J. Org. Chem. 1984,49,4761-4768
4761
Ergoline Synthons. 2.’ Synthesis of 1,5-Dihydrobenz[cd]indol-4(3H)-ones and 1,3,4,5-Tetrahydrobenz[cd]indol-4-amines Lawrence I. Kruse* and Michael D. Meyer‘ Department of Medicinal Chemistry, Smith K l i n e and French Laboratories, Philadelphia, Pennsylvania 19101 Received J u n e 5, 1984
A short (four intermediates) and high-yield (40-50%) synthesis of new tricyclic ergoline synthons 6-H-5a, and 6-methoxy-5b, substituted 1,5-dihydrobenz[cd]indol-4(3H)-ones,from 1H-indole-4-carboxaldehyde(6a)and 5-methoxy-1H-indole-4-carboxaldehyde (6b), respectively, is described. Sodium cyanoborohydride mediated reductive amination of 5a and 5b provides easy access to 1,3,4,5-tetrahydrobenz[cd]indol-4-amines, compounds which show specificity for serotonin and dopamine receptors. The new aldehyde 6b is prepared in several steps from ethyl 5-methoxy-1H-indole-2-carboxylate by bromination of the indole 4-position, a reaction whose regiochemistry is a consequence of stereoelectronic control. This synthetic sequence provides a new and practical route to 3,4-bridged indoles which proceeds without the need for protecting groups.
The pharmacological activities of ergot derivatives such as 1 are legion.’ Recent attempts at side-chain2and nuclear modifications3 and the synthesis of ergot “substru~tures”~ have produced pharmacological selectivity in structural relatives of 1. l. During the course of our
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l a , R1= CONEt2: R2 = H: R3= H: C9-lo=CH=C: LSD l b , R1=CONH350 OC dec; IR 3350,1570,1460cm-'; UV ,,A 206 nm ( t 17900),230 (18100),264 (6600),300 (8100); NMR (CDC13-Me2SO-ds)6 3.8 (s, 3 H), 4.16 (s, 2 H), 6.82 (d, 1 H, J = 9 Hz), 7.14 (d, 1 H, J = 9 Hz), 7.56 (s, 1 H), 8.2 (s, 1 H); mass spectrum, m l e 230, 213, 183, 168. Anal. Calcd for ClZHl&zO3: C, 62.60;H, 4.38;N, 12.17. Found C, 62.40;H, 4.49;N, 11.82. 6-Methoxy-4-nitro-1,3,4,5-tetrahydrobenz[c,d]indole (20b). A mixture of nitroolefin 19b (7.26g, 31.6 mmol) and methanol (0.5 L) was stirred vigorously in a 2-L flask during the slow (ca. 20 min) addition of sodium borohydride (18.25 g, 0.48 mol). During the addition, vigorous hydrogen evolution occurred, and the mixture became quite warm and finally attained a yellowbrown color. After stirring an additional 10 min, glacial acetic acid (ca. 45 mL) was added to a final pH of 5-6. The solution was concentrated and partitioned between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed sequentially with water, 5% aqueous sodium carbonate, and brine. The solution was dried and concentrated, and the solid residue was purified by flash chromatography using 2:l hexane-ethyl acetate as eluant to give 20b (6.5g, 89%) as a light yellow solid: mp 134-136 "C; Rf 0.44 with 2:l hexane-ethyl acetate as eluant. An analytical sample was recrystallized from ethyl acetate/hexane as yellow needles: mp 135-136 "C; IR 3400,1550, 1520 cm-'; UV,,A 208 nm (t 243001,224(26000),268 (5900),298 (5000);NMR 6 3.5-3.7 (m, 4 H), 4.05 (s, 3 H), 4.95-5.3 (m, 1 H), 7.1-7.5 (m, 3 H), 8.2 (br s, 1 H); mass spectrum, m / e 232, 186, 185. A n d Calcd for C12H12N203:C,62.06;H, 5.21;N, 12.06. Found C, 61.93,H, 5.18,N, 11.78. 6-Methoxy-l,5-dihydrobenz[cd]indol-4(3H)-one(5b). A mixture of indole 20b (1.16g, 5 m o l ) and methanol (25mL) was and stirred treated with solid sodium methoxide (0.3g, 5.5 "01) under argon until homogeneous. A solution made by mixing 20% aqueous titanium trichloride (17.5mL) with ammonium acetate (10.5 g) dissolved in water (35mL) was added, and the resulting dark suspension was stirred for 1 h. The mixture was shaken uigorously and decanted with diethyl ether (8 X 50 mL). The diethyl ether extracts were washed sequentially with water (3x 100 mL), 5% aqueous sodium carbonate (2X 100 mL), and brine, dried, and concentrated to give 5b (0.82 g, 81%) as an off-white solid mp 130-132 "C dec; R, 0.36 with 2:l hexane-ethyl acetate as eluant. An analytical sample was prepared by flash chroma-
J. Org. Chem., Vol. 49, No. 25, 1984 4767 tography with 2:1 hexane-ethyl acetate as eluant and recrystallization of the concentrated eluate from ethyl acetate/hexane: mp 130-132 OC dec; IR 3400,1705,1510cm-'; UV ,A, 220 nm (t 25700),268 (5800);NMR 6 3.72 (br s,4H), 3.85 (s, 3 H), 6.82 (d, 1 H, J = 9 Hz), 6.86 (s, 1 H), 7.14 (d, 1 H, J = 9 Hz), 7.8(br s, 1 H); mass spectrum, m / e 201. Anal. Calcd for Cl2H1,NO2: C, 71.63;H, 5.51;N,6.96. Found C, 71.23;H, 5.66;N, 7.10. 4-(2-Nitroethenyl)-lH-indole(17a). A mixture of 1Hindole-4carboxaldehyde(3g, 20.7 mmol), ammonium acetate (0.6 g), and nitromethane (30mL) was heated at 100 "C on a steam bath for 2 h, then diluted with ethyl acetate (150mL) and washed twice with water and once with brine, dried, and concentrated. The deep red solid was recrystallized from ethyl acetate to give 17a (3.36g, 86%) as two crops of red prisms: mp 156-158 "C; R, 0.56 with 1:l hexane-ethyl acetate as eluant. An analytical sample was recrystallized from ethyl acetate: mp 161-163 "C; IR 3350,1630,1570,1340cm-'; UV ,A, 218 nm (c 27700),256 (9600);NMR (CDC13-acetone-d6) 6 6.8 (br s, 1 H), 7.0-7.7 (m, 4 H), 7.85 (d, 1 H, J = 14 Hz), 8.35 (d, 1 H, J = 14 Hz); mass spectrum, m / e 188, 171,141,115. Anal. Calcd for C l ~ ~ z O C, , :63.82;H, 4.28;N, 14.88. Found C, 63.69;H, 4.27;N, 14.69. 4-(2-Nitroethyl)-lH-indole (18a). A mixture of indole 17a (3.19g, 17 mmol) and methanol (175mL) in a 500-mL flask was stirred vigorously during the slow (15 min) addition of sodium borohydride (2.04 g, 54 mmol). After the vigorous reaction subsided, the light yellow solution was stirred for 30 min, acidified to pH 6 by the addition of glacial acetic acid, and concentrated. The residue was partitioned between water and ethyl acetate, the aqueous layer was extracted twice with ethyl acetate, and the combined ethyl acetate layers were washed with water and brine. The organic layer was dried and concentrated, and the residue was purified by flash chromatography using 2:l hexane-ethyl acetate as eluant to give 18a (2.39g, 74%) as a yellow oil: Rf 0.48 with 2:l hexane-ethyl acetate as eluant. An analytical sample was prepared by bulb-to-bulb distillation [bp 160-170 "C (0.3 torr)]: mp 61-62 "C; IR 3420,1550,1540cm-'; UV,,A 218 nm (e 30300),274 (6000);NMR 6 3.52 (t, 2 H, J = 7 Hz), 4.68 (t, 2 H , J = 7 Hz), 6.5 (br s, 1 H), 6.8-7.3 (m, 4 H), 8.2(br s, 1 H); mass spectrum, m l e 190,143. Anal. Calcd for ClJ-Il,,N2OZ: C, 63.15;H, 5.30; N, 14.73.Found C, 63.19;H, 5.20; N, 14.52. 4-Nitro-l,5-dihydrobenz[cd]indole(19a). DMF' (5 mL) was stirred under argon in a 250-mLflask as phosphorous oxychloride (0.89mL, 9.6 mmol) was added. The solution was stirred for 5 min, and indole 18a (1.6g, 8.42 mmol) was added. The resulting yellow paste was stirred 15 min, a mixture of water (1.7 mL, 95 "01) and DMF (6.75mL) was added, and the quenched reaction was stirred an additional 10 min before the addition of a mixture of triethylamine (11.8mL, 85 mmol) and methanol (33mL). The resulting solution was heated at reflux for 20 min, water (42mL) was added slowly, the mixture was slowly cooled to ambient temperature, and the crystalline product was isolated by filtration. The precipitate was washed with 2:l water-methanol (25mL) and dried at 60 "C to give 19a (1.54g, 92%) as brown crystals. The crude product was placed as a solid on the top of a silica gel column (50 g, 3 X 20 cm) and eluted with ethyl acetate. When the eluate became slightly yellow, the next 800 mL was collected and concentrated to give 19a (1.44 g, 86%)as bronze-red crystals: mp 206-208 "C dec; R, 0.45 with 1:l hexane-ethyl acetate as eluant. An analytical sample was recrystallized from methanol as red needles: mp 209-210 OC dec; IR 3350,1650,1580, 1475 cm-'; UV A, 204 nm ( t 16500),224 (20300),260 (6600),288 (8100);NMR (CDC13-Me2SO-ds)6 4.35 (s, 2 H), 6.8-7.0 (m,1 H), 7.2(apparent d, 2 H, J = 6 Hz), 7.5 (s, 1 H), 8.15 (s, 1 H); mass spectrum, m / e 200,183,168,153. Anal. Calcd for C11H&02: C, 66.00;H, 4.03;N,13.99.Found C, 65.71;H, 3.95;N, 14.06. 4-Nitro-1,3,4,5-tetrahydro[cd]indole(20a). A solution of indole 19a (1.37g, 6.85 mmol) in methanol (170mL) was stirred rapidly in a 500-mL flask during the addition (40min) of sodium borohydride (4.82g, 0.128mol). After the addition was completed, the light yellow solution was stirred an additional 20 min and neutralized to pH 5 by the addition of glacial acetic acid. The solution was concentrated and partitioned between water and ethyl
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J. Org. Chem., Vol. 49, No. 25, 1984
acetate, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed twice with 5% aqueous sodium carbonate, and once with brine, then dried, and concentrated. The crude product was purified by flash chromatography using 2:l hexane-ethyl acetate as eluant to give 20a (1.22 g, 88%) as a yellow solid: mp 134-135 "C; Rf 0.45 with 2:l hexane-ethyl acetate as eluant. An analytical sample was recrystallized from ethyl acetate/hexane: mp 134-135 "C; IR 3420, 1620, 1540 cm-'; UV A, 224 nm (e 31 goo), 280 (5400); NMR (CDC1,-acetone-d6) 6 3.35-3.7 (m, 4 H), 4.8-5.15 (m, 1H), 6.7-7.2 (m, 4 H), 9.2 (br s, 1 H); mass spectrum, m / e 202, 154, 128. Anal. Calcd for Cl1H,$J2O2:C, 65.34; H, 4.98; N, 13.85. Found C, 65.02; H, 5.12; N, 13.77. 1,5-Dihydrobenz[cd]indol-4(3H)-one (5a). A solution of indole 20a (1.12 g, 5.54 mmol) in methanol (33 mL) was stirred under argon during the addition of solid sodium methoxide (0.33 g, 6.1 mmol). After 5 min, a solution prepared by mixing aqueous 20% titanium trichloride (19.4 mL) with a solution of ammonium acetate (11.6 g, 0.15 mol) in water (37.8 mL) was added, and the resulting mixture was stirred at ambient temperature for 45 min. The dark colored reaction mixture was shaken vigorously and decanted with diethyl ether (8 x 50 mL). The combined diethyl ether extracts were washed sequentially with water (2 X 100 mL), 5% aqueous sodium carbonate (2 x 100 mL), and brine. The solution was dried and concentrated, and the crude product was purified by flash chromatography using 1:l ethyl acetate-hexane as eluant to give 5a (0.68 g, 72%) as a white solid: mp 136-138 "C dec; Rf 0.41 with 40% ethyl acetate-hexane as eluant. An analytical sample was recrystallized from ethyl acetate/hexane as white needles: mp 146-147 "C dec; IR 3320,1700,1470 cm-'; UV A, 220 nm (e 32000), 276 (5700);NMR 6 3.76 (s,2 H), 3.88 (s, 2 H), 6.6-6.95 (br m, 2 H), 7.1-7.3 (m, 2 H), 8.1 (br s, 1 H); mass spectrum, m / e 171, 143, 115. Anal. Calcd for Cl1H9NO: C, 77.17; H, 5.30; N, 8.18. Found C, 77.37; H, 5.28; N, 7.98. 6-Met hoxy- 1,3,4,5-tetrahydrobenz[ cd Iindol-4-amine (2b, R, = H,) Hemioxalate. Platinum oxide (300 mg) was reduced under 60 psi hydrogen pressure in methanol (30 mL) for 30 min. Compound 20b (1.0 g, 4.31 mmol) was added, and the resulting solution was hydrogenated under 60 psi hydrogen pressure until hydrogen uptake ceased (ca. 2 h). The mixture was filtered, the filtrate was concentrated, and the residue was dissolved in chloroform and decolorized with activated carbon. The resulting mixture was filtered, and the filtrate was concentrated. The residue was dissolved in absolute ethanol (8 mL), and the solution was stirred and heated to near reflux as a solution of oxalic acid dihydrate (540 mg, 4.31 mmol) in absolute ethanol ( 5 mL) was added slowly. The mixture was diluted with acetone (10 mL), cooled at 0 "C, and filtered, and the precipitate was washed with acetone (2 x 10 mL), hot methanol (2 X 10 mL), and dried to yield 2b (R, = H2) hemioxalate (0.74 g, 70%): mp 26C-265 "C dec; IR 221 nm (e 25300), 275 (5760); 3250,2900,1680,1580cm-'; W A, NMR (D20-Me2SO-d6)6 2.8-3.6 (br m, 5 H total), 3.6 (s, 3 H), 6.82 (d, J = 8 Hz, 1 H), 7.05 (s, 1 H), 7.20 (d, J = 8 Hz, 1 H); chemical ionization (methane) mass spectrum, m / e (M + 1) 203. Anal. Calcd for C13H15NZO3: C, 63.15; H, 6.11; N, 11.33. Found C, 62.78; H, 6.27; N, 11.08. N,NN-Dimethyl-6-methoxy1,3,4,5-tetrahydrobenz[ cd ]indol-4-amine [2b, R2 = (CH,),] Oxalate. A solution of anhydrous dimethylamine (0.26 g, 5.76 mmol), dimethylamine hydrochloride (2.45 g, 30.0 mmol), and sodium cyanoborohydride (1.88 g, 30.0 mmol) in methanol (30 mL) was prepared. Ketone 5b (0.60 g, 3.0 mmol) was added, and the reaction was stirred a t ambient temperature for 1 h and poured into 5% aqueous sodium bicarbonate solution (100mL). The resulting mixture was extracted with ethyl acetate (3 X 50 mL), and the combined organic extracts were washed with 5% aqueous hydrochloric acid (3 X 30 mL). The acidic extracts were made basic with 20% aqueous sodium hydroxide and extracted with ethyl acetate (3 X 50 mL), and the
Kruse and Meyer combined organic extracts were washed with 10% aqueous sodium sulfate, dried, and concentrated to yield crude amine as a light yellow oil (0.66 g). The crude product was purified by flash chromatography using 5% diisopropylamine-ethyl acetate as eluant to yield 2b [R2 = (CH3),] (0.38 g, 57%) as a colorless oil: NMR 6 2.4 (9, 6 H), 2.5-3.4 (m, 5 H total), 3.8 (s, 3 H), 6.7 (br s, 1 H), 6.8 (d, J = 9 Hz, 1 H), 7.0 (d, J = 9 Hz, 1 H), 8.2 (br s, 1H). The free base was dissolved in methanol (10 mL) and treated with a solution of oxalic acid (0.156 g, 1.73 mmol) in methanol (5 mL). The crystalline product was collected and dried (25 "C, 0.1 torr) to yield the oxalate salt of 2b [& = (CH,),] (0.44 9): mp 215-217 "C dec; IR (KBr pellet) 3300,3060,1510 cm-'; UV A, 221 nm (c 23600), 276 (5500);chemical ionization (methane) mass spectrum, m / e 231. Anal. Calcd for Cl6H&05: C, 59.99; H, 6.29; N, 8.74. Found C, 59.74; H, 6.41; N, 8.87. N,N-Dimethyl-1,3,4,5-tetrahydrobenz[ cdlindol-4-amine [2a, & = (CH3)J. A solution of anhydrous dimethylamine (0.520 g, 11.6 mmol), dimethylamine hydrochloride (4.90 g, 60.0 mmol), and sodium cyanoborohydride (3.76 g, 60.0 mmol) in methanol (60 mL) was prepared. Ketone 5a (1.026 g, 6.0 mmol) was added, and the reaction was stirred at ambient temperature under N2 for 2 h. The reaction was poured into 5% aqueous NaHC0, solution (250 mL) and extracted with ethyl acetate (3 X 75 mL). The combined organic extracts were washed with 5% aqueous HCl(3 X 30 mL). The acidic extracts were made basic with 20% aqueous NaOH and then extracted with ethyl acetate (3 X 75 mL). The organic extracts were washed with 10% aqueous Na2S04, dried, and concentrated to yield the crude amine as light brown oil (0.980 g). Purification by flash chromatography using 5% diisopropylamineethyl acetate as eluant yielded 2a (0.55 g, 52%) as a colorless oil which crystallized on standing: NMR 6 2.5 (s, 6 H), 2.5-3.4 (m, 5 H), 6.8-7.3 (m, 4 H), 8.4 (br s, 1 H). The product was triturated with petroleum ether and dried to yield 2a [& = (CH,),] (0.52 g, 49%): mp 102 "C; IR (KBr pellet) 3140, 1610, 1445, 1345 cm-'; UV A, 222 nm (e 31000), 280 (5800); chemical ionization (methane) mass spectrum, m / e 201. Anal. Calcd for C13H16N2:C, 77.96; H, 8.05; N, 13.94. Found: C, 77.81; H, 8.19; N, 14.03. 1,3,4,5-Tetrahydrobenz[cd]indol-4-amine[2a, R2 = H,]. Platinum oxide (0.50 g) was reduced under 50 psi of hydrogen pressure in methanol (50 mL) for 30 min. The nitro compound 20a (1.0 g, 4.95 mmol) in methanol (100 mL) was added, and the resulting mixture was hydrogenated at 50 psi for 3 h. The reaction was filtered, and the filtrate was concentrated under reduced pressure to yield a light yellow oil (0.80 g). The crude product was purified by flash chromatography using 15% diethylamineethyl acetate as eluant to yield 2a as a colorless oil (0.58 g, 68%) which crystallized on standing: mp 119-121 "C; IR (KBr) 3340, 1608, 1450 cm-'; UV A, 222 nm (e 28400), 280 (5200); NMR 6 1.4 (br s, 2 H), 2.5-3.3 (m, 4 H), 3.3-3.7 (m, 1 H), 6.7-7.2 (m, 4 H), 8.1 (br s, 1 H); chemical ionization mass spectrum, m / e 173. Anal. Calcd for C11H12N2:C, 76.71; H, 7.02; N, 16.27. Found: C, 76.72; H, 7.26; N, 16.07.
Acknowledgment. W e thank Dr. C. Kaiser for helpful discussions and encouragement, Ms. E. Reich for microanalyses, and Mr. L. Killmer for GLPC/mass spectral analyses. Registry No. 2a (R2 = (CH3)2), 73625-11-3; 2a (R, = HJ, 77963-70-3; 2b (Rg = Hz)*'/2C2Hz04, 92622-92-9; 2b (R2 = (CH,),)C2H2O4,92622-94-1; 5a, 2731-96-6; 5b, 92622-95-2; 6a, 1074-86-8; 6b, 92623-00-2; 9,4792-58-9; 10,30933-69-8;10 (acid), 92622-97-4; 11, 92622-96-3; 12, 30933-70-1; 13, 92622-98-5; 14, 92622-99-6; 17a, 49839-99-8; 17b, 87149-47-1; Ma, 87149-48-2; 18b, 87149-50-6; 19a, 92623-03-5; 19b, 92623-01-3;20a, 92623-02-4;20b, 92623-04-6; N,N-dimethylacetamide, 127-19-5; nitromethane, 75-52-5.
