Conformational Studies by Dynamic NMR. 84. 1 Structure, Conformation, and Stereodynamics of the Atropisomers of N-Aryl-tetrahydropyrimidines Ma. Beatriz Garcia, 2 Stefano Grilli, Lodovico Lunazzi,* Andrea Mazzanti, and Liliana R. Orelli 2, * Department of Organic Chemistry “A.Mangini”, University of Bologna, Viale Risorgimento, 4, Bologna 40136, Italy lunazzi@ms.fci.unibo.it Received May 10, 2001 The existence of stereolabile atropisomers for a number of N-aryl-tetrahydropyrimidines in solution has been deduced from the observation of the anisochronous NMR signals of prochiral methylene groups. The interconversion barriers for these atropisomers have been measured by line shape analysis of dynamic NMR spectra at various temperatures: a Molecular Mechanics modeling resulted in good agreement with these values. In an appropriate case, distinct NMR signals for the two enantiomeric forms could be observed at ambient temperature in a chiral environment. Evidence was also obtained for an exchange process occurring between two conformers experiencing a very biased equilibrium. Single-crystal X-ray diffraction of one such compound yielded a molecular structure in good agreement with the results obtained by ab initio calculations. Introduction Diversely substituted tetrahydropyrimidines have in- teresting biological activity 3-5 and pharmacological prop- erties, acting as anthelmintics, 6 antidepressants, 7 and fungicides, 8 among others. In this context a number of yet unknown N-aryl-substituted tetrahydropyrimidines have been prepared, and the related stereochemical properties investigated here. In particular, hindered N-aryl-tetrahydropyrimidines such as 1-3 are expected to have the plane of the ortho- substituted phenyl ring significantly twisted with respect to the time-averaged dynamic plane of the six-membered pyrimidine ring. The existence of such an Ar-N stereo- genic axis would originate, in principle, a pair of stereo- labile enantiomeric forms (atropisomers) if the corre- sponding rotation rate is rendered sufficiently slow. Results and Discussion Ab initio calculations (RHF 3-21G* method 9 ) applied to the o-chloro derivative 1 indicate indeed that the C 2′ - C 1′ -N 1 -C 6 dihedral angle has a value of 72°, thus entailing the existence of two enantiomeric forms: in Figure 1 the computed structures predicted for this pair of enantiomers are displayed. A single-crystal X-ray diffraction of 1 confirms the theoretical results, in that shows that two of the four molecules within the crystal cell are the antipodes of the other two. The geometrical parameters determined in the solid state are quite similar to those computed for the isolated molecule, in particular the mentioned dihedral angle has a very similar value (71.1°). The experimental X-ray structures of the antipodes of 1 are also displayed in Figure 1. Whereas in the crystalline state the internal molecular motions are frozen, so that the mentioned atropisomers can be regarded as stable species, this is not the case in solution where the internal motions happen to be quite rapid. For this reason the existence of the atropisomers of 1 in solution can be inferred by investigating the NMR spectra at a temperature sufficiently low as to make the rate of the enantiomerization process, brought about by the rotation about the Ar-N stereogenic axis, negligible. Although the NMR spectra of a pair of enantiomers are indistinguishable, the presence of prochiral probes allows one to detect the asymmetry of the molecule. 10 In the present case the two hydrogens of each methylene moiety (1) Part 82. Casarini, D.; Lunazzi, L.; Mazzanti, A. Angew. Chem., Int. Ed. 2001, 40, 2536. Part 83. Grilli, S.; Lunazzi, L.; Mazzanti, A. J. Org. Chem. 2001, in press (Ms. JO010420m). (2) On leave of absence from the Departamento de Quimica Or- ganica, Facultad de Farmacia y Bioquimica, Universidad de Buenos Aires, Junin 956, Buenos Aires, 1113 Argentina (e-mail: lorelli@ ffyb.uba.ar). (3) Dunbar, P. G.; Durant, G. J.; Fang, Z. J. Med. Chem. 1993, 36, 842. (4) Dunbar, P. G.; Durant, G. J.; Rho, T. J. Med. Chem. 1994, 37, 2774. (5) Bernard, T.; Jebbar, M.; Rassouli, Y.; Himdi-Kabbab, S.; Hame- lin, J.; Blanco, C. J. Gen. Microbiol. 1993, 139, 126. (6) McFarland, J. W.; Howes, H. L. J. Med. Chem. 1972, 15, 365 and references quoted therein. (7) Weinhardt, K.; Wallach, M B.; March, M. J. Med. Chem. 1985, 28, 694. (8) (a) Carter, P. A.; Pfrengle, W. F. UK Patent Appl. GB 2,277,089 (1994). Chem. Abstr. 1994, 122, 31544a. (b) Carter, P. A.; Pfrengle, W. F. UK Patent Appl. GB 2,277,090 (1994). Chem. Abstr. 1994, 122, 31544b. (9) Computer package Spartan Pro 1.1 (10) Mislow, K.; Raban, M. Topics Stereochem. 1967, 1, 1. Jennings, W. B. Chem. Rev. 1975, 75, 307. Eliel, E. L. J. Chem. Educ. 1980, 57, 52. 6679 J. Org. Chem. 2001, 66, 6679-6684 10.1021/jo015743x CCC: $20.00 © 2001 American Chemical Society Published on Web 09/11/2001