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

<A NAME="RG29507ST-1A">1a</A> Cimanga K. De Bruyne T. Pieters L. Clayes M. Vlietinck A. Tetrahedron Lett.  1996,  37:  1703 

<A NAME="RG29507ST-1B">1b</A> Sharaf MHM. Schiff PL. Tackie AN. Phoebe CH. Martin GE. J. Heterocycl. Chem.  1996,  33:  239 

<A NAME="RG29507ST-1C">1c</A> Pousset J.-L. Martin M.-T. Jossang A. Bodo B. Phytochemistry  1995,  39:  735 

<A NAME="RG29507ST-2A">2a</A> Kansal VK. Potier P. Tetrahedron  1986,  42:  2389 

<A NAME="RG29507ST-2B">2b</A> Devarj R. Cushman M. Bioorg. Med. Chem. Lett.  1997,  7:  369 

<A NAME="RG29507ST-3">3</A> Molina A. Vaquero JJ. Garcia-Navio JL. Alvarez-Builla J. Pascual-Teresa B. Gago F. Rodrigo MM. Ballesteros M. J. Org. Chem.  1996,  61:  5587 

<A NAME="RG29507ST-4">4</A> Cimanga K. De Bruyne T. Pieters L. Vlietinck AJ. Turger CA. J. Nat. Prod.  1997,  60:  688 

<A NAME="RG29507ST-5A">5a</A> Peczynska-Czoch W. Pognan F. Kaczmarek L. Boratynski J. J. Med. Chem.  1994,  37:  3503 

<A NAME="RG29507ST-5B">5b</A> Kaczmarek L. Balicki R. Nantka-Namirski P. Peczynska-Czoch W. Mordarski M. Arch. Pharm.  1998,  321:  463 

<A NAME="RG29507ST-6A">6a</A> Molina P. Alajarin M. Vidal A. J. Chem. Soc., Chem. Commun.  1990,  1277 

<A NAME="RG29507ST-6B">6b</A> Molina P. Alajarin M. Vidal A. Sanchez-Andrada P. J. Org. Chem.  1992,  57:  929 

<A NAME="RG29507ST-6C">6c</A> Chen Y.-L. Hung H.-M. Lu C.-M. Li K.-C. Tzeng C.-C. Bioorg. Med. Chem.  2004,  12:  6539 

<A NAME="RG29507ST-6D">6d</A> Sundaram GSM. Venkatesh C. Syam Kumar UK. Ila H. Junjappa H. J. Org. Chem.  2004,  69:  5760 

<A NAME="RG29507ST-7">7</A> Molina P. Fresneda PM. Delgado S. Synthesis  1999,  326 

<A NAME="RG29507ST-8">8</A> Timari G. Soos T. Hajos G. Synlett  1997,  1067 

<A NAME="RG29507ST-9">9</A> Shi C. Zhang Q. Wang KK. J. Org. Chem.  1999,  64:  925 

<A NAME="RG29507ST-10">10</A> Kaczmarek L. Peczynska-Czoch W. Osiadacz J. Mordarski M. Sokalski WA. Boratynski J. Marcinkowska E. Glazman-Kusnierczyk H. Radzikowski C. Bioorg. Med. Chem.  1999,  7:  2457 

<A NAME="RG29507ST-11A">11a</A> Engqvist R. Bergman J. Org. Prep. Proced. Int.  2004,  36:  386 

<A NAME="RG29507ST-11B">11b</A> Alajarin M. Molina P. Vidal A. J. Nat. Prod.  1997,  60:  747 

<A NAME="RG29507ST-12A">12a</A> Takechi N. Ait-Mohand S. Médebielle M. Dolbier WR. Tetrahedron Lett.  2002,  43:  4317 

<A NAME="RG29507ST-12B">12b</A> Ait-Mohand S. Takechi N. Médebielle M. Dolbier WR. Org. Lett.  2001,  3:  4271 

<A NAME="RG29507ST-12C">12c</A> Médebielle M. Keirouz R. Okada E. Ashida T. Synlett  2001,  821 

<A NAME="RG29507ST-12D">12d</A> Dolbier WR. Médebielle M. Ait-Mohand S. Tetrahedron Lett.  2001,  42:  4811 

<A NAME="RG29507ST-13">13</A> Giuglio-Tonolo G. Terme T. Médebielle M. Vanelle P. Tetrahedron Lett.  2003,  44:  6433 

<A NAME="RG29507ST-14">14</A> Giuglio-Tonolo G. Terme T. Médebielle M. Vanelle P. Tetrahedron Lett.  2004,  45:  5121 

<A NAME="RG29507ST-15">15</A> Giuglio-Tonolo G. Terme T. Vanelle P. Synlett  2005,  251 

<A NAME="RG29507ST-16A">16a</A> Terme T. Crozet MP. Maldonado J. Vanelle P. In Electron Transfer Reactions in Organic Synthesis   Vanelle P. Research Signpost; Trivandrum: 2002.  p.1 

<A NAME="RG29507ST-16B">16b</A> Terme T. Beziane A. Vanelle P. Lett. Org. Chem.  2005,  2:  367 

<A NAME="RG29507ST-17A">17a</A> Amiri-Attou O. Terme T. Vanelle P. Molecules  2005,  10:  545 

<A NAME="RG29507ST-17B">17b</A> Kantevari S. Narasimhaji CV. Mereyala HB. Tetrahedron  2005,  61:  5849 

<A NAME="RG29507ST-18">18</A>

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.

<A NAME="RG29507ST-19">19</A> 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 

<A NAME="RG29507ST-20">20</A>

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.

<A NAME="RG29507ST-21">21</A> Porter JC. Robinson R. Wyler M. J. Chem. Soc.  1941,  620