Acid-catalysed cyclization of alpha;-oxo-anilides to 1,3-dihydro-3-hydroxyindol-2-ones

摘要

1556 J.C.S. Perkin IAcid-catalysed Cycl ization of a-0x0-anil ides to I ,3- Dihydro-3- hydroxy-i ndol-2-onesBy Hiromu Aoyama and Yoshimori Omote, Department of Chemistry, The UniversityofTsukuba, Sakuramura,Niihari, Ibaraki, JapanTadashi Hasegawa and Hiroaki Shiraishi, Department of Chemistry, Tokyo Kyoiku University, Otsuka,Tokyo, Japan.N-AIkyl-a-0x0-anilides undergo acid-catalysed cyclization at 25 "C to give the corresponding 1,3-dialkyl-l,3-dihydro-3-hydroxyindol-2-ones in high yields. The same anilides give 1,3-dialkyl-3-chloro-I ,3-dihydroindol-2-ones, when treated with concentrated hydrochloricacid at 80 "C. Reduction of the hydroxyindolones yields 1.3-dial kylindoles.DURING an investigation of the photochemical reactionsof amides,l N-alkyl-a-0x0-anilides were found to afford1,3-dihydro-3-hydroxyindol-2-ones on treatment withconcentrated hydrochloric acid.When N-methylpyruvanilide (la) was treated withconcentrated hydrochloric acid for 5 min at 25 "C,1,3-dimethyl-l,3-dihydro-3-hydroxyindol-2-one (2a),identical with an authentic sample,2 was obtained in-2can be explained in terms of protonation on the ketonecarbonyl oxygen followed by cyclization and deproton-ation (cj.the mechanism of the Bischler synthesis ofindoles 3).On the other hand, when the anilides (la-d) weretreated with concentrated hydrochloric acid at 85 OC,the corresponding 1,3-dialkyl-3-chloro-1,3-dihydroindol-2-ones (3a-d) were obtained, accompanied by smalla; R1 = R 2 = Me,R3 = Hb; R1c; ~1 = ~2 = Me,R3 = p - ~ ed ; ~1e; ~1 = ~2 = M ~ , R ~ = p - ~ ~ e e; R' = R Z = M e J R 3 = 5 - O M ef ; R' = R Z = Me,R3 = a - M eg; ~1 = R Z = M ~ , R ~ = ,,,-M~h ; R 1 = E ~ , R Z = M ~ , R ~ = Ha; R1 = R Z = Me,R3 = Hb; R' = Me,RZ = E t , R 3 = Hc; R ' = R Z = M e J R 3 = 5 - M ed ; R' = R Z = Me, R 3 = 5 - C L= Me,Rz = E t , R 3 = H= R Z = M ~ , R ~ = p - c ~f ; R1 = R Z = M e , R 3 = ? - M e9; R1 = R 2 = M e , R 3 = 6 - M eg';R' = R z = M e J R 3 = 4 - M eh; R' = E t , R 2 = M e , R 3 = H96 yield.The anilides (lb-h) also gave the corre- amounts of 1,3-dihydro-3-hydroxyindo1-2-ones (2a-d)sponding 1,3-dialkyl-l,3-dihydro-3-hydroxyindol-2-ones (see Table 2). Compounds (3a-d) were apparently(2b-h) in high yields. In the case of the meta-sub-stituted anilide (lg) the product was a 2 : 3 mixture oftwo positional isomers, (2g) and (2g').The results aresummarized in Table 1. The indoles (2b-h) wereCyclization of the 0x0-anilides (1) t o the chloroindolones (2)R 3RZ TABLE 1 R 2( 3 ) ( 4 1a; R' = R2 = Me,R3 = H a; R ' = R 2 = M eb; R' = Me,R2 = E t , R 3 = H b; ~1 = Me,R2 = ~t 5 25 965 25 94 c ; R1 = R 2 = Me,R3 = 5 - M e c ; ~1 = E ~ , R Z = M~5 25 91 d ; R 1 = R 2 = Me,R3 = 5 - C l4 80 80Reaction Reaction YieldsReactant time (min) temp. ("C) (I(14(1b)identified on the basis of spectral data and elementalanalyses.The formation of the 3-hydroxyindol-2-ones (2a-h)1 T. Hasegawa and H. Aoyama, J.C.S. Chem. Comm., 1974,743; T. Hasegawa, H. Aoyama, and Y. Omote, TetrahedronLetters, 1975, 1901.formed by reactions of the products (2a-d) withchloride anion; this was confirmed by the fact that thetreatment of compounds (2a-d) with concentratedhydrochloric acid under the same conditions gave thechloro-derivatives (3a-d) in similar yields.2 E.Giovanninni and J. Rosales, Helv. Chinz. Acta, 1963, 46,R. J. Sundburg. ' The Chemistry of Indoles,' Academic1332.Press, New York, 19701976 1557Since 1,3-dihydro-3-hydroxyindo1-2-ones can be con-verted into the corresponding indoles by reduction withlithium aluminium h ~ d r i d e , ~ the cyclization of cc-oxo-anilides was expected to be useful for the synthesis ofTABLE 2Cyclization of the oxo-anilides (1) to the chloroindolones (3)Reactant time (min) temp.("C) Yields (yo)Reaction Reaction( 1 4 3 86 (3a) 83; (2a) 153 85 (3b) 81; (2b) 163 85 (3c) SO; (2c) 15(3d) 71; (2d) 25(1b)(1c)(Id) 20 86some indoles. When the anilide (la) was treated withconcentrated hydrochloric acid and the crude productwas reduced with lithium aluminium hydride, 1,3-dimethylindoles (4a) was obtained in 78 yield. Theanilides ( l b and h) similarly afforded l-ethyl-3-methyl-indole (4b) (82) and 3-ethyl-l-methylindole (4h)(74), respectively.EXPERIMENTALGeneral Procedure for Cyclization of the u-Oxo-anilides(la-h) to the Hydroxyindolones (2a-h) .-A solution of theanilide (1) (500 mg) in concentrated hydrochloric acid(10 ml) was kept for 5-20 min at 25 "C (or 80 "C). Afteraddition of water the solution was extracted with ethylacetate three times.The organic layer was washed withsodium hydrogen carbonate solution and water, dried(MgSO,), and evaporated, and the crude product waspurified by chromatography or recrystallization.(i) 1,3-Dihydr0-3-hydroxy-l, 3-dimethylindol-2-one (2a)was identical with authentic material.(ii) l-Ethyl-l,3-dihydro-3-hydroxy-3-methylindol-2-one (2b)had m.p. 139-140.5"; v,,,(KBr) 3 330 and 1690 cm-l;S(CDC1,) 1.26 (3 H, t , J 7.2 Hz, CH,*CH,), 1.59 (3 H, s,and 6.80-7.50 (4 H, m, aromatic) (Found: C, 69.2; H,6.85; N, 7.25. C11H13NO2 requires C, 69.1; H, 6.85; N,(iii) 1,3-Dihydro-3-hydroxy-1,3,5-trimethylindol-2-one (2c)had 1ii.p. 158-160"; v-*(KBr) 3 330 and 1690 cm-1;G(CDCI,) 1.59 (3 H, s, 3-CH3), 2.47 (3 H, s, 5-CH3), 3.18(3 H, s, NCH,), 3.76 (1 H, s, OH), 6.74br (1 H, d, J 8.0 Hz,7-H), 7.16br(lH,dofd,J8.OandZ.OHz,6-H),and7.28br(1 H, d, J 2.0Hz, 4-H) (Found: C, 68.9; H 6.85; N, 7.25.C11H13NO2 requires C, 69.1; H, 6.85; N, 7.35).(iv) 5-ChZoro-l,3-dihydvo-3-hydroxy- 1,3-dirnethylindol-2-one (2d) had m.p.144.5-146"; v,,,(KBr) 3 300 and 1700cm-l; 6(CDCI,) 1.58 (3 H, s, 3-CH3), 3.17 (3 H, s, NCH,),3.40br (1 H, s, OH), 6.75br (1 H, d, J 9.0 Hz, 7-H), 7.29br(1 H, d of d, J 9.0 and 2.0 Hz, 6-H), and 7.37br (1 H, d,J 2.0 Hz, 4-H) (Found: C, 57.2; H, 4.75; N, 6.6.C1,H,C1N02 requires C, 56.75; H, 4.75; N, 6.7).(v) 1,3-Dihydr0-3-hydroxy-5 wzethoxy- 1,3-diwzethylindo1-2-one (2e) had m.p. 151-153"; v,,,(KBr) 3 300 and 1 690cm-l; S(CDC1,) 1.57 (3 H, s, 3-CH3), 3.16 (3 H, s, NCH,),3.82 (3 H, s, O-CH,), 6.80 (2 H, m, 6- and 7-H), and 7.10(1 H, rn, 4-H) (Found: C, 63.7; H, 6.3; N, 6.85.C,,HI,NO3 requires C, 63.75; H, 6.3; 6.75).(vi) 1,3-Dihydro-3-hydroxy-1,3,7-triwzethylie (2f)3-CH3), 3.44 (1 H, S, OH), 3.84 (2 H, q, J 7.2 Hz, CHJ,7.35).had m.p.140-141"; v,,.(KBr) 3 330 and 1 690 cm-l;(3 H, s, N-CH,), and 7.00-7.40 (3 H, m, aromatic) (Found:C, 69.0; H, 6.9; N, 7.25. CllHl9NO2 requires C, 69.1;H, 6.85; N, 7.35).(vii) 1,3-Dihydro-3-hydroxy-1,3,6-tr~methyl~ndol-2-o~e (2g),isolated from a mixture of (2g) and 1,3-dihydr0-3-hydroxy-1,3,4-trimethylindol-2-one (2g') by fractional recrystalliz-ation compound (2g') was not completely purified, hadm.p. 173-175.5"; v,,,(KBr) 3 330 and 1690 cm-l;(3 H, s, NCH,), 3.37 (1 H, s, OH), 6.65br (1 H, s, 7-H),6.86br (1 H, d, J 8.0 Hz, 5-H), and 7.27br (1 H, d, J 8.0 Hz,4-H) (Found: C, 69.5; H, 6.9; N, 7.35.C11H13NO2requires C, 69.1; H, 6.85; N, 7.35); compound (2g')showed G(CDC1,) 1.63 (3 H, s, 3-CH3), 2.47 (3 H, s, 4-CH3),3.14 (3 H, s, N-CH,), and 6.41-7.42 (3 H, m, aromatic).(viii) 3-Ethyl- lf3-dihydro-3-hydroxy- l-wzethylindol-2-one(2h) had m.p. 183-184"; vm(KBr) 3 350 and 1 690 cm-l;$(CD,),SO 0.58 (3 H, t, J 7.5 Hz, CH,*CH,), 1.81 (2 H,q, J 7.5 Hz, CH,), 3.08 (3 H, s, NCH,), 3.35br ( 1 H, s,OH), and 6.85-7.41 (4 H, m, aromatic) (Found: C, 68.8;H, 6.85; N, 7.25. C,,Hl,NO, requires C, 69.1; H, 6.85,General Procedure for Cyclization of the Oxo-anilides(la-d) to the Chloroindolones (3a-d) .-A solution of theanilide (1) (500 mg) in concentrated hydrochloric acid(10 ml) was heated to 85 "C for 3-20 min. After additionof water, the mixture was extracted with ethyl acetate threetimes and the organic layer was washed with sodiumhydrogen carbonate solution and water, and evaporated.The residue was chromatographed on silica gel to yield theproducts (3) accompanied by small amounts of the hydroxy-indolones (2).(i) 3-Chlwo-1,3-dihydro-l, 3-dimethylindol-2-one (3a) hadb.p.162-167" a t 3 mmHg; v,, (film) 1730 cm-1;G(CDC1,) 1.88 (3 H, s, 3-CH3), 3.22 (3 H, s, NCH,), and6.81-7.53 (4 H, m, aromatic) (Found: C, 61.1; H, 5.16;N, 7.15. CloH,oCINO requires C, 61.4; H, 5.15; N,7.15).(3b)had b.p. 168-173" a t 3 mmHg; vmaX (film) 1730 cm-1;G(CDC1,) 1.30 (3 H, t, J 8.0 Hz, CH,*CH,), 1.91 (3 H, s,3-CH3), 3.81 (2 H, q, J 8.0 Hz, CH,), and 6.85-7.60 (4 H,m, aromatic) (Found: C, 62.8; H, 5.75; N, 6.65.CIlH,,C1NO requires C, 63.0; H, 5.75; N, 6.7).(iii) 3-ChZoro-l,3-dihydro-l, 3,5-trimethylindoZ-2-one (3c)had m.p.100-102deg;; v,,,.(KBr) 1728 cm-l; S(CDC1,)NCH,), 6.74br (1 H, d, J 8.0 Hz, 7-H), 7.15br (1 H, d of d,J 8.0 and 1.5 Hz, 6-H), and 7.26br (1 H, d, J 1.5 Hz, 4-H)(Found: C, 63.2; H, 5.75; N, 6.75. C,,H,,ClNO requiresC, 63.0; H, 5.75; N, 6.85).(iv) 3,5-Dichloro-l, 3-dihydro-l,3-dimethylindoZ-2-one (3d)had m.p. 106-108"; v,,(KBr) 1730 cm-l; G(CDC1,)1.85 (3 H, S, 3-CH,), 3.20 (3 H, s, NCH,), 6.72br(1 H, d, J 9.0 Hz, 7-H), 7.26br (1 H, d of d, J 9.0 and2.0 Hz, 6-H), and 7.34br (1 H, d, J 2.0 Hz, 4-H) (Found:C, 52.5; H, 3.95; N, 6.3.Cl0H,CI2NO requires C, 52.2;H, 3.95; N, 6.1).General Procedure for Syntheses of the 1,3-DialkyZindole.s(4a, b, and h) from the Oxo-anilides (la, b, and h).-AS(CDC1,) 1.55 (3 H, S, 3-CH3), 2.55 (3 H, S, T-CH,), 3.47G(CDCI3) 1.55 (3 H, S, 3-CH3), 2.36 (3 H, S, 6-CH3), 3.14N, 7.35).(ii) S-chloro- l-ethyl- 1 , 3-dihydro-3-methyZindol-2-one1.86 (3 H, S, 3-CH3), 2.34 (3 H, S , 5-CH3), 3.19 (3 H, S,T. Bergman, Acta Clzem. Scand.. 1971. 25. 1277.5 E. F. -J. Janetzky and P. E. .Verkadej-Rec. Trav. chim.,1945. 65, 6911558 J.C.S. Perkin Isolution of the anilide (1) (1.0 g) in concentrated hydro-chloric acid (20 ml) was kept for 5 min at 25 "C. Afteraddition of water, the solution was extracted with ethylacetate three times and the organic layer was worked up asusual. The crude product was dissolved in dry ether(60 ml) . Lithium aluminium hydride (600 mg) was added,and the mixture was refluxed for 4 h, worked up as usual,and chromatographed on silica gel. Elution with benzenegave the indole (4).The indoles (4a and b) were identical with authenticmaterials: compound (4h) had b.p. 118-121" at 4 mmHg(lit.,6 96-97' a t 0.6 mmHg), v,,=(film) 3 050, 1612, and727 cm-l.6/152 Received, 23ud January, 1976