Original and Rapid Access to New Alkaloid Analogues of Neocryptolepine: Synthesis of Substituted 6-Methyl-6H-indolo[2,3-b]quinolines via TDAE Strategy

Abstract

We report herein an original and rapid synthesis of new substituted 6H-indolo[2,3-b]quinolines based on TDAE strategy from reaction between substituted o-nitrobenzyl chlorides and 1-methyl isatin followed by a one-pot reduction-cyclization-dehydration reaction.

TDAE - indolo[2,3-b]quinoline - alkaloids - reduction - 1-methyl isatin

References

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18

General Procedure for the Reaction of o -Nitrobenzyl Chloride (1a-e) and 1-Methyl Isatin (2), Using TDAE.
Into a two-necked flask equipped with a drying tube (silica gel) and a nitrogen inlet was added 6 mL of anhyd DMF solution of o-nitrobenzyl chloride (1a-e, 0.4 g, 1.8 mmol) and 1-methyl isatin (2, 0.8 g, 5.4 mmol, 3 equiv) at -20 °C. The solution was stirred and maintained at this temperature for 30 min and then the TDAE (0.42 g, 1.8 mmol) was added dropwise (via syringe). A red color immediately developed with the formation of a fine, white precipitate. The solution was vigorously stirred at -20 °C for 1 h and then warmed up to r.t. for 2 h. After this time TLC analysis (CH₂Cl₂) clearly showed that compounds (1a-e) was totally consumed. The orange-red turbid solution was filtered (to remove the octamethyl-oxamidinium dichloride) and hydrolyzed with 80 mL of H₂O. The aqueous solution was extracted with CHCl₃ (3 × 40 mL), the combined organic layers washed with H₂O (3 × 40 mL) and dried over MgSO₄. Evaporation of the solvent left an orange viscous liquid as crude product. Purification by silica gel chromatography (CH₂Cl₂) and recrystallization from EtOH gave the corresponding α-hydroxy derivatives.
New products: compound 3a: white solid; mp 176 °C. ¹H NMR (200 MHz, DMSO-d ₆): δ = 3.01 (s, 3 H), 3.25 (d, J _AB = 13.4 Hz, 1 H), 3.65 (d, J _AB = 13.4 Hz, 1 H), 6.20 (br s, 1 H), 6.70 (m, 1 H), 6.92 (m, 2 H), 7.26 (m, 2 H), 7.50 (s, 2 H), 7.78 (m, 1 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 25.9, 38.9, 75.6, 108.5, 122.3, 123.8, 124.2, 128.3, 129.4, 130.3, 132.1, 134.0, 142.8, 150.6, 176.8. The C-nitro was not observed in this experiment. Anal. Calcd for C₁₆H₁₄N₂O₄: C, 64.42; H, 4.73; N, 9.39. Found: C, 64.36; H, 4.80; N, 9.50. Compound 3b: yellow solid; mp 201 °C. ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.31 (s, 3 H), 3.01 (s, 3 H), 3.25 (d, J _AB = 13.3 Hz, 1 H), 3.64 (d, J _AB = 13.3 Hz, 1 H), 6.19 (br s, 1 H), 6.75 (m, 1 H), 6.92 (m, 2 H), 7.10 (s, 1 H), 7.26 (m, 2 H), 7.71 (m, 1 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 20.9, 25.9, 39.1, 75.7, 108.4, 122.2, 123.7, 124.4, 128.6, 129.3, 129.5, 130.4, 134.5, 142.6, 142.8, 148.2, 176.9. Anal. Calcd for C₁₇H₁₆N₂O₄: C, 65.38; H, 5.16; N, 8.97. Found: C, 65.60; H, 5.25; N, 9.08. Compound 3c: yellow solid; mp 206 °C. ¹H NMR (200 MHz, DMSO-d ₆): δ = 3.02 (s, 3 H), 3.24 (d, J _AB = 13.5 Hz, 1 H), 3.54 (d, J _AB = 13.5 Hz, 1 H), 6.22 (br s, 1 H), 6.75 (m, 1 H), 6.94 (m, 2 H), 7.29 (m, 2 H), 7.67 (m, 1 H), 7.93 (m, 1 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 25.9, 38.4, 75.2, 108.6, 122.4, 123.7, 124.0, 128.5, 129.4, 130.3, 131.9, 132.2, 135.7, 142.7, 151.0, 176.6. Anal. Calcd for C₁₆H₁₃ClN₂O₄: C, 57.75; H, 3.94; N, 8.42. Found: C, 57.90; H, 4.00; N, 8.49. Compound 3d: yellow solid; mp 233 °C. ¹H NMR (200 MHz, DMSO-d ₆): δ = 2.98 (s, 3 H), 3.36 (d, J _AB = 13.3 Hz, 1 H), 3.63 (d, J _AB = 13.3 Hz, 1 H), 3.70 (s, 3 H), 3.75 (s, 3 H), 6.19 (br s, 1 H), 6.76 (s, 1 H), 6.91 (m, 3 H), 7.25 (m, 1 H), 7.39 (s, 1 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 25.9, 38.9, 55.9, 56.0, 76.0, 107.9, 108.5, 115.6, 123.2, 123.8, 129.3, 130.5, 142.6, 142.9, 147.3, 151.3, 177.0. The C-nitro was not observed in this experiment. Anal. Calcd for C₁₈H₁₈N₂O₆: C, 60.33; H, 5.06; N, 7.82. Found: C, 60.37; H, 5.16; N, 7.80.

19 Artico M. Silvestri R. Pagnozzi E. Stefancich G. Massa S. Loi AG. Putzolu M. Corrias S. Spiga MG. La Colla P. Bioorg. Med. Chem.  1996,  837 

20

General Procedure for Reduction-Cyclization-Double Dehydration Step.
Iron powder (1.8 g, 33.6 mmol, 28 equiv) was added over a period of 0.5 h to a stirred solution of the appropriate starting material (3a-e,1.2 mmol) in glacial AcOH (68 mL) while heating at 110 °C, then the mixture was maintained at 110 °C for 48 h. After filtration on Celite^® the solvent was evaporated under reduced pressure and the residue was neutralized with an aq solution of NaHCO₃. After extraction with CHCl₃ (3 × 30 mL), the combined organic layers washed with H₂O (3 × 40 mL) and dried over MgSO₄. Evaporation of the solvent left a viscous liquid as crude product. Purification by silica gel chromatography (CH₂Cl₂) and recrystallization from EtOH gave the corresponding 6-methyl-6H-indolo[2,3-b]quinolines (4a-e).
New products: compound 4a: orange solid; mp 57 °C. ¹H NMR (200 MHz, CDCl₃): δ = 3.82 (s, 3 H), 7.27 (m, 2 H), 7.50 (m, 2 H), 7.74 (m, 1 H), 7.90 (m, 1 H), 8.00 (m, 1 H), 8.17 (m, 1 H), 8.44 (s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 27.4, 108.4, 117.8, 119.6, 120.1, 121.1, 122.6, 123.9, 126.9, 127.3, 127.8, 128.3, 128.6, 142.5, 146.6, 152.4. Anal. Calcd for C₁₆H₁₂N₂: C, 82.73; H, 5.21; N, 12.06. Found: C, 82.56; H, 5.38; N, 12.00.
Compound 4b: orange solid; mp 106 °C. ¹H NMR (200 MHz, CDCl₃): δ = 2.58 (s, 3 H), 3.99 (s, 3 H), 7.36 (m, 2 H), 7.57 (m, 2 H), 7.76 (s, 1 H), 8.09 (m, 2 H), 8.63 (s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 21.4, 27.7, 108.6, 118.1, 119.8, 120.5, 121.3, 124.1, 126.7, 127.2, 127.3, 127.9, 131.1, 132.4, 142.8, 145.3, 152.5. Anal. Calcd for C₁₇H₁₄N₂: C, 82.90; H, 5.73; N, 11.37. Found: C, 83.01; H, 5.85; N, 11.56.
Compound 4c: white solid; mp 164 °C. ¹H NMR (200 MHz, DMSO-d ₆): δ = 3.90 (s, 3 H), 7.34 (m, 1 H), 7.48 (m, 1 H), 7.62 (m, 2 H), 8.02 (m, 1 H), 8.13 (m, 1 H), 8.27 (m, 1 H), 9.06 (s, 1 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 27.7, 109.6, 118.0, 119.6, 120.4, 121.9, 122.4, 123.4, 125.8, 127.9, 128.6, 130.6, 133.5, 142.6, 146.6, 152.6. Anal. Calcd for C₁₆H₁₁ClN₂: C, 72.05; H, 4.16; N, 10.50. Found: C, 72.04; H, 4.24; N, 10.54.
Compound 4d: yellow solid; mp 216 °C. ¹H NMR (200 MHz, CDCl₃): δ = 3.97 (s, 3 H), 4.05 (s, 3 H), 4.09 (s, 3 H), 7.25 (s, 1 H), 7.27 (m, 1 H), 7.40 (m, 1 H), 7.48 (s, 1 H), 7.55 (m, 1 H), 8.10 (m, 1 H), 8.57 (s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 27.7, 56.0, 56.1, 106.2, 106.7, 108.5, 116.1, 119.0, 119.6, 120.5, 120.8, 125.9, 127.2, 142.0, 143.7, 147.2, 152.0, 152.2. Anal. Calcd for C₁₈H₁₆N₂O₂: C, 73.95; H, 5.52; N, 9.58. Found: C, 73.98; H, 5.57; N, 9.62.
Compound 4e: yellow solid; mp 193 °C. ¹H NMR (200 MHz, CDCl₃): δ = 3.94 (s, 3 H), 6.09 (s, 2 H), 7.21 (s, 1 H), 7.27 (m, 1 H), 7.40 (m, 1 H), 7.44 (s, 1 H), 7.54 (m, 1 H), 8.07 (m, 1 H), 8.49 (s, 1 H). ¹³C NMR (50 MHz, CDCl₃): δ = 27.6, 101.4, 103.5, 104.5, 108.6, 116.0, 119.6, 120.1, 120.3, 120.9, 126.3, 127.2, 142.0, 145.0, 145.3, 150.4, 151.8. Anal. Calcd for C₁₇H₁₂N₂O₂: C, 73.90; H, 4.38; N, 10.14. Found: C, 74.00; H, 4.40; N, 9.80.

21 Porter JC. Robinson R. Wyler M. J. Chem. Soc.  1941,  620