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Isoxazole—A Basic Aromatic Heterocycle : Synthesis, Reactivity and Biological Activity

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Isoxazole—A Basic Aromatic Heterocycle : Synthesis, Reactivity and Biological Activity International Journal of ChemTech Research CODEN (USA): IJCRGG ISSN: 0974-4290 Vol.8, No.7, pp 297-317, 2015 Isoxazole—A Basic Aromatic Heterocycle : Synthesis, Reactivity And Biological Activity S.S.Rajput1*, Dr. S.N.Patel2, Nilesh B. Jadhav3 1Department of Chemistry, SVS’s Dadasaheb Rawal College Dondaicha 425408, Maharashtra, India. 2Department of Chemistry, S.P.D.M.College, Shirpur 425405, Maharashtra, India. 3Department of Chemistry, S.P.D.M. College, Shirpur425405, Maharashtra, India. Abstract: This review summarizes the synthetic method , reactions and biological application of isoxazoles and summarizes recent development in their derivatives such as chalcone, 5- isoxazole penicillins,shiff base etc.over the last years.The biological activities of isoxazoles is also briefly discussed .Formation of isoxazoles & fused heterocyclic isoxazoles derivatives constitute an interesting class of heterocycles which have diverse biological activities. Keywords: Isoxazoles, biological activity, 5-isoxazole penicillin. 1. Introduction Substituted Isoxazoles are important compounds of many drugs and drug candidates. It is one of the most fundamental objectives of organic and medicinal chemistry is the design and synthesis of molecules having value human therapeutic agents. The diversity of biological activities and pharmaceutical uses have been attributed to them, such as isoxazole is a part of many active molecule possessing activities such as Anti- tubercular[1], Analgesic[2], Antipyretic[2], Anti-inflammatory[2][3], Antiplatelet[4], Anti-HIV[4], Antagonist activity[4], CNS depressant[5], Antifungal[6][7], Antibacterial[6][7][8], Anti-oxidant[7], Anticancer[9][10] . The Substituted isoxazole moiety 1 appears as an interesting precursor of many biologically active of the above class compounds. 4 3 5 N 2 O 1 Isoxazole 1 This review provides an overview of the synthesis and reactivity of isoxazole and its derivatives .In first part we intend to outline the general methods by which substituted isoxazole are prepared .The second and third parts are devoted to the chemical reactivity of substituted isoxazoles. 2. Synthetic Methods There have been a number of practically important routes to synthesize isoxazoles. S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 298 2.1 From furfuraldehyde using NH2OH.HCl A well established route for the synthesis of substituted isoxazole (4) was reported from chalcones . [11] by claisen- Schmidt condensation of aldehyde, acetophenone and NH2OH HCl.[Scheme 1] C H OH + R COCH 2 5 CHO 3 CH CH R O 40%NaOH O 3 1 2 O NH2OH.HCl CH3COONa O R= NH Br,NO ,Cl,F,CH 2 , 2 3 N R O 4 Scheme 1 2.2 By Knoevenagel Condensation using Sod.Ethoxide The convenient method was reported for synthesis of substituted isoxazoles in which Knoevenagel condensation of ethyl acetoacetate (6) and 1,3 diaryl -2-propen-1-one(5)using sodium ethoxide took place .The intermediate (8) was react with ethyl formate and sodium ethoxide gives compound (9) which on [12] reaction with NH2OH in acetic acid afforded substituted isoxazole (10)[Scheme 2] O O O NaOET CO2Et CO ET + 2 Ar Ar Ar Ar 6 5 7 O O HCO2ET OH Dry Benzene Ar Ar Ar Ar 10%NaOMe, 9 Dil.HCl 8 NH2OH ACOH O N Ar Ar 10 Scheme 2 2.3 Synthesis using Click Chemistry Approach The method includes transition metal catalyzed 1,3-dipolar cycloaddition of nitrile oxides(12) to alkynes (11)gives substituted isoxazoles(13)[Scheme-3][13] CF3 O n X H Cu(I) Cat. + NHPG PG N + N C O n Ar N Ar X CF3 13 12 11 Scheme 3 S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 299 . 2.4 From Glutaric acid using SOCl2,DMF/POCl3 and NH2OH HCl Glutaric acid (14) treated with amine using SOCl2 gives N-substituted phenyl glutarimides(15) which on diformylated using Vilsmeier –Haack Reaction afforded dihalovinyl aldehyde(16).The halovinylaldehyde on condensation with acetophenone gives chalcone (17)which underwent ring closer with NH2OH.HCl furnished isoxazoles(18)[Scheme-4][14] SOCl2 DMF,POCl3 OHC CHO HOOC COOH O N O 0-50C Cl N Cl NH2 14 R Reflux R 16 15 R O R'--C CH3 R' R' O O N N R' O O R' NH OH .HCl Cl N Cl 2 Cl N Cl CH3COONa in CH3COOH R R 17 18 Scheme 4 2.5 From Tetrazole derivative Treatment of Benzonitrile (19), sodium azide (20) in presence of DMF & Ammonium chloride furnished 5- phenyl tetrazole(21) .5-phenyl tetrazole treated with acetic anhydride resulting in the formation of acetyl tetrazole(22) which was condensed with substituted aldehydes followed by cyclization using [15] NH2OH.HCl furnished isoxazoles(24) which exhibited anticancer activity.[Scheme-5] CN N N a)DMF N Acetic anhydride + NaN3 N b)Ammonium chloride H SO H 2 4 19 20 21 N N N N a)substituted Aldehyde N N N N R b)KOH O COCH3 23 NH OH.HCl 22 2 N N N N N O 24 R Scheme 5 S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 300 2.6 Using 2-acetyl thiophene A convenient route for the substituted Isoxazole (28) is achieved by refluxing NH2OH.HCl with chalcone (27) in presence of ethanol.[Scheme-6][16]. R CH NaOH R S 3 + OHC S EtOH O O 27 26 25 NH2OH.HCl EtOH S R N O 28 Scheme 6 2.7 Microwave assisted synthesis of Isoxazole Microwave assisted synthesis of isoxazole (34) reported by author Kumudini Bhanat,Bharat Parashar . [17] and V.K.Sharma from Irradiation of Chalcone (33) with NH2OH HCl.[Scheme-7] O O O NC CH + 2 N C NH NH N C N N OC2H5 2 29 30 31 O NH2 R'--C6H5--CHO CONC.HCl O O N C N N N C N N O N O N 33 CH CH CH R R'--C6H4--CHO KOH NH2OH.HCl KOH 32 OH OH O N C N N N N O CH R 34 OH Scheme 7 2.8 Synthesis via [3+2] cycloaddition S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 301 The [3+2] cycloaddition reaction between alkynyl dimethyl silyl ethers (35) and aryl or alkyl nitrile oxide (36) gives isoxazolyl silanols (37).[Scheme-8][18] + R' N O 36 1.HEAT R 1 N O + 2.ACOH 2 Me Me Si R Me EtO Si R2 HO Me 37 35 Scheme 8 2.9 From cycloaddition of Azolylacetylenes to nitrile oxides Isoxazoles (43) have been synthesized from cycloaddition of enamines (40) with nitrile oxide (41) through the intermediate (42) [Scheme-9][19] Az Me2NCH(OMe)2 Az Me N-Methyl Imidazole NMe NMe 2 38 2 Az 40 Dioxane O H N Ar 42 Cl + N OH [ Ar N O ] -Me NH Ar --HCl 2 41 39 Az O N Ar 43 Scheme 9 2.10 From Benzofuran The reaction of 5-bromo-2-acetyl Benzofuran (44) with a different aromatic aldehydes (45) in presence of alkali gives chalcones (46) which on treatment with hydroxylamine hydrochloride afforded Isoxazole derivatives of Benzofuran(47)[Scheme-10][20] Br O Br O EtOH + R--CHO O O CH 3 45 46 R 44 NH2OH.HCl aq.NaOH Br Where R= C6H5,C6H4OH(P),C6H4Cl(P),C6H4OCH3(P),C6H4N(CH3)2 O R N O 47 [Analgesic,Antiinflamatory,Antimicrobial Activity] Scheme 10 S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 302 2.11 Synthesis via 1,3 dipolar cycloaddition of α,β unsaturated ester & nitrile oxides The multistep synthesis of isoxazole (52)(53) have been reported via 1,3 dipolar cycloaddition of α,β unsaturated ester and nitriles oxide by author W.Marek GOLEBIEWSKI .[Scheme-11][21] O OH H OH 5 N 1 H R R NaOH NCS N 5 Cl R 1 R 5 1 4 2 NH OH.HCl R R R R 2 DMF 4 2 3 R R R 4 2 3 R R R 48 3 R O 49 50 CH OEt CH2 Et3N O O O OEt O OEt N NBS/DMF N 5 R 1 5 1 R R R CH3COOK CH COOH 2 3 4 R 4 2 R R R 3 R 3 R 51 52 I)NaOH II)(COCl)2 III) HX O O Cl N 5 1 R R 4 2 R R 3 R 53 Scheme 11 2.12 Synthesis from oxime using NCS, HCl, DCM & Et3N, DCM Reagents The substituted aromatic aldehyde (54) treated with NH2OH.HCl , NaOAc gives oxime(55) which undergoes [3+2] cycloaddition with other chiral compound gives isoxazoline intermediate (56) which on [22] oxidation with MnO2 gives isoxazole derivatives (57)[Scheme-12] N OH I) NCS,HCl,DCM O NH OH.HCl,NaOAc II)Et N,DCM 2 H 3 H EtOH,H O Reflux 40 min 2 X X 55 54 O N O N O MnO2 X O Toluene X O 57 56 Scheme 12 S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 303 2.13 Synthesis from different oxime with different olefins An alternative , fast & clean method was reported for the synthesis of substituted isoxazole(63) & (67) from aromatic aldehyde (58) and carbomethoxy benzaldehyde (59).[Scheme-13][Scheme-14][23] CHO O O H OMe 59 58 + - CH3 P(Ph)3 Br NH2OH.HCl NaH NaHCO3 O CHCl ,Py N OH 3 + OMe NCS,TEA 61 60 O O N N CCl4 NBS CO2R CO2R 63 62 Scheme 13 CHO O O H OMe 59 58 NH2OH.HCl + - CH3 P(Ph)3 Br NaHCO3 NaH O CHCl3 ,Py OMe NCS,TEA + HO N 65 64 N N O O CCl4 NBS CO2R CO2R 67 66 Scheme 14 2.14 Aqueous one pot synthesis of isoxazole A novel one pot synthesis of isoxazoles (71) has been accomplished under microwave irradiation of three component reaction of 1,3 diketone (68) dimethyl formamide dimethyl acetal (69) and NH2OH.HCl (70).
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