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IJCB 47B(1) (2008) 129-135.Pdf Indian Journal of Chemistry Vol. 47B, January 2008, pp. 129-135 Conformational analysis of N1,N5-diacyltetrahydro-1,5-benzodiazepin-2-ones using NMR spectra and semiempirical MO calculations M Venkatraj*, S Ponnuswamy# & R Jeyaraman Department of Chemistry, Bharathidasan University, Tiruchirappalli 620 024, India E-mail: [email protected] Received 13 March 2007; accepted (revised) 27 September 2007 The stereochemistry of N1,N5-diacyltetrahydro-1,5-benzodiazepin-2-ones 4 and 5 have been studied using NMR spectral techniques and semiempirical MO calculations (AM1 and PM3 methods). The N1,N5-diacetyl- and N1,N5-dibenzoyltetrahydro-4-methyl-1,5-benzodiazepin-2-ones (4 and 5, respectively) prefer boat conformations BE with endo orientations of the acyl groups at N1 and exo orientations of the acyl groups at N5 positions. The X-ray crystal structure of N1,N5-dibenzoyltetrahydro-4-methyl-1,5- benzodiazepin-2-one 5 also supported the preference for the boat conformation (BE) with endo and exo orientations of benzoyl groups at N1 and N5 positions, respectively. Keywords: N1,N5-diacyltetrahydro-1,5-benzodiazepin-2-one, NMR spectra, semiempirical MO calculation, boat conformation, N1,N5-diacetyl, N1,N5-dibenzoyl 1,5-Benzodiazepines are well known for their bio- and benzoyl chloride, respectively, on the tetra- logical activity1-6. Some derivatives such as hydrobenzodiazepin-2-one 3 in dry benzene and lofendazam 1, Clobazam 2a and Triflubazam 2b are triethylamine (Scheme I). In the IR spectra of the used for the treatment of anxiety and neuroses diacylated compounds 4 and 5, the stretching bands including psychosomatic disturbances1a. It has been for both amine NH and amide NH were absent. The inferred, from a large number of Structure-Activity compounds 4 and 5 showed IR absorption bands at Relationship (SAR) studies, that the conformations of 1640, 1665 and 1720 and 1655, 1700 and 1715 the diazepines play a key role in deciding their cm-1, respectively. In the 1H NMR spectra of biological activity3-4. Hence it is of interest to compounds 4 and 5, the amine NH (δ 3.80) and introduce the conformation-directing moities, such as amide NH (δ 8.71) signals were absent. In the mass acyl groups, at the nitrogen site of benzodiazepines spectra, the molecular ion peaks were observed at and to study the stereochemical consequences on the m/z 260 and 384 and the fragmentation patterns seven membered rings of benzodiazepines. In corresponded to the diacetyl and dibenzoyl continuation of the work on the N-acyltetrahydro-1,5- derivatives, respectively. benzodiazepines5, the present article reports the The preferred conformations of the N1,N5-diacyl- stereochemistry of N1,N5-diacyltetrahydro-1,5-benzo- tetrahydro-1,5-benzodiazepin -2-ones 4 and 5 were diazepin-2-ones 4 and 5 using NMR spectra, X-ray derived from the 1H and 13C NMR spectral data in crystallography studies and semiempirical MO comparison with those of the parent amine 3 (ref. 6, calculations. Tables I and II). The SEFT (Spin Echo Fourier Transform), SFORD (Single Frequency Off Results and Discussion Resonance Decoupled) and NOESY spectra were The N1,N5-diacetyl- and N1,N5-dibenzoyltetra- used for the assignments. The coupling constants J3a,4a hydro-4-methyl-1,5-benzodiazepin- 2-ones, 4 and and J3e,4a were determined by irradiating the 5, were prepared by the action of acetic anhydride C4-methyl doublet and the corresponding dihedral 7 ⎯⎯⎯⎯⎯⎯ angles were estimated using DAERM . * R&D Centre, Synthite Industrial Chemicals Ltd., Kolenchery, It has been reported that the parent benzo- Cochin 682 311, India # Present Adress: Department of Chemistry, Government Arts diazepin-2-one 3 prefers to exist in a boat confor- mation on the basis of the vicinal coupling constants College (Autonomous) Coimbatore 641 018, India 130 INDIAN J. CHEM., SEC B, JANUARY 2008 H Me O O N N Cl N X N O Ph Ph 1 Lofendazam 2a X = Cl Clobazam 2b X = CF3 Triflubazam H O NH2 N HCl + CH3CH=CHCOOH NH 2 N Me H 3 H COMe O O N 9 1N 2 10 (CH3CO)2O 8 3 Et3N / benzene 7 11 N N 4 Me 6 5 Me H COMe 3 4 COPh O N C6H5COCl Et3N / benzene N Me COPh 5 Scheme I pin-2-ones 4 and 5, respectively, adopt endo orienta- of 7.5 (J3a,4a) and 4.2 Hz (J3e,4a) between H3a/H3e and 6b tions. The shielding/deshielding of C4-carbon signal H4 protons and also by X-ray crystallography . 13 1 13 in the C NMR spectra of the compounds 4 and 5 The H and C NMR spectra of the N1,N5-diacyl- tetrahydrobenzodiazepin-2-ones 4 and 5 showed compared to that of the parent 3 was used to decide isochronous nature of the proton and carbon signals at the orientation of the acyl groups at N5 end. It was room temperature indicating that either a fast rotation observed that the C4-carbon signal for the about N-CO bond or the N-C=O groups may adopt N1,N5-diacetyl derivative 4 (δ 51.92 ppm) was exo/endo orientations at N1 and N5 (Figure 1). shielded significantly compared to that of the parent diazepine 3 (δ 54.0 ppm). The shielding of C4-carbon Orientations of acyl groups at N1 and N5 signal by 2.08 ppm indicates that the acetyl group at The semiempirical MO calculations (AM1 and N5 position adopts the exo orientation (syn to C4). PM3 of MOPAC8) and X-ray crystallography9 The exo orientation of the acetyl group at N5 end is suggested that the acetyl and benzoyl groups at N1 supported by semiempirical MO calculations end in the N1,N5-diacyltetrahydro-1,5-benzodiaze- (Figure 1, endo-exo). VENKATRAJ et al.: CONFORMATIONAL ANALYSIS USING NMR AND MO CALCULATIONS 131 The C4-carbon signal for the N1,N5-benzoyl tion CE and around 0° for boat conformation BE. The derivative 5 was not shielded / deshielded signi- dihedral angle C10-N1-C2-C3 calculated from AM1 ficantly compared to that of the parent diazepine 3. and PM3 semiempirical MO calculations for the Hence, the X-ray crystal structure of 5 and semi- compound 4 were -4.24° and 3.47°, respectively. empirical MO calculations were utilized to predict the Hence, the molecule 4 prefers to adopt boat orientation of benzoyl group at N5. The semi- conformation BE. The heats of formation values from empirical MO calculations (AM1 and PM3) and AM1 and PM3 calculations (Tables III and IV) also X-ray crystallography predict the exo orientation of showed a preference for the boat conformation BE the benzoyl group at N5 (Figure 1, endo-exo). (Figure 3). The N1,N5-dibenzoyltetrahydro-4-methyl-1,5-benzo- Ring conformations diazepin-2-one 5 prefers boat conformation BE on the The N1,N5-diacetyl derivative 4 may prefer to adopt basis of the discussion made in the case of the any of the chair conformations CE, CA or the boat N1,N5-diacetyl derivative 4. The AM1 and PM3 cal- conformations BE, BA (Figure 2). In the chair CA culations and X-ray crystallographic studies showed a and boat BA forms, the coupling constants J3a,4a and preference for boat conformation BE with endo J3e,4a are expected to be around 2-5 Hz. But one of the orientation of the benzoyl group at N1 and observed coupling constants was larger (12.7 and 4.9 exo orientation of the benzoyl group at N5 (Figure 3). Hz). In addition, analysis using Dreiding models indicated that the chair CA and boat conformations X-Ray crystallography BA require an approximate cis (φ3a,4a) and trans In order to study the conformation of the ring and (φ3e,4a) angle of 60°. But the cis and trans angles orientations of the benzoyl groups in the solid state, calculated using DAERM from the coupling constant the crystal structure of N1,N5-dibenzoyltetrahydro-4- values were 169° and 49°, respectively. Hence, on the methyl-1,5-benzodiazepin-2-one 5 was solved. The basis of the observed coupling constants and seven membered ring adopts boat conformation9 calculated dihedral angles the possibility of the chair BE (Figure 4). The dihedral angle C2-C3-C4-C13 = CA and boat BA conformations was ruled out. -169.59° indicates the equatorial orientation of the Since the C2-C3-C4 part of the chair conformation methyl group. The dihedral angle C4-N5-C22-O23 = CE and boat conformation BE are almost similar, Table II ⎯ The vicinal coupling constant data (in Hz) and the protons at C3 and C4 are expected to show similar corresponding dihedral angles (in degrees) estimated using coupling constants. Hence, the coupling constants can DAERM of the N1,N5-diacyl tetrahydro-1,5-benzo not be used to decide the possibility between the diazepin-2-ones 4 and 5 and parent amine 3 conformations CE and BE. Thus, the choice between Compd J J the conformations CE and BE could be decided by 3e,4a 3a,4a φ3e,4a φ3a,4a using Drieding models which indicated that the 4 4.89 12.70 49 169 dihedral angle between the planes C10-N1-C2 and 5 5.73 11.47 44 164 N1-C2-C3 would be around 60° for chair conforma- 3 4.20 7.50 41 161 Table I ⎯ Spectral data of compounds prepared 4 and 5 1 13 Compd IR H NMR (CDCl3, δ, ppm) C NMR (CDCl3, δ, ppm) Mass (cm-1) (M+) 4 1720 (C(O)-N1- 1.13 (3H, d, Me at C4), 1.84 (3H, s, Me at N5), 18.6 (Me at C4), 22.8 (Me at N5), 27.8 (Me at 260 CO) 1665 1640 2.21 (1H, dd, H3A at C3), 2.49 (1H, dd, H3B N1), 43.0 (C3), 51.9 (C4), 129.0-130.2 (N1-CO, N5- at C3), 2.67 (3H, s, Me at N1), 5.23 (1H, m, (aromatic), 133.5, 136.6 (ipso), 169.5 (C2), CO) C4-H), 7.21-7.53 (4H, m, aromatic).
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