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What is it about?
This paper introduces a new three-component chemical process that efficiently transforms inexpensive nitro compounds, boronic acids, and trialkyl phosphites into tertiary aromatic amines. The method is highly versatile, accommodating various chemical groups on nitro and boronic acid components. Its uniqueness lies in not requiring transition-metal catalysts, making it cost-effective and environmentally friendly. Additionally, it can work alongside other metal-catalyzed methods, enabling the synthesis of diverse compounds, including special types like α-amino ester derivatives.
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Why is it important?
1. Sustainable and Transition-Metal-Free Synthesis: The paper introduces a novel method for synthesizing tertiary aryl amines without the need for transition-metal catalysts. Transition metals are often expensive and can pose environmental and toxicity concerns. The development of transition-metal-free reactions is, therefore, a significant advancement in the field of organic synthesis, contributing to more sustainable and eco-friendly practices. 2. Versatile Three-Component Reaction: The described three-component reaction is versatile, joining nitro compounds, boronic acids, and trialkyl phosphites. This versatility expands the scope of accessible tertiary aryl amines, providing a flexible and broadly applicable synthetic route. 3. Tolerance to Functional Groups: The method is reported to tolerate different functional groups, including halogens, esters, and other substituents. This tolerance enhances the compatibility of the reaction with diverse molecular structures, enabling the synthesis of a wide range of functionalized compounds. Eg, it has been applied to α-amino ester derivatives. 4. Application in Medicinal Chemistry: Tertiary aryl amines are important structural motifs found in various bioactive molecules and pharmaceuticals. The paper discusses the synthesis of N-alkyl diarylamines and α-amino esters, showcasing the potential applications of the developed method in medicinal chemistry and drug discovery. 5. Efficiency and Scalability: The presented reaction conditions are optimized for efficiency, and the authors demonstrate scalability by performing a 1 g-scale synthesis. This feature is crucial for practical applications in industry, where large-scale synthesis is often required. 6. Contribution to Sustainable Chemistry: The paper aligns with the growing emphasis on sustainable chemistry by proposing a transition-metal-free and scalable synthetic route. Sustainable methods are essential for minimizing the environmental impact of chemical processes in research and industry.
Perspectives
This paper contributes to the advancement of synthetic methodologies by providing an efficient, versatile, and sustainable approach to the synthesis of tertiary aryl amines, with potential applications in medicinal chemistry and beyond. The reaction's tolerance to various substituents, including compounds such as α-amino esters, suggests broad applications in bioactive molecule, pharmaceutical, and material synthesis. The emphasis on scalability, demonstrated through a successful 1 g-scale synthesis, indicates its potential for industrial applications. The paper is seen not only as a scientific contribution but also as a promising avenue for more sustainable and efficient chemical synthesis practices, inspiring researchers to adopt innovative and green approaches in their own work.
Professor Aurelio G CSAKY
Universidad Complutense de Madrid. Instituto Pluridisciplinar
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This page is a summary of: Transition‐Metal‐Free Three‐Component Synthesis of Tertiary Aryl Amines from Nitro Compounds, Boronic Acids, and Trialkyl Phosphites, Advanced Synthesis & Catalysis, November 2019, Wiley,
DOI: 10.1002/adsc.201901009.
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Organic Synthesis and Bioevaluation
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Synthesis of Di(hetero)arylamines from Nitrosoarenes and Boronic Acids: A General, Mild, and Transition-Metal-Free Coupling
The synthesis of di(hetero)arylamines by a transition-metal-free cross-coupling between nitrosoarenes and boronic acids is reported. The procedure is experimentally simple, fast, mild, and scalable and has a wide functional group tolerance, including carbonyls, nitro, halogens, free OH and NH groups. It also permits the synthesis of sterically hindered compounds.
Synthesis of Mono‑N‑Methyl Aromatic Amines from Nitroso Compounds and Methylboronic Acid
The selective synthesis of mono-N-methyl aromatic amines was achieved by the reaction of aromatic nitroso compounds with methylboronic acid promoted by triethylphosphite under transition metal-free conditions. The target compounds are constructed efficiently without overmethylation, under environmentally benign reaction conditions that do not require bases or reductants and therefore are of interest in pharmaceutical, agricultural, and chemical industries.
Synthesis of Flufenamic Acid: An Organic Chemistry Lab Sequence Using Boronic Acids and Nitrosoarenes under Transition-Metal-Free Conditions
A method for the synthesis of flufenamic acid, a nonstereoidal anti-inflammatory drug (NSAID) of the anthranilate family (fenams), is described as an experiment for the upper-division undergraduate organic chemistry laboratory. The key step is the formation of the diarylamine moiety of flufenamic acid by a novel reaction consisting of the coupling of nitrosobenzenes with boronic acids under transition-metal-free conditions. On the one hand, students can compare the performance of two different methods for the preparation of nitrosobenzenes (oxidation of amines and ipso-SEAr reaction on potassium organotrifluoroborates). On the other hand, they compare the yields of two complementary examples for the coupling of nitrosobenzenes with boronic acids. The reactions are followed by thin layer chromatography, and the products are purified by percolation or by column chromatography. Students are also tasked with the confirmation of the structure of the products based on melting point, infrared, 1H NMR, 13C NMR, and 19F NMR spectroscopy, and MS spectrometry.
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