Journal of Medicinal Chemistry
Article
MHz, chloroform-d) δ 145.4, 144.5, 144.2, 132.8, 130.2, 128.2, 127.4,
126.7, 125.9, 125.6, 119.4, 113.0, 67.8, 37.3, 28.5, 21.9.
129.3, 127.8, 126.6, 125.4, 125.0, 122.9, 115.3, 80.5, 67.4, 67.4, 37.0,
28.2, 21.6.
Synthesis of (E)-2-(2-(2-Nitro-5-(4-nitrostyryl)phenoxy)ethoxy)-
ethyl-4-methylbenzene-sulfonate 23 (Scheme 4). To an oven-dried
100 mL round-bottom flask purged with argon and fitted with a
magnetic stirring bar was added sodium hydride (0.80 g, 2.0 mmol,
60% dispersion in mineral oil). The flask was purged with argon, and
dry DMF 2.0 mL was added. The diethyl (4-nitrobenzyl) phosphonate
(15, 0.30 g, 1.1 mmol) was dissolved in dry DMF (2.0 mL), and the
NaH-DMF mixture was transferred via syringe to a flask. The mixture
was then stirred under argon at 0 °C for 1 h. The tosylated 4-
nitrobenzaldehyde (4, 0.360 g 1.0 mmol) was dissolved in dry DMF (2
mL) and added to the reaction mixture via syringe under argon at 0
°C. The reaction was stirred again for 2 h at 0 °C in the dark under
argon. The reaction was quenched with 25 mL of ice cold water, and
the compound precipitated out. It was then filtered under vacuum,
washed with water several times followed by diethyl ether, and used for
the next step without further purification. The yellow amorphous
(E)-2-(5-(4-((tert-Butoxycarbonyl)(ethyl)amino)styryl)-2-
nitrophenoxy)ethyl-4-methylbenzenesulfonate (17). The yellow
sticky solid product was eluted in a silica flash column with 15%
EtOAc:hexane. The yellow amorphous product yield 0.125 (40%). 1H
NMR (400 MHz, chloroform-d) δ 7.87 (d, J = 8.5 Hz, 1H), 7.84−7.80
(m, 2H), 7.50 (d, J = 8.5 Hz, 2H), 7.38−7.33 (m, 2H), 7.24 (d, J = 8.5
Hz, 2H), 7.22−7.19 (m, 1H), 7.18−7.16 (m, 1H), 7.11 (d, J = 1.7 Hz,
1H), 7.00 (d, J = 16.3 Hz, 1H), 4.48−4.35 (m, 4H), 3.70 (q, J = 7.1
Hz, 2H), 2.44 (s, 3H), 1.46 (s, 9H), 1.17 (t, J = 7.1 Hz, 3H). 13C NMR
(101 MHz, chloroform-d) δ 152.3, 145.4, 144.1, 143.1, 133.5, 132.7,
132.5, 130.1, 128.1, 127.4, 127.1, 126.7, 126.0, 119.3, 112.9, 80.50,
67.7, 67.6, 45.0, 28.5, 21.8, 14.1.
(E)-2-(5-(4-((tert-Butoxycarbonyl)(propyl)amino)styryl)-2-
nitrophenoxy)ethyl-4-methylbenzenesulfonate (18). The yellow
crystalline compound was eluted on a silica flash column in 15%
EtOAc:hexane. Yield 0.165 g (35%). 1H NMR (400 MHz, chloroform-
d) δ 7.87 (d, J = 8.5 Hz, 1H), 7.85−7.79 (m, 2H), 7.50 (d, J = 8.4 Hz,
2H), 7.35 (dt, J = 7.9, 0.7 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 7.21−7.19
(m, 1H), 7.18−7.16 (m, 1H), 7.11 (d, J = 1.7 Hz, 1H), 7.00 (d, J =
16.2 Hz, 1H), 4.46−4.37 (m, 4H), 3.67−3.57 (m, 2H), 2.44 (s, 3H),
1.60 (s, 1H), 1.57 (s, 1H), 1.45 (s, 9H), 0.89 (t, J = 7.4 Hz, 3H). 13C
NMR (101 MHz, chloroform-d) δ 152.3, 145.4, 144.1, 133.5, 132.7,
132.5, 130.1, 128.1, 127.4, 127.3, 126.7, 126.0, 119.3, 112.9, 80.5, 67.7,
67.6, 51.6, 28.5, 21.9, 21.8, 11.3.
(E)-2-(5-(4-((tert-Butoxycarbonyl)(isopropyl)amino)styryl)-2-
nitrophenoxy)ethyl-4-methylbenzenesulfonate (19). The yellow
amorphous compound was eluted on a silica flash column in 15%
EtOAc:hexane, yield 0.065 g (30%). 1H NMR (500 MHz, chloroform-
d) δ 7.87 (dd, J = 8.5, 2.0 Hz, 1H), 7.84−7.79 (m, 2H), 7.53−7.48 (m,
2H), 7.35 (d, J = 7.8 Hz, 2H), 7.23−7.17 (m, 2H), 7.14−7.09 (m,
3H), 7.06−7.00 (m, 1H), 4.57−4.46 (m, 1H), 4.42 (h, J = 4.3, 3.7 Hz,
4H), 2.44 (s, 3H), 1.39 (s, 9H), 1.13 (dd, J = 6.9, 2.0 Hz, 6H). 13C
NMR (126 MHz, chloroform-d) δ 154.9, 152.4, 145.4, 144.1, 140.2,
138.8, 134.8, 132.8, 132.6, 130.5, 130.2, 128.2, 127.3, 126.7, 126.5,
119.5, 113.1, 80.1, 67.8, 67.8, 28.6, 21.9, 21.8.
1
compound was dried under high vacuum, yield 0.390 g (80%). H
NMR (400 MHz, DMSO-d6) δ 8.31−8.25 (m, 2H), 7.95 (d, J = 8.4
Hz, 1H), 7.92−7.87 (m, 2H), 7.79−7.74 (m, 2H), 7.68 (d, J = 16.5
Hz, 1H), 7.64−7.55 (m, 2H), 7.42 (dd, J = 9.1, 3.0 Hz, 3H), 4.30 (t, J
= 4.6 Hz, 2H), 4.19−4.09 (m, 2H), 3.79−3.62 (m, 4H), 2.37 (s, 3H).
13C NMR (101 MHz, DMSO) δ 151.8, 146.7, 144.8, 143.1, 142.6,
138.5, 132.3, 131.2, 130.4, 130.1, 127.8, 127.6, 125.9, 124.2, 119.4,
113.1, 70.0, 69.1, 68.5, 68.2, 21.1.
(E)-2-(2-(2-Fluoroethoxy)ethoxy)-1-nitro-4-(4-nitrostyryl)benzene
(24). Compound (23, 0.15 g, 0.28 mmol) and Kryptofix 2.2.2. (K222
,
0.33 g, 0.85 mmol) with CsF (0.09 g, 0.57 mmol) as the source of
fluoride-19 were mixed together in a 100 mL round-bottom flask in
dry acetonitrile (20 mL), and the reaction was purged with argon. The
reaction mixture was heated at 80 °C for 4 h and monitored by TLC.
Once the reaction was complete, acetonitrile was evaporated under
reduced pressure, and the reaction was quenched with ice cold water.
The dark brown precipitate was filtered under vacuum and washed
with water several times and diethyl ether once. The light brown
amorphous product yield was 0.090 g, and 84% was used with further
purification. 1H NMR (400 MHz, chloroform-d) δ 8.26 (d, J = 8.3 Hz,
2H), 7.92 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 1.6
Hz, 1H), 7.25−7.18 (m, 3H), 4.60 (dt, J = 47.8, 4.0 Hz, 2H), 4.37 (t, J
= 4.7 Hz, 2H), 3.99 (t, J = 4.6 Hz, 2H), 3.88 (dt, J = 30.1, 3.8 Hz, 3H).
13C NMR (101 MHz, chloroform-d) δ 170.4, 156.3, 153.2, 136.1,
135.6, 134.5, 131.1, 131.1, 131.0, 130.5, 127.7, 127.6, 126.7, 124.5,
119.4, 117.5, 113.6, 105.3, 94.6, 86.6 (d, JC−F = 164 Hz), 70.1 (JC−F, J =
43 Hz). 19F NMR (376 MHz, chloroform-d) δ −100.01.
(E)-2-(5-(4-((tert-Butoxycarbonyl)(sec-butyl)amino)styryl)-2-
nitrophenoxy)ethyl-4-methylbenzenesulfonate (20). The yellow
sticky solid was eluted in 10% EtOAc:hexane, yield 0.040 g (15%).
1H NMR (400 MHz, chloroform-d) δ 7.88 (d, J = 8.5 Hz, 1H), 7.85−
7.80 (m, 2H), 7.53−7.49 (m, 2H), 7.37−7.33 (m, 2H), 7.23−7.20 (m,
1H), 7.18 (d, J = 1.9 Hz, 1H), 7.15−7.10 (m, 3H), 7.02 (d, J = 16.3
Hz, 1H), 4.45−4.38 (m, 4H), 4.23 (d, J = 7.0 Hz, 1H), 2.44 (s, 3H),
1.67−1.58 (m, 1H), 1.40 (s, 9H), 1.37−1.32 (m, 1H), 1.12 (d, J = 6.8
Hz, 3H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, chloroform-d)
δ 152.3, 145.4, 144.0, 134.6, 132.7, 132.5, 130.2, 130.1, 130.1, 128.1,
127.2, 126.7, 126.4, 119.4, 113.0, 80.1, 67.7, 67.7, 66.8, 55.2, 28.7, 28.5,
21.8, 19.7, 11.6.
(E)-4-(4-Aminostyryl)-2-(2-(2-fluoroethoxy)ethoxy)aniline (25).
To a 100 mL round-bottom flask with a magnetic stirring bar was
added tin(II) chloride (0.285 g, 1.5 mmol). (E)-2-(2-(2-fluoroethoxy)-
ethoxy)-1-nitro-4-(4-nitrostyryl)benzene (24, 0.050 g, 0.15 mmol) was
added to the tin(II) chloride solution of ethyl acetate (15 mL) and
ethanol (10 mL). The reaction mixture was refluxed under a water-
cooled condenser in an oil bath at 70 °C and stirred overnight open to
air. The reaction was monitored via TLC and after completion of the
reaction was cooled to room temperature, and the solvent was
removed by vacuum. The compound was dissolved in aq Na2CO3
(20%) until bubbles stopped forming and was washed with ethyl
acetate 3 times (30 mL × 3), water (50 mL × 2), followed by brine
(50 mL). The organic layer was dried over the MgSO4, filtered, and
concentrated to give the crude 25. The crude product was dissolved in
minimal DCM and purified on silica by flash column chromatography
with a mobile phase of EtOAc:hexane, and 25 was eluted in 10−15%
(E)-2-(2-Nitro-5-(4-nitrostyryl)phenoxy)ethyl-4-methylbenzene-
sulfonate (21). A yellow amorphous precipitate formed after
quenching with water and was then washed several times with water
and diethyl ether. The yellow amorphous product yield was 0.150 g
1
(75%). H NMR (400 MHz, DMSO-d6) δ 8.31−8.25 (m, 2H), 7.93
(d, J = 8.4 Hz, 1H), 7.91−7.86 (m, 2H), 7.79−7.74 (m, 2H), 7.65 (d, J
= 16.5 Hz, 1H), 7.60−7.52 (m, 2H), 7.42 (t, J = 8.2 Hz, 3H), 4.50−
4.34 (m, 4H), 2.39 (s, 3H). 13C NMR (101 MHz, DMSO) δ 151.7,
147.4, 145.7, 143.7, 143.2, 139.1, 132.6, 131.7, 131.1, 130.8, 128.5,
128.4, 128.2, 128.1, 126.5, 126.5, 124.8, 124.8, 124.7, 120.4, 113.6,
69.2, 67.6, 21.8.
1
(E)-2-(5-(4-((tert-Butoxycarbonyl)(methyl)amino)styryl)-2-
nitrophenoxy)ethyl-4-methylbenzenesulfonate (22). The yellow
crystalline compound was purified over a silica flash column in 20%
EtOAc:hexane, yield 0.240 g (50%). 1H NMR (500 MHz, chloroform-
d) δ 7.96 (s, 1H), 7.82 (d, J = 8.1 Hz, 2H), 7.62 (dd, J = 8.6, 2.2 Hz,
1H), 7.46 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.27 (s, 2H),
7.07−7.02 (m, 2H), 6.97 (d, J = 16.3 Hz, 1H), 4.45−4.33 (m, 4H),
3.29 (s, 3H), 2.46 (s, 3H), 1.49 (s, 9H). 13C NMR (126 MHz,
chloroform-d) δ 154.5, 150.3, 145.1, 143.6, 133.2, 132.3, 131.5, 129.9,
EtOAc:hexane yielding a sticky brown solid, yield 0.02 g, (49%). H
NMR (400 MHz, chloroform-d) δ 7.28−7.24 (m, 2H), 6.95 (d, J = 1.8
Hz, 1H), 6.90 (dd, J = 8.0, 1.8 Hz, 1H), 6.78 (s, 2H), 6.66−6.63 (m,
2H), 6.62 (d, J = 1.9 Hz, 1H), 4.68−4.61 (m, 1H), 4.57−4.49 (m,
1H), 4.27−4.15 (m, 2H), 3.90−3.86 (m, 2H), 3.86−3.80 (m, 2H),
3.79−3.72 (m, 3H). 13C NMR (101 MHz, chloroform-d) δ 146.2,
145.3, 136.1, 128.61, 128.4, 127.1, 125.3, 125.0, 120.4, 115.1, 115.0,
110.1, 81.8 (d, JC−F = 171 Hz), 69.4 (d, JC−F = 21.0 Hz). 19F NMR
(376 MHz, chloroform-d) δ −89.8 − −90.7 (m), −100.0.
3714
J. Med. Chem. 2016, 59, 3705−3718