296 J. Chem. SOC. (C), 1967 The Synthesis of 1 -Substituted 5-Hydroxy-2-phenylindole Derivatives from Quinones By S. N. Betkerur and S. Siddappa, Department of Chemistry, Karnatak University, Dharwar 3, India Ethyl P-benzylaminocinnamate and ethyl P-n-butylaminocinnamate have been prepared and condensed with benzoquinone, toluquinone, and 1.4-naphthoquinone to give 1 -substituted 5-hydroxy-2-phenylindole derivatives. 1 - Benzyl-5- hydroxy-2-phenylindole and 1 -n-butyl-5-hydroxy-2-phenylindole have been synthesised. THE reaction of ethyl p-aminocrotonate with quinone first described by Nenitzescul for the preparation of 5-hydroxy-2-methylindole has since been employed extensively for the synthesis of various 5-hydroxy- C. D. Nenitzescu, Bul. SOC. chim. Beograd, 1929, 11, 37.* (a) R. J. Beer, K. Clarke, H. F. Davenport, and A. Robert- son, J . Chem. Soc., 1951, 2029; (6) R. J. Beer, H. F. Davenport, and A. Robertson, J . Chem. Soc., 1953, 1262; (c) E. A. Steck, R. P. Baundage, and L. T. Fletcher, J. Org. Chem., 1959, 24, 2-methylindoles and their 1 -substituted derivatives.2 But the only instance of the extension of the above re- action for the synthesis of 2-aryl-5-hydroxyindoles re- ported so far, is the recent synthesis of 5-hydroxy- 1750; (d) A. N. Grinev, V. N. Ermakova, I. A. Melinikova, and A. P. Terentiev, Zhur. obschchei Kkim., 1961,31, 2303; (e) A. N. Grinev and V. I. Shvedov, Zhur. obshchei Khim., 1962, 32, 2614; (f) G. R. Allen, jun., C. Pidacks, and M. J. Weiss. Chem. and Ind., 1965, 52, 2096.Org. 297 2-phenylindole by Nenitzescu employing ethyl p-amino- inn am ate.^ During the present investigation ethyl p-benzylaminocinnamate (Ia) and ethyl p-n-butyl- aminocinnamate (Ib) which were conveniently prepared from benzoyl acetic ester and benzylamine or n-butyl- amine, respectively, have been employed in the Nenitzescu reaction. Benzoylacetic ester was treated with benzylamine to obtain ethyl p-benzylaminocinnamate (Ia).The ester (Ia) was condensed with quinone in ethanolic solution to obtain 1 -benzyl-3-ethoxycarbonyl-5-hydroxy- 2-phenylindole (IIa) which was hydrolysed to the acid (IIb). Decarboxylation of the acid yielded l-benzyl- 5-hydroxy-2-phenylindole (IIc) . The method of Beer et U L . ~ ~ gave only the acid without simultaneous hydro- lysis and decarboxylation.Condensation of the ester (Ia) with toluquinone and 1,4-naphthoquinone gave, similarly, l-benzyl-3-ethoxycarbonyl-5-hydroxy-6- methyl-2-phenylindole (IId) and 1-benzyl-3-ethoxycar- bonyl-5-hydroxy-2-phenyl-1H-benz[g]indole (IIIa) ,. re- spectively. Ethyl N-n-butyl-p-aminocinnamate (Ib) , similarly prepared from benzoylacetic ester and n-butyl- amine, was condensed with quinone, toluquinone, and 1,4-naphthoquinone to yield the corresponding indole derivatives (IIe) (IIh) and, (IIIb), respectively. Hydro- lysis and decarboxylation of (IIe) gave l-n-butyl- 5-hydroxy-2-phenylindole (IIg) . PhCO*CH,.CO2Et + RNHz -- PhC[NHR]:CH*CO,Et (1) a; R = CH,Ph COZEt HC' C RHNI 'Ph Y R R CH,Ph, CH,Ph, CH,Ph, CH,Ph, Bun, Bun, Bun, Bun, b ; R = Bun CO2Et HPph / (IIIa : R = CH2Ph) (IIIb: R = Bun) EXPERIMENTAL E t h y l P-Benzylaminocinnamate (Ia) .-Benzylamine (1 8 g.) was added to benzoylacetic ester (30 g.) with stirring during 3 hr.the mixture allowed to stand for additional 2 hr., then heated a t 90-95" for 6 hr. and set aside over- night. The ester (Ia) that separated was collected and crystallised from ethanol as colourless plates, m. p. 68- 8 Dan Raileanu and C. D. 1966, 10, 339. Nenitzescu, Rev. Roumaine Cha'm., 69" (27 g.) (Found: C, 76.52; H, 6.23; N, 5-27. ClBH1,N02 requires C, 76.88; H, 6.76; N, 4.98%). Ethyl P-n-Butylaminocinnavlaate (Ib) .-n-Butylamine (8 g.) was added to benzoylacetic ester (15 g.) in small portions with external cooling, allowed to stand at room temperature for 1 hr. and then heated at 70-80" for 10 hr. The mixture was set aside ovenight, extracted with ether, and the ethereal solution dried and the solvent removed. The residue, on distillation under reduced pressure, gave the ester (Ib), as a pale yellow oil, b.p. 174-175"/15 mm. (14 g.). It gave a picrate, m. p. 143" (Found: N, 12-20. CI1H2,N4O9 requires N, 11.77y0). l-Benzyl-3-ethoxycarbonyZ-5-hydroxy-2-~henylindole ( IIa) . -The ester (Ia) (10 g.) in absolute ethanol (50 ml.) was added to benzoquinone (6.5 g.) in absolute ethanol (70 ml.) with shaking. The mixture was allowed to stand a t room temperature for 1 hr. and was then heated under reflux for 5 hr. The mixture was set aside overnight, the solvent removed under reduced pressure and the residue purified by crystallisation from benzene to obtain (IIa) as colourless needles (5.5 g.), m. p.142-143" (Found: C, 77.18; H, 5.33; N, 4.07. C,,H,,NO, requires C, 77.62; H, 5.66; N, 3.77%). 1-BenzyZ-5-hydroxy-2-phenylindoZe-3-carboxylic A cid (IIb) . -The compound (IIa) was hydrolysed with aqueous potassium hydroxide, the acid was liberated and crystall- ised from benzene to obtain (IIb) as colourless plates, m. p. 208-209" (Found: C, 76-50; H, 4-61; N, 4-34. C22H17NO3 requires C, 76-96; H, 4.95; N, 4.08%). l-Benzyl-5-hydroxy-2-phenylindole (IIc) .-The acid (IIb) (1 g.) was placed in a small flask, heated to 209-210" and the temperature maintained for about 5 min. On cooling, the product was purified by crystallisation from benzene to obtain the indole (IIc) as colourless needles (0.58 g.), m. p. 178" (Found: C, 84-51; H, 5-83; N, 4-96.C,,H,,NO requires C, 84-28; H, 5-68; N, 4.68%). l-Benzy1-3-ethoxycarbonyl-5-~ydroxy-6-methyl-2-~henyl- indole (IId).-The ester (Ia) (5 g.) in the minimum- quantity of glacial acetic acid was added in small portions to a solution of toluquinone (4.7 g.) in glacial acetic acid (50 ml.). The mixture was heated under reflux for 1 hr. and the solvent removed under reduced pressure. The residue was crystallised from benzene to give (IId) as colourless needles (2-5 g.), m. p. 219" (Found: C, 77.71; H, 5.99; N, 4-01. C2,H2,N0, requires C, 77-91; H, 5-97; N, 3.64%). l-Benzyl-3-ethoxycarbonyl-5-hydroxy-2-phenyl- 1 H-benz[g] - indole (IIIa).-The ester (Ia) ( 5 g.) in glacial acetic acid (25 ml.) was cooled in ice and lJ4-naphthoquinone (5 g.) in glacial acetic acid (50 ml.) was added dropwise with shaking. The mixture was then heated at 70-80" for 8 hr.and set aside overnight. The solid that separated was collected, washed with acetic acid and crystallised from benzene to get (IIIa) as colourless needles (2.8 g.), m. p. 224" (Found: C, 80.08; H , 5.90; N, 3-78. C,,H,,NO, requires C, 79.80; H, 5.46; N, 3.25%). l-n-Butyl-3-ethoxycarbonyl-5-hyd~oxy-2-phenyZindoZe (IIe) . -The ester (Ib) was added dropwise to a solution of benzo- quinone (4 g.) in the minimum quantity of ethanol. The mixture was heated under reflux for 3 hr. and set aside overnight. The solvent was removed under reduced pressure and the residue crystallised from benzene to give R. Lukes and J. Kolubek, COX Czech. Chem. Comm., 1960, 25, 607.298 (IIe) as colourless needles (3.4 g.), m.p. 158' (Found: C, 74-51; H, 6.50; N, 4.55. C21H23N03 requires C, 74.78; l-n-Butyl-5-hydroxy-2-phenylindole-3-ca~boxylic A cid (IIf) . -The compound (IIe) was hydrolysed with aqueous sodium hydroxide, and the acid liberated was crystallised from benzene to give colourless plates, m. p. 184' (Found: C, 73.30; H, 5-90; N, 4.78. ClgHl,N03 requires C, 73.77; H, 6-15; N, 4.51%). l-n-ButyZ-5-hydroxy-2-Phenylindole (IIg) .-The acid (IIf) (1 g.) was placed in a dry flask and heated in an oil bath at 188-190" for 5 min. The flask was cooled and the product crystallised from benzene-light petroleum to give the indole (IIg), as colourless needles (0.56 g.), m. p. 140" (Found: C, 81.17; H, 7-40; N, 5-62. C,,HlgNO requires C, 81-50; H, 7.16; N, 5.28%).l-n-Butyl-3-ethoxy~arbonyl-5-hydroxy-6-methyl-2-~ henylin- dole (IIh).-The ester (Ib) (10 g.) was added dropwise to an ice-cooled solution of toluquinone (6 g.) in glacial acetic acid (30 ml.). The mixture was set aside at room temper- ature for 1 hr. and then heated at 55-60" for 3 hr. and H, 6-81; N, 4~16'7~). J. Chem. SOC. (C), 1967 finally set aside overnight. The solid which separated was collected, washed with glacial acetic acid and crystallised from benzene to give (IIh) as colourless needles (4 g.), m. p. 192" (Found: C, 74.92; H, 7-52; N, 4-20. C,,H,,NO, requires C, 75.16; H, 7.12; N, 3.99%). benz[g]indole (IIIb).-The ester (Ib) (10 g.) was added drop- wise to an ice-cooled solution of 1,4-naphthoquinone (7.5 g.) in glacial acetic acid (60 ml.). The mixture was set aside at room temperature for 1 hr. and then heated at 45-50" for 3 hr. and finally left overnight. The solid which separated was collected and crystallised from benzene to give (IIIb) as colourless needles (10 g.), m. p. 220" (Found: C, 77.13; H, 6-70; N, 3-40. C,,H2,N03 requires C , 77.52; H, 6.47; N, 3.62%). The authors thank Mr. V. A. Desai for the microanalyses and one of them (S. N. B.) is grateful to the Ministry of Scientific Research and Cultural Affairs, Government of India, for a Research Training Scholarship. l-n-Butyl-3-ethoxycarbonyl-5-hydroxy-2-~henyl- 1 H- [6/1072 Received, August 23rd, 19681