Influence of the N-Substituents on the Nucleophilicity and Lewis Basicity of N-Heterocyclic Carbenes

Levens, Alison; An, Feng; Breugst, Martin; Mayr, Herbert; Lupton, David W.

doi:10.1021/acs.orglett.6b01525

Cited by 74 publications

(75 citation statements)

References 62 publications

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“…These favorable preliminary results, with up to 10‐fold reduction in reaction time compared to known methods, encouraged us to fully optimize this NHC‐promoted disulfide metathesis reaction (Table ). Among the six NHC catalysts tested, imidazolylidenes 3A – 3C gave similar results with shorter reaction times than imidazolinylidene, triazolylidene and thiazolylidene catalysts ( 3D – 3E ), which is in good agreement with the nucleophilicity of these catalysts . Acetonitrile proved to be the best solvent (entries 2, 7, 8, Table ), hinting at a polar transition state for the rate‐limiting step of these reactions.…”

Section: Methodssupporting

confidence: 62%

“…Among the six NHC catalysts tested, imidazolylidenes 3A-3C gave similar results with shorter reactiont imes than imidazolinylidene,t riazolylidene and thiazolylidenec atalysts (3D-3E), which is in good agreement with the nucleophilicity of these catalysts. [19] Acetonitrilep rovedt ob et he best solvent (entries 2, 7, 8, Ta ble 1), hinting at ap olar transition state for the rate-limiting step of these reactions. The catalyst loading could be reduced to 5mol %w ithout affecting the equilibrium outcomes (entries 2 and 9-11, Table 1).…”

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confidence: 99%

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NHC‐Catalyzed Metathesis and Phosphorylation Reactions of Disulfides: Development and Mechanistic Insights

Crocker

Hussein

et al. 2017

Chemistry A European J

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The development of efficient methods for the metathesis and phosphorylation reactions of disulfide compounds is of widespread interest due to their important synthetic utility in polymer, biological, medicinal and agricultural chemistry. Herein, we demonstrate the use of N-heterocyclic carbenes (NHCs) as versatile organocatalysts to promote these challenging reactions under mild conditions. This metal- and oxidant-free protocol is operationally simple with very short reaction times. The interplay between the nucleophilicity and basicity of NHCs in these reactions were also elucidated by NMR studies and high-level ab initio calculations.

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Section: Methodssupporting

confidence: 62%

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confidence: 99%

NHC‐Catalyzed Metathesis and Phosphorylation Reactions of Disulfides: Development and Mechanistic Insights

Crocker

Hussein

et al. 2017

Chemistry A European J

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“…[15] We thus investigated the reaction using catalyst E [16] and obtained 3a in 72 %yield and 97:3 er at 50 8 8C. An achiral triazolium catalyst with the strong, and non-nucleophilic base KHMDS provided the desired dihydrobenzoxazinone 3a in moderate isolated yield at 30 8 8C(see the Supporting Information).…”

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confidence: 99%

Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

et al. 2019

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Ad irect decarboxylative strategy for the generation of aza-o-quinone methides (aza-o-QMs) by N-heterocyclic carbene (NHC) catalysis has been discovered and explored. This process requires no stoichiometric additives in contrast with current approaches.A za-o-QMs react with trifluoromethyl ketones through af ormal [4+ +2] manifold to access highly enantioenriched dihydrobenzoxazin-4-one products, which can be converted to dihydroquinolones through an interesting stereoretentive aza-Petasis-Ferrier rearrangement sequence.C omplementary dispersion-corrected density functional theory (DFT) studies provided an accurate prediction of the reaction enantioselectivity and lend further insight to the origins of stereocontrol. Additionally,acomputed potential energy surface around the major transition structure suggests ac oncerted asynchronous mechanism for the formal annulation.Dihydrobenzoxazinones are an important class of N-heterocyclic compounds widely found in pharmaceutical molecules and natural products. [1] Thedihydrobenzoxazinone structural motif is also commonly used as an intermediate for the construction of many other heterocyclicc ompounds. [2] Consequently,n ew synthetic methods for the preparation of enantioenriched dihydrobenzoxazinones could fuel further studies on this versatile compound class.T odate,the majority of asymmetric methods for dihydrobenzoxazinone synthesis has focused on the dihydrobenzoxazin-2-one substructure, using av ariety of methods including formal [4+ +2] cycloaddition of o-benzoquinone imides with ketenes, [3] Rhcatalyzed conjugate addition, [4] Ir-catalyzed hydrogenation, [5] and Brønsted acid-catalyzed transfer hydrogenation. [6] The isomeric dihydrobenzoxazin-4-one substructure is also prevalent in both natural products and drug candidates.Although several straightforward racemic syntheses of dihydrobenzoxazin-4-ones have been reported, enantioselective methods for their construction remain underdeveloped to date. [7] N-heterocyclic carbene (NHC) catalysis has emerged as ap owerful strategy for the construction of carbo-and heterocyclic compounds over the past decade. [8] NHC-catalyzed Umpolung reactions employing enals have provided access to numerous divergent nucleophilic species,i ncluding acyl anion, enolate,and homoenolate equivalents.In2011, Ye demonstrated that NHC catalysis could also access dienolate equivalents. [9] Following Yesp reliminary disclosure,s everal reports of reactions employing "azolium dienolates" generated from various carbonyl precursors have emerged. [10] Particularly,t he NHC-catalyzed g-functionalization of aromatic substrates [11] has received attention due to the innovative deployment of unconventional o-quinodimethanes (o-QDMs) as substrates (Scheme 1a). [12] In 2013, Chi and co-workers initially reported NHCbound o-QDM intermediates could be generated from omethyl heteroaryl aldehydes [11a] and o-methyl heteroaryl esters. [11b] Following these studies,s everal approaches to extend this reactivity to carbocyclic aromatic systems have emerged...

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“…8), substrates suited to the generation of unsaturated Lewis base adducts. [12,13] Of these catalyst C5 [14] was preferred giving b-lactone 7c in a > 99:1 enantiomeric ratio,a lbeit with poor diastereoselec- [10][11][12][13][14]. When attempted with triazolylidene A in THF, b-lactone 7a formed with modest yield, while the more nucleophilic IMes NHC B1 gave the same product as as ingle diasteroisomer (> 20:1 dr) and in 74 %yield ( [7][8][9].…”

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confidence: 99%

Enantioselective N‐Heterocyclic Carbene Catalysis via the Dienyl Acyl Azolium

2018

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Herein we report the enantioselective N-heterocyclic carbene catalyzed (4+2) annulation of the dienyl acyl azolium with enolates. The reaction exploits readily accessible acyl fluorides and TMS enol ethers to give a range of highly enantio- and diastereo-enriched cyclohexenes (most >97:3 er and >20:1 dr). The reaction was found to require high nucleophilicity NHC catalysts with mechanistic studies supporting a stepwise 1,6-addition/β-lactonization.

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Influence of the N-Substituents on the Nucleophilicity and Lewis Basicity of N-Heterocyclic Carbenes

Cited by 74 publications

References 62 publications

NHC‐Catalyzed Metathesis and Phosphorylation Reactions of Disulfides: Development and Mechanistic Insights

NHC‐Catalyzed Metathesis and Phosphorylation Reactions of Disulfides: Development and Mechanistic Insights

Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

Enantioselective N‐Heterocyclic Carbene Catalysis via the Dienyl Acyl Azolium

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