Strategies for the Selective Functionalization of Dichloropyridines at Various Sites
FULL PAPER
starting with 2-bromo-3,5-dichloropyridine (13); colorless needles
with 35% aqueous hydrogen peroxide (50 mL, 57 g, 60 mmol) and
(4.2 g, 88%); m.p. 151Ϫ152 °C. Ϫ 1H NMR: δ ϭ 8.51 (d, J ϭ a 3.0 aqueous solution (25 mL) of sodium hydroxide. The two-
2.1 Hz, 1 H), 7.98 (d, J ϭ 2.1 Hz, 1 H). Ϫ 13C NMR: δ ϭ 165.0, phase mixture was vigorously stirred for 2 h at 25 °C. The aqueous
146.0, 145.7, 138.3, 134.0, 131.6. Ϫ C6H3Cl2NO2 (192.00): calcd.
C 37.53, H 1.57; found C 37.61, H 1.59.
layer was decanted and washed with diethyl ether (3 ϫ 50 mL).
The organic solvent was evaporated and the residue crystallized
from 75% aqueous ethanol affording colorless needles (7.6 g, 69%);
2,6-Dichloro-4-pyridinecarboxylic Acid (17): As described for the
preparation of acid 14 from 2,6-dichloro-4-iodopyridine (16), again
working on a 25 mmol scale but carrying out the reaction with tert-
butyllithium (50 mmol) at Ϫ75 °C; m.p. 208Ϫ209 °C (ref.[29] 211
1
m.p. 192Ϫ194 °C. Ϫ H NMR*: δ ϭ 8.27 (s, 1 H), 6.95 (s, 1 H).
Ϫ
13C NMR*: δ ϭ 161.6, 149.0, 128.0, 118.6, 111.3. Ϫ C5H3Cl2NO
(163.99): calcd. C 36.62, H 1.84; found C 36.62, H 2.03.
1
°C); 4.3 g (89%). Ϫ H NMR*: δ ϭ 7.89 (s, 2 H). Ϫ 13C NMR*:
3,6-Dichloro-4(1H)pyridinone-2-carboxylic Acid (8): At Ϫ75 °C,
tert-butyllithium (50 mmol) in pentanes (30 mL) was added to a
solution of 2,5-dichloro-4(1H)pyridinone (7; 4.1 g, 25 mmol) in
tetrahydrofuran (90 mL). After 2 h at Ϫ75 °C, the mixture was
poured on an excess of freshly crushed dry ice. The solid remaining
after the evaporation of the volatiles was taken up in water
(100 mL). The aqueous phase was washed with diethyl ether (3 ϫ
25 mL), acidified to pH 1 and extracted with diethyl ether (3 ϫ
50 mL). After evaporation of the organic solvent, the residue was
crystallized from 70% aqueous methanol to give colorless needles
(3.0 g, 58%); m.p. 173Ϫ175 °C (decomp.). Ϫ 1H NMR: δ ϭ 7.03
(1 H). Ϫ 13C NMR: δ ϭ 165.1, 163.0, 148.8, 148.4, 118.2, 113.2.
Ϫ C7H3Cl2NO3 (208.00): calcd. C 34.65, H 1.45; found C 34.60,
H 1.48.
δ ϭ164.1, 150.5 (2 C), 145.0, 123.8 (2 C).
2,4-Dichloro-5-iodo-3-pyridinecarboxylic Acid (18): 2,4-Dichloro-3-
iodopyridine (9, 1.4 g, 5 mmol) was treated with lithium diisoprop-
ylamide (5 mmol) in tetrahydrofuran (10 mL) as described above
(see preparation of the isomer 10), but the mixture was poured
onto dry ice rather than being quenched with water. The acid was
isolated by extraction first into the alkaline aqueous phase and
then, after acidification, into dichloromethane (see above). 2,4-
Dichloro-3-pyridinecarboxylic acid and 2,4-dichloro-5-iodo-3-pyr-
idinecarboxylic acid (18) were isolated in a 2:3 ratio; 58%. Upon
trituration with chloroform, the main component was obtained
pure (0.4 g, 25%); m.p. 202Ϫ203 °C. Ϫ 1H NMR: δ ϭ 8.72 (s, 1
H). Ϫ 13C NMR: δ ϭ 164.7, 156.7, 149.5, 147.6, 131.8, 96.5. Ϫ
C6H2Cl2INO2 (317.90): calcd. C 22.67, H 0.63; found C 22.64, H
0.88.
Acknowledgments
2,6-Dichloro-4-iodo-3-pyridinecarboxylic Acid (20): As described in
the preceding paragraph, 2,6-dichloro-3-iodopyridine (2.7 g,
10 mmol) was converted into the acid 20, which was purified by
trituration with chloroform (15 mL) and sublimation; m.p.
227Ϫ228 °C (decomp.); 1.8 g (57%). Ϫ 1H NMR (D3CCOCD3):
δ ϭ 8.11 (s, 1 H). Ϫ 13C NMR: δ ϭ 166.2, 150.8, 145.5, 137.0,
134.1, 107.4. Ϫ C6H2Cl2INO2 (317.90): calcd. C 22.67, H 0.63;
found C 22.28, H 0.97.
This work was financially supported by the Schweizerische Na-
tionalfonds zur Förderung der wissenschaftlichen Forschung, Bern
(grant 20Ϫ55Ј303Ϫ98) and the Bundesamt für Bildung und Wis-
senschaft, Bern (grant 97.0083 linked to the TMR project
FMRXCT970129).
[1]
G. W. Gribble, M. G. Saulnier, Tetrahedron Lett. 1980, 21,
4137Ϫ4140; Heterocycles 1993, 35, 151Ϫ169 [Chem. Abstr.
1993, 119, 95281e].
2-Bromo-3,5-dichloro-4-pyridinecarboxylic Acid (19): In the same
manner, acid 19 was obtained from 4-bromo-3,5-dichloropyridine
(2.3 g, 10 mmol). Extraction, trituration and sublimation again af-
forded an analytically pure product as colorless tufts (1.1 g, 41%);
m.p. 200Ϫ202 °C. Ϫ 1H NMR: δ ϭ 8.56 (s, 1 H). Ϫ 13C NMR:
δ ϭ 163.2, 15.9, 148.4, 143.7, 140.8, 128.1. Ϫ C6H2Br2NO2
(270.90): calcd. C 26.60, H 0.74; found C 27.04, H 0.39.
[2]
´
`
´
F. Marsais, P. Breant, A. Ginguene, G. Queguiner, J. Or-
´
ganomet. Chem. 1981, 216, 139Ϫ147; F. Marsais, F. Trecourt,
´
´
P. Breant, G. Queguiner, J. Heterocycl. Chem. 1988, 25, 81Ϫ87.
M. Mallet, J. Organomet. Chem. 1991, 406, 49Ϫ56.
R. Radinov, C. Chanev, M. Haimova, J. Org. Chem. 1991, 56,
4793Ϫ4796.
[3]
[4]
[5]
[6]
A. D. Cale, T. W. Gero, K. R. Walker, Y. S. Lo, W. J. Welstead,
L. W. Jaques, A. F. Johnson, C. A. Leonard, J. C. Nolan, D.
N. Johnson, J. Med. Chem. 1989, 32, 2178Ϫ2199; spec. 2198.
G. Katsoulos, S. Takagishi, M. Schlosser, Synlett 1991,
731Ϫ732; M. Schlosser, G. Katsoulos, S. Takagishi, Synlett
1990, 747Ϫ748; S. Takagishi, G. Katsoulos, M. Schlosser, Syn-
lett 1992, 360Ϫ362; G. Katsoulos, M. Schlosser, Tetrahedron
Lett. 1993, 34, 6263Ϫ6264; R. Maggi, M. Schlosser, J. Org.
Chem. 1996, 61, 5430Ϫ5434; F. Mongin, R. Maggi, M.
Schlosser, Chimia 1996, 50, 650Ϫ652.
G. Rauchschwalbe, M. Schlosser, Helv. Chim. Acta 1975, 58,
1094Ϫ1099.
F. Mongin, O. Desponds, M. Schlosser, Tetrahedron Lett. 1996,
37, 2767Ϫ2770.
D. A. De Bie, H. C. van der Plas, Tetrahedron Lett. 1968, 9,
3905Ϫ3907.
M. G. Reinecke, H. W. Adickes, J. Am. Chem. Soc. 1968, 90,
511Ϫ513; M. G. Reinecke, H. W. Adickes, C. Pyun, J. Org.
Chem. 1971, 36, 2690Ϫ2692, 3820Ϫ3821.
S. Kano, Y. Yuasa, T. Yokomatsu, S. Shibuya, Heterocycles
1983, 20, 2035Ϫ2037; Chem. Abstr. 1984, 100, 6238p.
E. C. Taylor, D. E. Vogel, J. Org. Chem. 1985, 50, 1002Ϫ1004.
Miscellaneous: Formylation and Oxidation Products
3,6-Dichloro-2-pyridinecarbaldehyde (6): A solution of 2,5-dichloro-
pyridine (3.7 g, 25 mmol) and tert-butyllithium (25 mmol) in di-
ethyl ether (50 mL) and pentanes (15 mL) was kept 6 h at Ϫ100
°C before N,N-dimethylformamide (1.8 mL, 1.5 g, 25 mmol) was
added. After 30 min. at Ϫ100 °C and 30 min. at Ϫ75 °C, the mix-
ture was poured into water (50 mL), washed with diethyl ether (2
ϫ 20 mL), acidified to pH 2 and extracted with diethyl ether (3
ϫ 20 mL). After evaporation of the combined organic layers and
recrystallization from hexanes, white needles were obtained (3.5 g,
[7]
[8]
[9]
1
80%); m.p. 105Ϫ107 °C. Ϫ H NMR: δ ϭ 10.20 (s, 1 H), 7.81 (d,
J ϭ 8.5 Hz, 1 H), 7.49 (d, J ϭ 8.5 Hz, 1 H). Ϫ 13C NMR: δ ϭ
188.5, 150.0, 147.3, 142.0, 131.9, 129.1. Ϫ C6H3Cl2NO (176.00):
calcd. C 40.95, H 1.72; found C 41.18, H 1.82.
[10]
[11]
2,5-Dichloro-4(1H)pyridinone (7): At Ϫ75 °C, 2,5-dichloropyridine
(7.4 g, 50 mmol) was added to a solution of butyllithium (50 mmol)
and N,N,NЈ,NЈЈ,NЈЈ-pentamethyldiethylenetriamine (10 mL, 8.7 g,
50 mmol) in tetrahydrofuran (70 mL) and hexanes (30 mL). After
2 h at Ϫ75 °C, the mixture was treated with fluorodimethoxy-
boraneϪdiethyl ether[7,32] (9.3 mL, 8.3 g, 50 mmol) and at 0 °C
[12]
[13]
J. Fröhlich, C. Hametner, W. Kalt, Monatsh. Chem. 1996, 127,
325Ϫ330; J. Fröhlich, C. Hametner, Monatsh. Chem. 1996,
127, 435Ϫ443.
[14]
´
M. Mallet, G. Branger, F. Marsais, G. Queguiner, J. Or-
ganomet. Chem. 1990, 382, 319Ϫ332; P. Rocca, C. Cochennec,
Eur. J. Org. Chem. 2001, 1371Ϫ1376
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