802 J.C.S. Perkin ISynthesis of Pterofuran and VignafuranBy Richard P. Duffley and Robert Stevenson,* Department of Chemistry, Brandeis University, Waltham,The naturally occurring 2-arylbenzofurans pterofuran (8) and vignafuran (1 9) have been synthesized by shortprocedures involving reactions of a copper( I) arylacetylide with an ortho-halogenophenol.Massachusetts 021 54, U.S.A.PTEROFURAN, isolated from the heartwood of Pterocarpusiladicus, has been identified as 6-hydroxy-2-(3-hydroxy-2,4dimethoxyphenyl) benzofuran (S).l Its synthesis andthat of some derivatives were subsequently achieved forCHOI1 R.(7) I (41 R = H(5) R = CU I I(8) R = H(9) R =Ac(10) R = Methe purpose of structure confirmation, but the key step ofheterocycle formation (copper-catalysed reaction of adiazoacetophenone with a resorcinol monoether) sufferedfrom a low yield (2-9yo) andlor lack of specificity indirection of ring closure.We report here a short im-proved synthesis in which the heterocycle is constructedby the reaction of a readily obtained ortho-iodophenolwith the appropriate copper(1) arylacetylide. This is anadaptation of a procedure developed by Castro3+ andrecently used in the synthesis of natural norlignans.'The required acetylene (4) was readily obtained from2,6-dimethoxyphenol (1). Acid-catalysed acylation ofthe phenol (1) gave the acetophenone (2), which by aVilsmeier reaction gave the p-aryl- p-chloroacrylaldehyde(3). Without purification, this was treated with hot1 R. G. Cooke and I. D.Rae, Austral. J . Chem., 1964, 17, 379.9 R. G. Cooke and R. M. McQuilkin, Austral. J . Chem., 1969,C . E. Castro and R. D. Stephens, J . Org. Chem., 1963, 28,* R. D. Stephens and C. E. Castro, J . Org. Chem., 1963, 28,6 C. E. Castro, E. J. Gaughan, and D. C. Owsley, J . Org. Chem.,23,2396.2163.3313.1966, 81, 4071.aqueous base to induce deformylation and dehydrochlor-ination,8 and then reacetylated to give the acetylene (4)from which the copper(1) salt (5) was prepared by treat-ment with copper sulphate and hydroxylamine hydro-chloride in arqmonium hydroxide.6-Iodoresorcinol 3-benzoate (7) was readily obtainedby the action of iodine monochloride on resorcinolbenzoate (6). Coupling of compounds (5) and (7) waseffected by heating in pyridine, and basic hydrolysis ofthe product gave pterofuran (8) in 78% yield, character-ized as the diacetate (9) and the dimethyl ether (10).A recent investigation @ of the phytoalexins of cowpea,Vigna unguiculata (L.) Walp., infected with Colletotri-chum lilzdemuthialaum, revealed the presence of an anti-fungal arylbenzofuran, named vignafuran and identifiedas 2-(4-hydroxy-2-methoxyphenyl)-6-methoxybenzo-furan (19).It was synthesized in minute yield amonga mixture of isomers by a Hoesch reaction. We nowreport a synthesis by the same general halogenophenol-arylacetylide coupling reaction as above.The acetylene (14) was obtained from resacetophenone(11) by successive benzylation to give the 4-benzyl ether(12) and methylation to afford the 4-benzyl-%methyl(11) R' = R ~ = H(12) R' =CH2Ph.R2=H (14) R = H(13) R' =CH2Ph,R2=Me (15) R = Cu(16) (17) (18) R =CH,Ph(19) R = Hether (13), followed by conversion of the methyl ketoneinto the ethyne function by the Bodendorf procedure.8The known 2-bromo-5-methoxyphenol (17) lo was ob-tained by treatment of resorcinol methyl ether (16) at-20 "C with dioxan dibromide.Coupling of thecopper(1) acetylide (15) with (17) gave, in 34% yield,(I C. E. Castro, R. Havlin, V. K. Honwad, A. Malte, and S .MojB, J . Amer. Chem. SOC., 1969, 91. 6464.F. G. Schreiber and R. Stevenson, J.C.S. Perkin I, 1976,1514.K. Bodendorf and R. Mayer, Chem. Ber., 1965, 98, 3554.N. W. Preston, K. Chamberlain, and R. A. Skip, Phyto-chemistry, 1975, 14, 1843.lo G.P. Rice, J . Amer. ChPm. SOC., 1926, 48, 31251977 803vignafuran benzyl ether (18) , which on hydrogenolyticdebenzylation gave vignafuran (19), with n.m.r. and U.V.spectra in excellent agreement with those reported.EXPERIMENTALN.m.r. spectra were determined for solutions in [,HI-chloroform (unless otherwise stated) with tetramethylsilaneas internal standard.3-Acetyl-2,6-dimethoxy~henyl Acetate (2) .-Prepared from2,6-dimethoxyphenol as described,ll the ketone (2) had m.p.108-109" (lit., 110"); 6 2.33 (s, OAc), 2.58 (s, CO-CH,),3.87 (s, 2- and 6-OMe), 6.77 (d, J 9 Hz, H-5), and 7.68 (d, J 93-Ethynyl-2,6-dimethoxy#henyZ Acetate (4) .-(i) A solutionof the ketone (2) (10 g) in dimethylformamide (5 ml),cooled to 0 "C, was added with stirring t o the Vilsmeierreagent [from phosphoryl chloride (10 g) and dimethyl-formamide (10 ml)].The mixture was then heated at 60 "Cfor 4 h, kept at room temperature overnight, then pouredinto saturated sodium acetate solution and stirred for 1 h.The mixture was extracted with ether (3 x 75 ml) and theextract washed with water, dried, and evaporated to leave3-( l-chloro-2-formylvinyl)-2,6-dimethoxyphenyl acetate (3)as a dark oil, 6 2.35 (s, OAc), 3.98 (s, OMe), 4.05 (s, OMe),H-4), and 10.28 (d, J 7 Hz, CHO).(ii) A solution of the aldehyde (3) in dioxan (ca. 50 ml) wasadded dropwise to a boiling solution of sodium hydroxide( 5 g) in water (100 ml). The mixture was heated underreflux for 1 h, then cooled, diluted with water (100 ml),acidified with acetic acid, and extracted with ether (3 x 75ml).The extract was washed with sodium hydrogencarbonate solution and water, dried, and evaporated togive crude 3-ethynyl-2,6-dimethoxyphenol as a dark oil,6 3.25 (s, E C H ) , 3.78 (s, OMe), 3.97 (s, OMe), 6.00br (s, OH),6.53 (d, J 9 Hz, H-5), and 6.95 (d, J 9 Hz, H-4).(iii) The phenolic acetylene was heated on a steam-bathfor 1 h with pyridine-acetic anhydride (3 : 1) and the pro-duct worked up with ether. The resulting orange oil (4)showed 6 2.45 (s, OAc), 3.30 (s, C-CH), 3..73 (s, OMe), 3.87(s, OMe), 6.62 (d, J 9 Hz, H-5), and 7.20 (d, J 9 Hz, H-4).Cofiper(1) 3-Acetoxy-2,4-dimethoxyphenylacetylide (5) .-Hydroxylamine hydrochloride (900 mg) was added inbatches to a stirred solution of copper sulphate pentahydrate(1.6 g) in concentrated ammonium hydroxide (7 ml) andwater (25 ml) under nitrogen.The solution was cooled inan ice-bath for 15 min, then a solution of the acetylene (4)(1.39 g) in ethanol (50 ml) was added with stirring while ayellow precipitate developed. The solution was furtherdiluted with water (250 ml), and the product (5) filtered off,washed with water ( 5 x 20 ml), ethanol, and ether, andvacuum-dried (yield 1.20 g).6-Iodoresorcinol 3-Benzoate (7) .-Prepared as described l2from resorcinol benzoate l3 (6) by treatment with iodinemonochloride in acetic acid, this had m.p. 154-155" (1it.,l26- Hydroxy- 2- (3-hydro~y-2~4-dimethoxyphenyl) benzo furan(Pterofuran) (&?).-A mixture of the salt (5) (2.51 g) and theiodophenol (7) (3.04 g) in pyridine (50 ml) was heated underreflux (nitrogen atmosphere) for 23 h, then cooled, andstirred with concentrated ammonium hydroxide solution11 K. Brand and H.Collischonn, J . prakt. Chem., 1922, 103,329.l2 B. H. Nicolet and J. R. Samper, J . Amar. Chem. Soc., 1927,40, 1796.Hz, H-4).6.75 (d, J 7 Hz, GCH), 6.82 (d, J 9 Hz, H-5), 7.59 (d, J 9 Hz,153-1 55").(50 ml). It was then extracted with ether (3 x 100 ml) andthe extract washed successively with water, 10% potassiumcarbonate solution, water, and 10% hydrochloric acid,dried, and evaporated to leave a brown syrup. This washeated on a steam-bath for 1 h with potassium hydroxide(3 g) in water (100 ml). The mixture was poured onto icecontaining concentrated hydrochloric acid (20 ml) andworked up with ether to give an oil which crystallized frombenzene-ethanol yielding pterofuran (8) as fine needles(1.99 g), map.206" (lit.,l 208-208.5"), with U.V. absorptionin agreement with that reported; 6 [(CD,),SO] 3.87 (s, OMe),3.92 (s, OMe), 6.40 (s, OH), 6.83 (dd, J 2.5 and 8.5 Hz, H-5),7.01 (d, 8.5 Hz, H-4), 7.22 (s, H-3), 7.41 (d, J 9 Hz, H-5' or-6'), and 7.47 (d, J 9 Hz, H-6' or -5'). The diacetate,prepared with pyridine-acetic anhydride, had m.p. 135-135.5" (lit. ,1 135.5-136.5"), with concordant U.V. spectrum;6 2.32 (s, OAc), 2.38 (s, OAc), 3.87 (s, 2'- and 4'-OMe), 6.83(d, J 9 Hz, H-57, 6.98 (dd, J 8.5 and 2.5 Hz, H-5), 7.20(s, H-3), 7.30 (d, J 2.5 Hz, H-7), 7.56 (d, J 8.5 Hz, H-4), and7.83 (d, J 9 Hz, H-6').The dimethyl ether (10) , preparedwith dimethyl sulphate, showed 6 3.85, 3.88, 3.93, and 3.97(s, 4 OMe), 6.76 (d, J 9 Hz, H-5'), 6.85 (dd, J 8.5 and 2.58.5 Hz, H-4), and 7.66 (d, J 9 Hz, H-6').4-Benzyloxy-2-hydroxyphenyl Methyl Ketone ( 12) .-Pre-pared from resacetophenone (1 1) as described,14 the ketone(12) had m.p. 102-103" (lit.,14 103"; lit.,lS ill"), 8 [CDCI,-(CD,),CO] 2.50 (s, COCH,), 5.05 (s, PhCH,), 6.49 (dd, J 9and 2.5 Hz, H-5), 6.50 (d, J 2.5 Hz, H-3), 7.40 (s, Ph), 7.63(d, J 9 Hz, H-6), and 12.78 (s, OH).4-Benzyloxy-2-methoxyphenyl Methyl Ketone ( 13) ,-Amixture of the ketone (12) (15.5 g), anhydrous potassiumcarbonate (13.8 g), and methyl iodide (14.1 g) was stirred a troom temperature for 72 h in dimethyl sulphoxide (100 ml),then poured into saturated brine and extracted with ether.Evaporation of the washed and dried extract gave a syrupwhich was extracted with light petroleum (b.p.40-60 "C).Concentration of the extract gave the methyl ether (13) aspale yellow plates (9.70 g), m.p. 64-65" (Found: C, 74.9;H, 6.25. C1,H1,03 requires C, 75.0; H, 6.3%); 8 2.56 (s,COCH,), 3.84 (s, OCH,), 5.08 (s, PhCH,), 6.52 (d, J 2.5 Hz,H-3), 6.60 (dd, J 9 and 2.5 Hz, H-5), 7.40 (s, Ph), and 7.834-BenzyZoxy-2-methoxyphenylacetylene ( 14) .-(i) A solutionof the ketone (13) (3.60 g) in dimethylformamide (10 ml) wasadded dropwise to the reagent prepared by addition ofphosphoryl chloride (4 g) with stirring to dimethylformamide(4 ml) a t 0 "C.The mixture was heated a t 60 "C for 4 h,left at room temperature overnight, then poured into coldconcentrated sodium acetate solution (200 ml) and stirredfor 30 min. The precipitated orange oil was extracted withmethylene chloride, and the washed and dried extractevaporated to give crude 3-(4-benzyloxy-2-methoxyphenyl)-3-chloroprop-2-enal as a red-brown oil, 6 3.73 (s, OMe), 5.05(s, PhCH,), 6.55 (d, J 2.5 Hz, H-3'), 6.58 (dd, J 9 and 2.5Hz, H-6'), and 10.24 (d, J 7 Hz, CHO).(ii) The crude aldehyde was dissolved in dioxan (30 ml)and added dropwise to a hot solution of sodium hydroxide(15 g) in water (100 ml). The mixture was heated underHz, H-5), 7.07 (d, J 2.5 Hz, H-7), 7.17 (s, H-3), 7.46 (d, J(d, J 9 Hz, H-6).Hz, H-5'), 6.86 (d, J 7 Hz, C=CH), 7.40 (s, Ph), 7.66 (d, J 9l3 H.Kaufman and W. Kugel, Ber., 1911, 44, 753.l4 N. Adityachaudhury, C. L. Kirtaniya, and B. Mukherji,K. C. Gulati, S. R. Seth, and K. Venkataraman, J . Chem.Tetrahedron, 197 1, 27, 2 1 1 1.SOL, 1934. 1765J.C.S. Perkin Ireflux for 1 h, concentrated to half bulk, diluted with water(100 ml), and extracted with ether. The washed and driedextract was evaporated to give a residual oil which was dis-solved in benzene and filtered through a short column ofsilica gel. This gave the acetylene (14) as an oil (446 mg,16%), 6 3.20 (s, C-CH), 3.77 (s, OMe), 4.98 (s, PhCH,),6.44 (dd, J 9 and 2.5 Hz, H-5'), 6.47 (d, J 2.5 Hz, H-3'),7.34 (s, Ph), and 7.34 (d, J 9 Hz, H-6').Copper ( I) 4-Benzyloxy-2-methoxyphenylacetylide ( 15) .-This was prepared as for (5) as a yellow solid in 88% yield.2-Bromo-5-methoxy$henol (1 7) .-This was prepared by aprocedure l6 introduced for one-step monobromination ofresorcinol ethers.To a solution of m-methoxyphenol l 7(1 6) (5 g) in ether (100 ml) a t - 20 "C was added with stirringdioxan dibromide (10 g) in ether (25 ml). The mixture wasallowed to warm to room temperature, washed with water,and aqueous sodium hydrogen carbonate, dried, and evapor-ated. The residue was distilled through a Vigreux columnto yield the bromophenol in 83% yield as an oil, b.p. 104-105" at 3 cmHg (1it.,lo 152" a t 25 cmHg), 6 3.73 (s, OMe),3.54br ( s , OH), 6.39 (dd, J 8 and 2.5 Hz, H-2), 6.63 (d, J 2.5Hz, H-4), and 7.30 (d, J 8 Hz, H-3).Vignafuran Benzyl Ether (18) .-A mixture of the salt(15) (504 mg) and the bromophenol(l7) (340 mg) in pyridine(25 ml) was heated under reflux (nitrogen atomosphere) for24 h.The product was worked up as for pterofuran (8).Crystallization from ethanol gave 2-(4-benzyloxy-2-meth-18 D. C. Schlegel, C. D. Tipton, and K. L. Rinehart, J . Org.Chem., 1970, 35, 849.oxyphenyl)-6-methoxybenzofuran (18) (204 mg, 34%), m.p.1 1 1-1 16" (Found : M+, 360.136 59. C,,H,,O, requiresM , 360.136 16); 6 3.83 (s, OMe), 3.91 (s, OMe), 5.10 (s,PhCH,), 6.6-7.1 (m, 4 aryl H and H-3), 7.38 (s, Ph and 1aryl H), and 7.95 (d, J 9 Hz, H-6').Vignafuran (19).-A solution of the benzyl ether (18)(149 mg) in acetic acid (50 ml) was stirred with palladium-charcoal (10%; 50 mg) under hydrogen for 30 min (rapiduptake ceased). It was then filtered, diluted with water,and extracted with ether (3 x 50 ml). The extract waswashed with saturated hydrogen carbonate solution andthen 10% sodium hydroxide (3 x 25 ml). The latter wash-ings were acidified and re-extracted with ether, and thewashed and dried extract was evaporated. The residual oilwas chromatographed on a silica gel plate [developed bychloroform-ethanol (97 : 3)], and the major zone was elutedwith acetone t o give vignafuran (19) as a clear oil (38 mg,40y0), 6 3.84 (s, OMe), 3.90 (s, OMe), 6.53 (m, H-3' and -57,6.85 (dd, J 9 and 2 Hz, H-5), 7.05 (m, H-3 and -7), 7.43 (d,E 4.50), 224sh (4.16), 245sh (4.02), 283 (4.32), 308sh (4.47).320 (4.59), and 336 nm (4.57).J 9 Hz, H-4), 7.85 (d, J 9 Hz, H-6') ; A,,,. (EtOH) 210 (logA grant from the National Institutes of Health (GeneralMedical Sciences) is gratefully acknowledged.[6/1758 Received, 17th September, 1978117 W. H. Perkin, J. N. Ray, and R. Robinson, J."Chem. SOC.,1926, 941.0 Copyright 1977 by The Chemical Societ