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Synlett 2007(9): 1403-1406  
DOI: 10.1055/s-2007-980358
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Partha P. Mukhopadhyay, Okiko Miyata, Takeaki Naito*
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
Fax: +81(78)4417556; e-Mail: taknaito@kobepharma-u.ac.jp;
Further Information

Publication History

Received 15 February 2007
Publication Date:
23 May 2007 (online)

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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

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

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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.

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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.