Acta Chim. Slov. 2000, 47, 413-420. 413 STRUCTURE DETERMINATION OF 3-(2,2-DISUBSTITUTED ETHENYL)AMINO- SUBSTITUTED HETEROCYCLIC SYSTEMS† Lovro Selič, Branko Stanovnik * Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia Simona Golič Grdadolnik L01, Department of NMR and Molecular Modeling, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia † This paper is dedicated to the late Professor Drago Kolar Received 30-05-2000 Abstract Two structural issues, orientation on enamino double bond and relative positions of substituents on 3-amino group, on a series of 3-(2,2-disubstituted ethenyl)amino-substituted heterocycles, such as 4H-pyrido-[1,2-a]pyrimidin-4-ones 3, 5H-thiazolo[3,2-a]pyrimidin-5-ones 4, 4H-pyrido[1,2-a]pyridin-4-ones 5, 5,6,7,8-tetrahydro-2H-1-benzopyran-2-ones 6 and 2H-1-benzopyran-2-ones 7, were resolved using basic 1H NMR experiments. Introduction Recently, a series of 3-(2,2-disubstituted ethenyl)amino- substituted heterocycles such as 4H-pyrido[1,2-a]pyrimidin-4-ones 3, 5H-thiazolo[3,2-a]pyrimidin-5-ones 4, 4H-pyrido[1,2-a]pyridin-4-ones 5, 5,6,7,8-tetrahydro-2H-1-benzopyran-2-ones 6 and 2H-1-benzopyran-2-ones 7, were prepared from the corresponding alkyl 2-[2,2-disubstituted ethenyl]amino-3-dimethylaminopropenoates 2 (Scheme)1-7 As a part of this project, we now present a detailed study of structure of these compounds in the DMSO-d 6 solution. Results and discussion We encountered two structural issues regarding these compounds which had to be resolved: orientation on enamine double bond and relative positions of substituents on 3-amino group, and tried to solve them by the means of 1H NMR spectroscopy. The first issue was addressed in two ways: 1.) signals were characterized on the basis of the NH shift, since it depends significantly on the group which is located syn L. Selič, B. Stanovnik, S. Golič Grdadolnik: Structure determination of 3-(2,2-disubstituted ethenyl)- … 414 Acta Chim. Slov. 2000, 47, 413-420. relative to the NH group (data for the 5nh correlated to the Rsyn group is summarized in Table 1). Since the coupling constants for NHCH group indicate the anti orientation in NHCH fragment (J=12.2-15.0Hz), this method allows unambiguous determination of geometric isomers when R1 and R2 groups are COOR and COR, while in the case of R2 = CN, determination is not always possible. Scheme. The synthesis of 3-(2,2-disubstituted ethenyl)amino- substituted heterocycles O . H L R1,R2= COOMe, COOEt, COOBn, COMe, CN; R3= H, Me; R=H, Me,Cl, Br,OH; 2.) Second method is based on the comparison of the experimental and calculated chemical shift of the olefinic proton. Shifts were calculated using standard equation for trisubstituted olefins: 8h= 5.25+Zgem+Zcis+Ztrans (relevant NMR data is assembled in Tables 2 and 3). Since our heteroarylamino group is not found in tables,13 we had to extract the Zgem value from experimental data of compounds with identical R1 and R2 groups and compounds where isomers could be unambiguously determined with first method. L. Selič, B. Stanovnik, S. Golič Grdadolnik: Structure determination of 3-(2,2-disubstituted ethenyl)- … Acta Chim. Slov. 2000, 47, 413-420. 415 We found that Zgem value for 3-(4H-pyrido[1,2-a]pyrimidin-4-one)-ylamino group is Zgem = 1.43 ppm and for 3-(2H-1-benzopyran-2-one)-ylamino group Zgem= 1.21 ppm (Table 3). Thus calculated shifts for olefinic proton are in good agreement with experimental data (±0.05 ppm) for compounds where R1 and R2 is COOR or COMe. Table 1. Chemical shifts of the NH group (d ppm) correlated to the Rsyn group, recorded in DMSO-d6 RHN Rsyn Ranti R Rsyn CN COOR COR ROOC^~^ 8.60 - 8.70 9.10 - 9.15 10.70 - 10.85 ,NMe2 Roocr^i 9.20 - 9.30 9.50 - 9.80 11.40 - 11.60 0 10.30 - 10.45 10.85 - 10.87 12.50 - 12.70 LÇc; 0 10.30 - 10.45 10.40 - 10.70 12.40 - 12.55 dcc; R 10.30 - 10.35 10.30 - 10.75 12.45 - 12.55 Compounds where R1 = CN group, show two different types of signals for the CHNH structural element. Namely, major isomer of compound 3 show doublet (J=13-14 Hz) for NH between 10.85 and 10.87 ppm, and minor isomer singlet in 10.30-10.45 ppm interval.7 We assumed that majority of compounds exist in Z form with anti orientation of CHNH element and minority in E form with syn orientation of CHNH element. A group of Japanese scientists encountered the same phenomenon while studying the synthesis and L. Selič, B. Stanovnik, S. Golič Grdadolnik: Structure determination of 3-(2,2-disubstituted ethenyl)- … 416 Acta Chim. Slov. 2000, 47, 413-420. structures of alkyl N-(2-pyridyl)aminomethylenecyanoacetates. The structures of compound 3, where R1 = CN and R2= COOEt are presented in Figure 1. Figure 1 R N, ^/ N N O O anti-Z H' ^Y O C III N R syn-E O N H I O H O Since 1974, hydrogen bonds of polar CH groups with oxygen, nitrogen or halogen atom have been described extensively.9-12 The interaction between olefinic proton and ring oxo group in compounds 3-7 is in agreement with those descriptions. The Zcis value for CN group, with extended conjugation, which is not found in the tables,13 was determined from experimental shift of olefinic proton and assumption that Zgem for Z form of compound 3 is 1.43. Figure 2. Possible conformers of the heterocycles ^\^N H -nOe nOe O H-bond H R2 R1 A form Zgem=1.43 ^ N O ,H H R1 R2 B form H-bond A form B form L. Selič, B. Stanovnik, S. Golič Grdadolnik: Structure determination of 3-(2,2-disubstituted ethenyl)- … Acta Chim. Slov. 2000, 47, 413-420. 417 The second issue, the conformation of compounds 3-7 can not be determined directly with 1H NMR experiments, therefore NOESY experiments were conducted on selected compounds (entries 12, 15, 24, 27 and 28, Table 2). Compounds 3 showed NOE effect between H-C(2) proton and enamino group, while compounds 6 showed NOE effect between H-C(4) proton and olefinic proton, indicating that both types of compounds exist in less hindered A form (Figure 2). The origin of the difference is the hydrogen bond between the ring oxo group and olefinic proton, which is present in pyridopyrimidine series. Entries 21 and 22, namely 2H-1-benzopyranones, with methyl group attached at position 4 has Zgem value 1.43, indicating that these compounds exist in B form (Figure 2), due to steric hindrance and feature a hydrogen bond between the ring oxo group and olefinic proton. Table 2. Chemical shifts for NH and CH groups and Z/E ratio ¦NH2 OH CN •N Het-----NH R2 \= R1 Het-----NH R1 V R2 Entry Het R1 R2 SNH ÔCHNH Z/E Z E Z E 14 24 34 44 54 2-Methyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-3-yl 2,8-Dimethyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl 7-Chloro-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl 7,9-Dibromo-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl 9-Hydroxy-2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl COOEt COOEt COOEt COOEt COOEt COOEt COOEt COOEt COOEt COOEt ** ** ** ** ** 8.40 8.38 8.42 8.40 8.38 / / / / / L. Selič, B. Stanovnik, S. Golič Grdadolnik: Structure determination of 3-(2,2-disubstituted ethenyl)- … 418 Acta Chim. Slov. 2000, 47, 413-420. SNH ÔHNH Z/E Entry Het Ri R2 Z E Z E 63 4-Oxo-4H-pyrido[l,2-a]pyrimidin-3-yl COMe COMe 12.61 8.66 / 73 8-Methyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-3-yl COMe COMe 12.58 8.64 / 83 7-Chloro-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-3-yl COMe COMe 12.58 8.65 / 95 4-Oxo-4H-pyrido[l,2-a]pyrimidin-3-yl COOMe COMe * 12.68 * 8.77 10/90 105 8-Methyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-3-yl COOMe COMe 10.85 12.66 8.66 8.75 10/90 ll5 7-Chloro-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-3-yl COOMe COMe 10.88 12.66 8.68 8.76 10/90 125 4-Oxo-4H-pyrido[l,2-a]pyrimidin-3-yl COOBn COMe / 12.68 / 8.85 0/100 135 8-Methyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-3-yl COOBn COMe / 12.69 / 8.83 0/100 145 7-Chloro-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-3-yl COOBn COMe / 12.70 / 8.80 0/100 157 4-Oxo-4H-pyrido[l,2-a]pyrimidin-3-yl COOEt CN 10.87 10.40 8.71 8.54 67/33 167 8-Methyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-3-yl COOEt CN 10.86 10.32 8.67 8.49 67/33 177 7-Chloro-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-3-yl COOEt CN 10.86 10.46 8.72 8.56 67/33 183 1 -Cyano-4-oxo-4H-pyrido[ 1,2-a]pyridin-3-yl COMe COMe 12.77 8.58 / 195 1 -Cyano-4-oxo-4H-pyrido[ 1,2-a]pyridin-3-yl COOBn COMe * 12.85 * 8.76 9/91 207 1 -Cyano-4-oxo-4H-pyrido[ 1,2-a]pyridin-3-yl COOEt CN 9.06 11.00 8.68 8.32 85/15 214 4-Methyl-5,6,7,8-tetrahydro-2,5-dioxo-2H-1 -benzopyran-3 -yl COOEt COOEt 10.30 8.38 / 224 4,7,7-Trimethyl-5,6,7,8-tetrahydro-2,5 -dioxo-2H-1 -benzopyran-3 -yl COOEt COOEt 10.32 8.42 / 233 5,6,7,8-tetrahydro-2,5-dioxo-2H-l-benzopyran-3-yl COMe COMe 12.37 8.48 / 243 7,7-Dimethyl-5,6,7,8-tetrahydro-2,5 -dioxo-2H-1 -benzopyran-3 -yl COMe COMe 12.37 8.48 / 255 7,7-Dimethyl-5,6,7,8-tetrahydro-2,5 -dioxo-2H-1 -benzopyran-3 -yl COOMe COMe * 12.34 * 8.50 11/89 265 5,6,7,8-tetrahydro-2,5-dioxo-2H-l-benzopyran-3-yl COOBn COMe * 12.36 * 8.55 13/87 275 7,7-Dimethyl-5,6,7,8-tetrahydro-2,5 -dioxo-2H-1 -benzopyran-3 -yl COOBn COMe 10.69 12.36 8.46 8.57 12/88 L. Selič, B. Stanovnik, S. Golič Grdadolnik: Structure determination of 3-(2,2-disubstituted ethenyl)- … Acta Chim. Slov. 2000, 47, 413-420. 419 Entry Het Ri R2 SNH ÔCHNH Z/E Z E Z E 287 297 5,6,7,8-tetrahydro-2,5-dioxo-2H-1-benzopyran-3-yl 7,7-Dimethyl-5,6,7,8-tetrahydro-2,5 -dioxo-2H-1 -benzopyran-3 -yl COOEt COOEt CN CN 10.68 10.68 10.34 10.34 8.75 8.76 8.70 8.70 76/24 78/22 303 315 325 335 347 5,7-Dihydroxy-2-oxo-2H-1 -benzopyran-3-yl 5,7-Dihydroxy-2-oxo-2H-1 -benzopyran-3-yl 5,7-Dihydroxy-2-oxo-2H-1 -benzopyran-3-yl 7-Hydroxy-8-methyl-2-oxo-2H-1 -benzopyran-3-yl 5,7-Dihydroxy-2-oxo-2H-1 -benzopyran-3-yl COMe COOMe COOBn COOBn COOEt COMe COMe COMe COMe CN 12.49 * 12.47 10.36 12.47 / 12.55 10.73 / 8.46 8.44 8.48 8.45 8.54 / 8.57 8.67 / / 10/90 12/88 0/100 100/0 * Unambiguous determination was impossible, due to the overlaping of the signals. ** 1H NMR spectra of entries 1-5 were recorded in deuterated trifluoracetic acid, therefore the signals for NH are not visible; entries 6-34 were recorded in deuterated dimethylsulphoxyde; Reference for the synthesis of compound is given at each entry. Table 3. Z values for the selected groups COOR COOBn COR CN 2-oxo-Het-3-NH- 4-oxo-Het-3-NH- 7 . '-'cis 1.18 1.25 1.12 1.47 / / 7 '-'trans 0.55 / 0.87 / / / 7 zögem / / / / 1.21 1.43 Conclusions Zgem values, calculated from the NMR data of numerous compounds can be useful criteria for determination of conformers in described series of heterocyclic compounds. In addition, orientation on enamino double bond on the analoguous systems can be easily determined by the means of basic 1H NMR experiment and with the aid of the tables presented in this article. L. Selič, B. Stanovnik, S. Golič Grdadolnik: Structure determination of 3-(2,2-disubstituted ethenyl)- … 420 Acta Chim. Slov. 2000, 47, 413-420. Acknowledgements This work was supported by the Ministry of Science and Technology, Slovenia. References and Notes 1. G. Soršak, A. Sinur, L. Golič, B. Stanovnik, J. Heterocycl. Chem., 1995, 32, 921. 2. R. Toplak, L. Selič, G. Soršak, B. Stanovnik, Heterocycles 1997, 45, 555. 3. L. Selič, B. Stanovnik, J. Heterocycl. Chem., 1997, 34, 813. 4. L. Selič, S. Golič Grdadolnik, B. Stanovnik, Heterocycles 1997, 45, 2349. 5. L. Selič, S. Golič Grdadolnik, B. Stanovnik, Helv. Chim. Acta 1997, 80, 2418. 6. S. Strah, B. Stanovnik, S. Golič Grdadolnik, J. Heterocycl. Chem., 1997, 34, 263. 7. L. Selič, S. Golič Grdadolnik, B. Stanovnik, Heterocycles 1998, 49, 133. 8. S. Nigishaki, M. Ichiba, K. Shikomura, F. Yoneda, J. Heterocycl. Chem., 1971, 8, 759. 9. R. D. Green, Hydrogen Bonding by C-H Groups, Wiley Interscience, New York, 1974. 10. D. J. Sutor, J. Chem. Soc, 1963, 1105. 11. R. Taylor, O. Kennard, J. Am. Chem. Soc, 1982, 104, 5063. 12. Harlow, R.; Li, C; Sammes, M. P. J. Chem. Soc; PT I, 1984, 547. 13. M. Hesse, H. Meier, B. Zeeh, Spectroscopic Methods in Organic Chemistry, Georg Thieme Verlag, Stuttgart - New York, 1997, pp. 122. Povzetek Dve strukturni značilnosti, in sicer orientacija na enaminski dvojni vezi in relativna postavitev skupin na 3-amino skupini, na seriji 3-(2,2-disubstituiranih etenil)amino-substituiranih heterociklov, kot so npr. 4H-pirido-[1,2-a]pirimidin-4-oni 3, 5H-tiazolo[3,2-a]pirimidin-5-oni 4, 4H-pirido[1,2-a]piridin-4-oni 5, 5,6,7,8-tetrahydro-2H-1-benzopiran-2-oni 6 and 2H-1-benzopiran-2-oni 7, sta bili razrešeni s pomočjo osnovnih 1H NMR eksperimentov. L. Selič, B. Stanovnik, S. Golič Grdadolnik: Structure determination of 3-(2,2-disubstituted ethenyl)- …