Synthesis and Quantum-Chemical Studies of New Hybrid Heterocyclic Molecules Derived from 3-(Thiocyanatoacetyl)Coumarin

3-(Thiocyanatoacetyl)coumarin, prepared by a reaction of 3-(bromoacetyl)coumarin with KSCN, reacts with primary aryl amines to give new hybrid heterocyclic products, 3-(3-aryl-2-imino-2,3-dihydrothiazol-4-yl)-2Н-chromen-2-ones. The structures and conformational features of the products have been studied by the B3LYP-D3/6-311G(d,p) method.


Introduction
Coumarins belong to privileged scaffolds useful as a starting point for preparation of drug-like molecules [1]. We focused our interests on 3-thiocyanatoacetylcoumarins 1, which are readily available through the bromination of 3-acetylcoumarins followed by subsequent nucleophilic substitution of the bromine atom with the S-C≡N group [2][3][4]. Such thiocyanates have a high reactivity and are useful as reagents for preparation of polyfunctional and poly-heterocyclic structures. In general, α-thiocyanatocarbonyl compounds can be used in the synthesis of sulfur-containing heterocycles with a potential biological activity (for reviews, see References [5][6][7]).

Results and Discussion
Thus, the reaction of compound 1 with anilines in an acidic medium lead to the formation of hybrid polycyclic systems 2 bearing the iminothiazoline fragment (Scheme 1). Such coumarin derivatives are of practical interest as perspective candidates for bio-screening [8][9][10][11].  The presence of the imino group in the thiazole fragment provides very wide synthetic possibilities. Thus, the reaction of 2 with chloroacetyl chloride proceeds smoothly to give new chloroacetamides 3 (Scheme 2) useful as alkylating agents and capable of introducing hybrid polycyclic fragments into molecules.
The resulting compounds 2 were characterized using spectral methods (IR, NMR spectroscopy). In addition, quantum-chemical DFT (density functional theory) calculations of the most stable conformers of compound 2а (R = H) were performed ( Figure 1).

Scheme 2. The acylation of iminothiazolines 2.
The preliminary conformational analysis of 3-(2-imino-3-phenyl-2,3-dihydrothiazol-4-yl)-2H-chromen-2-one using the semi-empirical RM1 method showed that this molecule can exist as two conformers (s-trans and s-cis), which are due to rotation around the С8-С11 bond ( Figure 1). Since semiempirical methods in many cases led to incorrect results, further geometrical optimization and energy DFT calculations were performed using the well-known functional B3LYP. The D3 Grimme's correction was used to describe the dispersion contribution to the energy to allow one to discuss the effect of the Van der Waals forces. The choice of the split valence basis set 6-311(d, p) was due to a compromise between the accuracy and the time of the calculation. The molecular structures of these conformers that were optimized using the B3LYP-D3/6-311G (d, p) method are shown in Figure 1. According to the calculated data, the difference in energy between these conformations is 5.5 kJ/mol (the s-trans conformer is more stable). The C7-C8-C11-N12 torsion angle between the coumarin and thiazole fragments in the s-trans conformer is 24°, while the analogous C9-C8-C11-N12 angle in the s-cis conformer is 56°. It clearly points to the absence of conjugation between the heterocyclic cores. The C11-N12-C16-C21 torsion angle, which characterizes the mutual arrangement of the thiazole ring and aromatic ring in these conformers has somewhat closer values (45° and 55°, respectively).

3-(Thiocyanatoacetyl)coumarin (1).
3-Bromoacetylcoumarin (11.25 g, 0.05 mol) was placed in a flask and dissolved in 20 mL of acetone upon gentle heating. In the resulting solution, 5.8 g (0.06 mol) of potassium thiocyanate was added slowly with stirring. The formation of white precipitate (KBr) was observed. After 2 h, the reaction mixture was diluted with cold water, and the precipitated light-yellow solid was filtered off and recrystallized from acetone-EtOH. The yield was 7.7 g (67%). The purity of the product was checked by TLC (Sorbfil plates, "Imid Ltd." (Krasnodar)) using acetone: CCl4 1:1 mixture as an eluent.

Synthesis of 3-(2-imino-3-phenyl-2,3-dihydrothiazol-4-yl)-2H-chromen-2-one (2a)
Aniline (0.6 mL, 0.005 mol) was placed in a flask and neutralized with an equivalent amount of concentrated aq. HCl. The resulting hydrochloride was dissolved in EtOH. To the solution of PhNH2×HCl, a solution of 1.0 g (0.005 mol) of thiocyanatoacetylcoumarin (1) in a minimum volume of 1:1 DMF-EtOH mixture was added. A gaseous HCl was passed through the reaction mixture for 2 h. Then, the mixture was diluted with water to give a light-yellow precipitate. The yield of product (2a) was 1.0 g (64%). The purity of the product was checked by TLC (thin-layer chromatography) (Sorbfil plates, "Imid Ltd." (Krasnodar, Russia) using acetone: CCl4 1:1 mixture as an eluent. IR spectrum (ν, cm Funding: The reported study was funded by RFBR and Krasnodar region according to the research project № 19-43-230007.

Conflicts of Interest:
The authors declare no conflict of interest.