Synthesis and Characterization of Novel Thiazole Anchored Pyrazolyl Benzoxazoles

Introduction

Heterocyclic compounds are pharmacologically and medicinally very important because most of the drugs present in the market today are containing heterocyclic scaffolds. Benzoxazole derivatives exhibits anthelmintic¹, antiulcer², antitumor³, antimicrobial^4,5andanticancer⁶ activities. Benzoxazole containing compounds are also acts as RSK2 inhibitor⁷ and α₁-AR antagonist⁸.

Thiazole scaffold containing compounds are associated with anti-inflammatory⁹, cyclooxygenase-2 inhibitor¹⁰, analgesic¹¹,monoamine oxidases¹² and immunosuppressive¹³ activities. Pyrazole is one of the most important pharmacologically active heterocyclic compound. Pyrazole and its derivatives are associated with fungicidal¹⁴, anti-angiogenic¹⁵, antidiabetic¹⁶, antiparasitic¹⁷, antitubercular¹⁸, antimicrobial¹⁹ and antioxidant¹⁹ activities.

3-For mylchromoneis one of the class of chromone family. Chromone derivatives are known to have acetylcholinesterase inhibitor²⁰,antitumor²¹, breast cancer resistance protein ABCG2 inhibition²²activities.

The various pharmacological activities associated with benzoxazole, thiazole and pyrazole prompted us to synthesizesome novel thiazole anchored pyrazolyl benzoxazole  derivatives.

Experimental Section

(1-(4-(4-Bromophenyl)thiazol-2-yl)-1H-pyrazol-4-yl)(2-hydroxyphenyl)methanone 3a-e.

3-Formylchromone 1 (0.012 mol) was dissolved in 25 mL of ethanol with thiazolyl hydrazine 2 (0.012 mol). The reaction mixture heated under reflux for 40 min to get corresponding hydrazone. To the same reaction mixture 1.2 g KOH in 10 mL H₂O was added and heating was continued for 4 hr. After completion of reaction the contents were cooled to room temperature and poured into crushed ice. The resulting solution was neutralized with conc. HCl. The solid obtained was separated by filtration and crystallized from ethanol to afford compound 3.

3a

IR (KBr):3085 (O-H), 1656 (C=O), 1612 (C=N), 1109 (Ar-Cl), 1218 (C-O) cm^-1; ¹H NMR (DMSO-d₆): δ 7.40-7.82 (m, 7H, Ar-H), 8.21 & 8.97 (s, 2H, Pyrazole), 12.40 (s, 1H, O-H); MS: m/z:[M⁺] 493;Elem. Anal. Calcd.: C, 46.09; H, 2.04; N, 8.49; found: C, 46.12; H, 2.08; N, 8.53 %.

2-[(E)-{1-[4-(4-Bromophenyl)-1,3-thiazol-2-yl]-1H-pyrazol-4-yl}(hydroxyimino)methyl]phenol 4a-e:

Compound 3 (0.055 mol) was dissolved in 20 mL of ethanol in 150 mL conical flask. To this 10 mL of 20% KOH was added with constant stirring at 4⁰C, and to this hydroxylamine hydrochloride (1.1 mol) was added in portion wise. Further stirring was continued for 3-4 h at room temperature. Then reaction mixture was poured into crushed ice and acidified with acetic acid. The product obtained was separated by filtration and crystallized from ethanol to afford compound 4.

4a

IR (KBr): 3185 (OH), 1630 (C=N), 1113 (Ar-Cl) cm^-1; ¹H NMR (DMSO-d₆): 7.27-7.97 (m, 7H, Ar-H), 8.05-8.89 (s, 2H, pyrazole), 9.90 (s, 1H, -OH of oxime), 11.97 (s,1H, Ar-OH); MS: m/z:[M⁺] 508;Elem. Anal. Calcd.: C, 44.73; H, 2.17; N, 10.98; found: C, 44.77; H, 2.21; N, 11.02 %.

Table-1: Characterization data of synthesized compounds

Compd	R1	R2	R3	M.P. (0C)	Yield (%)
3a	Cl	H	Cl	202	69
3b	H	Me	Cl	248	64
3c	H	H	Cl	208	67
3d	H	H	Br	205	61
3e	H	H	Me	196	59
4a	Cl	H	Cl	256	57
4b	H	Me	Cl	254	60
4c	H	H	Cl	244	53
4d	H	H	Br	222	58
4e	H	H	Me	204	48
5a	Cl	H	Cl	268	51
5b	H	Me	Cl	290	57
5c	H	H	Cl	240	55
5d	H	H	Br	250	59
5e	H	H	Me	232	46

2-(1-(4-(4-Bromophenyl)thiazol-2-yl)-1H-pyrazol-4-yl)benzo[d]oxazole 5a-e:

Compound 4 (0.055 mol) were dissolved in 15 mL of POCl₃ in 50 mL RBF and the contents were heated under reflux for 2.5 h. After completion of reaction the contents were cooled to room temperature and poured into crushed ice, and neutralized by adding sodium acetate. The solid thus obtained was separated by filtration and crystallized from ethanol gave compound 5.

Scheme 1  Click here to View Scheme

 

5a

IR (KBr): 1586&1539 (C=N), 1239 (C-OC), 1114 (Ar-Cl) cm^-1; ¹H NMR (DMSO-d₆): δ 7.35-7.83 (m, 7H, Ar-H), 8.36&9.11 (s, 2H, Pyrazole); MS: m/z:[M⁺] 490;Elem. Anal. Calcd.: C, 46.37; H, 1.84; N, 11.38; found: C, 46.41; H, 1.88; N, 11.42 %.

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