One-Pot Three-Component Barbier-Type Reaction for the Synthesis of β-Nitroamines

Abstract

The combination of an aldehyde, bromonitromethane, and p-methoxyaniline in the presence of tin(II) chloride and titanium tetraethoxide allows a straightforward access to β-nitroamine derivatives. The use of solid paraformaldehyde results in the amino methylation of methylnitronate. On the other hand, chiral sugar-derived aldehydes furnished the corresponding nitrosugars in high yields and stereoselectivities.

Key words

one-pot reaction - β-nitroamine - bromonitroalkane - aza-Henry reaction - aminomethylation

• References and Notes

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• 15 General Procedure for the Synthesis of β-Nitroamines 4: To a solution of the corresponding aldehyde (0.50 mmol) in anhyd THF (1 mL), Ti(OEt)₄ (1.00 mmol) was added, followed by SnCl₂ (1.00 mmol) and p-anisidine (0.45 mmol). After 1 h, bromonitromethane (0.50 mmol) was added and the reaction mixture was stirred at r.t. over a period of 4 h. The excess of Ti(OEt)₄ was then decomposed by the slow addition of a solution of brine. The resulting suspension was filtered through a pad of Celite^® and the pad washed with EtOAc. The organic layer was separated and washed with aq 1 M HCl, H₂O, aq sat. solution of HNaCO₃ and brine, dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by flash column chromatography eluting with mixtures of EtOAc–hexane to yield β-nitroamines 4.
• 16 As examples of the obtained β-nitroamines, we present the analytical data: 4-Methoxy-N-(2-nitro-1-phenylethyl)benzenamine (4a): brown oil; R_f 0.23 (hexane–EtOAc, 3:1). ¹H NMR (300 MHz, CDCl₃): δ = 7.24–7.61 (m, 5 H), 6.73 (d, J = 9.0 Hz, 2 H), 6.58 (d, J = 9.0 Hz, 2 H), 6.23 (d, J = 7.4 Hz, 1 H), 5.09 (t, J = 6.7 Hz, 1 H), 4.69 (d, J = 6.7 Hz, 2 H), 3.71 (s, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 153.1 (C), 139.6 (C), 137.9 (C), 129.2 (2 × CH), 128.5 (CH), 126.4 (2 × CH), 115.6 (2 × CH), 114.8 (2 × CH), 80.0 (CH₂), 57.7 (CH), 55.6 (Me). MS (ESI⁺): m/z (%) = 273 (4) [M + H]⁺, 213 (7), 212 (100), 124 (7). HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₁₅H₁₇N₂O₃]⁺: 273.1239; found: 273.1233. IR (neat): 3375, 1554, 1511, 1378, 1243 cm^–1. N-(1-Cyclohexyl-2-nitroethyl)-4-methoxybenzenamine (4c): brown oil; R_f 0.22 (hexane–EtOAc, 3:1). ¹H NMR (300 MHz, CDCl₃): δ = 6.76 (d, J = 9.0 Hz, 2 H), 6.65 (d, J = 9.0 Hz, 2 H), 4.72 (dd, J = 12.3, 5.2 Hz, 1 H), 4.46 (dd, J = 12.3, 7.4 Hz, 1 H), 4.04–4.08 (m, 1 H), 3.73 (s, 3 H), 2.73 (s, 11 H). ¹³C NMR (75 MHz, CDCl₃): δ = 152.7 (C), 141.0 (C), 115.0 (2 × CH), 114.9 (2 × CH), 75.7 (CH₂), 60.9 (CH), 55.7 (Me), 43.0 (CH), 34.7 (2 × CH₂), 25.2 (CH₂), 21.6 (2 × CH₂). MS (ESI⁺): m/z (%) = 279 (6) [M + H]⁺, 234 (19), 216 (100), 214 (28). HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₁₅H₂₃N₂O₃]⁺: 279.1709; found: 279.1703. IR (neat): 3389, 1553, 1513, 1384, 1243 cm^–1.4-Methoxy-N-(2-nitroethyl)aniline (4i): orange oil; R_f 0.48 (hexane–EtOAc, 3:1). ¹H NMR (300 MHz, CDCl₃): δ = 6.81 (d, J = 8.9 Hz, 2 H, Ar), 6.61 (d, J = 7.2 Hz, 2 H, Ar), 4.32–4.59 (m, 2 H), 3.76–3.86 (m, 5 H). ¹³C NMR (75 MHz, CDCl₃): δ = 153.0 (C), 140.0 (C), 115.0 (2 × CH), 114.8 (2 × CH), 74.3 (CH₂), 55.7 (OMe), 42.3 (CH₂). MS (ESI⁺): m/z (%) = 197 (100) [M + H]⁺, 180 (21), 90 (12). IR (neat): 3400, 1558, 1375 cm^–1.
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• 21 Analytical Data of 3-O-Benzyl-5,6-dideoxy-1,2-O-isopropylidene-5-p-methoxyphenylamino-6-nitro-α-d-glucofuranose (4k): yellow oil; R_f 0.28 (hexane–EtOAc, 3:1); [α]_D ²⁷ –9.2º (c = 0.6 in CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 7.12–7.34 (m, 5 H), 6.54 (d, J = 9.0 Hz, 2 H), 6.34 (d, J = 9.0 Hz, 2 H), 5.83 (d, J = 3.6 Hz, 1 H), 4.67 (dd, J = 13.1, 3.9 Hz, 1 H), 4.44–4.59 (m, 3 H), 4.38–4.42 (m, 1 H), 4.17–4.24 (m, 3 H), 4.02 (d, J = 3.1 Hz, 1 H), 3.73 (s, 3 H), 1.47 (s, 3 H), 1.31 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 153.3 (C), 139.3 (C), 136.9 (C), 128.4 (2 × CH), 128.0 (CH), 127.9 (2 × CH), 116.3 (2 × CH), 114.9 (2 × CH), 112.1 (C), 104.9 (CH), 81.9 (CH), 81.2 (CH), 79.9 (CH), 75.8 (CH₂), 72.1 (CH₂), 55.6 (Me), 51.9 (CH), 26.7 (Me), 26.2 (Me). MS (ESI⁺): m/z (%) = 445 (100) [M + H]⁺, 444 (1), 316 (5), 289 (1), 288 (21). HRMS (ESI⁺): m/z [M + H]⁺ calcd for [C₂₃H₂₉N₂O₇]⁺: 445.1975; found: 445.1969. IR (neat): 3380, 1556, 1513, 1377, 1241 cm^–1.
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