Tautomeric equilibria of benzopyranoimidazoles: useful insights from quantum chemical calculation and NMR

The development of novel syntetic strategies for achieving compounds containing the coumarin nucleus condensed to several heterocycles has been the subject of our research for the latter few years. [1] Such heterocycles are pharmacologically relevant as CNS depressants, [2] growth inhibitors of mammalian cancer [3] and also phosphodiesterase VII inhibitors for treatment of immunity-associated diseases. [4] Recently we reported the synthesis of some substituted benzopyranoimidazolones, and we pointed out the possibility of such heterocycles to exist in solution in at least two tautomeric forms, the N3-H and the N1-H tautomers (Fig. 1). [5] The study and quantitative evaluation of prototropic tautomerism in heterocyclic compounds is of primary interest, influencing both reactivity and biological behavior, for example the ability of a drug to bind the active site of a target enzyme [6]. Unfortunately literature does not report any reliable structural information and neither experimental data concerning tautomerism on pyranoimidazolone nucleus. Furthermore RT NMR experiments conducted by us so far were able to evidence the presence of at least two tautomers only for compound 4d and the attempts previously reported by us to unequivocally assign the preferred tautomeric structure by NMR were unsuccessful. The only result was obtained by N-methylation of compound 4d, were just the N3-CH3 product was isolated both at high and low reaction temperatures. However the reaction condition adopted could have influenced the tautomeric equilibrium. On the other hand tautomerism has been successfully described on various substituted imidazoles by ab-initio and DFT calculations in both gas-phase and solution within the continuum solvent model or evaluating explicit solvent interactions. [7] In our previous work, where the main object was the development of a synthetic strategy for benzopiranoimidazoles, preliminary quantum chemical calculations explained only in part the tautomeric behavior observed, thus the need of a throughout theoretical and experimental investigation. The relative stability of all the possible tautomers for [1]benzopyrano[3,4-d]imidazol-4(3H)-ones, namely the N3-H (alpha tautomer), N1-H (beta tautomer), coumarin O-H (gamma tautomer) and C2-H (delta tautomer), has been evaluated by mean of HF and B3LYP calculations, including the solvent contribution by the SCRF PCM model. Furthermore the 13C and 1H chemical shifts were calculated by GIAO technique at the HF/6-311+G(2d,p) and B3LYP/TZVP levels of theory both in gas phase and in solution by using the PCM model for DMSO. The calculation of 13C chemical shifts by GIAO technique and the comparison with the experimental has been reported as one of the most reliable methods for the investigation of tautomeric equilibria in solution [8]. Finally, 1H NMR spectra were recorded in CD3COCD3 at 500 Mhz at variable temperature in a range from RT to –60°C in order to evidence the presence of the most probable tautomers by progressively lowering their interconversion rates. The combination of the above mentioned theoretical techniques and experimental NMR allowed us to demonstrate that: 1.The only relevant tautomeric equilibrium for benzopyranoimidazolones is between alpha and beta forms. 2.All compounds 4a-e are able to exhibit tautomeric equilibrium in polar solvents. 3.The interconversion rate between alpha and beta tautomers is fast, thus by NMR is possibile to detect the presence of both tautomers only at low temperatures, otherwise averaged signals are recorded. Bibliography 1.[a] E.M. Beccalli, A. Contini and P. Trimarco, Eur. J. Org. Chem., 2003, 3976-3984, [b] E.M. Beccalli, A. Contini and P. Trimarco, Tetrahedron Letters, 2004, 45, 3447-3449. 2.V. L. Savel’ev, N. T. Pryanishnikova, V. A. Zagorevskii, I. V. Chernyakova, O.S. Artamonova, V. V. Shavyrina, L. I. Malysheva, Khim. Farm. Zh. 1983, 17, 697-700; see Chem. Abstr. 1983, 99, 158325. 3.M. Trkovnik, V. Kalaj, D. Kitan, Org. Prep. Proced. Int., 1987, 19, 450-455 4.M. Eggenweiler, J. Rochus, M. Wolf, M. Gassen, O. Poeschke, Merck Patent Gmbh, Germany, PCT Int. Appl. 2001; see Chem. Abstr. 2001, 134, 331619. 5.See ref 1a 6.P. Pospisil, P. Ballmer, G. Folkers, L. Scapozza, Tautomerism of nucleobase derivatives and their score in virtual screening to thymidine kinase, Abstracts of Papers, 224th ACS National Meeting, Boston, MA, United States, August 18-22, 2002 7.[a] O. V. Shishkin, O. S. Sukhanov, L. Gorb and J. Leszczynski, PCCP, 2002, 4, 5359-5364. [b] G. -S. Li, M. F. Ruiz-Lopez, M. S. Zhang, B. Maigret, J. Mol. Struct. (Theochem), 1998, 422, 197-204. [c] E. D. Raczyńska, Anal. Chim. Acta, 1997, 348, 431-441. [d] G. A. Worth, P. M. King, W. G. Richards, Biochem. Biophys. Acta, 1989, 993, 134-136. [e] G. -S. Li, M. F. Ruiz-Lopez, M. -S. Zhang, B. Maigret, J. Phys. Chem., 1997, 101, 7885-7892. [f] F. J. Luque, J. M. Lopez-Bes, J. Cemeli, M. Aroztegui, M. Orozco, Theor. Chem. Acc., 1997, 96, 105-113. 8.[a] N. E. Campillo, C. Montero, J. A. Páez, J. Mol. Struct. (Theochem), 2004, 678, 83-89. [b] E. Kleinpeter and A. Koch, J. Phys. Org. Chem., 2001, 14, 566-576.