DESIGN AND SYNTHESIS OF SOME NOVEL THIAZOLE MOLECULES

DESIGN AND SYNTHESIS OF SOME NOVEL THIAZOLE MOLECULES

Jaysinh I. Jadeja and Mahesh M. Savant *

Department of Chemistry, Atmiya University, Rajkot, Gujarat, India.

ABSTRACT: A series of novel (Z)-3-((5-(2-((E)-arylidene) hydrazine-1-carbonyl)-4-methylthiazol-2-yl)amino)-2-cyano-3-(methylthio) acrylate 4a-t molecules have been synthesized and characterized by ¹H NMR, ¹³C NMRand mass spectral analysis. Starting from ethyl 2-amino-4-methylthiazole-5-carboxylate 1 was reacted with hydrazine hydrate to obtain carbohydrazide molecule 2. Furthermore, reaction of molecule 2 with various aldehyde and the adduct 3a-t formed was reacted with ethyl 2-cyano-3,3-bis(methylthio) acrylate to get novel thiazole derivatives 4a-t, furthermore it was reacted with lithium hydroxide to form acid containing novel thiazole molecule 5a. The significant features of this reaction procedure are novel, easy and less time consuming with analytically pure product formation.

Keywords: Thiazole, Hydrazide, N, S-heterocyle, Heterocycles, Ketene Dithioacetal

INTRODUCTION: Thiazole moiety is present in several medicinal compounds and natural sources. The first widely used antibiotic penicillin, also have thiazole moiety in its core structure. Numerous medicinal drugs available for various types of illness also hold thiazole moiety, as shown in Fig. 1. Thiazoles and their derivatives also play a significant role in the field of medicinal chemistry where they found to exhibit a wide variety of activities such as, antiviral ¹, antioxidant ², antituberculosis ³, antimicrobial ⁴, anticancer ⁵, anticonvulsant ⁶, anti-inflammatory ⁷, anti-infective ⁸, antidiabetic ⁹, anticonvulsant ¹⁰, antifungal ¹¹, antiepileptic ¹², antidepressant ¹³. Some of the thiazole molecules also showed inhibition against SARS-CoV-2 virus disease ^{14, 15}. Several procedures for synthesizing thiazole derivatives are described in the literature ^16-23.

Our continuous research in synthesizing various bioactive heterocyclic compounds ^{24, 25} motivated us to develop some novel thiazoles for medicinal interest.

FIG. 1: SEVERAL BIOACTIVE THIAZOLES I-V

EXPERIMENTAL SECTION:

MATERIAL AND METHODS: The melting points were determined on an electrothermal device using open capillaries and are uncorrected. Thin-layer chromatography was performed on precoated silica-gel 60 F254 (Merck), and compounds were visualized with UV light at 254 nm and 365 nm or with iodine vapor. The IR spectra were recorded on a Shimadzu FT-IR spectrometer using the ATR technique.

The ¹H and ¹³C NMR spectra were recorded on a Bruker AVANCE III (400 MHz) spectrometer in DMSO-d6. As an internal standard, chemical shifts are expressed in δppm downfield from Tetra-methylsilane (TMS). Mass spectra were recorded using a direct input probe on Shimadzu GCMS QP2010 Ultra mass spectrometer. All reactions were carried out under an ambient atmosphere. All reagents were purchased from Loba, Molychem, SRL and CDH and used without further purification.

General Procedure for the Synthesis of (E)-2-Amino-N'-benzylidene-4-methylthiazole-5-Carbohydrazide (3a-t): A mixture of compound 2 (10 mmol) and substituted benzaldehyde (10 mmol) in 10mL of MeOH and catalytical amount of glacial acetic acid was stirred and heated to reflux temperature for 1 hr.

After the completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice-cold water and neutralized with dil. HCl. The separated solid was filtered, washed with water and purified by recrystallization from DMF to afford crystals (3a-t).

General Procedure for the Synthesis of Ethyl (Z) - 3-((5-(2-((E)-arylidene) hydrazine-1-carbonyl)-4 – methylthiazol – 2 - yl) amino) – 2 - cyano-3-(methylthio) acrylate (4a-t): A mixture of 3a-t (10 mmol) and ethyl 2-cyano-3,3-bis (methylthio) acrylate (10 mmol) in 10 mL of DMF and anhydrous potassium carbonate (10 mmol) was stirred at room temperature for 1 h.

After the completion of the reaction, the reaction mixture was cooled to room temperature and poured into ice-cold water. The separated solid was filtered, washed with water and purified by recrystallization from DMF to afford pure compound (4a-t).

General procedure for the synthesis of (Z) - 3 -((5-(2 - ((E) - 4 - arylbenzylidene) hydrazine-1-carbonyl) -4-methylthiazol-2-yl)amino)-2-cyano-3-(methylthio) Acrylic Acid (5a): A mixture of 4a (10 mmol) and lithium hydroxide (20 mmol) in 10 mL of THF:MeOH:H₂O in the ration of 3:2:1 was stirred at room temperature for 6 h.

After the completion of the reaction, the reaction mixture was cooled to room temperature, poured into ice-cold water, and acidified using dilute HCl. The separated solid was filtered, washed with water, and purified by recrystallization from DMF to afford a pure compound (5a).

Ethyl (Z) - 3-((5-(2-((Z) – 4 - chlorobenzylidene) hydrazine – 1 - carbonyl) – 4 - methylthiazol- 2-yl) amino) – 2 - cyano -3-(methylthio)acrylate (4a):

Yellow Solid, Yield: 83%, mp 205-207 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 12.81 (s, 1H), 11.88 (s, 1H), 8.00 (s, 1H), 7.72 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.13 (d, J = 7.5 Hz, 2H), 2.54 (s, 3H), 2.33 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H); ¹H NMR (400 MHz, CDCl₃) δ 13.13 (s, 1H), 7.49 (d, J = 8.9 Hz, 2H), 6.93 (d, J = 9.0 Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 2.69 (s, 3H), 2.59 (s, 3H), 1.43 (t, J = 7.1 Hz, 3H), 1.38 (t, J = 7.1 Hz, 3H); ¹³C NMR (100 MHz, DMSO-d₆);184.56, 168.49, 165.73, 161.96, 155.58, 147.32, 136.58, 132.76, 131.93, 129.22, 127.78, 117.22, 95.47, 60.55, 17.34, 16.98, 15.04; MS (m/z): 463 (M⁺).Anal. Calcd. For C₁₉H₁₈ClN₅O₃S₂: C, 49.19; H, 3.91; N, 15.10; Found: C, 49.32; H, 3.89; N, 15.18.

Ethyl (Z) - 3-((5-(2-((Z) – 4 - bromobenzylidene) hydrazine – 1 - carbonyl) – 4 – methylthiazol - 2-yl) amino) - 2-cyano – 3 -(methylthio)acrylate (4b):

Yellow Solid, Yield: 91%, mp 231-233 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 12.83 (s, 1H), 11.91 (s, 1H), 7.98 (s, 1H), 7.69 – 7.57 (m, 4H), 4.14 (d, J = 8.1 Hz, 2H), 2.54 (s, 3H), 2.33 (s, 3H), 1.19 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆);184.55, 168.41, 165.39, 161.83, 154.89, 146.95, 136.57, 132.98, 131.82, 128.91, 128.03, 117.18, 95.50, 59.39, 17.60, 17.00, 15.18; MS (m/z): 508 (M⁺). Anal. Calcd. For C₁₉H₁₈BrN₅O₃S₂: C, 44.89; H, 3.57; N, 13.78; Found: C, 44.92; H, 3.76; N, 13.55.

Ethyl (Z) – 2 – cyano – 3 - ((5-(2-((Z)-4-methoxybenzylidene) hydrazine -1-carbonyl)-4 methylthiazol-2-yl) amino) – 3 - (methylthio) acrylate (4c):

Yellow Solid, Yield: 72%, mp 213-215°C; ¹H NMR (400 MHz, DMSO-d₆) δ 12.79 (s, 1H), 11.71 (s, 1H), 7.94 (s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 6.98 (d, J = 8.3 Hz, 2H), 4.12 (s, 2H), 3.81 (s, 3H), 2.55 (s, 3H), 2.33 (s, 3H), 1.16 (s, 3H); ¹³C NMR (100 MHz, DMSO-d₆);184.63, 168.39, 165.42, 162.78, 154.89, 146.97, 136.44, 132.98, 130.23, 126.66, 117.32, 115.11, 95.51, 59.55, 17.72, 17.02, 14.92; MS (m/z): 459 (M⁺). Anal. Calcd. For C₂0H₂₁N₅O₄S₂: C, 52.27; H, 4.61; N, 15.24; Found: C, 52.30; H, 4.59; N, 15.29.

Ethyl (Z) – 2 – cyano – 3 - ((4-methyl – 5 - (2-((Z)-4-nitrobenzylidene) hydrazine-1-carbonyl) thiazol-2-yl) amino)-3-(methylthio)acrylate (4d):

Yellow Solid, Yield: 67%, mp 228-230 °C; ¹H NMR (400 MHz, DMSO-d₆) δ 12.79 (s, 1H), 11.71 (s, 1H), 8.82 (d, J = 8.4 Hz, 2H), 8.24 (s, 1H), 8.92 (d, J = 8.3 Hz, 2H), 4.12 (d, J = 8.1 Hz, 2H), 2.55 (s, 3H), 2.33 (s, 3H), 1.16 (s, 3H); MS (m/z): 474 (M⁺).Anal. Calcd. For C₁₉H₁₈N₆O₅S₂: C, 48.09; H, 3.82; N, 17.71; Found: C, 48.01; H, 3.62; N, 17.60.

(Z) – 3 - ((5 - (2-((E) – 4 - chlorobenzylidene) hydrazine-1-carbonyl) – 4 – methylthiazol - 2-yl) amino) - 2 -cyano-3-(methylthio) acrylic acid (5a):

White Solid, Yield: 62%, mp 285-287°C; ¹H NMR (400 MHz, DMSO-d₆) δ 12.22 (s, 1H), 12.80 (s, 1H), 11.88 (s, 1H), ), 7.80 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.13 (d, J = 7.5 Hz, 2H), 2.54 (s, 3H), 2.33 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H); MS (m/z): 435 (M⁺); Anal. Calcd. For C₁₇H₁₄ClN₅O₃S₂: C, 48.09; H, 3.82; N, 17.71; Found: C, 48.12; H, 3.32; N, 17.54.

RESULTS AND DISCUSSION: We report newly synthesized molecules with thiazole in their main structure to find novel heterocyclic molecules. The compounds 4a-t were elucidated by inspecting their spectroscopic data, such as ¹H-NMR and Mass spectroscopy.

In the first step, Ethyl 2-amino-4-methylthiazole-5-carboxylate 1 and hydrazine hydrate reacted in MeOH at reflux temperature to get 2-amino-4-methylthiazole – 5 - carbohydrazide 2. Then compound 2 was reacted with various substituted aldehydes to obtain compound (E) – 2 – amino - N' – arylidene – 4 -methylthiazole – 5 – carbohy-drazide 3a-t. The compound 3a-twas reacted with ethyl 2-cyano-3,3-bis(methylthio)acrylate with potassium carbonate in DMF to obtain novel and highly functionalized derivatives of thiazole 4a-t as shown in Scheme 1. Furthermore, molecule 4a reacted with lithium hydroxide in tetrahydrofuran, methanol and water, forming another novel thiazole molecule 5a.

The ¹H-NMR graph of molecules revealed that methyl proton of ester seen at t 1.16-1.19 ppm (CH₃) which were triplet peaks, at s 2.33 ppm (SCH₃) for thiomethyl protons as a singlet peak. Thiazole methyl protons were detected at s 2.54-2.55 ppm (CH₃) as a singlet, ester methylene protons were seen at t 4.12-4.14 ppm (CH₃) which were triplet peaks. Aromatic region was seen between 7.58-8.82 ppm.

SCHEME 1: REAGENTS AND CONDITIONS: (A) NH₂NH₂.H₂O, MEOH, REFLUX, 1 H (B) R-C₆H₄CHO, CH₃COOH, MEOH, REFLUX, 1 H (C) ETHYL 2-CYANO-3,3-BIS(METHYLTHIO)ACRYLATE, K₂CO₃, DMF, RT, 1 H. (D) LIOH, THF, MEOH, H₂O, RT, 6 H

A singlet peak seen at s 7.94-8.24 ppm (CH) indicated the single proton. Thiazole NH proton were observed between s 11.71-11.91 ppm (NH) and acetamide protons were observed at s 12.79-12.83 ppm (NH) as a singlet. Acid hydrogen of 5a was detected at 13.33 ppm (COOH) in downfield. To improve the experimental conditions for the preparation of molecules 4a-t, several bases, such as anhydrous potassium carbonate and triethylamine were used in different solvents such as methanol, ethanol, tetrahydrofuran and acetonitrile. As a result, we found that the reaction of 3a-t with ethyl 2-cyano-3,3-bis(methylthio) acrylate was faster and gave thiazole derivatives 4a-t a good yield when potassium carbonate was used with DMF. Molecule 1 was synthesized according to the reported procedure by Meng²⁶. Furthermore, the reaction of molecule 1 with hydrazine hydrate was carried out using the reported procedure ²⁷.

Physicochemical Properties:

TABLE 2: PHYSICOCHEMICAL CHARACTERISTICS OF THE THIAZOLE MOLECULES 4A-T

^aYield is given for isolated product without purification. ^aAll products are in amorphous form.

CONCLUSIONS: In conclusion, a very efficient and easy technique for the synthesis of ethyl (Z)-3-((5-(2-((E)-arylidene) hydrazine-1-carbonyl)-4-methylthiazol-2-yl) amino)-2-cyano-3-(methylthio) acrylate 4a-t and (Z) – 3 - ((5 - (2 - ((E) – 4 -arylbenzylidene) hydrazine – 1 - carbonyl) – 4 -methylthiazol-2-yl) amino)-2-cyano-3-(methylthio) acrylic acid 5a have been synthesized which contains thiazole moiety in its core structure. The adopted method is simple, easy and novel. The synthesized molecules were characterized by various analytical techniques such as MS, ¹H and ¹³C.

ACKNOWLEDGEMENTS: Nil

CONFLICTS OF INTEREST: The authors declare that there is no conflict of interest regarding the publication of this article.

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    Jadeja JI and Savant MM: Design and synthesis of some novel thiazole molecules. Int J Pharm Sci & Res 2023; 14(4): 1986-91. doi: 10.13040/IJPSR.0975-8232.14(4).1986-91.

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