D. Audisio et al. / European Journal of Medicinal Chemistry 52 (2012) 44e50
49
654, 615, 583, 559. Anal. Calcd for C34H39N5O6S (645.77): C 63.24, H
6.09, N 10.84, found: C 62.91, H 6.27, N 10.44; 1H NMR (300 MHz,
CDCl3,
6.4.2. 3-(4-(4-Methoxyphenyl)-1H-1,2,3-triazol-1-yl)-1-methylq
uinolin-2(1H)-one (8b)
d
, ppm): 7.94 (d, 1H, J ¼ 8.3 Hz), 7.77 (d, 2H, J ¼ 8.3 Hz), 7.62
Brown solid (91%); m.p. 200e202 ꢀC. Rf ¼ 0.29 (CH2Cl2). 1H NMR
(dd, 1H, J1 ¼ 8.1 Hz, J2 ¼ 1.2 Hz), 7.52e7.40 (m, 3H), 7,32e7,26 (m,
5H); 7.13 (t, 1H, J ¼ 8.0 Hz), 4.46 (t, 2H, J ¼ 6.6 Hz), 3.67 (s, 3H), 2.39
(s, 3H), 2.09 (t, 2H, J ¼ 7.9 Hz), 1.78 (q, 2H, J ¼ 8.0 Hz), 1,54e1,41 (m,
(CDCl3, 300 MHz,
d
, ppm):
d
¼ 8.93 (s, 1H), 8.54 (s, 1H), 7.78 (d, 2H,
J ¼ 8.8 Hz), 7.68 (dd, 1H, J1 ¼ 8.0, J2 ¼ 1.0 Hz), 7,60 (m, 1H), 7.38 (d,
1H, J ¼ 8.5 Hz), 7.29 (m, 1H), 6.91 (d, 2H, J ¼ 8.8 Hz), 3.80 (s, 3H),
4H), 1,36e1,18 (m, 10H). 13C NMR (75 MHz, CDCl3,
d
ppm): 170.7,
3.78 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz,
d, ppm):
d
¼ 159.6,
160.2, 145.8 (2C), 144.8, 136.9, 133.9, 130.8, 129.9 (2C), 128.2 (2C),
127.9, 127.5, 124.6, 124.3, 123.0, 120.2, 119.7, 117.5, 114.0, 108.7, 81.0,
36.4, 30.4, 29.4, 29.3 (2C), 29.2 (2C), 28.0, 25.6, 25.0, 21.8; MS
(APCIþ) m/z: 646.2 [M þ H]þ.
156.5, 147.4, 138.7, 131.6, 129.8, 127.2 (2C), 126.7, 123.4, 123.1, 120.3,
119.2, 114.3, 114.2 (3C), 55.3, 30.3 ppm. MS (APCIþ): m/z ¼ 333.0
[M þ H]þ. IR:
n
e¼ 1650, 1597, 1470, 1245, 1021 cmꢃ1. Anal. Calcd for
C19H16N4O2 (332): C 68.66, H 4.85; N 16.86; found: C 68.97, H 4.99;
N 17.13.
6.3. General procedure for the preparation of 3-(N-substituted)
aminoquinolinones 7
6.4.3. 3-(4-(4-Fluorophenyl)-1H-1,2,3-triazol-1-yl)-1-methylqu
inolin-2(1H)-one (8c)
A
flame-dried resealable Schlenk tube was charged with
Yellow solid (60%); m.p. 228e230 ꢀC. Rf ¼ 0.24 (CH2Cl2). 1H NMR
Pd(OAc)2 (7.5 mg, 0.05 mmol, mol%), Xantphos (29 mg,
5
(CDCl3, 300 MHz,
d
, ppm):
d
¼ 9.00 (s, 1H), 8.57 (s, 1H), 7.84 (m, 1H),
0.05 mmol, 5 mol%), the solid reactant(s) (1.0 mmol of the bro-
moquinolin-2(1H)-one 6, 1.5 mmol of appropriate amine or amide)
and Cs2CO3 (651 mg, 2 mmol). The Schlenk tube was capped with
a rubber septum, evacuated and backfilled with argon; this evac-
uation/backfill sequence was repeated one additional time. The
liquid reactant(s) and 1,4-dioxane (2 mL) were added through the
septum. The septum was replaced with a teflon screwcap. The
Schlenk tube was sealed, and the mixture was stirred at 100 ꢀC for
10 h. The resulting suspension was cooled to room temperature and
filtred through celite eluting with ethyl acetate, and the inorganic
salts were removed. The filtrate was concentrated and purification
of the residue through a silica gel column chromatography gave the
expected product 7.
7.70 (d,1H, J ¼ 7.8 Hz), 7.62 (t,1H, J ¼ 7.2 Hz), 7.60 (s, 1H), 7.41 (d,1H,
J ¼ 8.4 Hz), 7.31 (t, 1H, J ¼ 7.1 Hz), 7.08 (t, 2H, J ¼ 8.8 Hz), 3.82 (s, 3H)
ppm. 13C NMR (CDCl3, 75 MHz,
d, ppm):
d
¼ 163.5, 160.2, 155.7,
145.8, 137.9, 130.8, 129.1, 129.1, 126.8, 126.6, 125.8, 122.6, 120.0,
118.4, 115.1, 114.8, 113.5, 29.5 ppm. MS (APCIþ): m/z ¼ 321.0
[M þ H]þ. IR:
n
¼ 1650, 1597, 1495, 1648, 1402, 1216, 1044, 809,
755 cmꢃ1 Anal. Calcd for C18H13FN4O (320.10): C 67.49 H 4.09 N
17.49; found: 67.98 H 4.61 N 17.91.
6.4.4. 3-(4-(4-(Dimethylamino)phenyl)-1H-1,2,3-triazol-1-yl)-1-
methylquinolin-2(1H)-one (8d)
Yellow solid (75%); m.p. 210e212 ꢀC. Rf ¼ 0.84 (CH2Cl2). 1H NMR
(CDCl3, 300 MHz,
d
, ppm):
d
¼ 8.95 (d, 1H, J ¼ 1.9 Hz), 8.62 (s, 1H),
7.84e7.75 (m, 3H), 7.67 (t, 1H, J ¼ 7.9 Hz), 7.46 (d, 1H, J ¼ 8.4 Hz),
6.3.1. 4-Methoxy-N-(6-methoxy-1-methyl-2-oxo-1,2-
dihydroquinolin-3-yl)benzamide (7c)
7.36; (t, 1H, J ¼ 7.5 Hz), 6.81 (d, 2H, J ¼ 8.5 Hz), 3.88 (s, 3H), 3.00 (s,
6H) ppm. 13C NMR (CDCl3, 75 MHz,
d
, ppm):
d
¼ 156.6, 150.4, 148.0,
Brown solid (77%); m.p.: 181e183 ꢀC; TLC: Rf: 0.69 (CH2Cl2); IR
(neat, cmꢃ1): 1690, 1597, 1529, 1496, 1367, 1317, 1236, 1174, 1030,
899, 843, 755, 622; 1H NMR (300 MHz, CDCl3): 9.33 (s, 1H), 8.78 (s,
1H), 7.91 (d, 2H, J ¼ 8.7 Hz), 7.26e7.24 (m, 1H), 7.08e7.04 (m, 2H),
6.97 (d, 2H, J ¼ 8.7 Hz), 3.86 (s, 3H), 3.84 (s, 3H), 3.78 (s, 3H). 13C
NMR (75 MHz, CDCl3): 165.2, 162.7, 157.5, 155.3, 129.9, 129.1 (2C),
128.3, 126.4, 121.9, 119.5, 117.1, 115.1, 113.9 (2C), 110.1, 55.5, 55.4,
30.3; MS (APCIþ) m/z: 339.0 [M þ H]þ.
138.7, 131.4, 129.8, 129.6, 126.8 (2C), 123.3, 119.5, 119.3, 118.6, 114.3,
112.5 (2C), 40.5 (2C), 30.3 ppm (one carbon is missed). (APCIþ): m/
z ¼ 346.0 [M þ H]þ. IR:
n
¼ 1656, 1597, 1224, 1022, 806, 764 cmꢃ1
.
Anal. Calcd for C20H1çNO (345.0): C 69.55, H 5.54, N 20.28; found: C
69.98, H 5.89, N 20.97.
Acknowledgements
The CNRS is gratefully acknowledged for financial support of
this research. We thank the European Union (EU) within the EST
network BIOMEDCHEM (MEST-CT-2005-020580) for a Ph.D. grant
to D. A., fellowship for L. C. and for financial support. Region Ile-de-
France is also acknowledged for support. Thanks also A. Solgadi for
performing mass spectra analysis (SAMM platform, Châtenay
eMalabry). Our laboratory BioCIS-UMR 8076 is a member of the
laboratory of Excellence LERMIT supported by a grant from ANR
(ANR-10-LABX-33).
6.4. General procedure for the preparation of triazoles 8
A flame-dried resealable 2e5 mL Pyrex reaction vessel was
charged with the solid reactant(s): CuTc (10 mol%), 3-
azidoquinolin-2(1H)-one 6d (1 mmol), alkyne (2 mmol) in EtOH
(6 mL). The reaction vessel was capped with a Teflon screwcap. The
reaction vessel was sealed, and then heated at 40 ꢀC (time: see
experimental section). The resulting suspension was cooled to
room temperature, filtered and washed with H2O and c-hexane to
afford the expected triazoles 8.
References
6.4.1. 1-Methyl-3-(4-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-
yl)quinolin-2(1H)-one (8a)
[2] S.L. Croft, G.H. Coombs, Trends Parasitol. 19 (2003) 502e508.
[3] A. Al-Qahtani, Y.M. Siddiqui, A.A. Bekhit, O.A. El-Sayed, H.Y. Aboul-Enein,
M.N. Al-Ahdal, Saudi Pharm. J. 17 (2009) 231e237.
[4] H.W. Murray, J.D. Berman, C.R. Davies, N.G. Saravia, Lancet 366 (2005) 1561.
[5] P.K. Sinha, K. Pandey, S.K. Bhattacharya, Indian J. Med. Res. 121 (2005)
407.
[6] WHO. Control of the Leishmaniases. Report of a meeting of the WHO Expert
Committee on the Control of Leishmaniases, Geneva, 22e26, March 2010.
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[8] (a) S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami, Anti-Cancer Agents Med.
Chem. 8 (2008) 761e782;
Brown solid (64%); m.p. 191e193 ꢀC. Rf ¼ 0.38 (CH2Cl2/EtOAc
9:1).1H NMR (CDCl3, 300 MHz,
d
, ppm):
d
¼ 9.01 (s,1H), 8.57 (s,1H),
7.70 (d, 1H, J ¼ 8.0 Hz), 7.59 (m, 1H), 7.40 (d, 1H, J ¼ 8.5 Hz), 7.31 (t,
1H, J ¼ 7.5 Hz), 7.10 (s, 1H), 6.67 (d, 1H, J ¼ 10.0 Hz), 3.88 (s, 6H), 3.83
(s, 3H), 3.82 (s, 3H) ppm. 13C NMR (CDCl3, 75 MHz, d, ppm):
d
¼ 156.5, 153.6 (2C), 153.1, 147.4, 138.7, 131.7, 129.9, 126.5, 126.0,
123.5, 120.9, 119.2, 114.4, 109.7, 102.9 (2C), 61.0, 56.2, 56.1, 30.3 ppm.
MS (APCIþ): m/z ¼ 393.0 [M þ H]þ. IR:
n
¼ 1651, 1593, 1471, 1235,
1126, 1002 cmꢃ1. Anal. Calcd for C21H20N4O4 (392.14): C 64.28, H
5.14, N 14.28; found: C 64.97, H 5.69, N 14.77.
(b) S. Messaoudi, J.-F. Peyrat, J.-D. Brion, M. Alami, Expert Op. Th. Pat. 21
(2011) 1501e1542.