Fluorination of benzofuran and ofN-acylindoles with trifluorofluorooxymethane

摘要

2604 J.C.S. Perkin IFluorination of Benzofuran and of N-Acylindoles with Trifluorofluoro-oxymethaneBy Derek H. R. Barton, Robert H. Hesse," Graham P. Jackman, and M. M. Pechet, Research Institute forMedicine and Chemistry, Cambridge, Massachusetts 021 42, U S A .The reactions of certain heteroaromatic substrates with trifluorofluoro-oxymethane gave CF30( F) and F (F) adducts.Subsequent reactions with base regenerated the heteroaromatic system substituted by fluoro or trifluoromethoxy.Under these conditions methyl 1 -acetylindol-3-ylacetate gave 1 -acetyl-2- hydroxy-3-methoxycarbonylmethylene-indoline.REACTION of trifluorofluoro-oxymethane with olefinsgives the expected electrophilic addition product butwith cis-stereochemistry.l Heteroaromatic substratesshould permit further study of regio- and stereo-selectivity.The reactions of benzofuran (la) and ofsubstituted indoles with trifluorofluoro-oxymethane aredescribed here.Benzofuran (la) gave three products with trifluoro-fluoro-oxymethane at -78 "C. Two were CF,O(F)(JH,H 0, J H , F 60 and 15, JF,Ca-,O 0 Hz), which was lesspolar than the major product, the cis-isomer (3a) (JIIBH 4,JH,F 62 and 17, Jp,CF,O 3.5 Hz). The third compoundwas the difluoro-adduct (3b), for which satisfactorymicroanalytical data were not obtained.The corresponding reaction of benzofuran (la) inmethanol gave, in addition to the adducts (2a) (&&yo),(3a) (2y0), and (3b) (9%), 2-fluoro-3-methoxy-2,3-dihydrobenzofuran (2b). The configuration assigneda; X = 0, R1 = R2 = Hb; X = 0, R1 = H, R2 =OCF,C; X = 0, R1 = H, R2 = Fd; X = 0, R1 = H, RZ = W ee; X = NH, R1 =R2 = Hg; X = NH, R1 = HI R2 = OCF3i ; X = NCHO, R1=Me, R 2 = Hf ; X = NAc, R1 = R2 = Hh; X = NH, R1 =HI R2 = Fj ; X = NCHO, R1 = Me, Rz = OCF3k; X = NH, R1 = Me, R2 = OCF3I ; X = NH, R1 = Me, R2 = Fmi X = NH, R1 = H, R2 = CH2=C02Hn; X = NH, R1 = H, R2 = CH2*C02Me0; X = NAc, R1 = H, R2 = CH2X02Me9; x = NAc, R1 = H, R2 = COoC02Mer ; X = NAc, R1 = H, R* = CH(OHbC02Mep; X = NH, R1 = H, R2 '= CO-COZMe(2) a; X = 0, R1 = H, Rz = OCF3a; X = 0, R1 = H, RZ = OCF3b; X = 0, RI = H, R2 = OMec i X = NAc, R1 = H, R2 = OCF3b; X = 0, R1 = H, R2 = FC; X = NAc, R1 = H, Rz = OCF3d; X = NAc, R1 = H, R2 Fadducts.Their constitution as 2-fluoro-3-trifluoro- to (2b) was based on coupling constants (see Experi-methoxy-derivatives followed from the n.m.r.spectra,showing a low-field signal in each case for the proton Both trans- (2a) and cis- (3a) 2-fluoro-3-trifluoro-geminal to fluorine. Analysis of coupling constants methoxy-2,3-dihydrobenzofuran gave 3-trifluorometh-suggested the identification of the trans-isomer (2a) oxybenzofuran (1 b) on reaction with ethanolic potassiummental section).D. H. R. Barton, L. J. Danks, A. K. Ganguly, R. H. Hesse, M. P. Mertes, L. J . Powers, and E. Shelter, J . Urg. Chew.,G. Tarzia, and M. M. Pechet, J.C.S. Perkin I , 1976, 101. 1971, 86, 18051977hydroxide. That the n.m.r. spectrum of the productexhibited a singlet at 8 7.5 (2-H) supported the regio-specificity of the formation of the adducts (2a) and (3a).The presumed difluoride (3b) also reacted with ethanolicpotassium hydroxide to give 3-fluorobenzofuran (lc).The trans-fluoro-methoxy-adduct (2b) with ethanolicpotassium hydroxide gave 3-methoxybenzofuran (Id).The reaction of indole (le) and some derivatives withtrifluorofluoro-oxymethane was also investigated.In-dole (le) and CF,OF gave only complex mixtures.However, on protection of the nitrogen atom, as in 1-acetylindole (If), a clean reaction with CF,OF wasobserved. The three products, separated by chromato-graphy, were identified as trans-l-acetyl-2-fluoro-3-trifluoromethoxy-2,3-dihydroindole (2c), the cis-isomer(3c), and l-acetyl-2,3-difluoro-2,3-dihydroindole (3d).The structures were fully consistent with spectral data.Again the constitution and relative configurationsfollowed from the n.m.r.spectra. The difluoride (3d)was probably of cis-stereochemistry. Reaction of theadducts with ethanolic potassium hydroxide gave 3-trifluoromethoxyindole (lg) and 3-fluoroindole (lh), thusconfirming the assigned constitutions.Fluorinat ion of crystalline 2-met hylindole- 1 -carbalde-hyde (li) with CF,OF gave an unstable product.Spectral data showed that this contained the trifluoro-methoxy-derivative (1 j). When the indole (li) wastreated with CF,OF and subsequently with sodiumhydroxide in methanol a mixture of 2-methyl-3-trifluoro-methoxyindole (1 k) and 3-fluoro-2-methylindole (11) wasobtained.The two compounds were separated byfractional crystallisation.The reaction of benzofuran (la) and of the varioussubstituted indoles with CF,OF must proceed by electro-philic fluorination at C-2 followed by nucleophiliccapture of the C-3 cation. There is some analogy forthis., I t is of interest that in the reactions of bothbenzofuran and N-acetylindole with CF,OF the pre-ponderant product (in total ratio 4 : 1) is the cis-isomer. This agrees with our earlier findings1 Incontrast, in the reaction of benzofuran when the nucleo-phile (MeO-) arises externally from the medium the onlyproduct detected is the trans-isomer (2b).Since reactions of both l-acetylindole (If) and 1-acetyl-2-methylindole (li) with CF,OF followed bytreatment with base gave the 3-fluoro- and 3-trifluoro-methoxy-derivatives, it was of interest to examine thereaction of a 3-alkylindole. Indol-3-ylacetic acid ( lm),an auxin, was chosen for study since substitution mightprovide biologically interesting derivatives.Reactionof methyl 1-acetylindol-3-ylacetate (lo) with CF,OFgave a mixture of two CF,O(F) adducts. The n.m.r.spectra suggested formulation as the diastereoisomericadducts (4). Clearly the fluoro- substituent was at theJ. C. Powers, ' The Chemistry of Heterocyclic Compounds,(Indoles Part II),' Wiley-Interscience, New York, 1972, p. 131.W. Reeve, R. S. Hudson, and C. W. Woods, Tetrahedron,1963, 19, 1243.R. Breslow, R. J. Corcoran, B. B. Snider, R. J . Doll, P. L.Khanna, and R. Kaleya, J .Amer. Chem. SOL, 1977, 99, 905.2-position (8, 6.5, J 60 Hz). Since the products wereunstable they were treated with base. Sodium hydrogencarbonate or methoxide in methanol, and 1,4-diaza-bicyclo[2.2.2]octane in dioxan or pyridine, gave mostlymixtures of polar products. 1,4-Diazabicyclo[2.2.2]-octane in THF gave a single major product. Analysisand mass spectral data indicated the compositionC,,H,,NO,. The ester and N-acetyl functions wereretained intact. In addition the n.m.r. spectrum of thecompound contained a proton signal coupled to both ahydroxy and a vinylic proton signal. Clearly the pro-duct was l-acetyl-2-hydroxy-3-methoxycarbonyl-methyleneindoline ( 5 ) , although the stereochemistrycould not be assigned. The U.V. spectrum suggestedthat the alternative methyl l-acetylindol-3-ylglycolate(lr) was not formed.This was confirmed by synthesis ofcompound (lr) as follows.Oxalylation and subsequent methaiiolysis of indole (le)gave methyl indol-3-ylglyoxylate (1 p) . N-Acetylationand subsequent reduction with aluminium amalgamgave the known but poorly characterised glycolatederivative (lr), clearly different from the fluorinationproduct (5).The methyleneindoliiie derivative (5) was inert tomanganese dioxide, neutral permanganate, or Sarrettreagent at room temperature. Reaction with Jonesreagent or dimethyl sulphoxide-acetic anhydride-pyridine gave, interestingly, the glyoxylate derivative(lq). In addition, on refluxing in aqueous acetic acidthe methyleneindoline derivative (5) gave the glycolatederivative (lr), identical with synthetic material.Mechanisms for the preparation and subsequent reactionsof the methyleneindoline derivative (5) are summarisedin the Scheme.In a recent publication on template functionalisationof steroids, Breslow has commented on our demon-stration of selective functionalisation of steroids andother compounds at tertiary positions using fluorineand suggested that these reactions are radical reactionsand not electrophilic replacements as we have advocated.Although most of the data can be interpreted in eitherway, the fact that steroids are substituted at C-14 withretention of configuration (14a) makes us disfavour thesuggestion of a radical intermediate.A radical at C-14would at once provide the mechanistic opportunity forthe formation of the more stable 14p-configuration,which we do not detect.Our interpretation of electro-philic replacement of hydrogen at a tertiary centre hasanalogy in oxyfun~tionalisation,~ a process which isviewed in similar mechanistic terms.A recent important publication 8 on radical fluorin-ation by photolysis of CF,OF also requires some modifi-cation. It is stated that ' Electrophilic fluorination of* D. H. R. Barton, R. H. Hesse, R. F. Markwell, RI. M. Pechet,and S. Rosen, J . Amer. Chem. SOC., 1976, 98, 3036.N. C . Deno, personal communication; G. A. Olah, N.Yoneda, and D. G. Parker, J . Amer. Chem. SOL, 1977, 99, 483,and references there cited; N. C. Den0 and L. A. Messer, J.C.S.Chem.Comm., 1976, 1051.J. Kollonitsch and L. Barash, J . Amer. Chem. SOC., 1976, 98,55912606 J.C.S. Perkin Iolefins as well as of activated aromatics by Cli,OF wasfirst described by Cady and Porter.' This statement isuntrue. Cady and Porter made an important contri-bution to CF,OF chemistry but all their reactions wereACAc AcH'( 5 ) -/Qc$ -6 oxidiseI ISCHEMEradical in character and involved deactivated (fluorin-ated) olefins. The first reference to the concept ofelectrophilic fluorination by fluoro-oxy-compounds isfrom this Institute.l*EXPERIMENTALM.p.s were determined with a Kofler hot-stage apparatus.1.r. spectra were recorded for potassium bromide discs(solids) or liquid films. U.V. and n.m.r. spectra wererecorded for solutions in methanol or deuteriochloroform(tetramethylsilane reference), respectively.Compoundsfrom chromatography are listed in order of increasingpolarity. Freon refers to trichlorofluoromethane.Reaction of Benzofuran (la) with Tri,fEuoro,fEuoro-oxy-R. S. Porter and G. H. Cady, J . Amer. Chem. SOC., 1957, 79,lo D. H. R. Barton, L. S. Godinho, R. H. Hesse, and M. M.5625, 5628.Pechet, Chem. Comm., 1968, 804.methane.-(a) In Freon. Gaseous CF,OF (600 ml) wasadded a t 10 ml min-l to benzofuran (la) (2.16 g) in Freon(500 ml) a t - 78 "C. The solution was purged with nitrogenand added to aqueous sodium hydrogen carbonate. Theorganic phase was washed with water, dried, and evaporated,and the residue was chromatographed on silica (400 g) togive (monitoring by g -1.c. ) trans-2-jluoro- 3-triJuoromethoxy -2,3-dihydrobenzofuran (2a) (590 mg, 15%) as an oil, vmax.1250 cm-l, A,,, 271sh ( E 1600), 276 (2 000), and 282 nm( 1 700), 6 7.4 (4 H, m, aryl H), 6.2 (1 H, d, J 60 Hz, 2-H),and 5.57 (1 H, d, J 15 Hz, 3-H), $* (p.p.m. upfield frominternal CFCI, 6, + 59 (3 F, OCF,) and + 138 (1 F, dd,J 60 and 15 Hz, 2-F) (Found: C, 48.8; H, 2.9; F, 34.15.C,H,F,02 requires C, 48.65; H, 2.7; F, 34.2%); cis-2-fluoro-3-tri,fEuoromethoxy-2,3-dihydrobenzofuran (3a) (1.74g, 43%) as an oil, v,. 1 250 cm-l, A,,, 269sh ( E 1 500),275 (2 loo), and 280 nm (1 800), 6 7.0 (4 H, m, aryl H)and 6.5-5.1 (2 H, ABX, J A ~ 4, 62, and 17 Hz), $* + 60(3 F, d, J 3.5 Hz) and + 140 ( 1 F, ddq, J 62, 17, and3.5 Hz) (Found: C, 48.8; H, 2.85; F, 34.05%); andcis-2,3-difluoro-2,3-dihydrobenzofuran (3b) (0.54 g, 19%) asan oil, v,,,,.1 040 cm-l, A,,, 276 (E 2 000) and 281 nm (1 900),6 7.2 (4 H, m, aryl H) and 6.8-5.3 (2 H, m, 2- and 3-H),$* + 145 (1 F, m) and + 198 (1 F, m), rn/e 156 ( M f ) .Reaction of benzofuran ( l a ) (2 ml) andCF,OF (600 ml gas) in methanol (200 ml) at -78 "C gaveon chromatography on Florisil (eluant hexane) trans-2-jluoro-3-methoxy-2,3-dihydrobenzofuran (2b) (0.60 g, 40%) asan oil, v,. 1 000 cm-l, lux. 268sh ( E 1 800), 275 (2 400), and282 nm (2 ZOO), 6 7.2 (4 H, m, aryl H), 6.15 ( 1 H, d, J 60Hz, 2-H), 4.8 ( 1 H, d, J 15 Hz, 3-H), and 3.5 (3 H, s, OMe),$* + 127 (dd, J 60 and 15 Hz) (Found: C, 64.5; H, 5.25;F, 11.15.C,H,FO, requires C, 64.3; H, 5.4; H, 11.3%).Reaction of the cis-Adduct (3a) with Base.-cis-2-Fluoro-3-trifluoromethoxy-2,3-dihydrobenzofuran (3a) (600 mg) wasadded to ethanolic 10% potassium hydroxide (10 ml) andthe mixture was heated to reflux for 24 h. The solutionwas partitioned between water and chloroform (3 x 10 ml)and the organic extract dried, evaporated, and distilled togive 3-trifluorornethoxybenzofuran ( lb) (300 mg, 55y0),b.p. 92" a t 70 mmHg, v,. 1 250 cm-l, A,,, 244 (E 9 200),275 (2 200), and 282 nm (2 400), 6 7.3 (4 H, m, aryl H) and7.6 (1 H, s, 2-H), #* + 61 ( s ) (Found: C, 53.5; H, 2.35; F,28.15. C,H,F,O, requires C, 53.5; H, 2.5; F, 28.2%).Reaction of the trans-adduct (2a) and base also gave 3-trifluoromethoxybenzofuran ( lb) .Reaction of the Difluoride (3b) with Base.-Similar reactionof the difluoride (3b) (300 mg) and ethanolic potassiumhydroxide gave 3-fluorobenzofuran (lc) (160 mg, 61 yo) as anoil, b.p.50" a t 0.5 mmHg, A,,,. 246 ( E 9 400), 276 (2 600)'and 280 nm (2 200), 6 7.4 (1 H, d, J 4.5 Hz, 2-H) and 7.5-7.0 (4 H, m, aryl H), $* + 177 (dd, J 4.5 and 1.5 Hz).Reaction of trans-2-Fluoro-3-rnethoxy-2,3-dihydrobenzofuran(2b) with Base.-Reaction of the adduct (2b) (200 mg) andethanolic 10% potassium hydroxide overnight at roomtemperature gave 3-methoxybenzofuran (Id) (105 mg,60%) as an oil, b.p. 80" a t 20 mmHg, A,,, 245 ( E 9 500),275 (2 200), and 281 nm (2 loo), 6 7.1 (1 H, s, 2-H), 7.6-7.0(4 H, m, aryl H), and 3.9 (3 H, s, OMe) (Found: C, 72.75;H, 5.25.Calc. for C,H,O,: C, 72.95; H, 5.45%).Fluorination of l-A cetylindole (If) .-Reaction of 1-acetylindole (If) 11 (2.0 g) and CF,OF (400 ml gas) in Freon11 I. M. Heilbron and H. M. Bunbury, ' Dictionary of OrganicCompounds,' vol. 111, Eyre and Spottiswood London, 1965, p,1846.(b) I n methanol197'7 2607(300 ml) at -78 "C gave on work-up and chromatographyon Florisil (eluant hexane-benzene, 1 : 1) trans- l-acetyl-2-fluoro-3-trzfluoromethoxy-2,3-dihydroindole (2c) (340 nig,10%) as an oil, vmx. 1 700 and 1300-1 160 cm-l, Am,. 237(e 14 000), 272 (1 080), 280 (1 250), and 287 nm (1 180),6 8.4 and 7 2 (4 H, 2 m, C,H,), 6.4 (1 H, d, J 60 Hz, 2-H),5.6 (1 H, d, J 16 Hz, 3-H), and 2.4 (3 H, s, NCOMe),+* + 59 (3 F, s, 3-OCF3) and + 139 br (1 F, d, J 70 Hz)(Found: C, 50.2; H, 3.1; F, 28.95; N, 5.3.C,,H,F,NO,requires C, 50.2; H, 3.45; F, 28.9; N, 5.3%); a mixtureof trans- (2c) and cis-adducts (3c) (0.83 g, 25%); cis-l-acetyl-2-fluoro-3-tr~fluo~omethoxy-2,3-dihydroindole (3c) ( 1.3g, 39%), m p . 70-71", vmsx. 1700 and 1300-1 150 cm-l,A,,, 240 (E 13 900), 276 (1 310), and 284 nm (1 130), 6 8.3and 7.1 (4 H , s m, C,H,), 6.8-5.3 (2 H, AB of ABX, ./AB5 Hz, 2- and 3-H), and 2.3 (3 H, s, NCOMe), $* + 61 (3 F,d, J 3 Hz, 3-OCF3) and + 154br (1 F, d, J 70 Hz, 2-F)(Found: C, 50.3; H, 3.35; F, 29.05; N, 5.2%); a mixtureof adducts (3c) and (3d) (0.20 g); and then l-acetyl-2,3-dijluoro-2,3-dzhydroindole (3d) (0.32 g, 13y0), m.p. 78-79',vmax. 1 700 cm I , A,. 240 (E 14 loo), 278 (1 340), and 285 nm( 1 190), 6 8 4 and 7.1 (4 H, 2 m, C,H,), 6.9-5.4 (2 H, m,2- and 3-H), and 2.4 (3 H, s, NCOMe), $* +158br (1 F , d,J 70 Hz) and + 203br (1 F, d, J 70 Hz) (Found: C, 60.75;H, 4.9; F, 18.9; N, 7.25.C,,H,F,NOrequiresC, 60.9; H,4.6; F, 19 25; N, 7.1%).Reaction of the cis-Adduct (3c) and Base.-Reaction of thecis-adduct (3c) (50 g) and potassium hydroxide (100 mg) inethanol ( 5 ml) for 1 h a t room temperature, work-up, andchromatography on silica (eluant benzene) gave 3-tViflUOrO-methoxyindole (lg) (30 mg, 65y0), m.p. 49-50' (fromhexane), urn,,. 3 450 and 1 250 cm-l, Amax, 266sh ( E 5 480) 270( 5 720), 277 ( 5 620), and 280sh nm ( 5 400), 8 7.8-6.9 ( 5 H,m, 1 H exch D,O) and 7.3 ( 1 H, s, 2-H), $* + 61 (s) (Found:C, 53.6; H, 3.05; F, 28.5; N, 7.05.C,H,F,NO requiresC, 53.75; H, 3.0, F, 28.35; N, 6.95%). Reaction of thetrans-adduct (2c) with ethanolic potassium hydroxide(complete in 5 min) gave 3-trifluoromethoxyindole ( lg) .Reaction of the Difluoride (3d) with Base.-The difluoride(3d) (25 mg) and ethanolic potassium hydroxide (1 h a t roomtemperature) gave, on work-up, 3-fluoroindole (lh) (25 mg,loo%), m p. room temp., v,,, 3 500 cm-l, A,. 274 (e 5 750),280 ( 5 960), 284sh ( 5 600), and 290 nm (4 680), 6 7.9-6.9(5 H, m, 1 H exch D,O), and 7.3br (1 H, s, 2-H), $* + 175br(s, W, 6Hz) (Found: C, 70.9; H, 4.35; F, 14.05; N, 10.35.C,H,FN requires C, 71.1; H, 4.5; F, 14.05; N, 10.35%).Fluorination of 2-Methylindole- l-carbaldehyde ( li) .--CF,-OF (450 ml gas) was added to 2-methylindole-l-carbalde-hyde ( l i ) l2 (2.5 g) in Freon (250 ml) and chloroform ( 5 ml)a t - 78 "C.Excess of CF,OF was removed by purging withnitrogen and sodium hydroxide (10 g) in methanol (200 ml)was added. After 1 h a t -78 "C benzene (300 ml) wasadded and the solution washed with water (3 x 200 ml),dried, evaporated, and chromatographed on Florisil(eluant benzene-hexane 2 : 1) to give 3-fluoro-2-methylindole(11) (0.25 g, 11 %) as pale yellow plates, m.p. 89-90" (fromhexane), vmax. 3 500 cm-l, A,,,. 224 (e 29 loo), 275 (6 400),281 (6 500), and 290 nm ( 5 300), 6 7.6-6.9 ( 5 H, m) and 2.3(3 H, d, J 2 Hz), $* + 180br (s, W, 7 Hz) (Found: C,72.6; H, 5 5 5 ; F, 12.6; N, 9.4. C,H,FNrequiresC, 72.45;H, 5.4; F, 12.75; N, 9.4%).Repeated crystallisation ofmaterial from the mother liquors from hexane and re-chromatography on Florisil (eluant hexane) gave 2-methyl-3-trifluoromethoxyindole ( lk) (0.42 g, 12 %) as pale yellowplates, m.p 49-50", vmax. 3 500 and 1 240 cm-l, A, 217(E 36 300), 230sh (8 loo), 271 (10 300), 280 (10 000), and287 nm (8 200), 6 7.6-6.9 (5 H, m) and 2.4 (3 H, s), $* + 60(s) (Found: C, 55.75; H, 4.0; F, 26.55; N, 6.55. C,,H,-F,NO requires C, 55.8; H, 3.75; F, 26.5; N, 6.5%).Reaction of 2-methylindole- 1-carbaldehyde ( li) with CF,OFand work-up without base gave an unstable oil, v,,,.(film) 1 710 and 1 250 cm-l, $* + 60.Acetylation of Methyl Indol-3-ylacetate (In) .-The ester(In) (9.5 g) was dried by azeotropic distillation with benzene(2 x 20 ml).The residue, potassium acetate (10 g), andacetic anhydride (50 ml) were heated to reflux for 1 h andpoured into water (500 ml), and the solution was extractedwith dichloromethane (2 x 50 ml). The extracts weredried, evaporated, and distilled to give methyl l-acetylindol-3-ylacetate (lo) (11.5 g, 85%) as a pale yellow solid, b.p.165" a t 0.1 mmHg, m.p. 65-67", v,,,. 1 745 and 1 710 cm-l,A,,, 238 ( E 19 loo), 260 (8 800), 268sh (7 700), 290 (6 650),and 299 nm (7 loo), 6 8.5-7.1 ( 5 H, m, aryl H), 3.7 ( 5 H ,s, OMe, CH,CO,), and 2.6 (3 H, s, NCOMe) (Found: C,67.55; H, 5.6; N, 6.2. C13Hl,N03 requires C, 67.6; H,5.65; N, 6.05%).Reaction of the Ester (lo) with Trifluorojluoro-oxymethme.-Reaction of the ester (lo) (0.46 g) and CF,OF (100 ml gas)in dichloromethane (50 ml) a t - 78 "C gave on work-up andchromatography on silica (eluant benzene) an oil, 6 8.4-7.0 (4H, m), 6.5 (1 H, d, J 60 Hz), 3.6 (3 H, 2 s, ratio 5 : l ) ,and 2.4 (3 H, 2 s, ratio 5 : l), $* + 52 (3 F, 2 d, J 10 Hz,ratio 5 : 1) and + 145br (1 F, d, J 60 Hz).The mixture intetrahydrofuran (25 ml) and 1,4-diazabicyclo~2.2.2]octane(400 mg) was stirred overnight. P.1.c. on silica (developingsolvent chloroform) gave l-acetyl-2-hydroxy- 3-methoxy-carbonylmethyleneindoline ( 5 ) (295 mg, 60%) as needles,m.p. 134-136' (from hexane), v,,,. 3 400, 1 740, and 1 710cm-l, Amx. 250 (E 21 200), 256 (21 500), 285 (16 200), 294sh(13 400), and 350 nm (7 300), 6 8.2-6.7 (4 H, m, C,H,),6.4 [l H, dd, J 4 and 2 Hz (with D,O d, J 2 Hz), 2-HI,6.2 (1 H, d, J 2 Hz, vinylic H), 5.0 (1 H, cl, J 4 Hz, exch.D,O, OH), 3.8 (3 H, s, CO,Me), and 2.4 (3 H, s, NCOMe)(Found: C, 62.8; H, 5.45; N, 5.65%; mle, 247.0854.C,,H,,NO, requires C, G3.15; H, 5.3; N, 5.6576; M ,247.084 5 ) .Oxalylation of Indole (le).-Oxalyl chloride (2.5 ml) wasadded with stirring over 15 min to indole (le) (3g) in anhyd-drous ether (50 ml) a t 0-5 "C.After a further 1 h anhy-drous methanol ( 5 ml) was added. Overnight stirring gavemethyl indol-3-ylglyoxylate (lp) (2 g, 38%) as plates, m.p.234-236" (from methanol) (lit.,* 230°), v,,,,. 3 30C, 1 740,and 1 630 cm-l, Amax, 255 ( E 9 600), 268 (9 500), 274 (8 loo),and 322 nm (9 700), 6 8.4 ( 1 H, s, 2-H), 8.2 (1 H, m, 7-H),7.3 (3 H, in), and 4.0 (3 H, s, C0,Me).Acetylation of the Glyoxylate (lp) .-The glyoxylate (lp)(0.50 g), potassium acetate (2 g), and acetic anhydride (10ml) were stirred together overnight, poured into water, andextracted with ether (2 x 50 ml).The extracts werewashed with aqueous ammonia and water, dried, and eva-porated to give methyl 1-acetylindol-3-ylglyoxylate (lq)(0.55 g, 91%) as plates, m.p. 130-132" (from benzene-hexane) (lit.,4 130-132"), v,,,, 1 740 and 1 670 cm-1,A,,,. 224sh ( E 13 300), 250 (10 loo), 264sh ( 7 400), 274(6 loo), and 317 nm (9 500), 6 8.8 (1 H, s, 2-H), 8.3 and 7.4(4 H, 2 m, C,H,), 4.0 (3 H, s, CO,Me), and 2.8 (3 H, s,NCOMe).Reduction of the Glyoxylate ( lq) .-Aluminium amalgam[from aluminium (100 mg)] was added to the glyoxylatel2 L.Alessandri and M. Passerini, Gazzetta, 1921, 51, 262J.C.S. Perkin I(0.20 g) in diethyl ether (10 ml) , methanol ( 1 ml), and water(0.5 ml). The solution was stirred for 1 h and filtered, andthe product was separated by p.1.c. on silica (developingsolvent chloroform-methanol, 50: 1) to give methyl 1-acetylindol-3-ylglycolate (lr) (150 mg, 74%) as needles,m.p. 120-121" (from hexane-diethyl ether) (lit.,4 121-123"), v,,,, 1740 and 1720 cm-l, lmX. 238 (E 16 800), 260(7 700), 267sh (6 goo), 290 (6 loo), and 299 nm (6 700),6 8.4 (1 H, m, 2-H), 7.4 (4 H, m, C,H,), 5.4 (1 H, s, CHCO,),3.7 (3 H, s, CO,Me), and 2.6 (3 H, s, NCOMe).Jones Oxidation of the Indoline Derivative ( 5 ) .-Theindoline (5) (100 mg) in acetone (2 ml) was titrated withJones reagent until an orange colour persisted. The solu-tion was added to water (20 ml) and extracted with chloro-form (2 x 5 ml). Evaporation of the organic phase andchromatography on silica gave methyl l-acetylindol-3-ylglyoxylate (lq), m.p. and mixed m.p. 130-133" (Found:C, 63.85; H, 4.75; N, 5.75. Calc. for C,,H,,NO,: C,63.65; H, 4.5; N, 5.7%).Oxidation of the Indoline Derivative (5) with DimethylSu2phoxide.-Acetic anhydride (0.5 ml) and pyridine (1drop) were added with stirring to the indoline derivative(5) (50 mg) in dimethyl sulphoxide (1 ml). After 1 h water(20 ml) was added and the solution extracted with ether(20 ml). The ether phase was washed with water (2 x 20ml), dried, and evaporated to give methyl l-acetylindol-3-ylglyoxylate (lq) (32 mg, 65%) (from hexane), identicalwith authentic material.Isomerisation of the Indoline Derivative (5) .-1-Acetyl-2-hydroxy-3-methoxycarbonylmethyleneindoline (5) (50 mg)and 50% aqueous acetic acid (2 ml) were heated on a steam-bath for 4 h. Ether (30 ml) was added and the solutionwashed with water (3 x 50 ml), dried, and evaporated.Crystallisation from hexane gave methyl l-acetylindol-3-ylglycolate (lr) (40 mg, 80%) as needles, identical withauthentic material.We thank Dr. A. G. M. Barrett for help in the preparation[7/964 Received, 8th June, 19771of this manuscript