Synthesis of Some Substituted 1,3,4-Oxadiazoles, Thiadiazoles and 1,2,4-Triazoles from Acid Chlorides

The conversion of some acid chlorides to substituted 1,3,4oxadiazole, 1,3,4-thiadiazoles and 1,2,4-triazoles is reported. Benzoyl chloride and 4nitrobenzoyl chloride were treated with hydrazine hydrate in ethanol to give acid hydrazides (1,2), The acid hydrazides were converted to 1substituted thiosemicarbazides (3,4) by this reaction with ammonium thiocyanate in ethanol. The later thiosemicarbazides were cyclized to substituted thiadiazoles (5,6) and triazoles (7,8) by their reaction with concentrated sulphuric acid and sodium hydroxide solution respectively. The hydrazones (9-12) were synthesised from acid hydrazides (1,2) by their reaction with substituted benzaldehyde in dioxane. The cyclization of hydrazones (9-12) with acetic anhydride gave substituted 1,3,4oxadiazole (13-16). The structures of synthesised Synthesis of Some Substituted 1,3,4-Oxadiazoles, Thiadiazoles and 1,2,4... 29 compounds were confirmed by IR, UV spectral data and physical means. Introduction The family of nitrogen containing five membered ring heterocyclic compounds were considered as an important class of compounds in medicinal chemistry because of their interesting diversified biological application. During the past years the evidences have also accumulated to demonstrate the efficacy of 1,3,4-oxadiazoles including antibacterial, anti-inflammatory, antimalarial, antiviral and insecticidal properties. The 5-(Furan-2-yl)-l,3,4-oxadiazole-2-thiol was synthesized from furan-2-carboxylic acid hydrazide by its reaction with sodium hydroxide and carbon disulfide in absolute ethanol. Schiff bases have also been widely reported to be biologically active compounds having antifungal, herbicidal and plant growth regulating properties. The Schiff bases were synthesized from acid hydrazide and substituted benzaldehyde as in the synthesis of 3-Chloro-N-(substituted phenylmethylidene)-l-benzo [b] thiophene-2-carbohydrazide from 3Chloro-2-hydrazino carbonyl benzo [b] thiophene with appropriate aromatic aldehydes in dioxane. 1,3,4-Thiadiazoles have been known to possess a wide spectrum of pharmacological, medical and biological activities. Substituted 1,3,4-thiadiazole was synthesized from reaction of substituted thiosemicarbazide in concentrated sulfuric acid as the synthesis of 2-(1naphthylamino)-5-(isomeric pyridyl)-1,3,4-thiadiazole (I) . Substituted 1,2,4-Triazoles are known to exhibit anticancer, Antileishmanial, anticonvulsant, antidepressant activity. For example, fluconazole (II) is used as an antimicrobial drug. The K. M. Daoud & E. Q. Mahmood & O. Th. Ali 30 synthesis of substituted 1,2,4-triazoles was achieved from substituted thiosemicarbazides by their reaction with aqueous sodium hydroxide In this paper the synthesis of some substituted 1,3,4-oxadidzole, 1,3,4thiadiazole and 1,2,4-triazole from acid chloride studied. Experimental All chemicals were purchased from Fluka and BDH Chemical Ltd. The melting points were measured on an Electrothermal 9300 Enginering LTD and are uncorrected. IR spectrum were recorded on Infrared Spectrophotometer Model Tensor 27, Bruker Co., Germany, using KBr discs. The UV spectrum were recorded on UV-Visible Shimadzu 1601 Spectrophotometer using ethanol as a solvent. Preparation of Benzohydrazide (1), 4-Nitrobenzohydrazide (2) The acid chloride (benzoyl chloride and 4-Nitrobenzoyl chloride) (0.01 mol) was dissolved in ethanol (50ml) ,hydrazine hydrate (2 ml) was added and the mixture was heated under reflux for (4 hours) the reaction mixture was evaporated under reduced pressure and the crude product was purified by crystallization from ethanol. Tables(l,2). Preparation of 1-Benzoyl thiosemicarbazide (3) and 1-(4Nitrophenyl) thiosemicarbazide(4) A mixture of compounds (l,2) (0.01 mol) ammonium thiocyanate (0.02 mol) and concentrated hydrochloric acid (5 ml) was refluxed for (8 hours) on cooling white solid crystals was formed filtered off, dried and recrystallized from ethanol-water. Tables(l,2). Preparation of 2-Phenyl-5-amino-l,3,4-thiadiazole(5) and 2-(4Nitrophenyl)-5-amino-l,3,4-thiadiazole(6) Substituted thiosemicarbazide (3 or 4) was dissolved in concentrated sulphuric acid (1 ml) then stirred at room temperature for (1 hour), after cooling water (25ml) was added. The precipitate was filtered, dried and recrystallized from ethanol, Tables(l,2) Preparation of 5-phenyl-l,2,4-triazole-3-thiol(7) and 5-(4Synthesis of Some Substituted 1,3,4-Oxadiazoles, Thiadiazoles and 1,2,4... 31 Nitrophenyl)-l,2,4-triazole-3-thiol(8) A mixture of substituted thiosemicarbazide (3or4) (0.0014mole) in sodium hydroxide solution IN (10ml) was heated at 80°C for (1 hour), water (15 ml) was added and the mixture acidified with dilute hydrochloric acid (pH=4.5). The precipitate was filtered off and recrystallized from ethanol. Tables(l,2). Preparation of Hydrazones(9-12) A mixture of compounds (1,2) (0.01 mol) and appropriate aromatic aldehyde (0.01 mol) in dioxane (50 ml) was refluxed for(4-8hours). The reaction mixture was concentrated under reduced pressure, cooled and the obtained solid was filtered washed with water and cold ethanol. Tables(1,2). Preparation of 2-Phenyl/aryl-4-acetyl-5-aryl-l,3,4-oxadiazole(13-16) A mixture of hydrazones (9-12)(0.01mol) and acetic anhydride (10ml) was refluxed for (3-4hours). The excess acetic anhydride was distilled off and the residue was poured onto crushed ice. The obtained solid was collected by filtration, washed with water and recrystallized from ethanol. Tables(l,2). Table (1): Physical properties of compounds(l-16) Comp.No. X Y m.p. C Color Yield % 1 H 214-215 Brown 83 2 NO2 99-100 Yellow 85 3 H 132-133 Dark brown 63 4 NO2 239-240 Pale yellow 82 5 H 201-202 Pink 82 6 NO2 195-196 Orange 87 7 H 132-133 Yellow 67 8 NO2 121-123 Brown 79 9 H OH 208-209 Dark orange 76 10 H NO2 179-181 Yellow 88 11 NO2 OH 118-119 Brown 77 12 NO2 NO2 259-260 Pale brown 78 13 H OH 283 Yellow 70 14 H NO2 278-280 Dark brown 86 15 NO2 OH 262-264 Orange 67 16 NO2 NO2 244 Brown 87 Results and Discussion The synthesis of some substituted 1,3,4-oxadiazoles, 1,3,4K. M. Daoud & E. Q. Mahmood & O. Th. Ali 32 thiadiazoles and 1,2,4-triazoles is reported Scheme-1. Acid chlorides (benzoyl chloride, 4-nitrobenzoyl chloride) were treated with hydrazine hydrate in ethanol, to give hydrazide (1,2) IR spectra of compound (1) show absorption bands at 3320(N-H), 1667(C=O), whereas compound (2) IR spectra showed absorption bands at vcm 3371(N-H), 1621(C=O), 1525, 1349 (asymatric, symatric NO2). Acid hydrazide (1,2) was treated with ammonium thiocyanate in ethanol to give compounds(3,4) respectively. The proposed reaction mechanism of thiosemicarbazid formation as follows. IR spectra of compound(3) shows absorption bands at 1659 (C=O), 3170(C-H aromatic). While compound (4) showed absorption bands at 1649(C=O), 1230(C=S), 1523, 1325 (NO2asy, sym). Substituted thiosemicarbazides(3,4) were treated with concentrated sulphuric acid, sodium hydroxide solution to give 1,3,4-thiadiazole (5,6) and 1,2,4triazole(7,8) respectively. The IR spectra of compounds (5,6) showed absorption band of (N-H) appeared at 3417-3443cm, (C=N) 15701602cm 1122-1218 (C=S). The proposed reaction mechanism of substituted 1,2,4-triazoles formation as follows: IR spectra of compounds (7,8) showed absorption band at 3451-3452 cm due to (N-H), 1623-1630cm (C=N). Compounds Synthesis of Some Substituted 1,3,4-Oxadiazoles, Thiadiazoles and 1,2,4... 33 (l,2) were treated with appropriated aromatic aldehyde in dioxane to give hydrazone (9-12). The IR spectra of compounds (9,10) showed absorption bands within the range 1667,1680 cm(C=O), 3318, 3350(N-H), 3006, 3107 (C-H aromatic), 1631,1630(C=N), while compounds (11,12) showed absorption band at 1690, 1660 (C=0), 1511,1518 (NO2 asymatric), 1346,1308 (NO2syfriatric). The hydrazone (9-12) were refluxed with excess of acetic anhydride to give substituted 1,3,4-oxadiazoles(13-16). The IR spectra for compounds (13,14) showed an absorption band between 1670, 1678 (C=0), 1650, 1638(C=N), while compounds (15,16) showed absorption bands at 1662,1683 (C=O), The U.V. spectrum data where due to n-* and -* transitions. Table (2). Table (2) : IR and U.V spectrum data for the synthesised compounds Comp. No. u cm -1 , KBr U.V. max nm EtOH 1 1667 (C=C)st),3052(CH-aromatic),2957 (CH-aliphatic),3320(N-H) 250,324 2 1621 (C=Ost),3371 (NH),3102 (CH-aromatic) 241,342 3 1659 (C=Ost), 1255(C=S),2983(CH-aliphatic), 225,318 4 1660 (C=0st),1230 (C=S),1523,1325(N02asy,sym) 234,346 5 1570 (C=N),3417 (NH),1122(OS) 242,358 6 1602 (C=N),3433 (NH),1218(C=S) 212,320 7 3451 (N-H), 1623(C=N) 219,298 8 3452 (N-H), 1630(C=N) 217,288 9 1667 (C=Ost),3006(CH-aromatic),1631 (C=N),3318 (NH) 232,322 1