Oxidative amination of pyridazines
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 4, April, 2004
851
same temperature for 15 min and concentrated to dryness. The
residue was worked up as described above and compound 4b was
obtained in a yield of 298 mg (66%) as colorless crystals.
3ꢀChloroꢀ4ꢀethylaminoꢀ6,8ꢀdimethylpyrimido[4,5ꢀc]pyridꢀ
azineꢀ5,7(6H,8H)ꢀdione (4c). A. Compound 4c was prepared
analogously to 4b from compound 5a (0.4 g, 1.8 mmol),
ethylamine (40 mL), and AgPy2MnO4 (0.28 g, 1.8 mmol) at a
temperature from –5 to 0 °C. The yield was 267 mg (55%).
B. A mixture of compound 5a (0.4 g, 1.8 mmol) and
AgPy2MnO4 (0.28 g, 1.8 mmol) in ethylamine (40 mL) was
stirred at a temperature from –5 to 0 °C for 24 h and concenꢀ
trated to dryness. The residue was extracted with boiling CHCl3
(40 mL). The extract was concentrated to ~5 mL and chromatoꢀ
graphed on a column (1.5×50 cm) with Al2O3 in CHCl3. 3ꢀEthylꢀ
6,8ꢀdimethylpyrrolo[2´,3´;3,4]pyrimido[4,5ꢀc]pyridazineꢀ
7,9(6H,8H )ꢀdione (7b) was isolated from the first yellow fracꢀ
tion with Rf 0.6 in a yield of 23 mg (5%) as brightꢀyellow needles,
m.p. 225—227 °C (cf. lit. data5). Compound 4c was isolated
from the colorless fraction with Rf 0.45 in a yield of 281 mg
(58%) as colorless crystals (after recrystallization from PriOH).
3ꢀEthylaminoꢀ6,8ꢀdimethylpyrimido[4,5ꢀc]pyridazineꢀ
5,7(6H,8H )ꢀdione (6b) was isolated from the yellow fraction
with Rf 0.2 in a yield of 4 mg (1%) as yellow crystals (after
recrystallization from PriOH), m.p. 211—213 °C (cf. lit. data6).
3ꢀChloroꢀ6,8ꢀdimethylꢀ4ꢀpropylaminopyrimido[4,5ꢀc]pyridꢀ
azineꢀ5,7(6H,8H )ꢀdione (4d). A. A solution of compound 5a
(227 mg, 1 mmol) in propylamine (40 mL) was stirred at 20 °C
for 15 min and then AgPy2MnO4 (385 mg, 1 mmol) was added.
The reaction mixture was stirred at 20 °C for 15 min and conꢀ
centrated to dryness. The residue was extracted with CHCl3
(30 mL) and the extract was concentrated to ~5 mL and
chromatographed on a column with Al2O3 in CHCl3. A colorꢀ
less fraction with Rf 0.55 was collected. The product was recrysꢀ
tallized from PriOH. Compound 4d was obtained in a yield of
218 mg (77%) as colorless crystals.
B. The reaction was carried out analogously to the method A
but the reaction mixture was kept at 20 °C for 24 h and concenꢀ
trated to dryness. The residue was extracted with CHCl3 (30 mL).
Three fractions were isolated on a column (1.5×50 cm)
with Al2O3 in CHCl3. 1,6,8ꢀTrimethylꢀ3ꢀpropylpyrroꢀ
lo[2´,3´;3,4]pyrimido[4,5ꢀc]pyridazineꢀ7,9(6H,8H )ꢀdione (7c)
was isolated from the yellow fraction with Rf 0.65 in a yield of
20 mg (7%) as brightꢀyellow needles, m.p. 174—175 °C (cf. lit.
data5). Compound 4d was isolated from the colorless fraction
with Rf 0.55 in a yield of 207 mg (73%) as colorless crystals (after
recrystallization from PriOH). 6,8ꢀDimethylꢀ3ꢀpropylaminoꢀ
pyrimido[4,5ꢀc]pyridazineꢀ5,7(6H,8H )ꢀdione (6c) was isolated
from the yellow fraction with Rf 0.26 in a yield of 3 mg (1%) as
yellow crystals (after recrystallization from PriOH), m.p.
161—162 °C (cf. lit. data6).
B. A mixture of compound 5 (227 mg, 1 mmol), butylamine
(40 mL), and AgPy2MnO4 (385 mg, 1 mmol) was kept at ~20 °C
for 24 h and concentrated to dryness. After extraction with CHCl3
and chromatography on a column with Al2O3 in CHCl3, three
fractions were collected. 3ꢀButylꢀ1ꢀethylꢀ6,8ꢀdimethylpyrꢀ
rolo[2´,3´;3,4]pyrimido[4,5ꢀc]pyridazineꢀ7,9(6H,8H )ꢀdione
(7d) was isolated from the first yellow fraction with Rf 0.7 in a
yield of 19 mg (6%) as brightꢀyellow needles, m.p. 118—119 °C
(cf. lit. data5). Compound 4f was isolated from the colorless
fraction with Rf 0.60 in a yield of 178 mg (60%) as colorless
crystals (after recrystallization from PriOH). 3ꢀButylaminoꢀ6,8ꢀ
dimethylpyrimido[4,5ꢀc]pyridazineꢀ5,7(6H,8H )ꢀdione (6d) was
isolated from the yellow fraction with Rf 0.25 in a yield of 3 mg
(1%) as yellow crystals (after recrystallization from PriOH),
m.p. 148—150 °C. IR, ν/cm–1: 3329 (N—H); 1712, 1670 (C=O).
1H NMR, δ: 0.95 (t, 6 H, (CH2)3Me, J = 7.3 Hz); 1.43 (m, 2 H,
(CH2)2CH2Me); 1.66 (m, 2 H, CH2CH2CH2Me); 3.43 (m,
2 H, CH2CH2CH2Me); 3.46 (s, 3 H, N(6)Me); 3.77 (s, 3 H,
N(8)Me); 4.87 (m, 1 H, NH); 7.31 (s, 1 H, H(4)).
Reaction of 3ꢀchloroꢀ6,8ꢀdimethylpyrimido[4,5ꢀc]pyridazineꢀ
5,7(6H,8H )ꢀdione 5a with cyclohexylamine and an oxidant. A soꢀ
lution of compound 5a (227 mg, 1 mmol) in cyclohexylamine
(40 mL) was stirred at 20 °C for 15 min and then AgPy2MnO4
(385 mg, 1 mmol) was added. The reaction mixture was stirred at
20 °C for 24 h and concentrated to dryness. After extraction with
CHCl3 and chromatography on a column with Al2O3 in CHCl3,
three fractions were collected. 3ꢀCyclohexylꢀ6,8ꢀdimethylꢀ1,2ꢀ
tetramethylenepyrrolo[2´,3´;3,4]pyrimido[4,5ꢀc]pyridazineꢀ
7,9(6H,8H )ꢀdione (7a) was isolated from the yellow fraction
with Rf 0.70 in a yield of 92 mg (25%) as yellow crystals (after
recrystallization from PriOH), m.p. 222—225 °C (cf. lit. data7).
Compound 4g was isolated from the colorless fraction with
Rf 0.50 in a yield of 97 mg (30%) as colorless crystals (after
recrystallization from PriOH). Compound 6a was isolated from
the yellow fraction with Rf 0.30 in a yield of 12 mg (4%) as
yellow crystals (after recrystallization from PriOH), m.p.
210—211 °C (cf. lit. data6).
6,8ꢀDimethylꢀ3ꢀpiperidinopyrimido[4,5ꢀc]pyridazineꢀ
5,7(6H,8H )ꢀdione (8). A solution of compound 5a (227 mg,
1 mmol) in piperidine (25 mL) was stirred at 20 °C for 15 min
and then AgPy2MnO4 (385 mg, 1 mmol) was added. The reacꢀ
tion mixture was stirred at 20 °C for 24 h and concentrated to
dryness. After extraction with hot CHCl3, chromatography on a
column with Al2O3 in CHCl3, and recrystallization from PriOH,
compound 8 was obtained in a yield of 194 mg (68%) as brightꢀ
yellow crystals, m.p. 154—156 °C (cf. lit. data3).
Reaction of compound 5a with diethylamine and an oxidant.
A solution of compound 5a (227 mg, 1 mmol) in diethylamine
(50 mL) was stirred at 20 °C for 15 min and then AgPy2MnO4
(385 mg, 1 mmol) was added. The reaction mixture was stirred
at 20 °C for 2 weeks and concentrated to dryness. After extracꢀ
tion with CHCl3 and chromatography on a column with Al2O3
in CHCl3, two fractions were collected. 3ꢀEthylꢀ6,8ꢀdimethylꢀ
pyrrolo[2´,3´;3,4]pyrimido[4,5ꢀc]pyridazineꢀ7,9(6H,8H )ꢀdione
(7b) was isolated from the first yellow fraction with Rf 0.6 in a
yield of 111 mg (43%) as brightꢀyellow needles (after recrystalliꢀ
zation from PriOH), m.p. 225—227 °C (cf. lit. data5). Comꢀ
pound 9 was isolated from the orange fraction with Rf 0.30 in a
yield of 24 mg (15%) as orange crystals (after recrystallization
from PriOH), m.p. 135—137 °C. IR, ν/cm–1: 1705, 1652 (C=O).
1H NMR, δ: 1.31 (t, 6 H, N(CH2Me)2, J = 7.3 Hz); 3.40 (s, 3 H,
3ꢀChloroꢀ4ꢀisopropylaminoꢀ6,8ꢀdimethylpyrimiꢀ
do[4,5ꢀc]pyridazineꢀ5,7(6H,8H )ꢀdione (4e) was prepared analoꢀ
gously to 4d (method A) from compound 5 (0.5 g, 2.2 mmol),
isopropylamine (70 mL), and AgPy2MnO4 (0.83 g, 2.2 mmol).
The yield was 495 mg (80%).
4ꢀButylaminoꢀ3ꢀchloroꢀ6,8ꢀdimethylpyrimido[4,5ꢀc]pyridꢀ
azineꢀ5,7(6H,8H )ꢀdione (4f). A. Compound 4f was prepared
analogously to 4d from compound 5a (227 mg, 1 mmol), butylꢀ
amine (40 mL), and AgPy2MnO4 (385 mg, 1 mmol). The
product was recrystallized from MeOH. The yield was
192 mg (64%).