The Trialkylsilyl Trick
1
0.34 g (53%). H NMR: δ 8.05 (dd, J ) 8.7, 5.9 Hz, 1 H), 6.49
2 Hz, 3 C) ppm. C10H16F2N2Si (230.33): calcd C 52.15, H 7.00;
found C 52.07, H 6.73.
(dd, J ) 11.2, 2.3 Hz, 1 H), 6.43 (ddd, J ) 8.3, 5.8, 2.3 Hz,
1H), 6.2 (s, broad, 1 H), 3.6 (s, broad, 2 H) ppm. 13C NMR: δ
170.3 (d, J ) 258 Hz), 164.1 (d, J ) 10 Hz), 150.2 (d, J ) 10
Hz), 103.1 (d, J ) 19 Hz), 93.1 (d, J ) 21 Hz) ppm. C5H6FN3
(127.12): calcd 47.24, H 4.76; found C 47.21, H 4.66.
3. 2,4,6-Trifluoropyridine Series. 2,6-Difluoro-4-ethoxy-
pyridine (9). When sodium (1.2 g, 50 mmol) had completely
dissolved in ethanol (50 mL), 2,4,6-trifluoropyridine (6.7 g, 50
mmol) was added at 0 °C. After 2 h, the mixture was
evaporated. Crystallization from hexanes afforded colorless
needles, mp 57-59 °C, yield 6.41 g (81%). 1H NMR: δ 6.28 (s,
2 H), 4.11 (q, J ) 7.0 Hz, 2 H), 1.45 (t, J ) 7.0 Hz, 3 H) ppm.
13C NMR: δ 171.8 (t, J ) 12 Hz), 162.9 (dd, J ) 241, 20 Hz, 2
C), 92.4 (symm. m, 2 C), 65.1, 14.2 ppm. C7H7F2NO (159.13):
calcd C 52.83, H 4.43; found C 52.82, H 4.43.
2,4-Difluoro-6-(dimethylamino)pyridine (14). 2,4-Di-
fluoro-6-(dimethylamino)-3-(trimethylsilyl)pyridine (13a; 12 g,
50 mmol) and tetrabutylammonium fluoride trihydrate (16 g,
50 mmol) were dissolved in tetrahydrofuran (50 mL). After 2
h at 25 °C, the solvent was evaporated and the residue
partitioned between water (25 mL) and diethyl ether (50 mL).
The organic phase was dried and distilled; colorless liquid, mp
29-31 °C, bp 75-77 °C/16 mmHg, yield 7.21 g (91%). 1H NMR:
δ 5.96 (dd, J ) 11.2, 1.6 Hz, 1 H), 5.85 (dt, J ) 8.3, 1.6 Hz, 1
H), 3.04 (s, 6 H) ppm. 13C NMR: δ 172.2 (dd, J ) 254, 14 Hz),
163.5 (dd, J ) 233, 17 Hz), 159.0 (dd, J ) 21, 14 Hz), 88.6 (dd,
J ) 23, 6 Hz), 83.5 (dd, J ) 43, 25 Hz), 37.6 (2 C) ppm.
C7H8F2N2 (158.15): calcd C 53.16, H 5.10; found C 53.22, H
5.35.
2,4-Difluoro-6-hydrazino-3-(triethylsilyl)pyridine (15b).
2,4,6-Trifluoro-3-(triethylsilyl)pyridine (12b; 74 g, 0.30 mol)
and hydrazine monohydrate (29 mL, 30 g, 0.60 mol) were
heated in tetrahydrofuran (0.10 L) for 2 h at 50 °C. After
evaporation of the solvent and addition of diethyl ether (75
mL), the organic phase was washed with water (50 mL).
4-Dimethylamino-2,6-difluoropyridine (10). At 0 °C,
2,4,6-trifluoropyridine (6.7 g, 50 mmol) was added to a 40%
aqueous solution (50 mL) of dimethylamine. After 45 min, the
solid formed was collected by filtration and crystallized from
chloroform; colorless needles, mp 120-122 °C, yield 6.80 g
1
(86%). H NMR: δ 5.91 (s, 2 H), 3.02 (s, 6 H) ppm. 13C NMR:
Evaporation of the solvent afforded a yellowish oil, n20
)
D
δ 163.1 (dd, J ) 236, 21 Hz, 2 C), 160.7 (t, J ) 12 Hz), 87.0
(symm. m, 2 C), 39.4 (2 C) ppm. C7H8F2N2 (158.15): calcd C
53.16, H 5.10; found C 52.86, H 4.97.
1.5226, yield 76.3 g (98%). 1H NMR: δ 6.8 (s, broad, 1 H), 6.33
(d, J ) 10.2 Hz, 1 H), 3.8 (s, broad, 2 H), 0.9 (m, 15 H) ppm.
13C NMR: δ 177.4 (dd, J ) 253, 17 Hz), 167.6 (dd, J ) 233, 22
Hz), 163.1 (dd, J ) 20, 15 Hz), 90.8 (dd, J ) 51, 36 Hz), 89.3
(dd, J ) 29, 5 Hz), 7.1 (3 C), 3.9 (t, J ) 2 Hz, 3 C) ppm.
C11H19F2N3Si (259.37): calcd C 50.94, H 7.38; found C 51.21,
H 7.31.
2,6-Difluoro-4-hydrazinopyridine (11). 2,4,6-Trifluoro-
pyridine (6.7 g, 50 mmol) and hydrazine monohydrate (4.9 mL,
5.0 g, 0.10 mol) were heated in tetrahydrofuran (50 mL) at 50
°C for 2 h. After the solvent had been evaporated, the residue
was triturated with water (25 mL) and hexanes (12 mL).
Crystallization from ethyl acetate afforded colorless platelets,
mp 200-202 °C, yield 6.17 g (85%). 1H NMR*: δ 9.3 (s, broad,
1 H), 6.48 (s, 2 H), 3.0 (s, broad, 2 H) ppm. 13C NMR*: δ 164.6
(dd, J ) 235, 20 Hz, 2 C), 161.0 (t, J ) 12 Hz), 89.5 (symm. m,
2 C) ppm. C5H5F2N3 (145.11): calcd C 41.38, H 3.47; found C
41.55, H 3.23.
2,4-Difluoro-6-hydrazinopyridine (16). 2,4-Difluoro-6-
hydrazino-3-(triethylsilyl)pyridine (15b; 13 g, 50 mmol) and
tetrabutylammonium fluoride trihydrate (16 g, 50 mmol) were
stored in tetrahydrofuran (50 mL) for 2 h at 25 °C. The solvent
was evaporated and the residue was triturated with water (25
mL) and hexanes (50 mL); colorless needles (from chloroform
and hexanes), mp 101-103 °C. yield 6.21 g (85%). 1H NMR: δ
6.37 (dd, J ) 10.0, 1.6 Hz, 1 H), 6.3 (s, broad, 1 H), 5.98 (dt, J
) 8.4, 1.7 Hz), 3.8 (s, broad, 2 H) ppm. 13C NMR: δ 172.6 (dd,
J ) 257, 14 Hz), 163.9 (dd, J ) 236, 17 Hz), 162.0 (dd, J ) 20,
14 Hz), 89.7 (dd, J ) 24, 5 Hz), 86.5 (dd, J ) 41, 25 Hz) ppm.
C5H5F2N3 (145.11): calcd C 41.39, H 3.47; found C 41.69, H
3.27.
2,4,6-Trifluoro-3-(trimethylsilyl)pyridine (12a). At -100
°C, 2,4,6-trifluoropyridine (6.7 g, 50 mmol) in tetrahydrofuran
(0.10 L) and butyllithium (50 mmol) in hexanes (32 mL) were
mixed. After 45 min at -100 °C, chlorotrimethylsilane (6.3 mL,
5.4 g, 50 mmol) and, after 45 min at -75 °C, water (25 mL)
were added. The product was collected as a colorless liquid
upon distillation, mp -17 to -16 °C, bp 69-71 °C/20 mmHg,
2,4-Difluoro-6-ethoxy-3-(trimethylsilyl)pyridine (17a).
Sodium ethoxide (1.7 g, 25 mmol) and 2,4,6-trifluoro-3-(tri-
methylsilyl)pyridine (12a; 5.1 g, 25 mmol) were mixed in
diethyl ether (50 mL). After 2 h at 25 °C, distillation afforded
n20 ) 1.4456, yield 9.24 g (90%). 1H NMR: δ 6.49 (dd, J )
D
7.7, 1.9 Hz,1 H), 0.38 (t, J ) 1.4 Hz, 9 H) ppm. 13C NMR: δ
177.8 (ddd, J ) 258, 16,12 Hz), 166.1 (ddd, J ) 241, 22, 18
Hz), 163.9 (ddd, J ) 244, 21, 18 Hz), 104.8 (ddd, J ) 48, 34, 6
Hz), 94.8 (ddd, J ) 38, 29, 7 Hz), -0.37 (t, J ) 3 Hz, 3 C)
ppm. C8H10F3NSi (205.25): calcd C 46.81, H 4.91; found C
46.94, H 4.83.
a colorless liquid, mp -6 to -4 °C, bp 83-85 °C/11 mmHg,
1
n20 ) 1.4673, yield 5.32 g (92%). H NMR: δ 6.22 (d, J ) 9.0
D
Hz, 1 H), 4.32 (q, J ) 7.04 Hz, 2 H), 1.37 (t, J ) 7.04 Hz, 3 H),
0.33 (t, J ) 1.3 Hz, 9 H) ppm. 13C NMR: δ 176.8 (dd, J ) 254,
16 Hz), 165.5 (dd, J ) 235, 21 Hz), 165.3 (dd, J ) 19, 17 Hz),
98.0 (dd, J ) 49, 34 Hz), 94.3 (dd, J ) 28, 7 Hz), 62.8, 14.4,
-0.2 (t, J ) 2.0 Hz, 3 C) ppm. C10H15F2NOSi (231.31): calcd C
51.92, H 6.54; found C 51.88, H 6.50.
2,4,6-Trifluoro-3-(triethylsilyl)pyridine (12b). Prepared
analogously as described above but working on a 0.10 mol scale
and using chlorotriethylsilane (17 mL, 15 g, 0.10 mol) as the
reagent; colorless liquid, bp 65-67 °C/1.6 mmHg; n20D 1.4630,
yield 20.8 g (84%). 1H NMR: δ 6.50 (dd, J ) 7.6, 1.9 Hz, 1 H),
0.9 (m, 15 H). 13C NMR: δ 178.2 (ddd, J ) 259, 16, 12 Hz),
166.5 (ddd, J ) 243, 22, 18 Hz), 164.0 (ddd, J ) 245, 20, 17
Hz), 102.3 (ddd, J ) 50, 35, 6 Hz), 94.8 (ddd, J ) 37, 30, 7
Hz), 7.1 (s), 3.8 (t, J ) 2.1 Hz). C11H16F3NSi (247.34): calcd C
53.42, H 6.52; found C 53.46, H 6.48.
2,4-Difluoro-3-(triethylsilyl)pyridine (18). 2,4-Difluoro-
6-hydrazino-3-(triethylsilyl)pyridine (15b; 39 g, 0.15 mol) and
copper(II) sulfate pentahydrate (75 g, 0.30 mol) were heated
in water (0.30 L) under reflux for 2 h. The product was isolated
as a colorless liquid by steam distillation followed by in vacuo
distillation, bp 85-86 °C/3 mmHg, yield 30.6 g (89%); n20
D
1
1.4781. H NMR: δ 8.18 (dd, J ) 8.9, 5.5 Hz, 1 H), 6.87 (ddd,
2,4-Difluoro-6-(dimethylamino)-3-(trimethylsilyl)pyri-
dine (13a). At 25 °C, 2,4,6-trifluoro-3-(trimethylsilyl)pyridine
(12a; 5.1 g, 25 mmol) was added to a 40% aqueous solution
(25 mL) of dimethylamine. After 45 min, the product was
extracted from the reaction mixture with diethyl ether (3 ×
25 mL). Evaporation and crystallization from chloroform
J ) 7.4, 5.6, 0.7 Hz, 1 H), 0.9 (m, 15 H). 13C NMR: δ 176.0 (dd,
J ) 259, 16 Hz), 168.4 (dd, J ) 235, 18 Hz), 150.2 (dd, J ) 19,
12 Hz), 109.8 (dd, J ) 24, 5 Hz), 105.4 (dd, J ) 51, 33 Hz), 7.2
(s), 3.8 (t, J ) 2.5 Hz). C11H17F2NSi (229.35): calcd C 57.61,
7.47; found C 57.43, H 7.38.
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afforded 5.47 g (95%) of colorless platelets, mp 43-45 °C. H
6-Bromo-2,4-difluoro-3-(triethylsilyl)pyridine (19). Bro-
mine (2.6 mL, 8.0 g, 50 mmol) was added to a solution of 2,4-
difluoro-6-hydrazino-3-(triethylsilyl)pyridine (15b; 6.5 g, 25
mmol) in chloroform (50 mL). The mixture was heated under
reflux for 4 h before being washed with a saturated aqueous
NMR: δ 5.92 (dd, J ) 11.2, 1.0 Hz, 1 H), 3.04 (s, 6 H), 0.30 (t,
J ) 1.3 Hz, 9 H) ppm. 13C NMR: δ 176.7 (dd, J ) 251, 17 Hz),
167.1 (dd, J ) 230, 22 Hz), 159.9 (dd, J ) 22, 15 Hz), 91.0 (dd,
J ) 51, 35 Hz), 88.7 (dd, J ) 29, 5 Hz), 37.6 (2 C), 0.1 (t, J )
J. Org. Chem, Vol. 70, No. 7, 2005 2499