Synthesis of isocoumarinsviaindanones

摘要

1438 J.C.S. Perkin ISynthesis of lsocoumarins via lndanonesBy Rachel H. Carter (net? Rayner), Roger M. Colyet, Robert A. Hill, and James Staunton,' UniversityTwo improved methods for the oxidative cleavage of indan-1 -ones to give isocoumarins have been developed.Syntheses of 6.8-dimethoxy-3-rnethyl- and 8-methoxy-3-methyl-isocoumarin are described.Chemical Laboratory, Lensfield Road, Cambridge CB2 1 EWA LARGE number of fungal metabolites are consideredto arise by cyclisation of a polyketide chain (1) of theCO, HOH CO-SCoA0( 1 1 ( 2 ) R = M e"OWOR0 OH( 3 )SCHEME Iappropriate length folded as shown in Scheme 1. TheC-acetylorsellinic acid (2) or isocoumarin (3) whichresults from this mode of cyclisation would then beconverted into compounds such as the pentaketidescitrinin and sepedonin or the hexaketides ascochitineand rubropunctatin, by a variety of oxidation, reduction,and alkylation reactions.2We plan to test some of these biosynthetic proposalsby carrying out incorporation experiments with theappropriate hypothetical precursors , and have thereforesought a convenient synthetic route to 3-alkyliso-1 W.B. Turner, ' Fungal Metabolites,' Academic Press,A. J. Birch and F. W. Donovan, Austral. J . Chenz., 1953, 6,London and New York, 1972.360.coumarins. Apart from being suitable for the introduc-tion of isotopic labels at selected positions in the targetmolecules, the chosen route had to be sufficiently flexibleto allow the synthesis of a wide range of differentlysubstituted isocoumarins, including compounds with (a)one or more hydroxy-groups at C-4, -5, -6, -7, or -8, (b)one or more methyl groups at C-4, -5, or -7, and (c) amethyl or other alkyl substituent at C-3.Of the established synthetic routes to isocoumarins,that based on the oxidative cleavage of indanones\QR- wR 0 0 /rR0(5)SCHEME 2(Scheme 2) seemed most likely to meet these require-ments.A wide range of suitable indanones can beprepared, by cyclisation of either an arylpropionic acid(4) or an acrylophenone (5).It is essential for the success of this approach to havea reliable general method of effecting the key oxidativeR. D. Barry, Chem. Rev., 1964, 2291976 1439cleavage of the indanone to the isocoumarin. Thetransformation has been carried out successfully with ahighly substituted indanone 4 by use of Triebs reagent,"but we have not found this to be a generally applicablemethod. Bayer-Villiger oxidation of a 8-alkylindanoneleads to a coumarin rather than an isocoumarin.6We have therefore investigated the oxidative cleavageof enol derivatives of 2-alkylindanones, and as a resulthave developed two convenient methods for the desiredtransformation.Exploratory studies were carried outon 5,7-dimethoxy-2-methylindan-l-one (6). In the firstmethod (Scheme 3) this was converted into the silylether (7) by treating the enolate with chlorotrimethyl-silane. On ozonolysis followed by oxidative work-upthis derivative afforded the hydroxy-ketone (9) ratherthan the expected 0x0-acid (10). Presumably the initialproduct of ozonolysis is an epoxide rather than anozonide; this anomalous behaviour has been observedwith other highly hindered alkenes.The conversion of(7) into (9) can also be effected by rn-chloroperbenzoicacid, though in lower yield. The final step of the desiredtransformation leading to (11) can be readily carried outby oxidative cleavage of (9) with periodate, presumablyvia the 0x0-acid (10).OSiMe3( 6 ) R = OMe (7) ( 8 12 = HJ0 CO C Fs(12) R =OMe (9)( 1 4 ) R = HMe 0(11) R = OMe (10)(15) R = HSCHEME 3The overall transformation of (6) into (11) could becarried out more conveniently, however, by ozonolysisT. Sassa, H. Aoki, and K. Munakata, Tetrahedron Letters,W. Triebs, Bey., 1939, 72, 1194; Angew. Chem.Internat.1968, 5703.Edn.. 1964, 3. 802.P. E. .Sonnet and J. E. Oliver, J . Heterocyclic Chem., 1974,11, 263.of the enol trifluoroacetate (12). The derivative wasreadily prepared by mild treatment of the indanone with - RocHo Me0(16) R = OMe(211 R = HCO,E tM eO(19) R = OMe( 2 4 ) R = HRm," Me0 -( 2 0 ) R = OMe( 2 5 ) R. = H(17) R = OMe.(22) R = Hi(18) R = OMe(23) R = H0(6) R = O M e(13) R = HSCHEME 4trifluoroacetic anhydride ; the ozonolysis proceeded in astraightforward manner and the isocoumarin (1 1) wasisolated directly and in excellent yield on work-up withdimethyl sulphide. This method proved equally effec-tive for the conversion of 7-methoxy-2-niethylindan 1-one into the corresponding isocoumarin [(13) (14)The indanones (6) and (13) required for this study wereconveniently prepared by cyclisation of the correspond-ing arylpropionic acids (Scheme 4).Differently substi-tuted indanones may, however, be more readily preparedby cyclisation of an acrylophenone.8 Both types ofsynthetic precursor can be labelled specifically a t anumber of positions by using standard labelled buildingblocks, so a convenient approach is now established forthe preparation of the wide range of specifically labelledisocoumarins required for our biosynthetic investigations.- ( 1 5 ~ .EXPERIMENTALh5.p.s were determined with a Kofler hot-stage apparatus.1.r. spectra were recorded with a Perkin-Elmer 257 spectro-photometer for solutions in chloroform unless otherwiseP. D.Bartlett and M. Stiles, J . Amer. Chem. Soc., 1956, 77,2806; P. S. Bailey and A. G. Lane, ibid., 1967, 89, 4473; R.Criegee, Amer. Chem. SOC. Advances in Chemistry Series, No. 21,1959, p. 133.J. H. Burckhalter and R. C. Fuson, J . Amer. Chem. Soc.,1948,70,4184; D. B. Bruce, A. J. S. Sorrie, and R. H. Thomson,J . Chem. Soc., 1953, 2403J.C.S. Perkin Istated. lH N.m.r. spectra were recorded with a VarianHAlOO or HAlOO D instrument for solutions in deuterio-chloroform unless otherwise stated (Me4Si as internalstandard).Diethyl 3,5-Dimethoxybenzylidenemalonate (1 7) .-A solu-tion of 3,5-dimethoxybenzaldehyde (1.83 g), diethyl malon-ate (1.60 g), piperidine (0.05 ml), and glacial acetic acid (0.15ml) in dry benzene (10 ml) was heated a t reflux in a Dean-Stark apparatus for 20 h.After cooling and dilution withether (20 ml) the solution was washed with 3~-sulphuricacid (20 ml), 10% sodium hydrogen carbonate solution(20 ml), 5% acetic acid (20 ml), and water (2 x 20 ml).Evaporation of the dried ethereal solution gave a paleyellow oil which crystallised (yield 3.26 g, 96%). Distil-lation (b.p. 160-170' a t 0.1 mmHg) gave diethyl 3,5-di-methoxybenzylidenemalonate as crystals, m.p. 47.5-48.5'(from pentane) (lit.,9 45-48'); vmaX. 1 720s, 1 63Ow, and1 590s cm-l; T 2.36 (1 H, s, ArH), 3.40 (2 H, d, J 2 Hz, ArH),3.52 (1 H, t, J 2 Hz), 5.66 (2 H, q, J 7 Hz, OCH,*CH,),5.70 (2 H, q, J 7 Hz, OCH,*CH,), 6.24 (6 H, s, OCH,), 8.66(3 H, t, J 7 Hz, O*CH2*CH,), and 8.70 (3 H, t, J 7 Hz,O-CH,.CH,).Diethy2 3,5-Dimethoxybenzylmalonate ( 18) .-A solution ofdiethyl 3,5-dimethoxybenzylidenemalonate (1.07 g) in dryethyl acetate (25 ml), was hydrogenated over 5% palladium-charcoal (0.1 g) at 20 'C and atmospheric pressure for 2 h(uptake 90 ml).The filtered solution was evaporated andthe resulting oil distilled (b.p. 150-152° at 0.05 mmHg) togive diethyl 3,5-dimethoxybenzylmalonate (0.945 g, 88%)(lit.,Q b.p. 140-145" at 0.2 mmHg) ; vmax (film) 1 730s and1600s cm-l; 7 3.68 (3 H, s, ArH), 5.86 (4 H, q, J 6 Hz,O*CH,CH,), 6.30 (6 H, s, OCH,), 6.36 (1 H, t, J 8 Hz,CH,-CH), 6.86 (2 H, d, J 8 Hz, CH,*CH), and 8.80 (6 H, t ,J 6 Hz, O-CH,*CH,).3-( 3,5-Dimethy@henyl)-2-methylpro~ionic Acid (20) .-Sod-ium (0.7 g) was allowed t o react with dry ethanol (120 ml).A solution of diethyl 3,5-dimethoxybenzylmalonate (6.9 g)in ethanol (20 ml) was then added and the mixture heatedto reflux.After 1 h a solution of methyl iodide (3.9 g) inethanol (20 ml) was added slowly and heating was continuedfor 1 h. The solution was concentrated, diluted with ether(50 ml), and then washed with water (50 ml), 3~ sulphuricacid (50 ml), and 10% sodium hydroxide (50 ml), dried, andevaporated. The product was a yellow oil (6.5 g, 90%);vmx. (film) 1 730s and 1 600s cm-l; T 3.70 (2 H, s, ArH),3.74 (1 H, s, ArH), 5.82 (4 H, q, J 8 Hz, O.CH,*CH,), 6.30(6 H, s, OCH,), 6.84 (2 H, s, ArCH,), 8.66 (3 H, s, CH,),and 8.76 (6 H, t, J 8 Hz, O*CH,*CH,).This product (1 1.5 g) was added to a solution of potassiumhydroxide (6 g) in water (60 ml) and the mixture was heatedat reflux for 30 h.After cooling, sulphuric acid (12 g) inwater (18 ml) was added and heating continued for 25 h.The product was extracted with ether (2 x 50 ml). Theethereal solution was extracted in turn with 10% sodiumhydrogen carbonate solution (2 x 50 ml). The acidifiedaqueous solution was extracted with ether (2 x 50 ml) andthe ethereal solution dried and evaporated to give a yellowoil (4.9 g, 61%). At 4 "C a sample slowly crystallised; re-crystallisation from pentane at - 25" gave 3-( 3,5-dimethoxy-phenyl)-2-nzethyZpropionic acid, m.p. 5 6 5 6 " (Found: C,64.2; H, 7.0. Cl,Hl,O, requires C, 64.3; H, 7.2%); vmX.3 200-2 800m, 1690-1 710s, and 1590s cm-l; 7 -0.84(1 H, s, CO,H), 3.68 (3 H, s, ArH), 6.26 (6 H, s, OCH,),6.8-7.5 (3 H, complex m, CH,.CH), and 8.80 (3 H, d, J6 Hz, CH,).5,7-Dimethoxy-2methylindan-l-one (6) .-Trifluoroaceticanhydride (18 ml) was added to a solution of 3-(3,5-di-methoxypheny1)-2-methylpropionic acid (4.5 g ) in trifluoro-acetic acid (80 ml) at 0 "C.The mixture was stirred a t thistemperature for 0.5 h, then evaporated, and the residue wasdissoIved in ether (50 ml). The ethereal solution waswashed with 10% sodium hydroxide solution (2 x 50 ml)and water (2 x 50 ml), then dried and evaporated to givean oil which crystallised t o afford solid 5,7-dimethoxy-2-methylindan-1-one (3.5 g, 85%). The product could bepurified by distillation (b.p.135-140" a t 0.1 mmHg) andby recrystallisation from ethyl acetate-hexane (1 : 1) asprisms, m.p. 76-79' (Found: C, 68.5; H, 6.5. C1,H1,O,requires C, 68.2; H, 6.3%); vmax 1 700s and 1610s cm-1;~3.56(lH,s,ArH),3.72(1H,s,ArH),6.l4(3H,s,OCH,),6.17 (3 H, s, 0-CH,), 6.6-6.9 (1 H, m, CH,*CH), 7.3-7.5(2 H, m, CH,*CH), and 8.76 (3 H, d, J 8 Hz, CH,).2-Hydroxy-5, 7-dimethoxy-2-methylindan-1-one (9) .-To asolution of di-isopropylamine (34 mg) in tetrahydrofuran(5 ml) cooled to -20 OC under nitrogen, was added 15%butyl-lithium in hexane (0.20 ml) followed, after 15 min bya solution of 5,7-dimethoxy-2-methylindan-l-one (49 mg)in tetrahydrofuran (2 ml). After 3 h at room temperature,chlorotrimethylsilane (120 mg) was added. After 15 minthe solvent was evaporated off and the residue dissolved inether (15 ml).The ethereal solution was washed withwater (15 ml), dried, and evaporated. The silyl ether waspurified by chromatography on silica gel [ethyl acetate-cyclohexane (1 : 1) as eluant] to give the silyl ether (43 mg,65%); vmx. (film) 1 630s and 1 600s cm-l; T 3.45 (1 H, d,J 1 Hz, ArH), 3.63 (1 H, d, J 1 Hz, ArH), 6.12 (6 H, s,OCH,), 6.91 (2 H, s, CH,), and 8.12 (3 H, s, CH,).A solution of the fore-going product (39 mg) in ethyl acetate (10 ml) was cooled to- 70 "C and ozonised oxygen (ca. 5% ; 20 1 h-l) was bubbledthrough for 15 min. The excess of ozone was removed bypassing nitrogen through the solution, which was thenevaporated, and the residue was treated with 4~-hydro-chloric acid (20 ml) for 2 h.The product was extractedwith ether (2 x 20 ml) and purified by chromatography onsilica gel (ethyl acetate-cyclohexane as eluant) to give 2-hydroxy-5,7-dimethoxy-2-methylindan-l-one (17 mg, 45%).The product crystallised from ether-hexane; m.p. 1 2 2 -124" (Found: C, 64.9; H, 6.1. C&1404 requires C, 64.85;H, 6.35%); vmax 3 400m, 1 700s, and 1 600s cm-l; T 3.56(1 H, s, ArH), 3.70 (1 H, s, ArH), 6.12 (3 H, s, OCH,), 6.16(3 H, s, OCH,), 6.91 (2 H, s, CH,), and 8.64 (3 H, s, CH,).(b) Oxidation with m-chloroperbenzoic acid. A solution ofthe silyl ether (42 mg) and wz-chloroperbenzoic acid (29 mg)in dichloromethane (25 ml) was stirred for 3 h. Water (25ml) was added and the organic layer separated. Theaqueous layer was extracted with ether (2 x 25 ml) andthe organic extracts were dried and evaporated to give amixture of products.The major product, separated bychromatography on silica gel [ethyl acetatexyclohexane(1 : 1) as eluant] was 2-hydroxy-5,7-dimethoxy-2-methyl-indanone (13 mg, 25%).Conversion of the Ketone (9) into 6,8-Dimethoxy-3-methylisocoumarin (1 1) .-2-Hydroxy-5,7-dimethoxy- 2-meth-ylindan-1-one (50 mg) was dissolved in a mixture of 1,4-dioxan (2 ml) and 2~-sulphuric acid (8 ml) , sodium periodate(110 mg) was added, and the mixture was stirred a t roomtemperature for 18 h. Water (50 ml) was added and the(a) Ozonolysis of the silyl ether.9 H. Newman and R. B. Angier, J . Org. Chem., 1966,31, 14511976solution was extracted with ethyl acetate (2 x 50 ml).Evaporation of the dried organic layer gave a residue whichwas purified by chromatography (dichloromethane aseluant) to yield 6,8-dimethoxy-3-methylisocoumarin (27 mg,54y0), m.p.157-160' (1it.,lo 157-158"); vmax. 1 740s,1 700m, 1 640s, and 1610s cm-l; T 3.59 (1 H, d, J 2 Hz,ArH), 3.71 (1 H, d, J 2 Hz, ArH), 3.92 (1 H, s, 4-H), 6.06(3 H, s, OCH,), 6.12 (3 H, s, OCH,), and 7.80 (3 H, s, CH,).4,6-Dimethoxy-2-methylinden-3yl Triflumoacetate ( 12) .-A solution of 5,7-dimethoxy-2-methylindan-l-one (510 mg)in trifluoroacetic anhydride (10 ml) was stirred at roomtemperature for 20 min. Evaporation gave dark blue-green iridescent plates, which on distillation (1 1P-116" and0.05 mmHg) afforded the trifluoroacetate as a pale yellowsolid (640 mg, 85%).Repeated distillation gave a whitepowder, m.p. 90-99" (Found: C, 55.7; H, 4.3%; m/e,302.0776. C,,H,,F,O, requires C, 55.6; H, 4.2%; M ,302.0764); vWx 1 800s, 1 660w, 1590s, and 1460m cm-l;7 3.44 (1 H, s, ArH), 3.66 (1 H, s, ArH), 6.26 (3 H, s, OCH,),6.30 (3 H, s, OCH,), 6.74 (2 H, s, CH,), and 8.08 (3 H, s,Conversion of the Tri$uoroacetate ( 12) into 6,s-Dimethoxy-3-methylisocoumarin (1 1) .-Ozonised oxygen (ca. 5% ; 20 1h-l) was passed through a solution of the trifluoroacetate (12)(750 mg) in ethyl acetate (50 ml) at -70 "C until thesolution became blue. The excess of ozone was removedby bubbling nitrogen through the solution, which was thentreated with dimethyl sulphide and allowed t o warm up t oroom temperature.After 1 h at this temperature thesolvent was evaporated off and the product recrystallisedfrom methanol t o give 6,8-dimethoxy-3-methylisocoumarinas plates (490 mg, 90%).Diethyl 3-Methoxybenzylidenemalonate (22) .-By themethod for the preparation of (17), 3-methoxybenzaldehyde(3.0 g) gave diethyl 3-methoxybenzylidenemalonate (5.88 g,95y0), b.p. 205-210° (Found: C, 64.8; H, 6.6. Cl,H,,Osrequires C, 64.7; H, 6.5%); vmax (film) 1 715s, 1 660m,1 6OOm, and 1 580m cm-1; T 2.32 (1 H, s, ArCH), 2.7-3.2(4 H, m, ArH), 5.67 (2 H, q, J 7 Hz, O*CH,*CH,), 5.70 (2 H,q, J 7 Hz, O*CH,-CH,), 6.23 (3 H, s, 0-CH,), 8.68 (3 H, t,J 7 Hz, O-CH,*CH,), and 8.72 (3 H, t , J 7 Hz, O*CH,*CH,).Diethyl 3-Methoxybenzylmalonate (23) .-By the methodfor the preparation of ( 18), diethyl 3-methoxybenzylidene-malonate ( 1.9 g) gave diethyl3-methoxybenzylmalonate ( 1.7 g,go%), b.p. 190-195' (Found: C, 64.3; H, 7.1.C15H2&5requires C, 64.3; H, 7.2%); vmx. (film) 1 730s, 1600s, and1 580s crn-l; T 2.7-3.3 (4 H, m, ArH), 5.85 (4 H, q, J 7 Hz,O.CH,*CH,), 6.35 (1 H, t, J 8 Hz, CH,*CH), 6.81 (2 H, d,J 8 Hz, CH,*CH), and 8.81 (6 H, t, J 7 Hz, CH,).Diethyl (3-Methoxybenzy1)methylmalonate (24) .-By themethod for the preparation of (19), diethyl 3-methoxy-benzylmalonate (3 g) gave diethyl (3-methoxybenzyl)methyl-malonate (2.1 g, 70%), b.p. 255-260' (Found: C, 65.4; H,7.8. C,,H,,O, requires C, 65.3; H, 7.5%); vmx. (film)1 730s, 1 600m, and 1 580m cm-l; T 2.7-3.4 (4 H, m, ArH),(333).lo J. Y . Lin, S.Yoshida, and N. Takakushi, Agric. and Biol.Chem. (Japan), 1972, 36, 606.5.82 (4 H, q, J 7 Hz, O*CH,.CH,), 6.29 (3 H, s, OMe), 6.82(2 H, s, CH,), and 8.69 (3 H, s, CH,).(3-Methoxybenzyl)methylmalonic A cid.-Diethyl (3-meth-oxybenzy1)methylmalonate (7 g) in 30% sodium hydroxidesolution (160 ml) was heated at reflux for 19 h. Aftercooling, the mixture was extracted with ether (3 x 50 ml),then acidified with concentrated hydrochloric acid. Thecloudy white solution was extracted with ethyl acetate (3 x50 ml). The organic layer was dried and evaporated togive (3-methoxybenzyl)methylmalonic acid (4.2 g, 75y0),which crystallised from ether-hexane as needles, m.p. 146-146" (Found: C, 60.5; H, 6.0. C,,Hl,Oa requires C, 60.5;H, 5.9%); vmx.(Nujol) 3 OOObr, s, 1 700s, and 1 600m cm-1;ArH), 3.18 (4 H, m, ArH), 6.27 (3 H, s, OCH,), 6.79 (2 H ,s, CH,), and 8.67 (3 H, s, CH,).7-Methoxy-2-methylindan-l-one ( 13) .-A solution of (3-methoxybenzy1)methylmalonic acid ( 1 g) in 30% sulphuricacid (50 ml) was heated at reflux for 16 h. After cooling,the solution was extracted with ether (3 x 50 ml). Evapor-ation of the dried ethereal solution gave 3-(3-methoxy-fihenyl)-2-methylpro$ionic acid (650 mg, 78%) as a viscousoil, vmX (film) 3 200br, s, L 700s, 1 600s, and 1 450s cm-1;T 0.7br (1 H, s, CO,H), 2.7-3.4 (4 H, m, ArH), 6.29 (3 H,s, OCH,), 6.9-7.5 (3 H, m, CH,*CH), and 8.85 (3 H, d, J6 Hz, CH,). The crude product was cyclised as in thepreparation of (6) to give a mixture of indanones fromwhich could be isolated (by chromatography on silica gelwith ether as solvent), 7-methoxy-2-nzethylindan- l-one (70mg, 15%), b.p.170-180' (Found: C, 74.8; H, 7.0. Cll-H1,02 requires C, 75.0; H, 6.9%); vmx (film) 1690s,1600s, 1460m, and 1260s cm-l; T 2.39 (1 H, d, J 8 Hz,ArH), 3.20 (2 H, m, ArH), 6.14 (3 H, s, OCH,), 6.68 (1 H,m, J 8 Hz, CHCH,), 7.39 (2 H, M, J 14 Hz, CH,), and 8.76(3 H, d, J 7 Hz, CH,). The major product was 5-methoxy-2-methylindan-l-one (280 mg, 60%), m.p. 62-65' (fromether-hexane) (Found: C, 75.1; H 6.7. C,,H,,O, requiresC, 75.0; H, 6.9%).8-Methoxy-3-methylisocoumari~ (15) .-After 30 min atroom temperature, a solution of 7-methoxy-2-methylindan-1-one (100 mg) in trifluoroacetic anhydride (10 ml) wasevaporated t o give the enol derivative (14) as an oil (120 mg,SOYo), vmx, (film) 1 800s, 1 600s, 1 260s, 1230s, and 1 160scm-l; T (CF,*CO,H) 3.08 (3 H, m, ArH), 6.14 (3 H,s, OCH,), 6.65 (2 H, s, CH,), and 7.99 (3 H, s, CH,).This oil (55 mg) was treated with ozonised oxygen as in thepreparation of ( 11) to give 8-methoxy-3-methylisocoumarin(34 mg, go%), which crystallised from ethanol as prisms,m.p. 109--110" (1it.,l1 104.5-110.5"), vmx. 1725s, 1660s,1595s, and 1565s cm-l; T 1.8-3.1 (3 H, m, ArH), 3.80(1 H, s, 4-H), 6.13 (3 H, s, OCH,), and 7.75 (3 H, s, CH,).Ltd. for a CAPS award to R. H. C.T [(CD,),CO] -0.89 (2 H, S, COZH), 2.83 (1 H, t , J 8 Hz,We thank the S.R.C. for support and Roche Products[6/028 Received, 6th January, 1976111 M. Matsui, K. Mori, and S. Arasaki, J. Agric. Chem. SOC.Japan, 1964, 28, 896