Defluorinative Multicomponent Cascade Reaction of Trifluoromethylarenes via Palladium Photoredox Catalysis
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Abstract:
The incorporation of aromatic difluoromethyl motifs has proven to be a fruitful strategy for enhancing the therapeutic profiles of modern pharmaceutical candidates. While the defluorofunctionalization of trifluoromethylarenes offers a promising pathway towards diverse aromatic difluoromethyl compounds, current methods are predominantly limited to two-component reactions. Multicomponent cascade reactions (MCRs) involving a transient aromatic difluoromethyl radical are still uncommon and highly sought after owing to their capacity to rapidly generate challenging molecular structures. In this study, we present a photocatalytic manifold that combines commercially available trifluoromethylarenes, feedstock dienes and various nucleophiles to achieve a modular defluorinative MCR. This method features mild reaction conditions and a broad substrate scope with excellent functional group compatibility. Furthermore, this protocol enables a previously unreported process of formal defluorinative editing for the resulting MCR aromatic difluoromethyl adducts. Preliminary mechanistic studies support the proposed photoinduced palladium catalytic cycle.Keywords:
Photoredox catalysis
Cascade reaction
Chemical vapor deposition (CVD) of palladium is at present not used commercially, despite the widespread use of palladium films in electronics and data storage, because suitable precursors are not available. New palladium precursors, ally (β‐diketonato)palladium(II) complexes (see Figure) are reported, along with the conditions required for the formation of pure palladium films by CVD. magnified image
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The unsaturated aza-heterocycles such as tetrahydropyridines pose significant applications in both drug discovery and development. However, the methods to construct polyfunctionalized tetrahydropyridines are still limited. Herein, we report a modular synthesis of tetrahydropyridines via copper catalyzed multicomponent radical cascade reaction. The reaction features mild conditions and broad substrate scope. In addition, the reaction could scale up to gram scale with similar yield. A variety of 1,2,5,6-tetrahydropyridines with C3 and C5 substituents could be assembled from simple starting materials. More importantly, the products could serve as versatile intermediate to access various functionalized aza-heterocycles which further demonstrates its utility.
Cascade reaction
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Reaction conditions
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Site-selective peptide functionalization provides a straightforward and cost-effective access to diversify peptides for biological studies. Among many existing non-invasive peptide conjugations methodologies, photoredox catalysis has emerged as one of the powerful approaches for site-specific manipulation on native peptides. Herein, we report a highly N-termini-specific method to rapidly access itaconated peptides and their derivatives through a combination of transamination and photoredox conditions. This strategy exploits the facile reactivity of peptidyl-dihydropyridine in the complex peptide settings, complementing existing approaches for bioconjugations with excellent selectivity under mild conditions. Distinct from conventional methods, this method utilizes the highly reactive carbamoyl radical derived from a peptidyl-dihydropyridine. In addition, this itaconated peptide can be further functionalized as a Michael acceptor to access the corresponding peptide-protein conjugate.
Photoredox catalysis
Transamination
Conjugate
Posttranslational modification
Bioconjugation
Reactivity
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Abstract Site‐selective peptide functionalization provides a straightforward and cost‐effective access to diversify peptides for biological studies. Among many existing non‐invasive peptide conjugations methodologies, photoredox catalysis has emerged as one of the powerful approaches for site‐specific manipulation on native peptides. Herein, we report a highly N ‐termini‐specific method to rapidly access itaconated peptides and their derivatives through a combination of transamination and photoredox conditions. This strategy exploits the facile reactivity of peptidyl‐dihydropyridine in the complex peptide settings, complementing existing approaches for bioconjugations with excellent selectivity under mild conditions. Distinct from conventional methods, this method utilizes the highly reactive carbamoyl radical derived from a peptidyl‐dihydropyridine. In addition, this itaconated peptide can be further functionalized as a Michael acceptor to access the corresponding peptide‐protein conjugate.
Photoredox catalysis
Transamination
Conjugate
Bioconjugation
Posttranslational modification
Reactivity
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Abstract Phosphine‐mediated deoxygenative nucleophilic substitutions, such as the Mitsunobu reaction, are of great importance in organic synthesis. However, the conventional protocols require stoichiometric oxidants to trigger the formation of the oxyphosphonium intermediates for the subsequent nucleophilic additions. Through dual catalysis of photoredox and cobaloxime, we realized a radical strategy for the catalytic formation of acyloxyphosphonium ions that enables direct amidation. The deoxygenative protocol exhibits a broad scope and has been used in the late‐stage amidation of drug molecules. In addition to batch reactions, a continuous‐flow reactor was developed, enabling rapid peptide synthesis on gram scale. The successful assembly of a tetrapeptide on the solid support further demonstrated the versatility of this photocatalytic system. Moreover, experimental and computational studies are consistent with the hypothesis of acyloxyphosphonium ions being formed as the key intermediates.
Photoredox catalysis
Amide
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Cascade reaction
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Substituted thiazoles are widely known as natural products, approved drugs, and a number of synthetic compounds as bioactive agents. Due to the worth of this heterocycle nucleus, a large number of synthetic methodologies have been reported over the years to synthesize its derivatives. In this perspective, recent advances in the synthesis of thiazole compounds by using domino/cascade and multicomponent approaches have been summarized.
Thiazole
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A one-pot, two-component InCl3-mediated cascade reaction has been developed. Starting from readily available β-keto ester and alkynal substrates, this cascade reaction provided highly functionalized 1-oxadecalins in good yields and excellent diastereoselectivities.
Cascade reaction
Component (thermodynamics)
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