A New Preparative Route to Substituted Carbazoles by Benzannulation

Abstract

A new regioselective pathway to substituted carbazole derivatives is described here. According to this procedure substituted 2-alkoxycarbonyl-4-acetoxy-9-(p-toluenesulfonyl) carbazoles are obtained by treatment of substituted 6-[2-(p-toluenesulfonyl­amino)-aryl]-3-alkoxycarbonylhex-3-en-5-ynoic acids with acetic anhydride in the presence of sodium acetate. The latter acids are prepared from the easily available substituted o-iodo-anilines by Sonogashira coupling with propargylic alcohol and Wittig reaction as the key steps. The described benzannulation reaction proceeds in regiospecific fashion and a range of substituents are tolerated.

annulations - enynes - carbazoles - phenols - heterocycles

References

1a Knölker H.-J. Reddy KR. Chem. Rev.  2002,  102:  4303 

1b Chakraborty DP. In The Alkaloids   Vol. 44:  Brossi A. Academic Press; New York: 1993.  p.257 

2 Zhang Y. Wada T. Sasabe H. J. Mater. Chem.  1998,  8:  809 

3 Sonntag M. Strohriegl P. Chem. Mater.  2004,  16:  4736 

4a Van Dijken A. Bastiaansen JJAM. Kiggen NMM. Langeveld BMW. Rothe C. Monkman A. Bach I. Stössel P. Brunner K. J. Am. Chem. Soc.  2004,  126:  7718 

4b Thomas KRJ. Lin JT. Tao Y.-T. Ko C.-W. J. Am. Chem. Soc.  2001,  123:  9404 

5 Biswas M. Mishra GC. Makromol. Chem.  1981,  182:  261 

6 Sunderg RJ. In Comprehensive Heterocyclic Chemistry II   Vol. 2:  Katritzky AR. Rees CW. Scriven EFV. Elsevier; Oxford: 1996.  p.119 

7a Kuwahara A. Nakano K. Nozaki K. J. Org. Chem.  2005,  70:  413 

7b Lee C.-Y. Lin C.-F. Lee J.-L. Chiu C.-C. Lu W.-D. Wu M.-J. J. Org. Chem.  2004,  69:  2106 

7c Liu Z. Larock RC. Org. Lett.  2004,  6:  3739 

7d Knölker H.-J. Krahl MP. Synlett  2004,  528 

7e Haider N. Käferböck J. Tetrahedron  2004,  60:  6495 

7f Crich D. Rumthao S. Tetrahedron  2004,  60:  1513 

7g Cai X. Snieckus V. Org. Lett.  2004,  6:  2293 

7h Smitrovich JH. Davies IW. Org. Lett.  2004,  6:  533 

7i Duval E. Cuny GD. Tetrahedron Lett.  2004,  45:  5411 

7j Knölker H.-J. Curr. Org. Synth.  2004,  1:  309 

7k Huang Q. Larock RC. J. Org. Chem.  2003,  68:  7342 

7l Back TG. Pandyra A. Wulff JE. J. Org. Chem.  2003,  68:  3299 

7m Rawat M. Wulff WD. Org. Lett.  2003,  6:  329 

7n Knölker H.-J. Chem. Commun.  2003,  1170 

7o Scott TL. Söderberg BCG. Tetrahedron  2003,  59:  6323 

7p Witulski B. Alayrac C. Angew. Chem. Int. Ed.  2002,  41:  3281 

7q Bedford RB. Cazin CSJ. Chem. Commun.  2002,  2310 

7r Venkatesh C. Ila H. Junjappa H. Mathur S. Huch V. J. Org. Chem.  2002,  67:  9477 

8 Serra S. Fuganti C. Moro A. J. Org. Chem.  2001,  66:  7883 ; and references cited therein

9 Serra S. Fuganti C. Synlett  2002,  1661 

10 Serra S. Fuganti C. Synlett  2003,  2005 

11 Yasuhara A. Sakamoto T. Tetrahedron Lett.  1998,  39:  595 

12a

2-Iodoaniline 8a is commercially available. The substituted 2-iodoanilines 8b, 8c and 8e were prepared from the commercially available 4-methylaniline, 2-nitro-4-methoxyaniline and 4-fluoroaniline, respectively, according to the procedure described by Ma et al. [12b] Ethyl 4-amino-3-iodobenzoate 8d and 4-nitro-2-iodoaniline 8f were prepared from commercially available ethyl 4-aminobenzoate and 4-nitroaniline, respectively by iodination according to the procedure described by Spivey et al. and Adimurthy et al., respectively. [12c] [d]

12b Ma C. Liu X. Li X. Flippen-Anderson J. Yu S. Cook JM. J. Org. Chem.  2001,  66:  4525 

12c Spivey AC. McKendrick J. Srikaran R. J. Org. Chem.  2003,  68:  1843 

12d Adimurthy S. Ramachandraiah G. Ghosh PK. Bedekar AV. Tetrahedron Lett.  2003,  44:  5099 

13a Sonogashira K. Tohda Y. Hagihara N. Tetrahedron Lett.  1975,  4467 

13b

The coupling reaction was performed in THF solution using 2 equiv of propargyl alcohol, Et₃N as base and an equimolar amount of copper and palladium catalysts (0.01 equiv). Iododerivatives 9d and 9f show low solubility in THF and a mixture of THF-DMF was used as solvent.

14

The Wittig reaction between aldehydes 11a-f and ylide 12 was performed in toluene-CHCl₃ solution. The amount of CHCl₃ was adjusted depending on the solubility of the starting aldehydes. The above-mentioned reaction proceeds slowly at r.t. (typically 2 d). Notably, worse results have been obtained by heating the reaction mixture.

15 For the preparation of this ylide see: Hudson RF. Chopard PA. Helv. Chim. Acta  1963,  46:  2178 

16a Only E-isomers of acids 13 were obtained (NMR analysis). The Wittig reaction of ylide 12 with the aldehydes affords the 3-(E)-alkylidene-succinic acid monoalkyl esters in a highly stereoselective way; for previous studies on this reaction see: Paquette LA. Schulze MM. Bolin D. J. Org. Chem.  1994,  59:  2043 

16b Röder E. Krauss H. Liebigs Ann. Chem.  1992,  177 

17

Acids 13a-f (50 mmol) were dissolved in acetic anhydride (48 mL, 0.5 mol). To this solution, anhyd NaOAc (8.2 g, 0.1 mol) and hydroquinone (275 mg, 2.5 mmol) were added in one portion. The obtained heterogeneous mixture was heated at reflux for 1 h under a nitrogen atmosphere. After cooling to r.t., the acetic anhydride was removed in vacuo and the residue was treated with EtOAc (300 mL) and H₂O (100 mL). The organic phase was separated, dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by chromatography and crystallization to give carbazoles derivatives 14a-f.
All new compounds were fully characterized. Selected analytical data:
Compound 13e: Anal. Calcd for C₂₂H₂₀FNO₆S: C, 59.32; H, 4.53. Found: C, 59.45; H, 4.55. Mp 154 °C. FT-IR (nujol): 670, 954, 1030, 1100, 1189, 1280, 1363, 1448, 1466, 1539, 1594, 1633, 1697 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.40 (3 H, t, J = 7.2 Hz), 2.31 (3 H, s), 3.54 (2 H, s), 4.36 (2 H, q, J = 7.2 Hz), 6.75 (1 H, s), 7.06-7.20 (2 H, m), 7.16 (2 H, d, J = 8.3 Hz), 7.58 (2 H, d, J = 8.3 Hz), 8.18 (1 H, q, J = 4.4 Hz), 8.27 (1 H, s), 11.25 (1 H, br s). MS (EI): m/z = 446 [M⁺ + 1], 445 [M⁺], 290, 262, 246, 216, 200, 172, 155, 91, 65.
Compound 14e: Anal. Calcd for C₂₄H₂₀FNO₆S: C, 61.40; H, 4.29. Found: C, 61.50; H, 4.30. Mp 197-198 °C (hexane-CHCl₃). FT-IR (nujol): 666, 861, 1027, 1087, 1175, 1207, 1299, 1369, 1417, 1472, 1591, 1722, 1763 cm^-1. ¹H NMR (250 MHz, CDCl₃): δ = 1.46 (3 H, t, J = 7.2 Hz), 2.27 (3 H, s), 2.49 (3 H, s), 4.47 (2 H, q, J = 7.2 Hz), 7.13 (2 H, d, J = 8.3 Hz), 7.27 (1 H, dt, J = 9.0, 2.5 Hz), 7.54 (1 H, dd, J = 8.2, 2.5 Hz), 7.69 (2 H, d, J = 8.3 Hz), 7.85 (1 H, s), 8.31 (1 H, dd, J = 9.0, 4.3 Hz), 8.86 (1 H, s). MS (EI): m/z = 470 [M⁺ + 1], 469 [M⁺], 427, 382, 354, 334, 315, 290, 272, 244, 227, 200, 171, 155, 139, 120, 91, 65.