)2'1' H AND 13 C NMR STUDY OF THE CONFORMATIONS OF THE ATROPISOMERS OF SOME 1-(1 1 -NAPHTHYL)-2,4-DIOXO- ( OR 2-THI0-4-0XO )-HEXAHYDRO-PYRIMIDINES*

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1 Journal of Molecular Structure, 128 (1985) Elsevier Science Publishers B.V., Amsterdam - Printed in The Netherlands 1 H AND 13 C NMR STUDY OF THE CONFORMATIONS OF THE ATROPISOMERS OF SOME 1-(1 1 -NAPHTHYL)-2,4-DIOXO- ( OR 2-THI0-4-0XO )-HEXAHYDRO-PYRIMIDINES* B. J. KURTEV, I. G. POJARLIEFF** and S. D. STh10VA Institute of Organic Chemistry, Bulgarian Academy of Sciences, 1113 Sofia (Bulgaria) R. S. BALTRUSIS, Z. H. BERESNEVICIUS, G. A. MACHTEJEV A and J. M. VIZGAITIS Polytechnical Institute, Kaunas , Lithuanian SSR (US.S.R.) (Received 30 October 1984) ABSTRACT The 'Hand 13 C NMR spectra of the atropisomers of 6-(or 5-)-methyl-1-(1 1 -naphthyl)- 2,4-dioxo-(or 2-thio-4-oxo)-hexahydro-pyrimidines, 1 to 4, are assigned on the basis of NOE. and double resonance experiments. The syn-anti configurations of the isomers of 6-methyl-2,4-dioxo-pyrimidine follow from the close similarity of the NMR parameters to those observed with the isomers of the 6-methyl-2-thio derivative of known configuration. That of the 5-methyl derivatives was assigned from NOE and magnetic anisotropy effects of the naphthalene ring and of the (thio)amide group. Allylic strain between the naphthyl and 6-methyl groups makes the axial conformation preferred in the anti isomers. In the syn isomers, however, the equatorial and axial conformations are approximately equally populated, apparently due to interference between the remote benzene ring and the axial methyl group. The equatorial conformation is preferred with the 5-methyl derivatives. INTRODUCTION Some of us showed recently [1] that the 1-(1 1 -naphthyl)-hexahydropyrimidines 1-4 give rise to stable atropisomers separable by thin layer chromatography. > R R' x 1 Me H 0 2 Me H s )2'1' 3 H Me 0 H H Me s R' s NH H 4 II 0 *Part XVII of the series "(3-Ureido Acids and Dihydrouracils". Part XVI. I. B. Blagoeva, A. H. Koedjikov and I. G. Pojarlieff, C.R. Acad. Bulg. Sci., 37 ( 1984) **To whom correspondence should be addressed /85/$ Elsevier Science Publishers B. V.

2 328 The 6-methyl-2-thio derivative 2 was studied in greatest detail: its syn and anti isomers were isolated and their configuration* determined by X-ray analysis. The two isomers were found by 1 H NMR to equilibrate in dimethyl sulphoxide solutions at temperatures higher than 130 C, the anti isomer was found to be slightly more stable. The present 1 H and 13 C NMR study was undertaken in order to obtain information on the configurations- of the isomer pairs of the remaining compounds, 1, 3, and 4, and on the conformations for ring inversion in solution. N-Substituents at an endo amide group in six-membered heterocycles give rise to allylic strain leading to favouring of axial conformations of neighbouring substituents [3]. Moderate preferences for the axial conformation were observed for several 1-aryl-6-methyl-dihydrouracils [3b] in dimethyl sulphoxide and trifluoroacetic acid. In the syn-anti isomers of the 1-naphthyl derivative 2, the 6-methyl group was found to be axial in the crystal state [1]. It was of interest to assess the tendency of a 1- naphthyl group in syn and in anti orientation to support an axial conformation of a neighbouring methyl group in solution. EXPERIMENTAL The preparation of the compounds studied is described in ref. 1. Only syn-2 was available as a separate isomer, the remaining compounds being studied as mixtures of isomers. The assignment of the signals to the individual isomers did not present any difficulties as they were present in different concentrations. All NMR spectra were recorded at ambient temperature with an internal D lock on a Bruker WM-250 spectrometer supplied with an Aspect 2000 Data System using saturated (ca. 2-3%) solutions in CDC1 3 against TMS as internal standard. Typical recording conditions for the 1 H NMR spectra were: spectral width 2.5 khz, pulse width 3 µs (flip angle ca. 50 ), pulse repetition time 6.6 s, 64 scans, 32 K of data memory. The accuracy of the chemical shifts was better than ±0.001 ppm, and the coupling constants were accurate to at least ±0.3 Hz. The samples for the NOE experiments were prepared by passing argon through solutions of the compounds studied for 15 min. For creation of the NOE, an irradiation time of 10 s under homogated conditions was used. A control experiment with irradiation far from the proton region (offset 3000 Hz) was also performed. Subtraction of the FID's with and without * Atropisomers are usually defined as isolable conformers [ 2], while their configuration is discussed in relation to optical activity. In the latter sense, the syn isomers of the 6-methyl derivatives are the (RS, SR)-diasteroisomers, while these of the 5-methyl derivatives are the (RR, SS)-diastereoisomers. We find it expedient to denote this isomerism as due to configuration to differentiate it from the conformations resulting from inversion of the pyrimidine ring.

3 irradiation followed by FT of the difference gave spectra consisting only of the signal due to the NOE. For assignment of the protons of the naphthalene ring, homonuclear decoupling experiments were carried out on syn-2 under the following recording conditions: spectral width 300 Hz, pulse width 5 µs (90 ), 256 scans, 8 K of data memory, irradiation power approximately 10 Hz. The 13 C NMR spectra were measured at MHz in 10 mm o.d. tubes. The recording conditions for the proton-noise and selectively decoupled spectra were as follows: spectral width 200 ppm, pulse width 10 µs, pulse repetition time 3.5 s, approximately scans, 16 K of data memory, decoupling power 1.5 and 0.2 W, respectively. The accuracy of the 13 C chemical shifts was better than ±0.03 ppm. RESULTS The NMR parameters for the pyrimidine ring protons are shown on Table 1. The 5-H and 6-H protons gave rise to ABX systems (A 2 X in 3). In the syn isomers of the 6-methyl derivatives 1 and 2, the assignment of the 5-H protons from the J-values was equivocal and this was done by means of an NOE experiment with the isomers of 2. Irradiation of the methyl groups enhanced the signals of the methylene protons in the cis position. The spectra obtained for the naphthalene ring protons were very similar in all compounds. The signals are grouped in four bands as shown in Fig. 1 for the case of the syn isomer of 2. The assignment of the and 8 1 -protons TABLE 1 'H chemical shifts, ppm from TMS, and coupling constants, Hz, of pyrimidine ring protons in the isomers of compounds 1-4 in CDC Compound 0 Me 55-Ha 0 6-H a 0 3-H Jtrans Jcis J55 (J66) JMeH,---..,. anti t syn c t c anti t 4.09 I syn c ot c anti b syn b anti t syn c t c at and c denote the position with respect to the neighbouring proton. bcoinciding chemical shifts.

4 330 (a) (b) 7,9 7, ,3 ppm Fig H NMR spectrum of the naphthalene ring protons of syn-2. (a) Calculated from the data given in Table 2. (b) Experimental. followed from the above NOE experiment: the signal of the 8 1 -proton was enhanced in the syn isomer and that of the 2 1 -proton in the anti isomer. Further, the assignment was carried out by means of double resonance spectra. Irradiation of the band at ca ppm transforms the remaining bands into singlets showing the lowest field doublet to be due to the and protons with approximately coinciding chemical shifts H was identified as a triplet which collapses to a doublet upon irradiation of either 2 1 -H or 4 1 -H. Irradiation of 5 1 -H or 8 1 -H simplified the spectra of the protons on the same ring to ABX systems. The data in Table 2 were finally obtained by iteration of the seven-spin system by means of the PANIC procedure (Bruker Manual 1981). The 13 C chemical shifts of the compounds studied (Table 3) are very similar apart from some differences due to variation in substitution. The assignment was based on comparison with data for uracil [ 4] and for various 1-substituted naphthalenes [5] and on selective decoupling experiments. The two signals at lowest field could be readily ascribed to the (thio )carbonyl carbon atoms. The chemical shift of 2-C should be greater than that of 4-C in the case of the thio compounds 2 and 4 because of the lower mean TABLE 2 1 H chemical shifts, Hz from ppm, and coupling constants, Hz, of naphthalene ring protons in syn Av J

5 331 TABLE 3 13 C chemical shifts, ppm from TMS, of the isomers of compounds 1-4 in CDC1 3 Carbons anti-1 syn-1 anti-2 syn-2 anti-3 syn-3 anti-4 sy n-4 - ""' CH excitation energy of a thiocarbonyl group and smaller with the dioxo compounds 1 and 3 due to the electron donation by the two adjacent nitrogen atoms. Those of 5-C, 6-C and QH 3 were assigned from the multiplicities observed in the off-resonance spectra. In the naphthalene ring, the wellseparated chemical shifts of the adjacent protons allowed 2 1 -C and 8 1 -C to be identified by means of selective decoupling. It should be noted that there is little or no shielding effect of the pyrimidine ring on the chemical shifts of 2 1 -C, indicating poor conjugation between the naphthalene moiety and the lone pair on 1-N. The chemical shifts of and 5 1 -C, as well as those of 3 1 -, and 7 1 -C could be determined as groups because the shifts of their adjacent protons approximately coincide. The assignments for these carbons, given in Table 3, are tentative and are based on the assumption that the effect on the shifts of a poorly conjugated nitrogen atom at position 1 of the naphthalene ring will be similar to that of a chlorine atom. The,,,.---- three quaternary atoms 1 1 -, and C were assigned from similar considerations [ 5]. DISCUSSION The assignment of syn-anti configuration to the isomers of the 6-methyl pyrimidine 1 is practically beyond doubt as their 1 H and 13 C spectra (Tables 1 and 3) repeat so very closely the characteristic differences exhibited by the spectra of the isomers of the 2-thio analogue 2 for which the configurations are available from X-ray analysis [1]. Before presenting the evidence for the assignments with the 5-methyl derivatives, the conformational preferences in solution will be discussed. The small Jf~ans_values observed for the anti isomers of 1 and 2 indicate that the axial conformation B, found in the crystal state, is largely retained

6 332 A B c D H~H CH 3 0 H H H E F in CDC1 3 solution. With the syn isomers, however, the medium Jf~art-!values of Hz show that both conformers C and Dare significantly populated. For a quantitative evaluation of the conformational equilibria, neat Jee and Jaa-values of 2 and 11.5 Hz have been recommended [6]. These yield 14 and 12% participation of the equatorial conformation A in the case of the anti isomers of 1 and 2 respectively, and 47 and 50% of C in the case of the syn isomers. For 6-methyldihydrouracil with no substituent at 1-N, J~"t'isvalues of ca. 10 Hz have been observed in various solvents while for a series of 1-aryl-6-methyldihydrouracils, including 1, now identified as the anti isomer, the Jf~ans_values ranged between Hz in DMSO which indicates that N-naphthyl and N-phenyl groups do not differ in their steric interactions with a neighbouring methyl group leading to a preferred axial conformation [ 3b]. The present results, however, show that with the syn isomers of 1 and 2, the axial conformation D is disfavoured due to strains arising between the remote benzene ring and the axial 6-methyl group in D and the effect of allylic strain is moderated.

7 Both isomers of the 5-methyl-2-thio derivative 4 show the large JJ~ans_ values expected for conformations E and F with equatorial methyl groups. For the dioxo-pyrimidine 3, only averages of JJ~ans and Jg~ were observed. The limiting values for these can be shown [3b, c],to be (Jaa + Jsa 6 e)/2 ca. 8.5 Hz and (Jee+ J 5 e 6 a)/2 ca. 3 Hz, i.e. again E and Fare indicated. The configurational assignments of the 5-methyl derivatives 3 and 4 is based on the following considerations. In an NOE experiment the separate doublets of the 6-methylene protons which have coinciding chemical shifts in each of the isomers of 3 were irradiated. In one of the isomers, this enhanced the intensity of the and 2 1 -protons of the naphthalene ring while with the other isomer only that of the 2 1 -proton. So the configurations can be assigned if a choice can be made in which molecule, E or F, the respective syn protons are close to each other. To solve this problem, the distances between the and 8 1 -protons and the 6a- and 6e-protons were calculated for varying torsions defined by (6-C)-(l-N)-(l 1-C)-(9 1 -C), the remaming geometry of the molecule being obtained from the X-ray data for syn-2 [l]. In the initial perpendicular position for both the anti and the syn isomers, the 8 1 -proton was calculated to be considerably closer to the syn 6-protons (2.7 and 2.5 A for anti and syn respectively) than the 2 1 -protons (3.2 and 3.0 A respectively). This apparently contradicts the experimental result so that in the real case the naphthalene rings should be rotated to a position giving close contacts for 2 1 -H in both isomers while retaining a close contact for 8 1 -H in only one of them. A stronger rotation which would bring the 8 1 -proton outside the NOE range is highly probable in the anti isomer because of the small distance of 2.3 A between 8 1 -H and 5a-H at 90. At 110 the distance between 2 1 -H and 6a-H is obtained as 2.89 A while that between 8 1 ~H and 6e-H is 3.23 A. In the syn isomer the distance between 2 1 -H and 5a-H is too large to be of importance but here again a rotation, although slighter, which moves away the closely situated 8 1 -H and 6a-H is likely. At -100, the (8 1 -H)- (6a-H) and (2 1 -H) ---(6a-H) distances are calculated as and A, respectively. This assignment of anti configuration to the isomer showing NOE only with the 2 1 -proton is further corroborated by the chemical shifts observed for the 8 1 -protons. As shown in Table 4, in the syn-anti pairs of isomers of the 6-methyl compounds 1 and 2, the 8 1 -protons appear at lower field in the syn isomers while the same applies for the 2 1 -protons in the anti isomers. 333 TABLE 4 'H chemical shifts, ppm from TMS, of the 2 1 and 8 1 protons of the naphthalene ring of the isomers of compounds 1-4 Protons anti-1 syn-1 anti-2 syn-2 anti-3 syn-3 anti-4 syn-4 2' '

8 334 According to the empirical models of Paulsen and co-workers [7] for the magnetic anisotropy of the (thio)amide group, a twist of the naphthalene ring away from the perpendicular position brings the proton moving closer to the C=O( S) group towards a deshielding zone and,the proton moving in the opposite direction to a more shielding zone. According to the X-ray data, the naphthalene ring in both isomers of 2 is tilted away from the axial methyl groups, the torsion angles with the (l-n)--(2-c) bond being and the directions of rotation agree exactly with the observed chemical shift differences. With the 5-methyl derivative 3, it is the isomer exhibiting NOE only with the 2 1 -proton that gives a signal for 8 1 -H at lower field, i.e. with an 8 1 -H rotated more strongly towards C=O. As already discussed, this is expected to be the case for the anti isomer. The 2 1 -protons in the 5-methyl derivatives have practically coinciding chemical shifts which could be due to smaller differences in torsion as 2 1 -H is further away from the 1-N-atom than 8 1 -H. These assignments are further supported by the chemical shift differences of the pyrimidine ring protons expected from the ring current effect of the naphthalene ring. The tables of Haigh and Mallion [8], recommended [9] to give better results in the deshielding region, and those of Johnson and Bovey [10] were used. The calculations were carried out with the X-ray analysis geometries [1] of the axial conformers of the two isomers of 2 assuming them to be the same with the equatorial conformer of the syn isomer (taken with a 50% population) as well as with the isomers of 3 and 4. The naphthalene moiety was treated as two separate benzene rings. As Table 5 shows, the predictions for the 6-methyl compounds are in reasonable agreement. Those for the 5-methyl compounds are nummerically not so good but all agree in sign. The experimental differences are rather small and probably better agreement could be obtained with correct naphthalene torsions for which, however, no firm data are available. As already mentioned the atropisomers of the 6-methyl-2-thiopyrimidine 2 TABLE 5,,.-- Predicted from ring-current effect of the naphthalene ring and observed (o anti - values, ppm osyn) Protons Calculated Observed Calculated Observed HM a JBb 1 2 HMa JBb 3 4 CH t c -0.06d t c afrom tables in ref. 8. hfrom tables in ref. 10. ccis to neighbouring proton. daverage equal to (Lio 6 t + Lio 6 c)/2. ttrans to neighbouring proton.

9 335 equilibrate upon heating in DMSO, the anti isomer being slightly more stable [l]. In the case of the 5-methyl-pyrimidines 3 and 4 equilibrium was reached upon heating for 20 min at 140 C in DMSO. The isomer assigned as anti was found to be more stable with both compounds, the isomer ratio being 1.8 and 1.5 for 3 and 4 respectively. This result is somewhat unexpected because the above-discussed proximity of 8 1 -H and 5a-H in the anti isomer could have made it a more strained structure. The 13 C chemical shifts in the isomer pairs of the compounds studied (Table 3) are rather similar, with the exception of perturbations of 1-2 ppm apparently caused by the presence of the 6-methyl group in 1 and 2. When compared to the respective 5-methyl compounds some shifts in sign correspond to a r-gauche effect (1 1 -C in 1 and 2 appears upfield) and to a a-syn effect (2 1 -C in anti-1 and 2 and 9 1 -C in syn-1 and 2 appear downfield). A general observation, however, is that within the isomer pairs of the 6- methyl derivatives, all carbon atoms which are close in space to the methyl group, 2 1 -C in anti and 8 1 -C and 9 1 -C in the syn isomers, or are presumably in a more strained position in the syn isomers, 1 1 -C, 6-C and QH 3, always appear at lower field. The differences in the 13 C chemical shifts of the isomer pairs of the 5-methyl compounds 3 and 4 were too small for any definite interpretation. It should be noted, however, that in the syn isomers, the chemical shifts, with few exceptions, are slightly larger than those of the anti isomers. ACKNOWLEDGEMENT We thank Drs J. Kaneti, P. Ivanov and I. Bangov for computational help and valuable advice. REFERENCES 1 R. C. Baltrusis, Z. H. Beresnevicius, I. M. Vizgaitis and Yu. V. Gatilov, Khim. Geterotsikl. Soedin., (1983) /"""' 2 L. Ernst, Chem. Unserer Zeit, 17 (1983 ) (a) B. J. Kurtev, M. J. Lyapova, S. M. Mishev, 0. G. Nakova, A. S. Orahovatz and I. G. Pojarlieff, Org. Magn. Reson., 21 (1983) 334. (b) S. Baltrusis, Z. H. Beresnevicius, A. H. Koedjikov, B. J. Kurtev, M. J. Lyapova, G. A. Machtjeva and I. G. Pojarlieff, C.R. Acad. Bulg. Sci., 36 (1983) 375. (c) A. H. Koedjikov and I. G. Pojarlieff, C.R. Acad. Bulg. Sci., 36 (1983) P. D. Ellis, R. B. Dunlap, A. L. Pollard, K. Seidman and A. D. Cardin, J. Am. Chem. Soc., 95 (1973) E. Kleinpeter and R. Borsdorf, 13 C-NMR-Spektroskopie in der organischen Chemie, Akademie-Verlag, Berlin, 1981, p A. R. Katritzky, M. R. Nesbit, B. J. Kurtev, M. J. Lyapova and I. G. Pojarlieff, Tetrahedron, 25 (1969) K. Todt and H. Paulsen, Z. Anal. Chem., 235 (1968) 29 ; H. Paulsen, K. Todt and H. Ripperger, Chem. Ber., 101 (1968) C. W. Haigh and R. B. Mallion, Org. Magn. Reson., 4 (1972) C. W. Haigh and R. B. Mallion, Prog. NMR Spectrosc., 13 (1980) C. E. Johnson and F. A. Bovey, J. Chem. Phys., 29 (1958) 1012.