Enabling Reductive C-N Cross-Coupling of Nitroalkanes and Boronic Acids by Steric Design of P(III)/P(V)=O Catalysts
Gen Li, Yuzuru Kanda, Seung Youn Hong and Alexander T. Radosevich*
*Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States,
Email: radosevich
mit.edu
G. Li, Y. Kanda, S. Y. Hong, A. T. Radosevich, J. Am. Chem. Soc., 2022, 144, 8242-8248.
DOI: 10.1021/jacs.2c01487
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Abstract
An organophosphorus-catalyzed C-N bond-forming reductive coupling of nitroalkanes with arylboronic acids and esters shows excellent chemoselectivity for the nitro/boronic acid substrate pair, allowing the synthesis of N-(hetero)arylamines rich in functionalization.
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proposed mechanism
Details
The article discusses a novel method for the reductive C−N cross-coupling of nitroalkanes with arylboronic acids using a specially designed organophosphorus catalyst. This method demonstrates excellent chemoselectivity and allows the synthesis of N-(hetero)arylamines with high functionalization. The key development is the identification of a sterically reduced phosphetane catalyst that operates within the P(III)/P(V)=O redox manifold, significantly improving the yield and selectivity of the desired C−N coupling reaction. Experimental and computational studies reveal that the catalyst's steric design impacts post-rate-limiting steps, favoring productive C−N coupling over side reactions. The method shows broad substrate scope, tolerating various functional groups and heterocyclic moieties, and is compatible with both primary and secondary nitroalkanes. The research highlights the potential of nitroalkanes as direct amination reagents and the versatility of the phosphetane core for catalyst optimization. The findings suggest strategic orthogonality with existing C−N coupling methods, providing new synthetic flexibility for bioactive molecule synthesis. The study also emphasizes the importance of oxazaphosphirane intermediates in the catalytic cycle and offers insights for further catalyst development.
General Procedure A (For primary nitroalkanes):
An oven-dried reaction tube described in the general material equipped with a magnetic stir bar was charged with boronic acid (0.30 mmol, 1.5 equiv), nitroalkane (0.20 mmol, 1.0 equiv) and P4•[O] (4.4 mg, 0.03 mmol, 15 mol%). The tube was capped with a septa cap, and then placed under N2 atmosphere and evacuated/backfilled 3x with N2. CPME (0.66 mL, 0.3 M) was added by syringe, followed by Ph2SiH2 (149 μL, 0.80 mmol, 4.0 equiv). The N2 inlet needle was removed and the septum was quickly replaced with a new septum cap. The reaction mixture was heated to 120 °C and stirred for the indicated time. Upon completion, the reaction was cooled to room temperature. The resulting crude was loaded on a pad of SiO2 and eluted with CHCl3/acetone to obtain a crude solution. The filtrate was concentrated under reduced pressure. The crude residues were purified by column chromatography to yield pure coupling products. Columns were primarily slurry packed with hexanes and mobile phase polarity was increased gradually to the mixture indicated. Note: hexanes = Hex, dichloromethane = DCM, ethyl acetate = EA.
General Procedure B (For secondary nitroalkanes):
An oven-dried reaction tube described in the general material equipped with a magnetic stir bar was charged with boronic acid (0.30 mmol, 1.5 equiv), MgO (40 mg, 1.0 mmol, 5.0 equiv), nitroalkane (0.20 mmol, 1.0 equiv) and P4•[O] (4.4 mg, 0.03 mmol, 15 mol%). The tube was capped with a septa cap, and then placed under N2 atmosphere and evacuated/backfilled 3x with N2. CPME (0.4 mL) and PivCN (0.27 mL) were added by syringe, followed by Ph2SiH2 (149 μL, 0.80 mmol, 4.0 equiv). The N2 inlet needle was removed and the septum was quickly replaced with a new septum cap. The reaction mixture was heated to 120 °C and stirred for the indicated time. Upon completion, the reaction was cooled to room temperature. The resulting crude was loaded on a pad of SiO2 and eluted with CHCl3/acetone to obtain a crude solution. The filtrate was concentrated under reduced pressure. The crude residues were purified by either column chromatography or preparative TLC (SiO2) to yield pure coupling products. Columns were primarily slurry packed with hexanes and mobile phase polarity was increased gradually to the mixture indicated. Note: hexanes = Hex, dichloromethane = DCM, ethyl acetate = EA.
Intermolecular Reductive C-N Cross Coupling of Nitroarenes and Boronic Acids by PIII/PV=O Catalysis
T. V. Nykaza, J. C. Cooper, G. Li, N. Mahieu, A. Ramirez, M. R. Luzung, A. T. Radosevich, J. Am. Chem. Soc., 2018, 140, 15200-15205.
G. Li, Z. Qin, A. T. Radosevich, J. Am. Chem. Soc., 2020, 142, 16205-16210.
S. Y. Hong, A. T. Radosevich, J. Am. Chem. Soc., 2022, 144, 8902-8907.
Key Words
arylamines, organocatalysis, diphenylsilane
ID: J48-Y2022
