An Approach in Synthesis of 1-Morpholino-2-phenylethane-1,2-dione Catalyzed by Copper (II) Bromide
A novel approach towards synthesis of α-Ketoamides was serendipitously found in acetophenone's reaction with a secondary amine catalyzed by copper (II) bromide. This methodology is a promising simple alternative to access biologically active compounds containing α-Ketoamides. Reactions were carried out at room temperature using dimethyl sulfoxide (DMSO) as solvent and catalyst loading at 10 mol %. The products were purified using a chromatographic method and analyzed extensively by spectroscopic methods, namely 1D (1H and 13C) and 2D NMR (HMBC and HSQC). The reaction of acetophenone and morpholine furnished a yield of 6%. Acetophenone derivatives bearing benzyl and acetyl groups were prepared from para-hydroxy acetophenone with 25% and 99% yields, respectively. The products were analyzed by spectroscopic method, namely 1H and 13C NMR. The presence of substituents, namely hydroxyl, benzyl, acetyl group, prevent the formation of α-Ketoamides. Formation of α-Ketoamides in this reaction condition was proposed as the result of the oxidation product in the catalytic cycle of Cu (II).
Y. Murakami, M. Takei, K. Shindo, C. Kitazume, J. Tanaka, T. Higa, and H. Fukamachi, Cyclotheonamide E4 and E5, New Potent Tryptase Inhibitors from an Ircinia Species of Sponge, J. Nat. Prod., 2002, 65, 259–261, DOI: https://dx.doi.org/10.1021/np010304e.
R. B. Perni, S. J. Almquist, R. A. Byrn, G. Chandorkar, P. R. Chaturvedi, L. F. Courtney, C. J. Decker, K. Dinehart, C. A. Gates, and S. L. Harbeson, Preclinical Profile of VX-950, a Potent, Selective, and Orally Bioavailable Inhibitor of Hepatitis C Virus NS3-4A Serine Protease, Antimicrob. Agents Chemother., 2006, 50, 899–909, DOI: https://dx.doi.org/10.1128/AAC.50.3.899-909.2006.
G. M. Dubowchik, J. L. Ditta, M. V. Vrudhula, B. DasGupta, J. Ditta, T. Chen, S. Sheriff, K. Sipman, M. Witmer, J. Tredup, D. M. Vyas, T. A. Verdoorn, S. Bollini, and A. Vinitsky, 2-Aryl-2,2-difluoroacetamide FKBP12 Ligands: Synthesis and X-ray Structural Studies, Org. Lett., 2001, 3, 3987, DOI: https://dx.doi.org/10.1021/ol0166909.
L. El Kaїm, R. Gamez-Montaño, L. Grimaud, and T. Ibarra-Rivera, New Palladium-catalyzed Aerobic Oxidative Cleavage and Cyclization of N-Aryl Peptide Derivatives, Chem. Commun., 2008, 1350. DOI: https://dx.doi.org/10.1039/B716849G.
C. Liu, Z. Yang, S. Guo, Y. Zeng, N. Zhu, X. Li, Z. Fanga, and K.Guo, Copper-TEMPO-catalyzed Synthesis of ɑ-Ketoamides via Tandem sp3C-H Aerobic Oxidation and Amination of Phenethyl Alcohol Derivatives, Org. Biomol. Chem., 2016, 14, 8570–8575, DOI: https://dx.doi.org/10.1039/C6OB01387B.
C. Zhang, and N. Jiao, Dioxygen Activation under Ambient Conditions: Cu-Catalyzed Oxidative Amidation−Diketonization of Terminal Alkynes Leading to α-Ketoamides, J. Am. Chem. Soc., 2010, 132, 28–29, DOI: https://dx.doi.org/10.1021/ja908911n.
C. Zhang, Z. Xu, L. Zhang, and N. Jiao, Copper‐Catalyzed Aerobic Oxidative Coupling of Aryl Acetaldehydes with Anilines Leading to α‐Ketoamides, Angew. Chem., Int. Ed., 2011, 50, 11088–11092, DOI: https://dx.doi.org/10.1002/anie.201105285.
X. Zhang, M. Wang, Y. Zhang, and L. Wang, A Novel and Metal-free Approach towards α-Ketoamides using a TBHP/I2-promoted Tandem Reaction of Amines with β-Diketones via C–C Bond Cleavage, RSC Adv., 2013, 3, 1311–1316, DOI: https://dx.doi.org/10.1039/C2RA22116K.
M. Lamani, and K. R. Prabhu, NIS‐Catalyzed Reactions: Amidation of Acetophenones and Oxidative Amination of Propiophenones, Chem. Eur. J., 2012, 46(18), 14638–14642, DOI: https://dx.doi.org/10.1002/chem.201202703.
Z. Zhang, J. Su, Z. Zha, and Z. Wang, A Novel Approach for the One-pot Preparation of α-Ketoamides by Anodic Oxidation, Chem. Commun., 2013, 49, 8982–8984, DOI: https://dx.doi.org/10.1039/C3CC43685C.
R. W. Evans, J. R. Zbieg, S. Zhu, W. Li, and D. W. C. MacMillan, Simple Catalytic Mechanism for the Direct Coupling of α‑Carbonyls with Functionalized Amines: A One-Step Synthesis of Plavix, J. Am. Chem. Soc., 2013, 135, 16074−16077, DOI: https://dx.doi.org/10.1021/ja4096472.
B. Q. He, X. Y. Yu, P. Z. Wang, and J. R. Chen, A Photoredox Catalyzed Iminyl Radical-triggered C–C bond Cleavage/addition/Kornblum Oxidation Cascade of Oxime Esters and Styrenes: Synthesis of Ketonitriles, Chem. Commun., 2018, 54, 12262–12265, DOI: https://dx.doi.org/10.1039/C8CC07072E.
L. Zhang, D. Lin, Y. Kusov, Y. Nian, Q. Ma, J. Wang, A. B. P. Leyssen, K. Lanko, J. Neyts, A. Wilde, E. J. Snijder, and H. Liu, α-Ketoamides as Broadspectrum Inhibitors of Coronavirus and Enterovirus Replication: Structure-based design, Synthesis, and Activity Assessment, J. Med. Chem., 2020, 63, 4562–4578, DOI: https://dx.doi.org/10.1021/acs.jmedchem.9b01828.
T. Meng, J. Han, P. Zhang, J. Hu, J. Fu, and J. Yin, Introduction of the α-Ketoamide Structure: En Route to Develop Hydrogen Peroxide Responsive Prodrugs, Chem. Sci., 2019, 10, 7156–7162, DOI: https://dx.doi.org/10.1039/C9SC00910H.
Copyright (c) 2020 Didin Mujahidin, Wiwin Mujiati, Anita Alni
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
The manuscript will be made open access under the term of the Creative-Commons Attribution-NonCommercial-NoDerivatives License which permits use, distribution and reproduction in any medium, provided that the contribution is properly cited, the use is non-commercial and no modifications or adaptations are made.