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Z. Sun et al.
Paper
Synthesis
Compound 15
Stirring was maintained for further 60 min. The reaction mixture was
cooled to r.t. and then evaporated to give the crude solid, which was
dissolved in CH2Cl2 (ca. 20 mL). The organic layer was washed with
H2O (ca. 20 mL) and brine (ca. 20 mL), and dried (Na2SO4). The solvent
was evaporated to afford the crude product. This was purified by sili-
ca gel column chromatography using CH2Cl2–2% MeOH as eluent;31
yield: 99 mg (88%); colorless solid; mp 147 °C.
1,6-Diaminohexane (27 mg, 0.23 mmol, 1.0 equiv) was added to a
solution of 3 (ca. 0.46 mmol) in anhydrous CH2Cl2 (15 mL), in a round-
bottomed flask filled with N2. The mixture was stirred overnight and
then the solvent was evaporated. The residue was recrystallized from
MeOH– CH2Cl2 (1/2 v/v) to give 15; yield: 124 mg (M = 899.18 g·mol–1
n = 0.138 mmol, 60%); light yellow solid; mp 219–221 °C.
,
IR (KBr): 3881, 3322, 2928, 2325, 2089, 1894, 1549, 1313, 1151, 1037,
IR (KBr): 3310, 2963, 2929, 1643, 1544, 1457, 1353, 1316, 1258, 1140,
1039, 1003, 869, 816, 757, 699 cm–1
914, 819, 699 cm–1
.
.
1H NMR (600 MHz, CDCl3): δ = 10.46 (s, 1 H), 8.92 (d, J = 7.80 Hz, 1 H),
8.02 (d, J = 7.20 Hz, 2 H), 7.91 (dd, J = 8.40, 1.20 Hz, 1 H), 7.55 (m, 4 H),
6.76 (s, 1 H), 4.91 (s, 2 H), 3.98 (d, J = 6.60 Hz, 2 H), 3.38 (br, 1 H), 2.27
(m, 1 H), 1.14 (d, J = 6.60 Hz, 6 H).
13C NMR (150 MHz, CDCl3): δ = 165.37, 159.30, 138.18, 137.94,
137.38, 137.31, 136.04, 135.09, 133.58, 131.85, 129.05, 127.09,
125.99, 120.72, 117.71, 116.16, 98.00, 64.96, 29.68, 27.96, 19.12.
1H NMR (300 MHz, DMSO-d6): δ = 10.29 (s, 2 H), 9.69 (s, 2 H), 9.16
(dd, J = 8.10, 1.20 Hz, 2 H), 8.75 (s, 2 H), 7.84 (dd, J = 8.40, 1.20 Hz, 2
H), 7.66 (s, 2 H), 7.59 (t, J = 8.10 Hz, 2 H), 7.34 (m, 10 H), 4.65 (d, J =
6.00 Hz, 4 H), 4.16 (d, J = 6.60 Hz, 4 H), 3.54 (s, 4 H), 2.22 (m, 2 H), 1.60
(s, 4 H), 1.38 (m, 4 H), 1.10 (d, J = 6.60 Hz, 12 H).
13C NMR (151 MHz, DMSO-d6): δ = 180.19, 164.38, 163.10, 149.88,
139.67, 138.78, 136.55, 128.71, 127.64, 127.30, 121.80, 119.10,
114.93, 99.64, 75.07, 43.80, 42.99, 28.67, 28.10, 26.64, 19.40.
MS (EI, 70 eV): m/z (%) = 349.7 (100, [M]+).
MS (ESI): m/z (%) = 896.93 (100.00, [M – H]–), 933.00 (12.05, [M + H2O
Anal. Calcd for C21H22N2O3: C, 71.98; H, 6.33; N, 8.0. Found: C, 70.85;
H, 7.91; N, 7.40.
+ OH]–).
Anal. Calcd for C50H58N8O4S2·H2O: C, 65.48; H, 6.59; N, 12.22. Found:
C, 65.03; H, 6.45; N, 12.15.
(8-Benzamido-4-isobutoxyquinolin-2-yl)methyl 2,3,4,5-Tetrafluo-
ro-6-iodobenzoate (22)
Methyl 8-Amino-4-isobutoxyquinoline-2-carboxylate (19)
To a 50 mL two-necked round-bottomed flask were added 21 (90 mg,
0.267 mmol), 2,3,4,5-tetrafluoro-6-iodobenzoic acid (17; 125 mg,
0.390 mmol), DIC (0.1 mL), and DMAP (5.0 mg) in CH2Cl2 (25 mL). The
reaction mixture was stirred for 18 h under N2 atmosphere. The re-
sulting solution was quenched with sat. aq NH4Cl (ca. 15 mL) and ex-
tracted with CH2Cl2 (3 × 30 mL). The combined organic extracts were
washed with brine (ca. 30 mL), dried (Na2SO4), and concentrated in
vacuo. The crude mixture was purified by silica gel column chroma-
tography using CH2Cl2–hexane (10:1) as eluent; yield: 119 mg (70%);
light yellow solid; mp 135–136 °C.
A mixture of methyl 4-isobutoxy-8-nitroquinoline-2-carboxylate (18;
300 mg, 0.99 mmol) dissolved in CH2Cl2 (10 mL) and 10% Pd/C (50 mg)
was stirred at r.t. under an atmosphere of H2 (20 bar) for 5 h. The solu-
tion was filtered over Celite and the filtrate was evaporated to dry-
ness. The residue was used directly in the next step.
Methyl 8-Benzamido-4-isobutoxyquinoline-2-carboxylate (20)
To a 100 mL two-necked round-bottomed flask equipped with a mag-
netic stirrer was added 19 (270 mg, 0.99 mmol) under N2 atmosphere.
Then, MeCN (ca. 40 mL) and Et3N (0.33 mL) were added to the flask.
After cooling the mixture to 0 °C, benzoyl chloride (140 mg, 1 mmol)
was added dropwise by using a syringe. The suspension was allowed
to reach r.t. and stirred overnight. When the reaction was complete,
the solvent was evaporated; the residue was dissolved in CH2Cl2 (ca.
50 mL) and washed with sat. aq NH4Cl (ca. 50 mL). The organic extract
was dried (Na2SO4), filtered, and the filtrate was evaporated to dry-
ness. The residue was purified by silica gel column chromatography
using CH2Cl2–hexane (5:2) as eluent; yield: 122 mg (33%); colorless
solid; mp 124 °C.
IR (KBr): 3832, 3351, 3157, 3071, 2961, 2877, 2643, 2325, 2107, 1991,
1919, 1739, 1662 (s), 1596, 1526, 1457, 1366, 1319, 1256, 1199, 1106,
1040, 983, 901, 799, 757, 695 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.65 (s, 1 H), 8.93 (dd, J = 7.60, 1.20
Hz, 1 H), 8.02 (m, 2 H), 7.91 (dd, J = 8.40, 1.20 Hz, 1 H), 7.52 (m, 4 H),
6.92 (s, 1 H), 5.66 (s, 2 H), 3.99 (d, J = 6.40 Hz, 2 H), 2.28 (m, 1 H), 1.12
(d, J = 6.80 Hz, 6 H).
13C NMR (101 MHz, CDCl3): δ = 177.45, 165.31, 163.07, 153.89,
138.93, 135.19, 134.12, 131.73, 128.73, 127.18, 126.60, 120.56,
117.40, 115.81, 99.44, 69.52, 28.14, 19.21. Due to the coupling with
19F, C-atoms at the fluorinated ring system were not observed.
19F NMR (376 MHz, CDCl3): δ = –112.18 (m, 1 F), –136.35 (m, 1 F),
–148.76 (m, 1 F), –151.89 (m, 1 F).
MS (EI, 70 eV): m/z (%) = 652.0 (96.42, [M]+).
IR (KBr): 3845, 3328, 2922, 2858, 2658, 2302, 2095, 1911, 1722, 1675,
1533, 1365, 1244, 1110, 1028, 981, 914, 771, 694 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 10.87 (s, 1 H), 8.95 (dd, J = 7.50, 1.50
Hz, 1 H), 8.11 (m, 2 H), 7.96 (dd, J = 8.40, 1.20 Hz, 1 H), 7.58 (m, 5 H),
4.07 (m, 5 H), 2.31 (m, 1 H), 1.17 (d, J = 6.90 Hz, 6 H).
13C NMR (150 MHz, CDCl3): δ = 165.74, 165.22, 163.13, 146.72,
138.97, 135.19, 134.94, 133.62, 131.86, 130.14, 128.78, 128.46,
128.44, 127.30, 122.07, 117.35, 115.63, 101.22, 52.91, 28.19, 19.21.
Anal. Calcd for C28H21F4IN2O4·0.5 H2O: C, 50.85; H, 3.35; N, 4.24.
Found: C, 51.01; H, 3.70; N, 4.29.
1-[2-(Hydroxymethyl)-4-isobutoxyquinolin-8-yl]-3-phenylurea
(24)
MS (EI, 70 eV): m/z (%) = 377.9 (100, [M]+).
Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.94;
H, 6.03; N, 7.22.
A mixture of methyl 4-isobutoxy-8-(3-phenylureido)quinoline-2-car-
boxylate (23; 121 mg, 0.31 mmol) and NaBH4 (116 mg, 3.07 mmol) in
THF (10 mL) was stirred at 65 °C for 30 min. Then, MeOH (2.5 mL) was
added dropwise during 30 min and effervescence was observed. Stir-
ring was maintained for further 60 min. The reaction mixture was
cooled to r.t. and then evaporated to give the crude product, which
was dissolved in CH2Cl2 (ca. 25 mL). The organic layer was washed
with H2O (ca. 20 mL) and brine (ca. 20 mL), and dried (Na2SO4). The
N-[2-(Hydroxymethyl)-4-isobutoxyquinolin-8-yl]benzamide (21)
A mixture of 20 (122 mg, 0.32 mmol) and NaBH4 (122 mg, 3.22 mmol)
in THF (10 mL) was stirred at 65 °C for 30 min. Then, MeOH (2.6 mL)
was added dropwise during 30 min and effervescence was observed.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 861–870