Functionalization of Benzylic C(sp<sup>3</sup>)H Bonds of Heteroaryl Aldehydes through N‐Heterocyclic Carbene Organocatalysis

Chen, Xingkuan; Yang, Song; Song, Baoan; Robin, Yonggui

doi:10.1002/anie.201305861

Cited by 179 publications

(59 citation statements)

References 90 publications

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“…[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. [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). [7] N-heterocyclic carbene (NHC) catalysis has emerged as ap owerful strategy for the construction of carbo-and heterocyclic compounds over the past decade.…”

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confidence: 99%

“…[7] N-heterocyclic carbene (NHC) catalysis has emerged as ap owerful strategy for the construction of carbo-and heterocyclic compounds over the past decade. [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). [9] Following Yesp reliminary disclosure,s everal reports of reactions employing "azolium dienolates" generated from various carbonyl precursors have emerged.…”

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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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Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

et al. 2019

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“…12 In 2013, Chi 13 and coworkers reported a NHC-catalyzed oxidative formal [4+2] cycloaddition of heteroaryl aldehydes and activated ketones. The benzaldehyde analogue was nonproductive in Chi’s reaction.…”

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N-Heterocyclic Carbene and Chiral Brønsted Acid Cooperative Catalysis for a Highly Enantioselective [4+2] Annulation

Chen

Rovis

2016

Synthesis

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“…For example, the Chi group has demonstrated the ability to access NHC enolates through the acylation of carbenes with highly activated aryl esters. 11 Recently, our group has employed a strategy which invokes the in situ formation of acyl azolium enolates 12,13 for the synthesis of dihydroquinolones. 14,15 In this study, carboxylic acids as simple and accessible starting materials provided an intermediate acyl imidazole for subsequent addition of an NHC.…”

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“…We have been exploring new strategies to enhance NHC reactivity and selectivity through the integration of Lewis base catalysis with other activation modes, including Lewis acids, 11b,19,20 Brønsted acids 21,22 and additional Lewis bases. 23 In this endeavour, we have developed additional activation modes such as Lewis base-promoted in situ electrophile generation.…”

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N-Heterocyclic carbene-catalyzed enantioselective annulations: a dual activation strategy for a formal [4+2] addition for dihydrocoumarins

2015

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A highly efficient asymmetric formal [4+2] annulation for the synthesis of dihydrocoumarins has been developed via an in situ activated NHC catalysis. Both electrophilic and nucleophilic species are generated in situ simultaneously whereby acyl imidazoles facilitated rapid formation of an NHC-enolate intermediate to afford the [4+2] dihydrocoumarin adducts.Coumarins and their substituted derivatives are found in numerous natural products and pharmaceuticals. 1 In particular, 3,4-dihydrocoumarins are prevalent in nature and have shown interesting biological activities such as aldose reductase and protein kinase inhibition, as well as anti-herpetic, anti-inflammatory, anti-oxidative, anti-aging and anti-cancer properties. 2 Given the significance of these compounds as important structural scaffolds in natural products and drug candidates, the synthesis of chiral dihydrocoumarin derivatives through catalytic and stereoselective processes is a high value endeavor. Most currently deployed conventional approaches for the synthesis of dihydrocoumarins require the use of transition metal catalysis. 3 However, there are opportunities to go beyond these processes and generate new, potentially more sustainable and selective approaches with complementary substrate scope and/or activation strategies. Within the area of organocatalysis, the Zeitler group reported an N-heterocyclic carbene (NHC)-catalyzed redox lactonization for the synthesis of unsubstituted, achiral dihydrocoumarins using ohydroxycinnamaldehydes. 4 Our group has also reported an NHC-catalyzed domino elimination/conjugate addition/acylation process for the synthesis of substituted coumarins. 5 Recently, the Hong group synthesized dihydrocoumarin derivatives including quaternary carbon center via asymmetric domino Michael/acetalization reactions and oxidation reaction using 2-hydroxynitrostyrene and 2-oxocyclohexanecarbaldehyde. 6 More recently, the Jørgensen group reported an asymmetric synthesis of 3,4-dihydrocoumarins by merging aminocatalysis with an NHC-catalyzed internal redox process. 7 Lastly, the deracemization process of α-aryl hydrocoumarins using chiral phosphoric acids dwas reported by the List group. 8 N-heterocyclic carbenes represent a potent class of catalysts for the formation of key C-C and C-X bonds via nontraditional Umpolung reactivity. 10 The development of novel approaches using NHC catalysis by employing activation strategies has drawn signficiant attention over the last few years. For example, the Chi group has demonstrated the ability to access NHC enolates through the acylation of carbenes with highly activated aryl esters. 11 Recently, our group has employed a strategy which invokes the in situ formation of acyl azolium enolates 12,13 for the synthesis of dihydroquinolones. 14,15 In this study, carboxylic acids as simple and accessible starting materials provided an intermediate acyl imidazole for subsequent addition of an NHC. 16 By using an acyl imidazole generated in situ, the undesired enal dimerization pathway t...

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Functionalization of Benzylic C(sp³)H Bonds of Heteroaryl Aldehydes through N‐Heterocyclic Carbene Organocatalysis

Cited by 179 publications

References 90 publications

Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

N-Heterocyclic Carbene and Chiral Brønsted Acid Cooperative Catalysis for a Highly Enantioselective [4+2] Annulation

N-Heterocyclic carbene-catalyzed enantioselective annulations: a dual activation strategy for a formal [4+2] addition for dihydrocoumarins

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Functionalization of Benzylic C(sp3)H Bonds of Heteroaryl Aldehydes through N‐Heterocyclic Carbene Organocatalysis

Cited by 179 publications

References 90 publications

Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

N-Heterocyclic Carbene and Chiral Brønsted Acid Cooperative Catalysis for a Highly Enantioselective [4+2] Annulation

N-Heterocyclic carbene-catalyzed enantioselective annulations: a dual activation strategy for a formal [4+2] addition for dihydrocoumarins

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Functionalization of Benzylic C(sp³)H Bonds of Heteroaryl Aldehydes through N‐Heterocyclic Carbene Organocatalysis