One-Pot and Three-Component Coupling Synthesis of Novel p-[(Benzothiazolylamino)(aryl/heteroaryl)methyl]phenols and Its Corresponding O-Tosylates under Catalyst- and Solvent-Free Conditions

Abstract

A catalyst- and solvent-free procedure has been developed for the synthesis of p-[( benzothiazolylamino)(aryl/heteroaryl)methyl]-functionalized phenols and its O-tosylates via one-pot three-component coupling reaction of thymol or carvacrol, aryl/heteroaryl aldehydes, and 2-aminobenzothiazoles with high selectivity. The present amino methylation process is convenient to perform even on large scale with a broad scope. The products were likely formed through the initial para attack of thymol on aldehydes to generate p-quinone methide intermediate and subsequent 1,6-aza-Michael addition of 2-aminobenzothiazoles on in-situ generated p-quinone methide intermediate.

Key words

three-component coupling (3CC) reaction - catalyst- and solvent-free - thymol - carvacrol - aryl/heteroaryl aldehydes - 2-aminobenzothiazoles - p-quinone methide - 4-[(benzothiazolylamino)(aryl/heteroaryl)methyl]phenols

Publication History

Received: 31 March 2024

Accepted after revision: 06 May 2024

Accepted Manuscript online:
06 May 2024

Article published online:
17 May 2024

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• 22 General Procedure 1: Synthesis of 4-[(Benzo[d]thiazol-2-ylamino)(phenyl)methyl]-2-isopropyl-5-methylphenol Derivatives (Table 2 and Scheme 3) To a 10 mL round-bottomed flask aldehyde (2.2 mmol), powdered thymol or carvacrol (2.0 mmol), and benzo[d]thiazol-2-amines (2.0 mmol) were added and mixed thoroughly at 20–30 °C under nitrogen atmosphere and the resulting reaction mass was introduced to the preheated oil bath at 150–160 °C for the appropriate time (Tables 2 and Scheme 3). After completion of the reaction as indicated by TLC (30% ethyl acetate in hexanes), the reaction mixture was allowed to cool. The solid mass was dissolved in ethyl acetate, concentrated, and purified by silica gel (Merck, 60–120 mesh) column chromatography with ethyl acetate/hexanes (3:7) to obtain the corresponding pure p-[( benzothiazolylamino)(aryl/heteroaryl)methyl]phenols 4a–j (Table 2 and Scheme 3). General Procedure 2: Gram-Scale Synthesis for Compounds 4d and 4g – Synthesis of 4-[(Benzo[d]thiazol-2-ylamino)(phenyl)methyl]-2-isopropyl-5-methylphenol Derivatives To a 50 mL round-bottomed flask aldehyde (5.5 mmol), powdered thymol (5.0 mmol), and benzo[d]thiazol-2-amines (5.0 mmol) were added and mixed thoroughly at 20–30 °C under nitrogen atmosphere, and the resulting reaction mass was introduced to the preheated oil bath at 150–160 °C for the appropriate time (Table 2). After completion of the reaction as indicated by TLC (30% ethyl acetate in hexanes), the reaction mixture was allowed to cool. The solid mass was dissolved in ethyl acetate, concentrated under reduced pressure, and crystalized with isopropyl alcohol (2 × 10 mL) to obtain the corresponding pure p-[(benzothiazolylamino)(aryl/heteroaryl)methyl]phenols 4b and 4e (Table 2). General Procedure 3 (Table 3, 5a-f) (i) To a 10 mL round-bottomed flask aldehyde (2.2 mmol), powdered thymol (2.0 mmol), and benzo[d]thiazol-2-amines (2.0 mmol) were added and mixed thoroughly at 20–30 °C under nitrogen atmosphere, and the resulting reaction mass was introduced to the preheated oil bath at 150–160 °C for the appropriate time (Table 3). After completion of the reaction as indicated by TLC (30% ethyl acetate in hexanes), the reaction mixture was allowed to cool. The solid mass was dissolved in ethyl acetate and concentrated under reduced pressure to dryness. The obtained residue was washed with ethyl acetate/hexanes (5:95) to obtain the crude products 5a′–f′ (Table 3). The resulting residue was subjected to O-sulfonylation. (ii) The above crude mixture was diluted with anhydrous dichloromethane (6 mL) and cooled down to 0–5 °C. Then, p-toluenesulfonyl chloride (3.0 mmol, 1.5 equiv) was slowly added portionwise into the above reaction mixture in the presence of excessive triethylamine (6.0 mmol, 3.0 equiv) and a catalytic amount of 4-dimethylaminopyridine (0.02 mmol, 1 mol%) at 0 °C. Then, the resulting reaction mixture was allowed to react at room temperature. After 4 h, the reaction mixture was quenched by adding water (15 mL), and the reaction mixture was extracted with dichloromethane (2 × 15 mL). The combined dichloromethane organic layers were dried over Na₂SO₄, concentrated under vacuum, and purified by column chromatography on silica gel (ethyl acetate/hexanes = 3/7) to give the corresponding O-tosylated p-[( benzothiazolylamino) (aryl) methyl]phenols 5a–f.