming reactions. High-throughput experimentation identified Ni(TMHD)2 as the optimal precatalyst for this reaction in contrast to the nickel-bipyridyl complexes typically employed in decarboxylative couplings, which predominantly furnished undesired C–O products. Computational work provides insight into the potential mechanistic underpinnings for the C–C vs. C–O selectivity for the nickel-diketonate complex.

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“…In contemporary medicinal chemistry, discovery teams must consider expansive biochemical, cellular, metabolic, and protein structure data sets to strike a balance of physiochemical properties, potency, and safety. , Among the various binding interactions that can occur between a small molecule drug and the targeted protein, the 3-D network of hydrogen bonding interactions is a key driver of potency …”

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confidence: 99%