Cathodic Reduction of Caffeine: Synthesis of an Amino-Functionalized Imidazole from a Biobased ReagentThis work was financially supported by Sapienza University of Rome (Project n. RM11715C7C8F258C).
Received: 09 February 2019
Accepted after revision: 24 March 2019
10 April 2019 (online)
Published as part of the Cluster Electrochemical Synthesis and Catalysis
The electrochemical reduction of caffeine, never carried out previously, yielded in DMF–Et4NBF4 N-formyl-N,1-dimethyl-4-(methylamino)-1H-imidazole-5-carboxamide, a highly functionalized imidazole product derived from the opening of the uracil ring. This reactivity is different from that of the methylated salt of caffeine, the cathodic reduction of which leads to the opening of the imidazole ring. Moreover, the product obtained by cathodic reduction, formylated at the exocyclic amide nitrogen, is different from that formed by treatment in an aqueous solution of sodium hydroxide followed by formylation. The latter is formylated at the exocyclic amine nitrogen.
References and Notes
- 1 Fredholm BB. Methylxanthines . Springer; Berlin Heidelberg: 2011
- 2a Huynh HV, Han Y, Jothibasu R, Yang JA. Organometallics 2009; 28: 5395
- 2b Landaeta VR, Rodríguez-Lugo RE, Rodríguez-Arias EN, Coll-Gímez DS, González T. Transit. Met. Chem. 2010; 35: 165
- 2c Luo F.-T, Lo H.-K. J. Organomet. Chem. 2011; 696: 1262
- 2d Zhang J.-J, Che C.-M, Ott I. J. Organomet. Chem. 2015; 782: 37
- 2e Herrmann WA, Schütz J, Frey GD, Herdtweck E. Organometallics 2006; 25: 2437
- 2f Kascatan-Nebioglu A, Melaiye A, Hindi K, Durmus S, Panzner MJ, Hogue LA, Mallett RJ, Hovis CE, Coughenour M, Crosby SD, Milsted A, Ely DL, Tessier CA, Cannon CL, Youngs WJ. J. Med. Chem. 2006; 49: 6811
- 2g Aweda TA, Ikotun O, Mastren T, Cannon CL, Wright B, Youngs WJ, Cutler C, Guthried J, Lapi SE. Med. Chem. Commun. 2013; 4: 1015
- 2h Bertrand B, Stefan L, Pirrotta M, Monchaud D, Bodio E, Richard P, Le Gendre P, Warmerdam E, de Jager MH, Groothuis GM. M, Picquet M, Casini A. Inorg. Chem. 2014; 53: 2296
- 3a Bredereck H, Kupsch G, Wieland H. Chem. Ber. 1959; 92: 566
- 3b Hori M, Kataoka T, Shimizu H, Imai E, Matsumoto Y, Miura I. Tetrahedron Lett. 1981; 22: 1259
- 3c Hori M, Kataoka T, Shimizu H, Imai E, Matsumoto Y. Chem. Pharm. Bull. 1985; 33: 3681
- 3d Makhloufi A, Frank W, Ganter C. Organometallics 2012; 31: 7272
- 3e Martins IL, Miranda JP, Oliveira NG, Fernandes AS, Gonçalves S, Antunes AM. M. Molecules 2013; 18: 5251
- 4 Rosal R, Rodríguez A, Perdigón-Melón JA, Petre A, García-Calvo E, Gómez MJ, Agüera A, Fernández-Alba AR. Chemosphere 2009; 74: 825
- 5 Clark PG. K, Lein M, Keyzers RA. Org. Biomol. Chem. 2012; 10: 1725
- 6 Švorc Ľ. Int. J. Electrochem. Sci. 2013; 8: 5755 ; and references therein
- 7 Pandolfi F, Mattiello L, Zane D, Feroci M. Electrochim. Acta 2018; 280: 71
- 8 Ohsaki T, Kuriki T, Ueda T, Sakakibara J, Asano M. Chem. Pharm. Bull. 1986; 34: 3573
- 9 Pasqua AE, Crawford JJ, Long D.-L. Marquez R. 2012; 77: 2149
- 10 Liu Y, Li D, Park C.-M. Angew. Chem. Int. Ed. 2011; 50: 7333
- 11 Chen L, Zou X, Zhao H, Xu S. Org. Lett. 2017; 19: 3676
- 12 Usually electrolyses at constant potential ensure the selectivity of the reduction, because of the choice of working potential, and they are thus preferred. Nonetheless, in this case the reduction peak of caffeine and the onset potential for the reduction of a solvent-supporting electrolyte system are really close, making yields higher than 50% unobtainable. Because of the simplified setup for a galvanostatic electrolysis (only two electrodes, no reference electrode), we thus opted for constant current electrolyses.
- 13 Dahm CE, Peters DG. J. Electroanal. Chem. 1996; 402: 91
- 14 Experimental Procedure Constant potential electrolysis was performed under a nitrogen atmosphere, at 25 °C, in a divided glass cell separated through a porous glass plug filled up with a layer of gel [i.e., methyl cellulose 0.5% vol dissolved in DMF–Bu4NBF4 (1.0 mol dm–3)]; Pt spirals (apparent area 0.8 cm2) were used as both cathode and anode. Catholyte: DMF (5 mL, 0.1 M DMF–Bu4NBF4). Anolyte: the same solvent as the catholyte (2 mL). Starting caffeine (0.5 mmol) [and water (1.0 mmol) when reported in Table 1] were present in the catholyte during electrolysis. The electrolysis was stopped after 3 F. At the end of the electrolysis, the solvent was eliminated under reduced pressure (15 Pa) and the crude reaction mixture was analyzed by 1H NMR spectroscopy. Product C was purified by flash column chromatography (eluent: CH2Cl2–MeOH 70:30) and two subsequent PLCs with the same eluent.
- 15 N-Formyl-N,1-dimethyl-4-(methylamino)-1H-imidazole-5-carboxamide C: 1H NMR (200 MHz, CD3OD): δ = 8.52 (s, 1 H, C H O), 7.56 (s, 1 H, C2 H ), 3.90 (s, 3 H, 1-N Me ), 3.15 (s, 3 H, 4-N Me ), 2.66 (s, 3 H, CON Me ) ppm. 13C NMR (50.3 MHz, CDCl3): δ = 162.5, 159.3, 143.5, 138.1, 120.1, 35.2, 34.1, 26.2 ppm. MS (ESI): m/z [M – 28 + H+] = 169.2. MS (EI): m/z (%) = [M]+. absent, 168 (12) [M+. – 28], 138 (4) [M+. – NMeCHO], 110 (85) (4) [M+. –CONMeCHO], 42 (100).