Autoxidation of 3,3′-dimethyl-2,2′-bi-indolyl

摘要

418 J.C.S. Perkin IAutoxidation of 3,3'- Dimethyl-2,Z'- bi-indolylBy A. 2. Britten,' Department of Pharmacy, University of Aston in Birmingham, Birmingham B4 7ETThe product obtained during dehydrogenation of 3-methyl-2- (3-methylindolin-2-y1)indole (1) with chloranil isshown to be 3-methyl-2-(3-methylindol-2-yl)-3H-indol-3-ol (4). which is produced via 3-hydroperoxy-3-methyl-2- (3-methylindol-2-yl)-3H-indole (3). The hydroperoxide results from the autoxidation of 3.3'-dimethyl-2.2'-bi-indolyl (2). Further autoxidation of the bi-indolyl (2) produces NNr-bis-(2-acetylphenyl)oxarnide (1 0).G. F. Smith, Department of Chemistry, University of Manchester, Manchester MI 3 9PLIN the dehydrogenation of 3-met hyl-2- (3-me t h ylindolin-2-y1)indole (1) with chloranil in boiling xylene, a yellowcolour developed on prolonged heating and a smallamount of a yellow product (A) was isolated.Thismaterial, C,,H,N,O, exhibited an intense U.V. absorp-tion (see the Figure, spectrum 1) in neutral ethanol,5.0 t t3 5 t , , , , ,250 350 L50 250 300 350n m.U.V. spectra: (a) - spectrum 1; ---- spectrum 2; _ . _ . _ spectrum 3 ; - * * spectrum 4; (b) - spectrum5 ; ---- spectrum 6which underwent a bathochromic shift of 50 nm onacidification (spectrum 2). The absorption could notbe correlated with any known chromophore. Thei.r. spectrum1 showed the presence of both NH andOH groups.A. Walters, M.Sc. Thesis, Manchester, 1958.2 G. Berti, A. Da Settimo. and D. Segnini, Tetrahedron Letters,1960, 28, 13.Reduction of the compound with sodium borohydrideyielded a colourless product (B), C,,H,,N,O, whichcontained the NH and OH groups (i.r.) and had aU.V.spectrum in neutral ethanol (Figure, spectrum 5)typical of an indole, and very similar to that of theindole (1). The absorption of compound (B) in acidsolution was remarkably different (see spectrum 6).The change was irreversible, and a new product wasisolated from the acidic solution. This product,m .p . 1 56-1 59", was identical with 3,3'-dime t hyl-2,2'-bi-indolyl (2), obtained from the dehydrogenationof the indole (1) with chloranil in benzene.2 The acid-catalysed conversion of the reduced product (B) intothe bi-indolyl (2) was accompanied by the loss of 1mol. equiv. of water from the product, and is readilyunderstood in terms of structure (5) for compound (B).This structure also accounts for the indole-like absorp-tion of the product.Compound (A) therefore appearsto be the 3H-indole (4).The conversion of the indolinylindole (1) into thehydroxy-3H-indole (4) is unlikely to be a direct process.Since dehydrogenation with chloranil in benzene isknown2 to yield 2,2'-bi-indolyl (a), it would appearthat this is an intermediate, which may be expectedto yield the hydroperoxy-3H-indole (3) on prolongedheating under reflux, owing to the propensity of 2,3-disubstituted indoles for autoxidation.3 The hydro-(a) R. J. S. Beer, L. McGrath, and H. Robertson, J . Chem.Soc., 1950, 2118, 3283; ( b ) R. J. S. Beer, T. Donavanik, andA. Robertson, J .Chem. SOG., 1954, 4139; (c) B. Witkop, J. P.Patrick, and RI. Rosenblum, J . Amer. Chem. Soc., 1951, 73,2188,2196,2641 ; ( d ) F. McCapra and Y. C. Chang, Chem. Comvn.,1966, 5221972 419peroxide would then decompose into the hydroxy-3H-indole (4), the isolated product (see the Scheme).This reaction scheme was verified as follows.When a solution of the 2,2’-bi-indolyl (2) in lightpetroleum was boiled under reflux for 4 h, a yellowH( 1 )colouration ensued and a yellow material was isolated,m.p. 146-172’. The product liberated iodine fromacidic potassium iodide solution and had a U.V.absorption identical with that of the alcohol (a), theproposed dehydrogenation product. Further heatingproduced another yellow product, m.p.164-180°,which although possessing the same U.V. absorption asthe first material, no longer liberated iodine. Treat-ment of 2,2‘-bi-indolyl (2) with oxygen in the presenceof a platinum catalyst gave a yellow product, m.p.146-155”, which liberated iodine but which afterattempted recrystallisation showed a larger meltingrange and no longer liberated iodine readily. Thehydroperoxide (3) was successfully synthesised whena solution of the 2,2’-bi-indolyl (2) in ethyl acetate-light petroleum containing a crystal of benzoyl peroxidewas left open to the atmosphere. After 6 h, a quantita-tive yield of the hydroperoxide (3) was isolated. Thei.r. spectrum of (3) showed the presence of an NH anda strongly hydrogen bonded OH group, and the U.V.absorption was identical with that of compound (A)(Figure, spectrum 1).An iodometric titration con-firmed the presence of one hydroperoxy-group. Cataly-tic hydrogenation gave the hydroxy-indoline (5), whichproduced the 2,2’-bi-indolyl (2) on treatment with acid.Mild reduction of the hydroperoxide with sodiumdithionite gave a product identical with the hydroxySH-indole (4). The identity of the chromophore in (4) wasestablished by the synthesis of N-(3-methylindol-2-ylmethy1ene)-j5-toluidine (6), whose U.V. absorptionin neutral solution (Figure, spectrum 3) is seen to besimilar to that of the 3H-indole (4) (spectrum l), andit shows a similar bathochromic shift (55 nm) in ethanolicacid solution (spectrum 4). The hydroperoxide (3)was stable in acid solution, from which it was recoveredunchanged. In polar solvents, some conversion intothe 3H-indolol (4) was observed, but no decompositionto the amide (7) was detected.This behaviour is incontrast to the conversion of the hydroperoxide (8)in polar solvents into the lactam (9).MeO.OH(11 1The production of the 3H-indolol(4) by direct autoxid-ation of the indolinylindole (1) is unlikely on theoreticalgrounds, and this was confirmed by recovering (1)unchanged after 2 days from a solution in ethyl acetate-light petroleum containing benzoyl peroxide. This isin agreement with the results of Berti et aL,2 who re-covered the indolinylindole (1) unchanged after treat-ment with oxygen. The inertness of compound (1)to auxoxidation, though surprising in view of thereported ease 3 of autoxidation of 2,3-disubstitutedindoles, is not exceptional.Both 2-methyl-3-phenyl-and 2,3-diphenyl-indole 3b and also 2- (4-hydroxyphenyl) -3-methyl- and 2-(2-methoxyphenyl)-3-met hyl-indole 4are resistant to autoxidation.The possibility of autoxidation of the 2,2’-bi-indolyl(2) to give the dihydroperoxide (11) was investigated.No such compound could be isolated, but passage of arapid stream of oxygen into a solution of the bi-indolyl(2) in boiling xylene for 4 h produced a colourlesscrystalline product. This compound, obtained in4 B. Robinson and M. V. Zubair, J . Chew. SOC. (C), 1971, 976420 J.C.S. Perkin Iquantitative yield, was identical with authentic NN'-bis-(2-acetylphenyl)oxamide (lo), which was also pro-treatment with acetic or sulphuric acid.2(12.3 mg), m.p.180-182", with spectral characteristics 1of the indolol (4).(b) The bi-indolyl (2) (72 mg) was dissolved in hot ethylacetate-light petroleum (25 ml) and a crystal (0.01 mg) ofbenzoyl peroxide was added. The solution was left a troom temperature, open to the atmosphere. After 6 h,the product (68 mg, 94) was filtered off, washed withduced from 3,3'-dimethyl-2,2'-bi-indolyl ozonide byEXPERIMENTALM.p.s were determined on a Kofler hot-stage apparatus.All solutions were dried with potassium carbonate unlessotherwise stated. U.V. spectra were recorded for ethanolicsolutions (unless otherwise stated) with a Unicam SP 500spectrophotometer. 1.r. spectra were recorded with aPerkin-Elmer model 2 1 double-beam apparatus.Lightpetroleum refers to that fraction withb.p. 60-80".3-Methyl-2- (3-methylindol-2-y1)-3H-indol-3-01 (4) .-3-Methyl-2-(3-methylindolin-2-y1)indole (640 mg) was heatedunder reflux with chloranil (610 mg) in redistilled xylene(75 ml) for 24 h. The mixture was cooled, filtered, andevaporated to dryness. The residue was taken up inether (100 ml) and extracted with 0.2~-sodium hydroxide(3 x 30 ml) to remove tetrachlorohydroquinone. Theethereal solution was dried and evaporated to dryness.The residue was chromatographed on an alumina column.Elution with benzene gave yellow needles (224 mg, 35the yields varied with the time of reaction over 20-40y0 ;other products included the bi-indolyl (2) and the hydro-peroxide (3)}, m.p.180-182 "C (from ethyl acetate-lightpetroleum) (lit.,l 182'), Am= 251 (log E 4-66) and 365 nm(4.70), in ethanolic 0+1~-HCl . 246 (log E 4.53), 320(4.41), and 415 nm (4.80).3-Methyl-2-( 3-rnethyZindoZ-2-yl)indolin-3-ol (5) .-The in-dolol (4) (250 mg) was dissolved in methanol (15 ml) witha drop of alkali and potassium borohydride (400 mg).The solution was gently heated under reflux until theyellow colour had disappeared, then diluted with water(20 ml) and extracted with ether (3 x 5 ml). The extractwas dried and evaporated under reduced pressure to yieldthe colourless amorphous indolinol (5) (240 mg, 96y0),fusing at 75-126". The compound would not recrystalliseand yielded no crystalline derivatives (Found: C, 77.0;H, 6.4.C,,H1,N@ requires c, 77.7; H, 6*5y0), Am.229 (log E 4-8) and 292 nm (4.12), Am= (ethanolic O-~N-HC~)246 (log E 4.41) and 318 nm (4.45). These latter absorp-tions are the same as for the 2,2'-bi-indolyl (2).3,3'-DimethyZ-2,2'-bi-indolyl (2) .-The indolinol (5) (70mg) was dissolved in methanol (4 ml) and dilute hydro-chloric acid (0.05 ml) was added. The solution wasdiluted with water and the solid which separated wasfiltered off to give colourless crystals (68 mg), m.p. 156-159" (from light petroleum) undepressed on admixturewith authentic 3,3'-dimethyl-2,2'-bi-indolyl (m.p. 163-164"). The i.r. and U.V. absorptions of this product areidentical with those of the authentic material.Oxidation of 3, 3'-Dirnethyl-2, 2'-bi-indolyl.-(a) The bi-indolyl (2) (80 mg) was dissolved in an excess of lightpetroleum and left to reflux, open to the atmosphere.After 4 h, a yellow solid, m.p.146-175", was isolatedfrom the pale yellow solution. The solid liberated iodinefrom acidified iodide solution. After a further 8 h underreflux, the yellow solid no longer gave the iodide test,and had m.p. 164-180". Three recrystallisations of thissecond yellow product gave a small amount of materialethyl acetate, and dried to yield fine yellow needlesof 3-hydrofieroxy-3-rnethyl-2- (3-methyEindol-2-yl)-3H-indole,m.p. 153-154.5" Found: C , 73-65; H, 5.35; M (iodo-metric titration), 292-5. C,,H,,N,O, requires C, 73.95 ;H, 5.5 ; M , 2921, Amax. 250 (log E 4.50) and 365 nm (4.68).Reduction of the Hydroperoxide (3) .-(a) The hydro-peroxide (3) (24.4 mg) was dissolved in ethyl acetate(5 ml) containing Adams catalyst (10 mg) and hydrogenwas passed through.Absorption ceased after uptake of2.1 mol of hydrogen. The solution was filtered, dried,and evaporated to yield a colourless, amorphous solid(24.01 mg), which would not crystallise, fusing at 75-122".The absorption spectra were identical with those of theindolinol (5). Treatment with acid gave the bi-indolyl(b) The hydroperoxide (28.9 mg) was dissolved in 2 ~ -sodium hydroxide (4 ml) and ethanol (1 ml). Sodiumdithionite (60 mg) was added and the solution was kepton a steam-bath for 1 h, diluted with water (15 ml), andextracted with ether (3 x 3 ml).The ethereal solutionwas dried and evaporated to yield a yellow oil (25 mg,86), which crystallised on scratching as yellow needles,m.p. 178-182' (from light petroleum-ethyl acetate),undepressed by admixture with authentic indolinol (4)(m.p. 180-182°).1 The spectra were identical with those(2).of (4).N- (3-Methylindol-2-ylmethy lene) -p-toluidine (6) .-3-Methylindole-2-carbaldehyde (1 1 mg) was heated underreflux with $-tohidine (7.5 mg) in methanol (0.5 ml).On cooling, pale yellow crystals of the toluidine (6) separatedout (15 mg, 87), m.p. 137-138' (from benzene) (Found:C, 82.0; H, 6.4. Cl,H1,N20 requires C, 82.3; H, 6.45y0),= 350 nm (log E 4-78), Am= (ethanolic OS~N-HC~) 237(log E 4-35), 307 (4.37), and 4.05 nm (4.79).Oxidation of 3-Methyl-2-( 3-methylindolin-2-y1)indole ( 1).-The indole (1) (1 26 mg) was dissolved in light petroleum-ethyl acetate (50 ml) and a crystal of benzoyl peroxide (0.023mg) was added. The solution was left open to the atmo-sphere. After 2 days, unchanged indole (1) (123 mg), m.p.126", was recovered from the solution. Berti et aL2 reportthat no peroxides are formed when oxygen is bubbledthrough a solution of the bi-indolyl.Action of Oxygen on 3,3'-Dimethyl-2,2'-bi-indolyZ (2) .-The bi-indolyl (2) (37 mg) was dissolved in redistilledxylene (25 ml). The solution was boiled and a rapidstream of oxygen was passed through it. The solutionturned yellow and after 6 h a colourless solid separatedout. The solid was collected, dried, and recrystallisedfrom morpholine to yield colourless needles of NN'-bis-(2-acetylpheny1)oxamide (10) (30 mg, 81), m.p. andmixed m.p. 261-264' (lit.,, 267").We thank Manchester University for financial supportand facilities for carrying out the work (A. 2. B.).1/1508 Received, August 19th, 1971