Journal of Medicinal Chemistry
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137.2, 148.9, 158.6; HRMS (ESI) m/z calculated for C19H17N4O3 [M
+ H]+ 349.1301, found 349.1305. Anal. (C19H16N4O3) C, H, N.
2-(((8-Hydroxy-5-nitroquinolin-7-yl)methyl)amino)acetonitrile
(17). 17 was synthesized according to the general procedure. The solid
obtained was resuspended in methanol and mixed for 5 h. The
undissolved residue was then filtered off and the filtrate evaporated.
The compound was subsequently purified by column chromatography
(CH2Cl2/MeOH, 20/1). Yield, 56% (610 mg); orange solid; mp
208.0−210.0 °C; IR (KBr) υ = 3290, 3071, 2821, 2583, 2231, 1909,
2670, 1513, 1471, 1346, 1303, 1279, 1248, 1118, 1019, 968, 816, 799,
6.9.4. General Procedure for Microwave-Assisted Synthesis of 5-
Nitro-8-quinolinylamines 38−48.37 A mixture of compound 27 (115
mg, 0.50 mmol), the desired amine (1.5 mmol), and CH3CN (2 mL)
was irradiated in the focused microwave equipment at 100 °C (80 or
150 W) for the indicated time (15 min to 2 h). After the reaction was
complete, the volatiles were removed under reduced pressure and the
residue was purified by silica gel radial chromatography.
8-(4-Methylpiperidin-1-yl)-5-nitroquinoline (42). The reaction
mixture was irradiated for 2 h at 150 W. Eluent for chromatography:
CH2Cl2/MeOH, 25/1. Yield, 118 mg (87%); brown oil; IR (NaCl
plates) υ = 2948, 2922, 1555, 1504, 1492, 1387, 1296, 1280, 1245,
1228, 1191, 1141, 1080, 971, 952, 814, 785, 741 cm−1; 1H NMR (500
MHz, DMSO-d6) δ 0.99 (d, J = 6.5 Hz, 3H, CH3), 1.41 (ddd, J = 16.0,
13.0, 3.5 Hz, 2H, piperidine-H), 1.65−1.74 (m, 1H, piperidine-H),
1.77 (dd, J = 13.0, 3.5 Hz, 2H, piperidine-H), 3.07−3.12 (m, 2H,
piperidine-H), 4.35 (d, J = 13.0 Hz, 2H, piperidine-H), 7.15 (d, J = 9.5
Hz, 1H, Ar-H), 7.76 (dd, J = 9.0, 4.0 Hz, 1H, Ar-H), 8.44 (d, J = 9.0
Hz, 1H, Ar-H), 8.90 (dd, J = 4.0, 1.5 Hz, 1H, Ar-H), 9.15 (dd, J = 9.0,
1.5 Hz, 1H, Ar-H); 13C NMR (126 MHz, DMSO-d6) δ 21.8, 30.4,
33.9, 51.6, 112.0, 123.3, 124.3, 128.1, 132.1, 134.4, 139.5, 147.4, 155.1;
HRMS (ESI) m/z calculated for C15H18N3O2 [M + H]+ 272.1394,
found 272.1387; purity by HPLC, 96.23%.
1
724, 668, 655 cm−1; H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 2H,
CH2), 4.02 (s, 2H, CH2), 7.83 (dd, J = 9.0, 4.0 Hz, 1H, Ar-H), 8.59 (s,
1H, Ar-H), 8.96 (dd, J = 4.0, 1.5 Hz, 1H, Ar-H), 9.09 (dd, J = 9.0, 1.5
Hz, 1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 38.4, 50.9, 116.1,
118.9, 121.5, 125.0, 129.7, 132.6, 133.9, 136.8, 148.7, 158.6; HRMS
(ESI) m/z calculated for C12H11N4O3 [M + H]+ 259.0831, found
259.0834. Anal. (C12H10N4O3) C, H, N.
6.9.2. Procedure for the Synthesis of 8-Cyanomethoxyquinoline
(26). To a solution of 8-hydroxyquinoline (22) (3.00 g, 20.69 mmol)
and Cs2CO3 (13.50 g, 41.44 mmol) in DMSO (10 mL),
bromoacetonitrile (1.30 g, 10.42 mmol, 0.8 mL) was added. The
mixture was stirred at room temperature. After 30 min, another
portion of bromoacetonitrile (1.30 g, 10.42 mmol, 0.8 mL) was added.
The reaction was complete after stirring for an additional 30 min.
Water (50 mL) was subsequently added and the product extracted
with EtOAc (3× 80 mL). The combined organic phases were dried
with Na2SO4, filtered, and removed under reduced pressure. The crude
product was purified by column chromatography (EtOAc/hexane, 1/
1) to yield 3.45 g (90%); pale yellow crystals; mp 118.5−120.5 °C; IR
(KBr) υ = 3462, 2962, 2936, 2869, 2361, 1617, 1572, 1501, 1470,
6.9.5. Procedure for the Synthesis of 4-Nitronaphthalen-1-yl
Methanesulfonate (51). To a solution of 4-nitro-1-naphthol (49)
(500 mg, 2.65 mmol) in CH2Cl2 (20 mL), methanesulfonyl chloride
(600 mg, 0.53 mmol) and dry Et3N (540 mg, 0.53 mmol, 0.73 mL)
were added under argon. The reaction mixture was stirred at room
temperature for 1 h. After the completion of the reaction, the mixture
was extracted with 1 M HCl (2× 50 mL) and water (1× 50 mL), dried
with Na2SO4, and filtered, and the solvent was removed under reduced
pressure to yield 680 mg (97%) of dark yellow crystals that were used
1
1383, 1314, 1268, 1111, 820, 793, 751 cm−1; H NMR (500 MHz,
1
in the next step without further purification. H NMR (500 MHz,
CDCl3) δ 5.19 (s, 2H, OCH2), 7.31 (dd, J = 7.5, 1.0 Hz, 1H, Ar-H),
7.47−7.54 (m, 2H, Ar-H), 7.59 (dd, J = 8.5, 1.0 Hz, 1H, Ar-H), 8.19
(dd, J = 8.5, 1.5 Hz, 1H, Ar-H), 8.95 (dd, J = 4.0, 1.5 Hz, 1H, Ar-H);
13C NMR (126 MHz, CDCl3) δ 55.0, 112.5, 115.1, 122.1, 123.1, 126.4,
129.8, 136.3, 140.4, 149.9, 152.0; HRMS (ESI) m/z calculated for
C11H9N2O [M + H]+ 185.0715, found 185.0717. Anal. (C11H8N2O)
C, H, N.
6.9.3. Procedure for the Synthesis of Compounds 27 and 28. To
a cooled (0 °C) solution of KNO3 (2.75 g, 27.20 mmol) in 97%
H2SO4 (4 mL, 74.7 mmol), compound 26 (1.00 g, 5.44 mmol) was
slowly added. The reaction mixture was initially stirred for 15 min at 0
°C and then for 1 h at room temperature. After the reaction was
complete, the mixture was rapidly poured into a cold, saturated,
aqueous solution of K2CO3. The precipitate that was formed was
filtered off and washed with water, and the products 27 and 28 were
separated and purified by column chromatography (CH2Cl2/MeOH,
20/1).
8-Cyanomethoxy-5-nitroquinoline (27). Yield, 85% (1.06 g);
yellow crystals; mp 194.0−197.0 °C; IR (KBr) υ = 3443, 3098,
2951, 2889, 2361, 1618, 1563, 1505, 1464, 1395, 1327, 1301, 1242,
1177, 1102, 995, 796, 741, 710 cm−1; 1H NMR (500 MHz, DMSO-d6)
δ 5.58 (s, 2H, OCH2), 7.52 (d, J = 9.0 Hz, 1H, Ar-H), 7.89 (dd, J =
9.0, 4.0 Hz, 1H, Ar-H), 8.62 (d, J = 9.0 Hz, 1H, Ar-H), 9.01 (dd, J =
9.0, 1.5 Hz, 1H, Ar-H), 9.06 (dd, J = 4.0, 1.5 Hz, 1H, Ar-H); 13C NMR
(126 MHz, DMSO-d6) δ 54.7, 108.4, 116.0, 122.0, 125.1, 126.9, 131.9,
138.2, 138.9, 150.8, 157.0; HRMS (ESI) m/z calculated for
C11H8N3O3 [M + H]+ 230.0566, found 230.0555. Anal.
(C11H7N3O3) C, H, N.
DMSO-d6) δ 2.24 (s, 3H, OSO2CH3), 7.63 (d, J = 8.5 Hz, 1H, Ar-H),
7.75 (ddd, J = 8.5, 7.0, 1.0 Hz, 1H, Ar-H), 7.82 (ddd, J = 8.5, 7.0, 1.0
Hz, 1H, Ar-H), 8.26−8.28 (m, 2H, Ar-H), 8.62 (dd, J = 8.5, 1.0 Hz,
1H, Ar-H).
6.9.6. Procedure for the Synthesis of 4-Nitronaphthalene-1-
pyrrolidine 52. The mixture of compound 51 (100 mg, 0.38 mmol)
and pyrrolidine (133 mg, 1.87 mmol) in EtOH (2 mL) was irradiated
in the focused microwave equipment at 100 °C (80 W) for 20 min.
Following this, the volatiles were removed under reduced pressure,
and the residue was purified by silica gel radial chromatography
(EtOAc/hexane, 1/5) to yield 6 mg (7%); orange crystals; mp 123.0−
125.0 °C; IR (KBr) υ = 3424, 2921, 2854, 2432, 1847, 1578, 1560,
1528, 1480, 1431, 1412, 1306, 1273, 1250, 1149, 1132, 946, 897, 758,
732 cm−1; 1H NMR (500 MHz, CDCl3) δ 2.05−2.07 (m, 4H,
pyrrolidine-H), 3.69−3.71 (m, 4H, pyrrolidine-H), 6.63 (d, J = 9.0 Hz,
1H, Ar-H), 7.43 (ddd, J = 8.5, 7.0, 1.0 Hz, 1H, Ar-H), 7.65 (ddd, J =
8.5, 7.0, 1.0 Hz, 1H, Ar-H), 8.24 (d, J = 9.0 Hz, 1H, Ar-H), 8.40 (dd, J
= 8.5, 1.0 Hz, 1H, Ar-H), 8.97 (dd, J = 8.5, 1.0 Hz, 1H, Ar-H); 13C
NMR (126 MHz, CDCl3) δ 26.0, 29.7, 53.2, 105.6, 124.0, 124.7, 125.9,
128.4, 128.8, 129.3, 135.7, 154.0; HRMS (ESI) m/z calculated for
C14H15N2O2 [M + H]+ 243.1128, found 243.1123. Anal.
(C14H14N2O2) C, H, N.
6.9.7. Procedure for the Synthesis of 2-Bromo-4-nitro-1-amino-
naphthalene (54). To a solution of BrCN (97%, 65.5 mg, 0.6 mmol)
in dry THF (5 mL), a solution of compound 50 (188 mg, 1.0 mmol)
in dry THF (3 mL) was slowly added under argon. After 24 h of
stirring at room temperature, additional amounts of BrCN (211 mg,
2.0 mmol) were added. The reaction mixture was stirred at 60 °C until
the starting material disappeared (24 h, monitored by TLC). The
solvent was evaporated and the crude product purified by column
chromatography (EtOAc/hexane, 1/1) to yield 137 mg (52%) of
yellow solid; mp 246.0−248.0 °C (lit.52 250 °C); IR (KBr) υ = 3472,
3368, 3229, 2921, 1810, 1618, 1561, 1513, 1482, 1441, 1403, 1349,
8-Acetamidoxy-5-nitroquinoline (28). Yield, 14% (174 mg); pale
yellow crystals; mp 227.0−231.0 °C; IR (KBr) υ = 3533, 2458, 2362,
1683, 1617, 1566, 1507, 1395, 1336, 1310, 1259, 1101, 1005, 818, 745,
1
593 cm−1; H NMR (500 MHz, DMSO-d6) δ 4.87 (s, 2H, OCH2),
7.24 (d, J = 9.0 Hz, 1H, Ar-H), 7.55 (br d, 2H, NH2), 7.86 (dd, J = 9.0,
4.0 Hz, 1H, Ar-H), 8.55 (d, J = 9.0 Hz, 1H, Ar-H), 9.01−9.04 (m, 2H,
Ar-H); 13C NMR (126 MHz, DMSO-d6) δ 68.2, 108.5, 122.6, 125.4,
128.0, 132.3, 138.1, 139.2, 150.8, 159.7, 169.3; HRMS (ESI) m/z
calculated for C11H10N3O4 [M + H]+ 248.0671, found 248.0673. Anal.
(C11H9N3O4) C, H, N.
1
1274, 1157, 1041, 992, 905, 835, 760, 686, 561 cm−1; H NMR (400
MHz, DMSO-d6) δ 7.51 (br s, 2H, NH2), 7.61 (ddd, J = 8.5, 7.0, 1.0
Hz, 1H, Ar-H), 7.79 (ddd, J = 9.0, 7.0, 1.0 Hz, 1H, Ar-H), 8.47 (dd, J =
8.5, 1.0 Hz, 1H, Ar-H), 8.56 (s, 1H, Ar-H), 8.80 (dd, J = 9.0, 1.0 Hz,
1H, Ar-H); 13C NMR (100 MHz, DMSO-d6) δ 97.5, 120.9, 123.5,
K
dx.doi.org/10.1021/jm301544x | J. Med. Chem. XXXX, XXX, XXX−XXX