Jul-Aug 2004
The Cleavage of Heterocyclic Compounds in Organic Synthesis II
635
Anal. Calcd. for C H NO : C, 45.51; H, 2.39; N, 6.63. Found:
6
Compound 3 (0.8 g, 3.8 mmol) was dissolved in a 5% aqueous
solution of potassium hydroxide (15 ml). Reaction mixture was
cooled to 0 °C and 35 % solution of hydrogen peroxide (8.8 ml)
was added. Reaction mixture was then left to stand at this tem-
perature for 30 minutes and then another 2 hours at room temper-
ature. The pH of the solution was then changed to 3-4 by adding
a 5 % solution of sulfuric acid. The precipitated solid was col-
lected by filtration, washed with 20 ml of cold water and dried to
yield 0.5 g (72.5 %) of compound 6.
8
C, 45.44; H, 2.11; N, 6.72.
5
1-(2-Amino-5-nitro-phenyl)-2-piperidin-1-yl-ethane-1,2-dione (4 a).
A solution of 5-nitroisatine (1) (0.4 g, 2.1 mmol) in methanol
(10 ml) was mixed with piperidine (0.5 ml, 5 mmol) and heated
to the boiling point. After cooling the resulting solid was col-
lected by filtration, washed with small amount of methanol and
air-dried to yield 0.34 g (58.9 %) of compound 4a, mp 193-197
1
°C ; ir: NH 3376, 3201; CO 1642; H nmr: δ 1.43 (m, 2H,
2
CH ); 1.61 (m, 4H, CH ); 3.26 (m, 2H, CH ); 3.61 (m, 2H, CH );
Method B.
2
6.97 (d, 1H, J = 9.3 Hz, H3); 8.13 (dd, 1H, J = 9.3 Hz, J = 2.7
2
2
2
5-Nitroanthranilic acid (1 g, 5.5 mmol) was dissolved in an
aqueous solution of potassium hydroxide (50 ml). Reaction mix-
ture was then refluxed for 60 minutes (with use of 5% KOH solu-
tion) or 12 hours (with use of 20% KOH solution). Then the reac-
tion mixture was cooled to laboratory temperature and pH of the
solution was changed to 3-4 by adding 5 % solution of sulfuric
acid. The precipitated solid was collected by filtration, washed
with cold water (100 ml) and dried to yield 0.8 g (79.4 %) of the
2
Hz, H4); 8.22 (d, 1H, J = 2.7 Hz, H6); 8.41 (s, 2H, NH ).
2
Anal. Calcd. for C H N O : C, 56.31; H, 5.45; N, 15.15.
13 15 3 4
Found: C, 56.21; H, 5.63; N, 14.99.
1-(2-Amino-5-nitro-phenyl)-2-morpholin-1-yl-ethane-1,2-dione
(4b).
A solution of 5-nitroisatine (1, 0.46 g, 2.4 mmol) in methanol
(10 ml) was mixed with morpholine (0.5 ml, 5.7 mmol) and
heated to the boiling point. After cooling the resulting solid was
collected by filtration, washed with small amount of methanol
product 6, mp 226-230 °C (water) (lit.[18] 228 °C). ir: CO 1673;
1
NO 1341; H nmr: δ 7.13 (d, 1H, J = 9 Hz, H3); 8.31 (dd, 1H, J
1
= 9 Hz, J = 3 Hz, H4); 8.54 (d, 1H, J = 3 Hz, H6).
2
and air-dried to yield 0.61 g (91 %) of product 4b, mp 208-211
1
°C; ir: NH 3387, 3195; CO 1630; H nmr: δ 3.34 (m, 2H, CH ),
2-Amino-5-nitrobenzoic Acid 2-Oxo-2-phenylethyl Ester (9).
2
3.54 (m, 2H, CH ), 3.68 (m, 4H, CH ), 6.97 (d, 1H, J=9 Hz, H3),
2
5-Nitroanthranilic acid (1 g, 5.5 mmol) was dissolved in
dimethylformamide (10 ml) and potassium carbonate (540 mg, 4
mmol) was added to the solution. The reaction mixture was
heated to 90° and stirred for 1 hour. Then the solution was cooled
to 20° and α-bromoacetophenone (0.8 g, 4 mmol) was added.
After stirring for 30 minutes the solution was poured into a 10 %
solution of natrium bicarbonate (50 ml) in water and ice. The pre-
cipitated solid was collected by filtration, washed with water and
dried to yield 0.8 g (51%) of product 7, mp 223-226 °C (acetone);
2
2
8.13 (dd, 1H, J =9 Hz, J =2.5 Hz, H4), 8.27 (d, 1H, J=2.5 Hz,
1
H6), 8.45 (brs, 2H, NH ).
2
2
Anal. Calcd. for C H N O : C, 51.61; H, 4.69; N, 15.05.
12 13 3 5
Found: C, 51.91; H, 4.83; N, 14.97.
4-[2-(2-Amino-5-nitro-phenyl)-2-oxo-acetyl]-piperazine-1-car-
boxylic Acid Ethyl Ester (4c).
A solution of 5-nitroisatine (1, 0.46 g, 2.4 mmol) in methanol
(5 ml) was mixed with carbethoxypiperazine (0.5 ml, 3.4 mol).
The resulting solid was collected by filtratioon, washed with a
small amount of methanol and air-dried to yield 0.74 g (88 %) of
1
ir: NH 3438, 3316; CO 1696; H nmr: δ 5.77 (s, 2H, CH ); 6.93
2
2
(d, 1H, J = 9.3 Hz, H3); 7.59 (t, 2H, J = 8 Hz, H3´); 7.72 (t, 1H, J
= 7.2 Hz, H4´); 7.83 (s, 2H, NH ); 8.01 (d, 2H, J = 8 Hz, H2´);
2
8.12 (dd, 1H, J = 9.3 Hz, J = 2.7 Hz, H4); 8.72 (d, 1H, J = 2.7
1
product 4c, mp 163-165 °C; ir : NH 3409, 3311; CO 1713; H
2
nmr: δ 1.18 (t, J=7 Hz, 3H, CH ), 3.35 (m, 4H, CH ), 3,49 (m,
1
2
Hz).
Anal. Calcd: for C H N O : C, 60.00, H, 4.03, N, 9.33.
Found: C, 60.26, H 4.17, N, 9.61.
3
2H, CH ), 3,67 (m, 2H, CH ), 4.02 (q, J=7 Hz, 2H, CH ), 6.97 (d,
2
2
2
2
J=9.5 Hz, 1H, H3), 8.13 (dd, J =9.5 Hz, J =2.5 Hz, H4), 8.25 (d,
15 12 2 5
1
J=2.5 Hz, 1H, H6), 8.46 (brs, 2H, NH ).
2
2
Anal. Calcd. for C H N O : C, 51.43; H, 5.18; N, 15.99.
3-Hydroxy-6-nitro-2-phenyl-1H-quinolin-4-one (10).
15 18 4 6
Found: C, 51.15; H, 5.22; N, 15.87.
Phenacylester of 5-nitroanthranilic acid 9 (0.5 g, 1.7 mmol)
was added to polyphosphoric acid (5 g), at 120º and the reaction
mixture was stirred for 1 hour at this temperature. The reaction
mixture was then diluted with cold water (30 ml) and cooled to a
room temperature. The pH of solution was adjusted between 7
and 8 by the addition of aqueous 10% sodium hydroxide solution
and the precipitated solid was collected, washed with 50 ml of
5-Nitroanthranilic Acid (7).
The 5-nitroisatine (1) (0.5 g, 2.6 mmol) was dissolved in solu-
tion of KOH (0.6 g, 10.7 mmol) in water (10 ml) and cooled in an
ice bath. Hydrogen peroxide 33 % (0.6 ml) was added dropwise.
After 30 minutes the solution was warmed to room temperature
and kept for the next two hours at which time the solution was
acidified with 10 % sulphuric acid to pH 1-2. The resulting solid
was collected by filtratoin, washed with water and dried to yield
water and dried to yield 0.3 g (68%), mp above 360 °C (methyl-
cellosolve); ir: NH 3425; C-H
1
3106; CO 1642; H nmr: δ
arom
7.57 (m, 3H); 7.79 (dd, 2H, J = 7.8 Hz, J = 1.5 Hz, H );
1
7.84 (d, 1H, J = 9.5 Hz, H8); 8.32 (dd, 1H, J = 9.5 Hz, J = 2.7
2
2-phenyl
0.46 g (98 %) mp 258-260 °C (lit.: [17] 254-255 °C ir: NH 3483,
1
2
3369; CO 1688; H nmr: δ 6.87 (d, 1H, J = 9.3 Hz, H3); 7.86 (s,
1
Hz, H7); 8.94 (d, 1H, J = 2.7 Hz, H5); 12.11 (s, 1H, NH).
2
2H, NH ); 8.06 (dd, 1H, J = 9.3 Hz, J = 2.7 Hz, H4); 8.59 (d,
1
Anal. Calcd. for C H N O : C, 63.83, H, 3.57, N, 9.92.
15 10 2 4
Found: C, 64.24, H, 3.35, N, 10.18.
2
1H, J = 2.7 Hz, H6).
2
Anal. Calcd. for C H N O : C, 46.16, H, 3.32, N, 15.38.
7
6 2 4
5-Nitroisatine Semicarbazone (11).
Found: C, 46.02, H 3.44, N, 15.11.
5-Nitro-2-hydroxybenzoic Acid (8).
Method A.
A solution of 5-nitroisatine (0.6 g, 3.1 mmol) in acetic acid (20
ml) was mixed with a solution of semicarbazide hydrochloride
(0.35, 3.1 mmol) in water (10 ml). The solution was boiled for 10