4,6,7-Trimethoxy-5-methylchromen-2-one, a new coumarin fromLeonotis nepetaefolia

摘要

2594 J.C.S. Perkin I4,6,7-Trimethoxy-5-methylchromen-2-one, a New Coumarin from Leo-notis nepetaefoliaBy Kozhiparambil K. Purushothaman and Sarada Vasanth, Captain Srinivasa Murti ResearchJoseph D. Connolly and Cecilia LabbQ, Department of Chemistry, University of Glasgow,Adyar, Madras, IndiaG12 8QQ4.6,7-Trimethoxy-5-methylchromen-2-one (1) has been isolated from Leonotis nepetaefolia and itsconfirmed by synthesis of the hydrolysis product, 2’-hydroxy-4’,5’-dimethoxy-6’-methylacetophenone2.3.5-trimethoxybenzaldehyde.DURING work on the diterpenoid constituents of Leonotisaepetaefolia we isolated a new coumarin, C1405,m.p. 209” v , ~ (CC1,) 1 727 cm-l. The n.m.r. spectrumrevealed the presence of three methoxy-groups (6 3.75,3.91, and 3.94), an aromatic methyl group (8 2.59), avinylic proton S 5.53 (1 H, s), and an aromatic protonS 6.68 (1 H, s).The similarity of the n.m.r. and U.V.A,, 225, 275infl, 287, 313, 327infl nm (E 20 000, 8 800,12 800, 15 000, and 11 OOO) spectra to those of siderin(4,7-dimethoxy-5-methylchromen-2-one)2 suggested twopossible structures, (1) and (2), for this compound. AMe OMeMe0OMe( 1 1 ( 2 )OMe MeMe0( 3 )( 4 ) R = H( 7 ) R = M eR( 5 ) R = C H O( 6 ) R = M edecision was facilitated by use of Eu(fod),-induced shifts,which have recently been shown3 to provide a readymethod for determining the substitution pattern incoumarins. The results strongly favoured structure (1) :the shifts of the various protons relative to H-3 were:H-8, 0.30; Me, 0.16; OMe,0.17,0.13, and 0.08 p.p.m.The corresponding shifts for the model compound (3)(5,7-dimethoxy-4-rnethylchromen-2-one) were : H-8,0.29 ;H-6, 0.14; 4-Me, 0.21; OMe, 0.10 and 0.07 p.p.m.Thet The isomeric 2’-hydroxy-3’, 4’-dime thoxy-6’-methylace to-1 K. I<. Purushothaman, S. Vasanth, and J. D. Connolly.K. K. Chexal, C. Fouweather, and J. S. E. Hollter, J.C.S.phenone has m.p. 94°.4J.C.S. Perkin I , 1974, 2661.Perkin I , 1975, 554.I nst i tut e,Glasgowstructure(4) fromsize of the relative shift of the aromatic proton indicates 3that it is attached to C-8.The presence of the 4-methoxy-group in structure (1)was confirmed by alkaline hydrolysis followed by acidichydrolysis, which resulted in decarboxylation to give theo-hydroxyacetophenone (4), m.p.76-77’ t v, (CCl,)3400 and 1620 crn-l; 6 2.5 (ArMe), 2.62 (CH,CO), 3.70and 3.84 (2 OMe), 6.32 (1 H, s, aromatic), and 13.08 (1 H,s, phenolic OH). This compound, which has not beendescribed previously, was synthesised in the followingway. 2,3,5-Trimethoxybenzaldehyde (5) (prepared fromo-vanillin ; see Experimental section) was subjected toWolff-Kishner reduction to afford the oily 2,3,5-trimeth-oxytoluene (6) a 2.17 (ArMe), 3.71 (6 H) and 3.80 (3 H)(3 OMe), and 6.27 and 6.33 (both d, J 3 Hz, H-4, and -6).Friedel-Crafts acylation of (6) with aluminium chlorideand acetyl chloride took place regiospecifically a t C-6 toyield 2’,4’, 5’- trimet hoxy-6’-me t h ylacetophenone (7), m .p.84” 8 2.17 (ArMe), 2.45 (CN,CO), 3.71, 3.80, and 3.88(3 OMe), and 6.40 (I H, s, H-3).The benzene-inducedshifts of the methoxy-groups of (7) (0.60, 0.43, and 0.11p,p.m.) support its assigned substitution pattern.Treatment of (7) with an excess of boron trichloride, areagent for the specific demethylation of o-methoxy-acylbenzenes,5 readily afforded the o-hydroxyaceto-phenone (4), identical with the hydrolysis product of thenatural compound (1). This synthesis confirmsstructure (1).EXPERIMENTALFor general details see ref. 1.IsoZatiort.-Dried powdered L. nefietaefolia (whole plant ;3 kg) was extracted with cold benzene. The extract wasconcentrated and left overnight. The precipitate of crudenepetaefolinol 1 was filtered off and the mother liquors werechromatographed over grade IV alumina.The chloroformeluate was rechromatographed and afforded a gum (100 mg)which solidified on trituration with ether. Crystallisationfrom methanol gave 4,6,7-trimethoxy-5-methylchronzen-2-one(l), m.p. 209--210’ (Found: C, 62.2; H, 5.4. C,,H,,O,requires C, 62.4; H, 5.65).A. I. Gray, R. D. Waigh, and P. G. Waterman, J.C.S. Chem.Cornrn., 1974, 632.W. Raker and H. Raistrick, J . Chem. SOC., 1941, 670.F. M. Dean, J. Goodchild, L. E. Houghton, J. A. Martin,R. B. Morton, R. Parton, A. VJ. Price, and N. Somvichien,Tetvahedron Letters, 1966, 415319762’-Hydroxy-4’, 5’-dimethoxy-6‘-methylacetophenone (4) .-The coumarin (1) (90 mg) was refluxed with methanolic 5potassium hydroxide (10 ml) for 2 h.The methanol wasremoved in VUCUO and the residue acidified with 5~-hydro-chloric acid, heated for 5 min, and extracted with ether.Crystallisation from cold hexane yielded the product (4),m.p. 76-77O, Amx- 220, 234, 277, and 318 nm (c 10500,8 500, 5 600, and 3 500) (Found: C, 62.6; H, 6.8. C,,H,,04requires C, 62.85; H, 6.7).2,3,5-TrimethoxybenzaZdehyde (5) .-o-Veratraldehyde ( 12g), prepared by methylation of o-vanillin under standardconditions with sodium hydride and methyl iodide indimethyl sulphoxide, was nitrated with concentrated nitricThe product (11.7 g), an equimolar mixture of the5- and 6-nitro-derivatives, was reduced and diazotised bythe method of Smith and Laf~rge.~ Fortuitiously, thecrude product (2.9 g) consisted mainly of the desired 2,3-dimethoxy-5-hydroxybenzaldehyde. It crystallised frommethanol as long needles (1.92 g), m.p. 141-144’ (lit.,8137”) 6 3.85 and 3.88 (2 OMe), 6.67 and 6.76 (both d, J 3 Hz,H - 4 and -6), and 10.28 (1 H, s, CHO).Methylation, asabove, afforded 3,3,5-trimethoxybenzaldehyde ( 5 ) ( 1.4 g) ,which crystallised from aqueous methanol as long needles,m.p. 67” (lit.,8 71”) 6 3.80, 3.85, and 3.88 (3 OMe), 6.73 and6.83 (both d, J 3 Hz, H-4 and -6), and 10.38 (1 H, s, CHO).2,3,5-TrimethoxytoZuene (6) .-The aldehyde (6) (1 g) indiethylene glycol was heated on an oil-bath a t 150 “C for2 h with an excess of hydrazine hydrate. An excess ofsolid potassium hydroxide was added and the mixtureheated at 180 “C for 3 h. Water was added and the solutionextracted with ether.Preparative t.1.c. of the crude pro-duct (0.57 g) gave 2,3,5-trimethoxytoZuene (6) as an oil (100mg), mle 182,2’,4’, 5’-Trimethoxy-6’-methylucetophenone (7) .-2,3,5-Tri-methoxytoluene (100 mg) was dissolved in an ethereal solu-tion of an excess of aluminium chloride, and an excess ofacetyl chloride was added dr~pwise.~ The mixture wasstirred at room temperature overnight, acidified with 5 ~ -hydrochloric acid, and heated on a steam-bath for 11.Extraction with ether and recrystallisation from hexaneafforded 2’,4‘, 5’-trimethoxy-6’-methyZacetophenone (7) (90 mg) ,m.p. 84”, vmx. (CC1,) 1697 cm-l, I,-. 224, 268, and 295 nm( E 10700, 4000, and 3500) (Found: C, 64.35; H, 7.25.C,,H,,O, requires C, 64.25; H, 7.2).2’-Hydroxy-4’, 5’-dirnethoxy-B’-methyZacetophenone (4) .-The trimethoxyacetophenone (7) (30 mg) in dichloromethanewas stirred a t 0 “C for 5 min with a large excess of borontrichloride. Water was added and the organic layer separ-ated. The crude product mas crystallised from cold hexaneto give 2’-hydroxy-4’,5’-dimethoxy-6’-methylacetophenone(4) (24 mg), m.p. 7-77’, identical with the hydrolysisproduct of (1).228 (E 5 300) and 283 nm (2 250).The Indian authors thank the Central Council for Res-earch in Indian Medicine and Homeopathy, Government ofIndia, New Delhi, for financial support.6/1461 Received, 26th July, 19761W. H. Perkin and R. Robinson, J . Chern. Soc., 1914, 2376.W. H. Perkin, R. Robinson, and F. W. Stoyle, J . Ghem. Soc.,1924, 2355. * L. E. Smith and F. B. Laforge, J . Ghem. SOL, 1931, 3072.0 Copyright 1976 by The Chemical Societ