Novel One-Pot Synthesis of N-Alkyl Arylamines from Oxime Ethers Using Organometallic Reagents

Abstract

A novel one-pot synthesis of α,α-disubstituted secondary arylamines from oxime ethers has been developed by two separate additions of organometallic reagents. As a related arylamine construction, very efficient synthesis of N-(diallyl)methyl arylamines is achieved via domino reactions involving addition-eliminative re­arrangement-addition reactions of acyclic and cyclic oxime ethers with allylmagnesium bromide.

Key words

one-pot synthesis - arylamine - oxime ether - Grignard reagent - organolithium reagent - rearrangement

References and Notes

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• 7b

  The Yamamoto group^3d has reported the N-O bond cleavage of oxime sulphonates by Grignard reagents to synthesize α,α-disubstituted amines.

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9

The addition product 6a was the only product isolated (63%) when the first reaction was continued for one hour without the second addition.

10

Typical procedure for the one-pot synthesis of amine 4m (Table 1, entry 14 ): The oxime ether 3d (100 mg, 0.67 mmol) was dissolved in dry toluene (5 mL) under N₂ and cooled to -78 °C. BF₃·Et₂O (0.1 mL, 0.80 mmol) was added and the mixture was stirred for 15 min. PhLi (1.92 mol/L in n-butyl ether, 0.42 mL, 0.80 mmol) was added dropwise over 15 min. After 1 h, the reaction mixture was allowed to warm up to -20 °C. Then n-BuLi (1.6 mol/L in n-hexane, 1.7 mL, 2.7 mmol) was added at -20 °C and the mixture was stirred at r.t. for 0.5 h. The reaction mixture was quenched at 0 °C with aq sat. NH₄Cl solution (0.5 mL) and extracted with CHCl₃ (3 × 10 mL). The extracts were combined, dried (MgSO₄) and concentrated under reduced pressure. The residue was purified by preparative TLC (n-hexane-EtOAc, 8: 1) to give the amine 4m (92 mg, 54%) as a pale yellow oil. IR (neat): 3413 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.35-7.17 (m, 5 H), 6.88 (br d, J = 8.5 Hz, 2 H), 6.42 (br d, J = 8.5 Hz, 2 H), 4.25 (t, J = 6.5 Hz, 1 H), 3.93 (br s, 1 H), 2.17 (s, 3 H), 1.81-1.73 (m, 2 H), 1.41-1.24 (m, 4 H), 0.88 (br t, J = 7.0 Hz, 3 H); ¹³C NMR (75.5 MHz, CDCl₃): δ = 145.2, 144.5, 129.5, 128.5, 126.7, 126.4, 126.2, 113.3, 58.5, 38.7, 28.5, 22.6, 20.3, 13.9; HRMS (ESI⁺): m/z calcd for C₁₈H₂₃N: 253.1830; found: 253.1828.

12

Typical procedure for the domino-type reaction in the synthesis of(diallyl)methylamine 8b (Table 3, entry 5): Allylmagnesium bromide (1 mol/L in Et₂O, 1.8 mL, 1.8 mmol) was added to a r.t. solution of oxime ether 3f (110 mg, 0.46 mmol) in dry CH₂Cl₂ (2.3 mL). After being stirred at the same temperature for 45 min, the mixture was quenched with aq sat. NH₄Cl solution (1 mL) at 0 °C, extracted with CHCl₃ (4 × 10 mL) and washed with brine. The organic phase was dried over MgSO₄ and concentrated under reduced pressure. The oily mass was filtered through a short column of silica gel to give compound 8b (133.3 mg) in quantitative yield, as a colorless oil. IR (neat): 3376 cm^-1; ¹H NMR (300 MHz, CDCl₃): δ = 7.46 (br d, J = 8.0 Hz, 2 H), 7.34 (br t, J = 8.0 Hz, 2 H), 7.24 (br t, J = 7.5 Hz, 1 H), 6.59 (br d, J = 8.5 Hz, 2 H), 6.28 (br d, J = 8.5 Hz, 2 H), 5.66-5.52 (m, 2 H), 5.08-4.99 (m, 4 H), 3.66 (s, 3 H), 2.79 (dd, J = 6.5, 13.5 Hz, 2 H), 2.63 (dd, J = 8.0, 13.5 Hz, 2 H); ¹³C NMR (75.5 MHz, CDCl₃): δ = 151.8, 145.2, 139.7, 133.4, 128.3, 126.6, 126.5, 118.7, 116.6, 114.3, 59.9, 55.5, 42.5; HRMS (ESI⁺): m/z calcd for C₂₀H₂₃NO: 293.1779; found: 293.1782.