7700 J. Am. Chem. Soc., Vol. 119, No. 33, 1997
Butora et al.
concentrated to 1/3 of its original volume, poured onto ice, and made
basic (pH ca. 8) with NaOH before extraction with ether (4×). The
combined organic extracts were dried (MgSO4), and the solvent was
removed at reduced pressure. The crude product was distilled under
reduced pressure (47-50°C, 0.5 mmHg) to give 212 g (68%) of
2-methoxy-5-bromopyridine as a colorless liquid, with spectral char-
acteristics identical to those published in the literature.10
6-Methoxy-3-pyridinecarboxaldehyde (14).8 Butyllithium (27.9
mL, 10 M solution in hexanes, 0.279 mol) was added dropwise to a
solution of 2-methoxy-5-bromopyridine (13; 50 g, 0.266 mol) in dry
tetrahydrofuran (500 mL) at -78 °C and the suspension stirred at -78
°C for 90 min. N,N-Dimethylformamide (39 mL, 0.532 mol) was then
added, dropwise, and stirring continued for a further 90 min. The
mixture was allowed to warm to room temperature and then it was
poured into NaHCO3 (aqueous saturated) and extracted with ether (3×).
The combined organic extracts were dried (MgSO4), and the solvent
was removed at reduced pressure to give 6-methoxy-3-pyridinecar-
boxaldehyde (36.4 g, quantitative) as a pale yellow solid. The physical
and spectral data were found to be identical to those published in the
literature.8
6-Oxopyridine-3-carboxaldehyde (16).9 A solution of 6-methoxy-
3-pyridinecarboxaldehyde (14; 36.4 g, 0.266 mol) was dissolved in HBr
(48% aqueous, 500 mL), and the temperature of the heating bath was
gradually raised to 150 °C over a period of 1 h. Gas evolution was
observed at 90-110 °C. The dark red-brown solution was allowed to
cool and concentrated to a light brown solid. MeOH (100 mL) and
acetone (50 mL) were added, and the solution was washed with ether
(3 × 500 mL). Water (100 mL) was then added and the pH adjusted
to ca. 7 with NaHCO3 (aqueous saturated). A small amount of brown
solid was removed by filtration and the filtrate concentrated to a tan
solid. This was taken into CHCl3/MeOH (7:3) and filtered through a
silica plug. Removal of the solvent at reduced pressure gave 6-ox-
opyridine-3-carboxaldehyde (32 g, 98%). The physical and spectral
data were found to be identical to those published in the literature.9
6-Methyl-3-oxo-4-[[(6-methoxypyridin-3-yl)methylene]amino]-
2,3,4,5-tetrahydro-1,2,4-triazine (18). A solution of the 4-amino-6-
methyl-3-oxo-1,2,3,4-tetrahydro-1,2,4-triazine (17; 3.84 g, 30 mmol,
as free base) and 6-methoxypyridine-3-carbaldehyde (14; 4.11 g, 30
mmol) in methanol (150 mL) was stirred at reflux overnight. The
solvent was removed at reduced pressure, and the remaining solid was
triturated with water (100 mL). The insoluble organic product was
filtered, washed with acetone (2 × 20 mL), and dried under vacuum
to yield 5.01 g (68%) of pure product as a white, crystalline material.
Rf ) 0.7 (chloroform/methanol, 7:3). Mp: 189-190 °C (precipitated
from MeOH). 1H NMR (300 MHz, DMSO-d6): δ 10.05 (s, 1H), 8.40
(d, J ) 1.7 Hz, 1H), 8.06 (dd, J ) 8.5, 2.2 Hz, 1H), 7.85 (s, 1H), 6.88
(d, J ) 8.8 Hz, 1H), 4.33 (s, 2H), 3.88 (s, 3H), 1.93 (s, 3H). 13C
NMR (75 MHz, DMSO-d6): δ 164.2, 147.1, 147.0, 143.9, 138.4, 135.9,
124.9, 111.2, 53.5, 47.6, 20.2. IR (KBr, 3%): 3289, 3118, 2995, 1685
cm-1. MS (EI): m/z (rel intens) 247 (27), 135 (34), 113 (67), 98 (100).
HRMS for C11H13N5O2: calcd 247.1069, found 247.1063 (δ ) 0.7).
For C11H13N5O2 Calcd: 53.43% C, 5.30% H, 28.33% N. Found:
54.24% C, 5.57% H, 28.21% N.
product was triturated with methanol (10 mL) and water (10 mL) and
dried under vacuum to yield 99 mg (95%) of the desired product as a
white crystalline material. Rf ) 0.25 (chloroform/methanol, 85:15,
dilute solution applied). Mp: over 250 °C (precipitated from H2O).
1H NMR (500 MHz, DMSO-d6): δ 11.85 (br s, 1H), 9.98 (s, 1H),
7.86 (dd, J ) 9.8, 2.5 Hz, 1H), 7.74 (s, 1H), 6.68 (d, J ) 2.5 Hz, 1H),
6.40 (d, J ) 9.3 Hz, 1H), 4.25 (s, 2H), 1.91 (s, 3H). 13C NMR (75
MHz, DMSO-d6); δ 161.9, 146.8, 143.3, 138.3, 136.7, 136.4, 120.3,
113.9, 47.2, 19.9. IR (KBr, 3%): 3113, 2927, 1690, 1664, 1596. MS
(FAB): m/z (rel intens) (M + H)+ 234 (100), 202 (14), 165 (32). HRMS
for C10H12N5O2: calcd: 234.2320, found 234.0988. For C10H11N5O2
Calcd: 51.50% C, 4.75% H, 30.03% N. Found: 50.36% C, 4.91% H,
29.26% N.
5-Methoxy-6-methyl-3-oxo-4-[(pyridin-3-ylmethylene)amino]-
2,3,4,5-tetrahydro-1,2,4-triazine (20). A 1000-mL beaker was charged
with a suspension of 6-methyl-3-oxo-4-[(pyridin-3-ylmethylene)amino]-
2,3,4,5-tetrahydro-1,2,4-triazine (1; 5.0 g, 23.017 mmol) and tetraethyl-
ammonium p-toluenesulfonate (0.8 g, 2.65 mmol) in methanol (800
mL). A direct current (6V, 200 mA) was passed through the reaction
mixture Via graphite electrodes (150 × 45 × 9 mm, held parallel at a
distance of 30 mm with a Teflon spacer). The oxidation was continued
until TLC showed complete disappearance of the starting material, about
24 h. The reaction mixture was treated with charcoal and filtered
through a plug of silica gel, and the volume was reduced to ap-
proximately 50 mL. The precipitated solid was filtered off and washed
with methanol/diethyl ether, 1:3 (2 × 20 mL). Drying under high
vacuum yielded 3.5 g (62%) of pure product, as a white crystalline
material. Note: In a trial experiment, a methanolic solution of
5-hydroxy-6-methyl-3-oxo-4-[(pyridin-3-ylmethylene)amino]-2,3,4,5-
tetrahydro-1,2,4-triazine (2) containing a spatula tip of p-toluenesulfonic
acid was stirred at reflux for 24 h. After chromatographic purification,
the O-methyl hemiaminal 20 could be obtained in approximately 30%
yield. Rf ) 0.52 (chloroform/methanol, 85:15). Mp: 167-168 °C
(MeOH). 1H NMR (500 MHz, DMSO-d6): δ 10.7 (s, 1H), 8.88 (d, J
) 2.0, 1H), 8.72 (s, 1H), 8.62 (dd, J ) 4.4, 1.5, 1H), 8.14 (dt, J ) 7.8,
2.0 Hz, 1H), 7.48 (dd, J ) 8.3, 4.9 Hz, 1H), 5.95 (s, 1H), 3.14 (s, 3H),
2.02 (s, 3H). 13C NMR (125 MHz, DMSO-d6): δ 151.0, 149.0, 147.9,
145.8, 142.2, 133.6, 130.3, 124.0, 82.6, 51.8, 18.9. IR (KBr, 3%):
3212, 3093, 2915, 1690, 1653 cm-1
. MS (EI): m/z (rel intens)
280.9824 (16), 248.1133 (32), 180.9888 (34), 130.9920 (41), 118.9920
(38), 68.9952 (100). HRMS (EI) for C11H14N5O2 (M + H)+: calcd:
248.1147, found 248.1133. For C11H13N5O2 (247.259) Calcd: 53.43%
C, 5.30% H, 28.32% N. Found: 53.10% C, 5.19% H, 28.35% N.
5-Methoxy-6-methyl-3-oxo-4-[[(6-methoxypyridin-3-yl)methylene]-
amino]-2,3,4,5-tetrahydro-1,2,4-triazine (21). A 1200-mL beaker was
charged with 6-methyl-3-oxo-4-[[(6-methoxypyridin-3-yl)methylene]-
amino]-2,3,4,5-tetrahydro-1,2,4-triazine (18; 1.4 g, 5.66 mmol) and
methanol (900 mL). To this suspension was added sodium methoxide
(5.0 g, 92.6 mmol), and a pale yellow solution resulted. A direct current
(1.7 V, 100 mA) was passed through the reaction mixture Via graphite
electrodes (150 × 40 × 10 mm, held parallel 30 mm apart with a Teflon
spacer). The conversion reached 50% after about 6 h, and was complete
after 14 h. The volume of the solvent was reduced to approximately
100 mL (rotavap), and the pH was adjusted with aqueous HCl (1 M)
to 7.0. Chloroform (300 mL) was added, and the solvent was distilled
off at reduced pressure. The solid residue was triturated with water
(20 mL) for 30 min. The undissolved product was filtered off, washed
with acetone (4 × 50 mL), and dried under high vacuum to yield 685
mg (44%) of pure product as a white crystalline material. Rf ) 0.7
(chloroform/methanol, 85:15). Mp: 162-163 °C (precipitated from
MeOH). 1H NMR (500 MHz, DMSO-d6): δ 10.63 (s, 1H), 8.45 (d, J
) 2.0 Hz, 1H), 8.10 (dd, J ) 8.8, 2.4 Hz, 1H), 6.91 (d, J ) 8.3 Hz,
1H), 5.89 (s, 1H), 3.90 (s, 3H), 3.14 (s, 3H), 2.01 (s, 3H). 13C NMR
(75 MHz, DMSO-d6, spiked with D2O): δ 165.1, 148.5, 148.3, 146.6,
142.5, 136.6, 124.5, 111.7, 82.4, 54.0, 52.0, 19.3. MS (FAB) m/z (rel
intens) (M + H)+ 278 (51), 185 (84), 152 (16), 111 (72). HRMS (FAB)
for C12H16N5O3: calcd 278.1250, found 278.1302. IR (KBr, 3%):
6-Methyl-3-oxo-4-[[(6-oxopyridin-3-yl)methylene]amino]-2,3,4,5-
tetrahydro-1,2,4-triazine (19). Method A. A solution of 6-oxopyr-
idine-3-carbaldehyde (16; 1.23 g, 10 mmol) and 4-amino-6-methyl-3-
oxo-1,2,3,4-tetrahydro-1,2,4-triazine hydrochloride 17 (1.64, 10 mmol)
in methanol (30 mL) was treated with sodium methoxide (0.54 g, 10
mmol) and heated to reflux overnight. The thick suspension was
allowed to cool to room temperature, and the solid product was filtered
off, washed with water (2 × 10 mL), and dried under vacuum to yield
2.3 g (98%) of the pure product as a white crystalline solid.
Method B. Pivaloyl chloride (60 mg, 0.493 mmol) was added to
the solution of 6-methyl-3-oxo-4-[[(6-methoxypyridin-3-yl)methylene]-
amino]-2,3,4,5-tetrahydro-1,2,4-triazine (18; 111 mg, 0.448 mmol) and
sodium iodide (81 mg, 0.538 mmol) in acetonitrile (15 mL), Via syringe.
Stirring at reflux temperature was continued for 12 h, when TLC
indicated complete disappearance of the starting material. The reaction
mixture was allowed to cool to room temperature. An aqueous solution
of sodium hydroxide (6.0 mL, 0.1 M) was added, and stirring was
continued for 1 h. The pH was adjusted to neutral with 0.1 M HCl,
and the solvent was removed at reduced pressure. The remaining crude
3240, 3118, 2954, 1690, 1654 cm-1
.
5-Methoxy-6-methyl-3-oxo-4-[[(6-oxopyridin-3-yl)methylene]am-
ino]-2,3,4,5-tetrahydro-1,2,4-triazine (22). A 1200-mL beaker was
charged with 6-methyl-3-oxo-4-[[(6-oxopyridin-3-yl)methylene]amino]-
2,3,4,5-tetrahydro-1,2,4-triazine (19; 0.7 g, 3.00 mmol) and suspended