Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

Abstract

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...

Synthesis of Ring-Fused, N-Substituted 4-Quinolinones Using pKa-Guided, Base-Promoted Annulations with Isatoic Anhydrides: Total Synthesis of Penicinotam

“…1 H NMR (400 MHz, DMSO- d 6 ): δ 7.90 (d, J = 8.3 Hz, 1H), 7.71 (d, J = 1.7 Hz, 1H), 7.52 (dd, J = 8.3, 1.5 Hz, 1H), 3.46 (s, 3H). Characterization matched the previous report …”

An Update of Transition Metal-Catalyzed Decarboxylative Transformations of Cyclic Carbonates and Carbamates

“…For example, Scheidt and co-workers disclosed an NHC-mediated [4 + 2] cycloaddition of isatoic anhydride and trifluoromethyl ketones. Various enantioenriched dihydrobenzoxazin-4-ones functionalized with a CF 3 group can be produced with this protocol (Scheme 13a) [63]. In this transformation, the generation of an NHC-bonded intermediate is vital for the success of the reactions.…”

Carbene‐Catalyzed Activation of Remote Nitrogen Atoms of (Benz)imidazole‐Derived Aldimines for Enantioselective Synthesis of Heterocycles

“… [7] In 2019, Scheidt and co‐workers disclosed that carbene could activate N ‐methylisatoic anhydrides for enantioselective N ‐nucleophilic addition reaction via aza ‐ o ‐quinone methides ( aza ‐ o ‐QMs) (Figure 1 a). [8a] In the same year we found that addition of a carbene catalyst to indole aldehydes at a remote site could enable an asymmetric NH functionalization [8b] . Very recently, independent studies reported by Biju, [9a] Hui [9b] and us [9c] showed that under the catalysis of NHCs the N ‐centered nucleophiles could be functionalized via the formation of aza ‐fulvene intermediates (Figure 1 a).…”