‘Wake-Up Call of A Sleeping Beauty’: Straightforward Synthesis of Functionalized β-(2-Pyridyl) Ketones from 2,6-Lutidine

Abstract

β-(2-Pyridyl) ketones are a unique class of heterocycles with valuable physicochemical properties and emerging relevance as pharmacophores. Herein we report a one-step process for the preparation of various substituted β-(2-pyridyl) ketones from the common starting material, 2,6-lutidine. Furthermore, we demonstrate the utility of this building block by synthesizing of a small set of antimalarial natural products.

Key words

β-(2-pyridyl) propanone - acylation - malaria - small-molecule natural-product analogues

• References and Notes

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• 9 General Procedure for the Preparation of Weinreb Amide
  Method A In a dry round-bottom flask, the corresponding carboxylic acid (1 equiv, 0.5 mmol) was added to a solution of SOCl₂ (20 equiv), and stirred under reflux over a period of 5 h. The excess of SOCl₂ was then removed under reduced pressure. Under inert atmosphere, the crude residue was taken into CH₂Cl₂, added dropwise to a solution of N,O-dimethylhydroxylamine hydrochloride (1.1 equiv) and pyridine (2.2 equiv) at 0 °C (NB: final concentration must not exceed 0.1 mol/L) and slowly warmed to r.t. After completion of the reaction, the crude mixture was diluted with CH₂Cl₂, and rinsed three times with water. The organic phase was decanted and was washed with a sat. solution of NaHCO₃, and neutralized with a solution HCl (1 M) until pH 7. The organic layers were dried over anhydrous MgSO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient of eluent from 100% heptane to 100% EtOAc) to afford the corresponding Weinreb amide. Method B Diisopropylethylamine (4 equiv, 0.1 mmol), followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1 equiv were sequentially added to a dry solution of the corresponding carboxylic acid (1 equiv) in CH₂Cl₂ and stirred for 10 min at r.t. N,O-Dimethylhydroxylamine hydrochloride (2 equiv) was added, and the resulting mixture was stirred until all starting materials were consumed (TLC and LC–MS monitoring). The crude reaction was quenched with a sat. aq NH₄Cl solution and extracted with EtOAc. The organic layers were washed with a sat. solution of NaCl, dried over anhydrous Na₂SO₄, and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient of eluent from 100% heptane to 100% EtOAc) affording the desired Weinreb amides. See the Supporting Information for full characterization and spectra.
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For examples of alternative syntheses of related systems, see:
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• 16 General Procedure for the Preparation of β-Keto-Pyridyls In a 50 mL dry three-neck round-bottom flask was introduced a solution of 2,6-lutidine (2 equiv, 0.09 mmol) in THF under argon. The solution was cooled to –78 °C and a solution of s-BuLi (1.4 M in cyclohexane, 2.3 equiv) was added dropwise to the reaction mixture, which was then stirred for 15–30 min at –78 °C. A solution of the electrophile of choice (1 equiv) in THF was then added dropwise and stirred for 15–60 min at –78 °C. The crude reaction was quenched with a sat. aq NH₄Cl solution at –78 °C and allowed to warm up to r.t. The aqueous phase was then extracted three times with EtOAc. The combined organic layers were washed with a sat. solution of NaCl, dried over anhydrous MgSO₄, and concentrated under reduced pressure. The crude residue was purified by flash chromatography (gradient of eluent from 100% heptane to 100% EtOAc) to afford the desired products (6a,b, 9 and 9′ series, and 12; for 15 see the Supporting Information). See the Supporting Information for full characterization and spectra. (±)-(4R)-4,8-Dimethyl-1-(6-methylpyridin-2-yl)non-7-en-2-ol (9n) Compound 9n was obtained in 69% yield as a colorless oil. The compound was isolated as a mixture of two diastereoisomers (dr = 2:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.54 (d, J = 7.4 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 6.97 (d, J = 7.3 Hz, 1 H), 5.18–5.06 (m, 1 H), 4.19–4.06 (m, 1 H), 2.96–2.76 (m, 2 H), 2.56 (s, 3 H), 2.13–1.91 (m, 2 H), 1.70 (s, 3 H), 1.62 (s, 3 H), 1.55–1.39 (m, 2 H), 1.34–1.11 (m, 3 H), 0.96 (dd, J = 6.6, 4.7 Hz, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 159.1, 156.7, 136.8, 130.6, 124.4, 120.6, 120.1, 68.6, 68.2, 44.3, 44.2, 43.1, 42.4, 37.5, 36.4, 28.8, 28.3, 25.2, 25.0, 24.9 ppm. LC–MS (t _R = 1.00 min for a 2 min run): m/z calcd for [C₁₇H₂₇NO + H⁺]: 262.4 [M + H]⁺. (±)-5-(4-Fluorophenyl)-5-hydroxy-6-(6-methylpyridin-2-yl)hexanoic Acid (12) Compound 12 was obtained in 78% yield as a white solid. ¹H NMR (400 MHz, (CD₃)₂SO): δ = 7.49 (t, J = 7.7 Hz, 1 H), 7.40 (dd, J = 8.8, 5.6 Hz, 2 H), 7.09–6.98 (m, 3 H), 6.90 (d, J = 7.6 Hz, 1 H), 3.26–3.08 (m, 2 H), 2.39 (s, 3 H), 2.08 (td, J = 7.8, 2.5 Hz, 2 H), 1.89–1.74 (m, 1 H), 1.67 (td, J = 13.4, 12.5, 4.7 Hz, 1 H), 1.51 (qd, J = 12.3, 7.5 Hz, 1 H), 1.18 (dt, J = 12.0, 5.8 Hz, 1 H) ppm. ¹³C NMR (101 MHz, (CD₃)₂SO): δ = 174.37, 161.65, 159.25, 157.89, 156.18, 142.80, 136.82, 127.41/127.34, 121.62, 120.78, 114.16, 113.95, 75.83, 47.93, 41.83, 33.93, 23.85, 18.94 ppm. LC-MS (t _R = 0.74 min for a 2 min run): m/z calcd for [C₁₈H₂₀FNO₃+H⁺]: 318.3 [M + H]⁺. (±)-6,8-Dimethoxy-3-[(6-methyl-pyridin-2-yl)methyl]isochroman-1-one (15) Compound 15 was obtained in 60% yield as a yellow oil. ¹H NMR (400 MHz, CDCl₃): δ = 7.57 (t, J = 7.5 Hz, 1 H), 7.17 (d, J = 7.4 Hz, 1 H), 7.07 (d, J = 7.6 Hz, 1 H), 6.41 (d, J = 2.2 Hz, 1 H), 6.30 (d, J = 2.2 Hz, 1 H), 4.92–4.83 (m, 1 H), 3.92 (s, 3 H), 3.87 (s, 3 H), 3.36–3.30 (m, 1 H), 3.23–3.12 (m, 1 H), 3.02–2.86 (m, 2 H), 2.57 (s, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 169.8, 166.3, 162.8, 158.3, 157.7, 143.1, 137.0, 122.4, 119.5, 108.6, 104.1, 98.5, 79.9, 55.8, 55.2, 39.8, 33.3, 24.6 ppm. LC–MS (t _R = 0.73 min for a 2 min run): m/z calcd for [C₁₈H₁₉NO₄+H⁺]: 314.3 [M + H]⁺.
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