Investigación

 

A Non-sterically Preferred Conformation in Bis-1,4-(2-methyl-4, 5-dihydro-1H-benzo[g]indolyl)benzene

 

Luis Chacón-García, Roberto Martínez* and María Isabel Chávez

 

Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán, 04510, México, D.F. E-mail: robmar@servidor.unam.mx

 

Recibido el 8 de abril del 2002.
Aceptado el 11 de junio del 2002.

 

Abstract

A conformational analysis of the title compound in solution is described. Results show that the preferred conformation is not the one expected from steric considerations. Change of the solvent from CDCl₃ to benzene-d₆ had no significant effect on the equilibrium.

Keywords: Conformational analysis, benzene 1,4-disubstituted, ¹H NMR.

 

Resumen

Se describe el análisis conformacional del compuesto nombrado en el título. Los resultados muestran que la conformación preferida no es la esperada a partir de consideraciones estéricas. El cambio de disolvente de CDCl₃ a benceno-d₆ no tuvo efecto significativo en el equilibrio.

Palabras clave: Análisis conformacional, benceno 1,4-disubstituído, RMN ¹H.

 

Dedicated to Dr. Barbarín Arreguín

 

Introduction

Biaryl compounds have attracted much attention because of their wide ranging utility [1-5] One of the most important properties of biaryls is their conformation, which is usually fixed due to a restriction of the free rotation between the rings (atropisomerism). This stereochemical property of biaryls has attracted interest from biological activity researchers because the vast majority of compounds that interact with biological systems require specific stereochemical characteristics. For this reason, specific atropisomers are biologically active, for example as components of antibiotics like vancomycin or in cardiovascular drugs like 4-aryl-1,4-dihydropyridines [6, 7]. Hence, study of the conformational properties of atropisomeric systems has become very important.

Since it was first reported in the 1920s, atropisomerism has been explained in terms of steric effects [8-11]. Although biaryls are the most common examples of atropisomerism, dipyrrylbenzene atropisomers have also been described [12]. It is noteworthy that m-substitution on the phenyl ring is considered to be the most important factor in freezing the conformation in all reported cases.

In order to study the conformation of molecules with potential cytotoxic activity, we describe here the conformational analysis of a bis 1,4-(2-methyl-4,5-dihydro-1 H-benzo[g]indolyl)benzene, a non previously described compound.

 

Results and Discussion

Compound 2 was prepared by a Paal-Knorr reaction between the 1,3-dicarbonyl derivative 1 and 1,4-phenylenediamine at reflux temperature (Scheme 1). Compound 1 was obtained from α-tetralone [13].

The ¹H NMR spectra of 2 at 300 °K in CDCl₃ (Fig. 1b) showed duplicity in both of the signals (6.31 and 6.57 ppm). Integration of these signals suggested that a mixture of at least two detectable isomers was present, in the ratio 1.3:1. To confirm the presence of conformers the temperature was varied, and a coalescence of the two broad signals was found at 328 °K (Fig. 1c). When the temperature was returned to 300 °K the starting spectrum was recovered, with no detectable change. The ¹³C NMR spectra did not show any duplicity at room temperature. When the temperature was decreased at 218 °K, however, a ¹H NMR spectrum with well-defined signals was obtained (Fig. 1a) that showed the expected duplicities. The broadness of the signals in the room temperature spectrum made assignation of the signals difficult; hence, the signals were assigned in the spectrum at 218 °K. COSY and HETCOR experiments confirmed the presence of two different species, and allowed the assignation of the set of signals corresponding to each conformer. This analysis showed that the set of signals denoted A in Fig. 1a (6.28, 6.86, 6.98 ppm) corresponds to one species, and the signals denoted B correspond to the other species (6.55 and 7.04 ppm), which was more populated. The set of signals denoted B generate a second order spectrum (irradiation at 7.04 converts the multiplet at 6.55 to a singlet ). ¹H NMR chemical shifts for compounds 2a and 2b are described in Table I.

The spectroscopic analysis outlined above demonstrates the presence of the two conformers 2a and 2b, which have a diastereomeric relationship. The next step was to determine which conformer represents the major population. While there is no direct way of knowing which of the signals corresponds to 2b, it is possible to determine which signal corresponds to 2a through the nuclear Overhauser effect (nOe). The nOe effect should be appreciable in 2a between one of the methyl groups and the signal at 6.28 or 6.55 ppm, due to the proximity between CH₃ and H-8. This interaction is possible only in 2a.

A NOESY experiment clearly showed that this interaction occurs between the signals at 6.28 and 2.23 ppm. It is surprising that these signals correspond to the less populated species. In other words, the major species in the equilibrium is 2b, which is not the conformation that would be expected from steric considerations. Numerically, the preferred conformation of 2b over 2a is not as big to receive special attention, but if it is considered that 2b is the less expected specie in the equilibrium, the matter becomes attractive. With the aim to compare the experimental results with theoretical methods, a semiempirical calculation with PM3 was carried out [14]. It was found that 2a was the preferred conformer, although the energy difference was 1 kcal / mol. Structures are shown in Fig. 2. Distance between H-9' and the closer CH₃-C-2" in 2a was found to be 3.6 Å, whereas distance between H9' and H9" in 2b was 2.6 Å.

The spectrum of the same mixture obtained in benzene-d₆ gave almost the same diastereomeric relation as that obtained in CDCl₃, which indicates that the dipolar moment is not the main factor causing conformation 2b to be the preferred over 2a. Further studies to find the factors responsible for this preference are in process.

 

Experimental

To a stirred solution of 1 (0.1 g, 0.5 mmol) in 5 mL of acetic acid at 80 °C, 1,4-diaminobenzene (0.027g, 0.25 mmol) was added. After 1h of reflux and magnetic stirring, acetic acid is neutralized with a solution of 5 % NaHCO₃ in water in a separation funnel with CH₂Cl₂. After reduction of the solvent, previously dried with Na₂SO₄, under reduced pressure, 2 was obtained pure, by chromatographic purification in silica gel 1:1 hexane/AcOEt (0.115g, 52 %) from the obtained mixture, as a yellow solid. ¹H NMR (300 MHz, CDCl₃, 300 °K): δ 2.16 (s, 3H), 2.7 (t, J = 7 Hz, 1H), 2.99 (t, J = 7 Hz, 1H), 5.99 (s, 1H), 6.3 and 6.56 (broad, 1H), 6.82 and 6.94 (broad, 1H), 6.94 (m, 1H), 7.42 (s, 2H); ¹³C NMR (75 MHz, CDCl₃, 300 °K): δ 12.9, 22.5, 30.9, 106.9, 120, 123, 126.6, 125.8, 128.2, 129.3, 129.7, 135.7, 139.6; IR (CHCl₃): 1516, 2937 cm^-1; HR-MS (EI): Estimated for C₃₂H₂₈N₂: 440.222; observed: 440.2274.

 

Acknowledgments

We thank CONACyT (32633-E) and DGAPA-UNAM (IN206598) for financial support. L. Chacón-García thanks CONACYT for a doctoral fellowship support. We also thank to R. Patiño, L. Velazco and J. Pérez for technical assistance. Contribution No. 1757 from Instituto de Química UNAM.

 

References

1. Fogassy, K.; Harmat, V.; Böcskei, Z.; Tárkányi, G.; Toke, L.; Faigl, F. Tetrahedron: Asymmetry 2000, 11, 4771-4780.         [ Links ]

2. Ishikara, K.; Yamamoto, H. J. Am. Chem. Soc. 1994, 116, 1561-1562.         [ Links ]

3. Andersen, N.G.; Parvez, M.; Keay, A. Org. Lett. 2000, 2, 2817-2820.         [ Links ]

4. Casas, J.; Najera, C.; Sansano, J.M.; González, J.; Saá, J.M.; Vega, M. Tetrahedron: Asymmetry 2001, 12, 699-702.         [ Links ]

5. Dusemound, C.; Mikami, M.; Shinkai, S. Chem. Lett. 1995, 157-158.         [ Links ]

6. Evans, D.A.; Dinsmore, C.J.; Evrard, D.A.; DeVries, K.M. J. Am. Chem. Soc. 1993, 115, 6426-6427.         [ Links ]

7. Koop, B.; Straub, A.; Shäfer, H.J. Tetrahedron: Asymmetry 2001, 12, 341-345.         [ Links ]

8. Christie, H.; Kenner, J. J. Chem. Soc. 1922, 121, 614-620.         [ Links ]

9. Rieger, M.;Westheimer, F.H. J. Am. Chem. Soc. 1950, 72, 19-28.         [ Links ]

10. Bott, G.; Field, L.D.; Sternhell, S. J. Am Chem. Soc. 1980, 102, 5618-5622.         [ Links ]

11. Eliel, E. Stereochemistry of Organic Compounds, John Wiley and sons, 1994; pp 160.         [ Links ]

12. Chang, Ch.; Adams, R. J. Am Chem. Soc. 1934, 56, 2089-2092.         [ Links ]

13. Chacón-García, L.; Martínez R. Eur. J. Med. Chem. 2002, 37, 261-266.         [ Links ]

14. Alchemy 2000, version 2.05. Tripos Inc. 1998.         [ Links ]