Molecules 2020, 25, 3859
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spectrometer (400 MHz for H, 100 MHz for 13C), (Rheinstetten, German). Chemical shifts were
reported in parts per million (ppm) as values relative to the internal chloroform (7.26 ppm for 1H and
77.16 ppm for 13C). Abbreviations for signal coupling are as follows: s, singlet; d, doublet; t, triplet; q,
quartet; m, multiplet. The visualization of NMR spectra could be found in the Supplementary Materials.
3.2. Total Synthesis of FA
3.2.1. Synthesis of 2-Bromo-5-(but-1-en-1-yl)pyridine (4)
To a solution of n-propyltriphenyl-phosphonium bromide (9.25 g, 24.0 mmol) in anhydrous THF
(25 mL) was added n-butyllithium (13.75 mL, 22.0 mmol, 1.6 M in hexane) dropwise at
78 ◦C and under
−
an argon atmosphere. The reaction mixture was stirred for 15 min and then heated to 0 ◦C for at least
1 h. After the reaction mixture was cooled to −78 ◦C, the solution dissolved 6-bromonicotinaldehyde
(5) (3.72 g, 20.0 mmol) in anhydrous THF (25 mL) was added. It was stirred for 15 min and then heated
to room temperature (RT); the reaction mixture was stirred at RT until the complete consumption
of starting material was observed by TLC (3 h). Aqueous saturated ammonium chloride (NH4Cl)
solution (10 mL) was added under vigorous stirring to quench the reaction. The volatiles (mainly THF)
were removed under reduced pressure and the aqueous phase was extracted with dichloromethane
(3 × 20 mL). The combined organic fractions were washed with water and brine, dried over anhydrous
sodium sulfate (Na2SO4) and evaporated under reduced pressure. The residue was purified by
flash column chromatography on silica gel using eluents (petroleum ether/ethyl acetate = 20/1) to
afford 2-bromo-5-(but-1-en-1-yl)pyridine (4) as a colorless oil (3.28 g, 77% yield). Major diastereomer.
1H-NMR (400 MHz, CDCl3)
δ 8.26 (s, 1H), 7.45–7.43 (m, 2H), 6.26 (dt, J = 11.6, 1.5 Hz, 1H), 5.83 (dt,
J = 11.6, 7.4 Hz, 1H), 2.31–2.25 (m, 2H), 1.06 (t, J = 7.5 Hz, 3H). 13C-NMR (100 MHz, CDCl3)
δ
150.1,
1
139.7, 138.4, 138.1, 132.7, 127.6, 123.5, 22.1, 14.3. Minor diastereomer. H-NMR (400 MHz, CDCl3)
δ
8.29 (d, J = 2.5 Hz, 1H), 7.53 (dd, J = 8.1, 2.5 Hz, 1H), 7.40 (d, J = 8.1, 1H), 6.39–6.29 (m, 2H), 2.25–2.21
(m, 2H), 1.11–1.10 (m, 3H). 13C-NMR (100 MHz, CDCl3)
26.3, 13.4.
δ 148.1, 139.7, 136.3, 135.1, 133.0, 127.9, 124.1,
3.2.2. Synthesis of 2-Bromo-5-butylpyridine (3)
A round bottom flask was charged with 2-bromo-5-(but-1-en-1-yl)pyridine (4) (3.28 g, 15.5 mmol),
then evacuated and backfilled with argon. After ethyl acetate (30 mL) and 10% Pd/C (1.65 g, 1.55 mmol)
were added under argon, the argon in the round bottom flask was replaced by hydrogen for at least
10 min. It was stirred at RT under a hydrogen atmosphere until the complete consumption of starting
material was observed by TLC (15 min). The resulting suspension was filtered through a compacted
diatomaceous earth layer eluting with dichloromethane (3
and evaporated under reduced pressure to afford a colorless oil. It was used directly as crude (3) in the
×
20 mL). The combined filtrate was collected
next step immediately.
3.2.3. Synthesis of Methyl 5-butylpicolinate (2)
The crude (3
), palladium (II) acetate (0.067 g, 0.30 mmol), 1,10-Bis(diphenylphosphino)ferrocene
(DPPF; 0.333 g, 0.60 mmol), trimethylamine (TEA; 2.98 g, 29.5 mmol) and methanol (12 mL, 294.8 mmol)
were dissolved in DMF (30 mL) and the solution was stirred under carbon monoxide (CO; 1.5 MPa) at
100 ◦C overnight. The reaction mixture was cooled to RT before most of the volatile components were
removed under reduced pressure. Saturated sodium chloride (NaCl) solution (100 mL) was added and
then the mixture was shaken vigorously. The solution was extracted with ethyl acetate (3 × 30 mL)
,
and the combined organic layers were washed with water and brine, dried (Na2SO4), filtered and
concentrated by evaporating under reduced pressure. The resulting residue was purified by flash
chromatography on silica gel using eluents (petroleum ether/ethyl acetate = 10/1) to afford the desired
methyl 5-butylpicolinate (
CDCl3) 8.55 (d, J = 1.8 Hz, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.64 (dd, J = 8.0, 1.8 Hz, 1H), 3.99 (s, 3H), 2.68
2
) (2.56 g, 85% yield over 2 steps) as a colorless oil. 1H-NMR (400 MHz,
δ