Synthesis of Imidazolo[5,4-b]carbazole-4,10-quinones

Abstract

The preparation of imidazolo[5,4-b]carbazole-4,10-quinones 9 is described. The key steps of the synthesis are selective halogen-metal exchanges on the imidazole 3 and subsequent addition to carbonyl groups of ethyl-3-formylindole-2-carboxylate 4.

Key words

quinone - imidazole - ellipticine - metalation

References

• 1 Furukawa H. Wu T.-S. Ohta T. Kuoh C.-S. Chem. Pharm. Bull.  1985,  33:  4132 
• 2 Rickards RW. Rothschild JM. Willis AC. de Chazal NM. Kirk K. Saliba KJ. Smith GD. Tetrahedron  1999,  55:  13513 
• 3 Saha C. Chowdhury BK. Phytochemistry  1998,  48:  363 
• 4 Wu T.-S. Huang S.-C. Wu P.-L. Lee K.-H. Bioorg. Med. Chem. Lett.  1994,  4:  2395 
• 5 Saulnier MG. Gribble GW. J. Org. Chem.  1983,  48:  2690 
• 6 Bergman J. Wahlström N. Yudina LN. Tholander J. Lidgren G. Tetrahedron  2002,  58:  1443 
• 7 Knölker H.-J. Reddy KR. Chem. Rev.  2002,  102:  4303 
• 8 Knölker H.-J. Reddy KR. Heterocycles  2003,  60:  1049 
• 9a Poumaroux A. Bouaziz Z. Fillion H. Domard M. Giraud J. Pétavy A.-F. Chem. Pharm. Bull.  1999,  47:  643 
• 9b Bouaziz Z. Ghérardi A. Régnier F. Sarciron M.-E. Bertheau X. Fenet B. Walchshofer N. Fillion H. Eur. J. Org. Chem.  2002,  1834 
• 10 Bernardo PH. Chai CLL. Elix JA. Tetrahedron Lett.  2002,  42:  2939 
• 11 Kelly TR. Zhao Y. Cavero M. Torneiro M. Org. Lett.  2000,  2:  3735 
• 12 Iddon B. Lim BL. J. Chem. Soc., Perkin Trans. 1  1983,  735 
• 14 Butz RH.-J. Lindell SD. J. Org. Chem.  2002,  67:  2699 
• 15 Abarbri M. Thibonnet J. Bérillon L. Dehmel F. Rottländer M. Knochel P. J. Org. Chem.  2000,  65:  4618 
• 20 Kuo S.-C. Ibuka T. Huang L.-J. Lien J.-C. Yean S.-R. Huang S.-C. Lednicer D. Morris-Natschke S. Lee K.-H. J. Med. Chem.  1996,  36:  1447 

13

Selected data for 3b: Yellow solid; mp 69-70 °C. IR (KBr): 1460, 1173, 1102 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 1.21 (t, J = 7.0 Hz, 3 H, CH₃), 3.55 (q, J = 7.0 Hz, 2 H, CH₂), 5.37 (s, 2 H, CH₂). ¹³C NMR (75 MHz, CDCl₃): δ = 14.9 (CH₃), 65.0 (CH₂), 77.2 (CH₂), 83.2 (Cq), 94.8 (Cq), 134.3 (Cq). MS (ESI): m/z = 413 [M + H⁺] for ³⁵Cl, 415 [M + H⁺] for ³⁷Cl.

16

Using standard conditions (esterification, Vilsmeier-Haack formylation, N-Boc-protection) the indole derivative 4 was prepared from commercially available indole-2-carboxylic acid in 94% overall yield.

17

Typical Procedure for Cyclisation: To a solution of 7a (131 mg, 0.2 mmol) in anhyd THF (5 mL), was dropwise added at -78 °C a 2.24 M solution of BuLi in hexanes (103 µL, 0.2 mmol). After 1 h at -78 °C, the reaction mixture was allowed to warm to r.t. and was then hydrolysed by a sat. aq solution of NH₄Cl. The solution was extracted with CH₂Cl₂ (3 ×), the combined organic layer was dried over MgSO₄ and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (CH₂Cl₂-MeOH, 98:2) to afford quinone 8a as a red solid in 48% yield. Mp >210 °C (MeOH). IR (KBr): 1676, 1649 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.12 (t, J = 7.0 Hz, 3 H, CH₃), 3.58 (q, J = 7.0 Hz, 2 H, CH₂), 5.75 (s, 2 H, CH₂), 7.28-7.38 (m, 2 H, H_Ar), 7.52 (d, J = 8.0 Hz, 1 H, H_Ar), 8.06 (d, J = 8.0 Hz, 1 H, H_Ar), 8.28 (s, 1 H, H_Ar), 12.99 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 14.7 (CH₃), 64.2 (CH₂), 74.8 (CH₂), 113.9 (CH), 115.3 (Cq), 121.4 (CH), 123.8 (Cq), 124.0 (CH), 125.9 (CH), 132.6 (Cq), 137.1 (Cq), 137.6 (Cq), 141.9 (Cq), 143.8 (CH), 173.6 (Cq), 174.6 (Cq). MS (ESI): m/z = 296 [M + H⁺]. HRMS (CI): m/z calcd for C₁₆H₁₄N₃O₃: 296.1035; found: 296.1035. Compound 8b was prepared similarly starting from 7b but was crystallised from MeOH after chromatography. Red solid; mp >210 °C (MeOH). IR (KBr): 1670, 1650 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 1.20-1.27 (m, 3 H, CH₃), 3.65-3.73 (m, 2 H, CH₂), 5.83 (s, 2 H, CH₂), 7.47-7.50 (m, 1 H, H_Ar), 7.98-8.05 (m, 2 H, H_Ar), 8.22 (d, J = 7.2 Hz, 1 H, H_Ar), 9.50 (s, 1 H, NH). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 14.8 (CH₃), 64.6 (CH₂), 74.0 (CH₂), 114.1 (CH), 115.2 (Cq), 121.5 (CH), 123.9 (Cq), 124.4 (CH), 126.2 (CH), 133.7 (Cq), 136.5 (Cq), 137.7 (Cq), 139.2 (Cq), 139.8 (Cq), 172.6 (CO), 173.9 (CO). MS (ESI): m/z = 330 [M + H⁺] for ³⁵Cl, 332 [M + H⁺] for ³⁷Cl. HRMS (CI): m/z calcd for C₁₆H₁₃ClN₃O₃: 330.0645; found: 330.0645.

18

Compounds 9 have been characterised by ¹H NMR, ¹³C NMR (except carbonyl signals), IR, MS and HRMS.

19

Selected data for 10: Mp >210 °C (MeOH). ¹H NMR (acetone-d ₆ ): δ = 1.12 (t, J = 7.0 Hz, 3 H, CH₃), 2.81 (s, 3 H, CH₃), 3.21 (s, 3 H, CH₃), 3.56 (q, J = 7.0 Hz, 2 H, CH₂), 5.84 (s, 2 H, CH₂), 7.15 (t, J = 7.9 Hz, 1 H, H_Ar), 7.35 (t, J = 7.9 Hz, 1 H, H_Ar), 7.49 (d, J = 7.9 Hz, 1 H, H_Ar), 8.15 (s, 1 H, H_Ar), 8.29 (d, J = 7.9 Hz, 1 H, H_Ar), 10.05 (s, 1 H, NH). ¹³C NMR (acetone-d ₆ ): δ = 11.5 (CH₃), 15.0 (CH₃), 15.2 (CH₃), 63.6 (CH₂), 76.4 (CH₂), 107.0 (Cq), 111.2 (CH), 113.8 (Cq), 118.9 (CH), 120.6 (Cq), 123.3 (CH), 125.4 (Cq), 125.5 (CH), 128.3 (Cq), 137.5 (Cq), 142.6 (Cq), 144.7 (Cq), 146.5 (CH). MS (ESI): m/z = 294 [M + H⁺]. HRMS (CI): m/z calcd for C₁₈H₂₀N₃O: 294.1606; found: 294.1606.