One-Pot Synthesis of Carbazole via Tandem Suzuki-Miyaura and Amination Reaction

Abstract

One-pot synthesis of carbazole from two aromatic rings was accomplished by a tandem Suzuki-Miyaura and amination reaction. Our novel phosphine ligand for both reactions efficiently mediates a sequential intermolecular biaryl formation and ring-closing amination.

phenylnaphthyl phosphane - intramolecular amination - Suzuki-Miyaura cross-coupling - carbazole

References and Notes

For recent review on carbazole derivatives, see:

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2 Chakraborty DP. The Alkaloids  1993,  44:  257 

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For reviews, see:

5b Miyaura N. Suzuki A. Chem. Rev.  1995,  95:  2457 

5c Suzuki A. J. Organomet. Chem.  1999,  576:  147 

6a Watanabe T. Ueda S. Inuki S. Oishi S. Fujii N. Ohno H. Chem. Commun.  2007,  4516 

6b Ackermann L. Althammer A. Angew. Chem., Int. Ed.  2007,  46:  1627 

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7a Yoshikawa S. Odaira J. Kitamura Y. Bedekar AV. Furuta T. Tanaka K. Tetrahedron  2004,  60:  2225 

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8 Furuta T. Kitamura Y. Hashimoto A. Fujii S. Tanaka K. Kan T. Org. Lett.  2007,  9:  183 

9

We have found that a Suzuki-Miyaura reaction of 12 and 13 mediated by ligand 1 provides biaryl product 14 even with the chloride, which is known as a low reactive halide (Scheme [2] ).

Scheme 2

10

Experimental Procedure for the Synthesis of Carbazole 5 (Table 1, Entry 6)
To a solution of 2-bromophenylboronic acid (2, 30 mg, 0.15 mmol) and 2-iodoaniline (3, 30 mg, 0.14 mmol) in toluene (0.5 mL) was added Pd₂ (dba)₃ (13 mg, 0.01 mmol), ligand 1 (6.9 mg, 0.02 mmol), and Cs₂CO₃ (134 mg, 0.41 mmol) at r.t. under an argon atmosphere, then the mixture was stirred at 100 °C for 2 h. The mixture was cooled to r.t., and then NaOt-Bu (16 mg, 0.17 mmol) was added and stirred at 100 °C for 19 h. After stirring, H₂O was added, and extracted with EtOAc. The organic layer was washed with H₂O, brine, dried over MgSO₄ and evaporated. The residue was purified by column chromatography on silica gel (benzene-EtOAc, 99:1) to afford the 9H-carbazole (5, 16 mg, 71%) as a colorless solid; R _f = 0.82 (benzene-EtOAc, 99:1). ¹H NMR (500 MHz, CDCl₃): δ = 8.08 (d, J = 7.9 Hz, 2 H), 8.03 (br s, 1 H), 7.50-7.40 (m, 4 H), 7.30-7.20 (m, 2 H). ¹³C NMR (68 MHz, CDCl₃): δ = 139.5, 125.8, 123.4, 120.3, 119.4, 110.6. MS-FAB: m/z = 168 [M + H]⁺. HRMS-FAB: m/z calcd for C₁₂H₁₀N [M + H]⁺: 168.0814; found: 168.0809.

11

An isolation and structure determination of complex 4′ was not tested.

12

Addition of Cs₂CO₃ (1.2 equiv) instead of NaOt-Bu gave no improvement of chemical yields to give 5 and 4 in 26% and 31%, respectively. This result also supports that the complex 4′ plays a role in preventing the ring closure to 5.

For recent reviews on biaryl phosphine ligand, see:

13a Shimizu H. Nagasaki I. Saito T. Tetrahedron  2005,  61:  5405 

13b Kočovsk P. Vyskočil . Smrčina M. Chem. Rev.  2003,  103:  3213 

14

Analytical Data of 9b
R _f = 0.52 (hexane-benzene, 2:3). ¹H NMR (500 MHz, CDCl₃): δ = 8.34 (s, 1 H), 8.23 (br s, 1 H), 8.10 (d, J = 7.9 Hz, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7.55-7.40 (m, 3 H), 7.35-7.25 (m, 1 H). ¹³C NMR (68 MHz, CDCl₃): δ = 140.9, 139.4, 127.3, 126.8, 123.2, 123.0, 122.9, 122.8, 122.72, 122.67, 122.6, 122.0, 121.6, 120.6, 120.3, 118.02, 117.96, 117.9, 117.8, 110.9, 110.6. MS-FAB: m/z = 236 [M + H]⁺. HRMS-FAB: m/z calcd for C₁₃H₉NF₃ [M + H]⁺ 236.0687; found: 236.0678.
Analytical Data of 9g
R _f = 0.20 (hexane-CH₂Cl₂, 1:1). ¹H NMR (500 MHz, CDCl₃): δ = 7.94 (d, J = 7.9 Hz, 1 H), 7.87 (br s, 1 H), 7.51 (s, 1 H), 7.40-7.25 (m, 2 H), 7.24-7.15 (m, 1 H), 6.87 (s, 1 H), 4.00 (s, 3 H), 3.93 (s, 3 H). ¹³C NMR (68 MHz, CDCl₃): δ = 149.4, 144.4, 139.4, 134.2, 124.2, 123.6, 119.20, 119.18, 115.3, 110.5, 102.7, 94.2, 56.6, 56.1. MS-FAB: m/z = 227 [M + H]⁺. HRMS-FAB: m/z calcd for C₁₄H₁₄NO₂ [M + H]⁺ 228.1025; found: 228.1022.

15a 4-Methoxycarbazole (9f) has been synthesized by Pd-catalyzed intramolecular arylation reaction as a minor product of regioisomeric mixture. See: Liu Z. Larock RC. Tetrahedron  2007,  63:  347 

15b 4-Vinyl-substituted carbazoles have been prepared from N-phenyl-3-iodoaniline and internal alkyne via a vinylic to aryl palladium migration. See: Zhao J. Larock RC. J. Org. Chem.  2006,  71:  5340 

2-Iodoaniline derivatives were readily obtained by ortho iodination of aniline as well as selective reduction of 2-iodonitrobenzene. For recent examples, see:

16a Das B. Krishnaiah M. Venkateswarlu K. Reddy VS. Tetrahedron Lett.  2007,  48:  81 

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17

The carbazole synthesis from aniline and 1,2-dihalobenzene was reported in ref. 6b.

18

Experimental Procedure (Table 4, entry 2)
To a solution of 2-aminophenylboronic acid (10, 15 mg, 0.11 mmol) and 1,2-diiodobenzene (11, 33 mg, 0.10 mmol) in 1,4-dioxane (0.33 mL) was added Pd(OAc)₂ (2.2 mg, 0.01 mmol), ligand 1 (5.0 mg, 0.01 mmol), and Cs₂CO₃ (98 mg, 0.30 mmol) at r.t. under an argon atmosphere, then the mixture was stirred at 80 °C for 24 h. The mixture was cool to r.t., and then NaOt-Bu (12 mg, 0.12 mmol) was added and stirred at 80 °C for 24 h. After stirring, H₂O was added, and extracted with EtOAc. The organic layer was washed with H₂O, brine, dried over MgSO₄, and evaporated. The residue was purified by column chromatography on silica gel (benzene-EtOAc, 99:1) to afford the 9H-carbazole (5, 13 mg, 76%) as a colorless solid.

19a Hutchinson I. Stevens MFG. Org. Biomol. Chem.  2007,  5:  114 

19b Ishiyama T. Itoh Y. Kitano T. Miyaura N. Tetrahedron Lett.  1997,  38:  3447 

20 Collibee SE. Yu J. Tetrahedron Lett.  2005,  46:  4453