The Synthesis of Naphtho[a]carbazoles and Benzo[c]carbazoles

Abstract

The synthesis of naphtho[a]carbazoles and benzo[c]carbazoles from indole precursors using a reaction mediated by potassium t-butoxide and light is described. The indole precursors were prepared utilizing Suzuki coupling methodology.

carbazoles - indoles - naphtho[a]carbazoles - benzo[c]carbazoles - Suzuki coupling

References

1a Husson H.-P. In The Alkaloids, Chemistry and Pharmacology   Vol. 26:  Brossi A. Academic Press, Inc.; Orlando: 1985.  Chap. 1. p.1-51  

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

2 Chakraborty DP. In The Alkaloids, Chemistry and Pharmacology   Vol. 44:  Cordell GA. Academic Press, Inc.; San Diego: 1993.  Chap. 4. p.257-364  

3 Leonard J. Nat. Prod. Rep.  1999,  16:  319 ; and previous reviews in this series

4 Gribble GW. Synlett  1991,  289 

5 Gribble GW. In The Alkaloids   Vol. 39:  Brossi A. Academic Press, Inc.; San Diego: 1990.  Chap. 7. p.239-352  

6 Routier S. Coudert G. Mérour J.-Y. Tetrahedron Lett.  2001,  42:  7025 

7 Bailly C. Qu X. Chaires JB. Colson P. Houssier C. Ohkubo M. Nishimura S. Yoshinari T. J. Med. Chem.  1999,  42:  2927 

8 Yous S. Andrieux J. Howell HE. Morgan PJ. Renard P. Pfeiffer B. Lesieur D. Guardiola-Lemaitre B. J. Med. Chem.  1992,  35:  1484 

9 Carini DJ. Kaltenbach RF. Liu J. Benfield PA. Boylan J. Boisclair M. Brizuela L. Burton CR. Cox S. Grafstrom R. Harrison BA. Harrison K. Akamike E. Markwalder JA. Nakano Y. Seitz SP. Sharp DM. Trainor GL. Sielecki TM. Bioorg. Med. Chem. Lett.  2001,  11:  2209 

10 de Koning CB. Michael JP. Rousseau AL. Tetrahedron Lett.  1998,  39:  8725 

11 de Koning CB. Michael JP. Rousseau AL. J. Chem. Soc., Perkin Trans. 1  2000,  1705 

Typical Experimental Procedures: The preparation of the three boronic acids was accomplished as follows:

12a

2-Methyl-1-naphthylboronic Acid 5a. n-Butyllithium (1.2 M, 3.9 cm³, 4.7 mmol) was added dropwise to a solution of 1-bromo-2-methylnaphthalene (1.01 g, 4.57 mmol) in THF (30 cm³) at -78 °C. The reaction mixture was stirred for 30 min at -78 °C, then B(OMe)₃ (1.39 g, 1.50 cm³, 13.4 mmol) was added. The resulting mixture was stirred at -78 °C for a further 30 min and then allowed to warm to r.t. The reaction mixture was acidified with aq 10% HCl solution and extracted with Et₂O (3 ¥ 30 cm³). The organic layer was then dried with MgSO₄ and concentrated under vacuum to afford an off-white crystalline material, 2-methyl-1-naphthyl-boronic acid 5a (0.74 g, 87%), which was used without further purification or characterization.

12b Budac D. Wan P. Can. J. Chem.  1996,  74:  1447 

12c

1-Methyl-2-naphthylboronic Acid 5b. n-Butyllithium (1.4 M, 2.1 cm³, 2.9 mmol) was added dropwise to a solution of 2-bromo-1-methylnaphthalene (0.50 g, 2.3 mmol) in THF (15 cm³) at
-78 °C. The reaction mixture was then treated as described above and B(OMe)₃ (0.70g, 0.75 cm³, 6.69 mmol) was added. An off-white crystalline material, 1-methyl-2-naphthylboronic acid 5b (0.39 g, 93%) was produced, which was used without further purification or characterization.

12d Parham WE. Reiff HE. Swartzentruber P. J. Am. Chem. Soc.  1956,  78:  1437 

12e 1,4-Dimethoxy-3-methyl-2-naphthylboronic Acid 5c. 2-Bromo-1,4-dimethoxy-3-methylnaphthalene was prepared according to: Adams R. Geissman TA. Baker BR. Teeter HM. J. Am. Chem. Soc.  1941,  63:  528 ; this was then treated as described above to afford the desired boronic acid 5c.

13

1-Methyl-2-(2-methyl-1-naphthyl)-1 H -indole-3-carbaldehyde 6. A solution of 2-bromo-1-methyl-1H-indole-3-carbaldehyde 4a (see ref. [11] ) (0.10 g, 0.42 mmol) in DME (2 cm³) was deoxygenated by passing N₂ through the mixture for 5 min. The deoxygenated mixture was added to Pd(PPh₃)₄ (10 mol%, 0.048 g, 0.04 mmol) and stirred under N₂ for 10 min at r.t. A solution of 2-methyl-1-naphthyl-boronic acid 5a (0.11 g, 0.59 mmol) in EtOH (1.5 cm³) was deoxygenated and added to the reaction mixture. The mixture was stirred for a further 10 min. A deoxygenated 2 M aq Na₂CO₃ solution (3.0 cm³, 6.0 mmol) was added and the reaction mixture stirred at r.t. for 5 min before being heated at reflux for 2 d. The mixture was cooled to r.t. and quenched with H₂O (20 cm³). The organic material was extracted with CH₂Cl₂ (3 ¥ 30 cm³) and the solvent was evaporated under reduced pressure. The crude product was subjected to column chromatography (2-10% EtOAc-hexane) to afford 1-methyl-2-(2-methyl-1-naphthyl)-1H-indole-3-carbaldehyde 6 as an off-white solid (0.13 g, 99%). Mp 146-147 °C. (Found: M⁺ 299.1307, C₂₁H₁₇NO requires M, 299.1310). IR (CHCl₃): ν_max =1655 (C=O) and 1579 (ArC=C) cm^-1. ¹H NMR (300 MHz, CDCl₃, Me₄Si): δ = 2.28 (3 H, s, ArCH₃), 3.42 (3 H, s, NCH₃), 7.23 (1 H, m, ArH), 7.35-7.51 (6 H, m, 6 ¥ ArH), 7.91 (1 H, d, J = 8.0 Hz, ArH), 7.96 (1 H, d, J = 8.5 Hz, ArH), 8.48 (1 H, m, Ar-H) and 9.45 (1 H, s, CHO). ¹³C NMR (75 MHz, CDCl₃): δ = 20.5 (ArCH₃), 30.2 (NCH₃), 109.8, 122.3, 123.3, 123.8, 125.0, 125.7, 127.4, 128.1 (¥ 2) and 130.2 (ArCH), 116.4, 124.4, 125.3, 131.7, 133.6, 137.3, 137.6 and 149.4 (ArC), 186.0 (CHO). MS: m/z (%) = 299 (100) [M⁺], 284 (38), 282 (55), 254 (19), 127.

14

11-Methyl-11 H -naphtho[2,1- a ]carbazole 10. t-BuOK (0.12 g, 1.1 mmol), was added to 1-methyl-2-(1-methyl-2-naphthyl)-1H-indole-3-carbaldehyde 7 (0.085 g, 0.28 mmol) dissolved in dry DMF (10 cm³), and the mixture was heated under N₂ at 80 °C while being irradiated with a high pressure mercury lamp through a quartz filter for 10 min. The reaction mixture was quenched with H₂O (50 cm³) and extracted into Et₂O (3 ¥ 50 cm³). The organic layer was dried with MgSO₄ and filtered. It was then evaporated and subjected to column chromatography (5-20% EtOAc-hexane) to afford the product 10 (0.045 g, 56%) as an off-white solid. Mp 213-216 °C. (Found: M⁺ 281.1209, C₂₁H₁₅N requires 281.1204). IR (CHCl₃): ν_max = 1617 and 1572 (ArC=C) cm^-1. ¹H NMR (300 MHz, CDCl₃, Me₄Si): δ = 4.43 (3 H, s, NCH₃), 7.33
(1 H, m, ArH), 7.50-7.71 (4 H, m, 4 ¥ ArH), 7.86 (1 H, d, J = 9.2 Hz, ArH), 7.94 (1 H, d, J = 7.6 Hz, ArH), 8.20 (1 H, d, J = 7.8 Hz, ArH), 8.35 (1 H, d, J = 8.7 Hz, ArH), 8.60 (1 H, d, J = 8.7 Hz, ArH), 8.71 (1 H, d, J = 9.2 Hz, ArH), 8.82 (1 H, d, J = 8.3 Hz, ArH). ¹³C NMR (75 MHz, CDCl₃): δ = 34.4 (NCH₃), 109.0, 114.8, 119.2, 119.5, 119.8, 121.0, 123.5, 125.3, 125.8, 126.1, 126.7 and 128.4 (ArCH), 120.7, 122.8, 129.7, 131.1, 131.2, 137.0 and 141.6 (ArC). MS: m/z (%) = 281 (100) [M⁺], 266 (22), 252 (3), 140(2).

15

This work is taken from the PhD of R. Pathak.

16

This work is taken from the MSc of J. M. Nhlapo.