PROTOTROPIC ISOMERIZATION OF DIHYDROPYRIDAZINECARBOXYLIC
437
1
(76%), mp 93°C. H NMR spectrum, δ, ppm: 1.10 s
(9H, t-Bu), 3.80 s (3H, OMe); 7.32–7.40 m (2H),
7.43–7.54 m (6H), and 7.76–7.83 m (2H) (Ph).
13C NMR spectrum, δC, ppm: 27.3 (CMe3), 52.9
(OMe), 84.5 (CMe3); 128.2 (2C), 128.4 (2C), 128.5
(2C), 129.0 (2C), 129.2, 130.0, 132.6, 133.0, 135.6,
136.5 (Ph, C4, C5); 151.5 and 157.8 (C3, C6), 163.7 and
165.0 (C=O). Found, %: C 70.79; H 5.67; N 7.13.
C23H22N2O4. Calculated, %: C 70.75; H 5.68; N 7.18.
OMe), 4.99 s (1H, 4-H); 7.12–7.18 m (3H), 7.18–
7.24 m (2H), 7.30–7.40 m (5H) (Ph); 8.53 br.s (1H,
NH). 13C NMR spectrum, δC, ppm: 42.0 (C4), 52.5 and
52.6 (OMe), 103.2 (C5); 126.8, 127.4, 127.9 (2C),
129.0 (2C), 129.3, 129.5 (2C), 129.9 (2C), 133.8,
136.5, 137.1 (Ph, C3, C6); 164.4 and 171.1 (C=O).
Found, %: C 68.55; H 5.27; N 7.82. C20H18N2O4. Cal-
culated, %: C 68.56; H 5.18; N 8.00.
5-tert-Butyl 3-methyl 4,6-diphenyl-1,4-dihydro-
pyridazine-3,5-dicarboxylate (IIIb). Yield 86%,
5-tert-Butyl 3-methyl 4,6-dipropylpyridazine-3,5-
dicarboxylate (IX). Potassium permanganate, 35 mg
(0.22 mmol), was added in one portion to a solution of
60 mg (0.185 mmol) of dihydropyridazine IVa in
4.0 ml of acetone, and the mixture was stirred for 5 h
at room temperature. The precipitate of MnO2 was
filtered off and washed with acetone (3×2.0 ml). The
filtrate was evaporated under reduced pressure, and the
uncrystallizable residue was purified by flash chroma-
tography. Yield 47 mg (79%), colorless oily substance.
1H NMR spectrum, δ, ppm: 1.00 t and 1.02 t (3H each,
Me, J = 6.5 Hz), 1.63 s (9H, t-Bu), 1.50–1.68 m and
1.77–1.92 m (2H each, β-CH2), 2.75–2.83 and 2.91–
2.99 m (2H each, α-CH2), 4.03 s (3H, OMe). 13C NMR
spectrum, δC, ppm: 14.0 and 14.3 (Me), 22.8 and 24.1
(β-CH2), 28.0 (CMe3), 31.5 and 36.1 (α-CH2), 53.0
(OMe), 84.6 (CMe3), 133.9 and 137.7 (C4, C5), 151.0
and 159.9 (C3, C6), 165.0 and 165.5 (C=O). Found, %:
C 63.38; H 8.10; N 8.65. C17H26N2O4. Calculated, %:
C 63.33; H 8.13; N 8.69.
1
mp 109°C. H NMR spectrum, δ, ppm: 1.12 s (9H,
t-Bu), 3.79 s (3H, OMe), 5.25 s (1H, 4-H), 7.20–
7.50 m (10H, Ph), 8.03 br.s (1H, NH). 13C NMR spec-
trum, δC, ppm: 27.6 (CMe3), 37.1 (C4), 52.6 (OMe);
80.3 (CMe-3), 101.3 (C5); 127.8 (2C), 128.2, 128.5
(2C), 128.6 (2C), 128.7 (2C), 129.1, 129.6, 134.6,
142.6, 145.2 (Ph, C3, C6); 164.2 and 165.1 (C=O).
Found, %: C 70.43; H 6.12; N 7.19. C23H24N2O4. Cal-
culated, %: C 70.38; H 6.16; N 7.14.
5-tert-Butyl 3-methyl 4,6-dipropyl-1,4-dihydro-
pyridazine-3,5-dicarboxylate (IVb). Yield 81%,
mp 62°C. 1H NMR spectrum, δ, ppm: 0.86 t and 0.96 t
(3H each, Me, J = 7.3 Hz), 1.50 s (9H, t-Bu), 1.20–
1.31 m (4H, β-CH2); 1.53–1.66 m (2H), 2.53–2.65 m
(1H), 2.68–2.81 m (1H) (α-CH2); 3.86 s (3H, OMe),
4.02 t (1H, 5-H, J = 7.0 Hz), 8.12 s (NH). 13C NMR
spectrum, δC, ppm: 13.7 and 14.1 (Me), 18.4 and 21.9
(β-CH2), 28.2 (CMe3), 31.0 and 32.4 (α-CH2), 35.2
(C4), 52.4 (OMe), 80.1 (CMe3), 99.9 (C5), 139.3 and
148.0 (C3, C6), 164.7 and 166.0 (C=O). Found, %:
C 63.09; H 8.68; N 8.57. C17H28N2O4. Calculated, %:
C 62.94; H 8.70; N 8.64.
General procedure for the acid-catalyzed iso-
merization of dihydropyridazines Ia–IVa. A solution
of 0.1 ml of concentrated hydrochloric acid in 1 ml of
methanol was added at 20°C to a solution of 0.3 mmol
of compound Ia–IVa in 2 ml of methanol. The mixture
was kept for 1 h, neutralized with NaHCO3, and
diluted with 15 ml of water. The resulting solution was
extracted with diethyl ether (2×10 ml), and the extract
was dried over MgSO4 and evaporated to isolate
isomerization product Ib–IVb.
Base-catalyzed isomerization of dihydropyrida-
zine (Ia). Dihydropyridazine Ia, 100 mg, was dis-
solved in 3 ml of methanol, 1 ml of a 0.2 M solution of
sodium methoxide in methanol was added under
stirring, and the mixture was kept for 1 h at 20°C
under nitrogen and treated with 30 ml of diethyl ether.
The ether solution was washed with an aqueous solu-
tion of sodium chloride, dried over Na2SO4, and evap-
orated under reduced pressure, and the residue was
subjected to flash chromatography to isolate 83 mg
(83%) of dihydropyridazine Ib as a colorless oily
substance.
Methyl 3,5-dimethyl-2,5-dihydropyridazine-4-
carboxylate (Ib) [1]. Yield 80%, oily substance.
1H NMR spectrum, δ, ppm: 0.94 d (3H, Me, J =
7.1 Hz), 2.23 s (3H, Me), 3.33 d.q (1H, 5-H, J = 4.8,
7.1 Hz), 3.68 s (3H, OMe), 6.77 d (1H, 6-H, J =
4.8 Hz), 7.80 br.s (1H, NH). 13C NMR spectrum, δC,
ppm: 17.7 and 18.1 (Me), 27.3 (C5), 50.6 (OMe), 94.9
(C4), 143.6 and 147.1 (C3, C6), 167.6 (C=O).
Based-catalyzed isomerization of dihydropyrid-
azine (IIa) [2]. Dihydropyridazine IIa, 50 mg, was
dissolved in 0.5 ml of DMSO, 25 mg of a 50% solu-
tion of potassium hydroxide in water was added, and
the mixture was stirred for 30 min under argon. The
mixture was diluted with 15 ml of water, and the
Dimethyl 4,6-diphenyl-1,4-dihydropyridazine-
3,5-dicarboxylate (IIb) [2]. Yield 94%, mp 153°C.
1H NMR spectrum, δ, ppm: 3.76 s and 3.87 s (3H each,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 48 No. 3 2012