First X-ray Crystal Structure Characterization, Computational Studies, and Improved Synthetic Route to the Bioactive 5-Arylimino-1,3,4-thiadiazole Derivatives

Abstract

N-arylcyanothioformamides are useful coupling components for building key chemical intermediates and biologically active molecules in an expedited and efficient manner. Similarly, substituted (Z)-2-oxo-N-phenylpropanehydrazonoyl chlorides have been utilized in numerous one-step heteroannulation reactions to assemble the structural core of several different types of heterocyclic compounds. Herein, we demonstrate the effectiveness of the reaction of N-arylcyanothioformamides with various substituted (Z)-2-oxo-N-phenylpropanehydrazonoyl chlorides to produce, stereoselectively and regioselectively, a range of 5-arylimino-1,3,4-thiadiazole derivatives decorated with a multitude of functional groups on both aromatic rings. The synthetic methodology features mild room-temperature conditions, large substrate scope, wide array of functional groups on both reactants, and good to high reaction yields. The products were isolated by gravity filtration in all cases and structures were confirmed by multinuclear NMR spectroscopy and high accuracy mass spectral analysis. Proof of molecular structure of the isolated 5-arylimino-1,3,4-thiadiazole regioisomer was obtained for the first time by single-crystal X-ray diffraction analysis. Crystal-structure determination was carried out on (Z)-1-(5-((3-fluorophenyl)imino)-4-(4-iodophenyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl)ethan-1-one and (Z)-1-(4-phenyl-5-(p-tolylimino)-4,5-dihydro-1,3,4-thiadiazol-2-yl)ethan-1-one. Similarly, the tautomeric structures of the N-arylcyanothioformamides and (Z)-geometries of the 2-oxo-N-phenylpropanehydrazonoyl chloride coupling partners were proven by X-ray diffraction studies. As representative examples, crystal-structure determination was carried out on (4-ethoxyphenyl)carbamothioyl cyanide and (Z)-N-(2,3-difluorophenyl)-2-oxopropanehydrazonoyl chloride. Density functional theory calculations at the B3LYP-D4/def2-TZVP level were carried out to rationalize the observed experimental findings.

Keywords: 1,3,4-thiadiazole; N-arylcyanothioformamide; density functional theory; hydrazonoyl chloride; isothiocyanate.

Figure 1

Examples of the 1,3,4-thiadiazole motif in several drugs and promising potential agents and its usefulness in chemical and bioactive agents.

Scheme 1

General preparation of the 1,3,4-thiadiazole nucleus from various routes and reactants.

Scheme 2

(a) Preparation of variously substituted N-arylcyanothioformamides 27a–x and (b) hydrazonoyl chlorides 29a–m. Reagents and conditions: (i) HCl/NaNO₂/H₂O/0–5 °C; (ii) 3-chloropentane-2,4-dione, CH₃COONa/EtOH/0–5 °C.

Figure 2

The crystal structure of (Z)-N-(2,3-difluorophenyl)-2-oxopropanehydrazonoyl chloride (29l) (Deposition Number 2179719). For bond distances (Å) and angles (deg), see Supplementary Materials Section.

Figure 3

The crystal structure of (4-ethoxyphenyl)carbamothioyl cyanide (27p) (Deposition Number 2179720). For bond distances (Å) and angles (deg), see Supplementary Materials Section.

Scheme 3

Synthetic approach to prepare different derivatives of variously substituted 5-arylimino-1,3,4-thiadiazoles 31–92.

Figure 4

Preparation of variously substituted 1,3,4-thiadiazole derivatives 31–92.

Figure 5

Truncated 1D and 2D NMR spectra of 1,3,4-thiadiazole 58: (a) ¹H-NMR; (b) ¹³C-CRAPT NMR; (c) ¹H-¹H-gDQFCOSY NMR; (d) ¹H-¹³C-gHSQC NMR; (e) ¹H-¹³C-gHMBC NMR.

Figure 6

Assigned ¹H- and ¹³C-NMR chemical shifts of 1,3,4-thiadiazole 58.

Figure 7

Thermal ellipsoid plots of (Z)-1-(5-((3-fluorophenyl)imino)-4-(4-iodophenyl)-4,5-dihydro-1,3,4-thiadiazol-2-yl)ethan-1-one (58) with ellipsoids drawn at 50% probability level (Deposition Number 2178549). For bond distances (Å) and angles (deg), see Supplementary Materials Section.

Figure 8

Thermal ellipsoid plots of (Z)-1-(4-phenyl-5-(p-tolylimino)-4,5-dihydro-1,3,4-thiadiazol-2-yl)ethan-1-one (88) with ellipsoids drawn at 50% probability level (Deposition Number 2178551). For bond distances (Å) and angles (deg), see the Supplementary Materials Section S472–S476.

Scheme 4

Proposed mechanism for the formation of substituted 5-arylimino-1,3,4-thiadiazoles from N-arylcyanothioformamide. The thioamide tautomerism of deprotonated reactant 27 is indicated by the double arrow in the middle panel.

Figure 9

Isosurface representation of the Frontier Molecular Orbitals (FMO) for HOMO (A) and LUMO (B) for the unreacted complex of 29 (bottom molecule) with 27 (top molecule). The HOMO for the intermediate state is shown in (C). The level of theory is B3LYP-D4/def2-TZVP. The isosurface value is +/− 0.05 a.u., with the green and blue regions corresponding to the positive and negative signs of the FMO, respectively. Color code for atoms: grey = C, blue = N, red = O, yellow = S, and white = H.

Figure 10

Electronic Density of States (DOS) of the unreacted complex of 29 with 27 at the B3LYP-D4/def2-TZVP level in implicit ethanol as solvent. Total DOS (black) and projected DOS on the reactant 29 (blue) and 27 (red) molecules. The overlap population DOS (OPDOS) is given by the green curve which shows the negligible overlap between MOs below the LUMO level. The vertical dashed line indicates the energy position of the HOMO. The eigenvalues of the Kohn–Sham are indicated by the vertical spikes. Energy units are in hartree and DOS is in hartree⁻¹.

Figure 11

Relaxed structure of the hydrogen-bonded complex between deprotonated 27 (with R = CH₃) at the bottom with an explicit ethanol molecule above. The violet dashes between H26 and N2 atoms indicate the intermolecular hydrogen bond. Color code for atoms: grey = C, blue = N, red = O, yellow = S, and white = H.

Scheme 5

Proposed synthetic approach to prepare different derivatives of variously substituted 5-thioxo-1,2,4-triazoles.