Synthesis and structure confirmation of 2,4-disubstituted thiazole and 2,3,4-trisubstituted thiazole as thiazolium bromide salts

The synthesis of 4-substituted 2-(2-arylhydrazinyl)thiazol-3-ium bromides and 4-aryl-2-(substituted amino)-3-(phenylamino)thiazol-3-ium bromide derivatives in high yields from the interaction of mono- and di-substituted thiosemicarbazides with phenacyl bromide derivatives is reported. The synthesized products have been elucidated using various spectroscopic tools such as IR, NMR, and mass spectrometry. Also the structure of three of the obtained compounds have been confirmed using X-ray crystallographic analyses, which showed that compounds 2-[2-(2,4-dinitrophenyl)hydrazinyl]-4-phenylthiazol-3-ium bromide and 4-phenyl-2,3-bis(phenylamino)thiazol-3-ium bromide crystals have a monoclinic shape and belonged to space group P21/c, whereas the crystals of 4-phenyl-2-(2-tosylhydrazinyl)thiazol-3-ium bromide show an orthorhombic shape with the space group Pbca


Introduction
Generally the thiazole core occurs in variety of pharmaceutical drugs [1]. For example, the water-soluble vitamin B1 thiamine possesses a thiazole ring within its structure [2]. In addition, the thiazole ring system appears in the bacitracin and penicillin antibiotics and plays a great role in the construction of synthetic drugs [1].

Reaction between 4-substituted thiosemicarbazides and phenacyl bromides
Herein, we investigate the reactions between 4-substituted thiosemicarbazides 1a-1d with phenacyl bromide derivatives (as α-halocarbonyl compounds) 2a and 2b in ethyl acetate at room temperature that resulted in the formation of 4-substituted-2-(2-substituted hydrazinyl)thiazol-3-ium bromide 3a-3g in high yields (84-93%) as showed in Scheme 1. The structures of the synthesized compounds 3a-3g were identified using various tools of spectroscopic analyses, and also the structure of 3a and 3d were confirmed using X-ray analyses.
In the IR spectrum of compound 3a, broad bands were observed at 3220 cm −1 due to NH, 3102 cm −1 because of aromatic-CH, at 1611 cm −1 due to C=N, at 1591 cm −1 attributed to aromatic C=C, and at 1535 and 1331 cm −1 due to NO 2 group.
The 1 H NMR spectra of 3a showed broad signals at δ = 10.20 ppm due to NH-attached directly to 2,4-dinitrophenyl moiety, while NH-attached to C-2 appeared at 10.63 ppm. The two NH-protons show downfield shift, attributed to the high deshielding caused by the di-nitro groups on the aromatic ring and the positive charge on thiazole-ring, respectively, as observed from the X-ray structure analysis of 3a. The thiazole-H occurred at 7.82 ppm as singlet signal. The aromatic protons appeared at 7.21-7.40 and 7.48-7.55 ppm due to the phenyl protons. The protons appeared at 8.34-8.43 and 8.83-8.92 ppm are of the 2,4-dinitrophenyl protons.
In 13 C NMR of 3a, signals at 115.6, 150.5, and 170.5 ppm due to thiazole C-5, C-4, and C-2 respectively, also the downfield shift attributed to the positive charge on the thiazole ring. The aromatic carbons appeared at the aromatic region as mentioned in the experimental part.
The mass spectrum of 3a showed that m/z = 443 (M + ) confirmed the formation of the thiazolium bromide products via the condensation between thiosemicarbazide 1a and phenacyl bromide 2a. The base peak at m/z = 358 resulted under liberation of HBr molecule.

Plausible mechanism for the formation of hydrazinylthiazolium bromide derivatives 3a-3g
The plausible mechanism for the formation of 3a-3g was demonstrated in Scheme 2 as follows: S-alkylation takes place via nucleophilic substitution and elimination of HBr molecule to give intermediate 4. Heterocyclization of 4 through nucleophilic attack of N 4 on the carbonyl-group followed by elimination of H 2 O molecule gives 6. In the presence of HBr the thiazolium bromide derivatives 3a-3g are formed.
In IR spectrum of 8a there are characteristic absorption bands that appeared at 3220-3175 cm −1 assigned to NHgroup vibrations, aromatic-CH vibrations observed in the From the 1 H NMR spectra of 8a it was cleared that broad singlet signals appeared downfield at δ = 9.88 ppm due to deshielded NH-proton, the downfield shift caused by the occurrence of the positive charge on the thiazole-ring, and the other NH-proton appeared within the aromatic protons.
The 13 C NMR showed signals at δ = 112.7, 138.0, and 168.6 ppm for thiazole C-5, C-4, and C-2, respectively. The aromatic carbons appeared at the characteristic region as illustrated in the experimental part.
The interaction between 7a-7e and 2a resulted in the formation of 4-aryl-2-(substituted amino)-3-(phenylamino)thiazol-3-ium bromide derivatives 8a-8e was supported from the mass spectrometry of compound 8a which showed m/z = 425 (M + ) this peak is due to the presence of HBr molecule and formation of the thiazolium salt and base peak m/z = 343 support the loss of HBr molecule.

Optimization of the reaction conditions between thiosemicarbazides and phenacyl bromides
Therefore, the optimized reaction conditions involved mixing equimolar amounts of compound 1a-1d or 7a-7e and 2a, 2b at room temperature in ethyl acetate (as dipolar aprotic solvent). The solvent, temperature, and the molar ratio of the reactants may all play a critical role on the reaction pathway and these variables were investigated. Different solvents such as tetrahydrofuran (THF), 1,2-dichloroethane, and acetonitrile were studied, but ethyl acetate proved to be the selective solvent. The main factor that controls the process to obtain the target products is to carry out the reactions at room temperature and ethyl acetate was the best solvent chosen to get high yields.
Increasing the amounts of compound 1a-1d or 7a-7e showed that there were no needs to improve the yields of products. The effect of different basic media was investigated, and ethyl acetate without any additive showed high activity.

Conclusion
Our studies resulted in the construction of novel two groups of substituted thiazolium salts 2,4-disubstituted and 2,3,4-trisubstituted thiazolium bromide derivatives in high yields via one step reaction and at ambient temperature in the presence of ethyl acetate as solvent. Simple and efficient procedures were used to synthesize the thiazolium bromides.

Experimental
Gallenkamp melting point apparatus was used to determine the melting points. IR spectra were recorded with Alpha, Bruker FT-IR instruments using potassium bromide pellets. NMR spectra were recorded for 1 H NMR at 400 MHz and 13 C NMR at 100 MHz on a Bruker AM 400 spectrometrer with TMS as internal standard (δ = 0 ppm), and data are reported as follows: chemical shift, multiplicity (s = singlet, t = triplet, q = quartet, m = multiplet, and br = broad). For 13 C-NMR, spectra were obtained with complete proton decoupling. Finnigan MAT instrument was used to record the mass spectra (70 eV, EI-mode). Elemental analyses for C, H, N, and S were carried out using an Elmer 306.

Synthesis of 4-aryl-2-amino-3-(phenylamino)thiazol-3-ium bromide derivatives 8a-8e
To a stirred solution of 0.198 g phenacyl bromide 2a (1.0 mmol) in 10 cm 3 ethyl acetate a solution of appropriate 1-phenyl-4-substituted thiosemicarbazides 7a-7e (1.0 mmol) in 15 cm 3 ethyl acetate was added portion wise and the mixture allowed to stirred at room temperature. During the stirring a precipitate was formed after a few minutes. The reaction mixture was left overnight, and the precipitate was collected through filtration, washed with ethyl acetate several times to obtain the final products 8a-8e in high purity and in good yields (88-97%).    Single crystal X-ray structure determination of 3a, 3d, and 8a

2-(Cyclohexylamino)-4-phenyl-3-(phenylamino)thiazol-3-ium bromide
The single-crystal X-ray diffraction study was carried out on a Bruker D8 Venture diffractometer with Photon II detector at 123(2) K using Cu-Kα radiation (λ = 1.54178 Å). Dual space methods (SHELXT) [31] were used for structure solution and refinement was carried out using SHELXL-2014 (full-matrix least-squares on F 2 ) [32]. Hydrogen atoms were refined using a riding model (H(N) free). Semi-empirical absorption corrections were applied.  Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/.