Sep-Oct 2003
Synthesis of Tricyclic Pyrido[2,3-b][1,4]-thiazines
853
1
for 16 hours. After this, the reaction mixture was concentrated
and the residue was purified by recrystallization from ethyl
acetate to give 1.10 g (61%) of 10, mp 185-188°; H nmr (deu-
2.37 g (94%) of 6, mp 308-312°; H nmr (deuteriochloroform/
dimethyl-d sulfoxide): δ 9.46 (s, 1H, NH), 9.24 (s, 1H, NH),
7.99 (dd, J = 4.7 Hz, J = 1.5 Hz, 1H, pyridine H), 7.25 (dd, J = 8.1
Hz, J = 1.5 Hz, 1H, pyridine H), 7.13 (dd, J = 4.7 Hz, J = 8.1 Hz,
6
1
teriochloroform/ dimethyl-d sulfoxide): δ 10.01 (s, 1H, NH/
6
1H, pyridine H), 4.12 (q, J = 7.1 Hz, 2H, OCH ), 3.64 (s, 2H,
OH), 9.29 (s, 1H, NH/ OH), 7.91 (dd, J = 4.6 Hz, J = 1.5 Hz, 1H,
pyridine H), 7.49 (dd, J = 8.1 Hz, J = 1.5 Hz, 1H, pyridine H),
2
13
CH ), 1.24 (t, J = 7.1 Hz, 3H, CH ); C nmr (dimethyl-d sul-
2
3
6
foxide): δ 154.8, 153.3, 145.0, 144.7, 131.8, 126.5, 122.2, 61.8,
25.2, 14.4; ms: m/z 252 (100), 206 (70), 149 (57).
7.04 (dd, J = 8.1 Hz, J = 4.6 Hz, 1H, pyridine H), 3.57 (s, 2H,
13
CH ); C nmr (deuteriochloroform/ dimethyl-d sulfoxide): δ
2
6
Anal. Calcd. for C H N O S: C, 47.61; H, 4.79; N, 22.21.
Found: C, 47.71; H, 4.66; N, 22.08.
141.6, 141.5, 140.6, 134.3, 122.7, 121.2, 25.5; ms: m/z 181
(100), 163 (73), 136 (100).
10 12
4 2
Anal. Calcd. for C H N OS: C, 46.40; H, 3.90; N, 23.19.
Found: C, 46.71; H, 3.79; N, 22.97.
7
7 3
2,4-Dihydro-1H-[1,2,4]triazolo[4,3-d]pyrido[2,3-b][1,4]thiazin-
1-one (7).
N-(3H-Pyrido[2,3-b][1,4]thiazin-2-yl)aminoacetaldehyde
dimethyl acetale (11).
A mixture of 2.52 g (10 mmoles) of 6 in 30 mL dry toluene and
1 mL of glacial acetic acid was refluxed for 24 hours. After this,
the reaction mixture was concentrated and the residue was puri-
A mixture of 1.96 g (10 mmoles) of 3 and 2.10 g (20 mmoles)
of aminoacetaldehyde dimethyl acetale in 50 mL dry methanol
was stirred at 40° for 55 hours. After this, the reaction mixture
was concentrated and the residue was purified by recrystalliza-
fied by recrystallization from toluene to give 1.53 g (74%) of 7,
1
mp 303-305°; H nmr (deuteriochloroform/ dimethyl-d sulfox-
6
ide): δ 12.22 (s, 1H, NH), 8.60 (dd, J = 8.2 Hz, J = 1.5 Hz, 1H,
pyridine H), 8.40 (dd, J = 4.5 Hz, J = 1.5 Hz, 1H, pyridine H),
1
tion from toluene to give 2.22 g (88%) of 11, mp 30°; H nmr
(deuteriochloroform): δ 8.06 (dd, J = 4.7 Hz, J = 1.5 Hz, 1H, pyri-
dine H), 7.32 (dd, J = 7.9 Hz, J = 1.5 Hz, 1H, pyridine H), 7.05
(dd, J = 7.9 Hz, J = 4.7 Hz, 1H, pyridine H), 4.98 (s, 1H, NH),
7.46 (dd, J = 4.5 Hz, J = 8.2 Hz, 1H, pyridine H), 4.30 (s, 2H,
13
CH ); C nmr (deuteriochloroform/ dimethyl-d sulfoxide): δ
2
6
152.2, 146.3, 146.0, 139.5, 129.1, 125.1, 121.6, 22.5; ms: m/z
206 (100).
4.57 (t, J = 5.1 Hz, 1H, CH), 3.67 (d, J = 5.1 Hz, 2H, CH ), 3.44
2
13
(s, 6H, CH ), 3.31 (s, 2H, CH ); C nmr (deuteriochloroform): δ
Anal. Calcd. for C H N OS: C, 46.59; H, 2.93; N, 27.17.
3
2
8
6 4
152.8, 145.0, 142.7, 140.7, 130.9, 121.6, 102.1, 54.3, 42.8, 26.9;
ms: m/z 253 (37), 222 (23), 165 (100).
Found: C, 46.79; H, 3.11; N, 26.92.
2-Acetyl-2,4-dihydro-1H-[1,2,3,5]thiatriazolo[5,4-d]pyrido[2,3-
b][1,4]thiazin-1-one (8).
Anal. Calcd. for C H N O S: C, 52.16; H, 5.97; N, 16.59.
11 15
3 2
Found: C, 51.81 H, 6.03; N, 16.33.
A suspension of 2.22 g (10 mmoles) of 4 in 30 mL thionyl
chloride was stirred for 48 hours. After this, the reaction mixture
was concentrated and the residue was purified by recrystalliza-
4H-[1,2,3,4]Tetrazolo[1,5-d]pyrido[2,3-b][1,4]thiazine (12).
To a suspension of 1.80 g (10 mmoles) of 9 in 30 mL 2 N
hydrochloric acid a solution of 1.032 g (15 mmoles) sodium
nitrite in 120 mL water was added dropwise at 5°. After stirring
for 24 hours the mixture was neutralized with a saturated solution
of sodium hydrogen carbonate and the precipitate was collected
by suction filtration and recrystallized from ethanol to give 0.89 g
1
tion from ethanol to give 1.05 g (39%) of 8, mp 160-163°; H
nmr (deuteriochloroform/ dimethyl-d sulfoxide): δ 8.30 (dd, J =
6
4.7 Hz, J = 1.5 Hz, 1H, pyridine H), 7.94 (dd, J = 8.2 Hz, J = 1.5
Hz, 1H, pyridine H), 7.34 (dd, J = 8.2 Hz, J = 4.7 Hz, 1H,
13
pyridine H), 4.25 (m, 2H, CH ), 2.43 (s, 3H, CH ); C nmr
2
3
1
(47%) of 12, mp 187°; H nmr (deuteriochloroform/ dimethyl-d
(deuteriochloroform/ dimethyl-d sulfoxide): δ 170.2, 146.4,
6
6
sulfoxide): δ 8.51 (dd, J = 4.7 Hz, J = 1.2 Hz, 1H, pyridine H),
145.3, 142.3, 129.5, 124.8, 121.8, 22.5, 21.3; ms: m/z 268 (35),
226 (42), 150 (100).
8.34 (dd, J = 8.1 Hz, J = 1.2 Hz, 1H, pyridine H), 7.48 (dd, J = 8.1
13
Hz, J = 4.7 Hz, 1H, pyridine H), 4.79 (s, 2H, CH ); C nmr (deu-
Anal. Calcd. for C H N O S : C, 40.29; H, 3.01; N, 20.88.
2
9
8 4 2 2
teriochloroform/ dimethyl-d sulfoxide): δ 147.4, 145.8, 145.3,
Found: C, 40.45; H, 2.80; N, 20.71.
6
126.9, 124.1, 120.3, 18.7; ms: m/z 191 (10), 162 (56), 136 (100).
N-(3H-Pyrido[2,3-b][1,4]thiazin-2-yl)hydrazine (9).
Anal. Calcd. for C H N S: C, 43.97; H, 2.64; N, 36.63. Found:
7
5 5
A mixture of 1.96 g (10 mmoles) of 3 and 2.0 mL of hydrazine
hydrate in 30 mL dry tetrahydrofuran was stirred for 24 hours.
After this, the reaction mixture was concentrated and the residue
was purified by recrystallization from ethanol to give 1.46 g
C, 44.21; H, 2.64; N, 36.42.
1H,4H-[1,2,4]Oxadiazolo[4,3-d]pyrido[2,3-b][1,4]thiazin-1-one
(13).
1
A mixture of 1.81 g (10 mmoles) of 10 and 1.78 g (11 mmoles)
of N,N'-carbonyldiimidazole in 50 mL of dry tetrahydrofuran was
stirred under reflux for 24 hours. After this, the reaction mixture
was concentrated and the residue was purified by recrystalliza-
tion from ethyl acetate to give 1.64 g (79%) of 13, mp 182-185°;
(81%) of 9, mp 274-276°; H nmr (deuteriochloroform/
dimethyl-d sulfoxide): δ 12.5 (s, 1H, NH), 7.97 (d, J = 4.5 Hz,
6
1H, pyridine H), 7.38 (d, J = 7.9 Hz, 1H, pyridine H), 7.14 (dd, J
= 4.5 Hz, J = 7.9 Hz, 1H, pyridine H), 5.5 – 4.2 (s, 2H, NH ), 3.59
2
13
(s, 2H, CH ); C nmr (deuteriochloroform/ dimethyl-d sulfox-
2
6
1
H nmr (deuteriochloroform/ dimethyl-d sulfoxide): δ 8.47 (dd,
ide): δ 146.0, 140.3, 136.0, 134.8, 121.9, 121.1, 27.8; ms: m/z
6
J = 4.7 Hz, J = 1.5 Hz, 1H, pyridine H), 8.44 (dd, J = 8.2 Hz, J =
1.5 Hz, 1H, pyridine H), 7.50 (dd, J = 8.2 Hz, J = 4.7 Hz, 1H,
180 (100), 136 (26).
Anal. Calcd. for C H N S: C, 46.65; H, 4.47; N, 31.09. Found:
C, 46.42; H, 4.33; N, 30.80.
7
8 4
13
pyridine H), 4.47 (s, 2H, CH ); C nmr (deuteriochloroform/
2
dimethyl-d sulfoxide): δ 154.7, 152.2, 147.0, 146.3, 127.5,
6
N-(3H-Pyrido[2,3-b][1,4]thiazin-2-yl)hydroxylamine (10).
125.0, 121.9, 21.0; ms: m/z 207 (100), 162 (33), 136 (51).
Anal. Calcd. for C H N O S: C, 46.37; H, 2.43; N, 20.28.
A mixture of 1.96 g (10 mmoles) of 3 and 1.39 g (20 mmoles)
8
5 3 2
Found: C, 46.53; H, 2.39; N, 20.26.
of hydroxylamine hydrochloride in 50 mL dry ethanol was stirred