Mechanism of Stereoinduction in Asymmetric Synthesis of Highly Functionalized 1,2-Dihydroquinolines and 2<i>H</i>-1-Benzopyrans via Nonracemic Palladacycles with a Metal-Bonded Stereogenic Carbon

To establish the synthetic utility of palladacycles, a stable racemic benzannulated azapalladacycle featuring a palladium-bonded sp3-hybridized stereogenic carbon was prepared and converted into a series of racemic 2,3,4-trisubstituted 1,2-dihydroquinolines via a regioselective insertion of activated alkynes (RC⋮CCOOEt). Analogous diastereomerically enriched azapalladacyle (92% de) and oxapalladacycle (64% de) were synthesized from arylpalladium(II) iodo complexes possessing a nonracemic spectator ligand ((1R,2R)-N,N,N‘,N‘-tetramethyl-1,2-diaminocyclohexane) via an intramolecular displacement of the iodide by an ester enolate. Absolute configurations of the metal-bonded stereocenters in the diastereomerically enriched palladacycles were unequivocally assigned, and the efficiency of stereoinduction was systematically studied. On the basis of these experiments, a plausible mechanism for the transfer of chirality from the nonracemic auxiliary ligand to the palladium-bonded stereogenic carbon was proposed. A restricted rotation about the palladium-aryl bond in arylpalladium(II) iodo complexes giving rise to atropisomers, as well as the nature of the leaving group (iodide or acetate), were found to play a crucial role in the chirality transfer process. Diastereomerically enriched palladacycles underwent a ligand exchange with triphenylphosphine followed by regioselective insertion of unsymmetrical alkynes to afford nonracemic 1,2-dihydroquinolines (six examples) in excellent 80−91% ee and 2H-1-benzopyrans (four examples) in 32−56% ee

Mechanism of Stereoinduction in Asymmetric Synthesis of Highly Functionalized 1,2-Dihydroquinolines and 2<i>H</i>-1-Benzopyrans via Nonracemic Palladacycles with a Metal-Bonded Stereogenic Carbon

To establish the synthetic utility of palladacycles, a stable racemic benzannulated azapalladacycle featuring a palladium-bonded sp3-hybridized stereogenic carbon was prepared and converted into a series of racemic 2,3,4-trisubstituted 1,2-dihydroquinolines via a regioselective insertion of activated alkynes (RC⋮CCOOEt). Analogous diastereomerically enriched azapalladacyle (92% de) and oxapalladacycle (64% de) were synthesized from arylpalladium(II) iodo complexes possessing a nonracemic spectator ligand ((1R,2R)-N,N,N‘,N‘-tetramethyl-1,2-diaminocyclohexane) via an intramolecular displacement of the iodide by an ester enolate. Absolute configurations of the metal-bonded stereocenters in the diastereomerically enriched palladacycles were unequivocally assigned, and the efficiency of stereoinduction was systematically studied. On the basis of these experiments, a plausible mechanism for the transfer of chirality from the nonracemic auxiliary ligand to the palladium-bonded stereogenic carbon was proposed. A restricted rotation about the palladium-aryl bond in arylpalladium(II) iodo complexes giving rise to atropisomers, as well as the nature of the leaving group (iodide or acetate), were found to play a crucial role in the chirality transfer process. Diastereomerically enriched palladacycles underwent a ligand exchange with triphenylphosphine followed by regioselective insertion of unsymmetrical alkynes to afford nonracemic 1,2-dihydroquinolines (six examples) in excellent 80−91% ee and 2H-1-benzopyrans (four examples) in 32−56% ee

Allylpalladium Umpolung in the Three-Component Coupling Synthesis of Homoallylic Amines

Homoallylic amines and α-amino esters were prepared via a Pd(II)-catalyzed coupling of boronic acids and 1,2-nonadiene with ethyl iminoacetate or aliphatic, aromatic, and heteroaromatic imines. The allylpalladium umpolung was induced by a Pd(OAc)2 catalyst with commercial phosphine ligands

Regio- and Diastereoselective Insertion of Allenes into Stable Oxapalladacycles with a Metal-Bonded Stereogenic Carbon. Preparation of Contiguously Substituted 3,4-Dihydro-2<i>H</i>-1-Benzopyrans

Insertion of monosubstituted allenes into stable oxapalladacycle I was studied. The aim of this work was to define steric and electronic parameters of allenes that would allow for a regio- and diastereoselective synthesis of 2,3-disubstituted 3,4-dihydro-2H-1-benzopyrans, which could not be prepared via related catalytic protocols. Allenes with electron-donating alkyl substituents R sterically unencumbered at the C-3 and C-4 carbons reacted with palladacycles I to afford benzopyrans IV in good yields (45−81%), exclusively as cis diastereomers. Less than 10% of the regioisomeric benzopyrans V was detected in the crude reaction mixtures. Methoxy 1,2-propadiene afforded benzopyran IV in 98% yield as the trans diastereomer in 92% de. In contrast, allenes with electron-withdrawing substituents yielded benzopyrans V with an E double bond exclusively. Nonracemic palladacycles featuring a palladium-bonded stereogenic carbon as the only element of asymmetry underwent the allene insertion with 63−93% retention of the stereochemical information, providing benzopyrans IV or V in 40−47% ee. These results demonstrated that O-bonded palladium enolates did not operate as predominant intermediates in the insertion process. The study highlights the configurational stability of carbon-bonded palladium ester enolates, especially notable in systems lacking chiral nonracemic auxiliary ligands

Copper-Catalyzed Multicomponent Cascade Process for the Synthesis of Hexahydro-1<i>H</i>-isoindolones

Copper-catalyzed coupling of imines, dienylstannanes, and acryloyl chlorides followed by a Diels−Alder reaction afforded hexahydro-1H-isoindolones. Diversification of the core via Pd-catalyzed cross-coupling defines a new modular approach to isoindolone combinatorial libraries

Regio- and Diastereoselective Insertion of Allenes into Stable Oxapalladacycles with a Metal-Bonded Stereogenic Carbon. Preparation of Contiguously Substituted 3,4-Dihydro-2<i>H</i>-1-Benzopyrans

Insertion of monosubstituted allenes into stable oxapalladacycle I was studied. The aim of this work was to define steric and electronic parameters of allenes that would allow for a regio- and diastereoselective synthesis of 2,3-disubstituted 3,4-dihydro-2H-1-benzopyrans, which could not be prepared via related catalytic protocols. Allenes with electron-donating alkyl substituents R sterically unencumbered at the C-3 and C-4 carbons reacted with palladacycles I to afford benzopyrans IV in good yields (45−81%), exclusively as cis diastereomers. Less than 10% of the regioisomeric benzopyrans V was detected in the crude reaction mixtures. Methoxy 1,2-propadiene afforded benzopyran IV in 98% yield as the trans diastereomer in 92% de. In contrast, allenes with electron-withdrawing substituents yielded benzopyrans V with an E double bond exclusively. Nonracemic palladacycles featuring a palladium-bonded stereogenic carbon as the only element of asymmetry underwent the allene insertion with 63−93% retention of the stereochemical information, providing benzopyrans IV or V in 40−47% ee. These results demonstrated that O-bonded palladium enolates did not operate as predominant intermediates in the insertion process. The study highlights the configurational stability of carbon-bonded palladium ester enolates, especially notable in systems lacking chiral nonracemic auxiliary ligands

Enantiocontrolled Synthesis of Spirooxindoles Based on the [5 + 2] Cycloaddition of a Tp(CO)₂Mo(pyridinyl) Scaffold (Tp = Hydridotrispyrazolylborate)

A [5 + 2] cycloaddition of the pyridinyl π-complex (−)-1 (98% ee) to methyleneoxindole 2 afforded the spirooxindole complex (−)-3 in high enantiomeric purity. Complex (−)-3 was converted to pyrrolidine (−)-8 (97% ee), which is related to potent cytotoxic analogues of the spirotryprostatins alkaloids

Mechanism of Stereoinduction in Asymmetric Synthesis of Highly Functionalized 1,2-Dihydroquinolines and 2<i>H</i>-1-Benzopyrans via Nonracemic Palladacycles with a Metal-Bonded Stereogenic Carbon

To establish the synthetic utility of palladacycles, a stable racemic benzannulated azapalladacycle featuring a palladium-bonded sp3-hybridized stereogenic carbon was prepared and converted into a series of racemic 2,3,4-trisubstituted 1,2-dihydroquinolines via a regioselective insertion of activated alkynes (RC⋮CCOOEt). Analogous diastereomerically enriched azapalladacyle (92% de) and oxapalladacycle (64% de) were synthesized from arylpalladium(II) iodo complexes possessing a nonracemic spectator ligand ((1R,2R)-N,N,N‘,N‘-tetramethyl-1,2-diaminocyclohexane) via an intramolecular displacement of the iodide by an ester enolate. Absolute configurations of the metal-bonded stereocenters in the diastereomerically enriched palladacycles were unequivocally assigned, and the efficiency of stereoinduction was systematically studied. On the basis of these experiments, a plausible mechanism for the transfer of chirality from the nonracemic auxiliary ligand to the palladium-bonded stereogenic carbon was proposed. A restricted rotation about the palladium-aryl bond in arylpalladium(II) iodo complexes giving rise to atropisomers, as well as the nature of the leaving group (iodide or acetate), were found to play a crucial role in the chirality transfer process. Diastereomerically enriched palladacycles underwent a ligand exchange with triphenylphosphine followed by regioselective insertion of unsymmetrical alkynes to afford nonracemic 1,2-dihydroquinolines (six examples) in excellent 80−91% ee and 2H-1-benzopyrans (four examples) in 32−56% ee

Copper-Catalyzed Multicomponent Cascade Process for the Synthesis of Hexahydro-1<i>H</i>-isoindolones

Copper-catalyzed coupling of imines, dienylstannanes, and acryloyl chlorides followed by a Diels−Alder reaction afforded hexahydro-1H-isoindolones. Diversification of the core via Pd-catalyzed cross-coupling defines a new modular approach to isoindolone combinatorial libraries

Copper-Catalyzed Multicomponent Cascade Process for the Synthesis of Hexahydro-1<i>H</i>-isoindolones

Copper-catalyzed coupling of imines, dienylstannanes, and acryloyl chlorides followed by a Diels−Alder reaction afforded hexahydro-1H-isoindolones. Diversification of the core via Pd-catalyzed cross-coupling defines a new modular approach to isoindolone combinatorial libraries