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). [Scheme-15][24] S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 304
O O n MeO Me + N + NH OH n MeO 2 O Me N O 68 69 70 71
Where n=0 , 1,3- cyclopentanedione n=1, 1,3-cyclohexanedione n=2, 1,3-cycloheptanedione
Scheme 15
2.15 Synthesis from tropolone
A mixture of 3-acetyl-5-bromo tropolone (72) and hydroxyl amine hydrochloride (73) in methanol and promoter was refluxed for 10 hrs to obtain isoxazole(74)[Scheme-16][25]
O O OH MeOH O NH OH.HCl + 2 N Reflux,10 hrs
O Br 73 Br 72 74
Scheme 16
2.16 Synthesis from Curcumin using NH2OH.HCl
A novel one spot synthesis of isoxazole (77) was reported by refluxing a mixture of Curcumin (75), [26] NH2OH.HCl (76) with catalytic amount of pyridine in ethanol. [Scheme-17]
O O O O
75 HO OH +
NH2OH.HCl 76
py,EtOH Refluxed,18hrs,80%
O N O O
HO OH 77
Scheme 17
2.17 Synthesis using p- chloro phenol
Multistep reaction on p-chloro phenol (78) provides the intermediate (85). The intermediate on treatment with hydroxyl amine hydrochloride afforded isoxazole (86) in good yield.[Scheme-18][27] S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 305
OH OCOCH (CH CO) O 3 3 2 AlCl3 OH
CH COONa 0 Cl 3 Cl 120 C Cl COCH3 78 79 80
Cl2 In ACETIC ACID
Cl Cl OH KOH/BVT OCOC6H5 NaOH, 10% Pyridine C H COCl COCH COCH 6 5 Cl 3 Cl 3 81 82
Cl Cl
OH R--CHO O R I2 EtOH,Py Cl COCH2COC6H5 EtOH Cl COC6H5 83 84 O
Cl Cl OH O R NH 2OH.HCl EtOH,Py COC H COC 6H 5 Cl 6 5 Cl O N R O 85 86
Scheme 18
2.18 Using Cycloaddition reaction of Aromatic aldoximes & propiolonitrile
A mixture of aromatic aldoximes (88),3-(4-methoxy phenyl)propiolonitrile(87) and chloramine –T in ethyl alcohol was refluxed afforded isoxazole derivatives (89)[Scheme-19][28]
CH N OH
MeO MeO CAT CN + EtOH CN R 1 1000C R ,3 hrs 87 2 O N 88 R 89 2 R 1
Scheme 19
2.19 Synthesis using copper catalyst
The quinolene carbaldehyde (90) is mixed with NH2OH.HCl & chloramine-T trihydrate is catalyzed [29] by CuSO4 with copper turnings afforded isoxazole derivatives(93)[Scheme-20] S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 306
O + N O H a)NH2OH.HCl,KOH
R b)TsN(Cl)Na. 3H2O N 1 N R1 90 91 +
O N Cu/CuSO4 R2 O
O R2 O N O R H O O N 1 O N H O 93 92
Scheme 20
2.20 Microwave induced synthesis of isoxazole
The p-amino acetophenone (94) on diazotization and coupling with N-methyl piperazine yield (95).In which Substituted aldehyde were added gives intermediate (96) which cyclised with hydroxylamine hydrochloride furnished isoxazole derivatives (97) by microwave assisted reaction.[Sheme-21 ][30]
N N N CH NH N 3 2 0 HCl+NaNO2 ,0-5 C
H3C H3C H C N 95 3 NH O O
94 40%KOH Conventional 4-6 hrs microwave 2-3 min CHO R
N N N CH N 3 NH2OH.HCl KOH R Conventional 8 hrs microwave 5-6 min O 96
N N N CH N 3
N O
97
R
Scheme 21
3. Chemical Reactions
3.1 Synthesis of bicyclic lactum of Isoxazoles
The synthesis of bicyclic lactum of isoxazoles (102) were reported by using alcohols of isoxazole (98) which on bromination , amination and by EDCI,DIEA , DMAP.[Scheme-22][31] S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 307
O O Br OH PBr , CH Cl , N N 3 2 2 R'NH2,Et3N,Anhydrous Benzne
0 Ar 0 C,30 min Ar CO Me Reflux 30min CO2Me 2 98 99
O O N NHR' N EDCI , DIEA , DMAP ,CH2Cl2 KOH in MeOH:H2O NHR' Ar CO2Me R.T ,1 hrs Ar R.T.45min CO2H 100 101
O N N R' Where R'= CH2Ph Ar O 102
Scheme 22
3.2 Microwave assisted synthesis of Schiff base
Isoxazole Schiff bases (105) obtained from 3-amino-5-methyl isoxazole (103) with substituted salicylaldehyde (104) using microwave assisted method [Scheme-23][32]
CH 3 R1 CH R 3 HO 2 M.W HO R O + 1 N NH O H 2 OHC R 3 N N C R 2 104 103 R 3 105
Scheme 23
3.3 Synthesis of isoxazole Azepine
Synthesis of Azepine began with bromothiophene (106) & isoxazole boronic ester(107) condensed via Suzuki reaction & which deprotected to primary alcohol (108) oxidation & imine formation with (s)- tert-butyl sulfinamide formed sulfinyl imine (109) which on addition of enolate of tert-butyl acetate gives sulfinamine (110) which was deprotected in acid condition & treat with iPrMgBr gives Lactum(111) which on treatment with PCl5 afforded imidoyl chloride(112) whichwas converted into Azepine(113) on deprotection & amide formation gives desired compound (114).[Scheme-24][33] S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 308
N O OH N O S Br i)Pd (dba) ,Sphos,K PO OAc 2 3 3 4, CO Me + 0 2 n-BuOH,100 C S CO Me 2 B O O ii)MeONa,MeOH 106 108
i)Swern Oxidation 107 ii)Ti(OEt)4, (S)-t-butyl sulfinyl amide
O N O S tBu O HN 2-(tert-butoxy-2-oxo ethyl) N S O CO tBu Zinc(II)Chloride, tBu N 2 CO Me CO Me 2 2 NMP,-100C S
S
110 109
i)HCl,MeOH ii)iPrMgBr ,THF
N N S O PCl ,CH Cl S O 5 2 2 CO2tBu CO2tBu N N Cl H 112 O 111
Pd(PPh3)4,K3CO4, 4-Chloro Phenyl boronic acid, N Toluene / Water S O O N
NH2 S O N 0 i) TFA,CHCl3,36 C CO2tBu N ii)HATU,NH4Cl,Et3N,CH2Cl2
Cl 114 113 Cl
Scheme-24
3.4 Synthesis of Novel Isoxazole derivatives
A Convenient synthesis of some isoxazole have been reported by the reaction of isoxazole derivatives with some reagents such as NH2OH.HCl,hydrazine hydrate,thiosemicarbazide & thiaurea via Michael addition to gives compound (116-119).Compound(119) was reacted with p-chloro benzaldehyde & glucose afforded compound (120,121) while compound (118) react with different halo compounds to gives (122-124).compound(115) reacted with malononitrile and acetoacetanilide to gives compounds(125,126). [Scheme-25][34] S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 309
H3C Ar NH2OH N NH O O 116
H3C Ar NH2NH2 Ar H3C N NH O N
N O 117 O X Ar 115 H C NH2 3 NH2 NH X=O,S N O N X H
118
H3C Ar NH2NHCSNH2 N N NH O N CS 2 H
119
H3C Ar Glucose N N O N CS N CH H (CH2OH)4 121 CH2OH H3C Ar
N N NH O N CS 2 H H3C Ar 119 N N H O N CS N C H OHC Cl
120 Cl S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 310
Ar Ar O Ar CHC6H4Cl H3C H C C H C 3 NH 3 2 ClCH2COOH N NH O N N O OHC Cl O N S ClC N O N S H2 O N S CH 2 2 Moles H 124 O 118 122
ClCH2CH2OCH2CH2Cl
Ar
H3C CH CH OCH CH Cl N 2 2 2 2 N O N S
CH2CH2OCH2CH2Cl
123
Ar Ar H C H3C 3 CN H3C CH (CN) COCH3 2 2 N N N Acetoacetanilide O O O NH2 O N O O Ph 125 115 126 Ac2O
Ar
H 3C CN
N NHCOCH O O 3 127
Scheme 25
3.5 Synthesis of phenacyl - imidazoles
Synthesis of imine (130) by mixture of phenyl (s-phenyl isoxazol -3 -yl) methanamine (129) & aldehyde .Then Boulton-Katritzky rearrangement of imine gives isoxazoles (131).[Scheme-26][35]
Ph Ph Ph Ph Ar CHO N NH2 O NH N Mont-K /Toluene N 2 ACOH N Ph 10 Ph O Ar O 600C Ph O 129 130 128 B.K tBuOK
DMF/N2
Ph Ph NH O N Ar
131
Scheme 26 S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 311
3.6 Reduction
The isoxazole alcohols(132) is oxidized by Dess-Martin Periodinane ,CH2Cl2 gives isoxazolyl aryl ketones(133) which on Corey-Bakshi-Shibata reduction using dimethyl sulfide borane furnished chiral isoxazole carbinols(134)[Scheme--27][36]
O R O Dess-Martin R BH .DMS 3 N R O 3 N 3 3 Periodinane HO N O (R)-diphenyl prolinol, H CH Cl HO 2 2 0 -45 C , CH Cl R2 R1 R2 R1 2 2 R2 R1 134 133 132
Scheme 27
3.7 Synthesis of substituted pyrrolyl furans
Synthesis by Sadighi cross-coupling using ZnCl2 of 3-bromo isoxazole(135) gives pyrrolyl isoxazole (136). Which convert in triisopropyl silyl derivatives (137). & treated NCS/Pd(OAc)2 gives chlorinated pyrrol (138) hydrogenolysis of over Pd/C in MeOH gives enaminone (139) which react with acid afforded pyrrolyl furans(140)[Scheme-28][37]
N H O O N NaH,ZnCl2 , N OBn OBn Cat.Pd(0) Br N 136 135 R
KH,TIPSOTf
O N O Cl NCS N OBn OBn Pd (II) N N TIPS TIPS 138 H (1 atm) 2 137 10% Pd/C MeOH, RT
O R NH O Cl 2 OH Cl Acid, R-OH O N N TIPS RT,1-4 hrs TIPS
UNSTABLE 140 139
Scheme 28
3.8 Synthesis of new Lead structure in isoxazole
The reaction of 5-amino -3-methyl-4-isoxazole carboxylic acid hydrazide(141) with mixture of S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 312 isopropanol & (hexanedione-2,5),(pentanedione2,4) and cyanogen bromide gives new lead structures: 5- amino-3-methyl-4-(2,5-dimethyl pyrrol –amino carbonyl)-Isoxazole RM54(142),5-amino-3-methyl-4-(3,5- dimethyl pyrazole carbonyl)-Isoxazole RM55 (143), & 5-amino – methyl -4-[2-(5-amino-1,3,4-oxadiazole)] – Isoxazole RM56(144)[Scheme-29][38]
H3C O O NH N N H C 2 H C N 3 N 3 N H H3C H O NH2 H C N N 3 O NH2 N NH O O 2 141 RM54 RM56 142 144
CH O 3
H3C N N N CH3 O NH2 RM-54 RM-55 Imminological activity RM-56 RM55 143
Scheme 29
3.9 Synthesis of metal complexes
The hot methanolic solution of isoxazole ligand (145) and hot methanolic solution of copper chloride (146) were mixed together and refluxed to afforded Cu-Complex(147).[Scheme-30][39]
R' N R' N O O 0 70-80 C R CuCl + 2 O O OH 2-3 hrs Cu R R 146 O 145 N R'
WHERE R,R'= I 147 R,R'=Br Structure Of Cu-complex
Scheme 30
3.10 Synthesis of Novel Isoxazole Derivatives
Synthesis of novel isoxazole reported by reaction of 5-(methyl thio)-3,4-diphenyl isoxazole(148) with chlorosulfonic acid afforded compound (149) which treated with Conc.NH4OH furnished compound (150)[Scheme-31][40] S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 313
SCH 3 SCH3 ClSO3H O O N N 149 ClO2S 148 Conc.NH4OH
SCH3
O N
H2NO2S 150
Scheme 31
4. Miscellaneous Reaction
4.1 Synthesis of novel Schiff base ligands and their metal complexes
Schiff bases are excellent ligands which are synthesized from condensation of primary amine with carbonyl group like MSBPMA (153) , NINIHI (156) , NHIIMC (159). The Co(II) , Ni(II) , Cu(II) & Zn(II) metal complexes have been synthesized compounds- (160,161,162)[Scheme-32][41] S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 314
O O H --H 2O S NH2 S N C + OHC N O N N O H C H HN 3 O H3C O Sulphametoxazole 152 {4-[(5-Methyl isoxazole-3-yl)Sulfonyl Benzyl diene]-N- [(E)-1-(2-pyrrol) methyl diene)[MSBPMA] (L1)} 151 153
Fig.-1
OH
N C N NH OH N H O N 2 H O 2 N + OHC N N O H H {N-[(E)-1H-imidazole-3yl)-N-[(imino methylidine) -(3-hydroxy-3-isoxazole)]} [NINIHI] (L ) Histamine 3-hydroxy-5-carbaldehyde 2 isoxazole 156 154 155
Fig.-2
OHC OH
OH N O O H O 2 N O N + CH O H2N O O Muscinol Chromine-2-carbaldehyde
157 158
{N-[3-hydroxy-3-isoxazol imino]methyl 4-oxo-4H chromine}
[NHIIMC](L3) 159 Fig.-3 S.S.Rajput et al /Int.J. ChemTech Res. 2015,8(7),pp 297-317. 315
OH OH OH R N 2 R OH2 O N H N N C H C M M H C H C N O N N R N OH 2 R OH OH2 OH N O Where- R= N R= S Where- N O M=Co(II),Ni(II),Cu(II),Zn(II) H3C O Complex M(II)(L ) .2H O 1 2 2 M=Co,Ni,Cu,Zn 160 . Complex M(II)(L2)2 2H2O 161
OH2 R
O O N OH H Where- R= N M O H C N O O M= Co,Ni , Cu ,Zn R . Complex M(II)(L3)2 2H2O OH2 162
(Complexes 160,161,162 have antimicrobial activity) .
Scheme 32
Conclusion
Isoxazoles are easily available and have high chemical reactivity. A series of heterocyclic compounds containing a five membered ring consisting of three carbon atoms united to first position oxygen and second position nitrogen atom .Substituted Isoxazoles are important compounds of many drugs & drug candidates .This survey was attempted to summarize the synthetic methods and reactions of isoxazoles.
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