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.

Key words

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

References and Notes

• 1a Bolton D. Forbes IT. Hayward CJ. Piper DC. Thomas DR. Thompson M. Upton N. Bioorg. Med. Chem. Lett.  1993,  3:  1941 
• 1b Love BE. Top. Heterocycl. Chem.  2006,  2:  93 
• 2 Moquin-Pattey C. Guyot M. Tetrahedron  1989,  45:  3445 
• 3 Kim J.-S. Shinya K. Furihata K. Hayakawa Y. Seto H. Tetrahedron Lett.  1997,  38:  3431 
• 4a Joseph B, Meijer L, and Liger F. inventors; Fr. Patent, FR  28976377.  ; Chem. Abstr. 2006, 144, 390900
• 4b Sennhenn P, Mantoulidis A, Treu M, Tontsch-Grunt U, Spevak W, McConnell D, Schoop A, Brückner R, Jacobi A, Guertler U, Schnapp G, Klein C, Himmelsbach F, Pautsch A, Betzemeier B, Herfurth L, Mack J, Wiedenmayer D, Bader G, and Reiser U. inventors; Int. Appl., WO  2006131552.  ; Chem. Abstr. 2006, 146, 62695
• 5a Levacher V. Boussad N. Dupas G. Bourguignon J. Queguiner G. Tetrahedron  1992,  48:  831 
• 5b Molina P. Fresneda PM. Sanz MA. Tetrahedron Lett.  1997,  38:  6909 
• 5c Molina P. Fresneda PM. Sanz MA. Foces-Foces C. Ramirez de Arellano MC. Tetrahedron  1998,  54:  9623 
• 6 Tanaka K. Kitamura M. Narasaka K. Bull. Chem. Soc. Jpn.  2005,  78:  1659 
• 7a Molina P. Fresneda P. Synthesis  1989,  878 
• 7b Bonini C. Funicello M. Spagnolo P. Synlett  2006,  1574 
• 8a Tahri A. Buysens KJ. Van Der Eycken EV. Vandenberghe DM. Hoornaert GJ. Tetrahedron  1998,  54:  13211 
• 8b Zhang Q. Shi C. Zhang HR. Wang KK. J. Org. Chem.  2000,  65:  7977 
• 8c Schmittel M. Rodriguez D. Steffen J.-P. Molecules  2000,  5:  1372 
• 9a Saito T. Ohmori H. Furuno E. Motoki S. J. Chem. Soc., Chem. Commun.  1992,  22 
• 9b Molina P. Alajarin M. Vidal A. Sanchez-Andrada P. J. Org. Chem.  1992,  57:  929 
• 10 Barun O. Patra PK. Ila H. Junjappa H. Tetrahedron Lett.  1999,  40:  3797 
• 11 Beccalli EM. Clerici F. Marchesini A. Tetrahedron  2001,  57:  4787 
• 12 Joseph B. Da Costa H. Mérour J.-Y. Léonce S. Tetrahedron  2000,  56:  3189 
• 13a Rocca P. Marsais F. Godard A. Queguiner G. Tetrahedron  1993,  49:  49 
• 13b Achab S. Guyot M. Potier P. Tetrahedron Lett.  1993,  34:  2127 
• 14 Iwaki T. Yasuhara A. Sakamoto T. J. Chem. Soc., Perkin Trans. 1  1999,  1505 
• 15a Saxena JP. Indian J. Chem.  1966,  4:  148 
• 15b Stephenson L. Warburton WK. J. Chem. Soc. C  1970,  1355 
• 15c Wieczorek J. Peczynska-Czoch W. Mordarski M. Kaczmarek L. Nantka-Namirski P. Arch. Immunol. Ther. Exp.  1986,  34:  315 
• 15d Dininno FP, Guthikonda RN, and Meurer LC. inventors; US Patent, US  5532261.  ; Chem. Abstr. 1996, 125, 167688
• 16a Semenov AA. Tolstikhina VV. Chem. Heterocycl. Compd. (Engl. Transl.)  1984,  20:  345 
• 16b Mehta LK. Parrick J. Payne F. J. Chem. Soc., Perkin Trans. 1  1993,  1261 
• 16c Katritzky AR. Lan X. Yang JZ. Denisko OV. Chem. Rev.  1998,  98:  409 
• 16d Vera-Luque P. Alajarin R. Alvarez-Builla J. Vaquero JJ. Org. Lett.  2006,  8:  415 
• 17 Zhang Z. Yang Z. Wong H. Zhu J. Meanwell NA. Kadow JF. Wang T. J. Org. Chem.  2002,  67:  6226 
• 22a Mayer S. Joseph B. Guillaumet G. Mérour J.-Y. Synthesis  2002,  1871 
• 22b Lee TH. Tong KL. So SK. Leung LM. Synth. Met.  2005,  155:  116 
• 23 Plug JM. Koomen G.-J. Pandit U. Synthesis  1992,  1221 
• 26 Schneller SW. Luo J.-K. J. Org. Chem.  1980,  45:  4045 
• 27 Yang X. Xi C. Jiang Y. Tetrahedron Lett.  2005,  46:  8781 

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.

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.