6170
A. Doudouh et al. / Tetrahedron 62 (2006) 6166–6171
3. Conclusion
1H), 7.54 (d, J¼7.6 Hz, 1H), 7.75 (t, J¼7.6 Hz, 1H). 13C
NMR (CDCl3): d¼15.4, 43.5, 121.9, 125.1, 139.7, 150.1,
A new superbasic reagent has been discovered by combining
TMSCH2LiandLiDMAEinhexane. Thisreagent,whenused
in a 2/1 ratio was found highly efficient for the C-2 lithiation
of sensitive chloro- and fluoropyridines. The metallation
occurred chemoselectively at 0 ꢀC without any trace of the
nucleophilic addition commonly observed with other alkyl-
lithiums even at lower temperatures. The usually tedious
regioselective control of 3-fluoropyridine lithiation was
achieved by simply adjusting the TMSCH2Li–LiDMAE
ratio to 1/1. Moreover, the low nucleophilicity of the base
allowed using only stoichiometric amounts of electrophilic
reagents. Although using the more expensive TMSCH2Li,
the newly reported C-2 lithiating reagent is a profound
improvement of the known BuLi–LiDMAE superbase for
lithiation of halopyridines. Work is now progressing to
further investigate the scope of the TMSCH2Li–LiDMAE
superbase especially with more electrophilic heterocycles.
155.3, 203.1.
4.2.2. Bis-(6-chloro-pyridin-2-yl)-methanone (1h). Yield,
1
80%. H NMR (CDCl3): d¼7.55 (d, J¼8.0 Hz, 2H), 7.87
(t, J¼7.5 Hz, 2H), 8.04 (d, J¼7.5 Hz, 2H). 13C NMR
(CDCl3): d¼124.1, 127.8, 139.5, 151.1, 153.7, 189.6.
Anal. Calcd for C11H6Cl2N2O: C, 52.20; H, 2.39; N,
11.07%. Found: C, 51.97; H, 2.23; N, 11.16%.
4.2.3. (3-Chloro-pyridin-2-yl)-phenyl-methanol (2d).21
1
Yield, 70%. H NMR (CDCl3): d¼5.31 (br s, 1H), 6.03 (s,
1H), 7.24–7.39 (m, 6H), 6.69 (dd, J¼7.9 and 1.3 Hz, 1H),
8.57 (dd, J¼4.8 and 1.3 Hz, 1H). 13C NMR (CDCl3): d¼
72.1, 123.8, 126.9, 128.1, 128.4, 128.5, 130.1, 137.9,
141.7, 146.2, 157.5.
4.2.4. (4-Chloro-pyridin-2-yl)-phenyl-methanol (3d).22
1
Yield, 80%. H NMR (CDCl3): d¼4.93 (br s, 1H), 5.72 (s,
1H), 7.17–7.41 (m, 7H), 8.44 (d, J¼5.8 Hz, 1H). 13C NMR
(CDCl3): d¼75.2, 121.9, 124.2, 127.1, 128.7, 128.8, 142.5,
149.1, 163.2.
4. Experimental
4.1. General
4.2.5. 2-Fluoro-6-methylsulfanyl-pyridine (4a).23 Yield,
All solvents were distilled and stored over sodium wire
before use. 2-Dimethylaminoethanol was distilled under
nitrogen and stored on molecular sieves. TMSCH2Li (FMC
Lithium) was used as a 0.92 M solution in hexanes. All re-
agents were commercially available and used as such except
for 4-chloropyridine, which was released from its hydro-
1
69%. H NMR (CDCl3): d¼2.55 (s, 3H), 6.59 (dd, J¼6.9
and 0.9 Hz, 1H), 7.07 (dd, J¼7.9 and 1.9 Hz, 1H), 7.59 (d,
J¼7.9 Hz, 1H). 13C NMR (CDCl3): d¼12.5, 104.1, 118.5,
140.65, 157.5, 163.4.
4.2.6. (6-Fluoro-pyridin-2-yl)-phenyl-methanone (4c).
Yield, 62%. 1H NMR (CDCl3): d¼7.15 (dd, J¼8.1 and
1.2 Hz, 1H), 7.46–7.60 (m, 2H), 7.62 (q, J¼6.9 Hz, 1H),
7.94–8.10 (m, 4H). 13C NMR (CDCl3): d¼112.8, 113.4,
122.3, 128.1, 131.2, 133.5, 142.2, 142.4, 160.2, 164.1,
192.1 ppm. Anal. Calcd for C12H8FNO: C, 71.64; H, 4.01;
N, 6.96%. Found: C, 71.35; H, 4.23; N, 6.69%.
1
chloride salt by basic treatment (aq K2CO3). H and 13C
NMR spectra were obtained in CDCl3 (unless otherwise
stated) on a Bruker AC400 instrument at 200 and 50 MHz,
respectively. GC experiments were performed on a Shimadzu
chromatograph (FID detection) through a 15 m capillary
HP1 column. Products 1a, 1c–e,4a 1f,18 2a–c,4b 3a–c4b and
4b18 were found spectroscopically identical to the previously
reported compounds.
4.3. General procedure for C-2 lithiation of 3-fluoro-
pyridine 5
4.2. General procedure for C-2 lithiation of chloro-
pyridines 1–3 and 2-fluoropyridine 4
TMSCH2Li (8 mL, 7.36 mmol) was added dropwise to a so-
lution of 2-dimethylaminoethanol (328 mg, 3.68 mmol) in
hexane (8 mL) at 0 ꢀC. After 30 min of stirring, a solution
of 5 (178 mg, 1.84 mmol) in hexane (8 mL) was then added
dropwise. The solution was then stirred for 1 h at the same
temperature and then treated at ꢁ78 ꢀC with a solution of
the appropriate electrophile (1.1 or 1.5 mmol for benzalde-
hyde) in THF (24 mL). The temperature was maintained at
ꢁ78 ꢀC for 1 h and at 0 ꢀC for 30 min. Hydrolysis was
then performed at this temperature with water (3 mL). The
reaction medium was then extracted with ether (10 mL),
the organic layer dried over MgSO4 and evaporated under
vacuum. The crude product was first subjected to GC analy-
sis and purified if needed by eluting with hexane–AcOEt
mixtures using a gradient from 95/5 to 90/10.
TMSCH2Li (6 mL, 5.52 mmol) was added dropwise to a
solution of 2-dimethylaminoethanol (164 mg, 1.84 mmol)
in hexane (6 mL) at 0 ꢀC. After 30 min of stirring, a solution
of the appropriate halopyridine (1.84 mmol) in hexane
(6 mL) was then added dropwise. The solution was then
stirred for 1 h (2 h for 3) at the same temperature and then
treated at ꢁ78 ꢀC with a solution of the appropriate electro-
phile (2.02 mmol), except for benzaldehyde (3.68 mmol), in
THF (18 mL). The temperature was maintained at ꢁ78 ꢀC
for 1 h and at 0 ꢀC for 30 min. Hydrolysis was then per-
formed at this temperature with water (10 mL). The reaction
medium was then extracted twice with ether (25 mL), the
organic layer dried over MgSO4 and evaporated under
vacuum. The crude product was first subjected to GC
analysis and purified if needed by chromatography on silica
gel eluting with hexane–AcOEt mixtures using a gradient
from 95/5 to 90/10.
4.3.1.3-Fluoro-2-methylsulfanyl-pyridine(5a). Yield, 87%.
1H NMR (CDCl3): d¼2.58 (s, 3H), 6.99 (m, 1H), 7.26
(dt, J¼8.5 and 0.9 Hz, 1H), 8.28 (dd, J¼5.9 and 1.5 Hz,
1H). 13C NMR (CDCl3): d¼12.1, 119.7, 120.6, 120.9,
145.1, 148.3, 158.6 ppm. Anal. Calcd for C6H6FNS: C,
50.33; H, 4.22; N, 9.78%. Found: C, 50.47; H, 4.18; N, 9.52%.
4.2.1. 6-Chloro-pyridine-2-carboxylic acid diethylamide
(1g).20 Yield, 32%. 1H NMR (CDCl3): d¼1.35 (t,
J¼7.3 Hz, 6H), 3.49 (q, J¼7.3 Hz, 4H), 7.38 (d, J¼7.6 Hz,