ChemInform Abstract: Decarboxylative Cross‐Electrophile Coupling of N‐Hydroxyphthalimide Esters with Aryl Iodides.

Huihui, Kierra M. M.; Caputo, Jill A.; Melchor, Zulema; Olivares, Astrid M.; Spiewak, Amanda M.; Johnson, Keywan A.; DiBenedetto, Tarah A.; Kim, Seo Young; Ackerman, Laura K. G.; Weix, Daniel J.

doi:10.1002/chin.201639066

Cited by 3 publications

(5 citation statements)

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“…We hypothesized that this challenge could be addressed by the union of two recent developments in cross-electrophile coupling: the finding that N-hydroxyphthalimide esters ketone synthesis is less convenient than amide synthesis mechanistic strategy for easy ketone synthesis from two esters (NHP esters) react under nickel catalysis to form alkyl radicals after decarboxylation 6 and the finding that acylnickel(II) intermediates can capture radicals to form ketones in high yield. 4e,7 Ketones could then be synthesized by the union of two activated esters -one tuned to form a metal acyl and one tuned to form a radical (Scheme 1).…”

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confidence: 99%

Ketones from Nickel-Catalyzed Decarboxylative, Non-Symmetric Cross-Electrophile Coupling of Carboxylic Acid Esters

Jiang

Cary

Beyer

et al. 2019

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A new strategy for the synthesis of ketones is presented based upon the decarboxylative coupling of N-hydroxyphthalimide (NHP) esters with S-2-pyridyl thioesters. The reactions are selective for the cross-coupled product because NHP esters act as radical donors and the thioesters act as acyl donors. The reaction conditions are general and mild, with over 40 examples presented, including larger fragments and the 20-mer peptide Exendin(9-39) on solid support.

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confidence: 99%

Ketones from Nickel-Catalyzed Decarboxylative, Non-Symmetric Cross-Electrophile Coupling of Carboxylic Acid Esters

Jiang

Cary

Beyer

et al. 2019

Preprint

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“…(NHP esters) react under nickel catalysis to form alkyl radicals after decarboxylation 6 and the finding that acylnickel(II) intermediates can capture radicals to form ketones in high yield. 4e,7 Ketones could then be synthesized by the union of two activated esters -one tuned to form a metal acyl and one tuned to form a radical (Scheme 1).…”

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confidence: 99%

“…For example, our previous coupling of an acid chloride with an NHP ester formed the ketone product, but the high reactivity of the acid chloride limited utility and a large excess was required for high yields. 6,9 Reactions that require a large excess of one component can be valuable, but limit application to complex or valuable fragments. Further, the use of unstable intermediates limits options in synthesis because no purification is possible.…”

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confidence: 99%

Ketones from Nickel‐Catalyzed Decarboxylative, Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

et al. 2019

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While the coupling of carboxylic acid derivatives to form new C-N and C-O bonds is a staple of organic synthesis and has been automated, the synthesis of the C-C bonds of ketones generally requires the use of reactive organometallic reagents incompatible with many functional groups. We demonstrate here a new approach to ketone synthesis that couples two different carboxylic acid esters, N-hydroxyphthalimide esters (NHP esters) and S-2-pyridyl thioesters (SPy esters), to form aryl-alkyl and dialkyl ketones in high yields. The keys to the approach are the use of a nickel catalyst with an electron-poor bipyridine or terpyridine ligand, a THF/DMA mixed solvent system, and ZnCl2 to enhance the reactivity of the NHP ester. The resulting reaction can be used to form ketones that have previously been difficult to access, such as hindered tertiary-tertiary ketones with strained rings and ketones with heterocycles. The conditions can be employed in the coupling of complex fragments, including a 20-mer peptide, an analogue of Exendin(9-39), on solid support. carboxylic acid esters. These first-generation conditions are already competitive with the best available methods and are particularly well-suited to challenging ketones, such as those with severe steric hinderance and those that incorporate heterocycles. The versatility of the method could even be extended to the coupling of larger, functionalized fragments, including peptides on solid support. Further improvements are underway, including one-pot methods, alternative substrate pairs, and expanding the types of ketones that can be synthesized. ASSOCIATED CONTENTSupporting Information. Detailed experimental procedures, supplementary optimization data, characterization data for all isolated products, and copies of NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.

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“…Applying these optimized conditions to a variety of different carboxylic acid pairs demonstrated that the chemistry was robust for the synthesis of dialkyl ketones and aryl-alkyl ketones (Scheme 2). Functional group compatibility included acidic N-H bonds (14,15,16,35) protected nitrogens (6,13,23,32) and protected alcohols (37, 39). Notably, an alkyl bromide (9) was tolerated, even though similar conditions are commonly employed in nickel-catalyzed couplings of alkyl bromides.…”

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confidence: 99%

“…NHP esters) react under nickel catalysis to form alkyl radicals after decarboxylation6 and the finding that acylnickel(II) intermediates can capture radicals to form ketones in high yield. 4e,7…”

mentioning

confidence: 99%

Ketones from Nickel-Catalyzed Decarboxylative, Non-Symmetric Cross-Electrophile Coupling of Carboxylic Acid Esters

Wang¹,

Cary²,

Beyer³

et al. 2019

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ChemInform Abstract: Decarboxylative Cross‐Electrophile Coupling of N‐Hydroxyphthalimide Esters with Aryl Iodides.

Abstract: A new method for the decarboxylative coupling of alkyl N‐hydroxyphthalimide esters with aryl iodides is presented.

Cited by 3 publications

References 1 publication

Ketones from Nickel-Catalyzed Decarboxylative, Non-Symmetric Cross-Electrophile Coupling of Carboxylic Acid Esters

Ketones from Nickel-Catalyzed Decarboxylative, Non-Symmetric Cross-Electrophile Coupling of Carboxylic Acid Esters

Ketones from Nickel‐Catalyzed Decarboxylative, Non‐Symmetric Cross‐Electrophile Coupling of Carboxylic Acid Esters

Ketones from Nickel-Catalyzed Decarboxylative, Non-Symmetric Cross-Electrophile Coupling of Carboxylic Acid Esters

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