E. Peter Kündig

Oxindole Synthesis by Direct Coupling of C sp 2H and C sp 3H Centers

An sp(2)/sp(3) get-together: A novel and efficient method can be used to synthesize 3,3-disubstitued oxindoles by the direct intramolecular oxidative coupling of an aryl C(sp(2))-H and a C(sp(3))-H center (see scheme; DMF = N,N-dimethylformamide).

Fused Indolines by Palladium‐Catalyzed Asymmetric CC Coupling Involving an Unactivated Methylene Group

Selectivity at high temperatures: Bulky, thermally stable, chiral palladium complexes generated from N-heterocyclic carbenes (NHCs; see picture) were successfully applied to the synthesis of highly enantioenriched trans-fused indolines. Remarkably, this reaction occurs at elevated temperatures with excellent asymmetric recognition of an enantiotopic C-H bond in an unactivated methylene unit.

Asymmetric C(sp3)-H/C(Ar) coupling reactions. Highly enantio-enriched indolines via regiodivergent reaction of a racemic mixture

N-Aryl, N-branched alkyl carbamates react with in situ generated chiral Pd-NHC catalysts by coupling a Pd-Ar moiety with an aliphatic C–H bond at high temperature to give enantioenriched 2-substituted and 2,3-disubstituted indolines. Prochiral precursors give single products with very high asymmetric induction. Chiral racemic precursors react in a regiodivergent reaction of a racemic mixture to yield enantioenriched indolines resulting from either methyl C–H activation or asymmetric methylene C–H activation. In favorable cases this can result in a complete separation of an enatiomeric mixture into two different highly enantioenriched indolines.

Highly diastereoselective coupling reactions between chiral benzaldehyde tricarbonylchromium complexes and activated double bonds

The amine catalyzed coupling reaction of acrylic derivatives with benzaldehydes (Baylis-Hillman reaction) is more efficient when the arene is complexed to the electrophilic Cr(CO)3 group. Reactions with planar chiral o-substituted benzaldehyde complexes are highly diastereoselective. 3-Hydroxy-2-methylenealkanoic acid derivatives can be obtained efficiently and with very high enantiomeric excess from readily accessible enantiomerically pure complexes. The configuration of the benzylic stereogenic center relative to the planar chirality of the arene complex was determined in one case by an X-ray structural analysis. The reaction has been extended to an o-anisaldehydeimine complex.

A Stable and Recoverable Chiral Ru Lewis Acid: Synthesis, Asymmetric Diels–Alder Catalysis and Structure of the Lewis Acid Methacrolein Complex

Ease of generation, stablity in solution at ambient temperature, high enantioselectivity in Diels-Alder reactions, efficient catalyst recovery, and large rate differences on variation of the anion are all characteristics of the new Ru Lewis acid [CpRu((S,S)-biphop-F)]+ (biphop-F=(C6 F5 )2 POCH2 (Ph)CH2 (Ph)OP(C6 F5 )2 ). The structure of complex 1 (L=methacrolein, Y=SbF6 ) provides evidence for a cooperative binding of the dienophile by both the Lewis acid and the anion.

Synthesis of 3,3-Disubstituted Oxindoles by Palladium-Catalyzed Asymmetric Intramolecular α-Arylation of Amides: Reaction Development and Mechanistic Studies

Palladium complexes incorporating chiral N-heterocyclic carbene (NHC) ligands catalyze the asymmetric intramolecular α-arylation of amides producing 3,3-disubstituted oxindoles. Comprehensive DFT studies have been performed to gain insight into the mechanism of this transformation. Oxidative addition is shown to be rate-determining and reductive elimination to be enantioselectivity-determining. The synthesis of seven new NHC ligands is detailed and their performance is compared. One of them, L8, containing a tBu and a 1-naphthyl group at the stereogenic centre, proved superior and was very efficient in the asymmetric synthesis of fifteen new spiro-oxindoles and three azaspiro-oxindoles often in high yields (up to 99 %) and enantioselectivities (up to 97 % ee; ee=enantiomeric excess). Three palladacycle intermediates resulting from the oxidative addition of [Pd(NHC)] into the aryl halide bond were isolated and structurally characterized (X-ray). Using these intermediates as catalysts showed alkene additives to play an important role in increasing turnover number and frequency.

Chiral Cyclopentadienyl-Iron and -Ruthenium Lewis Acids Containing the Electron-Poor BIPHOP-F Ligand: a Comparison as Catalysts in an Asymmetric Diels-Alder Reaction

Chiral iron and ruthenium Lewis acids: analogies and differences between the catalysts and the role of the anion in catalytic Diels-Alder reaction. In short: Fe catalysts are faster but Ru analogues are more stable and can be recovered quantitatively. Rational ligand design is shown to result in a large increase in chiral induction.

Planar chiral arene tricarbonylchromium complexes via enantioselective deprotonation / electrophile addition reactions

Sequential reaction of prochiral (η6-arene)Cr(CO)3 complexes with chiral amide bases and electrophiles yielded planar chiral complexes. Benzaldehyde acetal and phenyl carbamate complexes gave o-substituted products with 64 to 81% enantiomeric excess. With the benzaldehyde acetal complex, competitive benzylic deprotonation occurred. Enantiomeric purity of the substituted carbamate complexes could be increased to > 90% ee by fractional crystallization. The racemate crystallized selectively, leaving the enantiomerically enriched complex in solution.

Scope and mechanism of asymmetric C(sp3)–H/C(Ar)–X coupling reactions: computational and experimental study

Advances in the efficient palladium–NHC catalysed synthesis of highly enantioenriched 2,3-trans-fused and 2-alkyl indolines via asymmetric C(sp3)–H activation of an unactivated methylene/methyl group are reported. Very high asymmetric inductions (up to 99% ee) were achieved at reaction temperatures ranging from 120 to 160 °C. Factors influencing the efficiency of the reaction (halide, pseudohalide, N-protecting group) were investigated. The reaction pathway and enantioselection were probed by detailed density functional theory (DFT) calculations (M06-L functional). The combined theoretical and experimental study shows that the Pd–NHC catalysed C(sp3)–H arylation proceeds via a concerted metalation–deprotonation (CMD) mechanism. The CMD step is shown by DFT calculations and kinetic isotope effect measurements to be selectivity-determining. A good agreement between experimental enantioselectivities and calculated differences amongst diastereomeric activation barriers is observed.

Chiral Bidentate (Phosphinophenyl)benzoxazine Ligands in Asymmetric Catalysis

The new chiral bidentate (phosphinoaryl)benzoxazine ligands 2 were applied in asymmetric catalysis. Rhodium and copper complexes catalyzed the hydrosilylation of acetophenone and [4+2] cycloadditions with moderate enantioselectivity. Iridium complexes were used to hyrogenate di-, tri-, and tetrasubstituted alkenes, giving products with moderate to high enantiomer excesses. Enantioselective allylic substitution and Heck reactions catalyzed by [(phosphinoaryl)benzoxazine]palladium complexes occurred with high enantioselectivities. The results were similar to those obtained with the corresponding dihydro(phosphinoaryl)oxazole ligands. Comparison of the structures of (diphenylallyl)(benzoxazine)palladium and (diphenylallyl)(dihydrooxazole)palladium complexes showed that the coordination geometries and the chiral environments of the metal centers are very similar, which explains why the enantioselectivities induced by the two ligand classes are in the same range.