Babu, B R

Bhagat, S

Jain, S C

Rajwanshi, V K

Sinha, J

NOPR

Indian Journal ChemistryVol. 36B, August 1997, pp, 633 - 636Rapid CommunicationSolvent induced synthesis of spiro[Indole-pyran] system usingcondensation reactions t*S C Jain , S Bhagat, V K Rajwanshi, B R Babu & J SinhaDepartment of Chemistry, University of Delhi, Delhi 110007,IndiaReceived 23 June 1997 ; revised and accepted18 August 1997Reaction of indole-2,3-dione with 4-hydrox)'-2H-I-benzopyran-2-one 2 has been studied under differentmedia and a single one-step synthesis of a novelspiro[indole-pyran] system is achieved. Spiro[indole-3,7'-[ 6H, 7H,SH]pyrano[3,2-c;5,6-c1di[ l]benzopyran]-2(3H),6',S'-trione 4a, its N-methyl 4b and 5-fluoro 4eanalogues have been synthesised by the reaction ofindole-2,3-dione Ia, its N-methyl Ib and 5-fluoro Icderivatives respectively with 2 under different reactionconditions. All the synthetic spiro compounds 4a-c havebeen fully characterized on the basis of their IR, 'H andI3CNMR and mass spectral data.Spiro indoles are known for their broad spectrumof biological activities' . Of the various spiroindoles, spiro[indole-pyran] system attracted ourattention due to its pharmacological properties':'and also because of the scanty information availableon its synthesis". In view of this, we haveinvestigated the reaction of indole-2,3-dione 1a with4-hydroxy-2H-l-benzopyran-2-one 2, bothpossessing individual biological activities':", underdifferent reaction conditions and explored thepossibilities for the formation of a novel spiro[indole-pyran] system in one-pot reaction.The reaction of la with 2 in 1:2 ratio in glacialacetic acid, exclusively yielded a single colourlessproduct, the mass spectrum of which showed themolecular ion peak at mlz 453, corresponding to thet Part of the results have been presented at the InternationalSymposium on 'Perspectives in Bioorganic Chemistry' heldin New Delhi, India during 8-9 December 1994 and includedin Pure & App/ Chem, 68, 1996, 739molecular formula C2JI'5N07, thus indicating thattwo coumarin moieties are probably coupled withindole nucleus. Its IR spectrum showedcharacteristic absorption bands at 3400 (-OH),3132(>NH) and 1710 and 1655 cmTlactarncarbonyls). The 'H NMR spectrum showed amultiplet at 87.14 (H-6', H-6", H-T, and H-7") andtwo ortho- and meta- coupled double doublets at 88.32 (H-5' and H-5") and 7.88 (H-8' and H-8") thusaccounting for all the protons of both the coumarinnuclei. Further, it displayed two multiplets at 87.68(H-4 and H-7) and 7.50 (H-5 and H-6)corresponding to the protons of indole nucleus.Since 'H NMR did not provide any evidence for thecharacteristic signal of the proton at C-3 position inthe coumarin nucleus, it appeared that the proton ~tC-3 position in both the coumarin nuclei had takenpart in the condensation reaction with the freecarbonyl at C-3 position of indole nucleus. Further,the presence of hydroxyl group was confirmed byI3C NMR spectrum as carbon carrying OH groupappeared at 8 162.06. ElMS also showed thepresence of a prominent peak at mlz 435 due to lossof H20 from the molecule and another at mlz 407due to loss of a carbonyl group. These data supportthe structure for this compound as 3,3-bis-(2-oxo-4-hydroxy-2H-l-benzopyran-3-yl)indole-2-(lH)-one3a.However, when the above reaction was carriedout in absolute ethanol it resulted in the formationof a new compound that was found to be differentfrom 3a. It showed M+ peak at mlz 435,corresponding to the molecular formula C2JI13N06indicating again the presence of two coumarinmoieties along with an indole nucleus. Its IRspectrum showed absorptions at 3140 (>NH), 1735and 1660(lactam carbonyls), 1603(>C=C<) and1200 ern' (pyran ether linkage). The 'H NMRspectrum showed a multiplet at 8 7.14 (H-6', H-6",H-7' and H-7") and two ortho coupled doublets at 88.40 (H-5' and H-5") and 7.92 (H-8' and H-8")corresponding to the protons of both the coumarinnuclei. Besides these, multiplets at 0 7.72(H-4 andH-7) and 7.56 (H-5 and H-6) for protons of theindole nucleus were also observed. Further, its 13C634 INDIAN J CHEM . SEC B, AUGUST 1997R'y~-l+ CQI OrO~NAo ~ //IR OHla R=RI =H 2Ib R=CH3,RI =HIc R=H,RI =FNMR spectrum displayed a characteristic signal ato 100.83 for the presence of a C-3 spiro carbonatom of indole along with signals for carbonyls at 0178.42, 160.00 and 157.83. ElMS showed aprominent peak at mlz 379 due to the loss of twocarbonyl groups from the molecule. Considering theabove spectral data and their comparison with thoseof compound 3a, this compound was characterizedas spiro[indole-3,T-[6H,7H,8H]pyrano[3,2-c ; 5,6-c'[di]] ]benzopyran ]-2(3H),6',8'-trione (4a). Thespiro compound 4a was also obtained from 3a byrefluxing the latter in absolute ethanol, therebyconfirming its assigned constitution.Since, in general, fluoro- and N-alkyl-indolederivatives are known to be more soluble andpossess increased bioactivity', we were tempted tocarry out the above condensation reaction taking 1-methylindole-2,3-dione Ib and 5-fluoroindole-2,3-dione I e in place of la. Indole-2,3-dione I b whenrefluxed with 2 in absolute ethanol afforded twocompounds 4b and 3b, which were characterised asI-methylspiro[indole-3,T-[6H,7H,8H]pyrano[3,2-c; 5,6-c1di[ 1]benzopyran ]-2(3H),6',8'-trione 4b and3a R=RI =H3b R = CH3, R 1 = HN·IR4a R=H,RI =H4b R = CH3, R I = H4e R = H,Rl =F3,3 -bis-(· 2-oxo-4-hydroxy- 2H -l-benzopyran- 3-yl )-1-methylindole-2( 1H)-one 3b, respectively, on thebasis of their detailed spectral studies and similarityin spectral behaviour with compounds 4a and 3arespectively. As the yield of the spiro compound 4b,obtained above in a mixture, was poor we repeatedthe above reaction in glacial acetic acid andobtained surprisingly the desired compound 4b in80% yield.We also carried out the reaction of 5-fluoroindole-2,3-dione Ic with 2 in three differentmedia (neutral, acidic and alkaline) under refluxingconditions and obtained the desired spiro compound4e, characterized as 5-f1uorospiro[indole-3,7'-[6H,7H,8H]pyrano[3,2-c ; 5,6-c1di[1]benzopyian]-2(3H),6',8'-trione 4e in 85% yield only in alkalinemedium. However, no traces of 4e was observedwhen the reaction was performed in either neutral oracidic medium as in the case of la and lb.Experimental SectionGeneral. All melting points are uncorrected andwere determined in a sulphuric acid-bath. IR dataRAPID COMMUNlCA nONSwere recorded on a Shimadzu model IR-435spectrophotometer. IH NMR spectra were recordedeither on a Bruker AC 250 MHz or on a Perkin-Elmer R-32 model (90 MHz)spectrometer. l3CNMR spectra were recorded on a Bruker AC 62.89MHz instrument (chemical shifts were quoted in 8,ppm relative to internal standard tetramethylsilane).Mass spectra were recorded on a Varian MA T311A or a Jeol-JMS-OX 303 mass spectrophoto-meter. l-Methyl-indole-Zji-dione" and 5-fluoro-indole-z.B-dione" were prepared by literaturemethods.Reaction of indole-2,3-dione la with 4-hydroxy-2H-l-benzopyran-2-one 2 in glacialacetic acid. A mixture of la (1.47 g, 10 mmoles)and 2 (3.24 g, 20 mmoles) in glacial acetic acid (50mL) was refluxed in an oil-bath. The progress of thereaction was monitored by TLC. After 24 hr a lightyellow solid separated out which was filtered, driedand crystallised from glacial acetic acid to give 3aas white solid, yield 3.4g, m.p. 270° (dec); IR(KBr): 3400,3132,1710,1655,1573,1500,1495,1454, 1380, 1286, 1116,997,760 em", IH NMR(TFA-d), : 7.14 (m, 4H, H-6', H-6", H-7' and H-7"),7.50(m, 2H, H-5 and H-6), 7.68 (m, 2H, H-4 andH-7), 7.88 (dd, J=9.0 and 2.5Hz, H-8' and H-8"),8.32(dd, 2H, H-5' and H-5"), 10.42 (s, IH, >NH);13C NMR (TFA-d): 181.03, 162.06, 160.68,157.11, 152.11, 151.90, 140.16, 134.44, 126.56,125.55, 114.17, 123.00, 122.16, 121.94, 110.73;ElMS mlz (%) : 453(~, 18), 435(~-H20, 12),407(~ -H20-CO, 16), 391 (20), 369(5), 329(7),307(100), 292(22), 154(80), 136(80), 120(15),107(39).On the basis of the above spectral datacompound 3a was characterized as 3,3-bis-(2-oxo-4-hydroxy-2H-l-benzopyran-3-yl)-indol-2-(lH)-one.Reaction of 1a with 2 in absolute ethanol. Amixture of la (1.47g, 10 mmoles) and 2 (3.24g, 20mmoles) in absolute ethanol (50 mL) was refluxedfor 22 hr. A yellow solid that separated out wasfiltered, dried and crystallised from glacial aceticacid to give 4a as a light yellow solid, yield 2.8 g,m.p. 2800 (dec); IR (KBr): 3140, 3050, 1735, 1660,1603, 1573, 1200 em": IH NMR (TFA-d): 7.14 (m,4H, H-6', H-6", H-7' and H-7"), 7.56 (m, 2H, H-5635and H-6), 7.72(m, 2H, H-4 and H-7), 7.92(d, 2H,H-8' and H-8"), 8.40(d, 2H, H-5' and H-5"),10.46(s, IH, >NH); l3C NMR(TFA-d): 178.42,160.00, 157.83, 140.00, 134.16, 129.59, 125.83,100.83; ElMS m/z (%) : 435(~, 40), 379(~-2xCO, 28), 368(95), 334(31), 317(28), 308(32),293(12), 284(31), 265(48), 257(100), 255(78),251(68), 180(25), 163(95), 147(92).On the basis of the above spectral datacompound 4a was characterized as spiro[indole-3,7'-[ 6H,7H,8H ]pyrano[3,2-c;5,6-c1di[l]benzo-pyran]-2(3H),6',8'-trione.Synthesis of spiro [indole-3, 7' - [6H, 7H,8H]-pyrano-[3,2-c; 5,6-c1di[l]benzopyran]-2(3H), 6',8'-trione 4a. A suspension of 3,3-bis-(2-oxo-4-hydroxy- 2H -1- benzopyran-3-yl)-indole-2-( IH)-one 3a (1.5g) in absolute ethanol (50 mL) wasrefluxed for 6 hr. A clear yellow solution wasobtained. The progress of the reaction wasmonitored by TLC. On cooling the reaction mixture,a yellow solid separated out which was filtered,dried and crystallized from glacial acetic acid togive a light yellow solid, yield 1.2g. It wascomparable with compound 4a in all respects (Co-TLC, Co-IR and m.m.p).Reaction of f-methyl-indole-Ld-dione" Ib with2 in absolute ethanol. A mixtu re of 1b (1. 61 g, 10mmoles), and 4-hydroxy-2H-I-benzopyran-2-one 2(3.24 g, 20.0 mmoles) in absolute ethanol (50 mL)was refluxed for 70 hr. The solid that separated outwas filtered, dried and crystallized from glacialacetic acid to give l-methyl spiro[indole-3,7'-[6H,7H,8H] pyrano [3,2-c;5,6-c1di[1]benzopyran]-2(3H),6',8'-trione 4b as a light yellow solid, yield1.15 g, m.p. 270°; IR (KBr) : 2872, 1709, 1654,1600, 1480, 1452, 1360, 1332, 1244, 1212, 1192,1140, 1080 em"; IH NMR(TFA d) : 3.50(3H, >N-CH3), 7.05-8.40(m, 12H, Ar-H); ElMS m/z (%) :449(M+, 64), 421(M+-CO, 18), 392(~-CO-NCH3,11), 376(15), 336(32), 279(14), 262(39), 260(11),252(12), 233(l1), 215(12), 196(13), 162(10),149(44).The filtrate was concentrated under reducedpressure to dryness. TLC examination of the solidresidue, thus left, indicated the presence of anothercomponent which was different from the starting636 INDIAN J CHEM . SEC B, AUGUST 1997materials and compound 4b and hence labelled as3b. Compound 3b was purified by columnchromatography. Elution with ethyl acetate-benzene(20:80) gave 3,3-bis-[2-ox0-4-hydroxy-2H-l-benzo-pyran-3 -yl] -1-methylindole-2-( IH)-one ascolourless crystal, yield 1.35 g, m.p. 1450 ; IR(KBr): 3348, 3000, 1703, 1652, 1615, 1603, 1560, 1480,1458, 1372, 1312, 1292, 1212, 1080 ern". IH NMR(DMSO-d6) : 3.18(s, 3H, >N-CH3), 6.94(m, 2H, H-5 and H-6), 7.10(m, 4H, H-6', H-6", H-7' and H-7"), 7.27(dd, 2H, H-4 and H-7), 7.41(dd, 2H, H-8'and H-8"), 7.89(dd, 2H, H-5' and H-5"), 9.68(s,2H, 2xOH); \3C NMR (DMSO-d6) : 178.10,159.74, 155.09, 152.18, 149.37, 132.78, 131.84,131.57, 130.35, 127.94, 127.56, 124.51, 121.59,118.66, 116.47; ElMS mlz (%) : 440(M'+ 1-28,32),422(100), 379(10), 365(12), 320(92), 305(60),279(38),234(90), 186(29), 162(25), 146(42).Reaction of l-methylindole-2,3-dione Ib with 2in glacial acetic acid. A mixture of Ib (1.61g, 10.0mmoles) and 4-hydroxy- 2H -1-benzopyran- 2-one 2(3.24g, 20.0 mmoles) in glacial acetic acid (50 mL)was refluxed in an oil-bath for 70 hr. The solid thatseparated out was filtered, dried and crystallisedfrom glacial acetic acid to give the spiro compound4b, yield 3.5 g.Reaction of 5-fluoroindole-2,3-dione Ic with 2in absolute ethanol in the presence of diethylamine. A mixture of Ic (1.65g, 10.0 mmoles), 2(3.24, 20.0 mmoles) and diethylamine (0.5 mL) inabsolute ethanol (50 mL) was refluxed in an oil-bath for 72 hr. A pink solid that separated out wasfiltered, dried and crystallised from hot glacialacetic acid to give 5-fluorospiro[indole-3,7'-[6H,7H,8H J pyrano [3,2-c;5,6-c1di[lJbenzopyranJ-2(3H),6',8'-trione 4c as a light pink solid, yield 3.85g, m.p. 270°; IR (KBr) : 3160, 1732, 1655, 1600,1572, 1338, 1280, 1252, 1203, 1176, 1146, 1092,1032, 878 em"; IH NMR (DMSO-d6) : 7.03(d, IH,H-6), 7.30(d, IH, H-7), 7.54(m, 4H, H-6', H-6", H-7' and H-7"), 7.61(d, IH, H-4), 7.83(d, 2H, H-8'and H-8"), 8.46(d, 2H, H-5' and H-5"), 10.88(bs,IH, >NH); \3C NMR(DMSO-d6) : 178.20, 168.28,154.92, 152.07, 134.10, 131.00, 128.82, 125.26,123.82, 112.54, 115.52, 101.4; ElMS rnJz (%) :453(M+, 15), 452(10), 422(20), 396(10), 368(18),316(5), 262(18), 234(18), 173(8), 105(12).AcknowledgementThe authors express their sincere gratitude toDanish International Development Agency(DANIDA), Denmark and CSIR, New Delhi forfinancial assistance.References1 Joshi K C & Jain R, Heterocycles, 23, 1985,957.2 Ninamiya K, Japan Kokai TOkyo Koho, 80164, 683(1980); Gem Abstr, 95, 1981, 25036r.3 Kobayashi G & Matsuday, Japan Patent, 7025, 894,(1970); Gem Abstr, 74, 1971, 35291.4 Joshi K C, Dandia A, Baweja S & Joshi A, JHeterocyclic Chem, 26, 1989, 1097.5 Gaede K & Kluppers-Frisher G, Klin-Wochschr, 26,1948,720.6 Daniel L, Stanley C L & Gorden W D, J Med Chem, 8,1965,725.7 Joshi K C, Dandia A & Bhagat S, Indian J Chem, 29B,1990, 766.8 Mason J H & Ingleby R F, J Chem Soc, 1958,3639.9 Yen V Q, Buu-Hoy N P & Xuong N D, J Org Chem, 23,1958, 1858.

Solvent induced synthesis of spiro [Indole-pyran] system using condensation reactions

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Solvent induced synthesis of spiro [Indole-pyran] system using condensation reactions

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