New Strategies for the Functionalization of Carbonyl Derivatives via α-Umpolung: From Enolates to Enolonium Ions

Accounts of Chemical Research, Journal Year: 2023, Volume and Issue: 56(12), P. 1634 - 1644

Published: May 25, 2023

ConspectusUmpolung, a term describing the reversal of innate polarity, has become an indispensable tool to unlock new chemical space by overcoming limitations natural polarity. Introduced Dieter Seebach in 1979, this principle had tremendous impact on synthetic organic chemistry, offering previously inaccessible retrosynthetic disconnections. In contrast great progress made over past decades for generation effective acyl anion synthons, umpolung at α-position carbonyls (converting enolates into enolonium ions) long proved challenging and only recently regained traction. Aiming develop approaches α-functionalization capable complementing enolate our group initiated, nearly 6 years ago, program devoted α-umpolung carbonyl derivatives. Account, following overview established methods, we will summarize findings rapidly developing field. We focus two distinct, yet related, topics classes: (1) amides, where is enabled electrophilic activation, (2) ketones, using hypervalent iodine reagents. Our developed several protocols allow amide subsequent α-functionalization, relying activation. Over course investigations, transformations that are particularly enolate-based approaches, such as direct α-oxygenation, α-fluorination, α-amination amides well synthesis 1,4-dicarbonyls from substrates, have been unlocked. Based some most recent studies, method shown be so general almost any nucleophile can added amide. special emphasis placed discussion mechanistic aspects. It important note area involved shift focus, moving even further away carbonyl, development shall also detailed final subsection highlights latest investigations umpolung-based remote functionalization β- γ-positions amides. The second section Account covers more work dedicated exploration chemistry unlocked through use By placing context previous pioneering achievements, which mainly focused carbonyls, discuss skeletal reorganizations ions unique properties incipient positive charges α electron-deficient moieties. Transformations intramolecular cyclopropanations aryl migrations covered supplemented insight unusual nature intermediate species, including nonclassical carbocations.

Language: Английский

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Direct enantioselective α-amination of amides guided by DFT prediction of E/Z selectivity in a sulfonium intermediate

Chem, Journal Year: 2023, Volume and Issue: 9(6), P. 1538 - 1548

Published: March 30, 2023

Chiral amines are a highly important class of compounds for which powerful synthetic approaches remain in high demand. Herein, we report an unprecedented method the preparation chiral α-amino amides from cheap and abundant starting materials. Our strategy relies on direct amination using enantiopure sulfinamides. It involves [2,3]-sigmatropic rearrangement key sulfonium intermediate. We further show how quantum chemical calculations allow predictive insights into critical E/Z selectivity this amino-vinyloxy-sulfonium species.

Language: Английский

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Diversification of Acrylamide Polymers via Direct Transamidation of Unactivated Tertiary Amides

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(2), P. 1627 - 1634

Published: Jan. 8, 2024

Postpolymerization modification offers a versatile strategy for synthesizing complex macromolecules, yet modifying acrylamide polymers like poly(N,N-dimethylacrylamide) (PDMA) is notoriously challenging due to the inherent stability and low reactivity of amide bonds. In this study, we unveil novel approach direct transamidation PDMA, leveraging recent advances in unactivated tertiary substrates. By exploiting photoiniferter polymerization, extended ultrahigh-molecular-weight (UHMW) showcasing unprecedented postpolymerization synthetic exceeding 106 g/mol. We also designed copolymers comprising both moderately reactive N-methyl-N-phenyl amides, along with less reactive, fully alkyl-substituted N,N-dimethyl amides PDMA. This disparate enabled sequential, chemoselective by initially targeting more pendant aryl nucleophilic aromatic amines, second, transamidating untouched moieties aliphatic yielding uniquely diversified copolymer. work not only broadens scope strategies pioneering but provides robust platform design intricate particularly realm UHMW polymers.

Language: Английский

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Making Full Use of TMSCF₃: Deoxygenative Trifluoromethylation/Silylation of Amides

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(28), P. 19286 - 19294

Published: July 3, 2024

As one of the most powerful trifluoromethylation reagents, (trifluoromethyl)trimethylsilane (TMSCF3) has been widely used for synthesis fluorine-containing molecules. However, to best our knowledge, simultaneous incorporation both TMS- and CF3- groups this reagent onto same carbon products not realized. Herein, we report an unprecedented SmI2/Sm promoted deoxygenative difunctionalization amides with TMSCF3, in which silyl trifluoromethyl are incorporated into final product, yielding α-silyl-α-trifluoromethyl amines high efficiency. Notably, group could be further transformed other functional groups, providing a new method α-quaternary α-CF3-amines.

Language: Английский

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Merging SOMO activation with transition metal catalysis: Deoxygenative functionalization of amides to β-aryl amines

Science Advances, Journal Year: 2025, Volume and Issue: 11(3)

Published: Jan. 17, 2025

Singly occupied molecular orbital (SOMO) activation of in situ generated enamines has achieved great success (asymmetric) α-functionalization carbonyl compounds. However, examples on the use this mode transformations other functional groups are rare, and combination SOMO with transition metal catalysis is still less explored. In area deoxygenative functionalization amides, intermediates such as iminium ions were often to result formation α-functionalized amines. contrast, direct deoxygenation amides β-functionalized amines highly appealing yet remains scarcely investigated. Here, a arylation aryl halides was developed via multicatalysis iridium/photoredox/nickel/iridium, affording β-aryl high efficiency. The key reaction enamine synergy Ni-catalyzed arylation, which conjunction two compatible Ir-catalyzed reduction processes.

Language: Английский

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Free Amino Group Transfer via α‐Amination of Native Carbonyls

Angewandte Chemie International Edition, Journal Year: 2023, Volume and Issue: 62(28)

Published: April 28, 2023

Abstract We report herein a straightforward transfer of free amino group (NH 2 ) from commercially available nitrogen source to unfunctionalized, native carbonyls (amides and ketones) resulting in direct α‐amination. Primary α‐amino are readily produced under mild conditions, further enabling diverse situ functionalization reactions—including peptide coupling Pictet–Spengler cyclization—that capitalize on the presence unprotected primary amine.

Language: Английский

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Recent Applications of Trifluoromethanesulfonic Anhydride in Organic Synthesis

Angewandte Chemie International Edition, Journal Year: 2022, Volume and Issue: 62(10)

Published: Dec. 21, 2022

Abstract Trifluoromethanesulfonic anhydride has been widely used in synthetic organic chemistry, not only for the conversion of various oxygen‐containing compounds to triflates, but also electrophilic activation and further amides, sulfoxides, phosphorus oxides. In recent years, utilization Tf 2 O as an activator nitrogen‐containing heterocycles, nitriles nitro groups become a promising tool development new valuable methods with considerable success. addition, efficient radical trifluoromethylation trifluoromethylthiolation reagent due contained SO CF 3 fragment, significant progress made this area. This review summarizes applications above two aspects, aims illustrate role potential application synthesis.

Language: Английский

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Ti-Catalyzed Modular Ketone Synthesis from Carboxylic Derivatives and gem-Dihaloalkanes

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(27), P. 14884 - 14893

Published: June 26, 2023

Ketones are ubiquitous in organic synthesis. However, the general method to convert widely available carboxylic acids, unactivated esters, and amides into ketones remains elusive. Herein, we describe Ti-catalyzed modular ketone synthesis from derivatives easily accessed gem-dihaloalkanes. Notably, this protocol could achieve direct catalytic olefination of acids. This features a sequence electrophilic transformation good functional group compatibility allows rapid access various functionalized ketones. Preliminary mechanistic studies provide insights reaction pathway support intermediacy plausible alkylidene titanocene gem-bimetallic complexes.

Language: Английский

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1,2-Redox Transpositions of Tertiary Amides

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(40), P. 21745 - 21751

Published: Sept. 27, 2023

Reactions capable of transposing the oxidation levels adjacent carbon atoms enable rapid and fundamental alteration a molecule's reactivity. Herein, we report 1,2-transposition atom level in cyclic acyclic tertiary amides, resulting one-pot synthesis 1,2- 1,3-oxygenated amines. This transfer was facilitated by careful orchestration an iridium-catalyzed reduction with functionalization transiently formed enamine intermediates. A novel 1,2-carbonyl transposition is described, breadth this redox strategy has been further explored development aminoalcohol enaminone syntheses. The diverse β-functionalized amine products were shown to be multifaceted valuable synthetic intermediates, accessing challenging biologically relevant motifs.

Language: Английский

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Deoxygenative Nucleophilic Phosphonation and Electrophilic Alkylation of Secondary Amides: A Facile Access to Quaternary α-Aminophosphonates

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(7), P. 4357 - 4362

Published: Feb. 9, 2024

The widespread occurrence and synthetic accessibility of amides render them valuable precursors for the synthesis diverse nitrogen-containing compounds. Herein, we present a metal-free streamlined strategy quaternary α-aminophosphonates. This approach involves sequential deoxygenative nucleophilic phosphonation versatile electrophilic alkylation secondary in one-pot fashion. Notably, this method enables direct bis-functionalization with both nucleophiles electrophiles first time, simple derivatization leading to free α-aminophosphonates by hydrolysis. protocol has advantages operational simplicity, broad functional-group compatibility, environmental friendliness, scalability multigram quantities.

Language: Английский

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