Job/Unit: O42540
/KAP1
Date: 24-06-14 11:33:27
Pages: 6
L. Andernach, T. Opatz
FULL PAPER
corded on a Bruker Tensor 27 IR spectrometer equipped with a
PMA 50 module containing a single photoelastic modulator, with
4 cm–1 resolution and the instrument optimized at 1400 cm–1. A
100 μm BaF2 cell and CCl4 solutions of 1 with concentrations of
0.5 mol/L and 1.0 mol/L were used. All solution spectra were sol-
vent subtracted. Routine IR spectra were measured on the same
spectrometer with a diamond ATR unit.
temperature was raised to 0 °C and the reaction mixture stirred for
4 h at that temperature. Then, another portion (2 mL each) of the
two solutions was added over 40 min through syringe pumps. After
18 h, the mixture was quenched by adding water (20 mL) and ethyl
acetate (20 mL). The aqueous layer was extracted with ethyl acetate
(3ϫ 20 mL) and the combined organic layers were washed with
brine, dried with Na2SO4 and concentrated in vacuo. The residue
was purified by flash chromatography (cyclohexane/ethyl acetate,
1:1 v/v) to give 1 as white microcrystalline solid (33 mg, 0.17 mmol,
50% yield, 70% ee). Rf = 0.10 cyclohexane/ethyl acetate, 2:1, m.p.
40–42 °C. 1H NMR (400 MHz, CDCl3, 298 K): δ = 8.64 (d, J =
2.1 Hz, 1 H, 6-H), 8.07 (d, J = 8.1 Hz, 1 H, 3-H), 7.65 (dd, J = 8.1,
2.1 Hz, 1 H, 4-H), 3.98 (s, 3 H, OCH3), 3.66 (d, J = 2.0 Hz, 1 H,
2Ј-H), 3.04 (qd, J = 5.1, 2.0 Hz, 1 H, 3Ј-H), 1.47 (d, J = 5.1 Hz,
3 H, 3Ј-CH3) ppm. 13C NMR (101 MHz, CDCl3, 298 K): δ = 165.5
(C=O), 147.8 (C-6), 147.6 (C-2), 137.5 (C-5), 133.8 (C-4), 125.0 (C-
3), 59.8 (C-3Ј), 56.9 (C-2Ј), 53.0 (OCH3), 17.9 (3Ј-CH3) ppm.
HRMS (ESI): m/z calcd. for C10H11NO3Na [M + Na]+ 216.0637;
Computational Methods: All calculations were performed on stan-
dard desktop computers with Intel Core i7 CPUs by using Spar-
tanЈ10[2] and Gaussian09 rev. A.02.[8] The calculations were pre-
ceded by a thorough conformer search by using the MMFF force
field[3] and the algorithm to analyze conformer distributions as im-
plemented in SpartanЈ10. All four obtained low-energy conformers
were optimized at the B3LYP/6-31G(d,p)[4–7] level of theory by
using Gaussian09. Subsequently, they were further optimized at the
B3LYP/6-311G(d,p)[9] level treating solvation with the IEFPCM
model[10] for CCl4. A frequency analysis with the same DFT
settings was done with all four further optimized structures to ob-
tain the vibrational spectra. Boltzmann weighting with the relative
Gibbs energies from the thermochemical output of the frequency
calculations was carried out to receive the averaged spectra. The
calculated vibrational frequencies were scaled by an empirically de-
termined factor of 0.9805.
found 216.0634. IR (ATR): ν
= 2955, 1742, 1722, 1437, 1310,
˜
max
1241, 1132, 1122, 859, 709 cm–1.
The analytical data are consistent with the values from the litera-
ture.[1]
With the same procedure as described above carried out at –20 °C
over 92 h reaction time, 1 was obtained in 11% yield and 89% ee.
[α]2D5 = +20.9 (c = 0.43, CDCl3).
Synthesis: Melting points were determined in open capillary tubes
with a Krüss KSP-1N apparatus. The optical rotation was mea-
sured on a Jasco P-2000 polarimeter at 589 nm with a temperature-
controlled cuvette with 10 cm path length. NMR spectra were re-
corded with a Bruker Avance-II 400 MHz spectrometer (400 MHz
1H and 101 MHz 13C) equipped with a 5 mm BBFO probe by using
standard pulse sequences. Chemical shifts were referenced by using
Methyl 5-(3-Methyloxiran-2-yl)picolinate (rac-1): Olefin 4 (48 mg,
0.27 mmol) and 3-chloroperbenzoic acid (95 mg, 0.55 mmol) were
heated at reflux in dry dichloromethane (10 mL) for 6 h. The vola-
tiles were removed under reduced pressure. The residue was puri-
fied by flash chromatography (cyclohexane/ethyl acetate, 1:1 v/v)
to give rac-1 (12 mg, 0.06 mmol, 22% yield).
the solvent signals of CHCl3/CDCl3 (δH = 7.26 ppm, δC
=
77.16 ppm).[16] HRMS (ESI) spectra were recorded with a Waters
QTof-Ultima 3-Instrument with LockSpray-Interface and a suitable
external calibrant. Microwave reactions were carried out in a CEM
Discover monomode apparatus at the indicated maximum tem-
perature and power setting. Chiral HPLC for enantiomeric excess
determination was performed by using a Knauer HPLC system
with a K-1001 pump, a column oven, a K-2800 diode array UV
detector and a Chiralpak IB-3 column (250 mmϫ4.6 mm, 3 μm,
Daicel Corp.) with a flow rate of 2 mL/min hexane/ethanol 95:5.
TLC experiments were performed on alumina sheets coated with
silica gel (60F254, Merck). For flash chromatography silica gel (35–
70 μm, 60 Å, Acros) was used. Automated flash chromatography
was done by using a Biotage Isolera One equipped with a diode
array detector (200–400 nm). All solvents, starting materials and
reagents were purchased from commercial suppliers and used as
received unless otherwise noted. The solvents for chromatography
were distilled before use. The tetrakis(triphenylphosphine)palla-
dium(0) was prepared according to literature methods.[17,18]
Methyl 5-Bromopicolinate (3): 5-Bromopicolinic acid (2.56 g,
12.7 mmol) was dissolved in methanol (100 mL), sulfuric acid
(0.5 mL) was added and the reaction mixture heated at reflux for
117 h. After cooling to room temperature saturated sodium carb-
onate solution was added until the pH was above 9. The mixture
was extracted with dichloromethane. The organic layer was dried
with Na2SO4 and the volatiles were removed under reduced pres-
sure to give 3 as an off-white solid (2.37 g, 11.0 mmol, 86% yield).
Rf = 0.30 cyclohexane/ethyl acetate, 2:1, m.p. 99–100 °C. 1H NMR
(400 MHz, CDCl3, 298 K): δ = 8.78 (dd, J = 2.2, 0.8 Hz, 1 H, 6-
H), 8.02 (dd, J = 8.3, 0.8 Hz, 1 H, 3-H), 7.98 (dd, J = 8.3, 2.2 Hz,
1 H, 4-H), 4.00 (s, 3 H, OCH3) ppm. 13C NMR (101 MHz, CDCl3,
298 K): δ = 165.2 (C=O), 151.2 (C-6), 146.4 (C-2), 139.9 (C-4),
126.4 (C-3), 125.2 (C-5), 53.2 (OCH3) ppm. HRMS (ESI): m/z
calcd. for C7H6BrNO2Na [M + Na]+ 237.9480; found 237.9490. IR
(ATR): ν
= 3059, 2957, 1715, 1438, 1364, 1308, 1235, 1133,
˜
max
1008, 697 cm–1.
The analytical data are consistent with the values from the litera-
ture.[19]
Methyl 5-[(2R,3R)-3-Methyloxiran-2-yl]picolinate (1): Olefin
4
(60 mg, 0.34 mmol), tetrabutylammonium hydrogen sulfate (5 mg,
14 μmol) and 1,2:4,5-di-O-isopropylidene-d-erythro-2,3-hexodiuro-
2,6-pyranose (26 mg, 0.10 mmol) were dissolved under vigorous
stirring in a mixture of acetonitrile/dimethoxymethane (5.6 mL,
1:2, v/v) and a solution of Na2B4O7·10 H2O (0.05 m) in aqueous
Na2(EDTA) (4ϫ10–4 m, 4.0 mL, pH 9.0) and cooled to –10 °C.
Over a period of 2 h, a solution (6 mL) of Oxone (867 mg,
2.82 mmol) in aqueous Na2(EDTA) (4ϫ 10–4 m, 18 mL) and a
solution (6 mL) of potassium carbonate (817 mg, 6.27 mmol) in de-
ionized water (18 mL) were added through syringe pumps. After
stirring for 16 h, a further amount (3 mL each) of the two solutions
was added through syringe pumps over 1 h. After another hour the
(E)-Methyl 5-(Prop-1-en-1-yl)picolinate (4). Method A: Under a
nitrogen atmosphere, ester 3 (2.10 g, 9.70 mmol), (E)-1-propen-1-
ylboronic acid (1.00 g, 11.6 mmol), potassium carbonate (1.61 g,
11.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.12 g,
0.97 mmol) were dissolved in dry dimethylformamide (DMF;
40 mL) and heated at reflux for 5 h. Subsequently, the solvent was
removed in vacuo. The crude product was coevaporated with di-
ethyl ether (18 mL) and afterwards dissolved in chloroform and
washed with aqueous NaOH (1 m), dried with Na2SO4 and concen-
trated in vacuo. The residue was purified by flash chromatography
(cyclohexane/ethyl acetate, 2:1 v/v) to give 4 as white micro-
4
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