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Russ.Chem.Bull., Int.Ed., Vol. 53, No. 12, December, 2004
Kukushkin et al.
2ꢀ(Dimethylaminomethylene)ꢀ6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ
1Hꢀcarbazolꢀ1ꢀone (1) was prepared according to a known proꢀ
cedure5 from 6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀone
(2)4 and dimethylformamide dimethyl acetal (3).
MeCN, and dried in a desiccator to give crude product 9 (9.96 g,
83%). Recrystallization from MeCN (160 mL) gave acylamidine
9 (5.6 g, 46%), m.p. 173—175 °C.
1ꢀCyanoꢀ8ꢀmethylꢀ3,5,6,11ꢀtetrahydroꢀ2Hꢀpyriꢀ
do[4,3ꢀa]carbazolꢀ2ꢀone (10). A solution of compound 9 (3.5 g,
11 mmol) in 5 mL of Nꢀmethylpyrrolidone (NMP) was stirred at
155 to 160 °C for 1 h. The resulting suspension was cooled
to 10 °C, diluted with MeCN (20 mL), and stirred for 10 min.
The precipitate that formed was filtered off to give comꢀ
pound 10 (1.49 g, 49%). An analytically pure sample was obꢀ
tained by recrystallization from chloroform, m.p. 372—374 °C
(decomp.).
2ꢀChloroꢀ1ꢀcyanoꢀ8ꢀmethylꢀ6,11ꢀdihydroꢀ5Hꢀpyriꢀ
do[4,3ꢀa]carbazole (11). A. A mixture of compound 10 (1 g,
3.6 mmol), triethylamine hydrochloride (0.66 g, 5.4 mmol), and
POCl3 (7 mL) was refluxed for 5 h. The reaction mixture was
cooled and poured into ice. The precipitate was filtered off and
dried. The product was extracted with boiling benzene and the
extract was cooled, passed through a layer of L40/100 silica gel
(7×3.5 cm), and concentrated to a minimum volume. The crysꢀ
tals that formed were filtered off to give compound 11 (0.64 g,
61%), m.p. 269—271 °C (decomp.).
B. A mixture of compound 9 (1 g, 3.1 mmol), triethylamine
hydrochloride (0.56 g, 4.6 mmol), and POCl3 (7 mL) was reꢀ
fluxed for 1 h. The reaction mixture was worked up as described
in procedure A. The yield of compound 11 was 0.1 g (11%), m.p.
269—271 °C (decomp.).
1ꢀCyanoꢀ2ꢀmethoxyꢀ8ꢀmethylꢀ6,11ꢀdihydroꢀ5Hꢀpyriꢀ
do[4,3ꢀa]carbazole (12). A solution of MeONa prepared from
metallic Na (0.6 g, 26 mmol) and MeOH (11 mL) was added to
a suspension of compound 11 (0.4 g, 1.3 mmol) in 4 mL of
MeOH. The resulting suspension was refluxed for 6 h and
then cooled to 15 °C. The precipitate that formed was filꢀ
tered off, washed with water, dried, and recrystallized from
benzene (7.5 mL) to give compound 12 (0.2 g, 54%), m.p.
218—220 °C.
1ꢀCyanoꢀ3,8ꢀdimethylꢀ3,5,6,11ꢀtetrahydroꢀ2Hꢀpyriꢀ
do[4,3ꢀa]carbazolꢀ2ꢀone (13). A mixture of compound 8 (1 g,
3.7 mmol) and dimethylformamide dimethyl acetal (10 mL) was
refluxed for 6 h and then cooled to 15 °C. The precipitate that
formed was filtered off, washed with MeCN (2 mL), and
dried to give a crude product (0.85 g). Recrystallization from
dichloroethane (70 mL) gave compound 13 (0.54 g, 46%), m.p.
304—307 °C.
The filtrate containing an excess acetal, MeCN, and other
reaction products was evaporated to dryness in vacuo. The resiꢀ
due (0.3 g) was dissolved in benzene (30 mL) and the resulting
solution was passed through a layer of L40/100 silica gel
(1×3.5 cm). The solvent was removed in a rotary evaporator to
give a mixture (0.12 g, 11%) of compound 12 and 1ꢀcyanoꢀ2ꢀ
methoxyꢀ8,11ꢀdimethylꢀ6,11ꢀdihydroꢀ5Hꢀpyrido[4,3ꢀa]carbꢀ
azole (14) in the 55 : 45 ratio (1H NMR data). MS, m/z (Irel (%)):
303 [M1]+ (100), 289 [M2]+ (51).
2ꢀAminoꢀ8ꢀmethylꢀ6,11ꢀdihydroꢀ5Hꢀpyrimido[4,5ꢀa]carbꢀ
azole (4). A solution of EtONa prepared from metallic Na (0.83 g,
36 mmol) and anhydrous EtOH (30 mL) was added to a suspenꢀ
sion of guanidine hydrochloride (2.86 g, 30 mmol) in 5 mL of
anhydrous EtOH. The precipitate of NaCl that formed was filꢀ
tered off. The filtrate was added to a suspension of enamino
ketone 1 (1.60 g, 6.3 mmol) in 15 mL of anhydrous EtOH. The
stirred reaction mixture was refluxed for 8 h, cooled, and neuꢀ
tralized with AcOH. The precipitate was filtered off, washed
with water, dried in vacuo, and recrystallized from chloroform
(1.33 g from 110 mL) to give pure aminopyrimidine 4 (0.80 g,
50%), m.p. 248—251 °C.
8ꢀMethylꢀ3,5,6,11ꢀtetrahydroꢀ2Hꢀpyrimido[4,5ꢀa]carbꢀ
azoleꢀ2ꢀthione (5). A solution of EtONa prepared from Na metal
(1.38 g, 60 mmol) and anhydrous EtOH (40 mL) was added to a
mixture of enamino ketone 1 (5 g, 19.6 mmol) and thiourea
(4.5 g, 59.2 mmol) in 50 mL of anhydrous EtOH. The stirred
reaction mixture was refluxed for 2 h and worked up as described
for compound 4 to give pyrimidinethione 5 (4.5 g, 78%), m.p.
318—322 °C (decomp.). Compound 5 was not purified because
of its low solubility and thermal instability. MS, m/z (Irel (%)):
267 [M]+ (14), 240 [M – HCN]+ (12).
2ꢀBenzylthioꢀ8ꢀmethylꢀ6,11ꢀdihydroꢀ5Hꢀpyrimiꢀ
do[4,5ꢀa]carbazole (6). A solution of MeONa prepared from Na
metal (0.09 g, 4 mmol) and MeOH (3 mL) was added to a
suspension of pyrimidinethione 5 (1.06 g, 3.9 mmol) in 15 mL of
MeOH. The reaction mixture was stirred at 50 °C and benzyl
chloride (0.6 g, 4.7 mmol) was added. The mixture was kept at
50 °C for 3 h and cooled. The precipitate that formed was
filtered off, washed with water, and dried in vacuo to give a
crude product (1.14 g, 80%). Recrystallization from chloroꢀ
form (9 mL) gave benzylthiopyrimidine 6 (0.73 g, 52%), m.p.
154—157 °C.
1ꢀ(Dicyanomethylene)ꢀ6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀ
carbazole (7). A mixture of ketone 2 (5.97 g, 30 mmol),
malononitrile (2 g, 30 mmol), ammonium acetate (2.5 g,
32.5 mmol), and AcOH (5.94 g, 99 mmol) in 50 mL of toluene
was stirred at 105 °C for 5 h. On cooling, the precipitate that
formed was filtered off, washed with hexane (40 mL), and dried
at 100 °C to give a crude product (6.7 g). Double recrystallizaꢀ
tion from dichloroethane gave compound 7 (4.5 g, 61%), m.p.
251—255 °C.
Cyano(6ꢀmethylꢀ2,3,4,9ꢀtetrahydroꢀ1Hꢀcarbazolꢀ1ꢀylꢀ
idene)acetamide (8). A mixture of ketone 2 (30 g, 0.15 mol),
cyanoacetamide (37.8 g, 0.45 mol), ammonium acetate (38.5 g,
0.5 mol), and AcOH (30 g, 0.5 mol) in 120 mL of toluene was
stirred at 60 °C for 5 h. On cooling, the precipitate that formed
was filtered off and routinely treated to give crude product 8
(37.3 g, 90%). Recrystallization from DMF (95 mL) gave comꢀ
pound 8 (23.5 g, 59%), m.p. 212—216 °C (decomp.).
Nꢀ(Dimethylaminomethylene)cyano(6ꢀmethylꢀ2,3,4,9ꢀtetraꢀ
hydroꢀ1Hꢀcarbazolꢀ1ꢀylidene)acetamide (9). A suspension of
compound 8 (10 g, 37.7 mmol) and dimethylformamide diꢀ
methyl acetal (3) (8.8 g, 74 mmol) in 160 mL of MeCN was
stirred at 35 °C for 1 h. The reaction mixture was cooled to 15 °C
and the precipitate that formed was filtered off, washed with
References
1. M. D. Mashkovskii, Lekarstvennye sredstva. Posobie dlya
vrachei [Drugs. A Reference Book for Doctors], Torgsin,
Kharkov, 1997, 1, 543 pp.; 2, 592 pp. (in Russian).
Kukushkin
