788
T.P.C. Chierrito et al. / European Journal of Medicinal Chemistry 139 (2017) 773e791
®
automated flash chromatography (Biotage ), hexane: acetyl acetate
gradient, yield 7% (0.003 g).
149.5 (24), 148.8 (25), 148.4 (C10), 143.0 (C5), 130.3 (C8), 129.3 (C21
e C6), 127.1 (C7), 125.6 (C4), 124.0 (C9), 121.1 (C3), 107.4 (C26), 104.4
(C23), 65.2 (C11), 56.2 (C27), 56.1 (C28), 54.3 (C12, C16), 45.5 (C18),
38.7 (C17), 34.3 (C14), 33.3 (C19), 33.1 (C15), 31.8 (C13). HRMS (ESI):
IR: 1693; 1647; 2117 cmꢁ1. 1H NMR (400 MHz, CDCl
d
8.07e7.99
2H, m, H-9, H-6), 7.72 (1H, ddd, J ¼ 8.5, 6.9, 1.4 Hz, H-8), 7.51 (1H,
ddd, J ¼ 8.7, 4.9, 1.3 Hz, H-7), 7.48 (1H, s, H-3), 7.30 (1H, s, H-23), 6.91
3
)
(
þ
þ
m/z [M þ H ] calcd for C27
H29ClN
2
O
3
465.1939 found m/z [M þ H ]
(
3
2
1H, s, H-26), 6.69 (1H, dt, J ¼ 9.7, 1.7 Hz, H-17), 3.93 (3H, s, H-28),
465.1931.
.98 (3H, s, H-27), 3.83 (2H, s, H-11), 3.62 (2H, d, J ¼ 1.5 Hz, H-19),
.99 (2H, d, J ¼ 11.5 Hz, H-12eq, H-16eq), 2.33e2.45 (2H, m, H-13eq,
4.10.10. (E)2-((1-((4-Aminoquinolin-2-yl)methyl)piperidin-4-yl)
methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (14)
H-14), 2.26 (2H, dt, J ¼ 11,4, 3,4 Hz, 12-ax, 16-ax), 1.79e1.65 (3H, m,
1
3-ax, 15-ax, 15-eq). 13C NMR (101 MHz, CDCl
C2), 155.4 (C24), 149.5 (C25), 148.6 (C10), 146.6 (C5), 144.6 (C20),
39.7 (C17), 135.8 (C18), 130.4 (C8, C21), 128.7 (C6), 126.1 (C7),
22.2(C4, C9), 108.3(C3), 107.3 (C26), 105.1 (C23), 65.6 (C11), 56.3
3
)
d
192.6 (C22), 160.3
2
A mixture of [Pd(cinnamyl)Cl] (0.0083 g; 0.0160 mmol) and
(
1
1
BippyPhos (0.0273 g; 0.054 mol) in 1.5 mL of anhydrous dioxane,
was stirred for 5 min, at room temperature under argon protection.
After, was added NaOtBu (0.104 g; 1.08 mmol), and the chloride
intermediate 12 (0.080 g; 0.173 mmol), the mixture was stirred
(
(
4
C28), 56.2 (C27), 53.6 (C12 and C16), 37.1 (C14), 31.3 (C19), 29.7
þ
C13), 29.5 (C15). HRMS (ESI): C27
70.2187 found m/z [M þ H ] 470.2186.
H
27
N
5
O
3
m/z [M þ H ] calc
until the solubilization of 12. Then, was dropwise added a solution
þ
ꢀ
of dioxane-NH
4
OH (0.5 M), followed by heating at 110 C for 3 h.
The solvent was removed by reduced pressure, and the mixture
4.10.8. (E) 2-((1-((4-Chloroquinolin-2-yl)methyl)piperidin-4-yl)
resuspended in dichloromethane, filtered in filter PVDF 30 mm
methylene)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (12)
To a mixture of 5,6-dimethoxy-1-indanone (10) (0.0445 g;
0.45
m. After, the crude material was purified by flash chromatog-
raphy with dichoromethane:metanol gradient (0e15%). Yields 16%
(0.007 g). H NMR (300 MHz, CDCl3)
1
0
.2316 mmol) in anhydrous THF (1.5 mL) under argon protection
d
: 8.21 (1H, d, J ¼ 6.4 Hz, H-9),
was added EtONa 95% (0.0266 g; 0.3910 mmol), and stirred at room
temperature for 30 min. After, was dropwise added a solution of
aldehyde 8 (0,080 g; 0,2770 mmol) in THF (1,5 mL), and stirred for
7.99 (1H, d, J ¼ 8.3 Hz, H-6), 7.58 (1H, t, J ¼ 7.4 Hz, H-8), 7.4 (1H, t,
J ¼ 7.6 Hz, H-7), 7.19 (1H, s, H-26), 6.93 (1H, s, H-3), 6.85 (1H, s, H-
23), 6.50 (1H, d, J ¼ 9.4 Hz, H-17), 3.91 (3H, s, H-27), 3.85 (3H, s, H-
28), 3.69 (2H, s, H-11), 3.50 (2H, s, H-19), 2.86e2.75 (2H, m, H-12 eq,
H-16eq), 2.10e2.30 (3H, m, H-12ax, H-16ax, H-14), 1.66e1.46 (4H,
2
0 h. The mixture was partitioned with dichloromethane and NaCl
sat, the organic phase was concentrated under reduced pressure
and the crude material was purified by flash chromatography with
dichloromethane:ethyl acetate gradient. Yields: 86% (0,092 g);
13
3
m, H-13ax, H-13ax, H-15eq, H-15ax). C NMR (75 MHz, CDCl ) d:
191.6 (C22), 154.4 (C24), 148.5 (C25), 143.7 (C20), 138.2 (C17), 134.9
(C18), 132.2 (C21), 130.6 (C8), 124.6 (C7),121.4(C9), 122.1 (C6), 106.3
(C23), 103.9 (C26), 101.4 (C3), 61.4 (C11), 55.3 (C27), 55.1 (C28), 52.3
(C12 and C16), 35.6 (C14), 30.1 (C13 and C15), 28.7 (C19). HRMS
ꢀ
ꢁ1 1
mp:189e191 C. IR: 1688; 1656 cm . H NMR (400 MHz, CDCl
.22 (1H, d, J ¼ 9.3 Hz, H-9), 8.08 (1H, d, J ¼ 8.4 Hz, H-6), 7.80 (1H, s,
H-3), 7.75 (1H, ddd, J ¼ 8.4; 7.0; 1.4 Hz, H-8), 7.62 (1H, ddd, J ¼ 8.2;
.0; 1.0 H-7), 7.30 (1H, s, H-23), 6.91 (1H, s, H-26), 6.69 (1H, dd,
3
) d:
8
þ
þ
7
(ESI): m/z [M þ H ] calcd C27
H
29
N
3
O
3
444.2282 found m/z [M þ H ]
J ¼ 8.0; 1.7, H-17), 3.97 (3H, s, H-27), 3.93 (3H, s, H-28), 3.83 (2H, s,
444.2297.
H-11), 3.61 (2H, d, J ¼ 1.3 Hz, H-19), 2.94e3.02 (2H, m, H-16eq, H-
1
2eq), 2.32e2.42 (2H, m, H-13eq, H-14), 2.25 (2H, td, J ¼ 11.2;
4.10.11. 2-((1-((4-Aminoquinolin-2-yl)methyl)piperidin-4-yl)
methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (15)
3
.4 Hz, H-12ax, H-16ax), 1.67e1.78 (3H, m, H-13ax, H-15ax, H-
13
1
(
1
1
5eq). C NMR (400 MHz, CDCl
C14), 53.5 (C12, C16), 56.2 (C27), 56.3 (C28), 65.2 (C11),105.0 (C23),
07.2 (C26), 121.0 (C3), 124.0 (C9), 125.6 (C4), 127.1 (C7), 129.3 (C6),
30.3 (C8), 131.8 (C21), 135.8 (C18), 139.6 (C17), 143.1(C5), 144.5
C20), 148.4 (C10), 149.5 (C25), 155.3 (C24), 160.0 (C2), 192.6 (C22).
3
)
d: 29.5 (C19), 31.2 (C13, C15), 37.1
2
A mixture of [Pd(cinnamyl)Cl] (0.0083 g; 0.0160 mmol) and
BippyPhos (0.0273 g; 0.054 mol) in 1,5 mL of anhydrous dioxane,
was stirred for 5 min, at room temperature under argon protection.
After, NaOtBu was added to the mixture (104.0 mg; 1.08 mmol), and
the chloride intermediate 13 (0.022 g; 0.049 mmol) dissolved in
dioxane. Then, was dropwise added a solution of dioxane-NH
(0.5 M), followed by heating at 110 C for 5 h. The solvent was
removed by reduced pressure, and the mixture resuspended in
(
þ
HRMS (ESI): m/z [M þ H ] calcd for C27
H27ClN
2
O
3
463.1783, found
4
OH
þ
ꢀ
m/z [M þ H ] 463.1782.
4.10.9. 2-((1-((4-Chloroquinolin-2-yl)methyl)piperidin-4-yl)
dichloromethane, filtered in filter PVDF 30 mm 0.45
m. After, the
methyl)-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (13)
crude material was purified by analytical HPLC gradient methanol:
1
Under nitrogen atmosphere, the compound 12 (0.0600 g;
H
2
0 (TFA 0.1%), R
T
¼ 23 min. Yields 9% (0.002 g). H NMR (600 MHz,
12.9 mmol) was added in 1.00 mL of anhydrous pyridine and the
MeOD_ mm)
3
d
8.29 (1H, d, J ¼ 8.4 Hz, H-9), 7.95e7.89 (2H, m, H-6,
mixture was stirred for 10 min. After that was added NaBH
4
H-8), 7.70e7.62 (1H, m), 7.15 (1H, s, H-26), 7.07 (1H, s, H-23), 6.88
(1H, s, H-3), 3.94 (3H, s, MeO), 3.86 (5H, s, MeO, H-11), 3.31 (1H, m,
H-19a), 3.12e3.00 (2H, m, H-12 eq, H-16eq), 2.84e2.71 (2H, m, H-
16, H-19b), 2.43e2,36 (2H, m, H12ax, H16ax), 1.95e1.74 (2H, m, H-
13eq, H-15eq), 1.72e1.55 (1H, m, H-14), 1.53e1.33 (2H, m, H-13ax,
(
0.010 g; 0.264 mmol) in small portions, and let stirred for more
ꢀ
5
min at room temperature. Then, the mixture was heated at 60 C
ꢀ
for 20 min, cooled until 0 C, and at this point added 3 mL of a HCl
(
5%) solution and stirred for more 20 min. The mixture was parti-
13
tioned with dichloromethane. The solvent was removed by reduced
pressure, and the crude material was purified by flash chroma-
tography with dichoromethane:ethyl acetate gradient. Yields: 57%
H15ax). C NMR (151 MHz, MeOD) d 210.7(C22), 160.0(C4),
157.7(C24), 151.5(C24), 150.9(C21), 140.8(C10), 135.1(C8),
129.8(C20), 127.6(C7), 124.2(C9), 121.3(C6), 117.3(C5), 108.9(C23),
105.1(C3),102.8(C26), 60.5(C11), 56.7(C28), 56.4(C27), 54.9(C12 and
ꢀ
1
(
34.6 mg); mp: 159e160 C. H NMR (400 MHz, CDCl
dd, J ¼ 8.4, 0.9 Hz, H-9), 8.07 (1H, d, J ¼ 8.5 Hz, H-6), 7.78 (1H, s, H-
), 7.74 (1H, ddd, J ¼ 8.4, 6.9, 1.4 Hz, H-8), 7.61 (1H, ddd, J ¼ 8.2, 6.9,
.2 Hz, H-7), 7.17 (1H, s, H-23), 6.86 (1H, s, H-26), 3.96 (3H, s, H-28),
.90 (3H, s, H-27), 3.79 (2H, s, H-11), 3.25 (1H, dd, J ¼ 17.6, 8.1 Hz, H-
9a), 2.93 (2H, t, J ¼ 10.0 Hz, H-12eq, H-16eq), 2.78e2.67 (2H, m, H-
9b), 2.16 (2H, t, J ¼ 11.4 Hz, H-12ax, H-16ax), 2.00e1.89 (1H, m, H-
7a), 1.83e1.3 (6H, m, H-17b, H-14, H-13ax, H-15ax, H-13eq, H-
3
): 8.21 (1H,
C16), 46.5(C18), 39.6(C17), 34.0(C19), 33.5(C14), 32.2(C13 and C15).
þ
3
1
3
1
1
1
1
HRMS (ESI): m/z [M þ H ] calcd C27
31 3 3
H N O 446.2438 found m/z
þ
[M þ H ] 446.2414.
Author contributions
a
T.P.C.C. and I.C. performed the organic synthesis of compounds;
13
a
b
b,f
b
5eq). C NMR (101 MHz, CDCl
3
)
d
: 207.8 (C22), 155.5 (C2, C20),
S.P.M.; F.J.C.; J.J.B. contributed with the STD-NMR studies; C.R.;