The chemistry of fungi. Part LXXI. Synthesis of 3,5-dihydroxy-4-methylbenzoic acid

摘要

1382 J.C.S. Perkin IThe Chemistry of Fungi. Part LXX1.l Synthesis of 3,5-Dihydroxy-4-methylbenzoic AcidBy David R. Briggs and W. Basil Whalley,' The School of Pharmacy, The University of London, LondonA five-step synthesis of 3.5-dihydroxy-4-methylbenzoic acid from tri-O-methylgallic acid is described.WClN 1AXOUR syntheses2 of the sclerotiorin group of fungalmetabolites and of their numerous degradation productsuse 3,5-dihydroxy4-methylbenzoic acid as the startingmaterial. The supply of this deceptively simplesubstance has caused substantial problems since it isonly rarely available commercially and is extremelyinaccessible by the three previously reported syntheses.In the first method3 4-methylbenzoic acid is con-verted into the 3,5-bispotassiosulphonate, which is fusedwith potassium hydroxide.The fusion is most difficultto reproduce4 and usually furnishes largely (and fre-quently entirely) 3,5-dihydroxybenzoic acid, by oxidativeremoval of the methyl residue. The second5 method,which involves selective oxidation of p-orcinol dimethylether, is lengthy and gives the product in low yield, andthe starting material is expensive and not readilyavailable. The third preparation involves conversionof 3-methoxy-Z-methylphenol by lead tetra-acetate into2-acetoxy-3-met hoxy-met hylcyclohexa-3,5-dienone.1 Part LXX, M. Ahbab, A. D. Borthwick, J. W. Hooper,W. B. Whalley, G. Ferguson, and I?. C. Marsh, preceding paper.2 See, for example, R. W. Gray and W. B. Whalley, J . Ckem.SOC. (C), 1971, 3575 and references cited therein.(a) Y.Asahinaand J. Asano, Rer., 1933,66B. 687; (b) E. H.Charlesworth and R. Robinson, J . Chem. SOC., 1934, 1531.W. B. VVhalley (unpublished work) and personal com-munications from (the late) Alexander Robertson and (the late)Sir Robert Robinson and Dr. F. E. King.Hydrogen cyanide is then added to the ap-unsaturatedketonic system to yield the nitrile (l), which is methyl-ated. Sublimation of the methylation product furnishes3,5-dimethoxy-4-methylbenzonitrile (2), from which therequisite acid is obtained by hydrolysis and demethyl-ation-a low yielding multi-step process.None of these methods is suitable for large-scalepreparative operation, and after many unsuccessfulinvestigations we have devised a more practical syn-thesis from gallic acid, an inexpensive, easily availablematerial.Thus, Birch reduction of 3,4,5-trimethoxybenzoicacid, combined with an improved isolation procedure,gives 1,4-dihydr0-3,5-dimethoxybenzoic acid in 94yield. The n.m.r.spectrum of this acid exhibits long-range coupling, J1,4 6.5 Hz, a feature observed in other1,4-dihydrobenzenes.* 1,4-Dihydrobenzenes are con-sidered to exist in the boat form and the magnitude ofthis 1,4-coupling is regarded as indicative of stereo-s F. Fujikawa and T. Kobayashi, J . Pharm. SOC. Japan, 1944,64, 7.F. Wessely, J. Swoboda, and V. Guth, Monatsh., 1964, 95,649.(a) A. J. Birch, P. Hextall, and S. Sternhell, Austral. J .Chem., 1954, 7 , 266; (b) M. E. Kuehne and B. F. Lambert, J .Amer.Clzem. SOC., 1959, 81, 4278.E. L. Eliel, N. L. Allinger, S. J. Angyal, and G. A. Morrison,' Conformational Analysis,' Interscience, New York, 1965, p. 1251976 1383chemistry. Thus with 1,4-dihydro-4-phenyl-l-trityl-benzene the coupling constant (JIJ of 11 Hz has beenassigned to the ' cis ' structure (3), whereas the lowervalue (7.5 Hz) has been associated with the ' trans'structure (4), By analogy 1,4-dihydra-3,5-dimethoxy-benzoic may be assigned a similar ' trans ' structure.Demethylation of this acid yields (quantitatively) 3,5-dioxocyclohexanecarboxylic acid ( 5 ; R = H). By/ bsol;Me OAc MeR Meusing aqueous dioxan in a two-phase system we havesubstantially improved the process of Stetter andMeisel lo to yield the acid ( 5 ; R = Me), in 54 yield,identical with the product from the Birch reduction of3,5-dihydroxy4-met hylbenzoic acid.Bromination of the acid ( 5 ; R = Me) furnished aproduct which, in accord with the n.m.r.spectral data,is formulated as 2,6-dibromo-3,5-dihyamp;oxy4-methyl-benzoic acid, from which the halogen was removedalmost quantitatively by alkaline Raney nickel.A similar sequence of reactions with methyl 3,5-amp;0xo-cyclohexanecarboxylate gave methyl 3,5-dihydroxy-4-met hylbenzoat e.EXPERIMENTAL1,4-Dihydro-3,5-dimethoxybenzoic Acid.-Reduction of3,4,5-trimethoxybenzoic acid (24.5 g) , dissolved in ethanol(300 ml) and liquid ammonia (1 l), by addition of sodium(15 g) was complete in 0.5 h, and ammonium chloride (60 g)was then added.Next day the remaining solvent wasremoved under vacuum and the residue dissolved in ice-water (1 1) ; the solution was subjected to alternate additionof 10 hydrochloric acid (at -5 "C) and immediateextraction with dichloromethane. The yield of product issubstantially reduccd if extraction is carried out at a tem-perature exceeding ca. -5 "C. The total yield of 1,4-dihydro-3,5-dimethoxybenzoic acid, m.p. 106-107' (de-camp.) lit.,' 105" (decomp.) was 19.6 g (94) ; the productpossessed the requisite spectral properties.Methyl 3,5-Dioxocyclohexanecarboxylate.-(i) An excessof ethereal diazomethane was added, at 0 "C, to a solutionof 1,4-dihydro-3,5-dimethoxybenzoic acid (1 g) in methanol(25 ml), and 1 h later the excess of diazomethane and mostof the solvent were removed in vacuo.Hydrochloric acid(4 ; 10 ml) was added to the residue and 2.5 h later thesolid was collected and purified from aqueous methanol toyield methyl 3,5-dioxocyclohexanecarboxyZate in prisms, m.p.122' (Found: C, 56.5; H, 6.0. C8H1004 requires C, 56.5;H, 5.9), readily soluble in 2N-sodium hydrogen carbonate.(ii) An excess of diazomethane (in ether) was added to asolution of 1,4-dihydro-3,5-dimethoxybenzoic acid (1 g) inmethanol at 0 "C. Isolation of the product 15 min latergave methyl 1,4-dihydro-3,5-dimethoxybenzoate, whichformed unstable needles (0.8 g), m.p. 36" (from aqueousmethanol), 7 6.38 (6 H, s, C:C*OMe) and 6.28 (3 H, s,C0,Me). When this ester was stirred vigorously during30 min with hydrochloric acid (4; 10 ml), methyl 3,6-dioxocyclohexanecarboxylate (0.6 g) was formed, identicalwith that obtained from method (i).Treatment of this ester (0.5 g) in solution in methanol(80 ml) a t 0 "C with an excess of diazomethane gave methyl3-methoxy-6-oxocyclohex-3-enecarboxylate (0.5 g) in plates,m.p.72" (from ether) (Found: C, 68.5; H, 6.6. C,H1,O,requires C, 58.7 ; H, 6.5), insoluble in 2N-sodium hydrogencarbonate.4Methyl-3,5-dioxocyclohexanecarboxylate.-(i) A solutionof sodium hydroxide (15 ; 40 ml) was added to a solutionof 3,5-dioxocyclohexanecarboxylic acid (1 1.7 g) in water(20 ml) and dioxan (40 ml). Methyl iodide (10.7 g) wasadded to the cold, stirred solution, which was refluxed for16 h; a further addition of methyl iodide (1.1 g) was followedby refluxing for 4 h.The cold mixture was acidified with10 hydrochloric acid and maintained at 0 "C; severalcrops of yellow crystals were obtained; after separation ofeach batch, the solution was concentrated in vacuo. Purifi-cation from water gave 4methyl-3,5-dioxocyclohexanecar-boxylic acid (6.7 g ) in pale yellow prisms, m.p. 244"(decomp.) (Found: C, 55.9; H, 5.9. Calc. for C,H,,04:C, 56.5; H, 5.9) (1it.,lo m.p. 227").(ii) Reduction of 3,5-dimethoxy-4-methylbenzoic acid(1.0 g ) in liquid ammonia (50 ml) and ethanol (10 ml) byaddition of sodium (0.35 g) gave 1,4-dihydro-3,5-dimethoxy-kmethylbenzoic acid (0.4 g) in needles, m.p. 130" (fromether) (Found: C, 60.5; H, 7.1. C,,,Hl4O4 requires C,60.6; H, 7.1).Treatment of this acid (0.2 g) withhydrochloric acid (2 ; 5 ml) at 100 "C during 15 min gavea quantitative yield of 4-methyl-3,5-dioxocyclohexane-carboxylic acid, identical (t.l.c., i.r., and m.p. and mixedm.p.) with that prepared by method (i).3,5-Dihydroxy-4-methylbenzoic A cid.-(i) A suspension ofkmethyl-3,5-dioxocyclohexanecarboxylic acid ( 1.4 g) inacetic acid (40 ml) was treated (with stirring) with a solutionof bromine (3.1 g ) in acetic acid (20 ml) during 10 min.The resultant solution was stirred a t 65 "C during 1.5 h,and the solvent was removed in vucuo to yield 2,8-dibromo-3,5-dihydroxy-4-methylbenzoic acid as a yellow solid (2.8 g) .This was dissolved, without purification, in sodiumhydroxide ( 2 ~ ; 70 ml) at 0 "C, and Raney nickel alloy(2.7 g) was added in small portions. The mixture wasstirred overnight.Next day 3,5-dihydroxy-4-methyl-benzoic acid (1.1 g) was isolated, m.p. 264--265', identicalwith an authentic sample.(ii) Methylation of 4-methyl-3,5-dioxocyclohexanecarb-oxylic acid (1.1 g) in methanol at 0 "C with an excess ofethereal diazomethane gave methyl 3-methoxy-4-methyl-5-oxocyclohex-3-enecarboxylate (0.9 g) in needles, m.p. 95'(from ether) (Found: C, 60.5; H, 7.2. C,,H,,O, requiresC, 60.6; H, 7.1). When this ester (0.6 g) was stirredwith hydrochloric acid (4; 12 ml) during 15 min theproduct (0.5 g) separated from dichloromethane to yieldmethyl 4-~nethyl-3,5-dioxocyclohexanecarboxylate in squatprisms, m.p. 161-162.5' (Found: C, 58.5; H, 6.6.C,Hl,OpL. J. Durham, J. Studebaker, and M. J. Perkins, Chem.Comm., 1965, 466.lo H. Stetter and H. Meisel, Chew. Ber., 1957, 90, 2928requires C, 58.7; H, 6.5). A solution of this acid (0.28 g)in acetic acid (5 ml) was treated dropwise with bromine(0.65 g) dissolved in acetic acid (5 ml). After 2 h a t 55 "Cthe product was isolated and purified from carbon tetra-chloride to yield methyl 2,6-dibromo-3,5-dihydroxy-4-methyZ-benzoate in prisms (0.15 g), m.p. 161' (Found: C, 31.4;H, 2.6; Br, 46.1. C,H,Br204 requires C, 11.8; H, 2.4;Dr, 47.1). Treatment of this ester in 2~-sodiumhydroxide with an excess of Raney nickel during 1.5 hgave an almost quantitative conversion into 3,5-dihydroxy-4-methylbenzoic acid, identical (m.p., mixed m.p., t.l.c.,and i.r., n.m.r. , and mass spectra) with an authentic sample.3-Ethoxy-5-oxocyclohex-3-eneca~boxylic Acid.-A sus-pension of 3,5-dioxocyclohexanecarboxylic acid (0.35 g) inether (50 ml) was added to a suspension of sodamide fromsodium (1 g) in liquid ammonia (100 ml). After removalof the ammonia the resultant sodio-derivative was re-J.C.S. Perltin Ifluxed with ether (50 ml) containing ethyl iodide (20 ml)during 24 h, to yield 3-ethoxy-5-oxocycZohexanecarboxyli~acid (0.2 g) in prisms, m.p. 119" (from dioxan) (Found:C, 58.6; H, 6.4. C,H1204 requires C, 58.7; H, 6.5).Formed similarly, the 3-methoxy-derivative was identicalwith that prepared previously by an alternative process.M e t h y l 4,PDimethyl-3,5-dioxocyclohexanecarboxy~ate.-Methylation of methyl 3,5-dioxocyclohexanecarboxylate(0.2 g ) by the methyl iodide (1 g)-potassium carbonate(2 amp;-acetone (5 ml) method during 5 h gave methyl 4,4-dilstethyl-3,5-dioxocycZohexaneca~boxyEte (0.7 g) in needles,m.p. 65" (from ether) (Found: C, 60.9; H, 7.0. C,,H,,O,requires C, 60.6; H, 7.1).This work was carried out during the tenure of a TeachingFellowship (D. R. B.) a t The School of Pharmacy.5/2268 Received, 19th iVovembey, 1975