Final Report Summary - ANCNAC (Applications of new chiral nitrogen-based ligands in asymmetric catalysis)
The objectives of the 'Application of new chiral nitrogen based ligands in asymmetric catalysis' (ANCNAC) project are the use of nitrogen-based ligands as alternative of chiral phosphine-based ligands in asymmetric catalysis. The development of new synthetic methodologies, in special these which employ phosphorous-free ligands, would have a major impact in academia and industry as it would provide ready access to essentially new organic compounds.
During the first six months, we were focused in the synthesis of new families of phosphine free nitrogen-based ligands and their application in known or new catalysed reactions. As it was included in the mid-term report, several known reactions were tested: Cu(I) conjugate boration of beta-substituted cyclic enones, palladium(II)-catalysed conjugate phosphination of Michael acceptors, etc. but no reactivity or racemic products were obtained in all cases. Then, we decided to approach a new project maintaining the same idea as in the original one: application of the new synthetised hydrazones-based as alternative to phosphorous-based ligands. After analysing which organic reactions with great synthetic value remain still unsolved, we decided to focus on the ortho-directed borylation of arene C-H bonds due to the similarities of new hydrazone-pyridine ligands and Hartwig's bipyridine ligands.
Analysing Hartwig's mechanism for the borylation reaction of arenes C-H bonds controlled by steric factors, we speculated that perhaps the reason why borylation takes place in the less hindered C-H bonds is due to the lack of a coordination site in the proposed intermediate. Therefore, we decided to investigate the behaviour of potentially hemilabile N,N ligands, in which one of the nitrogen atoms is a weaker donor that is prone to dissociation and therefore able to generate the required coordination site. It was foreseen that an ideal ligand should still be a good donor in order to maintain a high level of reactivity as in the reference dtbpy-based system. After a preliminary screenings using different N,N-ligands, a complete ortho-regioselective C-H borylation was observed when a pyridino-hydrazone based ligand was used. Methodology was extended to a broad family of 1-naphthylisoquinolines, 2-arylpyridines and aromatic N,N-dimethylhydrazones, giving the corresponding ortho-borylated products with complete regioselectivity and good to excellent yields. Borylation methodology was also applied to the ortho,ortho'-diborylation of arenes considering that a general procedure for the directed o,o-dimetalation of benzene derivatives and subsequent functionalisation remains a challenging target in synthetic methodology. Increasing the ammount of catalyst to 2 mol % and forcing the reaction conditions (80 instead of 55 degrees of Celsius), aromatic N,N-dimethylhydrazones can be ortho,orhto'-diborylated using 2 equiv of B2Pin2. The diborylation reaction conditions optimised were then applied to a variety of para- and meta-monosubstituted substrates as well as 3,4- and even 3,5-disubstituted derivatives, affording in all cases the desired o,o'-diborylated N,N-dimethylhydrazones in near quantitative yields. Diborylation reaction tolerates the presence of electron-donating and electron-withdrawing groups. The most interesting synthetic application of the diborylated products is their use as intermediates for the introduction of two different electrophiles. Using the Suzuki-Miyaura reaction for the sequential functionalisation with two different aryl bromides, Ar1Br and Ar2B, the strategy for is based in the dissymmetric interaction of the hydrazone with the two Bpin moieties in the diborylated products, which proporcionates them different transmetalations and couplings to give arylation products. Controlling the conditions of the couplings with the first electrophile, which has to be soft, and harsher with the second, the unsymmetrical 2,6-diaryl derivatives could get obtained with excellent two steps yields. To illustrate further the synthetic value of the procedure, representative productswere used as substrates for the high-yielding transformations of hydrazones into aldehydes and monoperoxyphthalate (MMPP), respectively. Catalytic activity of the Ir-based catalyst could be increased by modification of electron properties of the pyridino-hydrazone ligands, and a more atom-economy boron source such as pinacolborane could be used giving the borylated products in high yields (Scheme 3, attached document).
With the C-H borylation projects in hands, we decided to focus in the development of the asymmetric version for the borylation of hindered 1-naphthylisoquinolines for the synthesis of borylated isoquinolines with axial chirality. Chiral hydrazone ligands were tested and the borylated product was obtained in a racemic. We could rationalise these results assuming that enantiomers can easily be transformed each other by the formation of an internal 'ate complex'. Currently, there is an ongoing project where racemic borylated products are used as substrates in the 'Asymmetric Synthesis of Heterobiaryls via Dynamic Kinetic Suzuki-Miyaura Cross-Couplings'.
The C-H bond borylation methodology has been also applied to the synthesis of fluorophores such as borylated arylisoquinolines (BAI) dyes. In a collaboration with Prof. Uwe Pischel (University of Huelva), we have developed a new family of molecular switches and sensors based in the introduction of boryl moiety in a arylisoquinoline system. The resulting fluorophores showed electronically tunable internal-charge-transfer (ICT) fluorescence emission in an ample spectroscopic window and could be switched by protonation of the isoquinoline or the formation of fluoroboronate complexes with the boronic acid ester. Currently, a new family of borylated products are being synthesised for their application as fluorescent thermometer, hydrogen peroxide (H2O2) and carbohydrates sensors in living systems, etc.
During the first six months, we were focused in the synthesis of new families of phosphine free nitrogen-based ligands and their application in known or new catalysed reactions. As it was included in the mid-term report, several known reactions were tested: Cu(I) conjugate boration of beta-substituted cyclic enones, palladium(II)-catalysed conjugate phosphination of Michael acceptors, etc. but no reactivity or racemic products were obtained in all cases. Then, we decided to approach a new project maintaining the same idea as in the original one: application of the new synthetised hydrazones-based as alternative to phosphorous-based ligands. After analysing which organic reactions with great synthetic value remain still unsolved, we decided to focus on the ortho-directed borylation of arene C-H bonds due to the similarities of new hydrazone-pyridine ligands and Hartwig's bipyridine ligands.
Analysing Hartwig's mechanism for the borylation reaction of arenes C-H bonds controlled by steric factors, we speculated that perhaps the reason why borylation takes place in the less hindered C-H bonds is due to the lack of a coordination site in the proposed intermediate. Therefore, we decided to investigate the behaviour of potentially hemilabile N,N ligands, in which one of the nitrogen atoms is a weaker donor that is prone to dissociation and therefore able to generate the required coordination site. It was foreseen that an ideal ligand should still be a good donor in order to maintain a high level of reactivity as in the reference dtbpy-based system. After a preliminary screenings using different N,N-ligands, a complete ortho-regioselective C-H borylation was observed when a pyridino-hydrazone based ligand was used. Methodology was extended to a broad family of 1-naphthylisoquinolines, 2-arylpyridines and aromatic N,N-dimethylhydrazones, giving the corresponding ortho-borylated products with complete regioselectivity and good to excellent yields. Borylation methodology was also applied to the ortho,ortho'-diborylation of arenes considering that a general procedure for the directed o,o-dimetalation of benzene derivatives and subsequent functionalisation remains a challenging target in synthetic methodology. Increasing the ammount of catalyst to 2 mol % and forcing the reaction conditions (80 instead of 55 degrees of Celsius), aromatic N,N-dimethylhydrazones can be ortho,orhto'-diborylated using 2 equiv of B2Pin2. The diborylation reaction conditions optimised were then applied to a variety of para- and meta-monosubstituted substrates as well as 3,4- and even 3,5-disubstituted derivatives, affording in all cases the desired o,o'-diborylated N,N-dimethylhydrazones in near quantitative yields. Diborylation reaction tolerates the presence of electron-donating and electron-withdrawing groups. The most interesting synthetic application of the diborylated products is their use as intermediates for the introduction of two different electrophiles. Using the Suzuki-Miyaura reaction for the sequential functionalisation with two different aryl bromides, Ar1Br and Ar2B, the strategy for is based in the dissymmetric interaction of the hydrazone with the two Bpin moieties in the diborylated products, which proporcionates them different transmetalations and couplings to give arylation products. Controlling the conditions of the couplings with the first electrophile, which has to be soft, and harsher with the second, the unsymmetrical 2,6-diaryl derivatives could get obtained with excellent two steps yields. To illustrate further the synthetic value of the procedure, representative productswere used as substrates for the high-yielding transformations of hydrazones into aldehydes and monoperoxyphthalate (MMPP), respectively. Catalytic activity of the Ir-based catalyst could be increased by modification of electron properties of the pyridino-hydrazone ligands, and a more atom-economy boron source such as pinacolborane could be used giving the borylated products in high yields (Scheme 3, attached document).
With the C-H borylation projects in hands, we decided to focus in the development of the asymmetric version for the borylation of hindered 1-naphthylisoquinolines for the synthesis of borylated isoquinolines with axial chirality. Chiral hydrazone ligands were tested and the borylated product was obtained in a racemic. We could rationalise these results assuming that enantiomers can easily be transformed each other by the formation of an internal 'ate complex'. Currently, there is an ongoing project where racemic borylated products are used as substrates in the 'Asymmetric Synthesis of Heterobiaryls via Dynamic Kinetic Suzuki-Miyaura Cross-Couplings'.
The C-H bond borylation methodology has been also applied to the synthesis of fluorophores such as borylated arylisoquinolines (BAI) dyes. In a collaboration with Prof. Uwe Pischel (University of Huelva), we have developed a new family of molecular switches and sensors based in the introduction of boryl moiety in a arylisoquinoline system. The resulting fluorophores showed electronically tunable internal-charge-transfer (ICT) fluorescence emission in an ample spectroscopic window and could be switched by protonation of the isoquinoline or the formation of fluoroboronate complexes with the boronic acid ester. Currently, a new family of borylated products are being synthesised for their application as fluorescent thermometer, hydrogen peroxide (H2O2) and carbohydrates sensors in living systems, etc.