4-Pentyn-1-ol, 5-(4-pyridinyl)- synthesis

Yield:191725-48-1 82%

Reaction Conditions:

Stage #1: 4-bromopyridine hydrochloridewith sodium hydroxide in ethyl acetate;
Stage #2: pent-1-yn-5-olwith bis-triphenylphosphine-palladium(II) chloride;copper(l) iodide;triethylamine for 0.333333 h;Reflux;Sonogashira Cross-Coupling;

Steps:

Synthesis of 10f and 10g

General procedure: 4-Bromopyridine hydrochloride (2.5 g) was partitioned between 1 N sodium hydroxide (20 mL) and ethyl acetate (3×20 mL). The organic layer was separated, dried over Na₂SO₄ and concentrated under vacuum. The resulting oil was dissolved in Et₃N (2.6 M) and degassed under nitrogen. 4-Pentyn-1-ol or 5-hexyn-1-ol (1.1 equiv) was added followed by bis(triphenylphosphine)palladium(II) chloride (0.01 equiv) and copper(I) iodide (0.02 equiv) and the reaction mixture stirred at reflux for 20 min. Aqueous work-up (ethyl acetate/H₂O) and purification by chromatography on silica gel (gradient 0-30% ethyl acetate in heptane) led to 9f and 9g in 82% and 21% yield, respectively. 9f: ¹H NMR (400MHz, CDCl₃) δ 8.52 (m, 2H), 7.25 (m, 2H), 3.82 (m, 2H), 2.58 (t, J=7.2Hz, 2H), 1.88 (m, 2H), 1.62 (m, 1H). 9g: ¹H NMR (400MHz, CDCl₃) δ 8.52 (m, 2H), 7.25 (m, 2H), 3.73 (m, 2H), 2.48 (t, J=7.2Hz, 2H), 1.74 (m, 4H), 1.51 (m, 1H). Compound 9f or 9g was dissolved in acetic acid (0.05 M) and the solution hydrogenated using a H-Cube continuous-flow hydrogenation reactor (ThalesNano) (20% Pd(OH)₂/C cartridge, 100 bars H₂, 90°C, 1mL/min). Once the hydrogenation was complete, the reaction mixture was concentrated and dried under vacuum. The resulting crude was dissolved in CH₂Cl₂ (0.4 M) and reacted with Et₃N (1.5 equiv) and di-t-butyl dicarbonate (1.2 equiv) at rt for 30 min. After aqueous work-up (CH₂Cl₂/H₂O) and purification by chromatography on silica gel (gradient 0-30% ethyl acetate in heptane), compounds 10f and 10g were isolated in 80% yield. 10f: ¹H NMR (400MHz, CDCl₃) δ 4.06 (s, 2H), 3.64 (t, J=6.8Hz, 2H), 2.66 (t, J=11.4Hz, 2H), 1.54-1.66 (m, 4H), 1.45 (s, 9H), 1.24-1.39 (m, 8H), 1.08 (m, 2H). 10g: ¹H NMR (400MHz, CDCl₃) δ 4.05 (s, 2H), 3.64 (dd, J=6.2, 10.6Hz, 2H), 2.63 (t, J=12.0Hz, 2H), 1.53-1.65 (m, 4H), 1.45 (s, 9H), 1.20-1.40 (m, 10H), 1.04 (m, 2H).

References:

Bazin, Hélène G.;Li, Yufeng;Khalaf, Juhienah K.;Mwakwari, Sandra;Livesay, Mark T.;Evans, Jay T.;Johnson, David A. [Bioorganic and Medicinal Chemistry Letters,2015,vol. 25,# 6,p. 1318 - 1323]