Tautomerism of hydroxychromenopyrazoles Laura Hernandez-Folgado ⇑ , José María Cumella, Paula Morales, Ibon Alkorta, José Elguero, Nadine Jagerovic ⇑ Instituto de Química Médica, CSIC, Juan de la Cierva 3, E-28006 Madrid, Spain article info Article history: Received 4 May 2011 Received in revised form 7 July 2011 Accepted 18 July 2011 Available online 9 August 2011 Keywords: Hydroxychromenopyrazole Molecular structure NMR spectroscopy B3LYP/6-311++G(d,p) calculations GIAO abstract Annular tautomerism (OHN and/or NHO) of hydroxychromenopyrazoles was studied by NMR- spectroscopy and B3LYP/6-311++G(d,p) theoretical calculations. The experimental chemical shifts of 4,4-dimethyl-7-pentyl-2,4-dihydrochromeno[4,3-c]pyrazol-9-ol have been compared with absolute shieldings calculations performed using the GIAO approximation. This study shows that the title compound exists mainly as an OHN tautomer in solution. Ó 2011 Elsevier B.V. All rights reserved. 1. Introduction In our early research program, a series of hydroxychromenopy- razoles have been prepared as potential cannabinoid ligands due to their structural similarity to THC and other classical cannabinoids such as cannabinol [1]. Some of these hydroxychromenopyrazoles showed high affinity and selectivity for CB 1 cannabinoid receptor vs. CB 2 . As a result of our interest in hydroxychromenopyrazole structure, in this paper we report a tautomerism study. Hydrox- ychromenopyazole can exist in two tautomeric forms a and b (Fig. 1) that differ in the nature of intramolecular hydrogen bonds. Prior to our studies [1], a synthesis of hydroxychromenopyraz- oles was reported by Press and Birnberg [2]. Based on spectral analysis the authors concluded that NH-hydroxychromenopyraz- oles only exist in the (N–HO) tautomeric form (Fig. 1 tautomer b) as a result from internal hydrogen binding with the phenolic oxygen. No relevant structural data supported this hypothesis. Moreover, the authors did not consider the (O–HN) hydrogen bond of tautomer a. Pyrazole tautomerism have been extensively studied, however, to our knowledge tautomerism data about 2(3)-o-hydrox- yphenylpyrazoles are scarce [3–6]. These data, published by some of us, suggested that in the solid state 2(3)-o-hydroxyphenylpyraz- oles exist as the O–HN tautomer and in solution as a mixture of both tautomers with a ratio being mainly affected by the nature of the 5(3)-pyrazole substituent. Therefore, considering the fact that hydroxychromenopyrazoles are 2(3)-o-hydroxyphenylpyrazole constrained analogues, studying their annular tautomerism is of interest. Thus, we describe the tautomers characterization by NMR and by theoretical studies of 4,4-dimethyl-7-pentyl-2,4-dihy- drochromeno[4,3-c]pyrazol-9-ol (1) as representative molecular structure of hydroxychromenopyrazoles. 2. Results and discussion Tautomer atom numbering of 4,4-dimethyl-7-pentyl-2,4-dihy- drochromeno[4,3-c]pyrazol-9-ol (1) used along this study has been arbitrary defined as showed in Fig. 2. 2.1. Experimental NMR spectroscopy study 1 H NMR spectrum of 4,4-dimethyl-7-pentyl-2,4-dihydrochro- meno[4,3-c]pyrazol-9-ol (1) was recorded in CD 3 OD at 213 K and 295 K. This study gave evidence for the existence of one or two tau- tomers. Shift and shape of H-3 signal is one of the main features to determine if one or two tautomers exist in solution. In the 1 H NMR spectrum at 213 K (Fig. 3) H-3 proton appears as a narrow singlet. This signal could be assigned to the proton of only one tautomer or it could be the average signals of the presence of both tautomers. Therefore, we performed the spectra at higher temperature. At 295 K the same narrow signal was found for H-3 (Fig. 3) indicating that this signal is not the result of a rapid prototropy in the NMR time scale, but it can be assigned to only one tautomer. Information provided by two-dimensional heteronuclear single quantum coherence (HSQC) and heteronuclear multiple quantum 0022-2860/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.molstruc.2011.07.031 ⇑ Corresponding authors. E-mail addresses: lhernandez@iqm.csic.es (L. Hernandez-Folgado), nadine@ iqm.csic.es (N. Jagerovic). Journal of Molecular Structure 1015 (2012) 162–165 Contents lists available at ScienceDirect Journal of Molecular Structure journal homepage: www.elsevier.com/locate/molstruc