Synthesis , Characterization and Computational Studies of Two Triazaspiro Tetracycles

Two new triazaspiro tetracycles have been synthesized, the compounds have been characterized using spectroscopy, microanalysis and single crystal X-ray diffractometry. The single crystal X-ray crystallography of 4-methyl-8I,10I,17I-triazaspiro[cyclohexane-1,9I-teracyclo[8.7.02,7.011,16]heptadecane]-1I(17),2I(7I),3I,5I,11I,13I,15I-heptaene (compound I) has been discussed. The DFT computed bond angles have been obtained for both compounds and contrasted with experimental results for compound I. The atoms that make up the frontier orbitals which contribute to the reactivity of the compounds have been discussed.


Introduction
The conversion of 2-(2'-aminophenyl)-1H-benzimidazoles to triazatetracycles provides a backbone on which to construct different tetracyclic compounds that are also biologically active.It is well known that amines undergo condensation reactions with aldehydes and ketones but utilization of this transformation in the formation of cyclic amines often requires a more intricate procedure.Thus, cyclic amines have been accessed via a sequence of deprotection followed by intermolecular reductive amination of Boc-protected amino ketones (Boc is tert-butyloxycarbonyl group) under asymmetric transfer hydrogenation conditions. 1 Cyclizations of diamines and ketones have also been catalyzed by HY zeolite at 50 °C under solvent-free conditions yielding benzodiazepines. 2 Benzodiazepine formation has also been reported to occur in the absence of a catalyst. 3A three-component allylation and cyanation reactions utilising a ketone and N-methoxyamine have been reported, and the high nucleophilicity of the N-methoxyamine and high electrophilicity of the corresponding iminium ion enable the concise synthesis of X-trisubstituted amines in a single step. 4A fourth method reported in the literature, the treatment of N-tosylaldimines with acetophenone at room temperature has been reported to give the corresponding N-tosyl β-amino ketones in high yields within 6-9 h.Subsequent reduction and cyclization of the compounds in this case afforded 2,4-disubstituted N-tosylazetidines, comprising a three step high-yielding synthesis from aldimines. 5welve N-glycosyl amines were synthesized using 4,6-O-benzylidene-D-glucopyranose and different substituted aromatic amines, including some diamines that resulted in bis-glycosyl amines.Another set of six N-glycosyl amines was synthesized using different hexoses and pentoses with 2-(o-aminophenyl)benzimidazole.In these reactions only the 2-amino group reacted with the hydroxyl groups of 2-(o-aminophenyl)benzimidazole. 6Reactions of substituted aldehydes with 2-(o-aminophenyl)benzimidazole have been reported to yield Schiff 's bases. 7The syntheses of 2-(2-nitrophenyl)-1-benzoyl-1H-benzimidazole derivatives and their reduction to the corresponding 2-benzimidazoylbenzamides have been reported.The compounds were cleanly and efficiently converted to the corresponding 6-arylbenzimidazo [1,2-c]quinazolines by microwave activation using SiO 2 -MnO 2 as a solid inorganic support. 8In our case the products were accessed via a solvent-free method.Some triazatetracycles have been synthesized heating 2-(2-aminophenyl)benzimidazole and aryl aldehydes under reflux in ethanol for 5 h. 9 Also triazatetracyclic compounds with substituents on the aryl ring have been synthesized from aminophenylbenzimidazole and substituted aryl aldehydes at room temperature in mixtures of ethanol and acetic acid. 10The synthesis of Odame and Hosten: Synthesis, Characterization and Computational ... 1,3,8-triazaspiro[4.5]decane-2,4-diones (spirohydantoins) as a structural class of pan-inhibitors of the prolyl hydroxylase (PHD) family of enzymes for the treatment of anemia has also been reported. 11his work presents the synthesis and characterization of two new triazaspiro tetracycles, their characterization with IR, NMR, GC-MS and microanalysis.The bond angles of compounds I and II computed using the functionals B3LYP, B3PW91 and wB97XD have been compared with experimental bond angles of compounds 1.

X-Ray Crystallography
X-Ray diffraction analysis of compound I was performed at 200 K using a Bruker Kappa Apex II diffractometer with monochromated Mo Kα radiation (λ = 0.71073 Å).APEXII 13 was used for data collection and SAINT, 12 for cell refinement and data reduction.The structures were solved by direct methods using SHELXS-2013, 13 and refined by least-squares procedures using SHELXL-2013, 14 with SHELXLE, 14 as a graphical interface.All non-hydrogen atoms were refined anisotropically.Carbon-bound H atoms were placed in calculated positions (C-H 0.95 Å for aromatic carbon atoms and C-H 0.99 Å for methylene groups) and were included in the refinement in the riding model approximation, with Uiso (H) set to 1.2Ueq (C).The H atoms of the methyl groups were allowed to rotate with a fixed angle around the C-C bond to best fit the experimen-tal electron density (HFIX 137 in the SHELX program suite, 13 with Uiso (H) set to 1.5Ueq (C).Nitrogen-bound H atoms were located on a difference Fourier map and refined freely.Data were corrected for absorption effects using the numerical method implemented in SADABS. 13

3. Computational Studies
All calculations were performed using the GAUSS-IAN program 15 (version 03).The crystal structure was used as an initial molecular geometry for compound I but compound II was drawn using GAUSSIAN VIEW 03 software.The output files were visualized via GAUSSIAN VIEW 03 software. 16The molecular structures of both compounds in the ground state were optimized using DFT with hybrid functionals B3LYP (Becke's three parameter hybrid functional using the LYP correlation functional), 17−18 B3PW91 and wB97XD with 6-31G++ (d,p) basis set.None of the predicted vibrational spectra having any imaginary frequency prove that optimized geometry is located at the lowest point on the potential energy surface.

1. General Studies
Aromatic protons in 1 H NMR were observed between 7.91 and 6.74 ppm for compound I, whilst the signals for compound II were observed between 7.91 and 6.71 ppm.The 1 H NMR spectrum of compound gave sig- Odame and Hosten: Synthesis, Characterization and Computational ... nals for aliphatic protons between 2.50 and 1.00 ppm for compound I and 2.34 and 0.93 ppm for compound II.The DEPT spectrum confirmed the presence of four methylene groups in both compounds.
The HMBC spectrum of compound I showed that the signal at 74.4 ppm is within three bonds of the signals at 6.74 an 6.80 ppm confirming the attachment of the carbonyl contributed by 4-methylcyclohexanone to the 2-aminophenyl moiety.In compound II the HMBC spectrum also showed that resonance at 75.1 ppm was with three bonds of the resonances at 115.8 and 113.2 ppm also confirming the attachment of the 3-methylcyclohexanone to the 2-aminophenyl moiety.Scheme 1 gives the synthesis overview for the formation of two triazaspiro tetracycles.
The proposed mechanism for the formation of triazaspiro tetracyclics is presented in Scheme 2. The reaction is thought to proceed by the attack of the carbonyl carbon of 3-methylcyclohexanone by the lone pair of electrons on the 2-aminophenyl group as shown in 2b.The formation of the hydroxyl group in 2c allows the lone pair of electrons on the nitrogen to attack the carbon of the hydroxyl group with the loss of water to form I.

Characterization of Crystal Structures
Compound I was recrystallized as a white solid from ethanol:THF (1:1).The computed and experimental crystallographic data and selected bond angles for compound I are provided in Tables 1 and 2. The ORTEP diagram for compound I at 50% ellipsoid is presented in Figures 2. Two independent structures were obtained for compound I and both structures have been computed and discussed.I crystallized in the monoclinic space group P21/n.
The experimentally determined bond angle of N13-C121-C126 for compound I was 122.7(1)° which deviates by between 1.0 to 1.2° for the computed bond angles of compounds I and II using the B3LYP, B3PW9 and wB97XD functionals at the 6-311+g(p,d) basis set.The computation of the bond angles of C122-C121-N13 for compounds I and II using the B3LYP, B3PW9 and wB97XD functionals and the 6-311+g(p,d) basis set gave deviations between 0 and 1.1° from the experimentally determined bond angle of 118.0(1)° for compound I.The C122-C11-N11 bond angle for compound I was experimentally determined as 119.5(1)°.The computed bond angles for compounds I and II using the B3LYP, B3PW9 and wB97XD functionals and the 6-311+g(p,d) basis set gave deviations of between 1.6 and 2.2°.The computed bond angles of C122-C11-N12 for compounds I and II using the B3LYP, B3PW9 and wB97XD yielded deviations of between 0.3 and 0.7° from the experimentally determined bond angle of compound I which was 126.7(1)°.The N11-C11-N12 bond angle for compound I obtained from experiment was 113.8(1)°.When computed using the B3LYP, B3PW9 and wB97XD functionals at the 6-311+g(p,d) basis set the results gave deviations between 1.1 and 1.8° from the experimental value.The C11-N11-C111 bond angle for compound I was experimentally determined as 106.2(1)°.Computation using the B3LYP, B3PW9 and wB97XD functional at the 6-311+g(p,d) basis set gave results which deviates from the experimental result by ±0.3°.The experimentally determined C11-N12-C112 bond angle for compound I was 104.3(1)°.

4. HOMO-LUMO Analysis
The HOMO and LUMO are the main orbitals that determine chemical stability of any species. 19The HOMO represents the ability to donate an electron whilst the LUMO represents the ability to accept an electron.The energy of the HOMO is directly related to the ionization potential whilst the energy of the LUMO is related to the electron affinity.The energy difference between HOMO and LUMO orbitals, known as the energy gap, determines the stability or reactivity of molecules. 20The energy gap is a critical parameter in determining molecular electrical transport properties because it is a measure of electron conductivity. 21The hardness of a molecule also corresponds to the gap between the HOMO and LUMO orbitals. 22or the different functional and basis sets the HOMO and LUMO are mostly delocalized over the 2-aminophe- nyl-1H-benzimidazole delocalized indicating that during charge transfer in a reaction the molecule is stabilized by delocalization of electrons over the 2-aminophenylbenzimidazole, regardless of the level of theory and the basis set used.Table 3 gives the frontier orbitals for compounds I and II using the B3PLYP, B3PW91 and wB97XD functional at the 6-31++ g(d,p) basis set.

Figure 1
Figure 1 gives the results of the 1 H NMR monitoring of the progress of the reaction of 4-methylcyclohexanone

Table 1 .
Crystallographic data and structure refinement summary for compound I

Table 2 .
Summary of theoretical and experimental bond angles of 4-methylcyclohexanone derivative as well as the computed bond angles of 3-methylcyclohexanone

Table 3 .
HOMO-LUMO orbitals of compounds I and II