Novel Benzotriazole-Triazole Conjugates Synthesis via CuAAC PDF

J. Chem. Sci. (2022)134:69 Ó Indian Academy of Sciences https://doi.org/10.1007/s12039-022-02073-x Sadhana (0123456789().,-volV)FT3](0123456...

J. Chem. Sci. (2022)134:69 Ó Indian Academy of Sciences https://doi.org/10.1007/s12039-022-02073-x Sadhana (0123456789().,-volV)FT3](0123456 789().,-volV) REGULAR ARTICLE An expeditious and clean synthesis of novel benzotriazole-triazole conjugates via Copper-catalyzed Azide-Alkyne cycloaddition click protocol (CuAAC) RASHMI SHARMA and ANIL KUMAR* Synthetic Organic Chemistry Laboratory, Faculty of Sciences, Shri Mata Vaishno Devi University, Katra, Jammu & Kashmir 182 320, India E-mail: [email protected] MS received 10 March 2022; revised 25 May 2022; accepted 26 May 2022 Abstract. A simple, efficacious, and regioselective synthesis of hitherto unreported benzotriazole-triazole conjugates via copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction between benzotriazole alky- nes and aryl azides has been described. The structure of the synthesized molecules has been explicitly confirmed by spectroscopic analysis (1H NMR, 13C NMR, and mass spectroscopy). Keywords. Benzotriazole alkynes; aryl azides; benzotriazole-triazole conjugates; Copper-catalysed azide- alkyne cycloaddition. 1. Introduction optical brightening agents31 and anti-corrosive agents.32,33 To fulfil the accrescent demand of novel effective Moreover, it was evident from the literature34–36 drugs, synthetic chemists are continuously making that the development of molecules that are synthesized efforts to discover drug molecules through the gen- by the conjugation of different pharmaceutical agents eration of novel series of bioactive compounds.1 has led to an improvement in biological activity. Benzo-fused analogue of triazole, also known as Despite having several biological applicabilities, there benzotriazole is gaining the conspicuous recognition are very few organic structures comprising both ben- as a potential therapeutic agent due to its rich array zotriazole and triazole moieties.37–39 In view of the of functionalities and is being widely recognized as pharmacological aspects of these two moieties and our a useful building block for the synthesis of a broad inclination toward the development of new organic and interesting range of biologically active hetero- bioactive scaffolds, we envisioned synthesizing a new cyclic compounds having anti-convulsant,2 anti-mi- family of heterocycles containing both benzotriazole crobial,3–5 anti-fungal,6,7 anti-inflammatory,8 anti- and triazole pharmacophores using the highly bacterial,9,10 anti-cancer,11,12 anti-depressant,13 anti- acclaimed copper-catalyzed azide-alkyne cycloaddi- tubercular,14,15 anti-viral16,17 properties (Figure 1). tion (CuAAC) reaction. On the other hand, triazole and its derivatives are The CuAAC method, developed independently by also known to have significant importance because Meldal and Sharpless, is potentially a useful route in of their broad spectrum of applications in medicinal the design and synthesis of a new array of compounds chemistry.18,19 Triazoles play a powerful role in the with excellent regiocontrol, favouring the synthesis of area of drug discovery because of their medicinal 1,4-disubstituted-1,2,3-triazoles in high yields.40 Fur- virtues like antimicrobial,20–22 analgesic,23 anti-tu- ther, it was reported that the catalytic moiety involved bercular,24,25 antiviral,26,27 anticancer28,29 activities in this protocol is Cu(I). Afterwards, several modified (Figure 1). Additionally, they are also extensively protocols were reported, however in all the cases, it used as an important constituent of herbicides,30 was established that the reaction proceeded either with *For correspondence Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s12039-022- 02073-x. 69 Page 2 of 11 J. Chem. Sci. (2022)134:69 H3C 2.1 General procedure for the synthesis N N N of hydroxybenzotriazole alkyne 3a-e N O N N H N N S N N O O To the stirred solution of 1.0 mmol of 1-hydroxy- Antimicrobial activity Antiviral activity Antiprotozoal activity benzotriazole in 3.0 mL of acetone, 1.5 eq. of potassium carbonate was added followed by the F H O O N N gradual addition of 1.2 eq. of propargyl bromide. The N N O S N N R N N reaction mixture was refluxed for 1-3 h until the N N N NH2 N N O O disappearance of the reactant as indicated by TLC. F COOH Ruf inamide Tazobactam our prototype The mixture was finally extracted with ethyl acetate (3930 mL). The organic layer was collected and washed with water (30 mL) and brine (20 mL) and Figure 1. Biologically active benzotriazole and triazole containing heterocyclic compounds. was dried using anhydrous Na2SO4. The solvent was then removed under reduced pressure, and the crude residue was further purified using column chro- the direct use of the Cu(I) salts or in situ generation of matography (silica 60-120, eluent: ethyl acetate-hex- Cu(I) species through the reduction/oxidation of ane), incurring the pure product in good to moderate Cu(II)/Cu(0) respectively.41,42 In addition, the com- 50-85% yields. 1H NMR, 13C NMR, and mass proportionation of Cu(II) and Cu(0) can also be spectral studies were carried out to characterize the employed to execute CuAAC reaction.43 structures of the resultant compounds. In view of the importance of benzotriazole and tri- azole pharmacophores, the effectiveness of CuAAC protocol, and our utmost interest in the synthesis of new heterocycles44,45 especially benzotriazole,46 2.2 Spectroscopic data of the synthesized herein, we report facile and expeditious access to a compounds previously unknown family of benzotriazole-triazole 2.2a 1-(prop-2-yn-1-yloxy)-1H-benzo[d][1,2,3] analogs through copper-catalyzed azide-alkyne triazole (3a): Yellow oil; 1H NMR (400 MHz, cycloaddition reaction between benzotriazole alkyne CDCl3) d 2.59 (t, J= 2.3 Hz, 1 H), 5.19 (d, J= 2.4 and aryl azides using copper acetate as a catalyst in Hz, 2 H,), 7.39 (t, J= 7.7 Hz,1 H), 7.52 (t, J= 7.6 Hz, methanol at room temperature in 34-98% yields. 1H), 7.70 (d, J= 8.3 Hz, 1 H), 8.01 (d, J= 8.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) d 68.28, 75.45, 2. Experimental 80.34, 107.06, 119.69, 121.36, 128.00, 145.11, 147.48 ppm. All the starting reactants and reagents were commer- cially available and were used without any further 2.2b 6-chloro-1-(prop-2-yn-1-yloxy)-1H-benzo[d] purification. The reaction was carried in an open glass [1,2,3]triazole (3b): White solid; M.p. 96-98 °C; 1H round-bottom flask. Thin layer chromatography (TLC) NMR (400 MHz, CDCl3) d 2.60 (t, J= 2.4 Hz, 1H), technique using silica gel plates (60 F254) was carried 5.19 (d, J= 2.4 Hz, 2H), 7.36 (dd, J= 8.9, 1.7 Hz, 1H), out in an appropriate mixture of hexane and ethyl 7.70 (d, J= 1.4 Hz, 1H), 7.94 (d, J= 8.9 Hz, 1H) acetate to monitor the progress of the reaction. All the ppm;13C NMR (100 MHz, CDCl3) d 67.79, 75.83, melting points were recorded on analab melting point 79.78, 109.30, 121.29, 126.24, 129.10, 134.91, 142.06 apparatus in open glass capillaries. HRMS was ppm; HRMS calc. for C9H7ClN3O [M?H]? 208.02, recorded on XEVO G2-XS QTof mass spectrometer found 208.03. and Bruker impact HD mass spectrometer. 1H NMR and 13C NMR spectral studies of benzotriazole alkynes 2.2c 6-fluoro-1-(prop-2-yn-1-yloxy)-1H-benzo[d] were carried in CDCl3 on Bruker 400 and 100 MHz, [1,2,3]triazole (3c): White solid; M.p. 48-50 °C; 1H respectively, whereas the 1H NMR and 13C NMR of NMR (400 MHz, CDCl3) d 2.62 (t, J= 2.4 Hz, 1H), the benzotriazole-triazole conjugates were recorded in 5.21 (d, J= 2.4 Hz, 2H), 7.19 (td, J= 9.1, 2.3 Hz, 1H), DMSO-d6 on Bruker 400, 101 MHz spectrometer 7.37 (dd, J= 7.4, 2.0 Hz, 1H), 8.01 (dd, J= 9.0, 4.4 Hz, respectively. Coupling constants (J) are given in Hertz 1H) ppm;13C NMR (100 MHz, CDCl3) d 67.79, 75.83, (Hz), whereas the chemical shifts (d) are given in parts 79.78, 109.30, 121.30, 126.24, 129.10, 134.91, 142.09 per million (ppm) and are relative to tetramethyl silane ppm; HRMS calc. for C9H7FN3O [M?H]? 192.05, (Me4Si) as internal standard. found 192.06. J. Chem. Sci. (2022)134:69 Page 3 of 11 69 2.2d 5-chloro-1-(prop-2-yn-1-yloxy)-1H-benzo[d][1, 1H), 7.53 (d, J= 3.7 Hz, 2H), 7.80 (s, 4H), 8.04 (d, J= 2,3]triazole (3d): Creamish white solid; M.p. 8.4 Hz, 1H), 9.03 (s, 1H) ppm; 13C NMR (101 MHz, 100-102 °C; 1H NMR (400 MHz, CDCl3) d 2.60 (t, DMSO-d6) d 72.64, 109.05, 119.71, 121.75, 122.18, J= 2.4 Hz, 1H), 5.22 (d, J= 2.4 Hz, 2H), 7.51 (dd, J= 124.92, 125.00, 127.46, 128.42, 132.91, 135.50, 8.8, 1.7 Hz, 1H), 7.67 (d, J= 8.8 Hz, 1H), 8.03 (d, J= 141.12, 142.64 ppm; HRMS (TOF MS ES?) calc. 1.1 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3) d for C15H11N6OBrNa [M?Na]? 393.01, found 393.01. 67.85, 75.85, 79.75, 110.59, 119.60, 127.29, 129.35, 130.83, 143.98 ppm; HRMS calc. for C9H7ClN3O 2.4c 1-((1-(4-methoxyphenyl)-1H-1,2,3-triazol-4-yl) [M?H]? 208.02, found 208.03. methoxy)-1H-benzo[d][1,2,3]triazole (5c): Brown solid; M.p. 140-142 °C; 1H NMR (400 MHz, 2.2e 6-nitro-1-(prop-2-yn-1-yloxy)-1H-benzo[d][1,2, DMSO-d6) d 3.83 (s, 1H), 5.76 (s, 2H), 7.13 (d, J= 3]triazole (3e): White solid; M.p. 130-132 °C; 9.0 Hz, 2H), 7.42 (ddd, J= 8.1, 5.6, 2.3 Hz, 1H), 7.53 1 H NMR (400 MHz, CDCl3) d 2.65 (t, J= 2.4 Hz, (d, J= 5.5 Hz, 2H), 7.71 (d, J= 9.0 Hz, 2H), 8.05 (d, 1H), 5.30 (d, J= 2.4 Hz, 2H), 8.19 (d, J= 9.1 Hz, 1H), J= 8.4 Hz, 1H), 8.88 (s, 1H) ppm; 13C NMR (101 8.30 (dd, J= 9.1, 2.0 Hz, 1H), 8.70 (d, J= 1.7 Hz, 1H) MHz, DMSO-d6): d 56.06, 73.23, 109.51, 115.40, ppm; 13C NMR (100 MHz, CDCl3) d 67.50, 75.91, 120.13, 122.39, 125.33, 127.96, 128.81, 130.13, 77.09, 79.35, 109.39, 120.11, 124.83, 128.15, 128.30, 141.12, 143.07, 159.95 ppm; HRMS (TOF MS ES?) 143.37 ppm; HRMS calc. for C9H7N4O3 [M?H]? calc. for C16H14N6O2Na [M?Na]? 345.11, found 219.04, found 219.05. 345.11. 2.4d 6-chloro-1-((1-(4-nitrophenyl)-1H-1,2,3-triazol 2.3 General procedure for the synthesis of (1H- -4-yl)methoxy)-1H-benzo[d][1,2,3]triazole 1,2,3-triazol-4-yl)methoxy-1H-benzo[d] (5d): Creamish white solid; M.p. 210-212 °C; [1,2,3]triazole 1 H NMR (400 MHz, DMSO-d6) d 5.81 (s, 2H), 7.45 (dd, J= 8.9, 1.9 Hz, 1H), 7.77 (d, J= 8.9 Hz, 1H), 8.09 To the stirred solution of aryl azide 4a-d (1.0 mmol) (d, J= 8.9 Hz, 1H), 8.18 (d, J= 9.1Hz, 2H), 8.47 (d, J= and hydroxybenzotriazole alkyne 3a-e (1.5 mmol) in 9.1 Hz, 2H), 9.23 (s, 1H) ppm; 13C NMR (101 MHz, methanol (1-2 mL), add copper acetate (1.0 mol%). DMSO-d6): d 73.16, 109.37, 121.36, 121.86, 126.06, The resultant reaction mixture was then stirred at 126.11, 126.30, 128.51, 134.00, 140.93, 141.79, ambient temperature for the appropriate time till the 141.88, 147.46 ppm; HRMS (TOF MS ES?) calc. reaction is completed. The resultant solid product is for C15H10N7O3ClNa [M ? Na]? 394.04, found then filtered and washed with methanol to get the pure 394.04. compounds. 2.4e 1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl) 2.4 Spectroscopic data of resultant compounds 5a-n methoxy)-6-chloro-1H-benzo[d][1,2,3]triazole (5e): White solid; M.p. 175-177 °C; 1H NMR (400 2.4a 1-((1-(4-nitrophenyl)-1H-1,2,3-triazol-4-yl)me MHz, DMSO-d6) d 5.78(s, 2H), 7.45 (dd, J= 8.9, 1.6 thoxy)-1H-benzo[d][1,2,3]triazole (5a): White solid; Hz, 1H), 7.73 (s, 1H), 7.82 (s, 4H), 8.09 (d, J= 8.9 M.p. decomposed at 240 °C; 1H NMR (400 MHz, Hz), 9.06 (s, 1H) ppm; 13C NMR (101 MHz, DMSO- DMSO-d6) d 5.81 (s, 2H), 7.41 (t, J= 6.9 Hz, 1H), d6) d 72.92, 108.96, 121.45, 121.85, 122.30, 125.27, 7.54 (q, J= 8.5 Hz, 2H), 8.04 (d, J= 8.4 Hz, 1H), 8.16 125.86, 128.16, 132.96, 133.54, 135.53, 141.04, (d, J= 8.9 Hz, 2H), 8.45 (d, J= 8.9 Hz, 2H), 9.22 (s, 141.37 ppm; HRMS (TOF MS ES?) calc. for 1H) ppm; 13C NMR (101 MHz, DMSO-d6) d 72.49, C15H10N6OBrClNa [M?Na]? 426.97, found 426.96. 109.04, 119.72, 120.84, 124.93, 125.39, 125.66, 127.41, 128.45, 140.50, 141.56, 142.64, 146.97 ppm; 2.4f 6-chloro-1-((1-(4-methoxyphenyl)-1H-1,2,3-tria HRMS calc. for C15H12N7O3 [M?H]? 338.09, found zol-4-yl)methoxy)-1H-benzo[d][1, 2, 3]triazole (5f): 338.10. Creamish white solid; M.p. 120-122 °C; 1H NMR (400 MHz, DMSO-d6) d 3.83 (s, 3H), 5.77 (s, 2H), 7.15 (d, 2.4b 1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl) J= 9.0 Hz, 2H), 7.45 (dd, J= 8.9, 1.9 Hz, 1H), 7.71 methoxy)-1H-benzo[d][1,2,3]triazole (5b): White (dd, J= 8.4, 5.13 Hz, 3H), 8.09 (d, J= 8.9 Hz, 1H), 1 solid; M.p. 157-159 °C; H NMR (400 MHz, 8.92 (s, 1H) pp; 13C NMR (101 MHz, DMSO-d6) d DMSO-d6) d 5.77 (s, 2H), 7.41 (dd, J= 8.3, 4.0 Hz, 56.07, 73.49, 109.37, 115.40, 121.83, 125.57, 126.22, 69 Page 4 of 11 J. Chem. Sci. (2022)134:69 128.62, 130.12, 133.90, 141.01, 141.76, 159.99 ppm; 2.4j 5-chloro-1-((1-(4-methoxyphenyl)-1H-1,2,3-tria HRMS (TOF MS ES?) calc. for C16H13N6O2ClNa zol-4-yl)methoxy)-1H-benzo[d][1,2,3]triazole (5k): [M?Na]? 379.07, found 379.07. White solid; M.p. 185-187 °C; 1H NMR (400 MHz, DMSO-d6) d 3.83 (s, 3H), 5.78 (s, 2H), 7.14 (d, J= 9.0 2.4.4a. d 6-fluoro-1-((1-(4-nitrophenyl)-1H-1,2,3-tri Hz, 2H), 7.58 (d, J= 1.1 Hz, 2H), 7.72 (d, J= 9.0 Hz, azol-4-yl)methoxy)-1H-benzo[d][1,2,3]triazole (5g) 2H), 8.23 (s, 1H), 8.89 (s, 1H) ppm; 13C NMR (101 Creamish white solid; M.p. 242-244 °C; 1H NMR MHz, DMSO-d6) d 56.07, 73.51, 112.29, 115.40, (400 MHz, DMSO-d6) d 5.18 (s, 2H), 7.34 (td, J= 9.4, 119.49, 122.42, 125.42, 126.95, 129.45, 129.92, 2.2 Hz, 1H), 7.53 (dd, J= 8.0, 2.0 Hz, 1H), 8.13 (dd, 130.11, 140.96, 143.63, 159.97 ppm; HRMS calc. for J= 9.1, 4.5 Hz, 1H), 8.19 (d, J= 9.0 Hz, 2H), 8.48 (d, C16H14N6O2Cl [M?H]? 357.08, found 357.09. J= 9.0 Hz, 2H), 9.25(s, 1H) ppm; 13C NMR (101 MHz, DMSO-d6): d 72.59, 95.11 (d, 2J= 29.3 Hz), 2.4k 1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)me 114.99 (d, 2J= 27.3 Hz), 120.90, 122.01 (d, 3J= 11.0 thoxy)-6-nitro-1H-benzo[d][1,2,3]triazole (5l): Pale Hz), 125.58, 125.73, 127.88 (d, 3J= 15.1 Hz,), 139.70, yellow solid; M.p. 172-175 °C; 1H NMR (400 MHz, 140.54, 141.48, 147.04, 161.98 (d, 1J= 246.8 Hz) DMSO-d6) d 5.78 (s, 2H), 7.45 (dd, J= 8.9,1.7 Hz, ppm; HRMS (TOF MS ES?) calc. for C15H10N7O3- 1H), 7.73 (d, J= 1.2 Hz, 1H), 7.83 (s, 4H), 8.09 (d, J= FNa [M?Na]? 378.07, found 378.07. 8.9 Hz, 1H), 9.06 (s, 1H) ppm; 13C NMR (101 MHz, DMSO-d6) d 72.90, 108.94, 121.43, 121.83, 122.28, 2.4g 1-((1-(4-bromophenyl)-1H-1,2,3-triazol-4-yl)me 125.24, 125.83, 128.14, 132.94, 133.52, 135.52, thoxy)-6-fluoro-1H-benzo[d][1,2,3]triazole (5h): 141.02, 141.35 ppm; HRMS calc. for C15H11N7O3Br Creamish white solid; M.p. 174-176 °C; 1H NMR [M?H]? 416.00, found 416.01. (400 MHz, DMSO-d6) d 5.77 (s, 2H), 7.33 (td, J= 9.3, 2.2 Hz, 1H), 7.48 (dd, J= 8.0, 2.1 Hz, 1H), 7.82 (s, 2.4l 6-chloro-1-((1-(3-methoxyphenyl)-1H-1,2,3-tria 4H), 8.12 (dd, J= 9.1, 4.5 Hz, 1H), 9.06 (s, 1H) ppm; zol-4-yl)methoxy)-1H-benzo[d][1,2,3]triazole (5m): 13 C NMR (101 MHz, DMSO-d6) d 77.91, 100.26 (d, Pale yellow solid; M.p. 135-137 °C; 1H NMR (400 2 J= 29.3 Hz), 119.97, 120.24 (d, 3J= 27.4 Hz), 127.17 MHz, DMSO-d6) d 3.85 (s, 3H), 5.78 (s, 2H), 7.09 (d, (d, 2J= 40.4 Hz), 133.09 (d, 3J= 15.2 Hz), 138.12, J= 7.0 Hz, 1H), 7.55-7.33 (m, 5H), 7.72 (s, 1H), 8.09 140.71, 144.85, 146.20, 167.13 (d, 1J= 247.5 Hz) (d, J= 8.6 Hz, 1H), 9.04 (s, 1H) ppm; 13C NMR (101 ppm; HRMS calc. for C15H11N6OBrF [M?H]? MHz, DMSO-d6) d 56.69, 72.99, 105.94, 108.96, 390.18, found 391.01. 112.32, 114.87, 121.43, 125.31, 125.84, 128.19, 131.00, 133.52, 137.35, 140.79, 141.35, 160.23 ppm; HRMS (TOF MS ES?) calc. for C16H13N6O2ClNa 2.4h 5-chloro-1-((1-(4-nitrophenyl)-1H-1,2,3-triazol [M?Na]? 379.07, found 379.07. -4-yl)methoxy)-1H-benzo[d][1,2,3]triazole (5i): Pale yellow solid; M.p. 140-142 °C; 1H NMR (400 MHz, 2.4m 1-((1-(3-methoxyphenyl)-1H-1,2,3-triazol-4-yl) DMSO-d6) d 5.83 (s, 2H), 7.61 (d, J= 10.6 Hz, 2H), methoxy)-6-nitro-1H-benzo[d][1,2,3]triazole (5n): 8.17 (d, J= 9.1 Hz, 2H), 8.24 (s, 1H), 8.47 (d, J= 9.1 Pale yellow solid; M.p. 170-172 °C; 1H NMR (400 Hz, 2H), 9.23 (s, 1H) ppm; 13C NMR (101 MHz, MHz, DMSO-d6) d 3.85 (s, 3H), 5.88 (s, 2H), DMSO-d6) d 73.20, 111.30, 119.53, 125.96, 126.12, 7.21–6.99 (m, 1H), 7.39 (d, J= 6.3 Hz, 2H), 7.50 (t, 126.85, 129.55, 140.93, 141.85, 143.65, 147.43 ppm; J= 8.4 Hz, 1H), 8.22 (dd, J= 9.1, 1.9 Hz, 1H), 8.34 (d, HRMS calc. for C15H11N7O3Cl [M?H]? 372.74, J= 9.1 Hz, 1H), 8.51 (d, J= 1.7 Hz, 1H), 9.09 (s, 1H) found 372.06. ppm; 13C NMR (101 MHz, DMSO-d6) d 56.07, 74.04, 106.28, 107.41, 112.67, 115.32, 120.11, 121.75, 2.4i 1-((1-(4-bromophenyl)-5-chloro-1H-1,2,3-triaz 125.64, 127.53, 131.39, 137.72, 141.13, 145.01, ol-4-yl)methoxy)-1H-benzo[d][1,2,3]triazole (5j): 147.44, 160.62 ppm; HRMS (TOF MS ES?) calc. Creamish White solid; M.p. 108-110 °C; 1H NMR for C16H13N7O4Na [M?Na]? 390.09, found 390.09. (400 MHz, DMSO-d6) d 5.79 (s, 2H), 7.58 (s, 2H), 7.81 (s, 4H), 8.29 (s, 1H), 9.03(s. 1H) ppm; 13C NMR (101 MHz, DMSO-d6) d 73.35, 111.28, 119.50, 3. Results and Discussion 122.22, 122.65, 125.52, 126.90, 129.49, 129.94, 133.34, 135.93, 141.40, 143.64 ppm; HRMS (TOF At the very onset, 1-hydroxybenzotriazoles (HoBT) MS ES?) calc. for C15H10N6OBrClNa [M?Na]? 2a-e were synthesized using the previously reported 426.97, found 426.966. protocol,47 as depicted in Scheme 1(A). Next, the J. Chem. Sci. (2022)134:69 Page 5 of 11 69 Next, the same reaction with copper (II) sulphate N Br N R N R N was attempted, which delivered the desired product in K2CO3 (1.5 eq.) N Acetone, reflux N 57% yield (Entry 4, Table 1). However, a further (1-3) hours O OH 2a-e (B) 3a-e increase in yield (60%) was observed with copper R= H, 6-Cl, 6-F, 3a= 85%, 3b= 70%, 3c= 73%, acetate as a catalyst (Entry 5, Table 1). Afterward, the 5-Cl, 6-NO2 3d= 81%, 3e= 50% reaction was investigated in methanol and water to R'N3 4a-d probe the effect of these solvents. Surprisingly, 70% NH2NH2 Cu(OAc)2.H2O (1mol%) (C) N yield was observed in methanol (Entry 6, Table 1) N R' (A) EtOH, Na2CO3 methanol, rt Heat N compared to 51% in water (Entry 7, Table 1). Notably, N X N N O the reaction gave maximum yield with copper acetate Y (1.0 mol%) in methanol without using any reducing NO2 R agent. X,Y = Cl/F 1 5a-n It is pertinent to mention that CuAAC is the most common protocol for click reaction and generally uses Scheme 1. Synthesis of benzotriazole-triazole conjugates. Cu(II) in the presence of reducing agents such as sodium ascorbate49 in order to reduce Cu(II) to Cu(I), which is an active catalytic entity involved. However, under the present protocol, no external reducing agent synthesis of benzotriazole alkyne 3, a key partner for was used. CuAAC was carried out by the propargylation of Further, to optimize the concentration of catalyst, 1-hydroxybenzotriazole 2 using the well-known strat- we raised the concentration of catalyst to 5.0 mol%, egy shown in the Scheme 1 (B). The structure of these but no improvement in product yield was observed benzotriazole alkynes has been characterized by (69%, Entry 8, Table 1), which indicated that spectroscopic techniques (1H NMR and 13C NMR). In 1.0 mol% of catalyst in methanol is the best condition 1 H NMR, the characteristic acetylenic proton is for the envisaged protocol. With the systematic opti- observed at delta 2.5 ppm clearly indicating the for- mization of the reaction conditions, the devised pro- mation of benzotriazole alkyne, which is further sup- tocol was employed on differently substituted ported by the 13C NMR and mass spectral studies. benzotriazole alkynes and aryl azides, the results of Similarly, a series of aryl azides 4a-d, the second which are shown in Table 2. The reaction proceeded coupling partner in click reaction, was synthesized efficiently in all the cases to deliver the desired pro- from arylamines using a method available in the duct in yields ranging from 34-98%. In order to check literature.48 the synthetic applicability of the developed protocol, With these benzotriazole alkynes 3a-e and azides the gram-scale reaction was performed. When the 4a-d in hand, we intended to synthesize the series of reaction was carried out with 6.0 mmol (1.04 gm) of target benzotriazole-triazole conjugates using the alkyne 3a and 4.0 mmol of aryl azide 4a under stan- azide-alkyne cycloaddition route described in dard conditions, 1.3 gm of 5a was obtained in 62% Scheme 1 (C). In this context, the focus was set up on yields. the optimization of the click reaction for the synthesis Using the above-optimized conditions, various of benzotriazole-triazole conjugate 5a from benzotri- substituted aromatic azides (for the CuAAC reaction) azole alkyne 3a and 1-azido-4-nitrobenzene 4a in with both electron-donating and withdrawing-groups acetonitrile at room temperature under catalyst-free present in ortho, para, and meta positions were used conditions (Entry 1, Table 1). for the synthesis of a series of novel benzotriazole- It was found that no product formation was triazole scaffolds. When either electron-donating or observed when copper (I) oxide was used as the sole electron-withdrawing substituents (–Br, –NO2, and catalyst (Entry 3, Table 1), but with copper (I) iodide, –OCH3) were present in the para position, the target the desired product was observed in 51% yield (Entry products were formed in good to excellent yields. 2, Table 1). The formation of the product is confirmed However, with aromatic azides having electron-do- by physical data and spectroscopic techniques. In nating or electron-withdrawing groups in the meta 1 H NMR, the characteristic singlet peaks displaying at position, there was a slight decrease in the yield of the delta 9.2 ppm and 5.81 ppm correspond to triazolyl desired product, whereas the yield was insignificant proton and methylene protons, respectively (Figure 2), with ortho-substituted azides. This decrease in the thereby confirming the formation of desired product, yield of the desired product may be attributed to which 13C NMR and HRMS further support. electronic effects. But when the benzotriazole alkynes 69 Page 6 of 11 J. Chem. Sci. (2022)134:69 Table 1. Optimization of the reaction conditions for CuAAC. Entry No. Catalyst (mol%) Solvent Time (min) Yield % 1 No catalyst CH3CN 120 No reaction 2 CuI (1) CH3CN 120 51 3 Cu2O (1) CH3CN 120 No reaction 4 CuSO4.5H2O (1) CH3CN 120 57 5 Cu(OAc)2 (1) CH3CN 120 60 6 Cu(OAc)2 (1) CH3OH 120 70 7 Cu(OAc)2 (1) H 2O 120 51 8 Cu(OAc)2(5) CH2OH 120 69 Figure 2. Representation of 1H NMR spectrum of 5a. having electron-withdrawing and electron-donating product which is confirmed by the characteristic 13 groups were used (Table 2), no significant substituent C NMR peak at delta 119 ppm.50 The formation of effects were observed. 1,4- vs 1,5-isomer has been very well studied by Further, the current protocol shows complete Creary et al. using 13C NMR spectral data.50 The regioselectivity in favour of the 1,4-disubstituted studies established that the 1,4-isomer shows a J. Chem. Sci. (2022)134:69 Page 7 of 11 69 Table 2. Substrate scope of the copper-acetate catalysed CuAACa. Entry Starting material Azide Product Time Yieldb (%) (minutes) 1 N N3 N NO2 120 70 N N N N N N N O 5a O NO2 2 N N3 N Br 120 97 N N N N N N N O 5b O Br 3 N N3 N OCH3 120 94 N N N N N N N O 5c O OCH3 4 N N3 N NO2 120 65 N N N N Cl N N N O 5d O NO2 Cl 5 N N3 N Br 120 83 N N N N N Cl N N O O 5e Br Cl 6 N N3 N OCH3 120 98 N N N N Cl N N N O O 5f OCH3 Cl 7 N N3 N NO2 120 70 N N N N F N N N O 5g O NO2 F 69 Page 8 of 11 J. Chem. Sci. (2022)134:69 Table 2. continued Entry Starting material Azide Product Time Yieldb (%) (minutes) 8 N N3 N Br 120 98 N N N N F N N N O 5h O Br F 9 Cl N N3 N NO2 120 96 N N N N N N N O 5i O NO2 Cl 10 Cl N N3 N Br 120 98 N N N N N N N O 5j O Br Cl 11 Cl N N3 N OCH3 120 75 N N N N N N O N 5k O Cl OCH3 12 N N3 N Br 120 82 N N N O 2N N N N N O O 5l Br NO2 13 N N3 OCH3 120 34 N N Cl N N N N O N N O OCH3 5m Cl 14 N N3 OCH3 120 50 N N N O 2N N N O N N N O OCH3 5n NO2 a Reaction conditions: Hydroxybenzotriazole alkyne (1.5 mmol), aryl azide (1 mmol), copper acetate (1 mol%), Methanol (1-2 mL). b Yields of pure isolated product. characteristic peak at d 120±3 ppm (Figure 3-A) in study, the presence of a consistent peak at 120±3 ppm 13 C NMR; however peak at d 133±3 ppm is observed in all the synthesized molecules 5a-n fully supports in the 1,5-isomer (Figure 3-B). However, in the current the exclusive formation of 1,4-disubstituted-1,2, J. Chem. Sci. (2022)134:69 Page 9 of 11 69 13 Figure 3. (A) Expanded C NMR spectrum of x50 (B) Expanded 13 C NMR spectrum of y50 (C) Expanded 13 C NMR spectrum of 5a. 3- triazoles (Figure 3-C). This is strictly in accordance of column chromatography. Biological screening of with literature records where copper catalysed reac- the synthesized molecules is currently underway and tions exclusively delivered 1,4-disubstituted product51 will be disclosed in due course of time. but ruthenium catalysed protocols were found to deliver 1,5-disubstituted product as a major product.52 After completion of the reaction, the product was Supplementary Information (SI) simply filtered followed by washing with methanol. The structure of the newly synthesized compounds Figures S1-S58 and all additional data for the com- 5a-n was fully characterized by 1H NMR, 13C NMR, pound characterization (1H NMR and 13C NMR and and mass spectroscopy. mass) is available at www.ias.ac.in/chemsci. Acknowledgments 4. Conclusions We are thankful to SAIF IIT Patna for providing HRMS To summarize, a novel series of benzotriazole-triazole data. RS thanks to Shri Mata Vaishno Devi University for conjugates have been synthesized from a wide range providing University Fellowship. of benzotriazole alkynes and aryl azides using a cop- per-catalyzed azide-alkyne cycloaddition route. The current protocol avoids using any reducing agent, References making this protocol a better route for synthesizing a variety of benzotriazole-linked triazole scaffolds. The 1. Taylor A P, Robinson R P, Fobian Y M, Blakemore D notable features of this method include simplicity, C, Jones L H and Fadeyi O 2016 Modern advances in cleaner reaction profiles, eliminating the use of heterocyclic chemistry in drug discovery Org. Biomol. Chem. 14 6611 reducing agents, and complete regioselectivity in 2. Pochaiah B, Meher C P, Srujana B, Swarnalatha P and favour of 1,4-disubstituted product. 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