Asymmetric Formal Nucleophilic o-Cresolylation with Morita–Baylis–Hillman Carbonates of 2-Cyclohexenones via Palladium Catalysis

Abstract

Here we report an asymmetric formal nucleophilic o-cresolylation reaction with the Morita–Baylis–Hillman (MBH) carbonates from 2-cyclohexanones and diverse aldehydes under palladium catalysis, by in situ generation of electron-neutral and HOMO-raised η2-Pd­(0)-dienone complexes via an oxidative insertion/π–σ-isomerization/β-H elimination activation sequence. The subsequent umpolung vinylogous addition to a variety of imines is realized upon Pd(0)-mediated π-Lewis base catalysis, finally furnishing o-cresolylated products followed by another cascade of a π–σ-isomerization/β-H elimination/aromatization process. Moderate to excellent diastereo- and enantioselectivity are achieved for substantial substrate assemblies by employing a newly designed bulky chiral phosphonamidite ligand, and the resultant multifunctional products can be facilely elaborated to access diverse enantioenriched architectures. In addition, the catalytic reaction pathway is finely illuminated by control experiments.

Asymmetric Inverse-Electron-Demand Oxa-Diels–Alder Reaction with Morita–Baylis–Hillman Carbonates of 2-Cyclopentenone via a Palladium-Catalyzed Umpolung Strategy

“…While similar regioselective umpolung addition reaction of the MBH carbonates from 2-cycloheptenone was observed, 4 it was intriguing that the MBH carbonates 1 from 2-cyclopentenone 6 exhibited a completely different regioselective reaction pattern under palladium catalysis. It was worth noting that the η 2 -Pd(0)-dienone complexes II at the exo-double bond were favorably generated, rendering the endo-double bond as a HOMO-raised dienophile in combination with a suitable electron-deficient heterodiene partner (Scheme 1c).…”

“…3 In contrast, recently we uncovered a new transformation pathway with the MBH carbonates derived from 2-cyclohexenone under cascade palladium catalysis, by in situ generating the key η 2 -Pd(0)dienone complexes I in the absence of nucleophiles. 4 The π-Lewis base activation 5 of Pd(0) umpolunged the reactivity of exo-β-carbon of the enone motif based on the principle of vinylogy, which could attack the imines enantioselectively to yield the formal o-cresolylation products after further cascade transformations (Scheme 1b).…”

“…The results indicated that dienone 4 should be the key intermediate for the current reaction, and the IED oxa-Diels−Alder reaction would be promoted by regioselectively forming the HOMO-raised η 2 -Pd(0)-dienone complex II, as proposed in Scheme 1c. 4 Moreover, preliminary density functional theory (DFT) calculations supported that the HOMO energy of compound 4 (−6.16 eV) was lower than that of corresponding η 2 -Pd(0)dienone complex II (−4.93 eV). 8 The multifunctionality of the oxa-Diels−Alder adducts enables versatile transformations.…”

“…While great progress has been made via Lewis base or other types of organocatalysis, the allylic feature of MBH adducts enables them as ideal precursors to generate electrophilic π-allylmetal complexes, especially under palladium or iridium catalysis, which can be assembled with diverse nucleophiles to deliver multifunctional allylic derivatives (Scheme a) . In contrast, recently we uncovered a new transformation pathway with the MBH carbonates derived from 2-cyclohexenone under cascade palladium catalysis, by in situ generating the key η 2 -Pd­(0)-dienone complexes I in the absence of nucleophiles . The π-Lewis base activation of Pd(0) umpolunged the reactivity of exo -β-carbon of the enone motif based on the principle of vinylogy, which could attack the imines enantioselectively to yield the formal o -cresolylation products after further cascade transformations (Scheme b).…”

Asymmetric Construction of Multifunctional γ-Lactams from 1,3-Dienes and α-Ketoamides via Pd(0)-π-Lewis Base Catalysis

“…Commonly used ( S )-BINAP L1 , as well as its analog ( S )-Segphos L2 , could promote the reaction but exhibited low efficiency in both reactivity and stereoselectivity (entries 2 and 3). SPINOL-derived phosphoramidite ligand L3 improved the yield and enantioselectivity significantly, albeit with poor diastereoselectivity (entry 4) . Further screenings of more ligands indicated that Tang’s chiral P-based ligand L4 and Trost’s phosphine-amide ligand L5 were ineffective (entries 5 and 6, respectively), while 1,2-aminoalcohol-drived bifunctional ligand L6 provided cis - 3a as the single diastereomer in a fair yield but with remarkable enantioselectivity (entry 7) .…”