Novel synthesis of quinazolino[3,2-a ][1,5]benzodiazepines: an experimental and computational study

5-Substituted 7-methyl-6,7-dihydroquinazolino[3,2-a ][[1,5]benzodiazepin-13(5 H )-one derivatives were synthesized in a one-step sequential acylation-cyclization reaction with a simple procedure from an appropriate 5-substituted 3-methyl-1,3,4,5-tetrahydro-2 H -1,5-benzodiazepin-2-one and 2-sulfinylaminobenzoyl chlorides. The mechanism of the heterocyclization reaction was studied by the DFT method using the B3LYP functional and 6-31+G(d, p) basis set.


Introduction
Benzodiazepines constitute an important class of psychopharmaceuticals due to their broad range of activities, in particular as tranquilizers, and they also have a traditional place in antiepileptic therapy. 1,2Moreover, benzodiazepines are effective as nonnucleoside inhibitors of HIV-1 reverse transcriptase. 3Therefore, the benzodiazepine nucleus is a well-studied pharmacophoric scaffold that has emerged as a core structure unit of various biological activities and the research in this area is very active. 4It is well documented that the pharmacological activity could be increased when an additional heterocyclic ring is fused to the heptatomic diazepine nucleus. 5Thus, considerable attention has been directed towards the synthesis of polycyclic 1,4-benzodiazepines, as well as the 1,5-isomers. 6Recently, many novel compounds containing heterocyclic ring systems such as triazole, thiazole, imidazole, quinoline, oxadiazole, pyran, oxazole, furan and pyrimidine annelated to the bicyclic 1,5-benzodiazepine have been synthesized by our [7][8][9][10][11][12] and other research groups. 6,13,14Fused quinazolinones are important heterocyclic compounds with widespread occurrence in alkaloids possessing diverse biological activity. 15Various methods for the synthesis of these alkaloids encompassing a quinazolino [1,4]benzodiazepine moiety in their skeleton have been developed and numerous research papers have recently appeared. 16,17s part of our current studies on the development of efficient methods for the preparation of polycyclic 1,5-benzodiazepines we investigated the synthesis of quinazolino [1,5]benzodiazepines. 18,19 A wide range of novel 6,7-dihydroquinazolino [3,2-a] [1,5]benzodiazepinone derivatives were synthesized in a two-step method involving (i) benzoylation of variously substituted 1,3,4,5-tetrahydro-1,5-benzodiazepin-2-ones with 2-nitrobenzoyl chloride, and (ii) a metal induced reductive N-heterocyclization of the obtained 2-nitrobenzoylamides.Although this method displayed notable advantages, such as mild reaction and simple operation, it is not suitable unfortunately for the transformation of appropriate 3-methyl substituted 1-(2nitrobenzoyl)-1,5-benzodiazepinone derivatives.Herein we report a novel procedure for the synthesis of 7-methyl-6,7-dihydroquinazolino[3,2-a] [1,5]benzodiazepinones from 5-substituted 3-methyl-1,5-benzodiazepin-2-one derivatives.
Also in this article, the quantum chemical analysis of acylation-cyclization reaction mechanism is presented by calculation of reaction stationary points: reactants (R), products (P), intermediates (I) and transition states (T) on the reaction potential energy profile. 20,21alculations of the intrinsic reaction coordinates (IRC) allow evaluate electron density changes along the reaction progress in the transformation from reactant to the final product.The most probable acylation-cyclization pathway is discussed in detail in the present study.Moreover, the variations of charge, bond order, and bonding character transformations on the reaction progress have been investigated.
In the course of these studies it was established that 3-methyl substituted 1-(2-nitrobenzoyl)amides 2 (R 1 =CH 3 ) did not cyclize under the reductive N-heterocyclization conditions and the appropriate tetracyclic 1,5-benzodiazepine derivatives were not formed.A theoretical computational investigation of the cyclization reaction mechanism revealed that the presence of substituents in a diazepine ring causes changes in the electron population of the frontier molecular orbitals.The presence of the electron donating 3-methyl substituent decreased the electrophilicity of the carbon C(2) atom of the heterocyclic C=O group, evoking thus the resistance for further intermolecular rearrangements. 18,19This exclusive behavior of starting 3methylsubstituted compounds prompted us to develop an effective synthetic method for the construction of polycyclic 1,5-benzodiazepine derivatives.
The IR spectra of quinazolinobenzodiazepines 5a-f, 8 and 9 show two (5a-d, 8 and 9) or one (5e,f) typical bands in the region of the carbonyl group at 1654-1706 cm -1 and C=N bond absorption peak at 1608-1619 cm -1 .The assignment of the NMR spectral lines was carried out using the substituents additivity rules, signal intensities, multiplicities, and NMR data of structurally related compounds. 18,19arbon atoms are marked arbitrarily in the Figure 1 (A-for compound 1d, B-for compounds 5af, and C-for compounds 8,9) for easier comparison and systematization of obtained data which are presented in the Experimental section.
Starting compounds 1a-f showed characteristic resonances of the NH group proton in region of 8.1-8.8 ppm and of the CO group carbon at 173.5-176.0ppm in 1 H and 13 C NMR spectra, respectively.The disappearance of these resonances in the NMR spectra suggested the formation of compounds 5a-f.The resonances of 3-CH 3 protons in the case of 5a-f compounds were shifted about 0.3 ppm downfield in comparison with starting compounds 1a-f.The integration of 1 H NMR spectra of the newly synthesized 7-methyl-6,7-dihydroquinazolino[3,2-a][1,5]benzodiazepin-13-ones showed the required number of aromatic protons: eight for 5a,b,d,e, thirteen for 5c,f and seven for compounds 8,9.The new characteristic resonances in 13 C NMR spectra in the region of 155.7-158.3ppm and at about 160 ppm assigned to C=N and to 1-CO groups carbon respectively also confirmed the predicted structures of compounds 5a-f.
The precursors 1e and 4 were selected as a model and the detailed reaction mechanism study was carried out using a transition state theory approach. 20,21,25,26Additionally the electron density transformation along the reaction minimal energy path was evaluated by calculation of Natural Bond Orbital (NBO) charges and Wiberg bond indexes (BI). 38he polarity of reaction conditions should play a very important role in stabilization of different intermediates and transition states. 26The acylation-cyclization reaction was modeled in the consideration of DCE solvent to simulate experimental conditions.
Three presumed most probable reaction pathways (I-III) analyzed on the basis of the known experimental investigations dealing with sulfinylamine and carbonyl group interaction and acylation reaction mechanism 39 for the theoretical study of acylation-cyclization reaction are presented in Scheme 5.
Thus, in reaction pathway (I) the attack of the carbon atom C(1') of 4 on the N(1) atom of 1e proceeds through transition structure T1 and transforms to intermediate I1 together with the migration of chloride and hydrogen atoms until HCl forms.The calculated Gibbs free energies of activation (∆G ‡ ) for pathway (I) were 41.13 and 32.17 kcal/mol in the gas phase and in the solvent, respectively.In pathway (II), the initial attack of N(2') and S(2') atoms of the 2sulfinylamino group of 4 on the C(2)=O(2') bond atoms proceeds via transition state T1' leading to intermediate I1'.The ∆G ‡ for pathway (II) were 61.49 and 42.09 kcal/mol in the gas phase and in the solvent, respectively.In pathway (III), the simultaneous interaction of both reacting centers, C(1') and the N(2') and S(2') atoms of 4 with N(1) and the C(2)=O(2') bond atoms of 1e accordingly, goes via transition state T1'' leading to the formation of the new N(1)-C(1'), C(2)-N(2'), S(2')-O(2) bonds in one step.The calculated ∆G ‡ for pathway (III) were 47.94 and 39.67 kcal/mol in the gas phase and in the solvent, respectively.The obtained results indicate that the reaction pathway (I) is the most energy-favorable pathway for initial interaction of chloride 4 with benzodiazepinone 1e.Considering this, we further focused our attention on the detailed description of this reaction pathway.The B3LYP/6-31+G(d,p) calculated geometric parameters of the reaction stationary points: R, T, I and P for pathway (I) located along the reaction coordinate are presented in Scheme 6.
The ∆G ‡ of T activation or I stabilization were calculated as the difference of free energies between T and the prereactive complexes (R or I) discussed throughout the text and shown in the reaction free-energy profile in Figure 2.   The relative B3LYP/6-31+G(d,p) Gibbs free energy (∆G ‡ (kcal/mol), relative to R) for all stationary points are given in Table S1.(Tables S1-S5 are listed in supplementary information file).The B3LYP/6-31+G(d,p) calculated total energies (E) and Gibbs free energies (G) with the imaginary frequency (νi) modes of transition states are listed in Table S2.The important for acylation-cyclization reaction progress bond distances (BD), Wiberg bond indexes (BI) and the charges on the selected atoms calculated using natural population analysis (NPA) for all stationary points are summarized in Tables S3 The detailed theoretical analysis of the interaction of 3,5-dimethyl-1,3,4,5-tetrahydro-2H-1,5benzodiazepin-2-one (1e) with 2-sulfinylaminobenzoyl chloride (4) showed that the acylationcyclization reaction can be described as sequential three-step process.Firstly, the pre-reactive reactant complex is activated to intermediate with stabilized Van der Waals interaction between Cl and H atoms. Secondly, the Van der Waals stabilized intermediate complex transforms to the cyclic tetragonal σ-bonded intermediate complex with the activation barrier of 38.18 kcal/mol suggesting that this step along the reaction path is rate limiting.Thirdly, the tetragonal σ-bonded intermediate transforms into the final product 5,7-dimethyl-6,7-dihydroquinazolino[3,2a] [1,5]benzodiazepin-13(5H)-one (5e) and SO 2 with the activation barrier of 8.68 kcal/mol.
During the acylation-cyclization reaction pathway, the transfer of the charge and π bond electron density is significant.This suggests the complicated nature of σ-and π-bonding transformations on the reaction path.The solvent influence on reaction rate points out that the solvents effectively lower the energy of reaction barrier and favor the reaction path.

Conclusions
A simple and efficient method for the preparation of 5-substituted 7-methyl-6,7-dihydroquinazolino[3,2-a][1,5]benzodiazepine-13-ones via a single acylation-cyclization process using readily available 2-sulfinylaminobenzoyl chlorides is described.Operational simplicity and good yields are the salient features of this method.This method may be applicable for the synthesis of libraries of fused polycyclic 1,5-benzodiazepin-2-ones.Furthermore, a detailed theoretical analysis of the acylation-cyclization reaction is described for the first time.

Computational details
The relevant stationary points were fully optimized in the gas phase using DFT method with hybrid density functional B3LYP using 6-31+G(d,p) basis set.Stationary points were further characterized as minima with all real frequencies or as transition states with only one imaginary frequency by computations of harmonic vibrational frequencies at the same theory level as geometry optimization.The connection between the different transition states and reaction intermediates was ensured by intrinsic reaction coordinate calculations. 27"∆G ‡ were calculated as the difference of free energies between transition states and intermediate complexes.Zeropoint energies and thermodynamic parameters at 298 K and 100 kPa were obtained from harmonic vibrational frequency calculations.In order to account for the solvent effects, the solvation energies were calculated on the gas-phase optimized structures with the self-consistent reaction field method on the basis of the polarized continuum model (PCM). 40In this work, single-point energy calculations at the PCM/6-31+G(d,p) level were carried out in DCE solution on the basis of the gas-phase optimized geometries as implemented in Gaussian03. 41

Scheme 5 .
Scheme 5. B3LYP/6-31+G(d,p) calculated possible reaction pathways (I-III) for acylationcyclization reaction of 1e and 4. Activation Gibbs free energies (∆G ‡ , kcal/mol) for gas phase (regular font) and for solvent phase (italic font) were taken as the difference between T and R of free energies.

Figure 2 .
Figure 2. Schematic relative Gibbs free-energy profile for the formation of 5e from 1e and 4 in the gas phase (dashed line) and solvent phase (solid line).∆G rel of activation and stabilization for gas phase (regular values) and solvent phase (italic values).