Direct Amination of Phenols under Metal-Free Conditions

Abstract

Herein, we disclose the metal-free synthesis of arylamines via the direct amination of phenols using aminating reagents. This reaction procedure uses easy accessible aminating reagents and provides a versatile synthetic route to a broad range of arylamines with various functionalities in good to excellent yield. By using a two-step route of amination and oxidative coupling reaction, we synthesized three naturally occurring carbazole alkaloids: murrayafoline A, mukonine, and clausenine from two commercially available phenols.

Key words

amination - phenols - metal-free - arylamines - carbazoles

• References and Notes

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• 21 General Procedure for the Synthesis of Amination Agents 7 and 8 A solution of 2-bromopropanoic acid (3.03 g, 20 mmol) in SOCl₂ (15 mL) was heated at reflux for 3 h. After removal of the excess SOCl₂ under vacuum, the resultant 2-bromopropanoyl chloride was used without further purification. 2-Bromopropanoyl chloride (20 mmol) was slowly added dropwise to a mixture of RNH₂ (20 mmol) and Et₃N (2.22 g, 22 mmol) in anhyd CH₂Cl₂ (30 mL) at 0 °C. The reaction mixture was warmed to r.t. and stirred for an additional 20 h. A solution of 1 M HCl (30 mL) was added, and the mixture was stirred for 10 min. The organic phase was separated, and the aqueous layer was extracted with CH₂Cl₂ (2 × 30 mL). The combined organic extracts were washed with H₂O (40 mL) and brine (40 mL) and then dried over MgSO₄, filtered, and concentrated in vacuo to give the product. Recrystallization from 95% EtOH gave the pure product. 2-Bromo-N-(furan-2-ylmethyl)propanamide (8d) White solid, yield 79%; mp 121–122 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.34–7.35 (m, 1 H), 6.82 (br s, 1 H), 6.30–6.32 (m, 1 H), 6.23–6.24 (m, 1 H), 4.39–4.44 (m, 3 H), 1.85 (d, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.2, 150.5, 142.4, 110.5, 107.7, 44.7, 37.2, 22.9 ppm. HRMS (EI): m/z calcd for C₈H₁₀BrNO₂ [M]⁺: 230.9895; found: 230.9904.
• 22 The Procedure for the Synthesis of Amination Agent 10 A solution of 2-bromopropanoic acid (3.03 g, 20 mmol,) in SOCl₂ (15 mL) was heated at reflux for 3 h. After removal of the excess SOCl₂ under vacuum, the residue was added slowly to a cold solution of aq NH₄OH and stirred for 2 h. The resulting white precipitate is collected by filtration to give 10 as a white crystalline powder. 2-Bromopropanamide (10)²⁵ White solid, yield 84%; mp 79–81 °C. ¹H NMR (400 MHz, CDCl₃): δ = 6.36 (br s, 2 H), 4.39 (q, J = 7.2 Hz, 1 H), 1.87 (d, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 172.2, 43.9, 22.9 ppm.
• 23 General Procedure for the Synthesis of Diarylamines and Alkylarylamines A mixture of phenols (1.0 mmol), KOH (56 mg, 1.0 mmol), and aminating reagent 7 (1.05 mmol or 1.05 mmol aminating reagent 8) in DMSO (3 mL) was stirred at 50 °C for 2 h. After the reaction period, 62 mg (1.1 mmol) of KOH was added, and the mixture was heated at 130 °C for 2–12 h. Sat. brine was added to the solution and cooled slowly to r.t. The aqueous phase was extracted with CH₂Cl₂ three times. The combined organic layers were washed with three portions of sat. brine and then dried over MgSO₄ and filtered. Solvent was removed under reduced pressure. The crude product was purified through column chromatography on 300–400 mesh silica gel with PE–EtOAc as eluent. 4-Bromo-N-(p-tolyl)aniline (3d) White solid, yield 93%; mp 95–96 °C. ¹H NMR (400 MHz, CDCl₃): δ = 7.32 (d, J = 8.4 Hz, 2 H), 7.11 (d, J = 8.0 Hz, 2 H), 6.99 (d, J = 8.0 Hz, 2 H), 6.87 (d, J = 8.4 Hz, 2 H), 5.59 (br s, 1 H), 2.33 (s, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 143.1, 139.5 131.9, 131.6 129.9, 119.3, 117.9, 111.7, 20.6 ppm. HRMS (EI): m/z calcd for C₁₃H₁₂BrN [M]⁺: 261.0153; found: 261.0156.
• 24 General Procedure for the Synthesis of Carbazoles²⁰ A test tube with a magnetic stirring bar was charged with diarylamines (0.5 mmol), Pd(OAc)₂ (5 mol%), K₂CO₃ (10 mol%), and pivalic acid (450 mg). The uncapped test tube is placed in an oil bath, and the mixture is stirred under air at at 110 °C for 16 h. The solution is then cooled to r.t., diluted with CH₂Cl₂, washed with a sat. aq solution of Na₂CO₃, dried over MgSO₄, filtered, and evaporated under reduced pressure. The crude product is purified by silica gel column chromatography to afford the corresponding coupling product.
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