Journal of Medicinal Chemistry
Article
mL), water (100 mL), and brine (150 mL) and then dried (MgSO4).
The solvent was removed in vacuo and the residue recrystallized from
ethanol. 2,4-Dinitro-2′,5′-dimethoxy-4′-pentyldiphenylether 6e was
isolated as a yellow crystalline solid (4.36 g, 11.17 mmol, 92.4%);
mp 85−87 °C (Found: C, 58.3; H, 5.7; N, 7.2%. C19H22N2O7 requires
chromatography, eluting with petroleum ether (60−80 °C):EtOAc
(70:30). 2,4-Dinitrophenoxy-4′-pentyl-2′,5′-benzoquinone 8d was
isolated as a yellow solid (2.36 g, 6.56 mmol, 96.7%). Recrystallization
from EtOH produced shiny yellow plates; mp 110−114 °C (Found:
C, 56.5; H, 4.4; N, 7.7%. C17H16N2O7 requires C, 56.7; H, 4.5; N,
7.8%.); m/z 383.1 (MNa)+; νmax/cm−1 2927 (C−H), 1673 and 1649
(CO), 1610 (CC), 1530 and 1342 (NO2), 1224 (C−O); δH (300
MHz, CDCl3) 0.83 (3H, t, J = 6.9 Hz, 5″-H), 1.26−1.29 (4H, m, 3″-H
and 4″-H), 1.43−1.48 (2H, m, 2″-H), 2.38 (2H, td, J = 7.8, 1.2 Hz, 1″-
H), 6.03 (1H, s, 6′-H), 6.53 (1H, t, J = 1.5 Hz, 3′-H), 7.31 (1H, d, J =
9.0 Hz, 6-H), 8.43 (1H, dd, J = 9.0, 2.7 Hz, 5-H), 8.88 (1H, d, J = 2.7
Hz, 3-H); δC (75 MHz, CDCl3) 13.9 (CH3, 5″-C), 22.4 (CH2, 3″-C or
4″-C), 27.6 (CH2, 1″-C), 28.9 (CH2, 2″-C), 31.45 (CH2, 3″-C or 4″-
C), 116.3 (CH, 6′-C), 122.5 (CH, 3-C), 123.6 (CH, 6-C), 129.4 (CH,
5-C), 130.6 (CH, 3′-C), 140.7 (quat, 2-C), 144.5 (quat, 4-C), 151.2
(quat, 4′-C), 151.8 (quat, 1-C), 155.3 (quat, 1′-C), 180.3 (quat, 2′-C),
186.6 (quat, 5′-C).
C, 58.5; H, 5.7; N, 7.2%.); m/z 390.1 (MH)+, 413.1 (MNa)+; νmax
/
cm−1 1608 (CC), 1536 and 1342 (NO2), 1212 and 1037 (C−O);
δH (300 MHz, CDCl3) 0.96 (3H, t, J = 6.9 Hz, 5″-H), 1.39−1.43 (4H,
m, 3″-H and 4″-H), 1.62−1.67 (2H, m, 2″-H), 2.66 (2H, t, J = 7.5 Hz,
1″-H), 3.755 (3H, s, 2′-OCH3), 3.82 (3H, s, 5′-OCH3), 6.76 (1H, s,
6′-H), 6.91 (1H, s, 3′-H), 6.96 (1H, d, J = 9.3 Hz, 6-H), 8.31 (1H, dd,
J = 9.3, 2.7 Hz, 5-H), 8.87 (1H, d, J = 3.0 Hz, 3-H); δC (75 MHz,
CDCl3) 14.1 (CH3, 5″-C), 22.6 (CH2, 3″-C or 4″-C), 29.6 (CH2, 2″-
C), 30.1 (CH2, 1″-C), 31.75 (CH2, 3″-C or 4″-C), 56.1 (CH3, 5′-
OCH3), 56.9 (CH3, 2′-OCH3), 105.6 (CH, 6′-C), 115.85 (CH, 3′-C),
117.4 (CH, 6-C), 122.0 (CH, 3-C), 128.65 (CH, 5-C), 131.0 (quat, 4′-
C), 138.3 (quat, 2-C), 139.3 (quat, 1′-C), 141.0 (quat, 4-C), 144.3
(quat, 2′-C), 152.2 (quat, 5′-C), 156.6 (quat, 1-C).
4.1.5.2. 2,5-Dinitrophenoxy-4′-pentyl-2′,5′-benzoquinone 15b.
Prepared from 2,5-dinitro-2′,5′-dimethoxy-4′-pentyldiphenylether
14b (1.41 g, 3.62 mmol). The crude product was purified by column
chromatography eluting with petroleum ether (60−80 °C):EtOAc
(75:25). 2,5-Dinitrophenoxy-4′-pentyl-2′,5′-benzoquinone 15b was
isolated as a yellow solid (1.19 g, 3.31 mmol, 91.4%). Recrystallization
from EtOH produced golden prisms; mp 91−94 °C (Found: C, 56.4;
H, 4.5; N, 7.8%. C17H16N2O7 requires C, 56.7; H, 4.5; N, 7.8%.); m/z
383.2 (MNa)+; νmax/cm−1 1676 and 1651 (CO, quinone), 1603
(CC), 1544 and 1343 (NO2), 1230 (C−O); δH (300 MHz, DMSO-
d6) 0.79 (3H, t, J = 6.9 Hz, 5″-H), 1.24−1.19 (4H, m, 3″-H and 4″-H),
1.42−1.35 (2H, m, 2″-H), 2.29 (2H, t, J = 6.9 Hz, 1″-H), 6.18 (1H, s,
6′-H), 6.675 (1H, s, 3′-H), 8.23 (1H, dd, J = 9.0, 2.4 Hz, 4-H), 8.32
(1H, d, J = 9.0 Hz, 3-H), 8.41 (1H, d, J = 2.4 Hz, 6-H); δC (75 MHz,
DMSO-d6) 14.3 (CH3, 5″-H), 22.3 (CH2, 3″-C or 4″-C), 27.75 (CH2,
2″-C), 28.6 (CH2, 1″-C), 31.4 (CH2, 3″-C or 4″-C), 115.1 (CH, 6′-
C), 119.8 (CH, 6-C), 122.2 (CH, 4-C), 127.9 (CH, 3-C), 131.2 (CH,
3′-C), 145.25 (quat, 2-C), 146.7 (quat, 5-C), 150.2 (quat, 4′-C), 151.1
(quat, 1-C), 156.6 (quat, 1′-C), 181.0 (quat, 2′-C), 187.65 (quat, 5′-
C).
4.1.6. 2,4-Diacetamido-4′-pentyl-2′,5′-benzoquinone 12c. To a
solution of 2,4-dinitrophenoxy-4′-pentyl-2′,5′-benzoquinone 8d (0.46
g, 1.26 mmol) in an EtOAc:MeOH (1:1, 20 mL) was added Pd/C 5%
(10% w/w of starting material). The resulting suspension was
hydrogenated in a Berghof apparatus for 3 h at a H2 pressure of 2.4
bar. Acetic anhydride (1.20 mL, 12.6 mmol) was added as soon as the
hydrogenation was stopped, and the resulting mixture was stirred at rt
overnight. The catalyst was removed by filtration through a pad of
Celite, which was washed several times with MeOH. The filtrate was
evaporated in vacuo, NaHCO3 (5%) added to the residue, and the
resulting mixture extracted with EtOAc (2 × 60 mL). The combined
organic layers were washed with NaHCO3 (5%, 70 mL) and brine
(100 mL) and dried (MgSO4). The solvent was removed in vacuo and
the crude product purified by column chromatography on silica eluting
with petroleum ether (60−80 °C):EtOAc (90:10). 2,4-Diacetamido-
4′-pentyl-2′,5′-benzoquinone 12c was isolated as a dark-orange
crystalline solid (0.48 g, 1.24 mmol, 98.3%). Recrystallization from
hexane:EtOAc produced red prisms, mp 90−93 °C (Found: C, 65.6;
H, 6.4; N, 7.2%. C21H24N2O5 requires C, 65.6; H, 6.3; N, 7.3%.); m/z
341.0 (M − CH3CO)−, 383.0 (M − H)−; νmax/cm−1 3357 (N−H),
3269 (N−H), 2955 (C−H), 2929 (C−H), 1726 (CO), 1663 and
1647 (CO, quinone), 1599 (CC), 1206 (C−O); δH (300 MHz,
THF-d8) 0.93 (3H, t, J = 6.9 Hz, 5″-H), 1.34−1.39 (4H, m, 3″-H and
4″-H), 1.48−1.55 (2H, m, 2″-H), 2.04 (3H, s, 2-Ac or 4-Ac), 2.07
(3H, s, 2-Ac or 4-Ac), 2.40 (2H, dt, J = 7.5, 1.2 Hz, 1″-H), 5.67 (1H, s,
6′-H), 6.59 (1H, br s, 3′-H), 6.98 (1H, d, J = 8.7 Hz, 6-H), 7.91 (1H,
dd, J = 9.0, 2.1 Hz, 5-H), 8.28 (1H, d, J = 2.1 Hz, 3-H), 8.63 (1H, s, 2-
NH), 9.31 (1H, s, 4-NH); δC (75 MHz, THF-d8) 13.3 (CH3, 5″-C),
22.3 (CH2, 3″-C or 4″-C), 23.0 (CH3, 2-Ac or 4-Ac), 23.1 (CH3, 2-Ac
or 4-Ac), 27.85 (CH2, 2″-C), 28.6 (CH2, 1″-C), 31.5 (CH2, 3″-C or
4″-C), 110.8 (CH, 6′-C), 112.5 (CH, 3-C), 114.9 (CH, 5-C), 120.7
(CH, 6-C), 130.45 (CH, 3′-C), 131.3 (quat, 2-C), 137.15 (quat, 1-C),
138.2 (quat, 4-C), 149.8 (quat, 4′-C), 158.2 (quat, 1′-C), 167.7 (quat,
4.1.4. 2,5-Dinitro-2′,5′-dimethoxy-4′-pentyldiphenylether 14b.
To a solution of 2,5-dimethoxy-4-pentylphenol 4e (2.07 g, 9.25
mmol) in dry DMF (30 mL), NaH (oil dispersion 60% w/w, 0.74 g,
18.50 mmol) was added in portions; when evolution of H2 stopped, a
solution of 2,5-dinitrofluorobenzene 13 (1.72 g, 9.25 mmol) in DMF
(10 mL) was added. After 5 h at RT, the deep-red solution was heated
at 50 °C for another 5 h. The reaction was allowed to cool to RT and
quenched with brine (100 mL). The resulting mixture was extracted
with DCM (3 × 80 mL) and the combined DCM layers washed with
water (100 mL) and brine (2 × 100 mL) and then dried (MgSO4).
The solvent was removed in vacuo and the residue subjected to
column chromatography, eluting with a solvent mixture of petroleum
ether (60−80 °C):Et2O (75:25). 2,5-Dinitro-2′,5′-dimethoxy-4′-
pentyldiphenylether 14b was isolated as a bright-orange solid (1.69
g, 4.33 mmol, 46.8%). Recrystallization from EtOH produced small
yellow needles; mp 77−79 °C (Found: C, 58.3; H, 5.65; N, 7.2%.
C19H22N2O7 requires C, 58.5; H, 5.7; N, 7.2%); m/z 391.2 (MH)+,
413.2 (MNa)+; νmax/cm−1 2853−2952 (C−H), 1629 (CC), 1531
and 1347 (NO2), 1209 and 1038 (C−O); δH (300 MHz, CDCl3) 0.84
(3H, t, J = 6.9 Hz, 5″-H), 1.25−1.30 (4H, m, 3″-H and 4″-H), 1.48−
1.55 (2H, m, 2″-H), 2.54 (2H, t, J = 8.1 Hz, 1″-H), 3.63 (3H, s, 2′-
OCH3), 3.70 (3H, s, 5′-OCH3), 6.63 (1H, s, 6′-H), 6.785 (1H, s, 3′-
H), 7.53 (1H, d, J = 2.4 Hz, 6-H), 7.83 (1H, dd, J = 9.0, 2.4 Hz, 4-H),
7.93 (1H, d, J = 8.7 Hz, 3-H); δC (75 MHz, CDCl3) 14.0 (CH3, 5″-C),
22.6 (CH2, 3″-C or 4″-C), 29.6 (CH2, 2″-C), 30.1 (CH2, 1″-C), 31.8
(CH2, 3″-C or 4″-C), 56.1 (CH3, 5′-OCH3), 56.9 (CH3, 2′-OCH3),
105.6 (CH, 6′-C), 112.6 (CH, 6-C), 115.9 (CH, 3′-C), 116.25 (CH,
4-C), 126.1 (CH, 3-C), 130.8 (quat, 4′-C), 139.5 (quat, 1′-C), 142.8
(quat, 5-C), 144.4 (quat, 2′-C), 150.4 (quat, 2-C), 152.2 (quat, 5′-C),
152.4 (quat, 1-C).
4.1.5. General Procedure for the Preparation of 2,4-Dinitro- and
2,5-Dinitrophenoxybenzoquinones 8d and 15b. The appropriately
substituted dinitro-2′,5′-dimethoxydiphenylether (1 mol equivalent)
was dissolved in CH3CN (50 to 500 mL); cerium(IV) ammonium
nitrate (3 mol equiv) was dissolved in the minimum amount of water
and added slowly. The yellow solution usually darkened upon addition
of the cerium(IV) ammonium nitrate solution, followed by the
formation of a yellow precipitate soon after the addition was complete.
The resulting mixture was stirred for a further 1 h. The CH3CN was
removed under reduced pressure and, whenever possible, the
precipitate formed was collected by filtration and washed with water.
It was then redissolved in DCM, the resulting solution dried (MgSO4),
and the solvent removed in vacuo. The resulting solid was
recrystallized from ethanol. When no precipitate formed and a yellow
oil/syrup was observed instead, the reaction mixture was extracted
twice with DCM and the combined organic layers washed once with
brine and dried (MgSO4). The solvent was removed under reduced
pressure and the residue either subjected to column chromatography
or recrystallized from EtOH.
4.1.5.1. 2,4-Dinitrophenoxy-4′-pentyl-2′,5′-benzoquinone 8d.
Prepared from 2,4-dinitro-2′,5′-dimethoxy-4′-pentyldiphenylether 6e
(2.65 g, 6.79 mmol). The crude product was purified by column
I
J. Med. Chem. XXXX, XXX, XXX−XXX