Carcinogenic nitrogen compounds. Part LXXXII. Polycyclic indoles by means of the Mouml;hlaundash;Bischler synthesis

摘要

1972 2573Carcinogenic Nitrogen Compounds. Part LXXXII.l Polycyclic lndoles byMeans of the Mohlau-Bischler SynthesisBy P. Bigot, G. Saint-Ruf," and (the late) N. P. Buu-HoLt Centre Marcel DBl6pine du C.N.R.S., 45-0rlBans-LaSource, FranceA modified technique for the Mohlau-Bischler indole synthesis gave access to a number of polycyclic indoles,among them derivatives of benzof indole and phenaleno I ,9-fg indole, which are potential carcinogens and/orleu kaemogens.WE have recently shown2 that the Mohlau-Bischlersynthesis (i.e. cyclisation of w-arylamino-ketones in thepresence of arylamine salts) is an excellent preparativeroute to 2-arylindoles. This reaction has now beenused for the preparation of a number of new polysub-stituted indoles and polynuclear indoles which are ofinterest as potential carcinogenic and/or leukaemogenicsubstances; indole itself and some of its more simplesubstituted derivatives are known to induce leukaemiain rodents3Since the Mohlau-Bischler method does not involve theuse of metal halides as catalysts, the introduction offragile heteroaromatic substituents presented no prob-lems: thus, the 2-fury1 (I; X = 0) and 2-thienyl (I;X = S) derivatives of 4,5,7-trimethylindole were easilyobtained from 2,4,5-trimethylaniline (pseudocumidine)and the appropriate a-bromo-ketone, and the corre-sponding 2-pyridyl derivative was prepared similarly.Me(I 1 (II1H HIrn) ( IY1A further advantage of the Mohlau-Bischler cyclisationis that there is no risk of isomerisation through methylN.P. Buu-Hoi, G. Saint-Ruf, D. Deschamps, and P. Bigot,Part LXXXI, D. C . Thang, C . X. Can, N. P. Buu-Hoi, and A. Lacassagne, N. P. Buu-Hoi', F. Zajdela, and N. D.t Deceased, 28th January, 1972. J . Chem. SOC. ( C ) , 1971, 2606.Xuong, Bull. Cancer, 1965, 42, 3. P. Jacquignon, J.C.S. Perkin I , 1972, 19322574 J.C.S. Perkin Idisplacement, as demonstrated by analysis of the n.m.r.spectral data of a number of indoles derived from pseudo-cumidine; all the spectra showed a signal (z 3.18-3.28)corresponding to the 6-proton shielded by the twoadjacent methyl groups.a-Arylaminodeoxybenzoins * proved particularlyprone to indolisat ion ; 4,5,7-trimethy1-2,3-diphenylindoleand l,Z-diphenyl-3H-benzeindole (11; R1 = R2 = Ph)were furnished in excellent yield.5 Other derivatives of3H-benzeindole were prepared; the properties of the2-phenyl derivative (m.p.175") differed considerablyfrom those indicated in the literature.6 A route toderivatives of lH-benzrflindole (111; R = H) involved 1,7-fgindoles (V) and S-aryl-SH-phenalenol ,Q-fgindoles(VI). Compounds (VI) are particularly interestingin view of their close structural relationship with benzo-alpyrene, one of the most potent carcinogens known.RH"bsol;bsol;use of 6-aminotetralin -in Mohlau-Bischler syntheses ;cyclisation of the o-amino-ketones derived from thisamine takes place at position 7 and thus gives substitutedWhilst aromatic diamines such iLs $-diaminobenzenebe easily cyclised to the corre- and bemidine5,6,7,8- tetrahydro-1 H-benz Iflindoles (IV) , which arethen dehydrogenated to (111).Proof of the h e a r P h C o . c H ~ , N H Q N ~ . c H I ~ ~ ~ h('1111)structure of these compounds was provided by the factthat the 2-phenyl derivative (111; R = Ph), m.p. 260",-displayed different physico-chemical properties fromderivatives (IV) showed an intense i.r. absorption bandtetrasubstituted benzene and hence of the absence ofortko-related protons.' sponding w-amino-ketones (VII) and (VIII) , similarThe Mohlau-Bischler synthesis was also successfully cyclisation of these last compounds furnished onlythose of 2-phenyl-3H-benzeindole ; furthermore, all the R Q co. c H2.N H Q--Q N H . c H p Q Rin the 800-850 cm-l region, characteristic of a 1,2,4,5- (MI)TABLE 1w-Arylamino-ketoneslU ArNHCHRCOAr'SubstituentsAr Ar' R M.p.("C) Formula2,4-Xylyl Ph Ph 125 C2ZHZlNO3,4-Xylyl Ph Ph 126 C2ZHZlNO3,5-Xylyl Ph Ph 134 C2ZHZlNOPh Ph 115 c a ,HZ 1N 0 2,3-Xylyl2,4,5-Me3C,H, Ph Ph 138 C23H23N02-Naphthyl Ph H 165 C16H15N02-Naphthyl Biphenyl-kyl H 190 C24H19N05,6,7,8-Tetrahydro-2-naphthyl Ph H 135 C16H19N05,6,7,8-Tetrahydro-2-naphthyl Ph Ph b 130 C24H23N02-Naphthyl ClC,H4 H 194 C,,Hl,CINO5,6,7.8-Tetrahydro-2-naphthyl Biphenyl-Pyl H 120 C44H23NO5,6,7,8-Tetrahydro-2-naphthyl p-CIC,H, H 140 Cl,Hl,CINO5-Acenaphthyl P-ClC,H, H a 175 C,H,,CINO5-Acenaphth yl Ph H 164 C20H17N06- Acenaphthyl Ph Me c 163 C21H17N05-Acenaphthyl 2-Naphthyl H b 173 C24H19N06-Acenaphthyl Indan-5-yl Hb 178 C23H21N05-Acenaphth yl 2-Thienyl Ha 150 C18H15N0SPyren-l-yl Ph Hb 162 C4H17N05-Acenaphthyl Biphenyl-4-yl H b 188 C26H21NO6- Acenaphthyl p-MeOC,H, H b 145 C21HlrINOZPyren-l-yl $-C1C,H4 Hb 186 C2,H,,ClN0Found ()C H N83.6 6.7 4.283-5 6.7 4.283.6 6-7 4.283-7 6-7 4-283.8 7.0 4.082.8 5.9 6.672.9 5.0 4.986.4 5-9 4.081.3 7.1 5.484.4 6.9 3.984.3 6-9 3-971.9 6.0 4.683.5 6.0 6.083.6 6.4 4.674.7 5.1 4.185.2 5.8 4.185.9 6.8 3.684-2 6.5 4.179.3 6.0 4.273.6 5.2 4.585-8 6.3 4.03.7Requires (yo)C H N83.7 6.7 4-483.7 6.7 4.483.7 6.7 4.483.7 6-7 4.483-8 7.0 4.282.7 5.8 5.473.1 4.8 4.785.4 5.7 4.181.5 7.2 5.384.4 6.8 4.184-4 6.8 4.172.1 6.0 4.783.6 6.0 4.983-7 6.3 4.674.6 5.0 4-385-4 5.7 4.285-9 5.8 3.884.4 6.6 4.379.6 6.0 4.473.7 5.1 4.786.9 6-1 4.23.8a Pale yellow needles, from ethanol or ethanol-benzene.From benzene. c From methanol. d From propanol.applied to the cyclisation of a-arylamino-ketones unidentified polymerisation products. Nevertheless, thederived from 5-aminoacenaphthene and l-aminopyrene, many examples of the formation of indoles reported hereleading, respectively, to 8-aryl-5,9-dihydro-4H-indeno- show, in line with our earlier observations,2 that the7 Cf., L. J. Bellamy, ' The Infrared Spectra of Complex * Cf. R. C. Elderfield, ' Heterocyclic Compounds,' Wiley, Molecules,' Methuen, London, 1958; R. N., Jones and C. Sandorfy,in ' Techniques of Organic Chemistry, ed. A. Weissberger,A. Bischler and P. Fireman, Bey., 1893, 26, 1346.Interscience, New York, 1966, vol. IX; D. G. O'Sullivan,t~ W. H. Ince, Annalen, 1889, 268, 35. Spectrochim. Acta, 1960, 16, 762.New York, 1952, vol. 3, p. 31972 2575Mohlau-Bischler synthesis is far superior to that ofFischer for the preparation of polycyclic 2-arylindoles.EXPERIMENTAL1.r. absorption spectra were determined for potassiumbromide discs with a Perkin-Elmer (model 457) spectro-Indoles 06,7-Dimethyl-2,3-diphenyl-4,7-Dimethyl-2, 3-diphenyl-6,6-Dimethyl-2,3-diphenyl-4,6-Dimethyl-2,3-diphenyl-6,7-Dimethyl-2,3-diphenyl-4,6,7-Trimethyl-2,3-diphenyl-PicratePicratePicratePicrateM.p. ("C)162163136142166160136146167170was cooled and the precipitate was washed with water andrecrystallised from ethanol, ethanol-benzene, or benzene ;yields 60-85 (see Table 1).Mohlau-BischZer Cyc1isation.-We used our modifiedtechnique,* the cyclisation being performed in an inertliquid (silicone oil), which avoids thermal decomposition ofthe w-amino-ketones and gives higher yields of indoles.AnTABLE 2Pol ysubs t i tu t ed indolesFound ()Formula C H N88.6 6.5 4.563.8 4.3 10.6C22H19N 88.8 6.6 4-5C22H19N 88.6 6.6 4.6C28H22N407 63.7 4.2 10.3C22H19N 88.5 6.4 4.6C22H19N 88.8 4.6 4.6C28H19NC28H22N407C28H22N407 63.6 4.4 10.9C28H28N407 63.5 4.4 10.8C23H21N 88-6 6.9 4.3Requires ()C H N88.8 6.4 4.763.8 4.2 10.688.8 6.4 4.763.8 4.2 10.688.8 6.4 4- 763.8 4.2 10.688.8 6.4 4.788.8 6.4 4.74.2 10.6 63.888.7 6-8 4.60 Recrystallised from ethanol, aqueous ethanol, or hexane, as colourless leaflets or prisms.Picrates crystallised from ethanol,as brown needles.TABLE 3Polycyclic indoles aZ-Phenyl-3H-benzeindole (11; R1 = Ph, R2 = H)2-(p-Chlorophenyl)-3H-benzeindole (I1 ; R1 = p-C1C,H4,2-(Biphenyl-4-yl)-3H-benzeindole (I1 ; R1 = p-C6H,*C6H4,6,6,7,8-Tetrahydro-2-phenyl-lH-benzlflindole (IV; R = Ph)2-(~-Chlorophenyl)-5,6,7,8-tetrahydro-l~-benz~indole (IV;R2 = H)R2 = H)R = +-ClC,H,)2- (Biphenyl-4-9) -6,6,7,8-tetrahydro-lH-benzfl indole (IV ;2-Phenvl-1H-benzrflindole I111 : R = PhlR = fl-C,amp;,*Camp;)6,9-Dihj.dro-8-phe~$l-4H-i~deno 1,7-fgindole (V ; R = Ph)Picrate8- (p-Chlorophenyl) -6,9-dihydro-4H-indeno 1,7-fg indole (V ;R p-ClC,H,)Picrate8- (13-Naphthyl) -6,9-dihydro-4H-indenol, 7-fglindole (V ;R = P-naphthyl)Dipicrate8- (BGhenyl-4-yl) -5,9-dihydro-4H-indeno1,7-fgindole (V;-.R = $-C,H,*C,H4)Picrate8- (Indan-5-yl)-6,9-dihydro-4H-indeno1,7-fgindole (V;R = indan-5-yl)PicrateM.p.1761692452012763062601642011901861972142602001971 R5( "C)---8- (p-Methoxyphenyl) -6, 9-dihydro-4H-indeno 1 , 7-fglindole (V ; 2608-Phenyl-SH-phenalenol,9-fgindole (VI ; R = Ph) 286S-(p-Chloropheny1)-9H-phenalenol, 9-jgJindole (VI ; 260R = p-MeOC,H4)R = p-c1c,H4) (decomp.)Found (yo)C H N89.0 5.6 6.678.0 4-5 4.989.9 6.6 4.687.2 7.0 5.676.6 5.8 4.889.3 6-5 4.188.6 6.4 5.889.1 6.6 6.062.6 3.7 10.978.9 4.8 4.658.3 3.2 10.389.9 5.6 4.265.8 3.1 12.690.4 6.6 3-866.6 3.9 9.889.3 6.3 4.464.4 4.3 10.483.9 6-8 4.591.2 4.7 4.282.2 4.0 3.8Requires ()C H N88.8 6-4 6.777.8 4.4 5.090.2 6.4 4.487.4 6.9 5.776.7 6-7 4.989.1 6.6 4.388.8 6.4 6.789.2 6-6 5.262.7 3.7 11.279.1 4.6 4.668.6 3.2 10.690.2 5.4 4.455.6 3.0 12.690.4 6.6 4.066.8 3.7 9-789.3 6.2 4.664.7 4.1 10.484.2 5.7 4-791.4 4.6 4.482.4 4.0 4.08 Recrystallised from cyclohexane, benzene, or ethanol-benzene, as colourless leaflets or prisms.Picrates or dipicrates crystal-lised from ethanol or ethanol-benzene as brown needles.meter; n.m.r. data were determined for solutions in2Hchloroform (internal reference, tetramethylsilane) witha Perkin-Elmer R-12 spectrometer.Preparation of w-AryZarnino-ketones.-An ethanolic solu-tion of equimolar amounts of the arylamine and the appro-priate o-bromo-ketone was heated under reflux for 4 h withhydrogen sodium carbonate in slight excess. The solution4xintimate mixture of the o-arylamino-ketone, the appropri-ate arylamine (2 mol. equiv.) and its hydrobromide (0.05mol. equiv.) in silicone oil was heated a t 230-250' for10-15 min. The mixture was cooled and the product waswashed with hexane and recrystallised from ethanol,benzene, or chlorobenzene ; yields 35-80y0 (see Tables2 and 3)2576 J.C.S. Perkin I2-Phe.lzyZ-lH-benzf~ilzdoZe (111 ; R = Ph) .-Heating for carcinogenic and zoxazolamine hydroxylase-inducing5,6,7,8-tetrahydr0-2-phenyl-lH-benzflindole (IV; R = H), activities ; results will be reported elsewhere.followed by sublimation in vucuo over 5 palladium-charcoal and recrystallisation from benzene, furnished theindole (111), m.p. 260" (see Table 3).The new indoles described are currently undergoing testsWe thank the Ligue franqaise 'Ontre le Cancer for aFellowship (to P. B.), and the S.E.I.T.A. for support.2/1075 Received, 11th May, 1972