Carbene‐Catalyzed Enantioselective Decarboxylative Annulations to Access Dihydrobenzoxazinones and Quinolones

Abstract

A direct 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. Aza‐o‐QMs react with trifluoromethyl ketones through a formal [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. Complementary 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, a computed potential energy surface around the major transition structure suggests a concerted asynchronous mechanism for the formal annulation.

HFIP‐Mediated Decarboxylative [4+3]‐Annulation of Azaoxyallyl Cations with Isatoic Anhydride

“…However, replacing Na 2 CO 3 with other inorganic (K 2 CO 3 , Cs 2 CO 3 , K 3 PO 4 ) or organic (Et 3 N, DBU, DABCO, DMAP) bases did not improve the yield, although the reaction rate of the first step was higher in all the cases. Then, 4 Å molecular sieves were added to prevent the hydrolysis of the amide or ester, and the yield increased slightly ( [17][18][19][20]. A further enhancement in the yield of 4 aa was observed upon increasing the reaction temperature, and the highest yield (79%) was achieved when second step was carried out under reflux ( Table 1, entry 21).…”

“…Through persistent research, we introduced de novo decarboxylative [4 + 3]annulation for the synthesis of seven-membered heterocycles, which has not been achieved to date (Scheme 2b). [17,18] Herein, we describe our work on the hexafluoro-2-propanol (HFIP)-mediated annulation reaction of aza-oxyallyl cations with isatoic anhydrides that affords seven-membered benzodiazepinediones.…”

Synthesis of Both Enantiomers of Nine‐Membered CF3‐Substituted Heterocycles Using a Single Chiral Ligand: Palladium‐Catalyzed Decarboxylative Ring Expansion with Kinetic Resolution

“…[8] Moreover,t he generation of stereogenic carbon centers directly attached to af luoro-functional group is fundamentally challenging. [9] Thus,t he development of efficient synthetic strategies for chiral, fluoro-functionalized and mediumsized nitrogen heterocycles remains asynthetic challenge that is arguably as ambitious as it is rewarding. [10] To address this topic, we have recently developed the multifarious synthon trifluoromethyl-benzo[d] [1,3]oxazinone (1)f or the synthesis of fluorinated heterocycles,a nd demonstrated Pd-catalyzed decarboxylative ring reconstruction reactions such as [4+ +1], [4+ +5],a nd related annulations ( Figure 1A).…”

Carbene‐Catalyzed Enantioselective Aromatic N‐Nucleophilic Addition of Heteroarenes to Ketones

“…Very recently, Scheidt and co-workers disclosed that N-methylisatoic anhydrides could serve as N-centered nucleophile precursors under the catalysis of NHCs and gave aza-o-QM intermediates to react with electrophilic ketone substrates (Scheme 1b, right). [28] Scheme 1. NHC-promoted carbon and heteroatom activations.…”