Intermolecular Rearrangement
886±902
AMX400 spectrometers. Chemical shifts are recorded with reference to
tetramethylsilane. Infrared spectra were obtained on a Perkin ± Elmer
1-Methoxy-2-pyridone: Five equal portions of a solution of 1 (R Me,
7
50.3 mg) in [D ]DMF (2.5 mL) were sealed in NMR tubes, and heated at
5
99B spectrophotometer (1% KBr pellet or 1% solution). Mass spectra
1408C. The initial spectrum exhibited peaks at d 8.24 ± 8.27 (d, 1H),
7.30 ± 7.35 (t, 1H), 7.23 (d, 1H), 7.04 (t, 1H), 4.03 (s, 3H). After 8.7 h, only
the spectrum of the product was evident, at d 7.95 ± 7.97 (dd, 1H), 7.40 ±
7.46 (dt, 1H), 6.51 ± 6.53 (dd, 1H), 6.21 ± 6.24 (m, 1H), 4.00 (s, 3H). In a
second experiment, a solution of 1 (R Me, 200 mg, 0.15 mmol), in DMF
(4 mL), was refluxed for 24 h. The solvent was removed under reduced
pressure and the residue was purified by column chromatography (ethyl
acetate/methanol, 1:1) to give a yellow oil, 144 mg (72%). 1H NMR
were obtained at Simon Fraser University by Mr. G. Owen on a Hewlett ±
Packard 5985GC/MS system operating at 70 eV and at the University of
British Columbia by Dr. G. Eigendorf on a Kratos MS50 system. Melting
points were determined on a Fisher ± Johns melting point apparatus and are
uncorrected. Microanalyses were carried out at Simon Fraser University by
M. K. Yang on a Carlos Erba model 1106 elemental analyzer. Analytical
thin-layer chromatography (tlc) was performed on precoated Merck silica
gel 60F-24 plates with aluminum backing. Spots were observed under
ultraviolet light and were visualized with 1% ceric sulfate. Column
chromatography was carried out with 230 ± 400 mesh silica gel (Merck).
Kinetic studies were performed in a Fisher high temperature oil bath
(CDCl
6.11 ± 6.15 (dt, 1H,), 4.06 (s, 3H,); C NMR (CDCl
135.1, 122.5, 105.0, 64.3; MS (EI): m/z: 125; C NO ´ 0.75H
calcd C 52.00, H 6.14, N 10.11; found C 52.23, H 6.20, N 11.22.
3
): d 7.50 ± 7.52 (dd, 1H), 7.28 ± 7.32 (dt, 1H), 6.65 ± 6.67 (dd, 1H),
13
3
): d 158.1, 138.4,
O (134.134):
6
H
7
2
2
(
silicone oil) fitted with a Thermotronic Devices Model 51 proportional
2
2
-Benzyloxypyridine-1-oxide: THF (10 mL), sodium metal (60.5 mg,
.6 mg-atom), and benzyl alcohol (2.1 g, 19 mmol) were added to a
temperature controller. The temperatures of kinetic experiments varied
between 139.2 and 140.88C, and are reported as 140 Æ 0.88C. Details of the
kinetic experiments and the analytical procedures employed have been
given earlier.
round-bottomed flask fitted with a magnetic stirrer and a condenser. The
mixture was stirred until all of the sodium had dissolved, and 2-
chloropyridine-1-oxide (308 mg, 2.4 mmol) was added in one portion.
The mixture was heated to reflux, stirred for 3 h, cooled to room
temperature, and treated with water (10 mL). Extraction with chloroform,
drying, and evaporation gave a white solid which was purified by column
chromatography (ethyl acetate, followed by methanol/ethyl acetate, 1:2).
Crystallization from ethyl acetate/hexane gave 0.34 g (73%) of 2-benzy-
2
-Chloropyridine-1-oxide: Chloroform (70 mL) and m-chloroperbenzoic
acid (14.6 g, 85 mmol) were added to a 250 mL three-necked flask fitted
with magnetic stirrer, condenser, and dropping funnel. The mixture was
stirred for 1 min and a solution of 2-chloropyridine (6.7 mL, 8.0 g,
7
0.5 mmol) in chloroform (30 mL) was added dropwise over 20 min. When
the addition was complete, the mixture was warmed to 65 ± 708C, stirred for
4 h, and then cooled to room temperature and poured, whilst being
[8]
1
loxypyridine-1-oxide. M.p. 108 ± 1098C (lit. m.p. 1078C ); H NMR
2
(
(
(
CDCl
3
): d 8.26 ± 8.28 (m, 1H, H6), 7.43 ± 7.46 (m, 2H, PhH), 7.33 ± 7.40
strirred, into ice-cold 3n sodium hydroxide (100 mL). This mixture was
stirred vigorously for 10 min and the layers were then separated. The
aqueous layer was extracted with chloroform (3 Â 150 mL), and the
combined organic extracts were dried and evaporated under reduced
pressure. The product was purified by chromatography on silica gel (ethyl
acetate) and crystallized from dichloromethane/ether/hexane (1:2:10) to
give 5.5 g (60%) of 2-chloropyridine-1-oxide as white plates. M.p. 63 ± 658C
m, 3H, PhH), 7.13 ± 7.17 (m, 1H, H4), 6.88 ± 6.92 (m, 1H, H5), 6.83 ± 6.85
m, 1H, H3), 5.44 (s, 2H, benzyl CH
13
2
); C NMR (CDCl
3
): d 157.95,
1
40.45, 135.03, 128.78, 128.65, 127.72, 126.98, 118.48, 112.58, 72.51; MS (EI):
m/z: 201; C12 (201.224): calcd C 71.63, H 5.51, N 6.96; found C 71.73,
H 5.64, N 6.79.
H
11NO
2
2
2
-Benzyl-a,a-[D ]oxy-6-[D]pyridine-1-oxide: THF (10 mL) and lithium
lit. m.p. 67 ± 68.58C,[ evacuated capillary); H NMR (CDCl
24]
1
aluminum deuteride (0.8 g, 19 mmol) were added to a round-bottomed
flask fitted with a magnetic stirrer and a dropping funnel. A solution of
freshly recrystallized benzoic acid (3 g, 24.6 mmol) in THF (15 mL) was
added dropwise over 5 min. Stirring was continued for 1 h, and saturated
sodium sulfate (10 mL) was then added dropwise, followed by solid
anhydrous sodium sulfate. The supernatant was decanted and concentrated
under reduced pressure. The residue was dissolved in water (20 mL) and
extracted with chloroform (3 Â 100 mL). The organic extract was dried and
evaporated, and the product was purified by column chromatography
(
3
): d 8.34 ±
.36 (m, 1H, H6), 7.49 ± 7.51 (m, 1H, H4), 7.18 ± 7.23 (m, 2H, H3, H5); 13
8
C
NMR (CDCl
(
3
3
): d 140.8 (C2), 127.2 (C3, C5) 125.6 (C6), 123.9 (C4); MS
EI): m/z: 131, 129 (ratio 25:75); C
5 4
H
NOCl (129.546): calcd C 46.36, H
.11, N 10.81; found C 46.45, H 3.14, N 10.74.
2
1
-Methoxypyridine-1-oxide. Methanol (15 mL) and sodium metal (390 mg,
7.0 mg-atom) were added to a round-bottomed flask fitted with magnetic
stirrer and condenser. When the sodium had dissolved, a solution of 2-
chloropyridine-N-oxide (2.0 g, 15.4 mmol) in methanol (10 mL) was added
dropwise over 10 min. The solution was refluxed for 1 h (after the addition
was complete), cooled, and the solvent was removed under reduced
pressure. The product was dissolved in water (30 mL) and extracted with
chloroform (4 Â 100 mL). The combined organic extracts were dried and
(
hexane/ethyl acetate, 5:1) to give 1.7 g (62%) of benzyl ± a,a-[D
2
]alcohol.
1
H NMR (CDCl
3
): d 7.32 ± 7.39 (m, 5H, PhH), 2.57 (s, 1H, OH); MS (EI):
m/z: 110. In the next step, THF (15 mL), sodium metal (37.6 mg, 1.6 mg-
atom), and benzyl-a,a-[D ]alcohol (1.05 g, 9.5 mmol) were stirred until the
sodium had dissolved, and 2-[D ]methoxy-6-[D]pyridine-1-oxide (135 mg,
.0 mmol) was added in one portion. The mixture was refluxed for 4.5 h,
2
3
evaporated to afford
a light yellow solid, which was purified by
1
chromatography (methanol/ethyl acetate, 1:1). Crystallization from ethyl
cooled, and treated with water (20 mL). The product was isolated by
chromatography, as described above, to give 0.139 g (65%) of the product.
M.p. 108 ± 1098C; H NMR (CDCl
acetate afforded white needles of 2-methoxypyridine-1-oxide, 0.97 g
50%). M.p. 73 ± 768C (lit. m.p. 78 ± 798C[ );
21]
(
(
6 7 2 2
C H NO ´ 1.0H O
1
3
): d 8.26 ± 8.28 (m, 0.3H, H6), 7.44 ±
143.142): calcd C 50.35, H 6.33, N 9.79; found C 50.46, H 6.22, N 9.84.
7
6
4
.46 (m, 2H, PhH), 7.32 ± 7.39 (m, 3H, PhH), 7.13 ± 7.17 (m, 1H, H4), 6.88 ±
Dissolution of a sample in boiling toluene, followed by slow crystallization
at room temperature gave a single large colorless tabular crystal, which was
submitted for x-ray crystallographic analysis.[
.89 (m, 1H, H5), 6.82 ± 6.85 (m, 1H, H3); MS (EI): m/z: 204, 203 (ratio,
.5:1).
18]
1
H NMR (CDCl
3
): d
1
-Benzyloxy-2-pyridone: A solution of 2-benzyloxypyridine-1-oxide
8
.27 ± 8.29 (m, 1H, H6), 7.28 ± 7.32 (m, 1H, H4), 6.89 ± 6.95 (m, 2H,
1
3
(100 mg, 0.5 mmol) in DMF (2 mL) was refluxed for 12 h. The solvent
was removed under reduced pressure, and the residue was purified by
column chromatography (ethyl acetate/hexane, 1:1). The product was
3 3
H3,H5), 4.08 (s, 3H, OCH ); C NMR (CDCl
1
1
): d 158.87, 140.18, 127.72,
�
1
17.63, 108.34, 57.25; IR (KBr): nÄ 1606, 1522, 1348 cm ; MS (EI) m/z:
25.
crystallized from hexane to give 87 mg (87%) of a white solid. M.p. 82 ±
2
-[D
3
]Methoxypyridine-1-oxide: Repetition of the above reaction with
48C (lit. m.p. 778C ); 1H NMR (CDCl
[8]
8
3
): d 7.36 ± 7.40 (m, 5H, Ar),
3
CD OD (10 mL), sodium metal (177 mg, 7.7 mg-atom) and 2-chloropyr-
idine-N-oxide (1.0 g, 7.7 mmol) gave 0.42 g (43%) of product. M.p. 73 ±
7
6
7.24 ± 7.28 (dt, 1H), 7.09 ± 7.11 (ddd, 1H), 6.68 ± 6.70 (ddd, 1H), 5.90 ± 5.94
13
(
dt, 1H), 5.29 (s, 2H); C NMR (CDCl
3
): d 158.9, 138.5, 136.7, 133.9,
1
68C; H NMR (CDCl
3
): d 8.27 ± 8.29 (m, 1H), 7.28 ± 7.32 (m, 1H), 6.89 ±
1
30.0, 129.3, 128.7, 122.9, 104.3, 78.4; MS (EI): m/z: 201; C12H11NO
2
.95 (m, 2H); MS (EI): m/z: 128.
(
201.224): calcd C 71.63, H 5.51, N 6.96; found C 71.48, H 5.35, N 7.03.
-Hydroxypyridine-1-oxide: solution of 2-methoxypyridine-1-oxide
0.1 g, 0.8 mmol) in concentrated hydrochloric acid (2 mL) was warmed
2
-[D ]Methoxy-6-[D]pyridine-1-oxide: The above reaction was repeated
3
2
(
A
3
with CD OD (10 mL), sodium metal (210 mg, 9.2 mg-atom) and 2-
chloropyridine-1-oxide (1.0 g, 7.7 mmol). When the addition was complete,
the reaction mixture was refluxed for 12 h. Isolation gave 0.36 g (36%) of 2-
to 90 ± 1008C, stirred for 16 h, and then cooled and evaporated under
reduced pressure. Crystallization from chloroform/hexane (1:5) gave 48 mg
1
[
D
3
]methoxy-6-[D]pyridine-1-oxide. M.p. 73 ± 768C; H NMR (CDCl
3
):
[21]
(
54%) of an off-white product. M.p. 148 ± 1498C (lit. m.p. 148 ± 1498C );
d 8.25 ± 8.27 (m, 0.2H, H6), 7.26 ± 7.30 (m, 1H, H4), 6.88 ± 6.93 (m, 2H);
1
H NMR (D
2
O): d 7.81 ± 7.73 (m, 1H), 7.46 ± 7.50 (m, 1H), 6.62 ± 6.65 (m,
MS (EI): m/z: 129, 128 (ratio, 4:1).
1
H), 6.45 ± 6.48 (m, 1H,); MS (EI): m/z: 111.
Chem. Eur. J. 1998, 4, No. 5
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0405-0899 $ 17.50+.25/0
899