Coupling Catalytic Alkene Hydroacylation and α-Arylation: Enantioselective Synthesis of Heterocyclic Ketones with α-Chiral Quaternary Stereocenters

Abstract

We report a strategy that combines alkene hydroacylation and enantioselective α-(hetero)­arylation reactions to form a wide variety of nitrogen-containing heterocyclic ketones bearing α-chiral quaternary stereogenic centers. Exo-selective, intramolecular Ni-catalyzed hydroacylations of N-homoallylindole- and N-homoallylpyrrole-2-carboxaldehydes form α-substituted six-membered heterocyclic ketones in up to 95% yield, while N-heterocyclic carbene (NHC) catalyzed hydroacylations of N-allylindole- and N-allylpyrrole-2-carboxaldehydes form α-substituted five-membered heterocyclic ketones in up to 99% yield. The racemic five- and six-membered products of Ni- and NHC-catalyzed hydroacylation reactions are readily transformed into heterocyclic ketones containing an α-chiral quaternary stereogenic center by enantioselective Ni-catalyzed α-arylation and α-heteroarylation reactions. The chiral, nonracemic products formed through a combination of alkene hydroacylation and α-(hetero)­arylation reactions are formed in moderate to high yields (44–99%) with excellent enantioselectivities (typically >95% ee). The identity of the precatalyst for Ni-catalyzed α-(hetero)­arylation is dictated by the identity of the α-substituted heterocyclic ketone starting material. α-(Hetero)­arylations of six-membered heterocyclic ketones occur at 65–85 °C in the presence of a catalyst generated in situ from Ni­(COD)2 and (R)-BINAP or (R)-DIFLUORPHOS. α-(Hetero)­arylation of five-membered heterocyclic ketones must be conducted at room temperature in the presence of an [((R)-BINAP)­Ni­(η2-NC-Ph)] precatalyst or a catalyst generated in situ from Ni­(COD)2, (R)-DIFLUORPHOS, and benzonitrile.

DTBP/TBHP‐Promoted Hydroacylation of Unactivated Alkenes

“…The hydroacylation can be accomplished via metal‐catalyzed C−H bond activation . Transition metals such as Rh,– Ru, Co, and Ni have been widely employed as catalysts in this field. However, most of these metals are expensive and toxic.…”

Chiral Oxazolidine‐Fused N‐Heterocyclic Carbene Complexes of Rhodium and Iridium and Their Utility in the Asymmetric Transfer Hydrogenation of Ketones

“…In this regard, the fusion of two immensely successful ligands in homogeneous catalysis, that is, oxazolidines and imidazole‐based N‐heterocyclic carbenes, has resulted in an interesting new breed of fused bicyclic N‐heterocyclic ligands derived from a hybrid oxazolidine–imidazole motif . In asymmetric catalysis, owing to their unique restricted rotation along the N–C bond housing the chiral substituent, this type of ligand exhibits promising enantioselectivities over conventional chiral ligands in many reactions such as the Michael addition, benzoin condensation, α‐arylation, Stetter reaction, Coates–Claisen rearrangement, and the hydration of α‐halo aldehydes . For example, under ligand‐assisted catalysis (LAC) conditions for the asymmetric Michael addition of 1,3‐diphenylpropane‐1,3‐dione and ( E )‐(2‐nitrovinyl)benzene, a fused bicyclic N‐heterocyclic carbene ligand with restricted rotation around the N–C bond, namely, (5a S ,10b R )‐2‐mesityl‐4,5a,6,10b‐tetrahydroindeno[2,1‐ b ][1,2,4]triazolo[4,3‐ d ][1,4]oxazin‐2‐ium tetrafluoroborate, exhibited a higher enantiomeric excess ( ee ) of 76 %, whereas another chiral N‐heterocyclic carbene ligand with free rotation around the N–C bond, namely, 1,3‐bis[( S )‐1‐phenylethyl]‐1 H ‐imidazol‐3‐ium tetrafluoroborate, showed no chiral induction under analogous conditions …”

Indole‐2‐Carboxaldehyde: An Emerging Precursor for the Construction of Diversified Imperative Skeleton

“…In 2016, A. Ghosh and co-workers reported a strategy that combined hydroacylation of alkenes and enantioselective-α-(hetero)arylation reactions to form various nitrogen-containing heterocyclic ketones with α-chiral quaternary stereogenic centers (Scheme 15). [67] It was observed that Ni-catalyzed exo selective, intramolecular hydroacylation reactions of N-homoallylindole-2-carboxaldehydes afforded α-substituted six-mem-bered heterocyclic ketones, whereas NHC-catalyzed hydroacylations of N-allylindole-2-carboxaldehydes afforded α-substituted five-membered heterocyclic ketones. The N-homoally-lindole-2-carboxaldehyde 8a underwent intramolecular hydroacylation, catalyzed by a Ni complex containing the Nadamantyl carbene ligand (L10) at 165°C to afford the Scheme 12.…”

“…Strategy for combining alkene hydroacylation and α-(hetero)arylation reactions. [67] unsaturated ester 109. The ester 109 underwent [4 + 2] cycloaddition reaction either in syn or anti mode to afford a mixture of two diastereomers 110a and 110b in 9 : 1 ratio in 63 % yield.…”