Synthesis of 1,4-Benzodiazepine-2,5-dione Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 211
4.05 (s, 1H), 3.80 (s, 3H), 3.73-3.61 (m, 1H), 1.95-1.55
(m, 2H), 1.44 (d, J ) 6.7, 2H), 0.98 (t, J ) 6.6, 3H); 13C
NMR (101 MHz, CDCl3) δ 170.51, 165.56, 151.69, 138.39,
134.82, 132.42, 132.23, 131.02, 130.65, 129.25, 122.71,
121.43, 117.18, 109.64, 66.58, 56.42, 51.28, 50.90, 30.21,
20.10, 13.79; ESI-MS m/z 871(MH+).
(d, J ) 11.3, 1H), 1.91 (d, J ) 11.7, 3H), 1.82-1.67 (m,
2H), 1.50 (m, 3H), 1.26-1.10 (m, 1H); 13C NMR (101 MHz,
CDCl3) δ 171.32, 165.92, 151.51, 138.16, 138.02, 135.55,
134.53, 132.59, 126.78, 125.57, 122.48, 119.53, 117.30,
109.80, 60.61, 56.36, 55.61, 31.25, 30.21, 25.65, 25.46,
25.16; ESI-MS m/z 898(MH+).
4-(4-(Benzo[d][1,3]dioxol-5-ylmethyl)-2,5-dioxo-2,3,4,5-
tetrahydro-1H-benzo[e][1,4]diazepin-3-yl)phenyl perfluo-
rooctylsulfonate 6{1,1,2}. Yield 63%. 1H NMR (400
MHz, CDCl3) δ 8.82 (s, 1H), 7.74 (d, J ) 7.7, 1H), 7.23 (t,
J ) 7.5, 1H), 7.00 (ddd, J ) 25.1, 16.6, 8.4, 7H), 6.79 (d,
J ) 7.8, 1H), 6.73 (d, J ) 7.9, 1H), 5.94 (s, 1H), 5.90 (t, J
) 4.6, 1H), 5.41 (s, 1H), 5.03 (d, J ) 14.3, 1H), 4.93 (d, J
) 14.2, 1H); 13C NMR (101 MHz, CDCl3) δ 170.40, 166.87,
148.93, 148.28, 147.76, 133.82, 132.49, 131.20, 129.70,
127.54, 126.58, 125.26, 122.72, 121.39, 119.85, 109.37,
108.51, 101.26; ESI-MS m/z 885(MH+).
4-(7-Chloro-4-cyclohexyl-2,5-dioxo-2,3,4,5-tetrahydro-
1H-benzo[e][1,4]diazepin-3-yl)phenyl perfluorooctylsul-
fonate 6{3,1,4}. Yield 52%. 1H NMR (400 MHz, CDCl3) δ
8.08 (s, 1H), 7.66 (t, J ) 3.5, 1H), 7.22-7.15 (m, 2H), 7.12
(dd, J ) 8.5, 2.5, 1H), 7.10-7.03 (m, 2H), 6.60 (d, J ) 8.6,
1H), 5.47 (s, 1H), 4.96 (tt, J ) 12.2, 3.5, 1H), 2.00 (d, J )
10.8, 1H), 1.89 (d, J ) 10.7, 3H), 1.78-1.61 (m, 2H),
1.56-1.32 (m, 3H), 1.22-1.07 (m, 1H); 13C NMR (101
MHz, CDCl3) δ 170.95, 165.29, 149.05, 134.58, 132.14,
132.01, 130.85, 130.77, 129.76, 126.58, 121.61, 121.14,
60.39, 55.63, 31.23, 30.09, 25.65, 25.44, 25.18; ESI-MS m/z
867(MH+).
4-(4-(Benzo[d][1,3]dioxol-5-ylmethyl)-8-chloro-2,5-dioxo-
2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-yl)phenyl
perfluorooctylsulfonate 6{4,1,2}. Yield 60%. 1H NMR (400
MHz, CDCl3) δ 8.70 (s, 1H), 7.60 (d, J ) 8.5, 1H), 6.92 (d,
J ) 14.2, 6H), 6.84 (d, J ) 7.3, 1H), 6.75-6.62 (m, 2H),
5.85 (s, 1H), 5.82 (d, J ) 1.1, 1H), 5.32 (s, 1H), 4.93 (d, J
) 14.3, 1H), 4.81 (d, J ) 14.4, 1H); 13C NMR (101 MHz,
CDCl3) δ 170.41, 166.06, 149.12, 148.31, 147.84, 138.40,
134.89, 133.62, 132.64, 129.41, 126.51, 125.86, 125.53,
122.76, 121.61, 119.63, 109.31, 108.52, 101.29, 65.06, 53.96;
ESI-MS m/z 919(MH+).
4-(4-(3,4-Dimethoxyphenethyl)-2,5-dioxo-2,3,4,5-tet-
rahydro-1H-benzo[e][1,4]diazepin-3-yl)-2-methoxyphe-
nyl perfluorooctylsulfonate 6{1,2,5}. Yield 65%. 1H NMR
(400 MHz, CDCl3) δ 8.27 (s, 1H), 7.74 (d, J ) 7.5, 1H),
7.25 (t, J ) 7.5, 1H), 7.08 (t, J ) 7.2, 1H), 7.04-6.93 (m,
1H), 6.84 (dd, J ) 13.2, 8.6, 3H), 6.72 (d, J ) 7.8, 3H),
5.44 (s, 1H), 4.31 (s, 1H), 4.04-3.92 (m, 1H), 3.89 (t, J )
9.9, 6H), 3.82-3.66 (m, 3H), 3.13 (s, 1H), 3.07-2.94 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 170.52, 166.83, 151.46,
149.01, 147.84, 138.18, 134.91, 133.60, 132.51, 130.99,
130.07, 127.72, 125.42, 122.43, 120.84, 119.96, 117.28,
111.99, 111.38, 109.73, 100.00, 66.89, 56.31, 55.91, 55.88,
52.75, 34.02; ESI-MS m/z 945(MH+).
4-(4-(Benzo[d][1,3]dioxol-5-ylmethyl)-7,8-dimethoxy-
2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]diazepin-3-
yl)-2-methoxyphenyl perfluorooctylsulfonate 6{2,2,2}.
1
Yield 64%. H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H),
7.09 (s, 1H), 7.04 (s, 1H), 6.89 (d, J ) 6.6, 1H), 6.83 (d, J
) 8.4, 1H), 6.69 (d, J ) 7.8, 1H), 6.50 (d, J ) 7.6, 1H),
6.36 (s, 1H), 6.09 (s, 1H), 5.91-5.79 (m, 2H), 5.28 (s, 1H),
5.18 (d, J ) 14.1, 1H), 4.51 (d, J ) 14.3, 1H), 3.82-3.66
(m, 6H), 3.58 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 170.26,
166.62, 152.56, 151.39, 148.27, 147.72, 146.65, 138.01,
135.26, 130.06, 128.48, 122.86, 122.15, 119.52, 116.95,
112.04, 109.80, 109.56, 108.54, 102.71, 101.27, 65.60, 56.21,
56.16, 53.98, 35.62; ESI-MS m/z 975(MH+).
4-(4-Cyclohexyl-7,8-dimethoxy-2,5-dioxo-2,3,4,5-tetrahy-
dro-1H-benzo[e][1,4]diazepin-3-yl)-2-methoxyphenyl per-
1
fluorooctylsulfonate 6{2,2,4}. Yield 64%. H NMR (400
MHz, CDCl3) δ 8.16 (s, 1H), 7.08 (s, 1H), 6.90 (d, J ) 8.3,
1H), 6.66 (d, J ) 10.2, 2H), 6.03 (s, 1H), 5.36 (s, 1H), 4.89
(dd, J ) 16.3, 7.7, 1H), 3.83-3.56 (m, 9H), 1.91 (d, J )
10.7, 1H), 1.81 (d, J ) 11.2, 3H), 1.71-1.52 (m, 2H), 1.37
(ddd, J ) 20.0, 14.8, 7.9, 3H), 1.09 (t, J ) 13.1, 1H); 13C
NMR (101 MHz, CDCl3) δ 170.91, 166.36, 152.24, 151.32,
146.65, 137.96, 136.19, 127.76, 122.25, 120.65, 117.22,
112.19, 109.73, 102.48, 60.74, 56.33, 56.14, 56.11, 55.42,
31.29, 30.28, 25.72, 25.52, 25.24; ESI-MS m/z 923(MH+).
General Procedure for the Synthesis of Compounds
8. To a reaction tube with a stirring bar was added compound
6 (0.033 mmol), 7 (0.028 mmol), Pd(pddf)Cl2 (1.0 mg), and
K2CO3 (9.0 mg, 0.066 mmol) in 900 µL of a 4:4:1 acetone/
toluene/H2O solvent. The reactions took place automatically
in a monomode microwave cavity (150 °C, 20 min) of a
Biotage Initiator single mode microwave reactor. HPLC was
used to monitor the reaction. After reaction completion, the
reaction mixture was washed with 0.8 mL of water, and the
organic layer was loaded onto a 2 g FluoroFlash SPE
cartridge directly and washed with 4:1 MeOH/H2O. The non-
fluorous fractions were collected and concentrated. Finally,
the fluorous fraction was eluted by MeOH for the reuse of
cartridge.
3-(Biphenyl-4-yl)-4-butyl-7,8-dimethoxy-3,4-dihydro-
1H-benzo[e][1,4]diazepine-2,5-dione 8{2,1,1,1}. Yield 56%.
1H NMR (400 MHz, CDCl3) δ 7.95 (d, J ) 23.4, 1H), 7.40
(d, J ) 7.5, 2H), 7.32 (t, J ) 7.6, 4H), 7.25 (dd, J ) 8.4,
6.1, 1H), 7.15 (s, 1H), 7.08 (d, J ) 7.1, 2H), 6.05 (s, 1H),
5.31 (s, 1H), 4.04 (s, 1H), 3.71 (d, J ) 14.9, 6H), 3.61 (ddd,
J ) 13.7, 7.3, 3.7, 1H), 1.71-1.54 (m, 2H), 1.37 (dd, J )
14.7, 7.4, 2H), 0.91 (t, J ) 7.3, 3H); ESI-MS m/z 445(MH+);
HR-MS calcd for C27H29N2O4 (M+H)+ 445.2127, found
445.2124.
4-(8-Chloro-4-cyclohexyl-2,5-dioxo-2,3,4,5-tetrahydro-
1H-benzo[e][1,4]diazepin-3-yl)-2-methoxyphenyl perfluo-
rooctylsulfonate 6{4,2,4}. Yield 77%. 1H NMR (400 MHz,
CDCl3) δ 8.44 (s, 1H), 7.65 (d, J ) 8.5, 1H), 7.01 (dd, J )
8.5, 2.0, 2H), 6.73 (dd, J ) 7.9, 6.0, 3H), 5.48 (s, 1H), 4.98
(ddd, J ) 12.0, 7.8, 3.6, 1H), 3.82 (d, J ) 10.3, 3H), 2.01
4-Benzyl-3-(biphenyl-4-yl)-7,8-dimethoxy-3,4-dihydro-
1H-benzo[e][1,4]diazepine-2,5-dione 8{2,1,3,1}. Yield 24%.
1H NMR (400 MHz, CDCl3) δ 7.43 (s, 3H), 7.35 (s, 2H),
7.30 (s, 5H), 7.23 (s, 4H), 6.92 (s, 2H), 6.03 (s, 1H), 5.36