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

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.

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, H_ar), 7.56-7.68 (m, 4 H, H-8, H_ar), 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.

22a Mayer S. Joseph B. Guillaumet G. Mérour J.-Y. Synthesis  2002,  1871 

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23 Plug JM. Koomen G.-J. Pandit U. Synthesis  1992,  1221 

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

26 Schneller SW. Luo J.-K. J. Org. Chem.  1980,  45:  4045 

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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.