PAPER
Pyridines Substituted with Five Different Elements
65
All operations were, unless otherwise indicated, performed at r.t.
without any special care being taken for the exclusion of air and
moisture. Microwave reactions were carried out on a Biotage Initi-
ator Sixty. Gradient column chromatography was performed on a
CombiFlash Companion, ISCO Inc. 1H NMR and 13C NMR spectra
were recorded at 400 MHz or 100 MHz, respectively, on a Bruker
DPX 400 spectrometer using the solvent residual peak as reference.
GC-MS was performed on a system supplied by Agilent Technolo-
gies, consisting of a 6890N G1530N GC, a G2614A auto-sampler,
G2613A injector and a G2589N mass spectrometer. The mass spec-
trometer was equipped with a chemical ionization (CI) ion source.
High-resolution mass spectra were recorded on a Waters (Micro-
mass) GCT Time of Flight mass spectrometer coupled to an Agilent
Technologies Gas Chromatograph 6890N series. Commercial sol-
vents and reagents were used as received.
mL, 3.60 mmol) in THF (15 mL) at 0 °C under N2. The resulting
mixture was stirred for 10 min and then cooled to –78 °C. A solu-
tion of compound 7 (456 mg, 3 mmol) in THF (5 mL) was added.
After 30 min at –78 °C, a solution of I2 (761 mg, 3.00 mmol) in THF
(5 mL) was added. The reaction mixture was stirred for 5 min at
–78 °C, then the cooling bath was removed, and the mixture stirred
at r.t. for 1 h. The mixture was quenched with 10% aq Na2S2O3 (5
mL) and the THF was removed in vacuo. CH2Cl2 (5 mL) was added
to the residue, the organic phase was separated, concentrated and
purified by gradient column chromatography (12 g silica gel col-
umn, elution with 0–30% EtOAc in heptane) to give a white solid
(435 mg, 52%).
1H NMR (400 MHz DMSO-d6): d = 8.50 (s, 1 H), 3.97 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 153.4, 148.7, 147.37, 116.3,
112.6, 81.7, 54.8.
CI-MS: m/z (%) = 279 ([M + 1]+, 100).
2,3-Difluoroisonicotinonitrile (5)
A mixture of 2,3-difluoro-4-iodopyridine (4; 16.87 g, 70 mmol),
CuCN (7.52 g, 84.00 mmol) and propionitrile (68 mL) was equally
distributed between 6 vials and heated for 3.5 h at 160 °C via micro-
wave irradiation. The combined mixtures were concentrated, dilut-
ed with CH2Cl2 (70 mL), filtered, and again concentrated. The
resulting residue was purified by gradient column chromatography
(120 g silica gel column, elution with 0–40% EtOAc in heptane) to
give an oil (9.86 g, quant.).
1H NMR (400 MHz, DMSO-d6): d = 8.30 (dd, J = 5.0, 1.0 Hz, 1 H),
7.97 (dd, J = 4.8, 4.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 152.1 (dd, 1JC,F = 242.6 Hz,
2JC,F = 12.8 Hz, 1 C), 146.2 (dd, 1JC,F = 276.2 Hz, 2JC,F = 30.7 Hz, 1
C), 142.6, 124.0, 112.4, 110.7.
HRMS: m/z calcd for C7H4FIN2O: 277.9352; found: 277.9347.
3-Fluoro-5-iodo-2-methoxy-6-(trimethylsilyl)isonicotinonitrile
(1)
A 2.5 M hexane solution of n-BuLi (0.151 mL, 0.38 mmol) was
added to a solution of 2,2,6,6-tetramethylpiperidine (53.3 mg, 0.064
mL, 0.38 mmol) in anhyd THF (2 mL) at 0 °C under N2. The result-
ing mixture was stirred for 15 min and then cooled to –78 °C. A so-
lution of compound 8 (50 mg, 0.18 mmol) in THF (1 mL) was added
dropwise to produce an orange solution. The reaction mixture was
stirred for 20 min. A solution of Me3SiCl (0.046 mL, 0.36 mmol) in
THF (1 mL) was added. After 45 min at –78 °C, the cooling bath
was removed and the mixture allowed to attain r.t. The mixture was
evaporated directly on silica gel (0.5 g) and purified by gradient col-
umn chromatography (4 g silica gel column, elution with 0–10%
EtOAc in heptane) to give a white solid (14 mg, 22%).
CI-MS: m/z (%) = 141.0 ([M + 1]+, 100).
3-Fluoro-2-oxo-1,2-dihydropyridine-4-carbonitrile (6)
A mixture of 2,3-difluoroisonicotinonitrile (5; 9.54 g, 68.10 mmol)
and aq 2 M HCl (85 mL) was equally distributed between 6 vials
and heated for 5 min at 150 °C via microwave irradiation. After
cooling to r.t., the mixtures were combined (the vials rinsed with
MeOH), concentrated, and dried in a vacuum oven overnight at
50 °C to give a solid (8.86 g, 94%).
1H NMR (400 MHz, CDCl3): d = 4.05 (s, 3 H), 0.62 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 151.9, 148.3, 134.8, 115.3, 113.9,
111.7, 55.1, 1.6.
CI-MS: m/z (%) = 351 ([M + 1]+, 100).
HRMS: m/z calcd for C10H12FIN2OSi: 349.9748; found: 349.9762.
1H NMR (400 MHz, DMSO-d6): d = 12.78 (br s, 1 H), 7.44 (dd,
J = 6.8, 1.3 Hz, 1 H), 6.48 (dd, J = 6.8, 5.1 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 154.9 (d, JC,F = 264.2 Hz, 1
C), 154.3 (d, JC,F = 23.8 Hz, 1 C), 132.5, 112.2, 107.0, 102.7.
3-Fluoro-2-(methylthio)isonicotinonitrile (9)
NaSMe (841 mg, 12.00 mmol) was slurried in MeCN (8 mL). A
mixture of 2,3-difluoroisonicotinonitrile (5; 1401 mg, 10 mmol) in
pentane (10 mL) was added in one portion. The biphasic mixture
was stirred vigorously at r.t. for 15 min, during which time a rise in
temperature was noted. The mixture was transferred to a separating
funnel with H2O (50 mL) and EtOAc (20 mL). The organic phase
was separated and the aqueous phase extracted with EtOAc (2 × 25
mL). The combined organic phases were washed with H2O (20 mL),
dried (MgSO4), and concentrated to an oil that solidified on stand-
ing (1680 mg, quant.).
1H NMR (400 MHz, DMSO-d6): d = 8.22 (dd, J = 5.0, 1.0 Hz, 1 H),
7.43 (dd, J = 5.0, 1.0 Hz, 1 H), 2.64 (d, J = 1.8 Hz, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 162.4 (d, JC,F = 240.0 Hz, 1
C), 146.2, 127.1, 124.9, 124.5, 114.3, 17.7.
CI-MS: m/z (%) = 139 ([M + 1]+, 100).
HRMS: m/z calcd for C6H3FN2O: 138.0229; found: 138.0232.
3-Fluoro-2-methoxyisonicotinonitrile (7)
To a slurry of pyridone 6 (8.86 g, 64.16 mmol) and Ag2CO3 (26.5
g, 96.24 mmol) in CHCl3 (200 mL) at r.t. under N2 was added MeI
(4.80 mL, 76.99 mmol). The resulting mixture was stirred at r.t. for
2 d and then filtered through Celite and concentrated. The resulting
residue was purified by gradient column chromatography (80 g sil-
ica gel column, elution with 0–30% EtOAc in heptane) to give an
oil that solidified on standing (2.78 g, 29%).
1H NMR (400 MHz, DMSO-d6): d = 8.20 (d, J = 5.1 Hz, 1 H), 7.50
(dd, J = 5.3, 3.8 Hz, 1 H), 4.01 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 153.8, 148.0 (d, JC,F = 276.0 Hz,
1 C), 142.1, 117.5, 111.8, 108.7, 54.5.
CI-MS: m/z (%) = 169 ([M + 1]+, 100).
HRMS: m/z calcd for C7H5FN2S: 168.0157; found: 168.0161.
3-Fluoro-5-iodo-2-(methylthio)isonicotinonitrile (10)
CI-MS: m/z (%) = 153 ([M + 1]+, 100).
2,2,6,6-Tetramethylpiperidine (339 mg, 0.407 mL, 2.40 mmol) was
dissolved in anhyd THF (10 mL) under argon and cooled to 0 °C. A
1.6 M hexane solution of n-BuLi (1.440 mL, 2.30 mmol) was added
dropwise over 1 min to produce a yellow solution. After 10 min, the
solution was cooled to –78 °C. A solution of compound 9 (336 mg,
2 mmol) in anhyd THF (3 mL) was added dropwise over 2 min. Af-
3-Fluoro-5-iodo-2-methoxyisonicotinonitrile (8)
A 2.5 M hexane solution of n-BuLi (1.380 mL, 3.45 mmol) was
added to a solution of 2,2,6,6-tetramethylpiperidine (509 mg, 0.611
Synthesis 2010, No. 1, 63–66 © Thieme Stuttgart · New York