Journal of Medicinal Chemistry
Article
2,2-Dimethyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
chroman-4-one (61h). The procedure used for the preparation of
compound 61c was used with 60h (200 mg, 0.76 mmol). The crude
residue was purified by flash chromatography on SiO2 using AcOEt/
petroleum ether (5:95 to 30:70). A yellow solid was obtained (m =
293 mg, quantitative). 1H NMR (CDCl3, ppm): δ 8.34 (d, J = 1.7 Hz,
1H), 7.86 (dd, J = 8.3 and 1.7 Hz, 1H), 6.89 (d, J = 8.3 Hz, 1H), 1.44
(s, 6H), 1.31 (s, 12H).
and 1.1 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 3.41−3.37 (m, 2H), 2.99−
2.95 (m, 2H).
6-(4-Oxo-1,2,3,4-tetrahydroquinolin-6-yl)picolinic Acid (62g).
Procedure D was followed using 6-bromopicolinic acid (24 mg, 0.12
mmol) and 61g (40 mg, 0.15 mmol). A brown solid was obtained (m
1
= 23 mg, 57%). H NMR (DMSO-d6, ppm): δ 8.40 (d, J = 2.3 Hz,
1H), 8.15 (dd, J = 8.8 and 2.3 Hz, 1H), 8.04 (dd, J = 8.0 and 1.2 Hz,
1H), 7.96 (t, J = 7.5 Hz, 1H), 7.19 (br s, 1H), 6.89 (d, J = 8.8 Hz, 1H),
3.53−3.48 (m, 2H), 2.62−2.57 (m, 2H).
4-Methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-di-
hydronaphthalen-1(2H)-one (61i). The procedure used for the
preparation of compound 61c was used with 60i (170 mg, 0.71
mmol). The crude residue was purified by flash chromatography on
SiO2 using AcOEt/petroleum ether (0:100 to 10:90). An off-white
6-(2,2-Dimethyl-4-oxochroman-6-yl)picolinic Acid (62h). Proce-
dure E was followed using 6-bromopicolinic acid (148 mg, 0.78 mmol)
and 61h (266 mg, 0.88 mmol). A white solid was obtained (m = 131
1
mg, 60%). H NMR (DMSO-d6, ppm): δ 8.52 (d, J = 2.2 Hz, 1H),
1
solid was obtained (m = 130 mg, 64%). H NMR (CDCl3, ppm): δ
8.38 (dd, J = 8.7 and 2.5 Hz, 1H), 8.18 (dd, J = 7.9 and 1.1 Hz, 1H),
8.04 (t, J = 7.7 Hz, 1H), 7.96 (dd, J = 7.6 and 1.1 Hz, 1H), 7.14 (d, J =
8.7 Hz, 1H), 2.78 (s, 2H), 1.44 (s, 6H).
8.46 (d, J = 1.4 Hz, 1H), 7.89 (dd, J = 7.7 and 1.4 Hz, 1H), 7.29 (d, J =
7.7 Hz, 1H), 3.12−3.01 (m, 1H), 2.82−2.71 (m, 1H), 2.62−2.52 (m,
1H), 2.27−2.16 (m, 1H), 1.92−1.81 (m, 1H), 1.36 (d, J = 7.1 Hz,
1H), 1.31 (s, 12H).
6-(5-Methyl-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)picolinic
Acid (62i). Procedure D was followed using 6-bromopicolinic acid (70
mg, 0.35 mmol) and 61i (130 mg, 0.45 mmol). A light-brown solid
6-(1-Ethyl-4-oxo-1,2,3,4-tetrahydroquinolin-6-yl)picolinic Acid
(62a). Procedure D was followed using 6-bromopicolinic acid (48
mg, 0.44 mmol) and 61a (88 mg, 0.29 mmol). A white solid was
1
was obtained (m = 28 mg, 28%). H NMR (DMSO-d6, ppm): δ 8.62
(d, J = 2.1 Hz, 1H), 8.37 (dd, J = 8.1 and 2.1 Hz, 1H), 8.22 (dd, J = 7.8
and 1.2 Hz, 1H), 8.07 (t, J = 7.7 Hz, 1H), 8.00 (dd, J = 7.7 and 1.2 Hz,
1H), 7.60 (d, J = 8.4 Hz, 1H), 3.22−3.13 (m, 1H), 2.83−2.73 (m,
1H), 2.69−2.58 (m, 1H), 2.28−2.17 (m, 1H), 1.93−1.81 (m, 1H),
1.40 (d, J = 7.0 Hz, 1H).
1
obtained (m = 49 mg, 57%). H NMR (CDCl3, ppm): δ 8.50 (d, J =
2.2 Hz, 1H), 8.13.(dd, J = 9.0 and 2.5 Hz, 1H), 8.08 (dd, J = 6.7 and
1.8 Hz, 1H), 8.00−7.93 (m, 2H), 6.89 (d, J = 9.2 Hz, 1H), 3.61−3.58
(m, 2H), 3.56 (q, J = 7.1 Hz, 2H), 2.80−2.76 (m, 2H), 1.26 (t, J = 7.1
Hz, 3H). LCMS m/z 297.2 [M + 1].
6-(4-(2-(Benzothiazol-2-yl)hydrazono)-1-ethyl-1,2,3,4-tetrahy-
droquinolin-6-yl) picolinic Acid (63a). Procedure B was followed
using compound 62a (30 mg, 0.1 mmol) and 2-hydrazinylbenzothia-
zole (17 mg, 0.1 mmol). A light-brown solid was obtained (m = 26 mg,
6-(9-Oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)picolinic
Acid (62b). Procedure D was followed using 6-bromopicolinic acid (83
mg, 0.41 mmol) and 61b (137 mg, 0.48 mmol). A light-brown solid
1
1
was obtained (m = 50 mg, 46%). H NMR (DMSO-d6, ppm): δ 8.33
59%). H NMR (DMSO-d6, ppm): δ 8.73 (d, J = 2.3 Hz, 1H), 8.06
(d, J = 2.0 Hz, 1H), 8.23 (dd, J = 7.9 and 2.1 Hz, 1H), 8.17 (dd, J = 7.8
and 1.1 Hz, 1H), 8.03 (t, J = 7.7 Hz, 1H), 7.96 (dd, J = 7.6 and 1.1 Hz,
1H), 7.42 (d, J = 8.0 Hz, 1H), 2.99−2.95 (m, 2H), 2.73−2.69 (m,
2H), 1.82−1.67 (m, 4H). LCMS m/z 282.1 [M + 1].
(dd, J = 8.8 and 2.3 Hz, 1H), 8.03−7.99 (m, 2H) 7.89 (dd, J = 6.1 and
2.4 Hz, 1H), 7.70 (br d, J = 7.8 Hz, 1H), 7.29−7.24 (m, 2H), 7.09−
7.04 (m, 1H), 6.93 (d, J = 8.9 Hz, 1H), 3.50 (q, J = 7.1 Hz, 2H), 3.36
(t, J = 6.8 Hz, 2H), 2.93 (t, J = 6.3 Hz, 2H), 1.13 (t, J = 7.0 Hz, 1H).
LCMS m/z 444.2 [M + 1]. HRMS calculated mass, 444.1489 [M + 1];
measured, 444.1487 [M + 1].
General Procedure E: 6-(7-Methyl-8-oxo-5,6,7,8-tetrahydronaph-
thalen-2-yl)picolinic Acid (62c). 6-Bromopicolinic acid (146 mg, 0.72
mmol), 61c (268 mg, 0.94 mmol), Pd(PPh3)2Cl2 (22 mg, 4 mol %),
and 348 μL of a 2 M sodium carbonate aqueous in 1.3 mL of a 1:1:1
mixture of water/DME/EtOH solution were stirred at 90 °C for 6 h.
After this time, the reaction was concentrated. The residue was
partitioned in a mixture of water/AcOEt. The aqueous phase was
extracted three times with AcOEt. The combined organic layers were
washed with water and brine and dried over Na2SO4 and concentrated.
The residues was purified by flash chromatography using SiO2
(petroleum ehter/AcOEt 5:95 to 50:50). An off-white solid was
obtained (m = 100 mg, 49%). 1H NMR (DMSO-d6, ppm): δ 8.62 (d, J
= 2.0 Hz, 1H), 8.34 (dd, J = 8.0 and 2.0 Hz, 1H), 8.22 (dd, J = 7.7 and
1.1 Hz, 1H), 8.07 (t, J = 7.7 Hz, 1H), 8.00 (dd, J = 7.6 and 1.1 Hz,
1H), 7.50 (d, J = 8.1 Hz, 1H), 3.18−2.97 (m, 2H), 2.77−2.65 (m,
1H), 2.23−2.15 (m, 1H), 1.91−1.77 (m, 1H), 1.19 (d, J = 6.8 Hz,
1H).
6-(6-Methyl-8-oxo-5,6,7,8-tetrahydronaphthalen-2-yl)picolinic
Acid (62d). Procedure D was followed using 6-bromopicolinic acid
(120 mg, 0.6 mmol) and 61d (222 mg, 0.77 mmol). A cream solid was
obtained (m = 84 mg, 39%). 1H NMR (DMSO-d6, ppm): δ 8.59 (d, J
= 1.9 Hz, 1H), 8.19 (td, J = 6.8 and 1.8 Hz, 2H), 8.10−8.02 (m, 2H),
7.44 (d, J = 8.0 Hz, 1H), 3.12−3.06 (m, 1H), 2.87−2.73 (m, 2H),
2.44−2.34 (m, 2H), 1.19 (d, J = 6.2 Hz, 3H).
6-(9-(2-(Benzothiazol-2-yl)hydrazono)-6,7,8,9-tetrahydro-5H-
benzo[7]annulen-2-yl)picolinic Acid (63b). Procedure B was followed
using compound 62b (27 mg, 0.1 mmol) and 2-hydrazinylbenzothia-
zole (15 mg, 0.1 mmol). A light-brown solid was obtained (m = 15 mg,
1
35%). H NMR (DMSO-d6, ppm): δ 8.19 (d, J = 1.9 Hz, 1H), 8.13
(dd, J = 7.9 and 1.1 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 8.04 (t, J = 7.6
Hz, 1H), 7.96 (dd, J = 7.5 and 1.1 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H),
7.35−7.30 (m, 2H), 7.23 (td, J = 6.2 and 1.2 Hz, 1H), 7.03 (td, J = 7.8
and 1.2 Hz, 1H), 2.80−2.74 (m, 4H), 1.77−1.73 (m, 2H), 1.64−1.60
(m, 2H). LCMS m/z 427.0 [M − 1]. HRMS calculated mass,
429.1380 [M + 1]; measured, 429.1383 [M + 1].
6-(8-(2-(Benzothiazol-2-yl)hydrazono)-7-methyl-5,6,7,8-tetrahy-
dronaphthalen-2-yl)picolinic Acid (63c). Procedure B was followed
using compound 62c (50 mg, 0.18 mmol) and 2-hydrazinylbenzo-
thiazole (29 mg, 0.18 mmol). A white solid was obtained (m = 38 mg,
1
49%). H NMR (DMSO-d6, ppm): δ 8.87 (d, J = 1.9 Hz, 1H), 8.15−
8.08 (m, 2H), 8.08 (dd, J = 8.0 and 2.0 Hz, 1H), 8.01 (dd, J = 6.5 and
2.2 Hz, 1H), 7.71 (d, J = 7.9 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.29−
7.24 (m, 2H), 7.10−7.05 (m, 1H), 3.65−3.63 (m, 1H), 3.10−2.98 (m,
1H), 2.82−2.76 (m, 1H), 2.02−1.82 (m, 2H), 1.15 (d, J = 7.1 Hz,
1H). LCMS m/z 429.3 [M + 1]. HRMS calculated mass, 429.1380 [M
+ 1]; measured, 429.1383 [M + 1].
6-(4-Oxochroman-6-yl)picolinic Acid (62e). Procedure D was
followed using 6-bromopicolinic acid (395 mg, 1.98 mmol) and 61e
(700 mg, 2.55 mmol). A cream solid was obtained (m = 434 mg, 81%).
1H NMR (DMSO-d6, ppm): δ 8.55 (d, J = 2.1 Hz, 1H), 8.38 (dd, J =
8.8 and 2.4 Hz, 1H), 8.18 (dd, J = 7.9 and 1.2 Hz, 1H), 8.04 (t, J = 7.7
Hz, 1H), 7.96 (dd, J = 7.6 and 1.1 Hz, 1H), 7.19 (d, J = 8.7 Hz, 1H),
4.62 (m, 2H), 2.87 (m, 2H).
6-(8-(2-(Benzothiazol-2-yl)hydrazono)-6-methyl-5,6,7,8-tetrahy-
dronaphthalen-2-yl)picolinic Acid (63d). Procedure B was followed
using compound 62d (50 mg, 0.18 mmol) and 2-hydrazinylbenzo-
thiazole (29 mg, 0.18 mmol). A white solid was obtained (m = 53 mg,
1
69%). H NMR (DMSO-d6, ppm): δ 8.81 (d, J = 1.7 Hz, 1H), 8.16−
8.09 (m, 2H), 8.07 (dd, J = 8.0 and 1.9 Hz, 1H), 8.02 (dd, J = 6.8 and
1.9 Hz, 1H), 7.73 (d, J = 7.7 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H), 7.28 (t,
J = 7.1 Hz, 1H), 7.09 (t, J = 8.0 Hz, 1H), 3.16 (dd, J = 17.6 and 3.7 Hz,
1H), 2.89 (dd, J = 15.4 and 2.4 Hz, 1H), 2.61−2.51 (m, 1H), 2.31−
2.22 (m, 1H), 2.08−1.94 (m, 1H), 1.10 (d, J = 6.5 Hz, 1H). LCMS m/
z 427.0 [M − 1]. HRMS calculated mass, 429.1380 [M + 1];
measured, 429.1378 [M + 1].
6-(4-Oxothiochroman-6-yl)picolinic Acid (62f). Procedure D was
followed using 6-bromopicolinic acid (67 mg, 0.33 mmol) and 61f
(125 mg, 0.43 mmol). A light-brown solid was obtained (m = 40 mg,
1
33%). H NMR (DMSO-d6, ppm): δ 8.73 (d, J = 2.0 Hz, 1H), 8.28
(dd, J = 8.4 and 2.2 Hz, 1H), 8.06 (t, J = 7.4 Hz, 1H), 7.99 (dd, J = 7.7
U
dx.doi.org/10.1021/jm400556w | J. Med. Chem. XXXX, XXX, XXX−XXX