A Simple and Regioselective Synthesis of Dihydropyrido[2,3-c]carbazoles via Iodocyclization

Abstract

An efficient and simple method for the synthesis of various iodo-substituted dihydropyridocarbazole derivatives has been developed via iodocyclization of N-propargylated 3-aminocarbazoles.

Key words

iodocyclization - 3-aminocarbazole - dihydropyridocarbazole

References and Notes

• 1a Gribble GW. In The Alkaloids   Brossi A. Academic Press; San Diego: 1990.  p.239-352  
• 1b Knölker H.-J. Reddy KR. Chem. Rev.  2002,  102:  4303 
• 1c Cordell GA. The Alkaloids  2008,  Vol. 65:  1-430  
• 1d Gribble GW. Synlett  1991,  289 
• 1e Gribble GW. Saulnier MG. Sibi MP. Obaza-Nutaitis JA. J. Org. Chem.  1984,  49:  4518 
• 2a Sainsbury M. Synthesis  1977,  437 
• 2b Alvarez M. Joule JA. In The Chemistry of Heterocyclic Compounds   Saxton JE. Wiley; Chichester: 1994.  p.261-278  
• 2c Nakamura I. Yamamoto Y. Chem. Rev.  2004,  104:  2127 
• 2d Gallagher PT. Science of Synthesis   Vol. 10:  Thieme; Stuttgart: 2000.  p.693-744  
• 3a Martínez-Esperõn MF. Rodríguez D. Castedo L. Saá C. Org. Lett.  2005,  7:  2213 
• 3b Tsuchimoto T. Matsubayashi H. Kaneko M. Shirakawa E. Kawakami Y. Angew. Chem. Int. Ed.  2005,  44:  1336 
• 4a Monks NR. Blankey DC. East SJ. Dowell RI. Caluete JA. Curtin NJ. Arris CE. Newell DR. Eur. J. Cancer  2002,  11:  1543 
• 4b Wang JC. Annu. Rev. Biochem.  1996,  65:  635 
• 4c LePez JB. DzXuong N. Gosse C. Paolett C. Proc. Natl. Acad. Sci. U.S.A.  1974,  71:  5078 
• 4d Auclair C. Arch Biochem. Biophys.  1987,  259:  1 
• 5a Stiborová M. Bieler CA. Wiessler M. Frei E. Biochem. Pharmacol.  2001,  62:  1675 
• 5b Stiborová M. Breuer A. Aimová D. Stiborová-Rupertová M. Wiessler M. Frei E. Int. J. Cancer  2003,  107:  885 
• 6a Larock RC. In Acetylene Chemistry. Chemistry, Biology, and Material Science   Diederich F. Stang PJ. Tykwinski RR. Wiley-VCH; New York: 2005.  Chap. 2. p.51-99  
• 6b Barluenga J. Gonzalez JM. Campos PJ. Asensio G. Angew. Chem., Int. Ed. Engl.  1988,  27:  1546 
• 6c Knight DW. Redfern AL. Gilmore J. J. Chem. Soc., Perkin Trans. 1  2002,  622 
• 6d Arcadi A. Cacchi S. Fabrizi G. Marinelli F. Moro L. Synlett  1999,  1432 
• 6e Fischer D. Tomeba H. Pahadi NK. Patil NT. Yamamoto Y. Angew. Chem. Int. Ed.  2007,  46:  4764 
• 6f Nishizawa M. Takao H. Yadav VK. Imagava H. Sugihara T. Org. Lett.  2003,  5:  4563 
• 6g Manarin F. Roehrs JA. Gay RM. Brandão R. Menezes PH. Nogueira CW. Zeni G. J. Org. Chem.  2009,  74:  2153 
• 7a Knight DW. Redfern AL. Gilmore J. Chem. Commun.  1998,  2207 
• 7b Arcadi A. Cacchi S. Giuseppe SD. Fabrizi G. Marinelli F. Org. Lett.  2002,  4:  2409 
• 7c Barluenga J. Vazque-Villa H. Ballesteros A. Gonzalez JM. J. Am. Chem. Soc.  2003,  125:  9028 
• 8a Yue D. Yao T. Larock RC. J. Org. Chem.  2005,  70:  10292 
• 8b Yue D. Yao T. Larock RC. J. Comb. Chem.  2005,  7:  809 
• 8c Yao T. Zhang X. Larock RC. J. Org. Chem.  2005,  70:  7679 
• 9a Yao T. Zhang X. Larock RC. J. Am. Chem. Soc.  2004,  126:  11164 
• 9b Larock RC. Yue D. Tetrahedron Lett.  2001,  42:  6011 
• 9c Zhang X. Campo MA. Yao T. Larock RC. Org. Lett.  2005,  7:  763 
• 9d Zhang X. Sarkar S. Larock RC. J. Org. Chem.  2006,  71:  236 
• 9e Waldo JP. Larock RC. Org. Lett.  2005,  7:  5203 
• 9f Waldo JP. Larock RC. J. Org. Chem.  2007,  72:  9643 
• 10a Kesharwani T. Worlikar SA. Larock RC. J. Org. Chem.  2006,  71:  2307 
• 10b Zhang X. Yao T. Campo MA. Larock RC. Tetrahedron  2010,  66:  1177 
• 10c Mehta S. Waldo JP. Larock RC. J. Org. Chem.  2009,  74:  1141 
• 11a Gaddam V. Ramesh S. Nagarajan R. Tetrahedron  2010,  66:  4218 
• 11b Gaddam V. Nagarajan R. Org. Lett.  2008,  10:  1975 
• 11c Sreenivas DK. Nagarajan R. Tetrahedron  2010,  66:  9650 

12

The CCDC deposition number for compound 6a is 800159. Formula: C₃₀H₂₅IN₂O₂S. Unit cell parameters: a = 9.8829 (15), b = 10.3179 (13), c = 14.554 (2), α = 80.103 (11), β = 72.103 (13), γ = 68.283 (13), space group P-1. The CCDC deposition number for compound 7a is 800160. Formula: C₂₃H₁₇IN₂. Unit cell parameters: a = 11.4798 (19), b = 10.4089 (15), c = 15.3963 (18), α = 90.00, β = 91.647 (12), γ = 90.00, space group P-1.

13

Preparation of 7-Ethyl-2-iodo-(4-methylphenylsulfonyl)-1-phenyl-4,7-dihydro-3 H -pyrido[2,3- c ]carbazole (6a) To a mixture of 9-ethyl-3-[4-methylphenyl(3-phenylpropyl)-
sulfonamido]-9H-carbazole (5a, 0.5 g, 1 mmol), iodine (0.8 g, 3 mmol), and NaHCO₃ (0.36 g, 2 mmol) was added MeCN (20 mL) at r.t. The reaction mixture was stirred for 4 h. The reaction mixture was then diluted with EtOAc, washed with sat. aq Na₂S₂O₃ (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (25 mL). The combined organic layers were dried over Na₂CO₃, filtered, and concentrated under the reduced pressure. Product was purified by column chromatography on silica gel (eluent: hexane-EtOAc) afforded 6a (0.48 g, 80%).
Mp 172-174 ˚C. IR (KBr): 3043, 2976, 2926, 1608, 1593, 1440, 1346, 1163, 1087, 883 cm^-¹. ^¹H NMR (400 MHz, TMS, CDCl₃): δ = 8.16 (1 H, d, J = 8.8 Hz, ArCH), 7.55 (4 H, d, J = 7.2 Hz, ArCH), 7.26-7.16 (4 H, m, ArCH), 7.08 (2 H, m, ArCH), 6.95-6.93 (2 H, m, ArCH), 6.60-6.57 (2 H, m, ArCH), 5.00 (2 H, br s, CH₂), 2.15 (3 H, s, CH₃), 1.44 (3 H, t, J = 6.8 Hz, CH₃). ^¹³C NMR (100 MHz, TMS, CDCl₃): δ = 143.5, 141.0, 140.0, 139.8, 139.4, 135.6, 130.6, 129.9, 129.2, 128.1, 127.7, 127.1, 126.1, 125.2, 124.2, 124.0, 121.8, 118.4, 118.3, 109.2, 107.9, 91.7 (arom. C), 59.8, 37.5, 21.3, 13.6 (aliph. C). MS (positive mode): m/z = 604 [M + H]. Anal. Calcd (%) for C₃₀H₂₅IN₂O₂S: C, 59.61; H, 4.17; N, 4.63. Found: C, 59.58; H, 4.10; N, 4.56.

14

Preparation of 7-Ethyl-2-iodo-1-phenyl-7 H -pyrido[2,3- c ]carbazole (7a) In a round-bottom flask equipped with a magnetic stirring bar, 7-ethyl-2-iodo-(4-methylphenylsulfonyl)-1-phenyl-4,7-dihydro-3H-pyrido[2,3-c]carbazole (6a, 0.5 mmol) was dissolved in a mixture of THF (20 mL) and MeOH (10 mL) at r.t. Cs₂CO₃ (1.5 mmol) was added to the clear solution. The resulting mixture was stirred at 50 ˚C, and the progress of the reaction was monitored. When the reaction was complete (12 h), the mixture was evapourated under vacuum. To the residue was added H₂O (20 mL), and the mixture was stirred at r.t. for 10 min. Then the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Product was purified by column chromatography on silica gel (eluent: hexane-EtOAc) afforded 7a (0.2 g, 60%).
Mp 178-180 ˚C. IR (KBr): 3126, 3055, 2972, 1614, 1591, 1504, 1444, 1379, 1253, 952 cm^-¹. ^¹H NMR (400 MHz, TMS, CDCl₃): δ = 9.27 (1 H, s, ArCH), 8.21 (1 H, d, J = 8.0 Hz, ArCH), 7.95 (1 H, d, J = 8.0 Hz, ArCH), 7.58-7.40 (6 H, m, ArCH), 7.27 (1 H, t, J = 8.0 Hz, ArCH), 6.64 (1 H, t, J = 8.0 Hz, ArCH), 5.78 (1 H, d, J = 8.0 Hz, ArCH), 4.5
(2 H, q, J = 8.0 Hz, CH₂), 1.48 (3 H, t, J = 4.0 Hz, CH₃). ^¹³C NMR (100 MHz, TMS, CDCl₃): δ = 153.2, 148.4, 145.5, 144.6, 138.8, 138.7, 131.2, 129.4, 129.0, 128.9, 125.8, 124.6, 124.1, 123.4, 118.9, 114.5, 114.1, 108.2, 100.1 (arom. C), 37.6, 14.1 (aliph. C). MS (positive mode): m/z = 449
[M + H]. Anal. Calcd (%) for C₂₃H₁₇IN₂: C, 61.62; H, 3.82; N, 6.25. Found: C, 61.31; H, 3.78; N, 6.31.