*2.2. Chemistry*

2.2.1. Synthesis of the New Compounds

The synthesis of new 4-[(4-bromophenyl)sulfonyl]benzoic acid derivatives **5**–**8** was performed according to the synthetic route, as outlined in Scheme 1.

**Scheme 1.** Synthesis pathway for the obtainment of new *N*-{4-[(4-bromophenyl)sulfonyl]benzoyl}-*L*valine analogs. Reagents and reaction conditions: (**a**) C6H5Br/AlCl3, reflux; (**b**) CrO3/CH3COOH, reflux [50]; (**c**) SOCl2, reflux, 30 h, 99% yield [46]; (**d**) (i) *L*-valine/NaOH, CH2Cl2, 0–5 ◦C, 30 min; (ii) rt (room temperature), 1 h; (iii) 2 N hydrochloric acid; 94% yield; (**e**) ethyl chloroformate/4-methylmorfoline, CH2Cl2, rt, 30 min, 90% yield; (**f**) C6H6/AlCl3, rt, 20 h, 80% yield; (**g**) C6H5CH3/AlCl3, rt, 20 h, 86% yield; (**h**) POCl3, reflux, 4 h, 91% (**8b**) and 94% (**8a**) yields.

The key starting material, 4-[(4-bromophenyl)sulfonyl]benzoic acid **3** was prepared by Friedel–Crafts sulfonylation of bromobenzene with commercially available tosyl chloride **1** in presence of aluminum trichloride, followed by oxidation of the sulfonation product (1-bromo-4-tosylbenzene) **2** with chromium trioxide in acetic acid [50]. The previously obtained compound **3** was then transformed by reaction with chlorinating reagent SOCl2 to the corresponding acyl chloride **4** [46,51], which was used in the next step in the raw state. Subsequently, the 2-{4-[(4-bromophenyl)sulfonyl]benzamido}-3-methylbutanoic acid **5** was synthesized via Schotten–Baumann-type *N*-acylation of *L*-valine with 4-[(4 bromophenyl)sulfonyl]benzoyl chloride **4** in dichloromethane at room temperature with a reaction yield of 94%. The 2-{4-[(4-bromophenyl)sulfonyl]phenyl}-4-isopropyl-4*H*-1,3 oxazol-5-one **6** was produced by intramolecular cyclodehydration of compound **5** in presence of ethyl chloroformate and 4-methylmorpholine at room temperature in 90% yield.

Then, the *N*-(1-aryl-3-methyl-1-oxobutan-2-yl)-4-[(4-bromophenyl)sulfonyl]benzamides **7a**,**b** were obtained via Friedel–Crafts acylation of aromatic hydrocarbons (benzene, toluene) with 2-oxazolin-5-one **6** using anhydrous AlCl3 as catalyst at room temperature in about 83% yield. Finally, the 5-aryl-2-{4-[(4-bromophenyl)sulfonyl]phenyl}-4-isopropyl-1,3-oxazoles **8a**,**b** were prepared via Robinson–Gabriel-type intramolecular cyclization reaction of the 2-acylamino ketones **7a**,**b** with phosphoryl trichloride at reflux in yields of 91% (**8b**) and 94% (**8a**). Structure elucidation of all newly synthesized *L*-valine derivatives was performed by means of spectral (UV/VIS, FTIR, NMR, MS) and elemental analyses.
