Periodic Reporting for period 1 - Cu-XAT (Development of Copper Catalyzed Strategies for the Amination of Alkyl Halides Using Halogen-Atom Tranfer: Going Beyond SN2 Chemistry)
Okres sprawozdawczy: 2021-08-04 do 2023-08-03
The overall objectives of this project the discovery, design and development of novel catalytic methods to streamline the synthesis of high-value materials.
We have completed two projects which have been published in high-quality journals with the Fellows as the co-first author.
In the first project, we realized a novel strategy merging halogen-atom transfer (XAT) and Cu-catalysis for the modular Suzuki−Miyaura-type cross-coupling between alkyl Iodides and aryl organoborons. The purpose of this project was to address the problem in the cross-coupling reactions for the construction of C(sp3)–C(sp2) bonds due to the limited reactivity of palladium and nickel catalysts with alkyl halides. The approach developed here used a cooperative strategy, based on XAT for the conversion of the iodides into the corresponding radicals, and copper catalysis for C–C bond formation with the aryl organoborn.
In the second project, we discovered that highly substituted phenols can be accessed through a cooperative strategy merging hydrogen-atom transfer (HAT) with Co-catalyzed desaturation using readily available cyclohexanones as materials. It is worth noting that hydrogen is the only side product, which increases the sustainability and the practicality of the reaction. Phenols are important fragments widely used in medicinal chemistry, agrochemistry and material science. Our strategy has established a platform to convert substituted cyclohexanones into value-added phenols in a highly sustainable manner.
We have completed two projects which have been published in high-quality journals with the Fellows as the co-first author.
In the first project, we realized a novel strategy merging halogen-atom transfer (XAT) and Cu-catalysis for the modular Suzuki−Miyaura-type cross-coupling between alkyl Iodides and aryl organoborons. The purpose of this project was to address the problem in the cross-coupling reactions for the construction of C(sp3)–C(sp2) bonds due to the limited reactivity of palladium and nickel catalysts with alkyl halides. The approach developed here used a cooperative strategy, based on XAT for the conversion of the iodides into the corresponding radicals, and copper catalysis for C–C bond formation with the aryl organoborn.
In the second project, we discovered that highly substituted phenols can be accessed through a cooperative strategy merging hydrogen-atom transfer (HAT) with Co-catalyzed desaturation using readily available cyclohexanones as materials. It is worth noting that hydrogen is the only side product, which increases the sustainability and the practicality of the reaction. Phenols are important fragments widely used in medicinal chemistry, agrochemistry and material science. Our strategy has established a platform to convert substituted cyclohexanones into value-added phenols in a highly sustainable manner.
We have developed a Cu-catalyzed Suzuki-Miyaura cross-coupling with distinct mechanism for the construction of C(sp3)–C(sp2) bonds . This reaction is of broad utility but extension to the construction of C(sp3)–C(sp2) bonds still remains challenging.
In order to address the problem, we have developed a Cu-catalyzed process with the aid of an α-aminoalkyl radical to activate the alkyl iodide by halogen-atom transfer process (XAT). As outlined on scheme 1A, XAT mediated by the α-amino radical constitutes the key step of the reaction, enabling the conversation of secondary alkyl iodides to the alkyl radicals. These alkyl radicals can be coupled with a number of activated boronic esters in the presence a copper catalyst to access molecules with complex structures by C(sp3)-C(sp2) bonds formation. Compared to previous methods, this work is distinguished by wide substrate scope (aryl, vinyl, allylic, benzyl and alkynyl boronic esters; alkyl iodides with complex structures). This reaction provides a modular platform for the diverse construction of Csp3-Csp2 bonds with readily available boronic esters and iodoalkanes.
This work was published in J. Am. Chem. Soc. 2022, 144, 1986 and has received great attention (cited by 22 and twittered by 61). Following the reactivity of the reaction, a remarkable advance has been made by another research group for the construction of Csp3-Csp2 bonds through the Ni-catalyzed cross-coupling of two electrophiles (ChemSusChem 2022, 15, e202200906). This not only demonstrates the significance of the α-amino radical-mediate XAT in cross-couplings but also further enhances the practicality of cross-coupling reactions given the stability, availability and cost efficiency of the electrophiles used in the reaction.
Phenols are widely found as important substructures in nature products as well as used as feedstock for the synthesis of high-added value products. For a very long time, synthesis of poly-substituted phenols has been challenging in organic chemistry because of the limited reactivity and chemoselectivity in the electrophilic aromatic substitution (SEAr) chemistry. To address this problem, we have developed a Co-catalyzed desaturation strategy, with which a number of substituted cyclohexnones can be finally converted to the pertinent phenols. Numerous methods to access functionalized cyclohexanones have been reported, which not only significantly enhances the structural diversity of the substrates for the desired transformation but also increases the practicality of the strategy. The desaturation of cyclohexanones proceeds via a cooperative process merging the anthraquinone catalyzed-hydrogen atom transfer (HAT) with Co-catalyzed HAT, generating hydrogen as the only side product. With the mechanism, a number of phenols bearing different functional groups or medicine-relevant groups at different positions have been accessed in a highly sustainable manner.
Recently, this work was published in Angew. Chem. Int. Ed. 2023, 62, e202301656. This reaction has provided a novel access to substituted phenols. Compared to the conventional SEAr, our reaction realized the synthesis of poly-substituted phenols that contradicts the rule of orienting effects, since the substitution pattern has been pre-determined by the synthesis of the corresponding cyclohexanones. Importantly, the dehydrogenation of the cyclohexanone is realized, catalytically. Therefore, our strategy has provided a complementary radical approach to its conventional 2-electron SEAr counterpart for a catalytic and sustainable access to densely functionalized phenols.
In order to address the problem, we have developed a Cu-catalyzed process with the aid of an α-aminoalkyl radical to activate the alkyl iodide by halogen-atom transfer process (XAT). As outlined on scheme 1A, XAT mediated by the α-amino radical constitutes the key step of the reaction, enabling the conversation of secondary alkyl iodides to the alkyl radicals. These alkyl radicals can be coupled with a number of activated boronic esters in the presence a copper catalyst to access molecules with complex structures by C(sp3)-C(sp2) bonds formation. Compared to previous methods, this work is distinguished by wide substrate scope (aryl, vinyl, allylic, benzyl and alkynyl boronic esters; alkyl iodides with complex structures). This reaction provides a modular platform for the diverse construction of Csp3-Csp2 bonds with readily available boronic esters and iodoalkanes.
This work was published in J. Am. Chem. Soc. 2022, 144, 1986 and has received great attention (cited by 22 and twittered by 61). Following the reactivity of the reaction, a remarkable advance has been made by another research group for the construction of Csp3-Csp2 bonds through the Ni-catalyzed cross-coupling of two electrophiles (ChemSusChem 2022, 15, e202200906). This not only demonstrates the significance of the α-amino radical-mediate XAT in cross-couplings but also further enhances the practicality of cross-coupling reactions given the stability, availability and cost efficiency of the electrophiles used in the reaction.
Phenols are widely found as important substructures in nature products as well as used as feedstock for the synthesis of high-added value products. For a very long time, synthesis of poly-substituted phenols has been challenging in organic chemistry because of the limited reactivity and chemoselectivity in the electrophilic aromatic substitution (SEAr) chemistry. To address this problem, we have developed a Co-catalyzed desaturation strategy, with which a number of substituted cyclohexnones can be finally converted to the pertinent phenols. Numerous methods to access functionalized cyclohexanones have been reported, which not only significantly enhances the structural diversity of the substrates for the desired transformation but also increases the practicality of the strategy. The desaturation of cyclohexanones proceeds via a cooperative process merging the anthraquinone catalyzed-hydrogen atom transfer (HAT) with Co-catalyzed HAT, generating hydrogen as the only side product. With the mechanism, a number of phenols bearing different functional groups or medicine-relevant groups at different positions have been accessed in a highly sustainable manner.
Recently, this work was published in Angew. Chem. Int. Ed. 2023, 62, e202301656. This reaction has provided a novel access to substituted phenols. Compared to the conventional SEAr, our reaction realized the synthesis of poly-substituted phenols that contradicts the rule of orienting effects, since the substitution pattern has been pre-determined by the synthesis of the corresponding cyclohexanones. Importantly, the dehydrogenation of the cyclohexanone is realized, catalytically. Therefore, our strategy has provided a complementary radical approach to its conventional 2-electron SEAr counterpart for a catalytic and sustainable access to densely functionalized phenols.
Phenols are widely found as important substructures in nature products as well as used as feedstock for the synthesis of high-added value products. For a very long time, synthesis of poly-substituted phenols has been challenging in organic chemistry because of the limited reactivity and chemoselectivity in the electrophilic aromatic substitution (SEAr) chemistry. To address this problem, we have developed a Co-catalyzed desaturation strategy, with which a number of substituted cyclohexnones can be finally converted to the pertinent phenols. Numerous methods to access functionalized cyclohexanones have been reported, which not only significantly enhances the structural diversity of the substrates for the desired transformation but also increases the practicality of the strategy. The desaturation of cyclohexanones proceeds via a cooperative process merging the anthraquinone catalyzed-hydrogen atom transfer (HAT) with Co-catalyzed HAT, generating hydrogen as the only side product. With the mechanism, a number of phenols bearing different functional groups or medicine-relevant groups at different positions have been accessed in a highly sustainable manner.
Recently, this work was published in Angew. Chem. Int. Ed. 2023, 62, e202301656. This reaction has provided a novel access to substituted phenols. Compared to the conventional SEAr, our reaction realized the synthesis of poly-substituted phenols that contradicts the rule of orienting effects, since the substitution pattern has been pre-determined by the synthesis of the corresponding cyclohexanones. Importantly, the dehydrogenation of the cyclohexanone is realized, catalytically. Therefore, our strategy has provided a complementary radical approach to its conventional 2-electron SEAr counterpart for a catalytic and sustainable access to densely functionalized phenols.
Recently, this work was published in Angew. Chem. Int. Ed. 2023, 62, e202301656. This reaction has provided a novel access to substituted phenols. Compared to the conventional SEAr, our reaction realized the synthesis of poly-substituted phenols that contradicts the rule of orienting effects, since the substitution pattern has been pre-determined by the synthesis of the corresponding cyclohexanones. Importantly, the dehydrogenation of the cyclohexanone is realized, catalytically. Therefore, our strategy has provided a complementary radical approach to its conventional 2-electron SEAr counterpart for a catalytic and sustainable access to densely functionalized phenols.