Palladium-Mediated Intramolecular C-O and C-C Coupling Reactions: An Efficient Synthesis of Benzannulated Oxazepino- and Pyranocarbazoles

Abstract

An efficient route towards the synthesis of benzannulated oxazepino- and pyranocarbazoles has been accomplished via palladium-catalyzed intramolecular C-O and C-C cross-coupling reactions, respectively.

Key words

C-O and C-C coupling - intramolecular arylation - palladium catalysis - oxazepinocarbazoles - pyranocarbazoles.

References and Notes

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18

General Procedure for the Preparation of 4 and 5
To 2-halobenzoic acid (2.5 mmol) was added SOCl₂ (2 mL). The solution was refluxed for 2 h, after which the excess of SOCl₂ was removed under reduced pressure, and the residual traces were then removed by coevaporation with dry toluene. The acid chloride was then added to a solution of 1-hydroxy-carbazole (2.5 mmol) and Et₃N (2 mL) in dry THF (10 mL) at 0 ˚C. After the addition of the acid chloride, the mixture was allowed to warm up to r.t. while stirring under a nitrogen atmosphere. After stirring overnight, the mixture was diluted with H₂O and neutralized with 4% HCl to pH 7. The precipitated amide was then filtered off and washed with 4% HCl and copious amounts of H₂O. The crude product was purified by chromatography using 1% EtOAc and afforded 4 and 5.
1-Hydroxy-9-(2-bromobenzoyl)-6-methylcarbazole (4a)
White solid; mp 126 ˚C; yield 0.682 g, 72%. IR (KBr): ν = 3432 (OH), 1646 (C=O) cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.42 (s, 3 H, CH₃), 6.86 (t, 1 H, J = 8.0 Hz, H-3), 7.13 (dd, 1 H, J _m  = 2.0 Hz, J _o  = 8.0 Hz, H-7), 7.21 (dd, 1 H, J _m  = 2.0 Hz, J _o  = 8.0 Hz, H-2), 7.58-7.62 (m, 2 H, H_arom), 7.67-7.71 (m, 2 H, H_arom), 7.75 (d, 1 H, J = 8.0 Hz, H-8), 7.85 (s, 1 H, H-5), 7.94 (dd, 1 H, J _m  = 2.0 Hz, J _o  = 7.5 Hz,
H-3′), 12.76 (s, 1 H, OH). ^¹³C NMR (125 MHz, CDCl₃): δ = 21.6 (CH₃), 111.0, 111.6, 116.8, 119.1, 120.2, 122.3, 122.9, 126.1, 126.5, 127.5, 128.3, 129.9, 131.8, 132.2, 132.8, 138.4, 139.3, 148.5, 165.7 (CO). LC-MS: m/z = 380 [M + H⁺]. Anal. Calcd (%) for C₂₀H₁₄BrNO₂: C, 63.32; H, 3.69; N, 3.69. Found: C, 63.34; H, 3.67; N, 3.72.

19

General Procedure for the Preparation of 6 and 7
To a solution of 1-hydroxycarbazole (3a-d, 2.5 mmol) in
dry CH₂Cl₂, 2-bromobenzoyl chloride, or 2-iodobenzoyl chloride (prepared as before) in dry CH₂Cl₂ solution (10 mL) was added, and the reaction mixture was heated to reflux for 12 h. The mixture was then washed with H₂O and brine solution and dried (Na₂SO₄). Evaporation of the CH₂Cl₂ gave a crude product which was purified by chromatography with PE-EtOAc (98:2) to afford 6 and 7.
6-Methyl-9 H -carbazol-1-yl 2-Bromobenzoate (6a) White solid; mp 147 ˚C; yield 0.682 g, 72%. IR (KBr): ν = 3389 (NH), 1741 (OC=O) cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.55 (s, 3 H, CH₃), 7.24-7.28 (m, 2 H, H_arom), 7.35 (d, 1 H, J = 8.0 Hz, H-8), 7.39 (dd, 1 H, J _m  = 1.0 Hz, J _o  = 8.0 Hz, H-4), 7.46-7.53 (m, 2 H, H_arom), 7.81 (dd, 1 H, J _m  = 1.5 Hz, J _o  = 7.7 Hz, H-2), 7.89 (s, 1 H, H-5), 7.97 (d, 1 H, J = 7.5 Hz, H-3′), 8.13 [dd, 2 H, J _m  = 2.0 Hz, J _o  = 7.5 Hz, H-6′ (overlapped with NH)]. ^¹³C NMR (125 MHz, CDCl₃): δ = 21.29 (CH₃), 110.66, 117.57, 117.98, 119.24, 120.29, 122.04, 123.52, 126.27, 127.38, 127.66, 129.18, 131.28, 131.68, 131.96, 133.25, 134.54, 135.59, 137.88, 163.93 (C=O). LC-MS: m/z = 380 [M + H⁺]. Anal. Calcd (%) for C₂₀H₁₄BrNO₂: C, 63.32; H, 3.69; N, 3.69. Found: C, 63.36; H, 3.70; N, 3.72.

20

General Procedure for the Preparation of 8
To a mixture of 4 or 5 (1 mmol), Bu₄NBr (1.5 equiv), and Cs₂CO₃ (1.5 equiv) in anhyd DMF (8 mL) was added Pd(OAc)₂ (10 mol%) and the flask placed in a pre-heated
oil bath at 110 ˚C for 2 h. After completion of the reaction, the mixture was cooled and diluted with H₂O. This was extracted with EtOAc. The combined organic extracts were washed with 1 M HCl, H₂O, brine and dried (Na₂SO₄). The solvent was removed by distillation, and the crude product was purified by column chromatography over silica gel using PE as the eluent to give the final compound 8. 13-Methylbenzo[ f ][1,4]oxazepino[4,3,2- l , m ]carbazol-9-one (8a)
White solid; mp 141 ˚C; yield 0.269 g, 90%. IR (KBr): ν = 1666 (C=O) cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.44 (s, 3 H, CH₃), 7.12 (d, 1 H, J = 8.0 Hz, H-3), 7.18 (t, 1 H, J = 8.0 Hz, H-2), 7.19 (t, 1 H, J = 7.5 Hz, H-7), 7.23 (d, 1 H, J = 8.0 Hz, H-5), 7.28 (d, 1 H, J = 8.0 Hz, H-12), 7.48 (t, 1 H, J = 7.5 Hz, H-6), 7.60 (d, 1 H, J = 7.0 Hz, H-1), 7.67 (s, 1 H, H-14), 8.05 (dd, 1 H, J _m  = 1.5 Hz, J _o  = 8.0 Hz, H-8), 8.55 (d, 1 H, J = 8.5 Hz, H-11). ^¹³C NMR (125 MHz, CDCl₃): δ = 21.42 (CH₃), 115.84, 116.94, 117.69, 120.07, 121.34, 124.73, 125.06, 125.52, 126.59, 128.89, 129.27, 129.79, 133.36, 134.51, 134.89, 137.66, 145.62, 156.51, 164.73 (C=O). LC-MS: m/z = 300 [M + H⁺]. Anal. Calcd (%) for C₂₀H₁₃NO₂: C, 80.27; H, 4.35; N, 4.68. Found: C, 80.21; H, 4.37; N, 4.73.

21

Complete cif files for compounds 4a and 9a were deposited with the Cambridge Crystallographic Data Centre, CCDC Deposit numbers 796527 and 796520. Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK [fax: [phone] or e-mail: [e-mail]].

22

General Procedure for the Preparation of 9
To a mixture of 6 or 7 (1 mmol), Ph₃P (20 mol%), and Cs₂CO₃ (2 equiv) in anhyd DMF (8 mL) was added Pd(OAc)₂ (10 mol%), and the mixture was placed in a pre-heated oil bath at 110 ˚C for 4 h. After completion of the reaction, the mixture was cooled and diluted with H₂O. This was extracted with EtOAc. The combined organic extracts were washed with 1 M HCl, H₂O, brine and dried (Na₂SO₄). The solvent was removed by distillation, and the crude was purified by column chromatography over silica gel using PE as eluent to give compound 9 as white solid.
10-Methylisochromeno[3,4- a ]carbazol-2(13 H )-one (9a)
Mp >300 ˚C; yield 0.254 g, 85%. IR (KBr): ν = 3305 (NH), 1719 (OC=O) cm^-¹. ^¹H NMR (500 MHz, CDCl₃): δ = 2.49 (s, 3 H, CH₃), 7.25 (d, 1 H, J = 8.0 Hz, H-11), 7.37 (d, 1 H, J = 8.0 Hz, H-12), 7.50 (t, 1 H, J = 8.0 Hz, H-4), 7.54 (d, 1 H, J = 8.0 Hz, H-7), 7.78 (d t, 1 H, J _m  = 2.0 Hz, J _o  = 8.0 Hz, H-5), 7.89 (s, 1 H, H-9), 7.93 (d, 1 H, J = 8.5 Hz, H-3), 8.16 (d, 1 H, J = 8.0 Hz, H-8), 8.38 (dd, 1 H, J _m  = 1.5 Hz, J _o  = 8.0 Hz, H-6), 8.56 (br s, 1 H, NH). ^¹³C NMR (125 MHz, CDCl₃): δ = 21.34 (CH₃), 102.32, 111.02, 116.10, 118.38, 118.66, 119.20, 120.46, 121.09, 124.52, 125.52, 126.92, 127.15, 128.00, 128.41, 132.07, 132.45, 133.05, 136.76, 158.12 (C=O). LC-MS: m/z = 300 [M + H⁺]. Anal. Calcd (%) for C₂₀H₁₃NO₂: C, 80.27; H, 4.35; N, 4.68. Found: C, 80.17; H, 4.33; N, 4.61.