Visible-light-mediated Regioselective Synthesis of Novel Thiazolo[3,2-b][1,2,4]triazoles: Advantageous Synthetic Application of Aqueous Conditions Journal: Organic & Biomolecular Chemistry Manuscript ID OB-ART-11-2021-002194.R1 Article Type: Paper Date Submitted by the Author: 14-Dec-2021 Complete List of Authors: Aggarwal, Ranjana; Kurukshetra University Faculty of Science, Chemistry Department; Council of Scientific & Industrial Research, National Institute of Science Communication and Policy Research Hooda, Mona; Kurukshetra University, chemistry Kumar, Prince; Kurukshetra University, CHEMISTRY Torralba, Maria; Universidad Complutense de Madrid, bDepartamento de Química Inorgánica I and CAI de Difracción de Rayos-X. Facultad de Ciencias Químicas. Organic & Biomolecular Chemistry 1 | P a g e Visible-light-mediated Regioselective Synthesis of Novel Thiazolo[3,2-b][1,2,4]triazoles: Advantageous Synthetic Application of Aqueous Conditions Ranjana Aggarwal,a,b* Mona Hooda,a Prince Kumar,a Mari Carmen Torralbac aDepartment of Chemistry, Kurukshetra University, Kurukshetra-136119, Haryana, India bCouncil of Scientific and Industrial Research-National Institute of Science Communication and Policy Research, New Delhi 110012, India cDepartamento de Química Inorganica, Facultad de Ciencias Químicas, Universidad Complutense de Madrid (UCM), E-28040, Madrid, Spain *Corresponding author: Prof. Ranjana Aggarwal, CSIR-National Institute of Science Communication and Policy Research, New Delhi, India. Tel: +91-9896740740 E-mails: ranjana67in@yahoo.com, ranjanaaggarwal67@gmail.com Page 1 of 26 Organic & Biomolecular Chemistry mailto:ranjana67in@yahoo.com mailto:ranjanaaggarwal67@gmail.com 2 | P a g e Visible-light-mediated Regioselective Synthesis of Novel Thiazolo[3,2-b][1,2,4]triazoles: Advantageous synthetic application of Aqueous Conditions Abstract From a green chemistry perspective, sustainable irradiations as the power source and water as solvent have certainly grabbed the attention of chemists in recent times as these efforts reduce hazardous ecological imprints of organic synthesis. In the present work, we have established an efficient, up-front and green protocol for the regioselective synthesis of novel functionalized thiazolo[3,2-b][1,2,4]triazoles. The visible-light-mediated catalyst-free reaction of diversely substituted α-bromodiketones, generated in situ by the reaction of NBS and 1,3-diketones, with 3-mercapto[1,2,4]triazoles in aqueous conditions afforded thiazolo[3,2-b][1,2,4]triazole derivatives in excellent yields. The structure of the regioisomer has been confirmed explicitly by heteronuclear 2D-NMR [(1H-13C) HMBC, (1H-13C) HMQC] spectroscopic and X-ray crystallographic studies. Radical initiating and trapping experiments supported the free radical mechanism for the cyclization. Keywords: visible-light, aqueous condition, regioselective, thiazolo[3,2-b][1,2,4]triazole, α- bromodiketones, 2D-NMR, X-ray crystallography Introduction Over the years, increasing environmental pollution and shortage of energy sources have encouraged researchers to explore green organic synthetic protocols to exterminate the dependency on non-renewable energy sources and polluting toxic solvents. Efforts have been made very recently towards the development of sustainable reaction media, especially, using water as solvent has aroused substantial attention in organic syntheses1. Organic transformations in aqueous conditions are always a preferable choice for chemists as water is a safe, cheap, non-toxic, non-polluting and non-flammable natural solvent available in abundance. A large variety of organic reactions have been established to take place in aqueous media2, sometimes with exceptional improvements, such as rapid reaction rates and better selectivity compared to results obtained using traditional organic media. Indeed, water has emerged as a suitable “solvent” for selected transformations in organic chemistry regardless of prejudged beliefs of its unsuitable dissolution capabilities3. Light-induced organic transformations4,5 include absorption of light by chemical substrates to excite electronically excited states from their ground states, where they undergo several physical and chemical transformations. In the recent past, a large number of environmentally Page 2 of 26Organic & Biomolecular Chemistry 3 | P a g e benign chemical transformations6 have been successfully established using visible-light strategies7–9, as it is a clean, renewable, low-priced and widely available energy source10. Design and development of new models of heterocyclic systems with improved pharmacological and biological potential have been the continued pursuit of the synthetic community, as most of the pharmaceuticals, medicinal and agronomy chemicals have been derived from the heterocyclic moieties. Literature survey revealed that 1,2,4-triazoles and their fused heterocyclic derivatives11–13 have perceived much attention due to their excellent biological and synthetic importance. The thiazole nucleus also acts as an important pharmacophore by interacting with the biological receptors with high affinity due to their ease of metabolism, high lipid solubility with hydrophilicity. 1,2,4-Trizoles nucleus fused with thiazole ring results in new heterocycles with improved biological activity. To the best of our knowledge there are three variants of thiazolotrizoles namely isothiazolo[3,2- c][1,2,4]triazole (I), thiazolo[2,3-c][1,2,4]triazole (II) and thiazolo[3,2-b][1,2,4]triazole (III) investigated in literature14 (Figure 1). N N N S N N N S N N N S isothiazolo[3,2-c][1,2,4]triazole thiazolo[3,2-b][1,2,4]triazolethiazolo[2,3-c][1,2,4]triazole I II III Figure 1. Different forms of thiazolotriazoles. Out of these three isomers, thiazolo[3,2-b][1,2,4]triazole is the most impressive and commonly used scaffold as it is endowed with diverse biological activities such as antimicrobial15–17, anticancer18,19, analgesics20,21, anti-inflammatory22–24, anticonvulsant22,26 , antioxidant27, plant growth regulation28, enzyme inhibitory29,30 and platelet aggregation inhibitory activity31. Synthetic strategies32 for thiazolo[3,2-b][1,2,4]triazoles involved mainly two routes: route a and b (Figure 2). While route a includes the formation of a thiazole ring onto a triazole structure by the reaction of 3-mercapto-1,2,4-triazoles with α-functionalized ketones33 or allyl bromide34, or reaction with 1,4-diphenylbut-2-yne-1,4-dione35 or one-pot reaction of mercaptotriazole, chloroacetic acid and aromatic aldehydes26,36, route b involves the construction of the triazole ring onto the thiazole moiety37 by the reaction 2- aminothiazoles with nitrile derivatives. Page 3 of 26 Organic & Biomolecular Chemistry 4 | P a g e N N N S a N N H N SH + Br ClCH2COOH + ArCHO oror O hal N S R NH2 + b ab O PhO Ph orRC N route route Figure 2. Literature reported retrosynthetic routes for construction of thiazolo[3,2- b][1,2,4]triazole core. Our research group has been actively engaged in the designing and development of environment-friendly protocols38 for the synthesis of diverse heterocyclic nuclei with bioactive profiles39,40. Presently, we are exploring the reaction of substituted unsymmetrical α-bromo-1,3-diketones with various binucleophiles41,42 using several factors such as energy source, media and the reactivity of the substrate to get an insight of regioselective control of the reaction. In continuation of our research program, herein, we established a simple and green procedure (based on route a) for the regioselective synthesis of thiazolo[3,2- b][1,2,4]triazole by the reaction of 3-mercapto[1,2,4]triazole with several unsymmetrical 1,3- diketones using visible light as a source of energy in the aqueous medium. The structure of the single regioisomer obtained was unequivocally characterized by heteronuclear 2D-NMR [(1H-13C) HMBC, (1H-13C) HMQC] spectroscopic and X-ray crystallographic studies. Result and Discussion Sherif et al14 reported the synthesis of thiazolo[3,2-b][1,2,4]triazoles via a one-pot reaction of 3-benzyl-1,2,4-triazole-5-thiol and aromatic ketones in acidified acetic acid (AcOH/H+). However, when the reaction of α-bromo-1-phenylbutane-1,3-dione 3a (generated in situ via solvent-free grinding of 1-phenylbutane-1,3-dione 1a with NBS 2) and 5-phenyl-4H-1,2,4- triazole-3-thiol 4a was performed under identical conditions (Figure 3), it led to the formation of a single product monitored on TLC. Spectral data of synthesized compound showed interesting outcomes as the peak of the methyl group from diketone was absent and a singlet of one proton intensity has been observed at δ 7.06 in 1H NMR spectrum, which indicates the expulsion of the acetyl group from diketone. IR spectrum also displayed the missing peak of corresponding carbonyl stretch. Page 4 of 26Organic & Biomolecular Chemistry 5 | P a g e N N N Ph S Ph 1a 5 AcOH/H2SO4 reflux Ph O CH3 O N N H N SHPh Ph O CH3 O Br 2 3a 4a N N N Ph S 6a CH3 Ph O NBS H Figure 3. Unexpected synthesis of 2,5-diphenylthiazolo[3,2-b][1,2,4]triazole via reaction of in situ generated α-bromo-1-phenylbutane-1,3-dione with 5-phenyl-4H-1,2,4-triazole-3-thiol. The structure of compound 5 was established as 2,5-diphenylthiazolo[3,2-b][1,2,4]triazole by comparing melting point and spectral data in the literature19, where the desired synthesis had been achieved by the condensation of acetophenone with mercaptotriazole in refluxing acetic acid. Therefore, we envisaged optimizing the reaction conditions for the novel highly substituted thiazolo[3,2-b][1,2,4]triazole derivatives through greener routes. We took α-bromo-1- phenylbutane-1,3-dione 3a and 5-phenyl-4H-1,2,4-triazole-3-thiol 4a as model substrates in different solvents (DCM, THF, CH3CN, DMF, MeOH, EtOH and H2O) and under solvent- free conditions (Table 1). It was observed that the reaction proceeded smoothly in solvent- free conditions (Table 1, entry 8) as well as in polar protic solvents (Table 1, entry 5-7) at room temperature or using conventional heating. Unfortunately, the reaction yields in these conditions were not satisfactory. Influenced with the advantages of visible light, the reaction between 3a and 4a was investigated using various solvents under visible light irradiations (Table 1, entry 9-13). Experimental studies showed that the reaction preceded efficiently in polar solvents H2O, MeOH and EtOH under visible-light irradiations but the best results were obtained using H2O as solvent (Table 1). Previously, bromination of 1,3-diketones using NBS at room temperature has been reported by our research group41 and others43. On exploring the reaction conditions for the bromination, we found that visible-light irradiation can be the best promoter. When 1- phenylbutane-1,3-dione 1a was added with NBS 2 under visible light in aqueous conditions at room temperature, the reaction was completed within 15 minutes as monitored with TLC. The reaction product was isolated and the structure was established as α-bromo-1- phenylbutane-1,3-dione 3a by matching the spectral and melting point data with literature43. α-Bromo-1,3-diketones 3a-j was then treated with mercaptotriazoles to obtain the final product. Page 5 of 26 Organic & Biomolecular Chemistry 6 | P a g e The reaction was also carried out in one-pot where 3a-j were used in situ and condensed with 5-aryl-4H-1,2,4-triazole-3-thiol derivatives 4a-b in similar aqueous conditions irradiated with visible-light to afford the target product with excellent yields. One-pot reaction yields were found better than the reaction proceeded in batch. Table 1. Optimization of reaction conditionsa Entry Solvent Heat/Visible-light Time Yield (%)b/c 1. DCM Rt 6 hr NRd 2. THF Reflux 4 hr 35/40 3. CH3CN Reflux 5 hr Trace 4. DMF Reflux 6 hr NRc 5. MeOH Reflux 3 hr 60/67 6. EtOH Reflux 3 hr 65/72 7. H2O Reflux 2 hr 40/54 8. Solvent-free Rt 1.5 hr 52/60 9. MeOH Visible-light 1 hr 70/75 10. EtOH Visible-light 50 min 74/80 11. H2O Visible-light 30 min 78/82 12. DMF Visible-light 3 hr 20/25 13. THF Visible-light 2 hr 42/45 aReaction conditions: a mixture of 3a (2 mmol), and 4a (2 mmol) in an appropriate solvent (10.0 mL) was processed in the indicated reaction condition. bIsolated yield of batch reaction. cIsolated yield of one-pot reaction. dN.R. = no reaction. The reaction of trielectrophilic (α1, α2, α3) unsymmetrical α-bromo-1,3-diketones 3 with trinucleophilic (β1, β2, β3) 3-mercapto-1,2,4-triazoles 4 may led to produce four possible regioisomers; 5-aroyl-2-aryl-6-methylthiazolo[3,2-b][1,2,4]triazole 6, 5-acetyl-2-aryl'-6- arylthiazolo[3,2-b][1,2,4]triazole 7, 6-aroyl-3-aryl-5-methylthiazolo[2,3-c][1,2,4]triazole 8, and 6-acetyl-3-aryl'-5-arylthiazolo[2,3-c][1,2,4]triazole 9 based on the electrophilicity difference of both the carbonyl groups Figure 4. Page 6 of 26Organic & Biomolecular Chemistry 7 | P a g e R O CH3 O Br 1 2 3 12 + 23 12 + 21 N S CH3 N S R O R O CH3 N N H N R1 SH 1 N N N N R1 2 + R1 3 12 + 33 12 + 31 N N N R1 S H3C O R N N N R1 S R O H3C 6 7 8 9 3 4 Figure 4. Possible regioisomeric structures. However, surprisingly, the reaction yielded only a single regioisomeric product in water under visible-light irradiations within 30 minutes as indicated by TLC. IR spectrum of 6a displayed a single absorption band at 1628 cm-1 due to stretching of the C=O group indicating the complete consumption of 1,3-diketone. Likewise, 13C-NMR studies showed a peak at δ 188.5 corresponding to the carbonyl group incorporated in the product. 1H-NMR studies demonstrated a single peak at δ 2.71 ppm validating one methyl group and ten protons in the chemical shift (δ) range of phenyl ring confirmed the successful condensation of two reactants to form (6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)(phenyl)methanone 6a. Under the optimized reaction conditions, a study on the substrate scope of 1,3-diketones and 3-mercaptotriazole was carried out and summarized in Table 2. It was concluded from the results that a wide range of unsymmetrical 1,3-diketones substituted with ortho-/meta-/para- /heteroaryl substituents exhibited great compatibility to this one-pot reaction protocol. 1,3- Diketones tethered with electron-releasing substituents irrespective of their position on aryl ring afforded the desired products in better yields in comparison to the electron-withdrawing substituents. Substitutions at para- position of aryl ring (6g, 6p) resulted in improved yields than the comparable yields of ortho- and meta- derivatives (6h-i, 6q). Mercaptotriazole with electron-donating groups, such as 4-methoxy, also afforded the corresponding triazolothiazole (6j-r) in excellent yield (77% and 94%). However the reaction of mercaptotriazoles with electron withdrawing group (such as -NO2) did not completed even after irradiation of 5 hours. Page 7 of 26 Organic & Biomolecular Chemistry 8 | P a g e R O CH3 O NO O Br N N H N SHR1 N N N R1 S O R CH3 1a-j 6a-r 1 2 3 4 5 67 8 Ph 4-FPh 4-ClPh 4-BrPh 4-OMePh4-MePh2,4-Cl2Ph 3-OMePhR = 2-OMePh 2-thienyl R1= Ph 4-OMePh R O CH3 O BrH2O, CFL 15 min. stirr 4a-b H2O, CFL, 30-45 min.3a-j 1.) NBS, H2O, CFL, stirr 2.) 4a-b, H2O, CFL, 30-45 min. 2 Figure 5. Regioselective synthesis of 5-aroyl-2-aryl-6-methylthiazolo[3,2-b][1,2,4]triazole. Table 2. Substrate Scope N N N S O CH3 N N N S O CH3 N N N S O CH3 6a; 82% 6b; 75% 6c; 77% N N N S O CH3 N N N S O CH3 N N N S O CH3 6d; 76% 6e; 73% 6f; 85% N N N S O CH3 N N N S O CH3 N N N S O CH3 6g; 88% 6h; 85% 6i; 84% F Cl Br Cl Cl Me OMe OMe N N N S O CH3 N N N S O CH3 N N N S O CH3 6j; 89% 6k; 78% N N N S O CH3 N N N S O CH3 N N N S O CH3 6m; 80% 6n; 77% 6o; 90% N N N S O CH3 N N N S O CH3 N N N S O CH3 6p; 94% 6q; 92% F Cl Br Cl Cl Me OMe OMe S MeO MeO MeO MeO MeO MeO MeOMeOMeO 6l; 80% 6r; 78% OMe Page 8 of 26Organic & Biomolecular Chemistry 9 | P a g e After completing the synthesis of (2-aryl'-6-methyl-thiazolo[3,2-b][1,2,4]triazol-5- yl)(aryl)methanone, we envisaged to assign unambiguous regioisomeric structure of the reaction product by heteronuclear 2D NMR experiments [(1H-13C) HMBC and (1H-13C) HMQC]. 2D NMR spectra exposed definitive evidence to support the structure of the regioisomeric product as 6a and 6j. The (1H-13C) HMBC as well as (1H-13C) HMQC of compounds (6-methyl-2- phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)(phenyl)methanone 6a shown cross peak of carbonyl carbon at δ 188.5 with a 2''/6''-H proton (δ 7.80-7.82) of aryl ring signifies the presence of carbonyl carbon with aryl ring, henceforth eliminating the possibility of regioisomers with acetyl group 7 and 9. Possibility for the formation of thiazolo[2,3-c][1,2,4]triazole 8 can also be ruled out as the HMBC spectrum of 6a does not show any correlated peak of methyl group protons at 6th position (δ 2.71) with C-2 carbon (δ 168.3). Thus, the structure can indisputably assigned as (6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)(phenyl)methanone 6a. Similar correlation results of (1H-13C) HMQC and (1H-13C) HMBC were observed for compound 6j as shown in Figure 6. N N N S CH3 O H N N N S CH3 O HO H3C N N N S O O 7.71-7.73 133.5 7.59-7.63 129.3 7.84-7.87 129.1 7.08-7.11 114.9 8.05-8.09 128.63.84 55.8 161.1 16 7. 5 12 3. 1 156.8 124.5 189.0 138.2 137.4 2.52 14.4 N N N S O 7.63-7.66 133.1 7.52-7.56 128.8 7.80-7.82 128.76 7.44-7.50 128.74 8.19-8.21 126.9 16 8. 3 13 0. 5 157.1 123.9 188.5 138.0 136.6 2.71 13.8 6a 6j 7.44-7.50 130.2 1' 2'3' 4' 5' 6' 1'' 2'' 3'' 4''5'' 6'' 1'' 2'' 3'' 4''5'' 6'' 1' 2'3' 4' 5' 6' 1 1 2 2 3 4 5 67 8 8 7 6 5 43 Figure 6. 1H (in violet) and 13C (in blue) chemical shifts of compound 6a and 6j and correlation depiction. X-ray Crystallographic studies X-ray crystallography gave the final validation of the structure as (2-(4-methoxyphenyl)-6- methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(phenyl)methanone 6j isomer. Efforts were made to grow crystals of several samples by gradual evaporation of solvents (ethanol+chloroform+ Page 9 of 26 Organic & Biomolecular Chemistry 10 | P a g e petroleum ether) at room temperature but only 6j was successfully furnished into a colourless needle-shaped single crystal. The crystalline structure of compound 6j was studied by single X-Ray diffraction. Compound 6j crystallized in monoclinic P21/n space group, containing one molecule per asymmetric unit. Figure 7 displays the ORTEP plot for 6j with the labeling scheme of corresponding asymmetric units. Compound 6j appears as the regioisomer thiazolo[3,2-b][1,2,4]triazole (III) as depicted in the ORTEP plot, according to the bond distances and the angle data summarized in the supplementary data. The molecule shows a planar fragment formed by the fused thiazolo- triazole ring and the R1 substituent, 4-MeOPh in this case, while the phenyl group R twists, as deduced from the data. In that sense, taking the fused rings as the reference, the dihedral angle that forms those with the phenyl substituent is 55.8(2)º and 3.8(2)º with the phenyl group. These results are in accordance with an electronic delocalization along with them, as deduced from the bond distances and the angle data. The methoxy group is nearly enclosed in this plane, being the corresponding O2 and C22 the farthest atoms with a distance from the main plane of 0.185(3) and 0.245(3) Å, respectively. On the contrary, the ketonic O1, in the middle of the fused and the phenyl rings, point out in the same direction as the sulphur atom to minimize the steric hindrance, probably due to the bending of phenyl substituents and the methyl on C6. The ketonic O1 atom keeps out from the main plane with a distance of 0.354(3) Å. The sulphur atom is asymmetric, situated in the thiazole ring in both compounds, as deduced from the data. Figure 7. ORTEP plot showing the labeling scheme for compound 6j. Page 10 of 26Organic & Biomolecular Chemistry 11 | P a g e Derivative 6j pack in columns along the b axis to minimize the steric hindrance of the molecule, showing only weak contacts between the O1 oxygen and aromatic hydrogen atoms of neighboring molecules, leading to the final packing shown in Figure 8. Figure 8. View of the crystal packing of 6j Mechanism involved The possible mechanistic route9,42,44 for the regioselective synthesis of (2-aryl'-6- methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(aryl)methanone 6a-r is outlined in Figure 9. To begin with, the visible-light assisted homonuclear fission of S-H bond of 3-mercapto- [1,2,4]triazoles 4 and C-Br bond of α-bromodiketone 3 to generate the free radicals 10 and 11, respectively, which mutually share their electron to form s-alkylated open chain structure 12. Bromine free radical then facilitates the homolytic cleavage of β3-N-H bond, which shifts to generate a new N-β2 triazole radical (more nucleophilic due to α-effect), which combined with the less sterically hindered carbonyl carbon and the oxygen atom was supported by the hydrogen free radical. The intramolecular combination of these free radicals generated the (2- aryl'-6-hydroxy-6-methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(aryl)methanone 13 which undergoes dehydration to yield (2-aryl'-6-methylthiazolo[3,2-b][1,2,4]triazol-5- yl)(aryl)methanone 6 as the exclusive product, show compatibility to our previous results42. To further support the plausible reaction mechanism, radical initiating and trapping experiments were carried out. Under the standard conditions, 2,2,6,6-tetramethylpiperidine-1- oxyl (TEMPO) was added to the reaction mixture. It has been found that the reaction was inhibited, with the yields of product 6a being only 20%, while in presence of free radical initiator; benzoyl peroxide, the condensation reaction was improved in terms of reaction yields (6a;90%) and reaction rate. These results indicate that a free radical pathway is involved. Page 11 of 26 Organic & Biomolecular Chemistry 12 | P a g e R O CH3 O S H Br -HBr R O CH3 O -H2O NN N H R1 S NN N H R1 3 4 10 6 11 S NN NR1 O R O H3C Br NN NR1 S OHH3C H O R-HBr NN N R1 S CH3 R O 12 13 H Figure 9. A plausible mechanism for the synthesis of thiazolo[3,2-b][1,2,4]triazoles 6a-r. Conclusion: In conclusion, we have developed a highly efficient synthetic protocol for the regioselective synthesis of (2-aryl'-6-methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(aryl)methanone 6a-r. Synthesis involves one-pot [3+2] cyclo-condensation of 1,3-diketones 1 with 3-mercapto- [1,2,4]triazoles 4 in presence of N-bromosuccinimide (NBS) 2 in water by stirring under visible-light irradiations. Single regioisomeric products were obtained in excellent yields and the structure of the regioisomers has been confirmed unequivocally by the laborious multinuclear NMR [(1H 13C) HMBC, (1H 13C) HMQC] spectroscopy. X-ray crystallographic studies validate the exclusive formation of single regioisomer as (2-aryl'-6- methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(aryl)methanone. A plausible mechanism involving free radical participation has also been proposed. This methodology reported herein offers an environmentally friendly way for the synthesis of functionalized thiazolo[3,2- b][1,2,4]triazoles. Studies engaged with the exploration of their biological applications are currently in progress. Experimental: General Methods: An electrical digital Melting Point Apparatus (MEPA) was used to examine melting points in open capillaries and are not corrected. Analytical TLC was performed using Merck Kieselgel 60 F254 silica gel plates and visualized under UV light (254 nm). The visible-light source with a lumen range of 2700-7000K (power 27 W) was placed 5 cm away from the reaction mixture. A borosilicate glass conical was used to experiment. IR spectra were recorded on Buck Scientific IR M-500 spectrophotometer in KBr pellets (υmax in cm-1), 1H (500 Hz) and 13C NMR (125 Hz) spectra for the analytical purpose were recorded on a Bruker instrument, using CDCl3 as a solvent and the chemical shifts are expressed in parts per million (ppm) and coupling constant J in Hz with TMS as internal standard. High-resolution mass spectra (HRMS) were measured in ESI+ mode at MRC, MNIT, Jaipur. 2D correlation spectra, (1H-13C) gs-HMQC and (1H-13C) gs-HMBC of samples were carried out at IIT, Mandi. Page 12 of 26Organic & Biomolecular Chemistry 13 | P a g e General method of Synthesis 3-Mercapto-1,2,4-triazoles30 and 1,3-diketones41,45 were prepared according to literature procedures. Commercially available NBS was used without any purification. General method for preparation of (2-aryl'-6-methylthiazolo[3,2-b][1,2,4]triazol-5- yl)(aryl)methanone (6) To a stirred solution of 1,3-diketone (1, 1.0 eq) in distilled water, 0.178 g of NBS (2, 1.0 eq) was added under visible-light irradiations. Reaction contents were allowed to stir for about 15 minutes. Subsequently, 3-mercapto-1,2,4-triazole (3, 1.0 eq) was added to the reaction mixture and stirred for further 30-40 minutes under the same reaction conditions till the finishing point was monitored on TLC. Excess water was distilled off under reduced pressure using a rotatory evaporator, the reaction product was neutralized with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. Solid obtained after evaporation of ethyl acetate was recrystallized with ethanol, filtered and dried to obtain the product in 73-94% yields. (6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)(phenyl)methanone (6a) White crystals; M. Pt. 115 ºC; Yield: 82%; IR (KBr) νmax (cm−1): 1628 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.21 – 8.19 (m, 2H, 2’,6’-H), 7.82 – 7.80 (m, 2H, 2”,6”-H), 7.67 – 7.63 (m, 1H, 4”-H), 7.56 – 7.52 (m, 2H, 3”,5”-H), 7.50 – 7.44 (m, 3H, 3’,4’,5’-H), 2.71 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ 188.5, 168.3, 157.1, 138.0, 136.6, 133.1, 130.5, 130.2, 128.8, 128.7, 128.7, 126.9, 123.9, 13.8. HRMS (ESI): m/z calcd for C18H13N3OS: 319.0779; found: 320.0781 [M+1]+; Elemental analysis: Calcd. for C18H13N3OS: C, 67.71; H, 4.07; N, 13.16% Found: C, 67.68; H, 4.06; N, 13.13%. (4-fluorophenyl)(6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)methanone (6b) Buff coloured solid; M.Pt. 151 °C; Yield 75%; IR (KBr) νmax (cm−1): 1643 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.22 – 8.19 (m, 2H, 2’,6’-H), 7.90 – 7.86 (m, 2H, 2”,6”-H), 7.51 – 7.46 (m, 3H, 3”,4’,5”-H), 7.25 – 7.21 (m, 2H, 3’,5’-H), 2.75 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ 187.0, 168.5, 166.8, 164.7, 157.0, 136.7, 134.3, 131.7, 131.6, 130.4, 128.8, 127.0, 123.4, 116.1, 13.9. 19F NMR (376 MHz, CDCl3) δ: -103.9. Page 13 of 26 Organic & Biomolecular Chemistry 14 | P a g e HRMS (ESI): m/z calcd for C18H12FN3OS: 337.0685; found: 338.0689 [M+1]+; Elemental analysis: Calcd. for C18H12FN3OS: C, 64.09; H, 3.56; N, 12.46% Found: C, 64.08; H, 3.55; N, 12.44%. (4-chlorophenyl)(6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)methanone (6c) Creamy white solid; M. Pt. 173.5 ºC; Yield: 77%; IR (KBr) νmax (cm−1): 1643 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.23 – 8.19 (m, 2H, 2’,6’-H), 7.80 – 7.77 (m, 2H, 2”,6”-H), 7.55 – 7.52 (m, 2H, 3”,5”-H), 7.51 – 7.47 (m, 3H, 3’,4’,5’-H), 2.75 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ = 187.2, 168.4, 157.0, 139.7, 136.9, 136.3, 130.4, 130.3, 130.2, 129.2, 128.7, 127.0, 123.3, 13.9. HRMS (ESI): m/z calcd for C18H12ClN3OS: 353.0390; found: 354.0392 [M+1]+; 356.0365 [M+1+2]+, (3:1); Elemental analysis: Calcd. for C18H12ClN3OS: C, 61.10; H, 3.39; N, 11.88% Found: C, 61.08; H, 3.35; N, 11.86 %. (4-bromophenyl)(6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)methanone (6d) Brownish solid; M. Pt. 181 ºC; Yield: 76%; IR (KBr) νmax (cm−1): 1643 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.23 – 8.19 (m, 2H, 2’,6’-H), 7.72 – 7.68 (m, 4H, 2”,3”,5”,6”- H), 7.51 – 7.47 (m, 3H, 3’,4’,5’-H), 2.76 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ = 187.5, 168.6, 157.1, 137.0, 136.8, 132.3, 130.5, 130.4, 130.4, 128.9, 128.4, 127.1, 123.4, 14.0. HRMS (ESI): m/z calcd for C18H12BrN3OS: 396.9884; found: 397.9888 [M+1]+; 399.9876 [M+1+2]+, (1:1); Elemental analysis: Calcd. for C18H12BrN3OS: C, 54.40; H, 3.02; N, 10.57% Found: C, 54.38; H, 3.00; N, 10.52%. (2,4-dichlorophenyl)(6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)methanone (6e) Brown crystals; M. Pt. 169 ºC; Yield: 73%; IR (KBr) νmax (cm−1): 1636 (C=O); 1H NMR (500 MHz, CDCl3) δ = 8.20 – 8.17 (m, 2H, 2’,6’-H), 7.55 (d, 1H, 4J=1.2 Hz, 3”-H), 7.50 – 7.46 (m, 3H, 3’,4’,5’-H), 7.44 (dd, 1H, 3J=8.2 Hz, 4J=1.2 Hz, 5”-H), 7.40 (d, 1H, 3J=8.2 Hz, 6”-H), 2.57 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ = 186.2, 168.7, 157.6, 137.8, 137.8, 136.6, 132.0, 130.5, 130.3, 129.3, 128.8, 127.9, 127.1, 125.6, 115.7, 13.0. Page 14 of 26Organic & Biomolecular Chemistry 15 | P a g e HRMS (ESI): m/z calcd for C18H11Cl2N3OS: 387.0000; found: 388.0004 [M+1]+, 389.9991 [M+1+2]+, 391.9982 [M+1+4]+ (9:6:1); Elemental analysis: Calcd. for C18H11Cl2N3OS: C, 55.67; H, 2.83; N, 10.82% Found: C, 55.62; H, 2.81; N, 10.78 %. (6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)(p-tolyl)methanone (6f) White solid; M. Pt. 153 ºC; Yield: 85%; IR (KBr) νmax (cm−1): 1636 (C=O); 1H NMR (500 MHz, CDCl3) δ = 8.20 (dd, 2H, 3J=7.7 Hz, 4J=1.5 Hz, 2’,6’-H), 7.74 (d, 2H, 3J=8.0 Hz, 2”,6”-H), 7.50 – 7.44 (m, 3H, 3’,4’,5’-H), 7.34 (d, 2H, 3J=8.0 Hz, 3”,5”-H), 2.72 (s, 3H, 4”-Me), 2.47 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ = 188.3, 168.3, 157.1, 144.4, 136.3, 135.4, 130.7, 130.3, 129.6, 129.2, 128.8, 127.1, 124.1, 21.9, 14.0. HRMS (ESI): m/z calcd for C19H15N3OS: 333.0936; found: 334.0940 [M+1]+; Elemental analysis: Calcd. for C19H15N3OS: C, 68.46; H, 4.50; N, 12.61% Found: C, 68.43; H, 4.49; N, 12.58 %. (4-methoxyphenyl)(6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)methanone (6g) Creamy white solid; M. Pt. 124 ºC; Yield: 88%; IR (KBr) νmax (cm−1): 1636 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.22 – 8.19 (m, 2H, 2’,6’-H), 7.88 – 7.84 (m, 2H, 2”,6”-H), 7.50 – 7.45 (m, 3H, 3’,4’,5’-H), 7.03 – 7.00 (m, 2H, 3”,5”-H), 3.91 (s, 3H, 4”-OMe), 2.73 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ = 187.0, 168.1, 163.9, 156.9, 135.7, 131.6, 130.6, 130.4, 130.2, 128.8, 127.0, 123.9, 114.1, 55.6, 13.9. HRMS (ESI): m/z calcd for C19H15N3O2S: 349.0885; found: 350.0890 [M+1]+; Elemental analysis: Calcd. for C19H15N3O2S: C, 65.32; H, 4.29; N, 12.03% Found: C, 65.29; H, 4.25; N, 12.00 %. (3-methoxyphenyl)(6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)methanone (6h) Whitish solid; M. Pt. 126 ºC; Yield: 85%; IR (KBr) νmax (cm−1): 1632 (C=O); 1H NMR (500 MHz, CDCl3) δ = 8.22 – 8.19 (m, 2H, 2’,6’-H), 7.51 – 7.46 (m, 3H, 3’,5’,5”- H), 7.44 (d, 1H, 3J=7.9 Hz, 4’-H), 7.41 – 7.38 (m, 1H, 6”-H), 7.32 (s, 1H, 2”-H), 7.20 – 7.16 (m, 1H, 4”-H), 3.88 (s, 3H, 3”-OMe), 2.74 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ = 188.4, 168.4, 159.9, 157.2, 139.4, 136.9, 130.6, 130.3, 129.9, 128.8, 127.0, 123.9, 121.3, 119.6, 113.2, 55.6, 14.0. Page 15 of 26 Organic & Biomolecular Chemistry 16 | P a g e HRMS (ESI): m/z calcd for C19H15N3O2S: 349.0885; found: 350.0888 [M+1]+; Elemental analysis: Calcd. for C19H15N3O2S: C, 65.32; H, 4.29; N, 12.03% Found: C, 65.28; H, 4.28; N, 12.02 %. (2-methoxyphenyl)(6-methyl-2-phenylthiazolo[3,2-b][1,2,4]triazol-5-yl)methanone (6i) Creamy solid; M. Pt. 142 ºC; Yield: 84%; IR (KBr) νmax (cm−1): 1632 (C=O); 1H NMR (500 MHz, CDCl3) δ = 8.21 – 8.17 (m, 2H, 2’,6’-H), 7.56 – 7.51 (m, 1H, 6”-H), 7.50 – 7.45 (m, 3H, 3’,4’,5’-H), 7.40 (dd, 1H, 3J=7.5 Hz, 4J=1.6 Hz, 4”-H), 7.12 – 7.08 (m, 1H, 5”-H), 7.03 (d, 1H, 3J=8.4 Hz, 3”-H), 3.82 (s, 3H, 2”-OMe), 2.57 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ = 188.3, 168.2, 165.0, 157.3, 156.7, 136.5, 132.9, 130.5, 130.2, 128.7, 128.4, 126.9, 124.1, 121.0, 111.5, 55.7, 12.8. HRMS (ESI): m/z calcd for C19H15N3O2S: 349.0885; found: 350.0889 [M+1]+; Elemental analysis: Calcd. for C19H15N3O2S: C, 65.32; H, 4.29; N, 12.03% Found: C, 65.30; H, 4.27; N, 12.01 %. (2-(4-methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(phenyl)methanone (6j) Whitish crystals, M. Pt. 178.5 ºC; Yield: 89%; IR (KBr) νmax (cm−1): 1622 (C=O); 1H NMR (500 MHz, CDCl3) δ: 8.09-8.05 (m, 2H, 2',6'-H), 7.87 – 7.84 (m, 1H, 2'',6''-H), 7.73-7.71 (m, 1H, 4''-H), 7.63-7.59 (m, 2H, 3'',5''-H), 7.11-7.08 (m, 2H, 3',5-H), 3.84 (s, 3H, 4'-OMe), 2.52 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ: 189.0, 167.5, 161.1, 156.8, 138.2, 137.4, 133.5, 129.3, 129.1, 128.6, 124.5, 123.1, 114.9, 55.8, 14.4 HRMS (ESI): m/z calcd for C19H15N3O2S: 349.0885; found: 350.0891 [M+1]+; Elemental analysis: Calcd. for C19H15N3O2S: C, 65.32; H, 4.29; N, 12.03% Found: C, 65.30; H, 4.24; N, 12.02%. (4-fluorophenyl)(2-(4-methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5- yl)methanone (6k) Buff coloured solid; M.Pt. 229.5 °C; Yield 78%; IR (KBr) νmax (cm−1): 1640 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.15 (d, 2H, 3J=10 Hz, 2',6'-H), 7.90 – 7.86 (m, 2H, 2'',6''-H), 7.25 – 7.19 (m, 2H, 3'',5''-H), 7.01 (d, 2H, 3J=10 Hz, 3',5'-H), 3.88 (s, 3H), 2.75 (s, 3H). Page 16 of 26Organic & Biomolecular Chemistry 17 | P a g e 13C NMR (125 MHz, CDCl3) δ 187.0, 174.4, 168.4, 161.3, 136.7, 134.3, 131.5, 131.4, 128.5, 123.0, 122.9, 116.2, 116.0, 114.1, 55.3, 13.9. 19F NMR (376 MHz, DMSO-d6) δ: -105.5. HRMS (ESI): m/z calcd for C19H14FN3O2S: 367.0791; found: 368.0795 [M+1]+; Elemental analysis: Calcd. for C19H14FN3O2S: C, 62.12; H, 3.81; N, 11.44% Found: C, 62.10; H, 3.78; N, 11.41%. (4-chlorophenyl)(2-(4-methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5- yl)methanone (6l) Creamy white solid; M. Pt. 181.5 ºC; Yield: 80%; IR (KBr) νmax (cm−1): 1640 (C=O); 1H NMR (500 MHz, CDCl3) δ = 8.15 – 8.12 (m, 2H, 2',6'-H), 7.79 – 7.76 (m, 2H, 2'',6''-H), 7.54 – 7.50 (m, 2H, 3'',5''-H), 7.01 – 6.98 (m, 2H, 3',5'-H), 3.87 (s, 3H, 4'-OMe), 2.73 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ 187.2, 168.4, 161.3, 157.0, 139.6, 136.9, 136.3, 130.2, 129.1, 128.5, 123.0, 122.9, 114.1, 55.3, 13.9. HRMS (ESI): m/z calcd for C19H14ClN3O2S: 383.0495; found: 384.0494 [M+1]+; 386.0468 [M+1+2]+, (3:1); Elemental analysis: Calcd. for C19H14ClN3O2S: C, 59.45; H, 3.65; N, 10.95% Found: C, 59.41; H, 3.64; N, 10.92 %. (4-bromophenyl)(2-(4-methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5- yl)methanone (6m) Creamy white solid; M. Pt. 189 ºC; Yield: 80%; IR (KBr) νmax (cm−1): 1636 (C=O); 1H NMR (500 MHz, CDCl3) δ = 8.16 – 8.13 (m, 2H, 2',6'-H), 7.71 – 7.68 (m, 4H, 2'',3'',5'',6''-H), 7.02 – 6.99 (m, 2H, 3',5'-H), 3.88 (s, 3H, 4'-OMe), 2.74 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ = 187.8, 168.8, 161.8, 157.4, 137.4, 137.2, 132.5, 130.7, 128.9, 128.6, 123.4, 123.3, 114.5, 55.8, 14.4. HRMS (ESI): m/z calcd for C19H14BrN3O2S: 426.9990; found: 427.9992 [M+1]+; 429.9973 [M+1+2]+, (1:1); Elemental analysis: Calcd. for C19H14BrN3O2S: C, 53.39; H, 3.27; N, 9.83% Found: C, 52.34; H, 3.26; N, 9.81 %. (2,4-dichlorophenyl)(2-(4-methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5- yl)methanone (6n) Page 17 of 26 Organic & Biomolecular Chemistry 18 | P a g e Brown solid; M. Pt. 190.5 ºC; Yield: 77%; IR (KBr) νmax (cm−1): 1632 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.14 – 8.10 (m, 2H, 2',6'-H), 7.55 (d, 1H, 4J=1.5 Hz, 3''-H), 7.44 (dd, 1H, 3J=8.5 Hz, 4J=1.5 Hz, 5''-H), 7.40 (d, 1H, 3J=8.5 Hz, 6''-H), 7.01 – 6.97 (m, 2H, 3',5'-H), 3.87 (s, 3H, 4'-OMe), 2.55 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ 186.1, 168.6, 161.4, 157.5, 137.7, 136.6, 134.0, 131.9, 130.4, 129.2, 128.6, 127.9, 125.1, 122.8, 114.1, 55.3, 12.9. HRMS (ESI): m/z calcd for C19H13Cl2N3O2S: 417.0106; found: 418.0108 [M+1]+, 420.0995 [M+1+2]+, 424.0978 [M+1+4]+ (9:6:1); Elemental analysis: Calcd. for C19H13Cl2N3O2S: C, 54.54; H, 3.11; N, 10.04% Found: C, 54.50; H, 3.10; N, 10.02 %. (2-(4-methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(p-tolyl)methanone (6o) Creamy white solid; M. Pt. 178 ºC; Yield: 90%; IR (KBr) νmax (cm−1): 1630 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.15 – 8.11 (d, 2H, 3J= 10 Hz, 2',6'-H), 7.73 (d, 2H, 3J= 10 Hz, 2'',6''-H), 7.33 (d, 2H, 3J= 10 Hz, 3'',5''-H), 6.99 (d, 2H, 3J=10 Hz, 3',5'-H), 3.87 (s, 3H, 4'-Me), 2.70 (s, 3H, 4''-Me), 2.46 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ 188.2, 168.1, 161.2, 157.0, 144.1, 136.2, 135.3, 129.4, 129.0, 128.4, 123.6, 123.1, 114.1, 55.3, 21.7, 13.9. HRMS (ESI): m/z calcd for C20H17N3O2S: 363.1041; found: 364.1044 [M+1]+; Elemental analysis: Calcd. for C20H17N3O2S: C, 66.11; H, 4.68; N, 11.57% Found: C, 66.10; H, 4.65; N, 11.55 %. (4-methoxyphenyl)(2-(4-methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5- yl)methanone (6p) White solid; M. Pt. 198.5 ºC; Yield: 94%; IR (KBr) νmax (cm−1): 1628 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.16 – 8.12 (m, 2H, 2',6'-H), 7.87 – 7.83 (m, 2H, 2'',6''-H), 7.03 – 6.98 (m, 4H, 3',5',3'',5''-H), 3.91 (s, 3H, 4''-OMe), 3.87 (s, 3H, 4'-OMe), 2.72 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ 186.9, 168.0, 163.7, 161.2, 156.9, 135.7, 131.5, 130.5, 128.4, 123.4, 123.2, 114.1, 114.0, 55.6, 55.3, 13.8. HRMS (ESI): m/z calcd for C20H17N3O3S: 379.0991; found: 380.0994 [M+1]+; Page 18 of 26Organic & Biomolecular Chemistry 19 | P a g e Elemental analysis: Calcd. for C20H17N3O3S: C, 63.32; H, 4.48; N, 11.08% Found: C, 63.29; H, 4.45; N, 11.04 %. (3-methoxyphenyl)(2-(4-methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5- yl)methanone (6q) Creamy white solid; M. Pt. 157.5 ºC; Yield: 92%; IR (KBr) νmax (cm−1): 1630 (C=O); 1H NMR (500 MHz, CDCl3) δ = 8.16 – 8.12 (m, 2H, 2',6'-H), 7.46 – 7.43 (m, 1H, 5''-H), 7.40 – 7.38 (m, 1H, 6''-H), 7.31 (dd, 1H, 4J=2.5 Hz, 4J=1.5 Hz, 2''-H), 7.18 (ddd, 1H, 3J=8.2 Hz, 4J=2.5 Hz, 4J=1.0 Hz, 4''-H), 7.01 – 6.98 (m, 2H, 3',5'-H), 3.88 (s, 3H, 4'-OMe), 3.87 (s, 3H, 3''-OMe), 2.73 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ = 188.4, 168.4, 161.4, 159.9, 157.2, 139.4, 136.9, 129.9, 128.6, 123.5, 123.2, 121.2, 119.5, 114.2, 113.2, 55.6, 55.4, 14.0. HRMS (ESI): m/z calcd for C20H17N3O3S: 379.0991; found: 380.0993 [M+1]+; Elemental analysis: Calcd. for C20H17N3O3S: C, 63.32; H, 4.48; N, 11.08% Found: C, 63.31; H, 4.43; N, 11.07 %. (2-(4-methoxyphenyl)-6-methylthiazolo[3,2-b][1,2,4]triazol-5-yl)(thiophen-2-yl)methanone (6r) Dark Brown solid; M. Pt. 171 ºC; Yield: 78%; IR (KBr) νmax (cm−1): 1622 (C=O); 1H NMR (500 MHz, CDCl3) δ 8.14 (d, 2H, 3J=9.0 Hz, 2',6'-H), 7.91 (d, 1H, 3J=4.0 Hz, 5''- H), 7.78 (d, 1H, 3J=4.0 Hz, 3''-H), 7.24 – 7.20 (m, 1H, 4''-H), 7.00 (d, 2H, 3J=9.0 Hz, 3',5'- H), 3.87 (s, 3H, 4'-OMe), 2.91 (s, 3H, 6-Me). 13C NMR (125 MHz, CDCl3) δ 178.7, 168.3, 161.3, 156.4, 143.4, 137.1, 134.9, 133.6, 128.4, 128.3, 123.1, 120.6, 114.1, 55.3, 13.6. HRMS (ESI): m/z calcd for C17H13N3O2S2: 355.0449; found: 356.0454 [M+1]+; Elemental analysis: Calcd. for C17H13N3O2S2: C, 57.46; H, 3.66; N, 11.83% Found: C, 57.43; H, 3.65; N, 11.80 %. X-ray crystallography Single crystal X-ray diffraction experiments were carried out for compound 6j in the “CAI de Difracción de Rayos X, UCM”. An adequate crystal was mounted on a Bruker Smart CCD diffractometer using Cu-Kα radiation (λ= 1.54178 Å). Page 19 of 26 Organic & Biomolecular Chemistry 20 | P a g e Data were collected at 298 K over a reciprocal space hemisphere using the 'Bruker APEX-II CCD' diffractometer software. The cell parameters were determined and refined by least- squares fit of all the reflections collected. The structure was solved by intrinsic phasing using the SHELXT solution program46 and refined by full matrix least squares on F2 using the SHEXL refinement package47 running in the Olex2 environment48. All non-hydrogen atoms were refined anisotropically. The hydrogen atoms were included with fixed isotropic contributions at their calculated positions determined by molecular geometry and refined riding on the corresponding carbon atoms. Further crystallographic details for the structure reported in this paper may be obtained from the Cambridge Crystallographic Data Centre, via www.ccdc.cam.ac.uk/data_request/cif, on quoting the depository number 2099149 (compound 6j). Table 3. Crystal and refinement data for 6j. Crystal Data 6j CCDC code 2099149 Empirical formula C19H15N3O2S Formula wt. 349.40 Temperature/K 297.0 Crystal system. Space group monoclinic P21/n a/Å b/Å c/Å  /°  /°  /° 8.5191(2) 10.3297(2) 18.8853(4) 90.0 96.6638(8) 90.0 V/Å3 1650.67(6) Z 4 Dc / g/cm3 1.410 µ / mm-1 1.894 F(000) 728.0  range/° 9.43 to 144.376 index ranges -10,-12,-23 to 10, 12, 22 reflections collected 36441 unique reflections [Rint] 3269 [Rint = 0.0471] completeness to theta 99.9% Page 20 of 26Organic & Biomolecular Chemistry 21 | P a g e data/restraints/params 3269/0/228 Goodness-of-fit on F2 1.061 R1 (reflns obsd) [I>2(I)] a 0.0468 (3030) wR2 (all data) b 0.1324 a R1=Fo-Fc/ Fo b wR2=[w(Fo 2-Fc 2)2]/ [w(Fo 2)2]} Associated content The Supporting Information includes additional experimental data, 1H, 13C, HMBC, HMQC, HRMS spectra and X-ray crystallographic studies results) for final compounds. Acknowledgment We are thankful to the Council of Scientific and Industrial Research (CSIR), New Delhi, India for kindly providing financial assistance to Mona Hooda for JRF & SRF (Grant 09/ 105(0236)/2016-EMR-I) and Prince Kumar as JRF (Grant 09/105(0302)/2020-EMR-I). Author contributions R.A. contributed to the conceptualization and development of the methodology, reviewed the manuscript, and supervised the project. P.K. and M.H. performed the experimental analysis and M.C.T. characterized the synthesized regioisomer through X-ray crystallographic studies. P.K., M.H. and M.C.T. wrote the manuscript. All authors contributed to the discussion and in improving the writing of the manuscript. Author information *Corresponding author: Prof. Ranjana Aggarwal, CSIR-National Institute of Science Communication and Policy Research, New Delhi, 110012 India. 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