10.1002/hlca.201900116
Helvetica Chimica Acta
HELVETICA
multiplicities: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad.
Flash column chromatography was performed on silica gel (Silica Gel 60N,
Kanto Chemical Co., Ltd.).
7.23 (d, J = 2.3 Hz, 1H); 7.04 (dd, J = 2.3, 8.6 Hz, 1H); 6.69 (d, J = 8.6 Hz,
1H); 6.25 (d, J = 9.7 Hz, 1H); 5.60 (d, J = 10.4 Hz, 1H); 2.16 (s, 3H); 1.43
(s, 6H). 13C-NMR (125 MHz, CDCl3): d 168.4; 149.8; 131.5; 131.0; 122.3;
121.6; 121.3; 118.9; 116.5; 76.3; 27.9; 24.4. ESI-HR-MS (pos.):
240.0994C13H15NNaO2+, [M+Na]+; calcd. 240.1000).
Synthesis of Aniline 13 (Scheme 2).
2,2-dimethyl-2H-chromen-6-amine (13). A solution of 12 (2.0 g, 9.2
mmol) in MeOH/concd. HCl (100 mL, v/v = 1/1) was stirred for 3 h under
reflux conditions and then cooled to room temperature, poured into 10%
NaOH. The residue was extracted with AcOEt (2 x 300 mL) and washed
with brine, and dried over MgSO4. The mixture was filtered through Alumina
pad, the solvent was removed. The residue was purified by column
chromatography (hexane/AcOEt = 6/1) to give 13 as colorless oil (1.5 g,
93%). IR (CHCl3): 3366 cm–1. 1H-NMR (500 MHz, CDCl3): d 6.60 (d, J = 8.0
Hz, 1H); 6.47 (dd, J = 2.9, 8.6 Hz, 1H); 6.37 (d, J = 2.9 Hz, 1H); 6.22 (d, J
= 9.8 Hz, 1H); 5.60 (d, J = 9.7 Hz, 1H); 3.19 (br s, 2H); 1.39 (s, 6H). 13C-
NMR (125 MHz, CDCl3): d 145.8; 139.8; 131.8; 122.5; 122.0; 116.9; 116.1;
113.4; 75.6; 27.6. ESI-HR-MS (pos.): 198.0897 (C11H13NNaO+, [M+H]+;
calcd. 198.0895.
4-Acetamidophenyl acetate (7). To a solution of 4-aminophenol (32.7 g,
300 mmol) and Et3N (92 mL, 660 mmol) in AcOEt (300 mL) was added
acetyl chloride (42.6 mL, 600 mL) at 0 °C. The resulting suspension was
warmed to room temperature and stirred for 16 h, poured slowly into water
(200 mL). The resulting mixture was extracted with AcOEt (3 x 300 mL)
and washed with brine, and dried over MgSO4. The solvent was removed,
and the residue was purified by recrystallization with Et2O to give 7 as
colorless powder (47 g, 81%). M.p. 149—150 °C. IR (CHCl3): 3441, 1759,
1688 cm–1. 1H-NMR (500 MHz, CDCl3): d 7.46-7.48 (br s, 1H), 7.46 (d, J =
8.6 Hz, 2H); 7.00 (d, J = 8.6 Hz, 2H); 2.28 (s, 3H); 2.14 (s, 3H). 13C-NMR
(125 MHz, CDCl3): d 169.8; 168.5; 146.9; 135.7; 122.0; 121.0; 24.5; 21.2.
ESI-HR-MS (pos.): 194.0818 (C10H12NO3+, [M+H]+; calcd. 194.0817).
N-(3-acetyl-4-hydroxyphenyl)acetamide (6). To 7 (23.2 g, 120 mmol)
and aluminium chloride (70 g, 525 mmol) was added sodium chloride (430
g, 513 mmol) at room temperature. The resulting solids was heated at
130 °C and stirred for 5 h. To the mixture was added slowly ice and 10%
HCl and stirred at 0 °C for 1 h. The resulting solids were filtered and the
residue was extracted with AcOEt (3 x 300 mL) and washed with brine, and
dried over MgSO4. The solvent was removed, and the residue was purified
by recrystallization with Et2O to give 6 as pale yellow powder (20.7 g, 89%).
M.p. 162—163 °C. IR (CHCl3): 3326, 1688, 1647 cm–1. 1H-NMR (500 MHz,
CDCl3): d 12.09 (br s, 1H); 8.14 (d, J = 2.9 Hz, 1H); 7.41 (br s, 1H); 7.32
(dd, J = 2.3, 8.6 Hz, 1H); 6.90 (d, J = 9.2 Hz, 1H); 2.60 (s, 3H); 2.16 (s, 3H).
Synthesis of Ketone 5 (Scheme 3).
Ethyl 4-[2-(2-ethoxy-2-oxoacetamido)benzamido]butanoate (15). To a
solution of 9 (11.4 g, 70 mmol) in AcOEt (300 mL) was added Et3N (30 mL,
215 mmol), 4-aminobutyric acid ethyl ester hydrogen chloride (12.9 g, 77
mmol), and N,N-dimethyl-4-aminopyridine (855 mg, 7 mmol) at room
temperature and stirred for 3 h under reflux conditions and then cooled to
room temperature. Ethyl chloroglyoxylate (8.9 mL, 80 mmol) was added to
the mixture, and stirred at room temperature for 16 h, poured into water.
The residue was extracted with AcOEt (2x 300 mL, v/v = 5/1) and washed
with brine, and dried over MgSO4. The solvent was removed, and the
residue was purified by column chromatography (hexane/AcOEt = 6/1) to
give 15 (7.6 g, 31%) as colorless powder. M.p. 110—111 °C. IR (CHCl3):
1707 cm–1. 1H-NMR (500 MHz, CDCl3): d 8.66 (d, J = 8.6 Hz, 1H); 7.55 (d,
J = 7.5 Hz, 1H); 7.50 (td, J = 1.8, 7.6 Hz, 1H); 7.15 (t, J = 7.4 Hz, 1H); 6.99
(br s, 1H); 4.40 (t, J = 6.9 Hz, 2H); 4.11 (q, J = 7.4 Hz, 2H); 3.51 (q, J = 6.5
Hz, 2H); 2.45 (t, J = 6.9 Hz, 2H); 1.95–1.99 (m, 2H); 1.73 (br s, 1H); 1.41
(t, J = 7.4 Hz, 3H); 1.23 (t, J = 7.4 Hz, 3H). 13C-NMR (125 MHz, CDCl3): d
174.1; 168.5; 160.7; 154.9; 138.3; 132.8; 126.8; 124.2; 121.4; 120.9; 63.5;
60.9; 40.0; 32.3; 24.0; 14.3; 14.1. ESI-HR-MS (pos.): 373.1376
13C-NMR (125 MHz, CDCl3): d 204.5; 168.7; 159.3; 129.3; 129.2; 122.7;
+
119.3; 118.8; 26.8; 24.4. ESI-HR-MS (pos.): 194.0819 (C10H12NO3
[M+H]+; calcd.194.0817).
,
N-(2,2-dimethyl-4-oxochroman-6-yl)acetamide (10). To a solution of 6
(20.7 g, 107 mmol) in MeOH (300 mL) was added a solution of pyrroridine
(20 mL, 487 mmol) in acetone (40 mL) at room temperature and stirred for
16 h. The resulting mixture was evaporated and the residue was diluted
with AcOEt (300 mL) and 5% HCl (150 mL). The combined layers were
extracted with AcOEt (2 x 300 mL) and washed with brine, and dried over
MgSO4. The solvent was removed, and the residue was purified by
recrystallization with Et2O to give 10 as pale yellow powder (21 g, 84%).
+
(C17H22N2NaO6 , [M+Na]+; calcd. 373.1376).
M.p. 159—161 °C. IR (CHCl3): 3362, 1682 cm–1
.
1H-NMR (500 MHz,
Ethyl
3-(4-ethoxy-2-oxobutyl)-4-oxo3,4-dihydroquinazoline-2-
CDCl3): d 7.93 (dd, J = 2.3, 8.6 Hz, 1H); 7.75 (br s, 1H); 7.67 (d, J = 2.9 Hz,
1H); 6.89 (d, J = 9.2 Hz, 1H); 2.69 (s, 2H); 2.16 (s, 3H); 1.43 (s, 6H). 13C-
carboxylate (8). To a solution of 15 (19.6 g, 56 mmol) in xylene (300 mL)
was added phosphorus chloride (12.2 mL, 140 mmol) at room temperature
and stirred for 2.5 h under reflux conditions and then cooled to room
temperature, poured into water. The residue was extracted with AcOEt (2
x 200 mL) and washed with brine, and dried over MgSO4. The solvent was
removed, and the residue was purified by column chromatography
(hexane/AcOEt = 6/1) to give 8 (12.5 g, 67%) as colorless oil. IR (CHCl3):
NMR (125 MHz, CDCl3): d 192.6; 168.7; 156.9; 131.5; 129.8; 119.9; 119.0;
+
117.4; 79.4; 48.9; 26.6; 24.3. ESI-HR-MS (pos.): 234.1129 (C13H16NO3
[M+H]+; calcd. 234.1130).
,
N-(4-hydroxy-2,2-dimethylchroman-6-yl)acetamide (11). To a solution
of 10 (21 g, 90 mmol) in MeOH (300 mL) was added NaBH4 (4.08 g, 108
mmol) at room temperature and stirred for 2 h, poured into 1% HCl, and
evaporated. The residue was extracted with AcOEt/CHCl3 (2x 300 mL, v/v
= 5/1) and washed with water, brine, and dried over MgSO4. The solvent
was removed, and the residue was purified by recrystallization with Et2O to
give 11 as colorless powder (19.5 g, 92%). M.p. 147—149 °C. IR (CHCl3):
3356, 1682 cm–1. 1H-NMR (500 MHz, CDCl3): d 7.51 (br s, 1H); 7.49 (d, J
= 2.3 Hz, 1H); 7.21 (dd, J = 2.3, 8.6 Hz, 1H); 6.70 (d, J = 8.6 Hz, 1H); 4.73
(dd, J = 6.3, 9.2 Hz, 1H); 2.34 (br s, 1H); 2.10 (dd, J = 6.3, 13.8 Hz, 1H);
2.08 (s, 3H); 1.80 (dd, J = 9.2, 13.8 Hz, 1H); 1.40 (s, 3H); 1.25 (s, 3H). 13C-
NMR (125 MHz, CDCl3): d 168.8; 150.3; 130.4; 124.8; 122.5; 120.5; 117.5;
75.6; 63.5; 42.5; 29.1; 25.8; 24.3. ESI-HR-MS (pos.): 236.1287
(C13H18NO3+, [M+H]+; calcd. 236.1287).
1736, 1682 cm–1 1H-NMR (500 MHz, CDCl3): d 8.23 (d, J = 7.5 Hz, 1H);
.
7.69–7.72 (m, 2H); 7.48 (td, J = 1.7, 8.6 Hz, 1H); 4.49 (q, J = 7.5 Hz, 2H);
4.12 (t, J = 7.4 Hz, 2H); 4.07 (q, J = 7.5 Hz, 2H); 2.37 (t, J = 7.4 Hz, 2H);
2.03-2.09 (m, 2H); 1.41 (t, J = 7.4 Hz, 3H); 1.19 (t, J = 6.3 Hz, 3H). 13C-
NMR (125 MHz, CDCl3): d 172.5; 161.5; 161.1; 147.2; 146.4; 134.6; 128.3;
128.0; 126.9; 121.9; 63.5; 60.6; 44.7; 31.4; 24.4; 14.3; 14.2. ESI-HR-MS
+
(pos.): 355.1270 (C17H20N2NaO5 , [M+Na]+; calcd. 355.1270).
8,9-Dihydro-7H-pyrido[2,1-b]quinazoline-6,11-dione
(5).
To
a
suspension of NaH (1.7 g, 72 mmol, 60 wt% mineral oil) in THF (90 mL)
was added a solution of 8 (12 g, 36 mmol) in THF (10 mL) at 0 °C. The
resulting solution was stirred for 16 h under reflux conditions, then cooled
to room temperature, and added water (2 mL). The solvent was removed.
After 15% HCl was added, the mixture was stirred under reflux conditions
for 16 h and cooled to room temperature, poured into 10% NaOH. The
residue was extracted with AcOEt (2 x 200 mL) and washed with brine, and
dried over MgSO4. The solvent was removed, and the residue was purified
by column chromatography (hexane/AcOEt = 4/1) to give 5 (2.4 g, 31%) as
N-(2,2-dimethyl-2H-chromen-6-yl)acetamide (12). A solution of 11 (14.1
g, 60 mmol) and p-toluenesulfonic acid (1 g, 6 mmol) in benzene/toluene
(300 mL, v/v = 1/1) was stirred for 5 h under reflux conditions and then
cooled to room temperature. The mixture was filtered through Alumina pad,
the solvent was removed. The residue was purified by recrystallization with
Et2O to give 12 as colorless powder (11.7 g, 90%). M.p. 124—125 °C. IR
pale yellow powder. M.p. 169—170 °C. IR (CHCl3): 1730, 1670 cm–1 1H-
.
NMR (500 MHz, CDCl3): d 8.31 (d, J = 8.6 Hz, 1H); 7.97 (d, J = 8.1 Hz, 1H);
7.81 (td, J = 1.2, 6.9 Hz, 1H); 7.59 (t, J = 7.5 Hz, 1H); 4.32 (t, J = 5.7 Hz,
(CHCl3): 3393, 1680cm–1 1H-NMR (500 MHz, CDCl3): d 7.29 (br s, 1H);
.
4
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