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What is it about?
This paper presents an innovative method for the selective synthesis of mono-N-methyl/Alkyl aromatic amines. We address the challenges associated with the synthesis of these compounds, which are common scaffolds in pharmaceutical, dye, and agrochemical compounds.
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Why is it important?
Innovative synthesis of mono-N-methyl aromatic amines: - 25 examples, yields up to 82% Extended synthesis to other mono-N-alkyl aromatic amines: - 15 examples, yields up to 78% Direct conversion from nitroso compounds and boronic acids: - Avoids overfunctionalization to secondary amines or ammonium salts - Reactions promoted by P(OEt)3: Transition-metal-free, Completed in 20 minutes at room temperature (rt) No need for: - Specially dried solvents, anhydrous conditions, reducing agents, bases, or other additives Low toxicity of subproducts: Bening triethyl phosphate and boric acid - Minimizes generation of hazardous substances - Applicable to contemporary industrial applications, eg, 1 g-scale synthesis of the benzothiazole-aniline derivative Pittsburgh compound B (PiB).
Perspectives
This paper introduces a transition metal-free method for selectively synthesizing mono-N-methyl aromatic amines, overcoming challenges associated with existing methods. The strategy utilizes nitroso compounds and methylboronic acid, demonstrating high selectivity even with electron-donating or withdrawing groups. The optimization of reaction conditions, including the use of P(OEt)3 as a promoter, is emphasized, leading to extensive synthetic scope and compatibility with labile functional groups. The scalability is showcased through the synthesis of a relevant compound on a 1 g scale, indicating potential industrial applicability, eg, in Alzheimer's disease studies. Overall, the research offers an efficient, environmentally friendly approach with broad applications, making it a significant contribution to synthetic chemistry.
Professor Aurelio G CSAKY
Universidad Complutense de Madrid. Instituto Pluridisciplinar
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Read the Original
This page is a summary of: Synthesis of Mono-N-Methyl Aromatic Amines from Nitroso Compounds and Methylboronic Acid, ACS Omega, August 2019, American Chemical Society (ACS),
DOI: 10.1021/acsomega.9b01608.
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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.
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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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