6-Methyl-2-nitro-1-phenyl-hept-4-en-3-ol

Abstract

In this short note, we report the synthesis of 6-methyl-2-nitro-1-phenyl-hept-4-en-3-ol by a LiAlH₄ catalyzed nitroaldol reaction for carbon-carbon bond formation. The title compound was characterized by ¹H-NMR, ¹³C-NMR, MS, IR and elemental analysis.

The nitroaldol or Henry reaction is a well known powerful carbon-carbon bond forming reaction. It is the base catalyzed addition of a nitroalkane to a carbonyl compound and gives access to various substrates. The nitroaldol product, a 2-nitroalkanol, can be easily transferred into other substance classes like nitro alkenes, 2-amino alcohols and α-nitro ketones [1,2]. All these substance classes are highly functionalized organic molecules and thus very useful in natural product synthesis. In the course of a natural product synthesis we explored the nitroaldol reaction for 1-nitro-2-phenylethane (1) and 4-methyl-2-pentenal (2) as substrates for the synthesis of 6-methyl-2-nitro-1-phenyl-hept-4-en-3-ol (3) (Scheme 1).

In this case, it is crucial to avoid elimination of water and 1,4-addition of the deprotonated nitroalkane to the α,β-unsaturated aldehyde. LiAlH₄ as catalyst achieves these requirements [3], because it is not basic enough for elimination of water and the coordination with Li⁺, that acts as Lewis acid, forms a transition state that avoids 1,4-addition. Because of the carefully controlled reaction conditions, including low temperature and high dilution of LiAlH₄, the reduction of the nitro group could not be observed [4].

Experimental

General

¹H-NMR was recorded on Bruker Avance 300 spectrometer and ¹³C-NMR on Bruker Avance 400 spectrometer at 300 K, chemical shifts are reported in relation to Me₄Si (δ = 0 ppm). The infrared spectrum was recorded on Bio-Rad FT-IR- FTS 155 spectrometer and for mass spectrometry a Finnigan MAT 95 spectrometer was used. LiAlH₄ and 4-methyl-2-pentenal (2) were used as purchased and 1-nitro-2-phenylethane (1) was synthesized according to common literature [5]. Solvents were purified and dried according to common procedures [6].

Synthesis of 6-methyl-2-nitro-1-phenyl-hept-4-en-3-ol (3)

The reaction was carried out under nitrogen atmosphere using standard schlenk techniques. 1-Nitro-2-phenylethane (3.8 g, 25 mmol) was added to a slurry of LiAlH₄ (27 mg, 0.7 mmol, 14 mol %) in dry THF (10 mL) at 0 °C. After 0.5 h 4-methyl-2-pentenal (0.50 g, 5.1 mmol) was added dropwise, subsequent stirring was continued for 24 h at 0 °C. The reaction mixture was quenched with HCl (1 M, 20 mL), allowed to warm to room temperature and extracted with dichloromethane (3 × 25 mL). The combined organic layers were dried with MgSO₄ and evaporated. The crude product was purified by flash chromatography (hexanes/ethyl acetate 9:1). Excess of 1-nitro-2-phenylethane (3.0 g, 20 mmol) was re-isolated for further reactions. 6-Methyl-2-nitro-1-phenylhept-4-en-3-ol was isolated as yellow oil in 56% yield. ¹H-NMR (300 MHz, CDCl₃): δ = 1.01 (dd, J = 6.7, 2.3 Hz, 6H), 2.24 (d, J = 5.8 Hz, 1H), 2.28–2.41 (m, 1H), 3.10–3.37 (m, 2H), 4.44 (dd, J = 13.4, 6.8 Hz, 0.6H), 4.52 (dd, J = 11.4, 4.5 Hz, 0.4H), 4.66–4.77 (m, 1H), 5.37–5.48 (m, 1H), 5.80–5.91 (m, 1H), 7.15–7.34 (m, 5H) ppm. ¹³C-NMR (100 MHz, CDCl₃): δ = 22.0, 30.9, 36.6, 73.2, 93.5, 123.8, 127.4, 127.5, 128.5, 128.8, 128.9, 129.0, 135.1, 144.0 ppm. MS (CI, NH₃): m/z (%) = 267.1 (100) [MNH₄⁺]. IR [cm⁻¹]: v = 699, 1017, 1548, 2962. Elemental analysis calculated for C₁₄H₂₀NO₃: C, 67.18; H, 8.05; N, 5.60; O, 19.18; found: C, 66.92; H, 8.19; N, 5.51.