The presentation of regioselectivity of 1-ethyl-3-[4-(6,7,8,9- tetrahydro-5Н-[1,2,4]triazolo[4,3-а]azepin-3-yl)phenyl]thiourea cyclization with α-bromoketone

An important step in creation of potential drugs is to confirm the structure of the compounds synthesized. This requires the use of modern physical and physico-chemical methods of research. Nowadays a promising scientific direction for searching biologically active substances is the study of 2-R-imino-1,3-thiazoline derivatives. Aim. To study regioselectivity of the cyclization reaction of 1-ethyl-3-[4-(6,7,8,9-tetrahydro-5Н-[1,2,4]triazolo[4,3-а] azepin-3-yl)phenyl]thiourea with 2-bromo-1-phenylethanone. Results. The true structure of the interaction product was determined by the methods of 1H NMR spectroscopy and X-ray analysis. Quantum chemical calculations of the electronic structure, geometry and thermodynamic parameters of the initial thiourea three tautomers were given. Activating energy of tautomer 1A belower than 1B one, the state of 1B has modest lower relative energy, consequently tautomer 1A is more credible state. Thus, the conclusion can be made that the reaction will proceed by 1-1A-3A. Experimental part. Quantum chemical calculations of the electronic structure, geometry and thermodynamic parameters of the initial thiourea three tautomers were determined by the density functional theory (DFT) methods using the GAUSSIAN W09 computer program. The effect of the solvent was considered within the framework of polarized continuum model (PCM). Conclusions. Based on the physico-chemical studies and quantum chemical calculations of the reaction cyclization direction the conclusion has been made that the cyclization reaction of 1-ethyl-3-[4-(6,7,8,9-tetrahydro5Н-[1,2,4]triazolo[4,3-а]azepin-3-yl)phenyl]thiourea 1 with 2-bromo-1-phenylethanone 2 is regioselective, and it leads to formation of more thermodynamically advantageous (stable) isomer 3A.

Выводы. На основе проведенных физико-химических исследований и квантово-химических расчетов направления прохождения реакции конденсации 1-этил-3- [4-6,7,8,9- The main task of pharmaceutical and organic chemistry is modeling of new biologically active substances and their synthesis. An important step in creation of potential drugs is to confirm the structure of the compounds synthesized. This requires the use of modern physical and physico-chemical methods of research.
Nowadays a promising scientific direction for searching biologically active substances is the study of 2-R-imino-1,3-thiazoline derivatives.
According to the literature data substances containing the iminothiazoline nucleus proved themselves as antimicrobial [1], anti-inflammatory and analgesic agents [2,3]; substances with triazole and azepine cycles showed themselves as antifungal [4] and anticorrosive [5] agents.

Materials and Methods
The synthesis was carried out by the condensation reaction of 1-ethyl-3-[4-(6,7,8,9-tetrahydro-5Н-[1,2,4]triazolo[4,3-а]azepin-3-yl)phenyl]thiourea 1 with 2-bromo-1-phenylethanone 2 according to the procedure described in the works [10,11]. Due to tautomerization of asymmetric thiourea 1 the reaction of cyclization is theoretically possible by directions A and B (Scheme): In the 1 H NMR-spectrum of compound 3 synthesized ( Fig. 1) the signals of aromatic protons as multiplets at 7.50-7.60 ppm (the aromatic system in position C-4 of the thiazole cycle) and as a doublets at 7.41 and 7.69 ppm (the aromatic system bound with an exocyclic Nitrogen atom), as well as the signal of the methine proton of the thiazole cycle as a singlet at 6.50 ppm were identified. A set of signals of the azepine cycle protons was presented in the spectrum as multipletes at 1.79-1.89, 3.10-3.25 and 4.20-4.30 ppm. The signals of the ethyl residue protons were at 3.90 ppm as a quartet (the methylene group bound with an endocyclic Nitrogen atom) and at 1.15 ppm as a triplet (the methyl group bound with the methylene group).
Quantum chemical calculations were conducted by the licensed version of the GAUSSIAN W09 program [12]. It allowed calculating the spatial structure and physico-chemical properties of molecular systems with high accuracy and reliability both in the gas-phase and the condensed state. Tautomers are different spatial configurations of the molecular system. The certain local minimum on the surface of the potential energy corresponds to every permanent configuration. For every spatial configuration of the molecular system, in particular for permanent and transitional configurations, it is possible to calculate energies and thermodynamic parameters, such as enthalpy, free energy, entropy, etc. Transition between two permanent configurations requires overcoming of a certain power barrier, i.e. passing through a saddle point on the surface of the potential energy. The system configuration in the saddle point corresponds to the transitional structure (between two local minima). The presence of one imaginary frequency in the vibration spectrum of the equilibrium structure found confirms that it is actually the transitional one. Activation energy was calculated as a difference in energies of the transitional and permanent struc- Within the framework of the model of the continuum polarized [13] a solvent is considered to be the continuous, homogeneous dielectric continuum characterized by the values of static and high-frequency dielectric constants. The molecule of the dissolved substance is located in the cavity with the solvent around it. The cavity is constrained by a set of spheres centered on the nuclei of atoms. Calculations were conducted for tautomers 1, 1A and 1B in a free state and in the medium to be polarized (water). The most popular B3LYP functional and a relatively new M06-2X functional were used. Using M06-2X it is possible to achieve greater accuracy when calculating thermodynamic and kinetic characteristics [14], even if simple basic sets, such as 6-31 + G(d), are applied.
Using the methods of B3LYP/6-31 + G(d) and M06-2X/6-31 + G(d) the spatial structure of molecules 1, 1A, 1B was optimized in the gas phase and in the water solution. The following energies and thermodynamic parameters were calculated: total energy, zero point energy (ZPE), enthalpy (∆Н), free Gibbs energy (∆G), entropy (S), dipole moments, etc. The relative energies and activation energies of tautomeric trans-formation for the transitional state 1↔1А and 1↔1В were also calculated. The best agreement was achieved with experimental data by using М06-2Х method.

Results and Discussion
The 1 Н NMR-spectrum of compound 3 can not give an unequivocal idea of the true structure of the interaction product. The analysis of the 1 H NMR-spectrum of compound 3 has shown the presence of only one set of proton signals. It indicates in favor of formation of one of the possible isomers (3А or 3В).
When comparing quantum chemical calculations of the relative energy of 1A and 1B tautomers (Fig. 4) the conclusion can be made that the reaction will proceed by 1→1A→3A.
Conflicts of Interest: authors have no conflict of interest to declare.