DFT Study of the Mechanism and Origin of Enantioselectivity in Chiral BINOL-Phosphoric Acid Catalyzed Transfer Hydrogenation of Ketimine and α‑Imino Ester Using Benzothiazoline

Benzothiazoline is an efficient reducing agent for the chiral BINOL-phosphoric acid catalyzed enantioselective transfer hydrogenation of ketimines and α-imino esters to afford the corresponding amines with high enantioselectivities. DFT studies (M05-2X/6-31G*//ONIOM­(B3LYP/6-31G*:HF/3-21G)) revealed the reaction mechanism and the origin of the high enantioselectivity in the present BINOL-phosphoric acid catalyzed transfer hydrogenation of ketimines and α-imino esters using benzothiazoline. The reaction mechanism is similar to that reported in the asymmetric transfer hydrogenation of ketimines using Hantzsch ester. Phosphoric acid simultaneously activates ketimine (α-imino ester) and benzothiazoline to form cyclic transition structures. The high enantioselectivity is attributed to the steric interaction between the substituents at the 3,3′-positions of BINOL-phosphoric acid and substrates. In contrast to the <i>C</i>₂-symmetrical Hantzsch ester, the readily tunable 2-aryl substituent of unsymmetrical benzothiazoline plays a significant role in the steric interaction, influencing the asymmetric induction. This feature is responsible for the advantage of benzothiazoline over Hantzsch ester

Theoretical Study on the Regioselectivity of Baeyer–Villiger Reaction of α‑Me‑, -F‑, -CF₃‑Cyclohexanones

The origin of the regioselectivity of the Baeyer–Villiger reaction of α-Me-, -F-, and -CF₃-cyclohexanones was investigated theoretically (MPWB1K/6-311++G**-PCM­(CH₂Cl₂)//MPWB1K/6-311G**-Onsager­(CH₂Cl₂)). Investigation of the energy profiles of the rearrangement step revealed the reality of the importance of conventional migratory aptitude based on the stabilization capability of partial positive charge generated during the migration step. We have divided the origin of the regioselectivity into two factors: (1) structural stability (steric repulsion, dipole interaction, etc.) and kinetic reactivity (energy barrier from the intermediate, i.e., cation stabilization capability). For α-CF₃-cyclohexanone, the migration tendency was mostly dependent on the kinetic reactivity; CF₃ substitution greatly increased the energy barrier. Noteworthy is the orientation of the CF₃ group at the transition state. The CF₃ group possessed the axial orientation overcoming the 1,3-diaxial repulsion, probably because of the strong dipole interaction between the CF₃ group and the leaving acid moiety. Striking results in the case of α-F- and -Me-cyclohexanone were that no difference in the energy barriers by the substituents could be observed. Especially in the case of α-Me substitution, structural stability operates in determining the most stable transition state, which is in contrast to the conventional understanding of the migratory aptitude based on the ability to stabilize partial positive charge

Chiral Phosphoric Acid-Catalyzed Oxidative Kinetic Resolution of Indolines Based on Transfer Hydrogenation to Imines

The oxidative kinetic resolution of 2-substituted indoline derivatives was achieved by hydrogen transfer to imines by means of a chiral phosphoric acid catalyst. The oxidative kinetic resolution was applicable to racemic alkyl- or aryl-substituted indolines, and the remaining indolines were obtained in good yields with excellent enantioselectivities

Chiral Magnesium Bisphosphate-Catalyzed Asymmetric Double C(sp³)–H Bond Functionalization Based on Sequential Hydride Shift/Cyclization Process

Described herein is a chiral magnesium bisphosphate-catalyzed asymmetric double C­(sp³)–H bond functionalization triggered by a sequential hydride shift/​cyclization process. This reaction consists of stereo­selective domino C­(sp³)–H bond functionalization: (1) a highly enantio- and diastereo­selective C­(sp³)–H bond functionalization by chiral magnesium bisphosphate (first [1,5]-hydride shift), and (2) a highly diastereo­selective C­(sp³)–H bond functionalization by an achiral catalyst (Yb­(OTf)₃, second [1,5]-hydride shift)

Chiral Magnesium Bisphosphate-Catalyzed Asymmetric Double C(sp³)–H Bond Functionalization Based on Sequential Hydride Shift/Cyclization Process

Described herein is a chiral magnesium bisphosphate-catalyzed asymmetric double C­(sp³)–H bond functionalization triggered by a sequential hydride shift/​cyclization process. This reaction consists of stereo­selective domino C­(sp³)–H bond functionalization: (1) a highly enantio- and diastereo­selective C­(sp³)–H bond functionalization by chiral magnesium bisphosphate (first [1,5]-hydride shift), and (2) a highly diastereo­selective C­(sp³)–H bond functionalization by an achiral catalyst (Yb­(OTf)₃, second [1,5]-hydride shift)

Construction of 1,3-Dithio-Substituted Tetralins by [1,5]-Alkylthio Group Transfer Mediated Skeletal Rearrangement

A novel skeletal rearrangement involving a [1,5]-alkylthio group transfer/cyclization sequence is described. Treatment of benzylidene malonates having a thioketal moiety at the homobenzyl position with a catalytic amount of Sc­(OTf)₃ afforded alkylthio group rearranged adducts in good chemical yields. Detailed investigation of the reaction mechanism revealed that an intramolecular conjugate addition/ring opening sequence (not through-space transfer) is the key to achieving this reaction

Construction of 1,3-Dithio-Substituted Tetralins by [1,5]-Alkylthio Group Transfer Mediated Skeletal Rearrangement

A novel skeletal rearrangement involving a [1,5]-alkylthio group transfer/cyclization sequence is described. Treatment of benzylidene malonates having a thioketal moiety at the homobenzyl position with a catalytic amount of Sc­(OTf)₃ afforded alkylthio group rearranged adducts in good chemical yields. Detailed investigation of the reaction mechanism revealed that an intramolecular conjugate addition/ring opening sequence (not through-space transfer) is the key to achieving this reaction

Chiral Magnesium Bisphosphate-Catalyzed Asymmetric Double C(sp³)–H Bond Functionalization Based on Sequential Hydride Shift/Cyclization Process

Described herein is a chiral magnesium bisphosphate-catalyzed asymmetric double C­(sp³)–H bond functionalization triggered by a sequential hydride shift/​cyclization process. This reaction consists of stereo­selective domino C­(sp³)–H bond functionalization: (1) a highly enantio- and diastereo­selective C­(sp³)–H bond functionalization by chiral magnesium bisphosphate (first [1,5]-hydride shift), and (2) a highly diastereo­selective C­(sp³)–H bond functionalization by an achiral catalyst (Yb­(OTf)₃, second [1,5]-hydride shift)

Chiral Magnesium Bisphosphate-Catalyzed Asymmetric Double C(sp³)–H Bond Functionalization Based on Sequential Hydride Shift/Cyclization Process

Described herein is a chiral magnesium bisphosphate-catalyzed asymmetric double C­(sp³)–H bond functionalization triggered by a sequential hydride shift/​cyclization process. This reaction consists of stereo­selective domino C­(sp³)–H bond functionalization: (1) a highly enantio- and diastereo­selective C­(sp³)–H bond functionalization by chiral magnesium bisphosphate (first [1,5]-hydride shift), and (2) a highly diastereo­selective C­(sp³)–H bond functionalization by an achiral catalyst (Yb­(OTf)₃, second [1,5]-hydride shift)

DFT Studies of Mechanism and Origin of Stereoselectivity of Palladium-Catalyzed Cyclotrimerization Reactions Affording <i>syn</i>-Tris(norborneno)benzenes

Pd-catalyzed cyclotrimerization reactions of enantiopure halonorbornene derivatives furnished <i>C</i>₃ or <i>C</i>_3<i>v</i> symmetric <i>syn</i>-tris­(norborneno)­benzenes with high <i>syn</i> selectivity. To elucidate the reaction mechanism as well as the stereoselectivity of the present Pd-catalyzed cyclotrimerization, DFT calculations were carried out. The promising reaction pathway consists of (1) sequential olefin insertion followed by an HX elimination reaction of halonorbornene with the norbornenylpalladium intermediate, (2) electrocyclization of the trienylpalladium intermediate with a lower activation barrier than a triene compound, and (3) the β-elimination of HPdX of the cyclohexadienylpalladium intermediate. In addition, the stereoselectivity would be controlled by the regioselectivity in the olefin insertion process (homo and hetero positions) and the symmetry breaking in the palladacyclic intermediate