Choudhary, Muhammad Iqbal

Iqbal, Rashid

Rama, Nasim H

Saeed, Aamer

Zamani, Khosrow

NOPR

Indian Jouma1 of ChemistryVol. 37R May 1998. pp. 480 - 483A facile three-step synthesis of (dl)-6,8dedihydroxyagrimonolideNasim H Rama'", Rashid Iqbal', Khosrow Zamani",Aamer Saeed' & Muhammad Iqbal Choudhury"'Department of Chemistry, Quid-I-Azam University,Islamabad-45320, PakistanbH.E.1. Research Institute of Chemistry, University of Karachi,Karachi-75270, PakistanReceived 6 May 1997; accepted (revised) 21 October 19973-[2-(4' -methoxyphenyl)ethyl]isocoumarin2 has beenprepared by the condensation of 4-methoxyphenyl-propanoyl chloride with homophthalic acid. Alkalinehydrolysis of2 yields the keto-acid 3 which is reconvertedback to 2 either by treatment with acetic anhydrideor withslightly acidified methanol. The keto-acid 3 on reactionwith methyl iodide or dry methanol in th~ presence of acatalytic amount of sulfuric acid affords the methyl keto-Ester-4. (dl)-6,8-Dedihydroxyagrimonolide6 is obtainedbyreduction of 3 to the racemic hydroxyacid 5 followed bycyclodehydrationusing acetic anhydride.Agrimonolide is a phenolic constituent of theRhizome of Agrimonia pilosa Ledeb, isolated' in1958. The determination of its structure wasextensively studied by Yamato et al.' who finallyconfirmed its structure by synthesis as 6,8-di-hydroxy-S{z-ethyl-I 4'-methoxyphenyl)-3, 4-dihy-droxyisocoumarin 1. In 1969, Arakawa'determined its absolute configuration as R. Liu4reported its strong anthelmintic activity againsttape worms. Scanning electron microscopic (SEM)obser-vations have shown that its anthelminticeffects are due to its destructive effect on the bodywalls of the tape worms.In this article we describe a facile three-stepsynthesis of 6,8-dedihydroxyagrimonolide 6(Scheme I) as model for the synthesis of agri-monolide 1 and to study its possible anthelminticeffects. Thus, direct condensation of 4-methoxy-phenylpropanoyl chloride with homophthalic acidat elevated temperature afforded the 3-[2-(4'-methoxyphenyl)ethyl]isocoumarin 2 which showeda characteristic 1H singlet at 0 6.20 for C4-H andthe lactonic carbonyl absorption at 1720 em".Alkaline hydrolysis of 2 afforded the keto-acid 3which showed a 2H singlet at 0 3.99 for C,-CH2.NoteThe absorption for ketonic and carbony groupswere observed at 1683 and 1716 em' respectively.Isocoumarin 2 was obtained by refluxing of 3 withacetic anhydride. Following an already reported"procedure, the keto-acid 3 when refluxed with dryacidic methanol for 8 hr furnished the keto-ester 4as indicated by TLC. It may be pointed out that thework-up of this reaction mixture involved the useof sodium bicarbonate which might havehydrolyzed the keto-ester 4 to 'the correspondingketo-acid 3 which under the work-up conditionswas converted back to the lactone 2, identical in allrespect with that prepared earlier. Methylation of 3with excess of methyl iodide or with dry acidicmethanol under reflux for 8 hr without usingsodium bcarbonate in the work-up also yielded themethyl keto-ester 4. The appearance of carbonylabsorptions at 1720 and 1684 ern' for ester andketo groups respectively in the IR spectrum and a3H singlet at 0 3.81 in the 'H NMR spectrum of 4confirmed the esterifi-cation. It is presumed thatsodium borohydride reduction of 3 afforded thecorresponding racemic hydroxyacid 5 (not isolated)which under the direct influence of aceticanhydride produced the (dl)-6,8-dedihydroxy-agrimonolide 6. The dihydroiso-coumarin 6exhibited the carbonyl absorption at 1715 em inthe IR spectrum and the typical ABX pattern of C3-H and the typical AB pattern of C4-H proton in the'H NMR spectrum. Thus, each proton of C4-H2showed a doublet of a doublet (0 2.87-2.90 and2.96-3.03 respectively). The multiplet for C3-H wasobserved at 0 4.45-4.52 .:Experimental SectionMelting points were taken in a melting pointapparatus (Toshniwal, India) and are uncorrected.IR spectra were recorded on a Hitachi 270-50 infrared spectrophotometer as KBr discs or asneat liquids. 'H NMR (500 MHz) spectra wererecorded in CDCh on a Bruker AM-500 instrumentusing TMS as internal standard and ElMS on aMAT-112-S machine.3-[2-( 4'-Methoxyphenyl)ethyIJisocoumarin 2.A mixture of homophthalic acid (1.1 g, 0.006mole) and 4-methoxyphenylpropanoyl chloride(4.4 g, 0.022 mole) was heated on an oil-bath atNOTES 481HO1OCC~:I~ 200"cC~ ~OMeAt:,zO 11 S% KOH I ElOH1- r~oJ:~~~t 6 .:0 - l6f'-~ OOOCH] ~c~ ~ ~1..0MeNaBH.o»<; ; ~ J6J0MeCQXl" <;»:COOHScheme I200°C for 3 hr. The residue after concentration was the mixture acidified with dil. hydrochloric acid,chromatographed over silica gel column using pet. extracted with dichloromethane (2x 15 ml.), driedether (60-80°) as eluant to give 3-[2-( 4' - (Na2S04), and solvent removed on a rotarymethoxyphenyl)ethyl]isocoumarin 2 (0.8 g, 0.0029 evaporator to yield a solid residue which wasmole, 46.6%) which was recrystallized from recrystallized from ethyl acetate and pet. ether (60-methanol, m.p. 84-86°; IR (KBr): 1720, 1665, 1615 80°) affording 3 (0.3 g, 0.00 I mole, 93.7%), m.p.ern"; IH NMR: 82.76-2.80 (2H, t, J=7.23 Hz, H- 128-29°; IR (KBr): 1715; 1683 em"; 'H NMR: 81'),2.95-2.99 (2H, t, .1=7.18 Hz, H-2'), 3.76 (3H, s, 2.78 (2H, t, J=6.93 Hz, H-3'), 2.87 (2H, t, J=7.1OMe),6.10(IH,s,H-4),6.79-6.84(2H,dt,J=3.03, Hz, H-4'), 3.76 (3H, s, OM e), 3.99 (2H, s, H-I'),5.13, Hz, H-3", H-5"), 7.09-7.13 (2H, dt, J=2.98, 6.79-6.83 (2H, d, J=8.62 Hz, H-3", H-5"), 7.09-5.06 Hz, H-2", H-6"), 7.25-7.31 (IH, d,J=7.76 Hz, 7.10 (2H, d, J=8.50 Hz, H-2", H-6"), 7.16-7.18H-5), 7.41-7.45 (lH, ddd, J=1.l2, 7.08, 8.19 Hz, (lH, d, J=7.41 Hz, H-3), 7.36-7.40 (lH, ddd,H-7), 7.62-7.66 (lH, ddd, J=1.35, 7.6, 8.89 Hz, H- J=1.l3, 7.61, 8.21 Hz, H-5), 7.50-7.54 (lH, ddd,6), 8.23-8.25 (lH, dd, J=0.65, 7.97, Hz, H-8); MS J=1.l6, 7.51, 8.64 Hz, H-4), 8.12-8.14 (IH, dd,(70 eV): mlz 280 (7.4%) [M+], 252 (23.7) J= l.l 4, 7.75 Hz, H-6), 10.2 (IH, S, D20[M+-CO], 118 (l00) [C'SH'603: Calcd 280.1099; exchangeable, COOH); MS (70 eV): mlz 298Found 280.1092 (MS)]. (3.1%) [M+], 280 (8.6) [M+-H20], 118 (100)2-[2-Oxobutyl-(4'-methoxyphenyl)]benzoic acid. [ClsHlS04]: Calcd 298.1205; Found 298.12103. A suspension of 2 (350 mg, 1.25 mmoles) in (MS).ethanol (15 mL) and potassium hydroxide (5%, 30 3-[2-(4'-Methoxyphenyl)ethyl]isocoumarin 2.mL) was refluxed for ~ hr. After cooling, ethanol Method A. Compound 3 (50 mg, 0.17 mmole) waswas removed by evaporation under reduced refluxed with acetic anhydride (0.5 mL) for 12 hr.pressure. Cold water (20 mL) was then added and After cooling, the reaction mixture was poured into482 INDIAN J CHEM, SEC.B, MAY 1998ice water (5 ml.), extracted with ethyl acetate(2x 10 mL). The extract was washed with sodiumbicarbonate (2x 10 mL, 5%), dried (Na2S04) andconcentrated to give an oily product whichsolidified on standing. It was recrystallized frommethanol to afford 2 (40 mg, 0.14 mmole, 85%),m.p. 84-86°, m.m.p. 85-86°. R; value, mass, highresolution mass, IR and IH NMR spectral datawere in good agreement with those of the alreadysynthesized 2.Method B. A solution of compound 3 (150 mg,0.5 mmole) in dry methanol (30 mL) and cone.sulfuric acid (as a catalyst) was refluxed for 8 hr.The reaction mixture was neutralized with solidsodium bicarbonate, filtered and methanol rotaryevaporated to afford an oil which solidified oncooling and recrystallized from diethyl ether tofurnish 2 (0.11 g, 3.9m mole, 78%), m.p. 84-86°,m.m.p. 84-86°.Methyl 2-[2-oxobutyl-( 4' -methoxyphenyl)] ben-zoate 4. Method A. Compound 3 (100 mg, 0.33mmole), methyl iodide in excess and anhydrouspotassium carbonate (1.0 g) in dry acetone (10 mL)were heated under reflux for 2 hr. The reactionmixture was filtered when hot. The cake waswashed with warm dry acetone (10 mL) and thesolvent evaporated in vacuo leaving an oil whichsolidified on standing and recrystallized from etherto afford 4 (90 mg, 0.29 mmole, 86%), m.p. 53-54°. IR (KBr): 1720, 1684 ern"; IH NMR: 82.82-2.85 (2H, t, J=7.16 Hz, H-3'), 2.86-2.89 (2H, t,J=7.07 Hz, H-4'), 3.78 (3H, s, OM e), 3.81 (3H, s,OMe), 4.05 (2H, s, H-I'), 6.79-6.83 (2H, dd,J=3.12, 5.28 Hz, H-3", H-5"), 7.09-7.12 (2H, dd,J=3.15, 11.60 Hz, H-2", H-6"), 7.14-7.18 (1H, d,J=0.91 Hz, H-3), 7.31-7.35 (1H, ddd, J=0.97, 3.62,7.61 Hz, H-5), 7.42-7.46 (IH, ddd, J=0.92, 3.68,7.62 Hz, H-4), 7.99-8.02 (1H, dd, J=1.16, 7.78 Hz,H-6); MS (70 eV): rn/z 312 (1.2%) [M+], 281(28.3) [M+-OMe], 280 (100) [M+-MeOH], 118(50.3) [CI9H2004:Calcd 312.1361; Found 312.1361(MS)].Method B. A solution of compound 3 (150 mg,0.5 mmole) in dry methanol (100 mL) and cone,sulfuric acid (two drops) was refluxed for 8 hr.water (50 mL) was then added and methanolremoved under reduced pressure. The reactionmixture was extracted with ether (2x20 mL). Thecombined extract was dried (Na2S04) and thesolvent removed under reduced pressure leaving anoil which solidified on standing. The crude solidwas recrystallized from diethyl ether. The isolatedcompound was further purified by preparativechromatography to furnish 4 (0.1 g, 3.2m mole,63.6%), m.p. 53-54°, m.m.p. 53°; IR (KBr): 1720,1680 ern"; IH NMR: 82.82-2.85 (2H, t, J=7.14 Hz,H-3'), 2.86-2.89 (2H, t, J=7.1 Hz, H-4'), 3.78 (3H,s, OMe), 3.81 (3H, s, OMe), 4.05 (2H, s, H-I'),6.79-6.83 (2H, dd, J=3.12, 5.28 Hz, H-3", H-5"),7.09-7.12 (2H, dd, J=3.15, 11.60 Hz, H-2", H-6"),7.14-7.18 (1H, d, J=0.91 Hz, H-3), 7.29-7.35 (1H,ddd, J=0.97, 3.62, 7.61 Hz, H-5), 7.43-7.47 (1H,ddd, J=O.92, 3.68, 7.62 Hz, H-4), 7.99-8.02 (I H,dd, J=1.16, 7.78 Hz, H-6); MS (70 eV): m/z 312(1.6%) [M+], 281 (25.3) [M+-OMe], 280 (100)[M+-MeOH], 118 (54.3) [CI9H2004: Calcd312.1361; Found 312.1361 (MS)].(dl)-6,8-Dedihydroxyagrimonolide 6. Com-pound 3 (150 mg, 0.5 mmole) was heated underreflux with sodium borohydride (0.15 g) inabsolute ethanol (20 mL) for 4 hr. Ethanol was thenrotatory evaporated and the residue diluted withcold water and acidified with dil. sulfuric acid togive a precipitate which was extracted with ethylacetate (2x 15 mL). The solvent was evaporated toleave a solid residue m (0.12 g). This crudecompound was dissolved in acetic anhydride (1.5mL) and heated under reflux for 2 hr. The reactionmixture was then cooled, water (15 mL) added andthe solid that separated out on stirring wasextracted with dichloromethane (2x 10 mL). Theextracts were combined, treated with sodiumbicarbonate (2x 10 mL, 5%), washed with water,dried (Na2S04) and filtered. Solvent was removedfrom the filtrate to give a solid which wasrecrystallized from methanol to furnish 6 (110 mg,0.39 mmole, 78%), m.p. 105-6°; IR (KBr): 1715,1610 ern"; IH NMR: 8 1.92-2.01 (1H, m, H-l'),2.13-2.22 (1H, m, H-I'),2.74-2.79 (lH, m, H-2'),2.81-.2.85 (1H, m, H-2'), 2.87-2.90 (AB pattern,IH, dd, Jvic=5.91, Jxem=9.23 Hz, H-4), 2.96-3.03(AB pattern, 1H, dd, Jvic=::II.34, Jgem= 16.22 Hz, H-4),3.76 (3H, s, OM e), 4.45-4.52 (1H, m, H-3), 6.80-6.84 (2H, dt, J=2.97, 5.12 Hz, H-3", H-5"), 7.11-7.14 (1H, dt, J=2.97, 5.09 Hz, H-2", H-6"), 7.19-7.23 (1H, d, J=7.56 Hz, H-5), 7.34-7.37 (l H, ddd,J=1.4, 7.51, 8.91 Hz, H-7), 7.48-7.52 (lH, ddd,J=1.4, 7.50, 8.90 Hz, H-6), 8.07-8.09 (1H, dd,J=1.26, 7.78 Hz, H-8); MS (70 eV): rn/z 282(43.2%) [M+], 254 (10.6), 118 (100) [ClsHlS03:Calcd 282.1256; Found 282.1249 (MS)].ReferencesI Yamato M, Yakugaku Zasshi, 78, 1958, 1086; 79, 1959,1069;79,1959,1029.2 Yamato M & Hashigaki K, Chern Pharm Bull, 24, 1976,NOTES 483200.3 Arakawa H, Torimoto N &. Masui M, Liebig's Ann Chern,728,1969, 152.4 Liu 0, Zhonghua Yixue Zashi, 62, 1982,336.5 Kaji H, Yamada M, Nozawa K, Kawai K & Nakajima S,Org Prep Proced Iru, 18, 1986,253.6 Saeed A, Iqbal R & Rama N H, J Chern Sac Pak, 17, 1995236.

A facile three-step synthesis of (dl)-6,8 dedihydroxyagrimonolide

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A facile three-step synthesis of (dl)-6,8 dedihydroxyagrimonolide

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