Continuous Synthesis of Aryl Amines from Phenols Utilizing Integrated Packed‐Bed Flow Systems

Ichitsuka, Tomohiro; Takahashi, Ippei; Koumura, Nagatoshi; Satō, Kazuhiko; Kobayashi, Shū

doi:10.1002/anie.202005109

Cited by 20 publications

(11 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Despite these advantages, this type of reaction has rarely been applied for the synthesis of amino acid compounds. Recently, we reported the continuous synthesis of aryl amines from cyclohexanones, which were prepared from the hydrogenation of phenols, by utilizing an integrated packed‐bed flow system [25] . In this protocol, amines and cyclohexanones, with styrene as a neutral hydrogen scavenger, were passed through a column reactor containing a heterogenous Pd(OH) 2 /C catalyst to afford the corresponding aryl amines in good to excellent yields.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we reported the continuous synthesis of aryl amines from cyclohexanones, which were prepared from the hydrogenation of phenols, by utilizing an integrated packed-bed flow system. [25] In this protocol, amines and cyclohexanones, with styrene as a neutral hydrogen scavenger, were passed through a column reactor containing a heterogenous Pd(OH) 2 /C catalyst to afford the corresponding aryl amines in good to excellent yields. This flow method was applicable for the stereoretentive N-arylation of l-phenylalanine methyl ester.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Stereoretentive N‐Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous‐Flow System

Ichitsuka

Komatsuzaki

Masuda

et al. 2021

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

The N-arylation of chiral amino acid esters with minimal racemization is a challenging transformation because of the sensitivity of the α-stereocenter. A versatile synthetic method was developed to prepare N-arylated amino acid esters using cyclohexanones as aryl sources under continuous-flow conditions. The designed flow system, which consists of a coil reactor and a packed-bed reactor containing a Pd(OH) 2 /C catalyst, efficiently afforded the desired N-arylated amino acids without significant racemization, accompanied by only small amounts of easily removable co-products (i. e., H 2 O and alkanes). The efficiency and robustness of this method allowed for the continuous synthesis of the desired product in very high yield and enantiopurity with high space-time yield (74.1 g L À 1 h À 1 ) and turnover frequency (5.9 h À 1 ) for at least 3 days.

show abstract

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Stereoretentive N‐Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous‐Flow System

Ichitsuka

Komatsuzaki

Masuda

et al. 2021

Chemistry A European J

Self Cite

View full text Add to dashboard Cite

show abstract

“…A multistep continuous flow reactor using heterogeneous Pd catalysts was established for the amination of phenols. [50] In the first stage where hydrogenation took place, Pd/C catalysts were packed in the column and in the second stage where condensation and dehydrogenation took place, Pd(OH) 2 /C were packed in the column. The integrated flow reactor afforded high conversions, productivity (up to 0.31 kg L À 1 day À 1 ) and enantioselectivity and was able to smoothly operate for one week.…”

Section: Packed Catalysts For Multistep Reactionsmentioning

confidence: 99%

Diverse Supports for Immobilization of Catalysts in Continuous Flow Reactors

Lin

Qiu

2022

Chemistry A European J

View full text Add to dashboard Cite

The rapid development of continuous flow processes is driving innovations in various chemical syntheses and industrial productions. Immobilizing catalysts in flow reactors allows transformations with high-efficiency and excludes the subsequent separation procedures. This concept outlines the approaches to incorporate catalysts within flow reactors, with particular focus on the application of additional supports including inorganic materials like silica, zeolite and reduced graphene oxide, polymeric materials like polymer packings, monoliths, cross-linked gels and polymer brushes, and other materials for specific conditions like transparent glass fibers and glass beads. Furthermore, advanced methods to develop ordered micro-/nanoarrays from internal walls of flow channels for immobilization of catalysts as well as application of innovative vortex fluidic devices are discussed to inspire new designs of supports for novel fluidic reactors with broad applications.

show abstract

“…2,67,78 Notably, such a transformation could also be realized in a continuous-flow reactor as reported by Kobayashi and co-workers recently. 77 As we further studied such direct phenol-amine coupling reactions with other substrates such as pyrrolidine, we found that, in the presence of a stronger hydride donor (NaBH 4 ) and a stronger acid (triflic acid), the pyrrolidine motif would be selectively rearomatized instead of the cyclohexyl moiety to afford N-cyclohexyl pyrrole (Scheme 13), 68 rather than the normal coupling product N-phenyl pyrrolidine as shown in Scheme 12. 2 This coupling reaction featured a formal aromaticity-transfer since the aromaticity of phenol was formally transferred to pyrrolidine with phenol being reduced to cyclohexyl motif and pyrrolidine being oxidized to pyrrole, highlighting good atom-and redox-efficiencies.…”

Section: Formal Reductive Couplingmentioning

confidence: 99%

“…Subsequently, anilines could be formed by the rearomatization of imine (or enamine) intermediates via dehydrogenation catalyzed by Pd/C. Overall, the mechanism involved a “dearomatization-condensation-rearomatization” sequence (Scheme b). ,, Notably, such a transformation could also be realized in a continuous-flow reactor as reported by Kobayashi and co-workers recently …”

Section: Formal Redox-neutral Coupling (Formal Phenol Direct Amination)mentioning

confidence: 99%

Coupling without Coupling Reactions: En Route to Developing Phenols as Sustainable Coupling Partners via Dearomatization–Rearomatization Processes

Qiu

Zeng

2020

Acc. Chem. Res.

View full text Add to dashboard Cite

Conspectus Transition-metal-catalyzed cross-coupling reactions represent one of the most straightforward and efficient protocols to assemble two different molecular motifs for the construction of carbon–carbon or carbon–heteroatom bonds. Because of their importance and wide applications in pharmaceuticals, agrochemicals, materials, etc., cross-coupling reactions have been well recognized in the 2010 Nobel Prize in chemistry. However, in the classical transition-metal-catalyzed cross-coupling reactions (e.g., the Suzuki–Miyaura, the Buchwald–Hartwig, and the Ullmann cross-coupling reactions), organohalides, which mainly stem from the nonrenewable fossil resources, are often utilized as coupling partners with halide wastes being generated after the reactions. To make cross-coupling reactions more sustainable, we initiated a general research program by employing phenols and cyclohexa(e)nones (the reduced forms of phenols) as pivotal feedstocks (coupling partners), instead of the commonly used fossil-derived organohalides, for cross-coupling reactions to build C–O, C–N, and C–C bonds. Phenols (cyclohexa(e)nones) are widely available and can be obtained from lignin biomass, highlighting their renewable and sustainable features. Moreover, water is expected to be the only stoichiometric byproduct, thus avoiding halide wastes. Notably, the cross-coupling reactions utilizing phenols/cyclohexa(e)nones are not based on the traditional transition-metal-catalyzed “oxidative-addition and reductive-elimination” mechanism, but via a novel “phenol-cyclohexanone” redox couple. This new working mechanism opens up new horizons of designing cross-coupling reactions via simple nucleophilic addition of cyclohexanones along with aromatization processes, thereby simplifying the design and avoiding laborious optimization of transition-metal precursors (e.g., Pd, Ni, Cu, etc.), as well as ligands in classical transition-metal-catalyzed cross-coupling reactions. Specifically, in this Account, we will summarize and discuss our related research work in the following three categories: “formal oxidative couplings of cyclohexa(e)nones”, “formal reductive couplings of phenols”, and “formal redox-neutral couplings of phenols”. The successes of these research projects clearly demonstrated our initial inspirations and rational designs to develop cross-coupling reactions without the “conventional cross-coupling conditions” by pushing the reaction frontiers from initial cyclohexanones, ultimately, to the sustainable phenol targets.

show abstract

Continuous Synthesis of Aryl Amines from Phenols Utilizing Integrated Packed‐Bed Flow Systems

Cited by 20 publications

References 34 publications

Stereoretentive N‐Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous‐Flow System

Stereoretentive N‐Arylation of Amino Acid Esters with Cyclohexanones Utilizing a Continuous‐Flow System

Diverse Supports for Immobilization of Catalysts in Continuous Flow Reactors

Coupling without Coupling Reactions: En Route to Developing Phenols as Sustainable Coupling Partners via Dearomatization–Rearomatization Processes

Contact Info

Product

Resources

About