Description:Field of Invention: 1,3,4-Oxadiazoles possess remarkable properties showcasing their potential for use in developing new drugs, materials, and other industrial applications. Some of the drugs that bear 1,3,4-oxadiazole moiety are Furamizole (antibacterial), Tiodazosin (antihypertensive) and Raltagravir (HIV-integrase inhibitor). The present invention discloses the synthesis and characterization of a new series of nineteen 1,3,4-oxadiazoles linked with 3,5-dimethylpyrazole moiety. This invention presents the heterocyclic synthesis offering a more efficient, sustainable and regioselective approach to obtain 1,3,4-oxadiazoles with an expectation of enhanced biological properties.
Background: 1,3,4-Oxadiazoles are an important class of oxygen and nitrogen containing heterocyclic compounds that have gained significant attention in various fields owing to their diverse chemical and biological activities. These compounds exhibit promising potential for applications in pharmaceuticals (Bioorg. Chem. 2021, 112, 104920; Pak. J. Pharm. Sci. 2020, 33, 871–876), materials science (Propellants Explos. Pyrotech. 2021, 46(6), 860-874; ACS Appl. Mater. Interfaces. 2022, 14(44), 49898-49908; New J. Chem. 2020, 44(16), 6643-6651), and agriculture (J. Agric. Food Chem. 2023, 71(6), 2804-2816; J. Agric. Food Chem. 2022, 70(26), 729-7940), and thus making them valuable targets for synthesis and further exploration in the field of medicinal chemistry. The conventional methods for synthesizing 1,3,4-oxadiazoles typically involve the reaction of appropriate acids or acid chlorides with amidoximes or hydrazides, followed by cyclization or reaction of an acyl hydrazide and carbon disulfide under basic conditions using alcohol as a solvent followed by the acidification (Eur. J. Med. Chem, 2010, 45, 4963-4967). From literature, it has been reported that the attachment of phenacyl or naphthacyl groups with azoles (Eur. J. Med. Chem, 2014, 81, 267-276; Med. Chem. Res. 2015, 24 (12), 4023-4036) and 1,3,4-oxadiazoles (Bioorg. Med. Chem., 2008, 16, 1822–1831; Molecules, 2017, 22, 2004) units leads to exhibit a broad range of medicinal properties. In view of the facts, there is always a need for the synthesis of a diverse range of new 1,3,4-oxadiazoles facilitating their widespread applications and development. The present invention provides the efficient and mild process for the synthesis of a new series of 1,3,4-oxadiazoles. This method utilizes a unique combination of reagents and appropriate reaction conditions to achieve high yields, shorter reaction times, and improved safety profiles. In the following sections, we provide a detailed description of the new synthesis protocol, supported by experimental results that demonstrate the successful synthesis of various 1,3,4-oxadiazoles using this approach.
Detailed description of the invention:
In view of the importance of 1,3,4-oxadiazoles in various fields, we synthesized a new series of 2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-arylethanone derivatives (6a-s) by the regioselective and mechanochemical solvent-free protocol. The structures of the synthesized oxadiazoles were established by analyzing their IR, 1H, 13C, 19F NMR and mass spectral data.
General method to synthesize 2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-arylethanones (6a-s) is outlined in Scheme-1. Initially, Methyl 3-(3,5-dimethyl-1H-pyrazol-1-yl)propanoate (2) was prepared from 3,5-dimethyl-1H-pyrazole (1) which was then treated with hydrazine hydrate at room temperature to synthesize the key intermediate 3-(3,5-Dimethyl-1H-pyrazol-1-yl)propanehydrazide (3). Then, 3 was treated with ethanolic KOH and CS2 at reflux for 8 hrs followed by acidification with conc. HCl to synthesize 5-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazole-2-thiol (4). The compound 4 was ground with a-bromoketones (5a-s) in the presence of K2CO3 as a base at appropriate temperature in solvent-free conditions which generated 2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-arylethanones (6a-s) regioselectively in good yields ranged from 73-95 %. The structures of all compounds were well established on the basis of spectroscopy.

Scheme-1: Synthesis of 2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-arylethanones (6a-s)

In 1H-NMR spectrum of 6a, appearance of characteristic signal as a singlet at d 5.70 due to 4-H of pyrazole ring confirms the attachment of 3,5-dimethylpyrazole moiety wih 1,3,4-oxadiazoles. The protons of 3-and 5-methyl group resonated at d 2.21 and 2.22, respectively (Eur. J. Med. Chem, 2014). The presence of two triplets at d 3.37-3.41 (3JH-H – 8 Hz) and 4.37-4.41 (3JH-H – 8 Hz) reveals the presence of –CH2-CH2- alkyl chain attached with oxadiazole and pyrazole ring, respectively. The presence of a singlet signal at d 4.90 confirms the presence of CH2 protons which resonated downfield as this group is attached with sulphur substituted to the carbon of the oxadiazole ring and carbonyl carbon. The presence of two multiplet and one doublet at around d 7.51-7.55 (m, 2H, 3'', 5''-H), 7.63-7.67 (m, 1H, 4''-H), 8.02-8.04 (d, 2H, 2'', 6''-H, 3JH-H – 8 Hz) confirms the presence of five aromatic protons of phenyl ring. Furthermore, appearance of characteristic signals in 13C-NMR spectrum at 148.20, 105.31, 139.31 are due to C-3, C-4, C-5 of pyrazole ring, respectively supported the formation of 6a. Also, 19F NMR of 6b shows a characteristic peak at d -100.78 due to the substitution of fluorine at position-4 of phenyl ring. Further, mass spectrum showed a molecular ion peak at m/z = 343 [M+1]+ which supported the formation of 6a with molecular formula C17H18N4O2S. These observations successfully resulted in the regioselective formation of 6a in excellent yield. IR spectrum of 6a showed the characteristics absorption bands at 1736 cm-1 due to C=O stretching vibration, 1674 – 1475 cm-1 due to C=N and C=C stretching vibrations, 1145- 1199 cm-1 due to C-O-C stretching vibrations of oxadiazole ring. Other derivatives were also characterized similarly.

Table-1: Molecular weight, percentage yields, color and melting points of synthesized compounds (6a-s)

S.No. Ar Molecular formula Molecular weight (g/mol) Yield (crude)
(%) Color Obs. Melting Point (°C)
1 C6H5- C17H18N4O2S 342.4 87 White solid 119
2 4-FC6H4- C17H17N4O2SF 360.4 95 White solid 125
3 4-ClC6H4- C17H17N4O2SCl 376.9 73 White solid 117
4 4-BrC6H4- C17H17N4O2SBr 421.3 92 White solid 115
5 4-CH3C6H4- C18H20N4O2S 356.4 91 Yellow solid 107
6 4-OCH3C6H4- C18H20N4O3S 372.4 88 White solid 108
7 4-C6H5C6H4- C23H22N4O2S 418.5 91 Yellow solid 109
8 4-CF3C6H4- C18H17N4O2SF3 410.4 87 White solid 99
9 4-OCF3C6H4- C18H17N4O3SF3 426.4 90 White solid 104
10 4-NO2C6H4- C17H17N5O4S 387.4 89 Brown solid 105
11 4-CNC6H4- C18H17N5O2S 367.4 86 Brown solid 140
12 3-FC6H4- C17H17N4O2SF 360.4 90 Yellow solid 78
13 3-BrC6H4- C17H17N4O2SBr 421.3 86 White solid 93
14 3-NO2C6H4- C17H17N5O4S 387.4 88 Brown viscous liquid ?
15 2-FC6H4- C17H17N4O2SF 360.4 92 Yellow solid 69
16 2-OCH3C6H4- C18H20N4O3S 372.4 90 White solid 107
17 2,4-F2C6H3- C17H16N4O2SF2 378.4 80 Yellow solid 106
18 3,4-Cl2C6H3- C17H16N4O2SCl2 411.3 75 Yellow solid 89
19 2-Naphthyl C21H20N4O2S 392.5 89 White solid 117

Synthesis of 2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-arylethanone (6a-s)
Compounds 6(a-s) were synthesized by grinding 4 (0.002 moles, 1eq) with 5(a-s) (0.002 moles, 1eq) in the presence of potassium carbonate (0.002 moles, 1eq) in a mortar-pestle with heating for 20-40 minutes. After completion of reaction, the obtained product was washed with water, filtered and dried and then recrystallized from ethanol (Scheme 1).

Characterization data of the compounds 6(a-s)

2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-phenylethanone (6a):
FTIR (?max) cm-1 1736 cm-1 (C=O str.), 1674 - 1475 cm-1 (C=N and C=C str.), 1145, 1199 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.21 (s, 3H, 3-CH3), 2.22 (s, 3H, 5-CH3), 5.78 (s, 1H, 4-CH), 4.90 (s, 2H, 2'-CH2), 3.37-3.41 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.37-4.41 (t, 2H, 2-CH2, 3JH-H - 8Hz), 7.51-7.55 (m, 2H, 3'', 5''-H), 7.63-7.67 (m, 1H, 4''-H), 8.02-8.04 (d, 2H, 2'', 6''-H, 3JH-H - 8Hz); 13C NMR (CDCl3, 400 MHz): d = 26.57 (C-1), 44.54 (C-2), 148.20 (C-3), 105.31 (C-4), 139.31 (C-5), 13.46 (CH3- C-3), 10.88 (CH3-C-5), 191.96 (C-1'), 41.47 (C-2'), 164.15 (C-7), 165.32 (C-6), 134.87 (C-1''), 128.97 (C-2'', 6''), 128.51 (C-3'', 5''), 134.26 (C-4''); MS (m/z): 343 [M+1]+
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-fluorophenyl)ethanone (6b):
FTIR (?max) cm-1 1741 cm-1 (C=O str.), 1675 - 1477 cm-1 (C=N and C=C str.), 1147, 1195 cm-1 (C-O str.) and 1231 cm-1 (C-F str.); 1H NMR (CDCl3, 400 MHz): d = 2.21 (s, 3H, 3-CH3), 2.23 (s, 3H, 5-CH3), 5.78 (s, 1H, 4-CH), 4.87 (s, 2H, 2'-CH2), 3.37-3.41 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.38-4.42 (t, 2H, 2-CH2, 3JH-H - 8Hz), 7.18-7.22 (m, 2H, 3'', 5''-H), 8.06-8.09 ( m, 2H, 2'', 6''-H ); 13C NMR (CDCl3, 400 MHz): d = 26.57 (C-1), 44.52 (C-2), 148.20 (C-3), 105.34 (C-4), 139.36 (C-5), 13.43 (CH3- C-3), 10.89 (CH3-C-5), 190.44 (C-1'), 41.16 (C-2'), 165.37 (C-6), 164.04 (C-7), 131.39 (C-1''), 131.30 (d, C-2'', 6'', 3JC-F - 9.6 Hz), 116.22 (d, C-3'', 5'', 2JC-F - 22.1 Hz), 166.05 (d, C-4'', 1JC-F - 128.5 Hz); 19F NMR (CDCl3, 80 MHz): d = -100.78 (s, 1F, F-C-4''); MS (m/z): 361 [M+1]+
1-(4-Chlorophenyl)-2-((5-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)ethanone (6c):
FTIR (?max) cm-1 1737 cm-1 (C=O str.), 1697 - 1475 cm-1 (C=N and C=C str.), 1157, 1200 cm-1 (C-O str.) and 773 cm-1 (C-Cl str.); 1H NMR (CDCl3, 400 MHz): d = 2.20 (s, 3H, 3-CH3), 2.21 (s, 3H, 5-CH3), 5.77 (s, 1H, 4-CH), 4.84 (s, 2H, 2'-CH2), 3.36-3.40 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.36-4.40 (t, 2H, 2-CH2, 3JH-H - 8Hz), 7.48-7.50 (d, 2H, 3'', 5''-H, 3JH-H - 8Hz), 7.96-7.98 ( d, 2H, 2'', 6''-H, 3JH-H - 8Hz ); 13C NMR (CDCl3, 400 MHz): d = 26.57 (C-1), 44.51 (C-2), 148.21 (C-3), 105.31 (C-4), 139.27 (C-5), 13.46 (CH3- C-3), 10.88 (CH3-C-5), 190.87 (C-1'), 41.11 (C-2'), 165.41 (C-6), 163.93 (C-7), 133.22 (C-1''), 129.91 (C-2'', 6''), 129.33 (C-3'', 5''), 140.85 (C-4''); MS (m/z): 377 [M+1]+ and 379 [M+1+2]+ in the ratio showing typical chlorine isotope profile [3:1]
1-(4-Bromophenyl)-2-((5-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)ethanone (6d):
FTIR (?max) cm-1 1740 cm-1 (C=O str.), 1697 - 1475 cm-1 (C=N and C=C str.), 1159, 1200 cm-1 (C-O str.) and 551 cm-1 (C-Br str.); 1H NMR (CDCl3, 400 MHz): d = 2.21 (s, 3H, 3-CH3), 2.22 (s, 3H, 5-CH3), 5.78 (s, 1H, 4-CH), 4.84 (s, 2H, 2'-CH2), 3.37-3.40 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.38-4.41 (t, 2H, 2-CH2, 3JH-H - 8Hz), 7.66-7.68 (d, 2H, 3'', 5''-H, 3JH-H - 8Hz), 7.88-7.90 ( d, 2H, 2'', 6''-H , 3JH-H - 8Hz); 13C NMR (CDCl3, 400 MHz): d = 26.57 (C-1), 44.51 (C-2), 148.21 (C-3), 105.33 (C-4), 139.30 (C-5), 13.45 (CH3- C-3), 10.89 (CH3-C-5), 191.09 (C-1'), 41.08 (C-2'), 165.41 (C-6), 163.93 (C-7), 132.23 (C-1''), 129.96 (C-2'', 6''), 129.65 (C-3'', 5''), 133.62 (C-4''); MS (m/z): 421 [M+1]+ and 423 [M+1+2]+ in the ratio showing typical bromine isotope profile [1:1]
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(p-tolyl)ethanone (6e):
FTIR (?max) cm-1 1740 cm-1 (C=O str.), 1670 - 1473 cm-1 (C=N and C=C str.), 1149, 1216 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.22 (s, 3H, 3-CH3), 2.22 (s, 3H, 5-CH3), 5.78 (s, 1H, 4-CH), 4.89 (s, 2H, 2'-CH2), 3.38-3.41 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.38-4.41 (t, 2H, 2-CH2, 3JH-H - 8Hz), 2.45 (s, 3H, 4”-CH3), 7.92-7.94 (d, 2H, 3'', 5''-H, 3JH-H - 8Hz), 7.31-7.33 ( d, 2H, 2'', 6''-H , 3JH-H - 8Hz); 13C NMR (CDCl3, 400 MHz): d = 26.58 (C-1), 44.55 (C-2), 148.19 (C-3), 105.32 (C-4), 139.36 (C-5), 13.44 (CH3- C-3), 10.89 (CH3-C-5), 191.56 (C-1'), 41.52 (C-2'), 165.26 (C-6), 164.29 (C-7), 132.38 (C-1''), 128.63 (C-2'', 6''), 129.64 (C-3'', 5''), 145.38 (C-4''), 21.80 (CH3-C-4''); MS (m/z): 357 [M+1]+
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-methoxyphenyl)ethanone (6f):
FTIR (?max) cm-1 1740 cm-1 (C=O str.), 1643 - 1451 cm-1 (C=N and C=C str.), 1159, 1231 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.20 (s, 3H, 3-CH3), 2.21 (s, 3H, 5-CH3), 5.77 (s, 1H, 4-CH), 4.86 (s, 2H, 2'-CH2), 3.36-3.40 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.37-4.40 (t, 2H, 2-CH2, 3JH-H - 8Hz), 3.90 (s, 3H, 4''-OCH3), 6.96-6.99 (d, 2H, 3'', 5''-H, 3JH-H - 12Hz), 7.99-8.01 ( d, 2H, 2'', 6''-H , 3JH-H - 8Hz); 13C NMR (CDCl3, 400 MHz): d = 26.57 (C-1), 44.55 (C-2), 148.19 (C-3), 105.30 (C-4), 139.30 (C-5), 13.46 (CH3- C-3), 10.88 (CH3-C-5), 190.41 (C-1'), 41.36 (C-2'), 165.23 (C-6), 164.38 (C-7), 130.91 (C-1''), 127.86 (C-2'', 6''), 114.14 (C-3'', 5''), 164.40 (C-4''), 55.61 (OCH3-C-4''); MS (m/z): 373 [M+1]+
1-([1,1'-Biphenyl]-4-yl)-2-((5-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)ethanone (6g):
FTIR (?max) cm-1 1740 cm-1 (C=O str.), 1683 - 1479 cm-1 (C=N and C=C str.), 1149, 1196 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.23 (s, 3H, 3-CH3), 2.24 (s, 3H, 5-CH3), 5.80 (s, 1H, 4-CH), 4.94 (s, 2H, 2'-CH2), 3.40-3.43 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.40-4.43 (t, 2H, 2-CH2, 3JH-H - 8Hz), 7.74-7.76 (d, 2H, 3'', 5''-H, 3JH-H - 8Hz), 8.10-8.12 ( d, 2H, 2'', 6''-H , 3JH-H - 8Hz), 7.65-7.67 (d, 2H, 8'', 12''-H, 3JH-H - 8Hz), 7.42-7.53 (m, 3H, 9'', 10'', 11''-H); 13C NMR (CDCl3, 400 MHz): d = 26.59 (C-1), 44.54 (C-2), 148.18 (C-3), 105.37 (C-4), 139.48 (C-5), 13.42 (CH3- C-3), 10.91 (CH3-C-5), 191.55 (C-1'), 41.48 (C-2'), 165.31 (C-6), 164.23 (C-7), 133.52 (C-1''), 129.14 (C-2'', 6''), 127.56 (C-3'', 5''), 146.97 (C-4''), 139.47 (C-7''), 129.06 (C-9'', 11''), 128.57 (C-8'', 12''), 127.32 (C-10''); MS (m/z): 419 [M+1]+
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(trifluoromethyl)phenyl)ethanone (6h):
FTIR (?max) cm-1 1740 cm-1 (C=O str.), 1689 - 1475 cm-1 (C=N and C=C str.), 1128, 1163 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.21 (s, 3H, 3-CH3), 2.22 (s, 3H, 5-CH3), 5.78 (s, 1H, 4-CH), 4.88 (s, 2H, 2'-CH2), 3.38-3.41 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.38-4.41 (t, 2H, 2-CH2, 3JH-H - 8Hz), 8.14-8.16 (d, 2H, 3'', 5''-H, 3JH-H - 8Hz), 7.79-7.81 ( d, 2H, 2'', 6''-H, 3JH-H - 8Hz); 13C NMR (CDCl3, 400 MHz): d = 26.57 (C-1), 44.49 (C-2), 148.21 (C-3), 105.34 (C-4), 139.34 (C-5), 13.43 (CH3- C-3), 10.87 (CH3-C-5), 191.20 (C-1'), 41.05 (C-2'), 165.50 (C-6), 163.75 (C-7), 137.59 (C-1''), 128.90 (C-2'', 6''), 126.05 (q, C-3'', 5'', 3JC-F-3.7 Hz), 135.40 (q, C-4'', 2JC-F-33 Hz), 123.37 (d, CF3-C-4'', 1JC-F-272.9 Hz); 19F NMR (CDCl3, 80 MHz): d = -61.28 (s, 3F, CF3-C-4''); MS (m/z): 411 [M+1]+
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-(trifluoromethoxy)phenyl)ethanone (6i):
FTIR (?max) cm-1 1738 cm-1 (C=O str.), 1678 - 1483 cm-1 (C=N and C=C str.), 1160, 1206 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.20 (s, 3H, 3-CH3), 2.21 (s, 3H, 5-CH3), 5.77 (s, 1H, 4-CH), 4.86 (s, 2H, 2'-CH2), 3.36-3.40 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.36-4.40 (t, 2H, 2-CH2, 3JH-H - 8Hz), 8.08-8.10 (d, 2H, 2'', 6''-H, 3JH-H - 8Hz), 7.33-7.35 (d, 2H, 3'', 5''-H , 3JH-H - 8Hz); 13C NMR (CDCl3, 400 MHz): d = 26.56 (C-1), 44.50 (C-2), 148.22 (C-3), 105.31 (C-4), 139.26 (C-5), 13.45 (CH3- C-3), 10.86 (CH3-C-5), 190.56 (C-1'), 41.02 (C-2'), 165.44 (C-6), 163.89 (C-7), 120.61 (C-3'', 5''), 130.66 (C-2'', 6''), 133.08 (C-1''), 153.38 (d, C-4'', 3JC-F = 1.7 Hz), 120.23 (q, OCF3-C-4'', 1JC-F = 259.4 Hz), ; 19F NMR (CDCl3, 80 MHz): d = -55.62 (s, 3F, OCF3-C-4''); MS (m/z): 427 [M+1]+
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(4-nitrophenyl)ethanone (6j):
FTIR (?max) cm-1 1740 cm-1 (C=O str.), 1676 - 1483 cm-1 (C=N and C=C str.), 1516, 1342 cm-1 (NO2 str.), 1147, 1194 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.19 (s, 3H, 3-CH3), 2.22 (s, 3H, 5-CH3), 5.77 (s, 1H, 4-CH), 4.88 (s, 2H, 2'-CH2), 3.36-3.40 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.36-4.40 (t, 2H, 2-CH2, 3JH-H - 8Hz), 8.20-8.22 (d, 2H, 2'', 6''-H, 3JH-H - 8Hz), 8.35-8.37 (d, 2H, 3'', 5''-H , 3JH-H - 8Hz); 13C NMR (CDCl3, 400 MHz): d = 26.56 (C-1), 44.47 (C-2), 148.23 (C-3), 105.33 (C-4), 139.40 (C-5), 13.47 (CH3- C-3), 10.88 (CH3-C-5), 190.79 (C-1'), 40.90 (C-2'), 165.63 (C-6), 163.52 (C-7), 139.25 (C-1''), 129.64 (C-2'', 6''), 124.15 (C-3'', 5''), 150.85 (C-4''); MS (m/z): 388 [M+1]+
4-(2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)acetyl)benzonitrile (6k):
FTIR (?max) cm-1 1740 cm-1 (C=O str.), 1686 - 1471 cm-1 (C=N and C=C str.), 2230 cm-1 (C=N str.), 1164, 1200 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.19 (s, 3H, 3-CH3), 2.21 (s, 3H, 5-CH3), 5.77 (s, 1H, 4-CH), 4.85 (s, 2H, 2'-CH2), 3.36-3.39 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.36-4.39 (t, 2H, 2-CH2, 3JH-H - 8Hz), 8.12-8.14 (d, 2H, 2'', 6''-H, 3JH-H - 8Hz), 7.82-7.84 (d, 2H, 3'', 5''-H , 3JH-H - 8Hz); 13C NMR (CDCl3, 400 MHz): d = 26.56 (C-1), 44.48 (C-2), 148.24 (C-3), 105.33 (C-4), 139.22 (C-5), 13.47 (CH3- C-3), 10.88 (CH3-C-5), 190.96 (C-1'), 40.82 (C-2'), 165.59 (C-6), 163.57 (C-7), 137.91 (C-1''), 128.95 (C-2'', 6''), 132.79 (C-3'', 5''), 117.39 (C-4''), 117.60 (CN-C-4''); MS (m/z): 368 [M+1]+
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(3-fluorophenyl)ethanone (6l):
FTIR (?max) cm-1 1740 cm-1 (C=O str.), 1697 - 1483 cm-1 (C=N and C=C str.), 1237 cm-1 (C-F str.), 1153 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.21 (s, 3H, 3-CH3), 2.22 (s, 3H, 5-CH3), 5.78 (s, 1H, 4-CH), 4.86 (s, 2H, 2'-CH2), 3.37-3.40 (t, 2H, 1-CH2), 4.38-4.41 (t, 2H, 2-CH2), 7.49-7.55 (m, 1H, 4''-H), 7.81-7.83 (d, 1H, 6''-H , 3JH-H = 8 Hz), 7.33-7.38 ( m, 1H, 5''-H), 7.70-7.72 (d, 1H, 2''-H, 3JH-H = 8 Hz); 13C NMR (CDCl3, 400 MHz): d = 26.59 (C-1), 44.51 (C-2), 148.28 (C-3), 105.33 (C-4), 139.29 (C-5), 13.45 (CH3- C-3), 10.87 (CH3-C-5), 190.84 (d, C-1', 4JC-F-2.3 Hz), 41.20 (C-2'), 165.44 (C-6), 163.87 (C-7), 115.24 (d, C-2'', 2JC-F = 22.7 Hz), 130.74 (d, C-5'', 3JC-F = 7.7 Hz), 162.89 (d, C-3'', 1JC-F = 249.2 Hz), 124.34 (d, C-6'', 4JC-F = 3.1 Hz), 121.34 (d, C-4'', 2JC-F = 21.5 Hz), 136.88 (d, C-1'', 3JC-F = 6.4 Hz); 19F NMR (CDCl3, 80 MHz): d = -108.63 (s, 1F, F-C-3''); MS (m/z): 361 [M+1]+
1-(3-Bromophenyl)-2-((5-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)ethanone (6m):
FTIR (?max) cm-1 1739 cm-1 (C=O str.), 1697 - 1479 cm-1 (C=N and C=C str.), 679 cm-1 (C-Br str.), 1163, 1202 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.20 (s, 3H, 3-CH3), 2.22 (s, 3H, 5-CH3), 5.77 (s, 1H, 4-CH), 4.84 (s, 2H, 2'-CH2), 3.37-3.40 (t, 2H, 1-CH2, 3JH-H = 8 Hz), 4.37-4.40 (t, 2H, 2-CH2, 3JH-H = 8 Hz), 7.76-7.78 (d, 1H, 4''-H, 3JH-H = 8 Hz), 7.94-7.96 (d, 1H, 6''-H , 3JH-H = 8 Hz), 7.39-7.43 ( t, 1H, 5''-H, 3JH-H = 8Hz), 8.15 (s, 1H, 2''-H); 13C NMR (CDCl3, 400 MHz): d = 26.58 (C-1), 44.51 (C-2), 148.22 (C-3), 105.32 (C-4), 139.31 (C-5), 13.46 (CH3- C-3), 10.89 (CH3-C-5), 190.73 (C-1'), 41.12 (C-2'), 165.44 (C-6), 163.84 (C-7), 131.48 (C-5''), 130.54 (C-2''), 136.57 (C-4''), 123.30 (C-3''), 127.03 (C-6''), 137.07 (C-1''); MS (m/z): 421 [M+1]+ and 423 [M+1+2]+ in the ratio showing typical bromine isotope profile [1:1]
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(3-nitrophenyl)ethanone (6n):
FTIR (?max) cm-1 1738 cm-1 (C=O str.), 1697 - 1482 cm-1 (C=N and C=C str.), 1531, 1348 cm-1 (NO2 str.), 1161, 1204 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.19 (s, 3H, 3-CH3), 2.22 (s, 3H, 5-CH3), 5.77 (s, 1H, 4-CH), 4.89 (s, 2H, 2'-CH2), 3.36-3.40 (t, 2H, 1-CH2, 3JH-H = 8 Hz), 4.37-4.40 (t, 2H, 2-CH2, 3JH-H = 8 Hz), 8.49-8.51 (d, 1H, 4''-H , 3JH-H = 12 Hz), 8.36-8.38 (d, 1H, 6''-H , 3JH-H = 8 Hz), 7.74-7.78 (t, 1H, 5''-H, 3JH-H = 8 Hz), 8.85 (s, 1H, 2''-H); 13C NMR (CDCl3, 400 MHz): d = 26.57 (C-1), 44.47 (C-2), 148.26 (C-3), 105.34 (C-4), 139.29 (C-5), 13.44 (CH3- C-3), 10.88 (CH3-C-5), 190.14 (C-1'), 40.68 (C-2'), 165.61 (C-6), 163.53 (C-7), 123.37 (C-2''), 128.34 (C-4''), 130.35 (C-5''), 134.02 (C-6''), 136.24 (C-1''), 148.54 (C-3''); MS (m/z): 388 [M+1]+
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(2-fluorophenyl)ethanone (6o):
FTIR (?max) cm-1 1738 cm-1 (C=O str.), 1682 - 1479 cm-1 (C=N and C=C str.), 1214 cm-1 (C-F str.), 1149, 1103 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.20 (s, 6H, 3, 5-CH3), 5.77 (s, 1H, 4-CH), 4.78 (d, 2H, 2'-CH2), 3.36-3.39 (t, 2H, 1-CH2, 3JH-H = 8 Hz), 4.37-4.41 (t, 2H, 2-CH2, 3JH-H = 8 Hz), 7.17-7.22 (m, 1H, 3''-H), 7.26-7.30 (m, 1H, 5''-H), 7.58-7.63 (m, 1H, 4''-H), 7.93-7.96 (m, 1H, 6''-H); 13C NMR (CDCl3, 400 MHz): d = 26.57 (C-1), 44.50 (C-2), 148.15 (C-3), 105.37 (C-4), 139.54 (C-5), 13.35 (CH3- C-3), 10.87 (CH3-C-5), 189.71 (C-1', d, 3JC-F = 4.0 Hz), 44.42 (C-2'), 165.26 (C-6), 163.85 (C-7), 116.81 (C-3'', d, 2JC-F = 23.5 Hz), 123.40 (C-1'', d, 2JC-F = 12.7 Hz), 124.91 (C-5'', d, 4JC-F = 3.2 Hz), 131.10 (C-6'', d, 3JC-F = 2.0 Hz), 135.93 (C-4'', d, 3JC-F = 9.2 Hz), 162.16 (C-2'', d, 1JC-F = 255.2 Hz); 19F NMR (CDCl3, 80 MHz): d = -105.49 (s, 1F, F-C-2''); MS (m/z): 361 [M+1]+
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(2-methoxyphenyl)ethanone (6p):
FTIR (?max) cm-1 1738 cm-1 (C=O str.), 1645 - 1479 cm-1 (C=N and C=C str.), 1159, 1110 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.21 (s, 6H, 3, 5-CH3), 5.77 (s, 1H, 4-CH), 4.85 (s, 2H, 2'-CH2), 3.36-3.39 (t, 2H, 1-CH2, 3JH-H = 8 Hz), 4.37-4.40 (t, 2H, 2-CH2, 3JH-H = 8 Hz), 3.99 (s, 3H, 2''-OCH3), 7.01-7.07 (m, 2H, 3'',5''-H), 7.54-7.58 (t, 1H, 4''-H, 3JH-H = 8 Hz), 7.88-7.90 (d, 1H, 6''-H , 3JH-H = 12 Hz); 13C NMR (CDCl3, 400 MHz): d = 26.59 (C-1), 45.64 (C-2), 148.17 (C-3), 105.29 (C-4), 139.30 (C-5), 13.45 (CH3- C-3), 10.89 (CH3-C-5), 192.77 (C-1'), 44.56 (C-2'), 165.05 (C-6), 164.58 (C-7), 55.78 (OCH3, C-2''), 111.67 (C-3''), 121.05 (C-1''), 124.99 (C-5''), 131.29 (C-6''), 135.20 (C-4''), 159.31 (C-2''); MS (m/z): 373 [M+1]+
1-(2,4-Difluorophenyl)-2-((5-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)ethanone (6q):
FTIR (?max) cm-1 1739 cm-1 (C=O str.), 1672 - 1477 cm-1 (C=N and C=C str.), 1261 cm-1 (C-F str.), 1153, 1221 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.20 (s, 3H, 3-CH3), 2.21 (s, 3H, 5-CH3), 5.77 (s, 1H, 4-CH), 4.75 (s, 2H, 2'-CH2), 3.36-3.40 (t, 2H, 1-CH2, 3JH-H = 8 Hz), 4.36-4.40 (t, 2H, 2-CH2, 3JH-H = 8 Hz); 6.93-6.98 (m, 1H, 3''-H), 7.01-7.05 ( m, 1H, 5''-H), 7.99-8.05 (m, 1H, 6''-H); 13C NMR (CDCl3, 400 MHz): d = 26.57 (C-1), 44.51 (C-2), 148.21 (C-3), 105.30 (C-4), 139.29 (C-5), 13.44 (CH3- C-3), 10.87 (CH3-C-5), 188.25 (d, C-1', 3JC-F-4.5 Hz), 44.29 (d, C-2', 10.3), 165.35 (C-6), 163.72 (C-7), 120.11 (dd, C-1'', 2JC-F-13.1 Hz, 4JC-F-3.6 Hz), 162.99 (dd, C-2'', 1JC-F-257.7 Hz, 3JC-F-12.7 Hz), 105.12 (dd, C-3'', 2JC-F-27.4 Hz, 2JC-F-25.7 Hz), 112.85 (dd, C-5'', 2JC-F-21.6 Hz, 4JC-F-3.2 Hz), 133.24 (dd, C-6'', 3JC-F-10.8 Hz, 3JC-F-3.9 Hz), 166.53 (dd, C-4'', 1JC-F-259.3 Hz, 3JC-F-12.5 Hz); 19F NMR (CDCl3, 80 MHz): d = 96.83 (s, 1F, F-C-4''), 100.71 (s, 1F, F-C-2''); MS (m/z): 379 [M+1]+
1-(3,4-Dichlorophenyl)-2-((5-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)ethanone (6r):
FTIR (?max) cm-1 1738 cm-1 (C=O str.), 1676 - 1475 cm-1 (C=N and C=C str.), 1147, 1198 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.25 (s, 3H, 3-CH3), 2.26 (s, 3H, 5-CH3), 5.84 (s, 1H, 4-CH), 4.82 (s, 2H, 2'-CH2), 3.44-3.48 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.45-4.49 (t, 2H, 2-CH2, 3JH-H - 8Hz), 7.60-7.62 (d, 1H, 6''-H, 3JH-H = 8Hz), 7.86-7.87 (d, 1H, 5''-H, 3JH-H = 4Hz), 8.11 (s, 1H, 2''-H); 13C NMR (CDCl3, 400 MHz): d = 26.54 (C-1), 44.42 (C-2), 147.85 (C-3), 105.74 (C-4), 140.59 (C-5), 13.01 (CH3- C-3), 10.97 (CH3-C-5), 189.97 (C-1'), 40.88 (C-2'), 165.24 (C-6), 163.87 (C-7), 127.51 (C-6''), 130.42 (C-5''), 131.11 (C-2''), 133.78 (C-3''), 134.37 (C-1''), 138.99 (C-4''); MS (m/z): 411 [M]+, 413 [M+2]+, 415 [M+4]+ in the ratio showing typical chlorine isotope profile [9:6:1]
2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-(naphthalen-2-yl)ethanone (6s):
FTIR (?max) cm-1 1740 cm-1 (C=O str.), 1691 - 1475 cm-1 (C=N and C=C str.), 1157, 1190 cm-1 (C-O str.); 1H NMR (CDCl3, 400 MHz): d = 2.22 (s, 3H, 3-CH3), 2.23 (s, 3H, 5-CH3), 5.78 (s, 1H, 4-CH), 5.06 (s, 2H, 2'-CH2), 3.38-3.42 (t, 2H, 1-CH2, 3JH-H - 8Hz), 4.38-4.42 (t, 2H, 2-CH2, 3JH-H - 8Hz), 7.59-7.68 (m, 2H, Ar), 7.90-8.07 (m, 4H, Ar), 8.58 (s, 1H, Ar); 13C NMR (CDCl3, 400 MHz): d = 26.60 (C-1), 44.54 (C-2), 148.23 (C-3), 105.32 (C-4), 139.33 (C-5), 13.47 (CH3- C-3), 10.90 (CH3-C-5), 191.93 (C-1'), 41.69 (C-2'), 165.35 (C-6), 164.29 (C-7), 123.60 (C-3''), 127.23 (C-5''), 127.90 (C-4''), 128.94 (C-6''), 129.21 (C-7''), 129.73 (C-1''), 130.74 (C-8''), 132.15 (C-2''), 132.40 (C-9a''), 136.03 (C-10a''); MS (m/z): 393 [M+1]+
, Claims:Claims:
I/We claim:
1. The synthesis of new series of 2-((5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazol-2-yl)thio)-1-arylethanones with Formula 1 where Ar may be -C6H5, 4-FC6H4, 4-ClC6H4, 4-BrC6H4, 4-CH3C6H4, 4-OCH3C6H4, 4-C6H5C6H4, 4-CF3C6H4, 4-OCF3C6H4, 4-NO2C6H4, 4-CNC6H4, 3-FC6H4, 3-BrC6H4, 3-NO2C6H4, 2-OCH3C6H4, 2-FC6H4, 3,4-Cl2C6H3, 2,4-F2C6H3, 2-acetonaphthyl.

Formula I
2. The green synthetic protocol for the compounds as claimed in claim 1 comprising the step of reacting 5-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazole-2-thiol (0.002 moles, 1eq), a-bromoketones (0.002 moles, 1eq) and potassium carbonate (0.002 moles, 1eq) at temperature upto 90 °C for 20 – 40 minutes.
3. The process, as claimed in claim 2, where 5-(2-(3,5-dimethyl-1H-pyrazol-1-yl)ethyl)-1,3,4-oxadiazole-2-thiol (4) converted into final product 6 under solvent-free reaction condition by grindstone methodology.
4. The process, as mentioned in claim 1, wherein the desired products (6a-s) synthesized regioselectively.
5. The process as claimed in claim 2, wherein the yield of 73 - 95 % can be achieved.
6. A process as recited in claim 2, wherein the temperature required is 55 °C as minimum to 90 °C as maximum during the whole process.