C. J. A. Ribeiro et al. / Bioorg. Med. Chem. xxx (2016) xxx–xxx
5
tion through Celite and the filtrate evaporated to afford compound
7 (lit. 39) as a dark colored oil; 421.5 mg (99% yield); 1H NMR
(300 MHz, CDCl3) d (ppm): 8.60 (dd, J = 4.2, 1.6 Hz, 1H), 7.94 (dd,
J = 8.3, 1.6 Hz, 1H), 7.31 (dd, J = 8.3, 4.2 Hz, 1H), 6.58 (d,
J = 2.6 Hz, 1H), 6.47 (d, J = 2.6 Hz, 1H), 4.99 (br s, 2H), 3.87 (s, 3H).
(49.0 mg, 0.150 mmol, 50% yield). Mp 138–139 °C; IR (KBr, selected
peaks): 3726, 2962, 1813, 1723, 1589, 1526, 1345 cmÀ1 1H NMR
;
(300 MHz, Acetone-d6) d (ppm): 9.60 (br s, 1H, NH), 8.71 (dd,
J = 4.2, 1.6 Hz, 1H, HAr), 8.24 (dd, J = 8.4, 1.6 Hz, 1H, HAr), 7.91 (d,
J = 2.4 Hz, 1H, HAr), 7.55 (dd, J = 8.4, 4.2 Hz, 1H, HAr), 7.05 (d,
J = 2.4 Hz, 1H, HAr), 4.87 (t, J = 6.5 Hz, 2H, OCH2CH2), 3.94 (s, 3H,
OCH3), 1.95–1.83 (m, 2H, OCH2CH2), 1.63–1.48 (m, 2H, CH2CH3),
1.01 (t, J = 7.4 Hz, 3H, CH2CH3).13C NMR (75 MHz, Acetone-d6) d
(ppm): 188.19 (C@O), 185.54 (C@O), 180.47 (Cq), 169.39 (Cq),
159.18 (CqAr), 147.32 (CHAr), 136.16 (CHAr), 135.55 (CqAr), 135.32
(CqAr), 130.52 (CqAr), 123.69 (CHAr), 108.19 (CHAr), 101.32 (CHAr),
74.78 (OCH2), 56.12 (OCH3), 32.73 (CH2), 19.30 (CH2), 13.93
(CH3). MS (ESI) m/z calcd for C18H18N2O4: 326, found 327 [M+H]+.
4.2. General procedure for compounds 5a–b, 5e
A reaction mixture of 8-amino-6-methoxyquinoline derivative
7
or 11 (1 equiv), 3,4-dibutoxy-3-cyclobutene-1,2-dione (8a,
1.2 equiv) in dry methanol (1 ml/mmol of compound 7 or 11)
was heated at reflux for 16–24 h, under nitrogen atmosphere.
The solvent was removed under reduced pressure and the crude
product was purified by flash chromatography on silica gel using
as eluent a gradient from n-hexane (100%) to n-hexane/EtOAc
(1:2), followed by preparative TLC (n-Hexane/EtOAC 2:1).
4.3. General procedure for compounds 5c–d
A reaction mixture of 8-amino-6-methoxyquinoline derivative
4.2.1. 3-Butoxy-4-({3-[(6-methoxyquinolin-8-yl)amino]propyl}
amino)cyclobut-3-ene-1,2-dione (5a)
Following the general procedure, starting with 11a (50.0 mg,
0.216 mmol), 8a (56 lL, 0,259 mmol) in 2.2 ml of dry methanol
11
(1.0 equiv),
3,4-dibutoxy-3-cyclobutene-1,2-dione
(8a,
1.2 equiv), and NEt3 (1.0 equiv) in dry butanol (1 ml/mmol of com-
pound 11) was heated at reflux for 48 h, under nitrogen atmo-
sphere. The solvent was removed under reduced pressure and
the residue obtained dissolved in EtOAc. The mixture was then
washed with water (2Â), dried over anhydrous Na2SO4, and the
solvent removed under reduced pressure. The crude product was
purified by flash chromatography on silica gel using as eluent a
gradient from n-hexane (100%) to n-hexane/EtOAc (1:2), followed
by preparative TLC (n-Hexane/EtOAC 2:1).
(reaction time: 24 h), compound 5a was obtained as brown oil
(32.3 mg, 0.084 mmol, 39% yield). IR (KBr, selected peaks): 2928,
1802, 1701, 1597, 1522 cmÀ1 1H NMR (300 MHz, Acetone-d6) d
;
(ppm): 8.52 (dd, J = 4.2, 1.5 Hz, 1H, HAr), 8.04 (d, J = 8.3 Hz, 1H,
Ar), 7.88–7.58 (m, 1H, NH), 7.38 (dd, J = 8.3, 4.2 Hz, 1H, HAr),
H
6.48 (d, J = 2.4 Hz, 1H, HAr), 6.45 (br s, 1H, NH), 6.29 (d, J = 2.4 Hz,
1H, HAr), 4.69–4,54 (m, 2H, OCH2CH2), 3.86 (s, 3H, OCH3), 3.86–
3.77 (m, 1H, NH2, partially obscured by OCH3 signal), 3.72–3.60
(m, 1H, NCH2), 3.47 (q, J = 6.4 Hz, 1H, NCH2), 2.16–2.07 (m, 2H,
CH2), 1.79–1.59 (m, 2H, OCH2CH2), 1.48–1.30 (m, 2H, CH2CH3),
0.87 (t, J = 7.2 Hz, CH2CH3); 13C NMR (75 MHz, Acetone-d6) d
(ppm): 189.90 (C@O), 183.92 (C@O), 177.82 (Cq), 173.98 (Cq),
160.49 (CqAr), 146.63 (CqAr), 145.11 (CHAr), 136.18 (CqAr), 135.48
(CHAr), 130.81 (CqAr), 122.79 (CHAr), 97.06 (CHAr), 92.69 (CHAr),
73.38 (CH2-butoxi), 55.45 (OCH3), 43.09 (NCH2), 40.58 (NCH2),
32.69 (CH2-butoxi), 30.55 (CH2), 19.21 (CH2-butoxi), 13.90 (CH3). MS
(ESI) m/z calcd for C21H25N3O4 383, found 384 [M+H]+.
4.3.1. 3-Butoxy-4-({2-[(6-methoxyquinolin-8-yl)amino]ethyl}
amino)cyclobut-3-ene-1,2-dione (5c)
Following the general procedure, starting with 11c (51.4 mg,
0.237 mmol), 8a (61 lL, 0.284 mmol), and NEt3 (33 lL,
0.237 mmol) in 2.4 mL of dry butanol, compound 5c was obtained
as brown oil (39.1 mg, 0.106 mmol, 45% yield). IR (KBr, selected
peaks): 3254, 2930, 1802, 1701, 1597, 1522 cmÀ1
;
1H NMR
(300 MHz, Acetone) d (ppm): 8.50 (dd, J = 4.2, 1.6 Hz, 1H, HAr),
8.05 (d, J = 8.3, 1H, HAr), 7.87–7.70 (m, 1H, NH), 7.38 (dd, J = 8.3,
4.2 Hz, HAr), 6.66 (br s, 1H, NH), 6.51 (s, 1H, HAr), 6.41 (s, 1H,
HAr), 4.65–4.46 (m, 2H, OCH2CH2), 4.02–3.91 (m, 1H, NCH2), 3.87
4.2.2. 3-Butoxy-4-({3-[(6-methoxyquinolin-8-yl)amino]butyl}
amino)cyclobut-3-ene-1,2-dione (5b)
Following the general procedure, starting with 11b (44.1 mg,
0.180 mmol), 8a (47 lL, 0,216 mmol) in 1.8 ml of dry methanol
(s, 3H, OCH3), 3.84–3.73 (m, 1H, NCH2), 3.72–3.61(m, 2H, NCH2),
1.77–1.58 (m, 2H, OCH2CH2), 1.47–1.31 (m, 2H, CH2CH3), 0.90
(dd, J = 7.4 Hz, CH2CH3); 13C NMR (75 MHz, Acetone-d6) d (ppm):
189.82 (C@O), 183.87 (C@O), 177.91 (Cq), 174.28 (Cq), 160.47
(CqAr), 146.34 (CqAr), 145.19 (CHAr), 136.20 (CqAr), 135.49 (CHAr),
130.84 (CqAr), 122.84 (CHAr), 97.36 (CHAr), 93.06 (CHAr), 73.39
(CH2-butoxi), 55.49 (OCH3), 44.12 (NCH2), 44.01 (NCH2), 32.59
(CH2-butoxi), 19.21 (CH2-butoxi), 13.93 (CH3). MS (ESI) m/z calcd for
(reaction time: 24 h), compound 5b was obtained as brown oil
(15.0 mg, 21% yield). IR (KBr, selected peaks): 2926, 1802, 1701,
1605, 1522 cmÀ1 1H NMR (300 MHz, Acetone-d6) d (ppm): 8.52
;
(dd, J = 4.2, 1.5 Hz, 1H, HAr), 8.04 (dd, J = 8.3, 1.3 Hz, 1H, HAr), 7.67
(br s, 1H, NH), 7.38 (dd, J = 8.3, 4.2 Hz, 1H, Ar), 6.48 (d,
H
C
20H23N3O4: 369, found 370 [M+H]+.
J = 2.5 Hz, 1H, HAr), 6.29 (d, J = 2.5 Hz, 1H, HAr), 6.17 (d, J = 8.9 Hz,
1H, NH), 4.66–4.32 (m, 2H, OCH2CH2), 3.94–3.75 (m, 5H, OCH3,
CH, NCH2), 3.73–3.56 (m, 1H, NCH2), 2.15–1.95 (m, CHCH2, par-
tially obscured by acetone) 1.78–1.49 (m, 2H, OCH2CH2), 1.40–
1.24 (m, 5H, CH2CH3, CHCH3), 0.96–0.78 (m, 3H, CH2CH3). 13C
4.3.2. 3-Butoxy-4-({5-[(6-methoxyquinolin-8-yl)amino]pentyl}
amino)cyclobut-3-ene-1,2-dione (5d)
Following the general procedure, starting with 11d (153.4 mg,
0.591 mmol), 8a (153 lL, 0.284 mmol), and NEt3 (82 lL,
NMR (75 MHz, Acetone-d6)
d
(ppm): 189.89 (C@O), 183.84
0.591 mmol) in 5.9 mL of dry butanol, compound 5d was obtained
as light brown semi-solid (84.9 mg, 0.206 mmol, 35% yield). IR
(KBr, selected peaks): 3257, 2933, 1807, 1703, 1613, 1519,
(C@O), 177.74 (Cq), 173.84 (Cq), 160.48 (CqAr), 145.80 (CqAr),
145.07 (CHAr), 136.18 (CqAr), 135.53 (CHAr), 130.92 (CqAr), 122.80
(CHAr), 97.42 (CHAr), 92.61 (CHAr), 73.27 (CH2-butoxi), 55.46
(OCH3), 46.15 (CH), 42.58 (NCH2), 38.17 (CH2), 32.56 (CH2-butoxi),
20.89 (CHCH3), 19.18 (CH2-butoxi), 13.88 (CH3-butoxi). MS (ESI) m/z
calcd for C22H27N3O4: 397, found 398 [M+H]+.
1349 cmÀ1 1H NMR (300 MHz, Acetone-d6) d (ppm): 8.51 (dd,
;
J = 4.2, 1.6 Hz, 1H, HAr), 8.04 (dd, J = 8.3, 1.6 Hz, 1H, HAr), 7.74–
7.48 (m, 1H, NH), 7.37 (dd, J = 8.3, 4.2 Hz, 1H, HAr), 6.47 (d,
J = 2.5 Hz, 1H, HAr), 6.30 (br s, 1H, NH), 6.27 (d, J = 2.5 Hz, 1H,
HAr), 4.72–4,59 (m, 2H, OCH2CH2), 3.86 (s, 3H, OCH3), 3.75–3.63
4.2.3. 3-Butoxy-4-[(6-methoxyquinolin-8-yl)amino]cyclobut-3-
ene-1,2-dione (5e)
(m, 1H, NCH2), 3.58–3.44 (m, 1H, NCH2), 3.38–3.27 (m, 2H,
NCH2), 1.87–1.67 (m, 6H, 2NCH2CH2, OCH2CH2), 1.65–1.50 (m,
2H, CH2), 1.50–1.35 (m, 2H, CH2CH3), 0.92 (t, J = 7.4 Hz, 3H, CH2-
CH3). 13C NMR (75 MHz, Acetone-d6) d (ppm): 189.99 (C@O),
183.85 (C@O), 177.77 (Cq), 173.94 (Cq), 160.56 (CqAr), 146.85
Following the general procedure, starting with 7 (52,7 mg,
0.303 mmol), 8a (79
lL, 0,364 mmol) in 3.0 ml of dry methanol
(reaction time: 16 h), compound 5e was obtained as a yellow solid