Unambiguous Assignment of the 1H- and 13C-NMR Spectra of Propafenone and a Thiophene Analogue

Full and unambiguous asssignment of all 1H- and 13C-NMR resonances of the free bases as well as the hydrochloride salts of the antiarrhythmic agent propafenone and a thiophene analogue in different solutions (DMSO-d6, CDCl3) is reported.

Although some NMR data of propafenone-like molecules have been reported [5][6][7][8] in most cases full assignments are missing and to the best of our knowledge no 13 C-NMR data for the parent compound 1 have been published. Thus, the present communication deals with the completely assigned 1 H-and 13 C-NMR spectra of propafenone and its thiophene analogue 2 [9], obtained by combined application of one and two-dimensional standard NMR techniques.

Results and Discussion
Complete and unambiguous assignments of all proton and carbons resonances were achieved on the basis of chemical shift considerations, coupling information (APT [10] and 'gated decoupled' 13 C-NMR spectra), and NOE-difference [11], COSY45 [12], HMQC [13], and 1D-TOCSY [14] spectra as well as on long-range INEPT experiments with selective excitation [15]. The numbering of atoms used in the discussion and in Tables 1 and 2 is given in the formulas of Scheme 1.

H-NMR Spectra
Whereas the aromatic region of the 1 H-NMR spectra of the investigated compounds is easy to interpret (AX-system for thiophene protons of 2, four different signals of H-3, H-4, H-5, and H-6 of propafenone (1) -with the long-range coupling 5 J(H-3,H-6) not resolved) the aliphatic part of the spectra is much more complex. Although -at first sight -the signal of protons H B in some cases seem to have a pseudo-triplet structure, the nuclei attached to carbons A and B give rise to a spin-system consisting of four non-equivalent protons (ABMN), with the accurate coupling constants and chemical shifts not directly extractable from the higher order multiplets. Thus, in Table 1 only the centers of the signals due to protons A and B are given. The protons of the O-CH 2 -CH(OH)-CH 2 -N substructure formally establish an ABMXY spin-system, the chiral carbon center D causing more or less nonequivalence of the adjacent diastereotopic protons H C and H C' , as well as of H E and H E' (see Figure 1 for 1•HCl in DMSO-d 6 ). In DMSO-d 6 solutions, the signal due to H D of 1•HCl is additionally split by a vicinal coupling to the acidic OH proton. However, in many cases the corresponding chemical shifts and coupling constants of this substructure can be determined with sufficient accuracy. In principle, methylene protons H F /H F' and H G /H G' of the propylamino moiety are also non-equivalent, the signal of H F /H F' showing more deviation from a first order pattern than that of H G /H G' (Figure 1). Expectedly, hydrochloride salt formation in general leads to larger chemical shifts for the proton signals of the aminoalcohol moiety compared with those of the corresponding free bases.

C-NMR Spectra
The 13 C chemical shifts and some selected 13 C, 1 H spin coupling constants are collected in Table 2. The data show a high degree of consistency, in nearly all cases the chemical shifts for carbons of the aminoalcohol chain (carbons C-H) are somewhat reduced when switching from the free bases to the hydrochloride salts (the opposite trend as observed for the corresponding 1 H chemical shifts). It should be mentioned that a good estimation of the 13 C chemical shifts in 1 could be performed using the CSEARCH-program [16], the difference between the predicted (also given in Table 2) and observed values is less than 3.8 ppm for all carbon atoms.

Conclusions
We have presented the complete 1 H-and 13 C-NMR chemical shifts of propafenone (1) and its thiophene analogue 2 as well as some selected spin-spin coupling constants.

Experimental
The NMR spectra were obtained using a Varian UnityPlus spectrometer (300 MHz for 1 H, 75 MHz for 13 C) from DMSO-d 6  Hz/data point for the 1 H-NMR spectra and 0.5 Hz/data point for the 13 C-NMR spectra. Propafenone hydrochloride was obtained from Sigma-Aldrich Chemical Company (USA), its thiophene analogue 2•HCl was prepared according to the literature [9]. The corresponding free bases were obtained by treatment of aqueous solutions of the hydrochlorides with an excess of potassium carbonate and subsequent extraction with dichloromethane. The base 2 gave a satisfactory elemental analysis (calcd. for C 19 H 25 NO 3 S: C 65.68; H 7.25; N 4.03. Found: C 65.52; H 7.21; N 3.93) and showed a melting point of 60 °C (the re-solidified product had a mp of 71 °C).