Structural and conformational study of 3-methyl-2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9α-ol

Journal of Molecular Structure, 293 (1993) 49-54 Elsevier Science Publishers B.V., Amsterdam

49

STRUCTURAL AND CONFORMATIONAL STUDY OF 3-METHYL-2,4DIPHENYL-3-AZABICYCLO[3.3.1]NONAN-9a-OL I.Iriepaa,

B. Gil-Alberdia, E. Galveza, J. Sanz-Aparicig,

I. Fonsecab, and J. BellanaW

aDpto. Q. Organica, Univ. de Alcala de Henares, Madrid, Spain b Instituto Rocasolano, Dpto. de Rayos X, C.S.I.C., Madrid, Spain c Instituto de Optica, C.S.I.C., Madrid, Spain

The infrared, lH and l3C nmr spectra of 3-methyl-2,4-diphenyl-3azabicyclo[3.3.llnonan-9a-ol (II) have been examined in several media. To assist in interpretation of the spectroscopic data, the crystal structure has been determined by X-ray diffraction. The bicyclic system adopts a flattened chair-chair conformation. The methyl, phenyl and OH groups are in equatorial position with respect to the piperidine ring. The crystal structure is stabilized by means of O-H...0 intermolecular hydrogen bonding.

1. INTRODUCTION At present, we have focused our attention in the synthesis of different acyl derivatives of the 3-methyl-2,4-diphenyl-3azabicyclo[3.3.llnonan-Sa-ol as potential new 5-HT3 antagonists. In this line, we wish to report in this paper the structural and conformational studies of the compound 3-methyl-2,4-diphenyl-3azabicyclo[3.3.llnonan-9a-ol (II) in order to determine its preferred conformations both in solution and in the solid state.

2. EZPEHIMENTAL Table 1 gives a summary of the experimental data for X-ray diffraction and calculation procedures of compound II. The poor quality of the crystals made it difficult to solve the structure. A first set of data using MO& radiation, with 23%

observed reflections for a 20 criterion, did not led to any solution. A new Cu& data set with 55% of the reflections being observed for a 30 criterion allowed the analysis to be succesful. The IR spectra for compound II were recorded on a Perkin-Elmer 599B Spectrophotometer in the solid state (RBr) and in CDC13 solutions (0.04 Ml using 0.2 mm NaCl cells. Spectra for very dilute Ccl4 solutions in the 3600-2500 cm-l region were taken with 4 cm quartz cells. Indene and polystyrene were used for instrument calibration and the reported waves numbers are estimated to be accurate to within +4cm-l. Compounds II y III were obtained by reduction of the ketone I with sodium borohydride Cl] (Scheme 1).In this case, the separation of compounds II and III were carried out by crystallization from hexane.

0022-2860/93/$06.00 0 1993 Elsevier Science Publishers B.V. All rights reserved.

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H OH II

0

HO H Scheme 1

III

TABLE 1. Experimental data and structure refinement procedures.

Crystal dab Formula: Symmetry: Unit cell determination: Unit cell dimensions (“1 Packing: V(Aj3, Z: Dc(g.cm-3),M,F(000): v (cm-l): Technique:

Number of reflexions: Measured: Observed: Range of hkl: Value of Rint: on and refm Solution: Refinement: H atoms: w-scheme Final AF peaks: Final R and Rw: Computer and programs: Scattering factors: Anomalous dispersion

C21&xrW

Monoclinic, PZ/n Least-squares fit from 60, reflexions (9~42”) 16.274 (Q6.414 (Q32.573 (1) 90.0,90.119 (2), 90.0 3399.7 (1),8 1.2012,307.4,1328 5.276 Four circle diffractometer: Philips PW llOO.Bisecting geometry. Graphite oriented monochromator: Cuka w scans, scan width: 1.5’ up Bmax. 65” 5819 3184 (30 (I) criterion) -20 20,o 80 39 0.02 Direct methods and Fourier synthesis Full-matrix L.S. on Fobs Difference synthesis and geometrical calculations Empirical as to give no trends in vs. and 0.32 el A3 0.075,0.075 Vax6410,Multan80[2l,Xray System 131,Pesos141,Parst151 Int.Tables for X-Ray Crystallography 161 Int. Tables for X-Ray Crystallography

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TABLE 2Selected bond distances (A> with e.s.d.‘s in parentheses Bond OlOC4 Nl-C2 Nl-C6 Nl-Cl1 C2-C3 C2-cl2 c3-c4 c3-c9 c4-c5 C5-C6 c5-c7 C6-c 18 C7-C8 C&C9 cl2-Cl3 cl2-Cl7 c13-Cl4 c14-Cl5 C15-Cl6 C16-Cl7 C 18-Cl9 C 18-C23 c19-c20 c20-c21 c21-c22 C22-C23

Mol. A 1.431(6) 1.485(5) 1.478(6) 1.476(6) 1.548(7) 1.504(7) 1.518(7) 1.533(8) 1.525(5) 1.549(7) 1.531(8) 1.520(5) 1.519(9) 1.528(g) 1.382(5) 1.384(8) 1.387(8) 1.39919) 1.379(9) 1.384(g) 1.392(8) 1.369(8) 1.389(9) 1.357(13) 1.37801) 1.399(9)

Mol. B 1.429(5) 1.476(6) 1.492(6) 1.470(7) 1.539(5) 1.515(7) 1.522(7) 1.536(8) 1.508(7) 1.537(5) 1.529(8) 1.518(7) 1.523(8) 1.532(7) 1.396(7) 1.378(8) 1.385(g) 1.366UO) 1.386(g) 1.400(9) 1.380(8) 1.393(9) 1.386(8) 1.368(12) 1.38401) 1.395(9)

Figure 1. Pluto view of the molecule, showing the numbering scheme

TABLE 3. Some torsional angles (“1 with e.s.d.‘s in parentheses.

Bond

Mol. A

Mol. B

Nl-C2-C12-Cl3 Nl-C2-C12-Cl7 C3-C2-C 12-Cl3 C3-C2-C 12-C 17 Nl-C6-C18-C 19 Nl-C6-C18-C23 C5-C6-C18-Cl9 C5-C6-C18-C23

-150.8(4) 29.8(6) 82.3(5) -97.1(6) 152.8(5) -27.7(7) -80.7(6) 98.9(6)

155.9(4) -28.2(7) -76.3(5) 99.6(6) - 155.9(5) 26.7(7) 76.0(6) -101.5(6)

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TABLE 4. Interatomic distances and angles in the hydrogen bonds (A>

A-H


H...B&

OlOB-HlOB 0.8( 1) 0 lOA-HlOA 0.7(l)

HlOB...OlOA (a) 1.9(l) HlOA...OlOB (b) 2.3(l)

A...B(A)

A-H...B(“)

OlOB...OlOA (a) 2.752(5) OlOA..OlOB (b) 2.789(5)

OlOB-HlOB..OlOA(a) 175(7) OlOA-HlOA..OlOB(b) 126U)

(a) X, Y,

2

(b) 1/2-X, Y, 1/2-Z

Figure 2. Packing in the unit cell, The four type of aromatic Ph-Ph interactions are shown.

TABLE 5. Ph-Ph interactions

RINGS

GG’

a

G’P

GG’l

S’G

fi

Symmetry

4vs. 1’ 2vs.3’ 3vs.2’ 2vs.4’

4.9 5.0 5.1 5.5

64 65 66 81

4.8 4.8 4.9 5.1

0.0

3.3 3.4 2.8 3.4

114 119 156 143

0.5-x, -l+Y, 0.5-z x, l+Y, z l-x, -Y, -z 1+x Y, z

1.1 1.2 2.0

For each possible Ph...Ph’ interaction the following parameters are given: GG’, the distance between centroids; a, the angle between L.S. planes; G’P, the distance from G’ to the L.S. plane of the first ring; GG’l, the distance from G to the projection of G’ onto the L.S. plane of ring one; S’G, the distance from the closest substituent of the second ring to the centroid of the first one; p, the angle C’-H’...G at this substituent. All distances are in A and angles in degrees. The symmetry operation refers to the second ring.

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3. REXXJLTS AND DISCUSSION 3.1.

-II

Description

and

discussion

of

Figure 1 shows a view of molecules together. Bond distances in Table 2 are as expected. The crystal presents two independent molecules in the assymetric unit, both having similar geometry with very slight differences in the torsions at the bonds linking the phenyl rings to the bicycles (Table 3). The molecules present a pseudo-mirror plane through Cl1 Nl C4 010. The bicycle system is in a chair-chair conformation, flattened at Nl and C8 atoms. Molecules are held together by means of an hydrogen bond between different hidroxylic groups. Table 4 gives the geometry of this interesting hydrogen bonding pattern, which form tetramers around the crystallographic two-fold axis defining a local pseudo four-fold inversion axis, as can be observed in Figure 2. Packing in the crystal is also characterized by aromatic interactions. The features of the four different Ph-Ph interactions are given in Table 5, ring 1 being atoms C12A-C17A, ring 2: C18AC23A, ring 3: C12B-C17B and ring 4: C18BC23B. Following previous work on aromatic compounds [71 some geometrical parameters have been described in an attemp to rationalize this kind of interactions 181. By means of these a benzene-type T-shape parameters, arrangement is deduced for all the important interactions found in the title compound (Table 5), all of them having a C-H bond of one ring pointing directly towards the centroid of the other. The first two relate the above described tetramers in an helical way along the two-fold, thus along b. The other two show preferred direction along a and c axes and so tetramers in a arranging the tridimensional pattern.

The infrared spectrum of II showed in the solid state a strong band at about 3365 cm-l attributed to the stretching vibration of intermolecularly bonded OH groups. The absence of OH...N bonds, observed in other azabicyclic compounds, may be due to steric hindrance of the aryl groups in 2 and 4 positions. Upon dilution in CC4 (0.001 M) or CDC13 (0.04 M) the corresponding hydrogen bonded OH band disappeared and a sharp band at 3622-3610 cm’ 1 appeared which is assigned to free OH groups. 33.NMRspcctra Assignments of proton and carbon resonances have been made on the basis of the literature data for of 3-phenethyl-3azabicyclo[3.3.1lnonan-9a-ol and related systems [91. The spectra were recorded in CDC13 and C6Dg at 300 Mhz. In order to clarify the assignment of the signals and to deduce the proton magnetic parameters, double resonance experiments were performed . 3.4. Conformational study Compound II adopts in CDCl3 and C6D6 solutions a flattened chair-chair conformation in which the cyclohexane ring is more flattened than the piperidine moiety; this is due to the fact that in the flattening of the piperidine ring the phenyl groups would be shifted to “endo” positions in the bicyclic system, with the concomitant steric hindrance. The N-CH3 group is in equatorial position. These conclusions are supported by the following: In the lH NMR spectra, the WI/~ value for the Hl(5) signals ( _ 8 Hz) corresponds to a flattened chair-chair conformation for the bicyclic system.

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The 3J H2(4),x - Hl(5) - 3 Hz accounts for a dihedral angle about 60”. In compound II, 3J H2(4), - Hl(5) is smaller than 3J H6(8)ax - H1(5), therefore, the dihedral angle H2(4),x - C - C -H1(5) is greater than H6(8>, - C - C - Hl(5). In all cases 3J H6(8),, - Hl(5) is greater than 3J H6(8),, - Hl(5) and 3J H6(8), - H7eq is greater than 3J H6(8),, H7eq consequently, the dihedral angles H6(8),, - C - C - Hl(5) and H6(8)cq - C - C H7,q are greater than H6(8)ax - C - C Hl(5) and H6(8)ax - C - C - H7eq respectively. The twin-chair conformation is unambiguously confirmed by the 13C spectrum and its comparation with that of l3-granatanol 1101 and related systems [lll.Chemical shifted of C7 is the most significant carbon parameter for the conformational analysis for this compound. The observed chemical shifted (20.50 ppm) is similar to the reported value for P-granatanol (19.8 ppm) so, both compounds should adopt the same preferred conformation in solution, a flattened chair-chair form. The N-CH3 13C chemical shift of compound II of about 45 ppm is the same value as that found in equatorial N-CH3 substituted piperidines [ll. In compound II, A6 H7,x - H7,, _ 1.2 ppm was attributed to the field effect exerted by the N lone pair on H7ax. In summary, several strands of evidence establish that 3-methyl-2,4diphenyl-3-azabicyclo[3.3.llnonan-9a-ol adopt in CDC13 and C6Dg solutions a flattened chair-chair conformation in which the cyclohexane ring is more flattened. The N-CH3 group is in equatorial position. REFERENCES 1. I. Iriepa, B. Gil-Alberdi and E. Galvez, J. Heterocyclic. Chem., 29 (1992) 519.

2. P.Main, S.J. Fiske, S.E.Hull, L. Lessinger, G.Germain, J. P. Declercq and M. M.Woolfson. MULTAN80. A System of Computer Programs for Automatic Solution of Crystal Structures from X-Ray Diffraction Data. Univs. of York, England and Louvain, Belgium, 1980. 3. J.M.Stewart,F.A.Kundell and J.C. Baldwin. The XRAY80 System of Crystallographic Programs, Computer Science Center, Univ. of Maryland, USA, 1980. 4. M. Martinez-Ripoll and F.H. Cano. PESOS. A Computer Program for the Automatic Treatment of Weighting Schemes. Instituto Rocasolano, CSIC, Madrid, Spain, 1975. 5. M. Nardelli, Comput. Chem., 7 (1983) 95. 6. International Tables for X-Ray Crystallography. Kynoch Press, Vol. IV. Birmingham, 1974. 7. G. R. Desiraju, Crystal Engineering. The Design of Organic Crystals. Elsevier Science Publishers B.V. The Netherlands, 1989. 8. A. Albert and F. H. Cano, Contactos, a Computer Program to Study Interactions between Phenyl Rings, Instituto Rocasolano, CSIC, Madrid, Spain, 1991. 9. M. S. Arias, E. Galvez, I. Ardid, J. Bellanato, J. V. Garcia-Ramos, F. Florencio and S. Garcia-Blanco, J. Mol. Struct, 161(1987) 151. 10. J. R. Wiseman and H. 0. Krabbenhoft, J. Org. Chem., 40 (1975) 3222. 11. M. L. Galvez, B. Fonseca, A, Pharm. Sci.,

Izquierdo, M. S. Arias, E. Rico, I. Ardid, J. Sanz, I. Orjales and A. Innerarity, J. 80 (1991) 554.