G. Liu, H. Kim, P. Wang et al.
European Journal of Medicinal Chemistry 219 (2021) 113427
4
9
.1.20. (E/Z)-N-(9-((2-(2-Aminoethoxy)pyridin-3-yl)methylene)-
H-fluoren-2-yl)-2-hydroxyacetamide (30c)
To a solution of compound 29 (43 mg, 0.1 mmol) in CH Cl
2 2
7.38e7.24 (m, 2.5H), 7.21 (dd, J ¼ 8.1, 2.0 Hz, 0.5H), 7.04 (td, J ¼ 7.6,
1.1 Hz, 0.5H), 6.93 (ddd, J ¼ 9.7, 7.3, 5.0 Hz, 1H), 4.46 (q, J ¼ 5.7 Hz,
2H), 3.15 (dt, J ¼ 21.9, 5.0 Hz, 2H), 2.52 (tt, J ¼ 8.0, 4.8 Hz, 0.5H), 2.35
(tt, J ¼ 7.8, 4.8 Hz, 0.5H), 1.09 (dt, J ¼ 6.9, 3.5 Hz, 1H), 1.00 (dt, J ¼ 6.9,
(
2 mL) was added HOBt (15 mg, 0.1 mmol), EDCI (39 mg, 0.2 mmol)
13
and DMAP (2.5 mg, 0.02 mmol). The reaction was stirred at rt
overnight and then diluted with water (10 mL). The mixture was
extracted with CH
concentrated in vacuo to provide the intermediate, which was used
directly in the next step without further purification.
3
3.4 Hz, 1H), 0.90e0.80 (m, 2H). C NMR (75 MHz, CDCl ) d 160.51,
146.87, 146.80, 140.86, 140.54, 139.80, 139.59, 139.13, 138.50, 138.42,
137.30, 137.12, 136.71, 136.63, 136.23, 136.03, 135.86, 128.93, 128.58,
126.99, 126.47, 123.88, 122.74, 122.02, 121.98, 121.64, 120.60, 120.36,
120.14, 119.74, 119.46, 119.43, 118.61, 118.21, 117.33, 116.99, 114.75,
2
Cl
2
2 4
(3 ꢁ 5 mL), dried over Na SO , filtered, and
The intermediate was dissolved in CH
added TFA (342 mg, 3.0 mmol). The reaction was stirred at rt
overnight and then treated with saturated NaHCO (5 mL). The
mixture was extracted with CH Cl SO
(3 ꢁ 10 mL), dried over Na
filtered, concentrated and purified by silica gel column chroma-
tography (CH Cl /MeOH) to give 30c as a pale-yellow foam. Yield
2
Cl
2
(2 mL) was slowly
65.86, 65.06, 40.55, 40.07, 29.79, 29.69, 5.43. HRMS (ESI) calcd for
þ
C
H N
24 24 3
O
3
S, 434.1538 [M þ H] ; found, 434.1530.
3
2
2
2
4
,
4
9
.1.23. (E/Z)-3-((9-((2-(2-Aminoethoxy)pyridin-3-yl)methylene)-
H-fluoren-2-yl)amino)-3-methylbutan-1-ol (32)
2
2
Compound 31 was synthesized from 2-nitro-9H-fluorene and 3-
methylbut-3-en-1-ol following a literature procedure [31]. Yield
1
1
8 mg, 46% (two steps). H NMR (300 MHz, CDCl
3
)
d
8.88 (s, 0.35H),
8
.64 (s, 0.65H), 8.17e8.15 (m, 1H), 8.06 (d, J ¼ 1.8 Hz, 0.35H),
1
1
0
(
1
53 mg, 57%. H NMR (300 MHz, Chloroform-d)
d
7.69 (dt, J ¼ 7.6,
7.89e7.85 (m, 1.0H), 7.77e7.73 (m, 1.35H), 7.61e7.43 (m, 3.3H),
.9 Hz, 1H), 7.62 (d, J ¼ 8.1 Hz, 1H), 7.51 (dt, J ¼ 7.4, 0.9 Hz, 1H), 7.36
7
.39e7.23 (m, 2.65H), 7.06e6.92 (m, 1.35H), 4.41e4.39 (m, 2H), 4.13
td, J ¼ 7.5, 1.2 Hz, 1H), 7.25 (td, J ¼ 7.4, 1.2 Hz, 1H), 7.12 (d, J ¼ 2.0 Hz,
13
(
s, 0.7H), 4.05 (s, 1.3H), 3.02 (s, 5H). C NMR (75 MHz, CDCl
170.82, 170.62, 160.90, 160.73, 146.88, 141.06, 140.11, 139.61,
39.50, 139.25, 138.84, 137.68, 137.38, 137.11, 137.05, 136.59, 136.41,
36.00, 135.43, 128.82, 128.50, 126.72, 126.25, 123.92, 121.65, 121.37,
20.62, 120.43, 120.13, 120.10, 119.92, 119.60, 119.47, 119.33, 117.06,
3
)
H), 6.91 (dd, J ¼ 8.2, 2.1 Hz,1H), 3.96 (t, J ¼ 5.9 Hz, 2H), 3.86 (s, 2H),
.55 (S, 1H), 1.94 (t, J ¼ 5.9 Hz, 2H), 1.34 (s, 6H).
d
1
1
1
3
The synthesis of compound 32 from 31 was conducted by
following a procedure similar to that used to prepare compound 5
from compound 4. The title compound was obtained as a yellow
1
16.77, 116.02, 112.27, 67.46, 62.06, 62.02, 40.96, 40.87. HRMS (ESI)
1
foam. Yield 31 mg, 36% (two steps). H NMR (300 MHz, CDCl
3
)
þ
calcd for C23
22
H N
3
O
3
, 388.1661 [M þ H] ; found, 388.1654.
d
2
8.21e8.17 (m, 1H), 7.93 (dd, J ¼ 7.4, 1.9 Hz, 0.4H), 7.82 (dd, J ¼ 7.3,
.0 Hz, 0.6H), 7.72 (d, J ¼ 7.5 Hz, 0.6H), 7.55 (t, J ¼ 7.0 Hz, 1H),
4
9
.1.21. (E/Z)-N-(9-((2-(2-Aminoethoxy)pyridin-3-yl)methylene)-
H-fluoren-2-yl)-2-fluoropropanamide (30d)
7
(
2
.51e7.40 (m, 2.4H), 7.34e7.22 (m, 2H), 7.02e6.95 (m, 1.4H), 6.87
dd, J ¼ 8.1, 2.0 Hz, 0.4H), 6.83 (d, J ¼ 2.2 Hz, 0.6H), 6.65 (dd, J ¼ 8.2,
.2 Hz, 0.6H), 4.45e4.38 (m, 1H), 3.89 (t, J ¼ 6.2 Hz, 0.8H), 3.67 (t,
J ¼ 6.7 Hz, 1.2H), 3.24 (s, 4H), 3.07e2.98 (m, 2H), 1.94 (t, J ¼ 6.2 Hz,
Compound 30d was prepared by a procedure similar to that
used to prepare compound 30c from compound 29. The title
compound was obtained as a yellow foam. Yield 52 mg, 49% (two
13
0
(
1
1
.8H), 1.68 (t, J ¼ 6.7 Hz, 1.2H), 1.34 (s, 2.4H), 1.13 (s, 3.6H). C NMR
75 MHz, CDCl 161.01, 160.89, 146.74, 146.53, 145.50, 145.36,
41.79, 140.45, 139.87, 139.50, 139.38, 138.61, 138.39, 137.64, 137.55,
36.07, 132.90, 132.01, 128.82, 128.50, 125.56, 125.40, 123.87, 120.62,
20.36, 120.33, 120.30, 120.26, 120.19, 120.01, 119.85, 119.58, 118.92,
steps). 1H NMR (300 MHz, CDCl
8
7
)
d
8.36 (d, J ¼ 6.3 Hz, 0.5H),
.23e8.11 (m, 2H), 7.97 (dd, J ¼ 7.3, 1.9 Hz, 0.5H), 7.89e7.86 (m, 1H),
.79e7.76 (m, 0.5H), 7.65e7.61 (m, 2H), 7.55 (s, 0.5H), 7.52e7.46 (m,
3
3
) d
2
0
H), 7.39e7.27 (m, 1.5H), 7.08e7.00 (m, 1H), 6.94 (dd, J ¼ 7.3, 5.0 Hz,
1
.5H), 5.23 (q, J ¼ 6.8 Hz, 0.25H), 5.15 (q, J ¼ 6.8 Hz, 0.25H), 5.07 (q,
118.48, 116.93, 116.74, 112.95, 111.84, 67.43, 59.78, 59.10, 54.83,
J ¼ 6.8 Hz, 0.25H), 4.98 (q, J ¼ 6.8 Hz, 0.25H), 4.45e4.39 (m, 2H),
5
3.78, 43.12, 42.09, 40.91, 40.72, 29.69, 28.66, 28.42. HRMS (ESI)
3
.07e3.03 (m, 2H), 1.94 (s, 2H), 1.74 (d, J ¼ 6.8 Hz, 0.75H), 1.68e1.65
þ
calcd for C26
H
30
N
3
O
2
, 416.2338 [M þ H] ; found, 416.2328.
13
(
d
1
1
m, 1.5H), 1.59 (d, J ¼ 6.8 Hz, 0.75H). C NMR (75 MHz, CDCl
168.82,168.58,168.34,161.17,161.13,147.08,146.98,140.87,140.24,
39.55, 139.51, 139.45, 138.66, 138.17, 137.11, 136.98, 136.84, 136.58,
36.08, 135.94, 135.41, 128.79, 128.44, 126.81, 126.42, 124.05, 122.10,
22.01, 120.90, 120.46, 120.28, 120.13, 119.98, 119.61, 119.56, 119.35,
3
)
4.1.24. (E/Z)-3-((3-((2-fluoro-9H-fluoren-9-ylidene)methyl)
pyridin-2-yl)oxy)propan-1-amine (35a)
To a solution of 2-fluoronicotinaldehyde (250 mg, 2.0 mmol)
and tert-butyl (3-hydroxypropyl)carbamate (700 mg, 4.0 mmol) in
1
1
19.30, 116.80, 116.59, 116.32, 112.62, 88.93 (d, J ¼ 183 Hz), 88.85 (d,
J ¼ 184 Hz), 68.32, 68.26, 41.32, 41.21, 18.60, 18.31. HRMS (ESI) calcd
DMF (10 mL) was added Na
mixture was stirred at 110 C for 12 h, and then water (50 mL) was
2
CO
3
(424 mg, 4.0 mmol). The reaction
þ
ꢀ
for C24
H23FN
3
O
2
, 404.1774 [M þ H] ; found, 404.1761.
added. The mixture was extracted with EtOAc (3 ꢁ 20 mL), washed
4
9
.1.22. (E/Z)-N-(9-((2-(2-Aminoethoxy)pyridin-3-yl)methylene)-
H-fluoren-2-yl)cyclopropanesulfonamide (30e)
with water (3 ꢁ 20 mL), dried over Na
2 4
SO , filtered, concentrated in
vacuo and purified by silica gel column chromatography (hexane/
ethyl acetate) to give compound 34a as a colorless oil in 64% yield.
Compound 35a was prepared from 34a by a procedure similar to
that used to prepare compound 5. The title compound was ob-
2 2
To a solution of compound 29 (86 mg, 0.2 mmol) in CH Cl
(
3
mL) was added cyclopropanesulfonyl chloride (42 mg,
0
.3 mmol). The reaction mixture was stirred at rt for 2 h. Water was
1
added and the mixture was extracted with CH
dried over Na SO , filtered, concentrated in vacuo. The intermediate
was directly used in the next step without further purification.
The intermediate was dissolved in CH Cl (2 mL) was slowly
added TFA (342 mg, 3.0 mmol). The reaction was stirred at rt
overnight and then treated with saturated NaHCO (5 mL). The
mixture was extracted with CH Cl SO
(3 ꢁ 10 mL), dried over Na
filtered, concentrated and purified by silica gel column chroma-
tography (CH Cl /MeOH) to give 30e as a pale-yellow foam. Yield
7 mg, 78% (two steps). H NMR (300 MHz, CDCl
.9 Hz, 1H), 7.88 (dd, J ¼ 7.3, 1.8 Hz, 0.5H), 7.80 (dd, J ¼ 7.3, 1.8 Hz,
.5H), 7.77e7.70 (m, 1H), 7.60e7.49 (m, 3H), 7.46 (s, 0.5H),
2
Cl
2
(3 ꢁ 10 mL),
tained as a yellow solid. Yield 23 mg, 54% (two steps). H NMR
2
4
(300 MHz, CDCl
3
)
d
8.24e8.22 (m, 1H), 7.91 (dd, J ¼ 10.2, 7.4 Hz,1H),
7.80 (d, J ¼ 7.4 Hz, 0.5H), 7.66e7.47 (m, 4H), 7.40e7.29 (m, 1.5H),
2
2
7.21 (dd, J ¼ 10.2, 2.3 Hz, 0.5H), 7.10e6.95 (m, 2.5H), 4.53e4.49 (m,
13
3
2H), 2.95e2.78 (s, 4H), 2.02e1.93 (m, 2H). C NMR (75 MHz, CDCl )
3
d 164.42, 163.62, 161.34, 161.18, 160.40, 147.30, 147.17, 141.49, 141.37,
2
2
2
4
,
140.62, 139.42, 139.29, 138.38, 138.18, 138.06, 137.41, 136.69, 136.65,
136.61, 136.46, 135.13, 128.85, 128.50, 126.75, 126.31, 124.03, 122.63,
122.43, 120.66, 120.60, 120.53, 120.48, 119.52, 119.34, 119.23, 119.18,
116.54, 116.46, 115.68, 115.43, 115.37, 115.12, 111.45, 111.12, 107.98,
2
2
1
6
1
3
)
d
8.12 (dd, J ¼ 5.0,
107.66, 63.99, 63.92, 38.69, 32.04, 29.67. HRMS (ESI) calcd for
þ
0
C
22
H20FN
2
O, 347.1559 [M þ H] ; found, 347.1556.
15