Description:Field of Invention: This invention describes the synthesis and characterization of new series of 2-(Bromosubstituted arylamino)-4-arylthiazoles by stirring N- Bromosubstituted arylthioureas with various derivatives of phenacyl bromide in ethanol.
Background:
Due to physiological properties of Nitrogen and Sulfur containing heterocycles, they have significant impact in discovery of new lead compounds as potential drug candidates. Different substituted compounds containing thiazole ring as a part of their core structure have plethora of biological activities (RSC Adv. 2016, 6, 19271, J. Med. Chem. 2006, 49, 4327, Bioorg. Med. Chem. Lett. 2007, 17, 2414). Moreover, thiazole ring is a part of various biologically potent molecules like Ritonavir, Sulfathiazole, Tiazofurin, as well as have displayed pharmaceutical applications such as anti-HIV, antibacterial, antibiotics and antitubercular (Eur. J. Med. Chem. 2012, 49, 172, Bioorg. Med. Chem. 2007, 15, 3997, Eur. J. Med. Chem. 2007, 42, 1272). Therefore, new molecules were designed with substitution at different position of thiazole, specifically, substitution either at position-2 and -4 or one of them which have significant biological potential and these substitutions provide the compounds with various biological features depending on how the substitutents differ from one another (Synth. Commun. 2021, 51, 670–700). 2-Aminothiazole which belongs to the major area of interest of medicinal chemists incorporated in various drugs like sudoxicam, abafungin, cefdinir and famotidine (Eur. J. Med. Chem. 2021, 210, 112953, Eur. J. Med. Chem. 2016, 109, Eur. J. Med. Chem. 89–98, 2023, 256, 115434–115434). Moreover, presence of electron-withdrawing group like 4-bromophenyl directly attached to thiazole nucleus enhances the anticancer and antimicrobial potential (BMC Chem. 2019, 13, 60). Furthermore, 2-(N-Bromoarylamino)-4-arylthiazoles act as anti-Alzheimer agents which have potential to be Gp 130 agonist by increasing pSTAT3 mimetic NH that have tendency to protect neurons from excitotoxicity and amyloid-beta (ACS Chem. Neurosci. 2017, 9, 462–468). In addition, N-Bromoarylamino substituted compounds have potential to exhibit insecticidal activity against polyphagous insect (Phosphorus, Sulfur, and Silicon and the Related Elements 2010, 185, 1321–1331).
Keeping aforementioned facts in mind, we designed to synthesize new derivatives of thiazoles containing 2,4-Dibromophenyl and 2,4,6-Tribromophenyl amino substitutents at position-2 of thiazole ring. All synthesized compounds were characterized on the basis of analysis of their spectroscopic data.

Detailed Description of the Invention:
Considering the biological significance of 4-bromophenyl substituted thiazoles and extending our work to synthesize new potent heterocycles, 2-Aminoaryl-4-arylthioazole derivatives were synthesized. Initially, (2a-b) were synthesized in dry acetone in which benzoyl chloride was treated with ammonium thiocynate results in formation of benzoyl isothiocynate which reacts with aniline to form benzoyl substituted aryl thiourea and further benzoyl group was removed by hydrolysis which resulted in formation of respective N-aryl thiourea derivatives. By using Hantzsch thiazole method, reaction of phenacyl bromides (1) and N-bromosubstituted thioureas (2a-b) results in formation of 2-(N-arylamino)-4-arylthiazoles. Physical data of synthesized compounds are mentioned in Table-1.

Scheme-1: Synthesis of 2-(Bromosubstituted arylamino)-4-arylthiazoles (3a-g or 4a-g)
Table-1: Reaction times and percentage yields and observed melting points of the synthesized compounds
Sr. No. Compd. Ar T1 (min) Yield (%) Color
Observed M.pt.
(?)
1 3a C6H5 30 78 White 160
2 3b p-FC6H4 35 51 White 163
3 3c p-ClC6H4 25 59 White 214
4 3d p-BrC6H4 40 56 White 209
5 3e p-CH3C6H4 30 60 White 155
6 3f p-OCH3C6H4 20 72 White 139
7 3g p-NO2C6H4 25 58 Yellow 255
9 4a C6H5 15 78 White 184
10 4b p-FC6H4 10 60 White 204
11 4c p-ClC6H4 20 74 White 214
12 4d p-BrC6H4 15 65 White 223
13 4e p-CH3C6H4 15 69 White 179
14 4f p-OCH3C6H4 10 75 White 195
15 4g p-NO2C6H4 20 60 Yellow 139

In IR spectra of phenyl thiourea derivatives (2a-b), NH2 group have shown two absorption bands corresponding to symmetric and asymmetric stretching in the range 3400-3110 cm-1 conversely absorption band at 3230-3100 cm-1 attributed to NH symmetric peak. Targeted compounds (3a-g or 4a-g) have shown two absorption peaks; one corresponding to NH in 3100-3400 cm-1 region, another are C-S and C=N stretching peak in 1560-1520 and 1350-1220 cm-1 region, respectively. For compounds 1a-g, 1H NMR spectra have shown singlet at d 4.45-4.60 ppm attributes to CH2 protons. These CH2 proton resonate downfield due to electron-withdrawing effect of directly attached carbonyl and bromine groups. Aromatic protons resonate in their respective region d 7¬¬ 9 ppm. In 1H NMR spectra of bromosubstituted thioureas (2a-b), NH proton resonated downfield at d 10 ppm whereas NH2 protons appeared upfield as a broad signal at d 4 ppm. Furthermore, disappearance of NH2 and -CH2 protons of intermediate confirms the formation of targeted compounds. In 3a-g and 4a-g, thiazole shows 5-H protons resonates in region d 6.69-7.75 ppm and NH proton, which is D2O exchangeable, appeared downfield as a broad signal in the region d 9.67-9.88 ppm. Aromatic protons of phenyl rings appeared as multiplet in aromatic region. Further, in 13C NMR spectrum, three characteristic peaks in the region d 160, 150 and 110 ppm corresponding to C-2, C-3 and C-5 gave the firm evidence to support formation of thiazole ring. In 19F NMR spectra, F-signal appeared at d -114 ppm which depicts the presence of fluorine in compounds.

General procedure for the synthesis of N-(2,4-Dibromophenyl)-4-phenylthiazol-2-amine (3a-g) and 4-Phenyl-N-(2,4,6-tribromophenyl)thiazol-2-amine (4a-g)
Substituted thiourea derivatives (2a-b) (0.001 mol) were dissolved in ethanol and added sodium bicarbonate (0.001 mol) and phenacyl bromide (1a-h) (0.001 mol) to it. The reaction mixture was stirred until complete precipitation at room temperature i.e. 30 ?. Reaction progress was monitored by thin layer chromatography using a 4:1 hexane:ethylacetate mixture. After complete precipitation, solid obtained was filtered and washed with chilled water and ethanol, noted melting point.
Physical and characterization data of the synthesized compounds are given below
N-(2,4-Dibromophenyl)-4-phenylthiazol-2-amine 3a. FTIR:?max (cm-1): 3388 (N-H str.), 1588 (C=N str.), 1543 (C=C str.); 1H NMR (400 MHz, CDCl3, dH): 8.22 (d, 1H, 6'-H, 3JH-H = 8.85Hz ), 7.79 (m, 2H, 2'', 6''-H), 7.63 (d, 1H,3'-H), 7.4 (dd, 1H, 4'-H 3JH-H = 8.85, 2.25 Hz), 7.34 (m, 2H, 3'', 5''-H),7.25 (m, 1H, 4''-H), 6.85 (s, 1H, 5-H); 13C NMR (101 MHz, CDCl3, d): 162.24, 151.80, 137.28, 134.65, 134.32, 131.55, 128.13, 126.12, 119.23, 114.14, 112.22, 103.31
N-(2,4-Dibromophenyl)-4-(4-fluorophenyl)thiazol-2-amine 3b. FTIR:?max (cm-1): 3388 (N-H str.), 1589 (C=N str.), 1539 (C=C str.); 1H NMR (400 MHz, CDCl3, dH): 8.18 (d, 1H, 6'-H, 3JH-H = 8.8 Hz), 7.74 (m, 2H, 3'', 5''-H), 7.62 (d, 1H, 4'-H JH-H = 1.2 Hz), 7.40 (d, 2H, 5'-H, NH); 7.02 (d, 1H, 2'', 6''-H, 3JH-H = 8.8 Hz), 6.77 (s, 1H, 5-H); 13C NMR (101 MHz, CDCl3, d): 163.89, 162.37, 161.43, 150.80, 137.18, 134.68, 131.55, 130.63, 130.60, 127.88, 127.80, 119.19, 115.72, 115.51, 114.24, 112.27, 102.83
4-(4-Chlorophenyl)-N-(2,4-dibromophenyl)thiazol-2-amine 3c. FTIR:?max (cm-1): 3374 (N-H str.), 1588 (C=N str.), 1543 (C=C str.); 1H NMR (400 MHz, CDCl3, dH): 9.67 (s, 1H, NH), 8.29 (d, 1H, 6'-H, 3JH-H = 8.85Hz), 7.87 (d, 2H, 3'', 5''-H), 7.60 (dd, 1H, 3'-H JH-H = 8.85, 2.25 Hz), 7.46 (m, 3H, 2'',6'',5-H); 13C NMR (101 MHz, CDCl3, d): 163.57, 148.29, 138.30, 134.46, 133.09, 131.89, 131.07, 128.49, 127.23, 123.15, 114.28, 114.06, 105.56
4-(4-Bromophenyl)-N-(2,4-dibromophenyl)thiazol-2-amine 3d. FTIR:?max (cm-1): 3366 (N-H str.), 1586 (C=N str.), 1533 (C=C str.); 1H NMR (400 MHz, CDCl3, dH): 9.67 (s, 1H, NH), 8.28 (d, 1H, 6'-H, 3JH-H = 8.85Hz), 7.87 (m, 1H, 3'-H, 3JH-H = 2.3 Hz), 7.81 (d, 2H, 3'', 5''-H), 7.60 (m, 3H, 5',2'',6'',-H), 7.47 (s, 1H, 5-H); 13C NMR (101 MHz, CDCl3, d): 163.60, 148.34, 138.30, 134.47, 133.44, 131.41, 131.08, 127.55, 123.19, 120.49, 114.31, 114.11, 105.67
N-(2,4-Dibromophenyl)-4-(p-tolyl)thiazol-2-amine 3e. FTIR:?max (cm-1): 3384 (N-H str.), 1582 (C=N str.), 1508 (C=C str.); 1H NMR (400 MHz, CDCl3, dH): 8.19 (d, 1H, 6'-H, 3JH-H = 8.8Hz), 7.71 (m, 2H, 2'',6''-H) 7.61 (d, 1H, 3'-H, 3JH-H = 2.25 Hz), 7.38 (dd, 1H, JH-H = 8.85, 2.2 Hz), 6.81 (m, 2H, 3'', 5''-H), 6.69 (s, 1H, 5-H), 3.76 (s, 3H, 4”-CH3); 13C NMR (101 MHz, CDCl3, d): 162.12, 159.60, 151.57, 137.34, 134.62, 131.51, 127.42, 127.35, 119.14, 114.07, 114.01, 112.16, 55.36
N-(2,4-Dibromophenyl)-4-(4-methoxyphenyl)thiazol-2-amine 3f. FTIR:?max (cm-1): 3374 (N-H str.), 1589 (C=N str.), 1517 (C=C str.); 1H NMR (400 MHz, CDCl3, dH): 8.18 (d, 1H, 6'-H, 3JH-H = 8.85Hz), 7.61 (d, 2H, 2'',6''-H, 3JH-H = 8.81Hz) 7.58 (d, 1H, 3'-H, 3JH-H = 2.2 Hz), 7.36 (dd, 1H, JH-H = 8.85, 2.25 Hz), 7.12 (d, 2H, 3'', 5''-H, 3JH-H = 7.95 Hz), 6.75 (s, 1H, 5'-H), 2.29 (s, 3H, 4”-OCH3); 13C NMR (101 MHz, CDCl3, d): 162.12, 151.87, 137.96, 137.33, 134.62, 131.66, 131.53, 126.05, 119.18, 114.04, 112.19, 102.54, 21.33
N-(2,4-Dibromophenyl)-4-(4-nitrophenyl)thiazol-2-amine 3g. FTIR:?max (cm-1): 3388 (N-H str.), 1588 (C=N str.), 1543 (C=C str.); 1H NMR (400 MHz, CDCl3, dH): 9.78 (s, 1H, NH), 8.27 (m, 3H, 6', 3'',5''-H), 8.11 (d, 2H, 2'',6''-H) 7.8 (d, 1H, 3'-H, 3JH-H = 2.3 Hz), 7.78 (s, 1H, 5'-H), 7.61 (dd, 1H, 4'-H JH-H = 8.8, 2.25 Hz); 13C NMR (101 MHz, CDCl3, d): 163.98, 147.46, 146.16, 140.19, 138.15, 134.53, 131.13, 126.37, 123.97, 123.47, 114.63, 114.38, 109.60
4-Phenyl-N-(2,4,6-tribromophenyl)thiazol-2-amine 4a. 1H NMR (400 MHz, CDCl3, dH): 9.88 (s, 1H, NH), 8.05 (s, 2H, 3',5'-H), 7.76 (m,2H, 3'',5''-H) 8.15 Hz), 7.36 (d, 2H, 2'',6''-H), 7.26 (m, 1H, 4''-H), 7.19 (s, 1H, 5'-H); 13C NMR (101 MHz, DMSO, d): 165.28, 138.28, 134.77, 134.07, 128.48, 128.40, 127.41, 125.49, 124.88, 120.18, 114.06, 102.88
4-(4-Fluorophenyl)-N-(2,4,6-tribromophenyl)thiazol-2-amine 4b. 1H NMR (400 MHz, CDCl3, dH): 9.86 (s, 1H, NH), 8.10 (s, 2H, 3',5'-H), 7.82 (m, 2H, 3'',5''-H) 7.23 (m, 3H, 5',2'',6''-H); 13C NMR (101 MHz, DMSO, d): 165.39, 162.42, 160.48, 134.78, 130.81, 127.46, 124.95, 120.38, 120.32, 115.34, 115.17, 102.79
4-(4-Chlorophenyl)-N-(2,4,6-tribromophenyl)thiazol-2-amine 4c. 1H NMR (400 MHz, CDCl3, dH): 9.86 (s, 1H, NH), 8.06 (s, 2H, 3',5'-H), 7.76 (m,2H, 3'',5''-H) 8.15 Hz), 7.42 (d, 2H, 2'',6''-H), 7.28 (s, 1H, 5'-H); 13C NMR (101 MHz, DMSO, d): 165.46, 134.78, 133.09, 133.06, 131.79, 128.43, 127.19, 124.96, 120.37, 103.96.
4-(4-Bromophenyl)-N-(2,4,6-tribromophenyl)thiazol-2-amine 4d. 1H NMR (400 MHz, CDCl3, dH): 9.88 (s, 1H, NH), 8.12 (s, 2H, 3',5'-H), 7.74 (d,2H, 3'',5''-H 3JH-H = 8.15 Hz), 7.62 (d, 2H, 2'',6''-H 3JH-H = 8 Hz), 7.35 (s, 1H, 5'-H); 13C NMR (101 MHz, DMSO, d): 165.51, 163.60, 134.80, 134.48, 131.42, 131.35, 131.10, 127.55, 127.51, 123.20, 120.39.
4-(4-Tolyl)-N-(2,4,6-tribromophenyl)thiazol-2-amine 4e. 1H NMR (400 MHz, CDCl3, dH): 9.84 (s, 1H, NH), 8.05 (s, 2H, 3',5'-H), 7.63 (d,2H, 3'',5''-H 3JH-H = 8.15 Hz), 7.17 (d, 2H, 2'',6''-H 3JH-H = 8 Hz), 7.09 (s, 1H, 5'-H), 2.29 (s, 3H, 4''-CH3); 13C NMR (101 MHz, DMSO, d): 165.20, 149.50, 138.49, 136.70, 134.77, 131.44, 128.96, 125.43, 124.67, 120.10, 101.93, 20.6
4-(4-Methoxyphenyl)-N-(2,4,6-tribromophenyl)thiazol-2-amine 4f. 1H NMR (400 MHz, CDCl3, dH): 9.87 (s, 1H, NH), 8.05 (s, 2H, 3',5'-H), 7.68 (d,2H, 3'',5''-H 3JH-H = 8.8 Hz), 6.93 (d, 2H, 2'',6''-H 3JH-H = 8.85 Hz), 6.99 (s, 1H, 5'-H), 3.76 (s, 3H, 4''-OCH3); 13C NMR (101 MHz, DMSO, d): 165.16, 158.67, 138.68, 126.83, 124.82, 124.69, 119.95, 119.93, 113.77, 100.76, 54.98.
4-(4-Nitrophenyl)-N-(2,4,6-tribromophenyl)thiazol-2-amine 4g. 1H NMR (400 MHz, CDCl3, dH): 9.96 (s, 1H, NH), 8.08 (s, 2H, 3',5'-H), 8.24 (m,2H, 3'',5''-H) 8.15 Hz), 8 (d, 2H, 2'',6''-H), 7.63 (s, 1H, 5'-H); 13C NMR (101 MHz, DMSO, d): 165.81, 148.01, 146.07, 140.31, 137.38, 134.84, 133.92, 131.13, 126.31, 125.08, 125.05, 123.94, 120.69, 108.24.
, Claims:1. The compounds with Formula-I where Ar may be C6H5, 4-F-C6H4, 4-Cl-C6H4, 4-Br-C6H4, 4-CH3-C6H4, 4-OCH3-C6H4, 4-NO2-C6H4, 4-CF3-C6H4, 4-OCF3-C6H4, 4-C6H5-C6H4, 4-CN-C6H4, 2-Naphthyl, 3-acetylcoumarin and a process for the synthesis of 2-(Bromosubstiutted arylamino)-4-arylthiazoles derivatives.

Formula I
2. Synthetic protocol for the compounds claimed in claim 1 comprising steps of reacting Substituted thiourea derivative (2a-b) (0.001 mol, 1eq)) and different substituted phenacyl bromides (1a-g) (0.03 moles, 1eq) at temperature 30 ? for 10 to 40 min.
3. The process as claimed in claim 2, wherein the yields in range of 51-78 % can be achieved.