Photochemistry of ethyl 2-cyano-1,2-dihydroquinoline-1-carboxylates (Reissert compounds): synthesis of 2-cyanomethylinodole-1-carboxylates

摘要

1976 2587Photochemistry of Ethyl 2-Cyano-1.2-d i hydroquinol ine-I -carboxylates(Reissert Compounds) : Synthesis of 2-Cyanomethylindole-1 -carboxyl-atesBy Masatumi Ikeda," Saeko Matsugashita, and Yasumitsu Tamura, Faculty of Pharmaceutical Sciences,Osaka University, 133-1, Yamada-kami, Suita, Osaka, JapanIrradiation of ethyl 2-cyano-l,2-dihydroquinoline-l -carboxylates (Reissert compounds) gives ethyl N- o- (3-cyanoallenyl)phenylcarbamates, which are readily converted into ethyl 2-cyanomethylindole-1 -carboxylates bytreatment with alumina.IN recent years the photochemistry of 1,2-amp;hydronaph-thalenes and their heterocyclic analogues has beeninvestigated extensively. As noted previously,2g ir-radiation of ethyl 2-cyano-l,2-dihydroquinoline-1 -carb-oxylates (Reissert compounds) (1) gives allenic com-pounds (2) which can be transformed into ethyl 2-cyanomethylindole-l-carboxylates (3).Because theesters (3) are considered to be potential synthetic pre-cursors of 2-substituted indole derivatives otherwise avail-able only by multi-step proce~ses,~ we have investigatedthis photochemical reaction in some detail. We describehere the synthesis of several ethyl 2-cyanomethylindole-l-carboxylates (3) as well as a procedure for their large-scale synthesis.The starting Reissert compounds (1) were synthesisedfrom the corresponding quinolines essentially as describedby Popp and his co-workers.*For preparative purposes, irradiation of an etherealsolution of the cyano-ester (la) with a 350 W high-pressure mercury lamp through a glass filter at 0-5 "Cgave the most satisfactory results.The reaction wasconveniently followed by n.m.r. spectroscopy. Thephotochromic behaviour of the starting material (la)can also be used as indicator of the progress of the reac-tion. Thus, a dark brown colour was present until allthe starting material had been consumed, and at the endof the reaction a yellow solution was obtained. Asdescribed later, the initial photoproduct is the alleniccompound (2a). However, since it was difficultto isolate this material (2a) in pure state,? the pro-duct was converted directly into ethyl 2-cyanomethyl-indole-l-carboxylate (3a), either by treatment of thephotolysate with alumina (in large-scale runs) or bypreparative t.1.c.on alumina or silica gel (in small-scaleruns). In a typical experiment, indole-l-carboxylate(3a) was isolated in 83 overall yield from 2.0 g of (Ia).Although the reaction can also be satisfactorily performedby irradiation in a Pyrex tube in 100 mg-scale runs, pro-longed irradiation or large-scale experiments led to ant Compound (2a) was partially transformed into (3a) during$ Quinoline Reissert compounds show no i.r. cyano-absorption.6(a) R. C . Cookson, S. M. de B. Costa, and J. Hudec, Chem.Comm., 1969, 1272; (b) H. Kleinhuis, R. L. C. Wijting, and E.Havinga, Tetrahedrovz Letters, 1971, 255; (c) K. Salisbury, ibid.,Q. 737; ( d ) H. Heimgarter, H.-T. Hansen. and H. Schmid. Helv.work-up.c h i m . Aamp;, 1972, 55,-3005; (e) D.A. Seeley, J . Amer. Chem. SOC.,1972, 94, 4378.increase in the amount of polymeric material, presum-ably owing to decomposition of the allenic compoundformed, and a resulting decrease in the yield of (3a).That ether is the solvent to be preferred was indicated bythe observation that the reaction of (la) in cyclohexane,benzene, methylene chloride, or acetone in either glassor Pyrex was slower than that in ether and gave a com-plex mixture from which (3a) was isolated in lower yields.Temperature is a critical factor. For example, when asolution of (la) in ether was irradiated in a glass tubeat 20 "C for 15 h, most of the starting material was re-covered, with small amounts of impurities, in spite of thefact that the colour change was observed.That the initial photoproduct from irradiation of (la)in ether is the allene (2a) was suggested from the spec-tral data of the crude material obtained after evaporationof the solvent.The i.r. spectrum (CHC1,) showed in-tense absorption a t 3 420 (NH), 2 220 (EN),$ 1 950(C=C=C), and 1 720 cm-1 (GO), and the n.m.r. spectrumexhibits two doublets ( J 6.6 Hz) at 6 6.85 (1 H) and 5.62(1 H) attributable to two allenic protons. Treatment ofthe crude (2a) with alumina or silica gel gave (3a) in goodyields.The structure of (3a) was apparent from spectral com-parisons (see Experimental section) with ethyl indole-l-carboxylate and from some interconversions describedlater. The formation of (3a) from (2a) is considered toproceed by base- or acid-catalysed intramolecularcyclisation.7* (a) B.Singh, J . Amer. Chem. Soc., 1968, 90, 3893; 1969, 91,3670; (b) K. R. Huffman, M. Burger, W. A. Henderson, jun.,M. Joy, and E. F. Ullman, J . Org. Chem., 1969, 34, 2407; (c) A.Padwa and G. A. Lee, J.C.S. Chem. Comm., 1972, 795; J . Org.Chem., 1975, 40, 1142; ( d ) P. T. Izzo and A. S. Kende, Tetra-hedron Letters, 1966, 5731 ; (8) J. Kolc and R. s. Becker, J . Amer.Chem. SOC., 1969, 91, 6513; J . Chem. SOC. (B), 1972, 17; (f) B. SLukjanow, M. I. Knjazschanski, J. W. Rewinski, L. E. Niworozs-chkin, and W. I. Minikin, Tetrahedron Letters, 1973, 2007;(g) M. Ikeda, S. Matsugashita, and Y . Tamura, J.C.S. Chem.Comm., 1973, 922; ( h ) M. Ikeda, S. Matsugashita, F. Tabusa, H.Ishibashi, and Y .Tamura, J.C.S. Chem. Comm., 1974, 433;1975, 575; (i) M. Ikeda, S . Matsugashita, and Y . Tamura, Chem.and Pharm. Budl. (Japan), 1976, 24, 1400.For example, see W. Schindler, Helv. Chim. A d a , 1957, 40,2156.F. D. Popp, L. E. Katz, C. W. Klinowski, and J. M. Wefer,J . Org. Chem., 1968, 33, 4447.F. P. Popp, Adv. Heterocyclic Chem., 1965, 9, 1.S. Kasparek and R. A. Heacock, Canad. J . Chem., 1966,44,2805.7 M. C. Caserio, ' Selective Organic Transformations,' ed.B. S. Thygarayan, Wiley, London, 1970, vol. 1, p. 2722588 J.C.S. Perkin IApplication of the procedure to ethyl 6-methyl- (lb),7-methyl- (lc), and 6-methoxy- (Id) 2-cyano-1,Z-di-hydroquinoline-1-carboxylates gave the correspondingindole-l-carboxylates (3b-d) but in much lower yields(see Experimental section).Ethyl 2-cyano-3-methyl-1,2-dihydroquinoline-l-carboxylate (If), was stable underthese photolysis conditions. Irradiation of ethyl 2-cyano-l,2-dihydro-4-methylquinoline- 1 -carboxylat e (1 e)in ether followed by treatment with alumina gave twoation of an ethanolic solution of (la) in a glass tubeproduced the ethanol adduct (7) in 4 4 4 6 yield. Thisreaction was not temperature-dependent and irradiationseither at 2 or at 20 "C gave essentially the same results.The structure of (7) was assigned on the basis of spectraldata. The i.r. spectrum (CClk) showed absorption a t3 360 (NH), 2 210 ( E N ) , and 1740 cm-l (GO), and theU.V. spectrum exhibits absorptions at 223 and 284 nmsimilar to those of N- (o-methylphenyl) carbamate (236R'R'ICN IC02EtNH I c o p( 7 )products : the indole-l-carboxylate (3e) and ethylendo-l-cyano-1 , la,2,6b-tetrahydro-6b-methylcyclo-propbindole-2-carboxylate (2,3-homoindole) (4) in 34and 16 yields, respectively.2h In this case no photo-chromism was observed.The structure of (4) and themore detailed study on the photoisomerisation to (4) willbe reported in a subsequent paper.Indole-l-carboxylates (3) were converted into 2-cyano-methylindoles (6) by mild hydrolysis. Thus, althoughalkaline hydrolysis of (3a) with potassium hydroxide inrefluxing ethanol resulted in 2-methylindole (5), presum-ably via indole-acetic acid which is known to be readilydecarboxylated,s treatment of (3a) with potassium car-bonate in ethanol at room temperature gave 2-cyano-methylindole (6a) in quantitative yield.Similar treat-ment of (3e) gave 3-methylindole-2-acetonitrile (6b) in79 yield.In contrast to the photoreaction of (la) in ether, irradi-(6) a; R = Hb ; R = M eand 280 nm). Its n.m.r. spectrum reveals a doubledoublet centred at 6 7.71 (Hb), a doublet with smallsplitting a t 6 5.45 (H,), and a doublet at 6 5.30 (Ha) withJab 8 and Jbc 12 Hz. In addition, a broad NH peak at 88.28 and signals of two ethoxy-groups and aromatic pro-tons are observed. The cis-stereochemistry of thedouble bond was tentatively assigned from the couplingconstant ( J 12 Hz) of the two olefinic proton^.^ An ana-logous reaction is the photolysis of a 2,2-disubstitutedchromen in ethanol.2cRecently conjugated aza-polyene structures of type(8) have been proposed for the coloured species observedin the low temperature photolysis (at 77 K) of 1,2-dihydroquinolines.2e The same photochromic behaviourwas observed with (la-d) under the photolysis condi-8 W.Schindler, Helv. Chim. Ada, 1958, 41, 1441.P. Laszlo and P. von R. Schleyer, Bull. SOC. chim. Frawe,1964, 871976 2589tions (in either ether or ethanol) we employed. On thebasis of this observation and documented examples ofthe photolytic behaviour of 1 ,Z-dihydronaphthalenes,lwe previously suggested that the photoisomerisation(l) - ( 2 ) involves (8) as intermediate.2g However,our preliminary mechanistic study has shown that thisreaction is mechanistically different from that of thecarbocyclic system and the aza-polyene (8) is not aprecursor of the allene (3).The details will be reportedlater.EXPERIMENTALN.m.r. spectra were determined with a Hitachi R-22spectrometer (90 MHz ; tetramethylsilane as internal stand-ard). 1.r. spectra were recorded with a Hitachi EPI-G2spectrophotometer, U.V. spectra with a Hitachi 124 spectro-photometer, and mass spectra with a Hitachi RMU-6Dinstrument a t 70 eV. Irradiations were carried out withan Eikosha 350 W high-pressure mercury lamp. Merck PF,,,alumina was used for preparative layer chromatographyReissert Comfiounds ( la-f) .-Reissert compounds (1)were prepared from the corresponding quinolines accordingto the method of Popp and his co-~orkers.~ Ethyl 2-cyano-1,2-dihydroquinoline- l-carboxylate ( la) (27 ) had m.p.68-69" (from ethanol) (lit.,4 70-72") ; the 6-methyl deriva-tive (lb) (49) had m.p.120-121" (from ethanol) (Found:C, 69.3; H, 5.9; N, 11.5. Cl,Hl,N,O, requires C, 69.4; H,5.8; N, 11.6); the 7-methyl derivative (lc) (35) hadm.p.79-80" (from ethanol) (Found: C, 69.3; H, 5.8; N, 11.5);the 6-metlzoxy-derivative (Id) (46) had m.p. 87-88" (fromethanol) (Found: C, 65.0; H, 5.2; N, 10.85. C14Hl,N,0,requires C, 65.1 ; H, 5.5; N, 10.85) ; the 4-methyl deriva-tive (le) (59) had m.p. 80-81" (from ethanol) (Found:C, 69.4; H, 5 . 8 ; N, 11.6); the 3-methyl derivative (If)(32) had m.p. 81-82" from light petroleum (b.p. 60-80"C) (Found: C, 69.3; H, 5.8; N, 11.75).Irradiatioiz of the Cyano-ester (la).-(A) Isolation of theallene (2a) and its conversion into the indole- l-carboxylate (3a).A solution of ( l a ) (150 mg) in ether (20 ml) was irradiated in aPyrex tube a t 2 "C until the starting material had disappeared(10 h ; checked by n.m.r.spectroscopy). The ether was re-moved in vacuo to give an oil consisting essentially of theallene (2a) ; vmx. (CHC1,) 3 420, 2 220, 1 950, and 1 720 cm-l;8 (CDCl,) 7.0-7.65 (4 H, m, aromatic), 6.85 (1 H, d, J 6.6Hz, allenic), 5.62 (1 H, d, J 6.6 Hz, allenic), 4.18(2 H, q, J 7 Hz, CO,*CH,*CH,), and 1.22 (3H, t ,J 7 Hz, CO,CH,CH,). The crude (2a) (103 mg) was sub-jected to p.1.c. (benzene) t o give ethyl 2-cyanomethylindole-l-carboxylate (3a) (67), m.p.121" from light petroleum (b.p.60-80 "C) (Found: C, 68.2; H, 5.4; N, 12.3. Cl,H1,N,O2requires C, 68.4; H, 5.3; N, 12.3); vmax. (KCl) 2 250 and1725 cm-l; A,, (EtOH) 225, 253, 261, 281, and 291 nm(log~4.31,4.09,4.07, 3.50,and3.54); S(CDC1,) 8.1 (m, l H ,H-7), 7.1-7.6 (3 H, m, aromatic), 6.75br (1 H, s, H-3), 4.56(2 H, q, J 7 Hz, CO,*CH,CH,), 4.16br (2 H, s, CH,*CN),and 1.51 (3 H, t , J 7 Hz, CO,CH,*CH,); m / e 228 (M+).Use of silica gel (Merck GF,,,) and benzene as solvent gavethe similar result.(13) Preparative procedure. A solution of (la) (2 g) inether (300 ml) in an immersion apparatus (glass filter) was(p.1.c.) firradiated a t 2 "C until the starting material had dis-appeared (18 h). To the photolysate was added alumina(Woelm neutral) (2 g) and the mixture was stirred for 5 11a t room temperature.The alumina was filtered off andconcentration of the filtrate afforded (3a) (1.67 g, 83).A solution of (la) (100 mg) inethanol (14 ml) was irradiated in a glass tube at 2 "C untilthe starting material had disappeared (15 h ; checked byt.1.c.). The ethanol was evaporated off and the residuewas submitted to p.1.c. (benzene) to afford ethyl 0-(3-cyano-l-etJzoxyal1yl)phenylcarbama~~ (7) (55 mg, 46o/b), m.p. 73-74"from light petroleum (b.p. 60-80 "C) (Found: C, 65.5; H,6.7; N, 10.0. Cl,Hl,N,03 requires C, 65.7; H, 6.6; N,10.2) ; vmax. (CCl,) 3 360, 2 210, and 1 740 cm-l; 6 (CDC1,)8.28br (1 H, s, NH), 8.03 (1 H, d, J 8 Hz, aromatic), 6.9-7.5(3 H, m, aromatic), 6.71 (1 H, dd, Jbc 12.0, Jab8.0Hz, Hb),4.22 (2 H, q, 7 Hz, CO,*CH,*CH,), 3.60 (2 H, q, J 7 Hz, O-CH,.CH,), 1.17 (3 H, t , CO,*CH,*CH,), and 1.14 (3 H, t, OCH,*CH,); A,,,.(EtOH) 223 and 284 nm (log E 4.22 and 3.07);in/e 274 (M+). Irradiation of the same solution of (la) a t20 "C also gave the adduct (7) (44).Irradiation of the Cyano-esttw (lb).-(A) A solution of (lb)(300 mg) in ether (40 ml) was irradiated in a Pyrex tube a t2 "C for 10 h. The ether was evaporated off and the residuewas subjected to p.1.c. (benzene) to give the indole (3b) (20nig, lay0), m.p. 108-109" from light petroleum (b.p. 60-80 "C) (Found: C, 69.3; H, 5.9; N, 11.3. Cl,Hl,N,O, re-quires C, 69.4; H, 5.8; N, 11.6); vmx. (KC1) 2 250 and1 730cm-1; 6 (CDCl,) 7.93 (1 H, d, J 9 Hz, H-7), 7.29br (1 H,s,H-4),7.12(1H,dd, JgandgHz,H-6),6.64(lH,s,H-3),4.52 (2 H, q, J 7 Hz, CO,CH,*CH,), 4.12br (2 H, s, CH,.CN), 2.41 (3 H, s, CH,), and 1.50 (3 H, t , J 7 Hz, CO,*CH,*CH,); A,, (EtOH) 232, 256, 263sh, 286, 290, and 297 nm(log E 4.39, 4.14, 4.11, 3.53, 3.56, and 3.56) ; wt/e 242 (Mf).The remaining product consisted mainly of the startingmaterial and polymeric material.Prolonged irradiationresulted in an increase in the amount of polymeric material.(B) A solution of (lb) (150 mg) in ether (20 ml) was irra-diated in a glass tube a t 2 "C. Samples were removed every5 h and analysed by n.m.r. spectroscopy. The starting ma-terial was 5074 consumed after 15 h. Separation of themixture by p.1.c. (benzene) gave (3b) in poor yield.Irradiation of the Cyano-ester (lc) .-(A) A solution of (lc)(300 mg) in ether (40 ml) was irradiated in a Pyrex tube a t2 "C for 10 h and concentrated.The indole (3c) was isolatedby p.1.c. (benzene) in 17 yield (25 mg); m.p. 98-99"from light petroleum (b.p. 60-80 "C) (Found: C, 69.4; H,5.8; N, 11.5. Cl,Hl,N,O, requires C, 69.4; H, 5.8; N,11.6); vmx. (KC1) 2 250 and 1740 cm-l; 6 (CDCl,) 7.92br(1 H, s, H-7), 7.38 (1 H, d, J 8 Hz, H-4), 7.06br (1 H, d,C0,-CH,*CH,), 4.11br (2 H, s, CH,*CN), 2.49 ( 3 H, s, CH,),and 1.50 (3 H, t, J 7 Hz, CO,*CH,*CH,); A,,, (EtOH)227, 259, 263sh, 283sh, 288sh, and 294 nm (log E 4.15, 3.95,3.94, 3.20, 3.08, and 3.08); mle 242 (amp;I+).( B ) Irradiation of the same solution of (lc) in a glass tubeat 2 "C for 15 h gave a mixture of (lc) (major) and severalphotoproducts including the allene (2c).Irradiation of the Cyano-ester (Id) .-(A) A solution of (Id)(150 mg) in ether (20 ml) was irradiated in a Pyrex tube at2 "C for 10 h.The indole (3d) was isolated by p.1.c. (benzene)in 10 yield (15 mg) ; m.p. 114-1 15" from light petroleum(b.p. 60-80 "C) (Found: C, 64.9; H, 5.5; N, 10.8. C14-H14N,0, requires C, 65.1; H, 5 . 5 ; Y, 10.85); vmx. (KC1)(C) Iradiation in ethanol.5.45 (1 H, d, Jbc 12.0 Hz, HJ, 5.30 (1 H, d, Jab 8.0 Hz, Ha),J 8 Hz, H-5), 6.65 (1 H, S, H-3), 4.53 (2 H, 9, J 7 Hz2590 J.C.S. Perkin I2 250 and 1 720 cni-1; 6 (CDCl,) 7.95br (1 H, d, J 10 Hz,H-7), 6.96 (1 H, s, H-4), 6.9Obr (1 H, d, J 10 Hz, H-6), 6.68br(1 H, s, H-3), 4.53 (2 H, q, J 7 Hz, CO,*CH,CH,), 4.15br (2H, s, CH,*CN), 3.86 (3 H, s, OCH,), and 1.51 (3 H, t, J 7 Hz,CO,-CH,*CH,); Amax.(EtOH) 240, 261, 297, and 307 nm(log E 4.48, 4.23, 3.71, and 3.69); m/e 258 (amp;I+).(B) Irradiation of the same solution of (Id) in a glass tubea t 2 "C for 15 h and work-up gave (3d) in poor yield.Irradiation of the Cyano-ester (le) .-(A) A solution of (le)(300 mg) in ether (40 ml) was irradiated in a Pyrex tube at2 "C for 8 h and concentrated. The residue was submittedto p.1.c. (benzene) to give compounds (3e) and (4) in 32 and10 yields, respectively. The indole (3e) had m.p. 88-89'from light petroleum (b.p. 30-60 "C) (Found: C, 69.4; H,5.9; hi, 11.3. C,,H,,N,O, requires C, 69.4; H, 5.8; N,11.6); vm,JKC1)2250and1 715cm-l; 6(CDC13)8.1(1H,in, H-7), 7.1-7.5 (3 H, m, H-4, -5, and -6), 4.55 (2 H, q,J 7 Hz, CO,*CH,*CH,), 4.10 (2 H, s, CH,CN), 2.26 (3 H,s, CH,), and 1.51 (3H, t, J 7 Hz, CO,.CH,*CH,) ; A,,,.(EtOH)229, 263, 286, and 294 (log E 4.32, 4.06, 3.37, and 3.37) ; m/e242 (M+). The physical and spectral data of (4) will bedetailed in a subsequent paper.(B) Irradiation of the same solution of (le) in a glass tubea t 2 "C for 15 h and work-up as above gave (3e) and (4) in34 and 16 yields, respectively.2-Methylindole (5).-A mixture of the indole (3a) (350mg) in ethanol (10 ml) and 10 potassium hydroxide (10ml) was refluxed for 3 h and the solvent was evaporated offin vacuo. The residue was acidified (dil. HC1) and extractedwith chloroform. The dried extract was concentrated andthe residual solid was recrystallized from light petroleum(b.p. 60-80 "C) to give (5) in quantitative yield; m.p. 58-59" (1it.,lo 59").Indole-2-acetonitrile (6a) .-A suspension of the indole (3a)(190 mg) and potassium carbonate (190 rng) in methanol(15 ml) was stirred at room temperature for 1 h. The po-tassium carbonate was filtered off, the filtrate was concen-trated, and the residual solid was recrystallized from lightpetroleum (b.p. 80-100 "C) to give the nitrile (6a) (127mg, 98), m.p. 103-104" (lit.,, 96-98').3-Melhylindole-2-acetonitvile (fib) .-By using the sameprocedure as above, the n i t d e (Gb) was obtained from (3a)(100 mg) in 79 yield; m.p. 90-91" from Iight petroleum(b.p. 60-80 "C) (Found: C, 77.6; H, 5.9; N, 16.5.C,,H,,,N, requires C, 77.6; H, 5.9; N, 16.5); v,,,. (KCl)3 350 and 2 250 cm-l; 8 (CDC1,) 7.9-8.2br (1 H, s, NH),7.0-7.6 (4 H, m, aromatic), 3.77 (2 H, s, CH,*CN), and 2.23(3 H, s, CH,).6/1362 Received, 12th July, 1976110 W. Madelung, Ber., 1912, 45, 1128