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Synlett 2007(14): 2237-2241  
DOI: 10.1055/s-2007-985566
LETTER
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 6-Substituted Pyrido[2,3-b]indoles by Electrophilic Substitution

Cédric Schneidera, David Gueyrarda, Florence Popowyczb, Benoît Josephb, Peter G. Goekjian*a
a ICBMS, CNRS, UMR5246, Laboratoire Chimie Organique 2 - Glycochimie, Université de Lyon, Université Lyon 1, Bât. 308, CPE ­Lyon, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Fax: +33(4)72448349; e-Mail: peter.goekjian@univ-lyon1.fr;
b ICBMS, CNRS, UMR5246, Laboratoire Chimie Organique 1, Université de Lyon, Université Lyon 1, Bât. 308, CPE Lyon, 43, Bd du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
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Publikationsverlauf

Received 14 May 2007
Publikationsdatum:
13. August 2007 (online)

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Abstract

Regioselective electrophilic aromatic substitutions, acylation, bromination, and formylation, of unprotected pyrido[2,3-b]indole (α-carbolines) at the C-6 position are described. Alter­native conditions for the nitration were investigated, which led to the ­unexpected appearance of the minor C-8 isomer.

Key words

electrophilic aromatic substitutions - regioselectivity - heterocycles - acylations - halogenation - azacarbazole

    References and Notes

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18

Typical Procedure for Acylation: At r.t. and under an inert atmosphere, AlCl3 (714 mg, 5.36 mmol, 4.5 equiv) and acetyl chloride (178 µL, 2.38 mmol, 2 equiv) were added to a suspension of 4a (0.2 M, 200 mg, 1.19 mmol) in anhyd CH2Cl2. The mixture was stirred at reflux until completion of the reaction (monitored by TLC). In the case of methyl oxalyl chloride and oxalyl chloride, the chloride was added as a 50% solution in CH2Cl2 and the reaction was stirred at r.t. The resulting mixture was then cautiously quenched at 0 °C with H2O. The mixture was extracted with a mixture of EtOAc-DMF (99:1). The resulting organic layer was washed with a sat. aq NaHCO3 solution and brine, dried over MgSO4, filtered, and solvents were removed under reduced pressure. Trituration of the crude residue from MeOH followed by filtration afforded 6-acetylpyrido[2,3-b]indole 5a (168 mg) as a white solid. The filtrate was evaporated and purified by flash chromatography [gradient: EtOAc-PE (1:1) → EtOAc] to give additional 5a (26 mg); yield: 78%; mp 242 °C (MeOH). IR (KBr): 3045, 1668, 1602, 1571, 1496, 1468, 1246, 763, 710 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 12.21 (br s, 1 H, NH), 8.90 (d, J = 1.5 Hz, 1 H, H-5), 8.67 (dd, J = 1.7, 7.7 Hz, 1 H, H-4), 8.47 (dd, J = 1.7, 4.9 Hz, 1 H, H-2), 8.08 (dd, J = 1.5, 8.5 Hz, 1 H, H-7), 7.56 (d, J = 8.5 Hz, 1 H, H-8), 7.29 (dd, J = 4.9, 7.7 Hz, 1 H, H-3), 2.67 (s, 3 H, Me). 13C NMR (75 MHz, DMSO-d 6): δ = 197.0 (CO), 151.6 (C), 145.7 (CH), 141.8 (C), 129.9 (CH), 129.2 (C), 127.0 (CH), 123.0 (CH), 120.1 (C), 116.2 (C), 115.9 (CH), 111.3 (CH), 26.7 (Me). MS (EI): m/z = 210 [M+·]. Anal. Calcd for C13H10N2O: C, 74.27; H, 4.79; N, 13.32. Found: C, 74.35; H, 4.81; N, 13.26.

19

Analytical Data of Compound 6: The compound 6 was obtained by flash chromatography [gradient: EtOAc-PE (1:1) → EtOAc]; yield: 90%; white solid; mp 207 °C (MeOH). IR (KBr): 3049, 2850, 1734, 1622, 1599, 1496, 1473, 1408, 1234, 1201, 752 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 12.5 (br s, 1 H, NH), 8.86 (d, J = 1.5 Hz, 1 H, H-5), 8.74 (dd, J = 1.6, 7.8 Hz, 1 H, H-4), 8.52 (dd, J = 1.6, 4.9 Hz, 1 H, H-2), 8.05 (dd, J = 1.5, 8.6 Hz, 1 H, H-7), 7.66 (d, J = 8.6 Hz, 1 H, H-8), 7.33 (dd, J = 4.9, 7.8 Hz, 1 H, H-3), 4.00 (s, 3 H, Me). 13C NMR (75 MHz, DMSO-d 6): δ = 186.2 (CO), 165.3 (CO), 152.7 (C), 147.9 (CH), 143.2 (C), 129.7 (CH), 127.9 (CH), 125.1 (CH), 123.4 (C), 120.7 (C), 116.4 (CH), 115.3 (C), 112.0 (C), 52.9 (Me). MS (ESI): m/z = 255 [M + H+]. Anal. Calcd for C14H10N2O3: C, 66.14; H, 3.96; N, 11.02. Found: C, 66.22; H, 4.03; N, 10.92.

20

Analytical Data of Compound 7: The compound 7 was obtained by trituration from MeOH; yield: 71%; white solid; mp >295 °C (MeOH). IR (KBr): 3219, 1682, 1597, 1493, 1476, 1405, 909, 746 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 12.73 (br s, 1 H, OH), 12.18 (br s, 1 H, NH), 8.83 (br s, 1 H, H-5), 8.66 (dd, J = 1.6, 7.6 Hz, 1 H, H-4), 8.47 (dd, J = 1.6, 4.9 Hz, 1 H, H-2), 8.06 (dd, J = 1.7, 8.6 Hz, 1 H, H-7), 7.55 (d, J = 8.6 Hz, 1 H, H-8), 7.27 (dd, J = 4.9, 7.6 Hz, 1 H, H-3). 13C NMR (75 MHz, DMSO-d 6): δ = 167.9 (CO), 152.5 (C), 146.8 (CH), 141.7 (C), 129.2 (CH), 127.9 (CH), 123.5 (CH), 121.9 (C), 120.2 (C), 115.8 (CH), 115.4 (C), 111.0 (CH). MS (EI): m/z = 212 [M+·]. HRMS (EI): m/z calcd for C12H8N2O2: 212.0586; found: 212.0584.

21

Analytical Data for Compound 8: The compound 8 was obtained by flash chromatography [gradient: EtOAc-PE (1:1) → EtOAc]; yield: 78%; white solid; mp 212 °C (MeOH). IR (KBr): 3040, 1647, 1603, 1565, 1494, 1466, 1254, 769, 702 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 12.29 (br s, 1 H, NH), 8.65-8.67 (m, 2 H, H-4, H-5), 8.48 (dd, J = 1.5, 4.9 Hz, 1 H, H-2), 7.90 (dd, J = 1.5, 8.0 Hz, 1 H, H-7), 7.76-7.79 (m, 2 H, Har), 7.56-7.68 (m, 4 H, H-8, Har), 7.26 (dd, J = 4.9, 8.0 Hz, 1 H, H-3), 13C NMR (75 MHz, DMSO-d 6): δ = 195.5 (CO), 152.6 (C), 147.0 (CH), 141.7 (C), 138.3 (C), 132.0 (CH), 129.5 (2 × CH), 129.4 (CH), 128.7 (CH), 128.6 (C), 128.5 (2 × CH), 124.3 (CH), 120.4 (C), 115.9 (CH), 115.5 (C), 111.1 (CH). MS (ESI): m/z = 273 [M + H+]. Anal. Calcd for C18H12N2O: C, 79.40; H, 4.44; N, 10.29. Found: C, 79.48; H, 4.44; N, 10.29.

24

Typical Procedure and Analytical Data for Compound 9: At -78 °C and under an inert atmosphere, AlCl3 (714 mg, 5.36 mmol, 4.5 equiv) was added portionwise to a suspension of 4a (0.02 M, 200 mg, 1.19 mmol) in anhyd CH2Cl2. After stirring for 5 min, α,α-dichloromethyl methyl ether (318 µL, 3.57 mmol, 3 equiv) was added dropwise to the mixture. The reaction mixture was stirred at -78 °C and then allowed to warm to r.t. for 12 h. The resulting mixture was then cautiously quenched at 0 °C with H2O and extracted with a mixture of EtOAc-DMF (99:1). The combined organic layers were washed with a sat. aq NaHCO3 solution, dried with MgSO4, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (EtOAc-PE, 1:1) to afford 9 (100 mg, 46%) as a white solid; mp 262 °C (MeOH). IR (KBr): 3043, 3014, 2824, 1690, 1604, 1569, 1470, 1410, 761 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 12.35 (br s, 1 H, NH), 10.06 (s, 1 H, CHO), 8.79 (d, J = 1.1 Hz, 1 H, H-5), 8.66 (dd, J = 1.1, 7.7 Hz, 1 H, H-4), 8.50 (dd, J = 1.5, 4.9 Hz, 1 H, H-2), 7.99 (dd, J = 1.5, 8.5 Hz, 1 H, H-7), 7.64 (d, J = 8.5 Hz, 1 H, H-8), 7.30 (dd, J = 4.7, 7.7 Hz, 1 H, H-3). 13C NMR (75 MHz, DMSO-d 6): δ = 191.9 (CO), 152.6 (C), 147.1 (CH), 142.8 (C), 129.3 (CH), 128.9 (C), 127.5 (CH), 124.9 (CH), 120.6 (C), 116.1 (CH), 115.4 (C), 111.7 (CH). MS (EI): m/z = 196 [M+·], 195 [M+·- H], 167 [M+·- H - CO]. Anal. Calcd for C12H8N2O: C, 73.46; H, 4.11; N, 14.28. Found: C, 73.15; H, 4.39; N, 14.28.

25

Typical Procedure and Analytical Data for Compound 10: At r.t. and under an inert atmosphere, a solution of bromine (1.2 equiv, 0.7 M) in anhyd CH2Cl2 was added to a suspension of 4a (0.45 M, 200 mg, 1.19 mmol) in anhyd CH2Cl2. The mixture was stirred for 1 h at r.t. Excess bromine was destroyed by addition of a sat. aq Na2S2O3 solution. The resulting mixture was extracted with EtOAc-DMF (99:1). The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. Trituration of the crude residue from MeOH followed by filtration afforded 10 (241 mg). The filtrate was evaporated and purified by flash chromatog-raphy [gradient: EtOAc-PE (1:1) → EtOAc] to give additional 10 (27 mg); yield: 91%; mp 250 °C (MeOH, lit. [15a] mp 266-270 °C). IR (KBr): 3052, 1604, 1586, 1493, 1448, 768, 610 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 11.95 (br s, 1 H, NH), 8.56 (dd, J = 1.5, 7.7 Hz, 1 H, H-4), 8.45 (dd, J = 1.5, 4.7 Hz, 1 H, H-2), 8.43 (d, J = 1.9 Hz, 1 H, H-5), 7.58 (dd, J = 1.9, 8.5 Hz, 1 H, H-7), 7.46 (d, J = 8.5 Hz, 1 H, H-8), 7.23 (dd, J = 4.7, 7.7 Hz, 1 H, H-3). 13C NMR (75 MHz, DMSO-d 6): δ = 152.0 (C), 146.9 (CH), 137.5 (C), 129.2 (CH), 128.9 (C), 123.8 (CH), 122.3 (C), 115.4 (CH), 114.3 (C), 113.2 (CH), 111.4 (C). MS (EI): m/z = 246 [M+·]. HRMS (EI): m/z calcd for C11H7BrN2: 245.9793; found: 245.9797

28

The higher temperature required using the more reactive BF4NO2 salt suggests a possible involvement of an N-nitro intermediate. Further studies are underway to clarify the origin of the selectivity.

29

Analytical Data for Compound 13: mp >295 °C (MeOH) (lit. [15a] mp >320 °C). IR (KBr): 3066, 1612, 1587, 1573, 1498, 1456, 1327, 749 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 12.58 (br s, 1 H, NH), 9.25 (d, J = 2.2 Hz, 1 H, H-5), 8.80 (dd, J = 1.7, 7.8 Hz, 1 H, H-4), 8.54 (dd, J = 1.7, 4.8 Hz, 1 H, H-2), 8.35 (dd, J = 2.2, 9.0 Hz, 1 H, H-7), 7.65 (d, J = 9.0 Hz, 1 H, H-8), 7.35 (dd, J = 4.8, 7.8 Hz, 1 H, H-3). 13C NMR (75 MHz, DMSO-d 6): δ = 153.0 (C), 147.9 (CH), 142.6 (C), 140.5 (C), 130.2 (CH), 122.2 (CH), 120.3 (C), 118.4 (CH), 116.6 (CH), 115.5 (C), 111.6 (CH). MS (ESI): m/z = 214 [M + H+]. HRMS (ESI): m/z [M + H+] calcd for C11H7N3O2: 214.0617; found: 214.1017.

30

Analytical Data for Compound 14: mp 253 °C (MeOH). IR (KBr): 3046, 1600, 1573, 1525, 1474, 1362, 732 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 12.15 (br s, 1 H, NH), 8.63 (dd, J = 1.5, 7.7 Hz, 1 H, H-4), 8.62 (d, J = 7.7 Hz, 1 H, H-7), 8.58 (dd, J = 1.5, 4.8 Hz, 1 H, H-2), 8.35 (d, J = 8.2 Hz, 1 H, H-5), 7.43 (dd, J = 7.7, 8.2 Hz, 1 H, H-6), 7.36 (dd, J = 4.8, 7.7 Hz, 1 H, H-3). 13C NMR (75 MHz, DMSO-d 6): δ = 152.4 (C), 147.6 (CH), 132.1 (C), 131.9 (C), 128.9 (CH), 128.1 (CH), 124.5 (C), 122.1 (CH), 118.9 (CH), 116.5 (CH), 114.0 (CH). MS (EI): m/z = 213 [M+·]. HRMS (EI): m/z calcd for C11H7N3O2: 213.0538; found: 213.0535.