The Use of Umbelliferone in the Synthesis of New Heterocyclic Compounds

New coumarin derivatives, namely 7-[(5-amino-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one (4), 5-[(2-oxo-2H-chromen-7-yloxy)methyl]-1,3,4-thiadiazol-2(3H)-one (5), 2-[2-(2-oxo-2H-chromen-7-yloxy)acetyl]-N-phenylhydrazinecarbothioamide (7), 7-[(5-(phenylamino)-1,3,4-thiadiazol-2-yl)methoxy]-2H-chromen-2-one (8) and 7-[(5-mercapto-4-phenyl-4H-1,2,4-triazol-3-yl)methoxy]-2H-chromen-2-one (9) were prepared starting from the natural compound umbelliferone (1). The newly synthesized compounds were characterized by elemental analysis and spectral studies (IR, 1H-NMR and 13C-NMR).


Introduction
Lactones constitute a large and diverse group of biologically active plant chemicals that have been identified in several plant families [1][2][3]. Coumarin and its derivatives represent one of the most active classes of compounds, possessing a wide spectrum of biological activity [4][5][6][7]. Many of these compounds have proved to be active as antibacterial [8,9], antifungal [10], anti-inflammatory [11], OPEN ACCESS anticoagulant [12], anti-HIV [13] and antitumor [14] agents. Coumarins also have superior thermal stability and outstanding optical properties, including an extended spectral response, high quantum yields and superior photostability. Optical applications of these compounds, such as laser dyes, nonlinear optical chromophores, fluorescent whiteners, fluorescent probes, polymer science, optical recording and solar energy collectors, have been widely investigated [15][16][17][18][19]. The chemistry of thiosemicarbazones has received considerable attention because of their variable bonding modes, promising biological implications, structural diversity, and ion-sensing ability [20][21][22]. Thiazolidinones substituted in the 2-position, its derivatives and analogues exhibit unusually high in vitro activity against Mycobacterium tuberculosis [23][24][25]. In the current study we aimed to synthesize some new coumarins derived from umbelliferone (7-hydroxycoumarin) and thiazoles, with predictable biological activities. The chemical structures of the synthesized compounds were proven by IR, NMR spectra and elemental analysis data.
In the IR spectrum of ethyl 2-(2-oxo-2H-chromen-7-yloxy)acetate (2) the lactone carbonyl stretching frequency was observed at 1759 cm −1 , whereas the ester carbonyl stretching appeared at 1717 cm −1 , and a C-H aliphatic stretching frequency appeared at 2987 cm −1 that was not seen in the IR spectrum of the starting material umbelliferone, in addition of the disappearance of the hydroxyl group. In the 1 H-NMR spectrum of compound 2, a 3H triplet was observed at 3.126 ppm due to the ester CH 3 protons and a quartet at 3.81 ppm due to the ester CH 2 protons. The isolated CH 2 protons were observed downfield as a singlet (2H) at 4.770 ppm and triplet (2H) at 5.260, 5.239 and 5.27. The coumarin alkene C-H appeared at 5.416 ppm. The protons of the aromatic ring were observed as quartet (7.472, 7.457, 7.413, 7.216 ppm for C 6 -H), quintet (7.565 7.543, 7.537, 7.525, 7.519 ppm for C 5 -H) and doublet, 7.895 ppm, 7.871 ppm for C8-H. The 13 C-NMR spectrum analysis for compound 2, combined with the information from 1 H-NMR experiments, can be considered enough to guide future synthetic work.
In the IR spectrum of 2-(2-oxo-2H-chromen-7-yloxy)acetic acid (3) the lactone carbonyl stretching frequency was observed at 1755 cm −1 , whereas the carboxylic acid carbonyl stretching appeared at 1724 cm −1 , and the hydroxyl group appeared as a broad band at 2975-3170 cm −1 . In the 1 H-NMR spectrum, the CH 2 protons were observed downfield as a singlet (2H) at 4.83 ppm, and triplet (2H) at 5.311, 5.3 and 5.28. The C-H (alkene) of coumarin appeared at 5.418 ppm. The protons of the aromatic ring were observed as quartet (7.47, 7.455, 7.411, 7.207 ppm for C 6 -H), triplet (7.555 7.531, 7.527 ppm for C5-H) and doublet (7.90 ppm, 7.876 ppm) for C8-H. The 13 C-NMR spectrum analysis for compound 3, combined with the information from 1 H-NMR experiments, can be considered enough to prove the structure of compound 3.
The IR spectrum is good evidence for formation of compound 4. The absence of a hydroxyl group at 2975-3170 cm −1 , and appearance of a new band at 3302 and 3343 cm −1 , and a lactone carbonyl stretching frequency at 1749 cm −1 were observed. In the 1 H-NMR spectrum, a singlet (thiadiazole-NH 2 ) at 4.94 ppm and the C-H (alkene) of the coumarin appeared at 5.76 ppm and 5.891. The protons of the aromatic ring were observed as multiplet (7.51-7.28). In the 13 C-NMR, 163.5 and 176.4 were new and due to the heterocyclic ring carbons.
The IR spectrum of compound 5 showed a carbonyl group at 1713 cm −1 , in addition to an amino group at 3297 cm −1 . In the 1 H-NMR; the coumarin C-H (alkene) protons appeared at 5.81 ppm (singlet) and 6.43 ppm (singlet) and the singlet (NH) at 5.31 ppm. In the 13 C-NMR the thiadiazole ring carbonyl carbon atom appears at very low field (171.2).
Hydrazinolysis of compound 2 with hydrazine hydrate afforded 2-(2-oxo-2H-chromen-7yloxy)acetohydrazide (6) in good yield. The IR spectra of compound 6 showed absorption bands in the 3351.3, 3287.1 cm −1 region (hydrazide NH-NH 2 ), 1689.2 cm −1 (amide-C=O carbonyl stretching), and 1761.5 cm −1 (lactone-C=O carbonyl stretching). The 1 H-NMR spectrum exhibited a singlet due to the -CO-NH-NH 2 proton at δ 7.93 ppm. For compound 7, the IR spectrum has the following characteristic absorption bands: ν N-H (3367.6, 3301.2, 3278.9 cm −1 ); ν C=O (1763 lactone; 1692.7 amide carbonyl cm −1 ), ν C=S (1258.5 cm −1 ). In the IR spectrum of compound 8, no absorption band at 1692.7 cm −1 was detected, indicating the absence of the amide carbonyl group, which is evidence for the conversion of compound 7 to compound 8. Also, in the IR spectrum of the new heterocyclic compound 8 a stretching band characteristic of the C=N group from the thiadiazole nucleus appeared at 1620.6 cm −1 . Although two types of tautomers, thione or thiole, could be expected from the cyclization of compound 7, under basic conditions, only the thione type compound 9 was observed. The existence of the thione form predominantly in the solid state is demonstrated by the presence of two absorption bands at 1257 cm −1 and 3389.3 cm −1 belonging to the ν C=S and ν NH groups, respectively, and by absence of ν SH . In the 13 C-NMR spectra of new heterocyclic compounds 8 and 9 the absence of the signals for the ester carbonyl and the absence of a thiocarbonyl carbon in compound 8, confirmed that cyclization of compound 7 took place. In compound 9 the signal at 168.4 ppm indicated that in solution this compound exists predominantly in the thione tautomeric form (Scheme 3). Scheme 3. Tautomerization of thione.

Atomic Charges and Stabilities
The theoretical studies for compound 5 revealed that the atomic charges have been affected by the presence of the ring substituent. The minimized geometry is shown in Figure 1, where the calculated atomic charges for the compound are also indicated. It can be seen from Figure 1

Density Function Theory (DFT)
DFT calculations were performed for compounds 5 and 8. Optimized molecular structures of the most stable forms are shown in Figure 3. Their calculated energies and relative energies are presented in Table 1. Molecular orbital calculations provide a detailed description of orbitals including spatial characteristics, nodal patterns and individual atom contributions. The contour plots of the frontier orbitals for the ground state of 5 and 8 are shown in Figure 4, including the Highest Occupied Molecular Orbital (HOMO) and the Lowest Unoccupied Molecular Orbital (LUMO). It is interesting to see that both orbitals are substantially distributed over the conjugation plane. It can be seen from the Figure 4 that the HOMO orbitals are located on the substituted molecule while LUMO orbitals resemble those obtained for the unsubstituted molecule and therefore the substitution has an influence on the electron donation ability, but only a small impact on electron acceptance ability [27]. The orbital energy levels of HOMO and LUMO of compounds 5 and 8 are listed in Table 2. It can be seen that the energy gaps between HOMO and LUMO is about 0.11 and 0.008 H.a. for the compounds 5 and 8, respectively. The lower value in the HOMO and LUMO energy gap explain the eventual charge transfer interaction taking place within the molecules. The dipole moments of compounds 5 and 8, were also calculated and listed in Table 3. The dipole moment for compounds 5 is oriented inwards, while the dipole moment for compounds 8, is oriented outwards.

General
The chemicals used for the synthesis were supplied by Sigma-Aldrich. Purity of the compounds was checked on thin layer chromatography (TLC) plates (Silicagel G) using the solvent systems benzene-ethyl acetate-methanol (40:30:30, v/v/v) and toluene-acetone (75:25, v/v). The spots were located under UV light (254 and 365 nm). The IR spectra were obtained on a Thermo Scientific, Nicolet 6700 FT-IR spectrometer (without KBr or CsI pellets). The 1 H-NMR spectra were obtained on a Jeol jnm-ECP400 FT-NMR system. Elemental microanalysis was carried out using a model 5500-Carlo Erba C.H.N elemental analyzer instrument. A Gallenkamp M.F.B.600.010 F melting point apparatus was used to measure the melting points of all the prepared compounds.

DFT
The molecular drawings of the nine thio compounds were plotted using Visualization Materials Studio 5.5. All quantum chemical calculations were performed using Density Functional Theory (DFT) as implemented in the Materials Studio 5.5 software. DMol 3 model was employed to obtain quantum chemical parameters and to optimize the molecules' geometry. These calculations employed an ab initio, generalized gradient approximation (GGA) with the Lee-Yang-Parr correlation functional (BLYP) functional and Double Numerical d-functions (DND) basis set. This approach is shown to yield favorable geometries for a wide variety of systems. The following quantum chemical indices were calculated: the energy of the highest occupied molecular orbital (HOMO), the energy of the lowest unoccupied molecular orbital (LUMO) and dipole moment.

Conclusions
In this study, the compounds 2-9 were synthesized, and characterized using various spectroscopic methods and elemental analysis. The synthesized compounds were studied theoretically and the atomic charges, heat of formation and stereochemistry were estimated, and it was found that compounds 5 and 8 are not planar.