An Efficient Synthesis of New Aza-Substituted Indoles via Michael-Type Addition

Abstract

An efficient method has been developed for the synthesis of new aza-substituted indoles. The methodology involves a two-step synthesis. The first step involves the Michael addition of indoline with various Michael acceptors. The other includes the oxidation of the indoline ring in the Michael adducts to an indole

Key words

alkylation - indoline - Michael addition - oxidation - catalyst

References and Notes

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37

Representative Procedure - Synthesis of 3-(1 H -Indol-1-yl)cyclohexanone (4)
To a solution of indoline (500 mg, 4.19 mmol) and cyclohex-2-enone (429 mg, 4.19 mmol) in MeCN (15 mL) was added DMAP (25 mg, 0.05 mmol). The mixture was stirred at r.t. for 24 h. After evaporation of the solvent, the crude product 3-(indolin-1-yl)cyclohexanone (3) was purified by crystalli-zation from EtOAc-hexane (pale yellow crystals, 850 mg, 94%, mp 235-236 ˚C).
^¹H NMR (400 MHz, CDCl₃): δ = 7.08-7.03 (m, =CH, 2 H), 6.64 (t, J = 7.6 Hz, =CH, 1 H), 6.42 (d, J = 7.6 Hz, =CH, 1 H), 3.82-3.75 (m, CH, 1 H), 3.49-3.43 (m, CH₂, 1 H), 3.38-3.31 (m, CH₂, 1 H), 2.98 (t, J = 8.2 Hz, CH₂, 2 H), 2.60-2.57 (m, CH₂, 1 H), 2.56-2.50 (m, CH₂, 1 H), 2.47-2.41 (m, CH₂, 1 H), 2.33-2.25 (m, CH₂, 1 H), 2.16-2.07 (m, CH₂, 2 H), 1.86-1.70 (m, CH₂, 1 H), 1.69-1.60 (m, CH₂, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 210.0, 150.2, 130.1, 127.6, 124.8, 117.9, 107.3, 55.0, 46.7, 43.9, 41.3, 28.5, 28.4, 22.9.
To a solution of 3-(indolin-1-yl)cyclohexanone (1.00 g, 4.65 mmol) in CH₂Cl₂ (10 mL) was added activated MnO₂ (869 mg, 10 mmol). The mixture was then stirred at r.t. for 24 h. After filtration, the mixture was evaporated in vacuo to give 3-(1H-indol-1-yl)cyclohexanone (4) as yellow oil (890 mg, 90%). ^¹H NMR (400 MHz, CDCl₃): δ = 7.65 (dd, J = 7.8, 2.0 Hz, =CH, 1 H), 7.35 (d, J = 8.4 Hz, =CH, 1 H), 7.26-7.20 (m, =CH, 2 H), 7.16-7.12 (m, =CH, 1 H), 6.57 (d, J = 2.9 Hz, =CH, 1 H), 4.72-4.66 (m, CH, 1 H), 2.94-2.91 (m, CH₂, 1 H), 2.90-2.77 (m, CH₂, 1 H), 2.56-2.40 (m, CH₂, 2 H), 2.35-2.30 (m, CH₂, 1 H), 2.25-2.10 (m, CH₂, 2 H), 1.85-1.78 (m, CH₂, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 208.2, 135.7, 128.9, 124.0, 122.0, 121.5, 120.1, 109.6, 102.6, 54.4, 48.4, 41.1, 31.6, 22.5.