Use of cyclohexylisocyanide and methyl 2-isocyanoacetate as convertible isocyanides for microwave-assisted fluorous synthesis of 1,4-benzodiazepine-2,5- dione library

Article abstract of DOI:10.1021/cc900157w

A new protocol in which cyclohexylisocyanide and methyl 2-isocyanoacetate are used as convertible isocyanides for Ugi/de-Boc/cyclization/Suzuki synthesis of biaryl-substituted 1,4-benzodiazepine-2,5-diones has been developed. Ugi reactions of Boc-protecte

Full text of DOI:10.1021/cc900157w

206
J. Comb. Chem. 2010, 12, 206–214
Use of Cyclohexylisocyanide and Methyl 2-Isocyanoacetate as
Convertible Isocyanides for Microwave-Assisted Fluorous Synthesis of
1,4-Benzodiazepine-2,5-dione Library
Hongyu Zhou,†,‡ Wei Zhang,§ and Bing Yan*,†,‡
St. Jude Children’s Research Hospital, Memphis, Tennessee 38105, School of Chemistry and Chemical
Engineering, Shandong UniVersity, Jinan, 250100, China, and Department of Chemistry, UniVersity of
Massachusetts Boston, 100 Morrissey BouleVard, Boston, Massachusetts 02125
ReceiVed October 4, 2009
A new protocol in which cyclohexylisocyanide and methyl 2-isocyanoacetate are used as convertible
isocyanides for Ugi/de-Boc/cyclization/Suzuki synthesis of biaryl-substituted 1,4-benzodiazepine-2,5-diones
has been developed. Ugi reactions of Boc-protected anthranilic acids, fluorous benzaldehydes, amines, and
cyclohexylisocyanide or methyl 2-isocyanoacetate were carried out at room temperature. Microwave-promoted
de-Boc/cyclization reactions afforded 1,4-benzodiazepine-2,5-diones (BZDs). Suzuki coupling reactions further
derivatized the BZD ring by removing the fluorous tag and introducing the biaryl group. A thirty three-
member biaryl-substituted BZD library containing four points of diversity was prepared by microwave-
assisted solution-phase fluorous parallel synthesis.
Introduction
amino and ester groups instead of the amino and amide
groups (Scheme 1, bottom).
The synthesis of 1,4-benzodiazepine-2,5-diones (BZDs)
has received much attention because of their wide range of
biological utilities.1-4 Multicomponent reactions (MCRs)
such as Ugi four-component reactions have been employed
for the construction of BZD scaffolds.5-12 MCRs have the
capability to build target scaffolds with maximal substitution
diversities through a simple reaction process.13-15 MCR-
based strategy has been developed for solution phase,5 solid
phase,16-19 ionic liquid,20 and fluorous synthesis21 of BZD
scaffolds.
Reported in this paper is a new method to synthesize BZDs
using the Ugi/de-Boc/cyclization approach. It was developed
based on our recent discovery of using cyclohexylisocyanide
and methyl 2-isocyanoacetate as convertible isocyanides. We
have found that under microwave irradiation for 20 min at
150 °C, de-Boc/cyclization occurred between the amino
group and the amide bonds (Scheme 2, bottom). However,
under conventional heating of refluxing MeOH at 70 °C for
12 h, only deprotected product was detected by LC-MS
analysis (Scheme 2, top).
In 1996 the Armstrong group introduced 1-isocyanocy-
clohexene as a convertible isocyanide for Ugi reactions.22,23
This convertible isocyanide has been used in the Ugi/de-
Boc/cyclization synthesis of BZDs (Scheme 1, top).4,24-27
The cleavage of cyclohexenylamino group from the amide
bond occurs through the formation of an oxazolinium-5-
one intermediate followed by a nucleophilic reaction with
the amino group.23,28-30 The utility of 1-isocyanocyclohex-
ene is limited because it is not commercially available and
not so convenient to prepare in house. Commercially
available cyclohexylisocyanide31-33 and methyl 2-isocy-
anoacetate18 have been used for Ugi reactions. But because
of cyclohexylamino and methylacetylamino groups are
relatively stable and not so easy to cleave, they are generally
used as non-convertible isocyanides. We have employed
cyclohexylisocyanide in the fluorous parallel synthesis of a
BZD library.21 The de-Boc/cyclization occurred between the
Results and Discussion
The Ugi/de-Boc/cyclization using cyclohexylisocyanide or
methyl 2-isocyanoacetate as convertible isocyanides is
highlighted in Scheme 3. The first step of Ugi condensation
was performed at room temperature in MeOH using Boc-
protected anthranilic acid 1a, 4-chlorobenzaldehyde 2a,
piperonylamine 3a, and cyclohexylisocyanide 4a (Scheme
3). The precipitate formed at the beginning of the reaction
disappeared after stirring at room temperature for 24 h. The
reaction mixture turning to clear is an indication of comple-
tion which was confirmed by LC-MS analysis. The Ugi
product 5a was isolated in 75% yield. The reaction could
be finished in 10 h if conducted at 50 °C and gave 5a in
88% yield. For the de-Boc/cyclization reaction, 1:1 TFA-
MeOH was found to be an optimal ratio. The reaction was
completed in 20 min at 150 °C under microwave irradiation
to afford product 6a in 63% yield. When methyl 2-isocy-
anoacetate was used for Ugi reaction, product 5b was isolated
in 91% yield, and the cyclization product 6a was isolated in
59% yield.
* To whom correspondence should be addressed. E-mail:
bing.yan@stjude.org.
† St. Jude Children’s Research Hospital.
‡ School of Chemistry and Chemical Engineering, Shandong University.
§ University of Massachusetts Boston.
10.1021/cc900157w  2010 American Chemical Society
Published on Web 11/30/2009

Synthesis of 1,4-Benzodiazepine-2,5-dione Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 207
Scheme 1. Ugi/de-Boc/Cyclization Synthesis of BZDs
Scheme 2. Microwave-Assisted Synthesis of BZDs
to neutralize the reaction mixtures. The crude products were
purified by F-SPE and compounds 6 were collected in the
second fraction of 100% MeOH. Sixteen F-BZD products 6
were obtained in 31-97% yields (Table 1). The average
purity of the raw products checked by LC-MS at UV214nm
1
was 93%. All products were characterized by H and 13C
NMR analysis (Supporting Information S6-S21).
Six boronic acids 7{1-6} were used for Suzuki coupling
reactions following the conditions reported in our previous
paper (Scheme 5).21,37 The reactions were carried out under
microwave irradiation using 0.04 equiv of Pd(dppf)Cl2 as a
catalyst, 0.9 equiv of K2CO3 as a base, and 4:4:1 acetone/
toluene/H2O as a co-solvent. Thirty-one of thirty-three
designed products 8 were obtained (Table 2). The final
products were isolated by F-SPE and collected in the first
fraction of 4:1 MeOH/H2O or by flash chromatography. The
structure and purity of all products were determined by LC-
MS at UV214nm, and the yield and purity were listed in Table
2. Representative compounds were further characterized by
high resolution mass spectrometry, 1H and 13C NMR analysis
(Supporting Information S21-S37).
We next extended the Ugi/de-Boc/cyclization reactions for
fluorous parallel synthesis of BZDs 6. Two fluorous ben-
zaldehydes 2{1-2},21,34-37 five Boc-protected anthranilic
acids 1{1-5},38-40 five amines 3{1-5}, and two isocyanides
4{1-2} were used for Ugi reactions (Scheme 4). During the
reaction validation, we found that Ugi reaction with 1{5}
failed, probably because of the low solubility of 1{5} in
MeOH. The introduction of the fluorous tag in general did
not affect the reactivity of aldehydes. The optimal ratio of
1:2:3:4 for Ugi reactions was found to be 1.25:1:1.25:1.25
through a series of optimizations. A slightly excess of non-
fluorous components was used to consume fluorous aldehyde
2 and make fluorous Ugi (F-Ugi) product 5 as the only
fluorous compound in the reaction mixture. In this way 5
can be easily purified by fluorous solid-phase extraction (F-
SPE). The excess non-fluorous starting materials and byprod-
ucts were removed by F-SPE and collected in the first
fraction of 4:1 MeOH/H2O, while F-Ugi products 5 were
collected in the second fraction of 100% MeOH. Nine F-Ugi
products 5 from cyclohexylisocyanide 4{1} and seven F-Ugi
products 5 from methyl 2-isocyanoacetate 4{2} were pre-
pared. The average yield for 5 was 80%. The crude products
were directly used for next step reaction without further
purification.
The de-Boc/cyclizations were performed under microwave
heating. The F-Ugi products 5 were dissolved in 10 equiv
of 1:1 TFA/MeOH (v/v) and heated at 150 °C for 20 min
under microwave irradiation. For most reactions, only target
fluorous BZD (F-BZD) products 6 were obtained. However,
for 6{3,2,1} and 6{4,2,4} two main spots were found by TLC
analysis. The byproducts were confirmed to be the de-Boc
but non-cyclized F-Ugi products by LC-MS analysis. In these
cases, a second round of microwave reactions was performed
to push the reaction to completion. Upon the completion of
the cyclization reactions, 1 N aq. NaOH was added dropwise
Conclusions
A new Ugi/de-Boc/cyclization/Suzuki strategy for the
synthesis of biaryl-substituted 1,4-benzodiazepine-2,5-diones
has been developed. Under microwave heating cyclohexy-
lisocyanide and methyl 2-isocyanoacetate were used as
convertible isocyanides for the cyclization reaction to form
BZDs. The optimized solution-phase condition has been
employed for fluorous parallel synthesis. Fluorous benzal-
dehyde was used as a tagged-component to simplify inter-
mediates and final products purification by simple F-SPE.
A four diversity points BZD library containing 31 members
was synthesized to demonstrate the efficiency of library
synthesis involving MCR, microwave heating, and fluorous
separation.
Experimental Section
The chemical reagents were purchased from Sigma-
Aldrich (St. Louis, MO) and used without further purification.
LC-MS were performed on a Waters system equipped with
a Waters 2795 separation module, a Waters 2996 PDA
detector, and a Micromass ZQ detector. A C18 column (2.0
µm, 2.0 × 50 mm) was used for the separation. The mobile

208 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Scheme 3. Optimization of Microwave Synthesis of a BZD
Zhou et al.
Scheme 4. Microwave-Assisted Flourous Synthesis of BZDs
phases were methanol and water containing 0.05% trifluo-
roacetic acid. A linear gradient was used to increase from
10:90 v/v methanol/water to 100% methanol over 4.0 min
and decrease to 10:90 v/v methanol/water over 6.5 min at a
flow rate of 0.5 mL/min. The UV detection was at 214 nm.
Mass spectra were recorded in positive ion mode using
electrospray ionization (ESI). NMR spectra were recorded
on a Bruker 400 MHz NMR spectrometer using d-chloroform
(CDCl3) as solvent. Microwave assisted parallel synthesis
was carried out on a Biotage Initiator single mode microwave
reactor equipped with an automatic sample loader. GeneVac
HT-12 Series II was used for the evaporation and concentra-
tion of samples after F-SPE. FluoroFlash SPE cartridges were
purchased from Fluorous Technologies, Inc. (Pittsburgh, PA).
Synthesis of tert-Butyl 2-((benzo[d][1,3]dioxol-5-ylm-
ethyl)(1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxoeth-
yl)carbamoyl)phenylcarbamate 5a. Piperonylamine (15 µL,
0.117 mmol) and 4-chlorobenzaldehyde (17 mg, 0.117 mmol)
were dissolved in 1.0 mL of methanol. The mixture was
stirred at room temperature for 1 h, and Boc-protected
anthranilic acid (28 mg, 0.117 mmol) and 1-isocyanocyclo-
hexane (15 µL, 0.117 mmol) were added in sequence. The
resulting solution was stirred at room temperature overnight.
After reaction completion, the reaction mixture was poured
into a saturated sodium chloride solution and extracted twice
with EtOAc. The organic layer was concentrated in vacuum,
and the residue was purified by flash column chromatography
on silica gel. A 64 mg portion of pure product was eluted
1
with 1:3 hexane/EtOAc (yield 88%). H NMR (400 MHz,
CDCl3) δ 8.37 (s, 1H), 8.09 (d, J ) 7.4, 1H), 7.49-7.12
(m, 6H), 6.99 (d, J ) 6.4, 1H), 6.54 (d, J ) 7.8, 1H), 6.27
(s, 2H), 6.00-5.81 (m, 2H), 5.73 (s, 1H), 5.45 (s, 1H), 4.50
(s, 1H), 4.26 (d, J ) 15.8, 1H), 3.80 (dt, J ) 14.6, 7.1, 1H),
1.89 (d, J ) 9.4, 2H), 1.75-1.42 (m, 12H), 1.42-1.22 (m,
2H), 1.20-0.82 (m, 3H); 13C NMR (101 MHz, CDCl3) δ
171.82, 168.25, 153.22, 147.63, 146.73, 136.31, 134.74,

Synthesis of 1,4-Benzodiazepine-2,5-dione Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 209
Table 1. Characterization of the Representative Compounds
6{R1,R2,R3}
Table 2. Characterization of the Representative Compounds
8{R1,R2,R3,R5}
entry
compound
R4
yielda
purityb
MW(found)c
entry
compound
yielda
purityb
MW(found)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
6{2,1,1}
6{2,1,3}
6{2,2,1}
6{2,2,3}
6{1,1,1}
6{3,1,1}
6{1,1,3}
6{1,2,1}
6{3,2,1}
6{1,1,2}
6{3,1,4}
6{4,1,2}
6{1,2,5}
6{4,2,4}
6{2,2,2}
6{2,2,4}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{1}
4{2}
4{2}
4{2}
4{2}
4{2}
4{2}
4{2}
31
36
44
48
64
87
76
79
97
62
52
60
65
77
64
64
95
98
98
96
98
97
98
>99
>99
94
83
92
90
69
94
82
867
901
897
931
807
841
841
837
871
885
867
919
945
897
975
923
1
2
3
4
5
6
7
8
8{2,1,1,1}
8{2,1,3,1}
8{2,2,1,2}
8{2,2,3,3}
8{2,2,3,6}
8{1,1,1,5}
8{1,1,1,2}
8{1,1,1,4}
8{3,1,1,1}
8{1,1,3,2}
8{1,1,3,3}
8{1,2,1,3}
8{1,2,1,5}
8{1,2,1,4}
8{3,2,1,5}
8{3,2,1,6}
8{1,1,2,1}
8{1,1,2,3}
8{1,1,2,4}
8{3,1,4,2}
8{3,1,4,4}
8{3,1,4,5}
8{4,1,2,1}
8{4,1,2,6}
8{1,2,5,2}
8{1,2,5,3}
8{1,2,5,5}
8{4,2,4,6}
8{2,2,2,1}
8{2,2,2,4}
8{2,2,2,6}
8{2,2,4,2}
8{2,2,4,3}
56
24
20
28
27
55
31
50
67
47
35
26
42
0
39
34
59
59
40
25
44
47
47
26
35
38
0
96
91
97
92
93
96
93
94
95
96
89
88
91
0
98
96
87
92
96
94
95
>99
95
95
94
82
0
445
478
525
535
565
427
435
375
419
469
445
441
457
494
491
505
463
489
453
495
435
487
497
553
573
549
602
532
553
543
609
551
527
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
a The yield (%) was calculated by the weight of the solid after F-SPE
purification. b The purity (%) was based on the integration area of
HPLC peaks detected at 214 nm. c MW (found) was determined by
HPLC/ESI MS.
Scheme 5. Cleavage of Fluorous Tags by Suzuki Coupling
Reactions under Microwave Irradiation
22
22
20
26
21
43
94
95
90
90
91
96
a The yield (%) was calculated by the weight of the solid after F-SPE
purification. b The purity (%) was based on the integration area of
HPLC peaks detected at 214 nm. c MW (found) was determined by
HPLC/ESI MS.
136.19, 135.01, 132.54, 131.45, 130.67, 128.93, 126.64,
122.66, 120.58, 108.01, 107.58, 101.03, 80.42, 63.98, 52.40,
41.50, 28.36.
133.16, 131.29, 130.62, 128.83, 126.62, 124.74, 122.46,
120.54, 107.95, 107.54, 100.99, 80.31, 77.40, 77.29, 77.09,
76.77, 64.23, 52.73, 49.03, 32.65, 32.62, 28.36, 25.43, 24.79,
24.72.
Synthesis of 4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(4-
chlorophenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-
dione 6a. Compound 5a or 5b was dissolved in 400 µL of
MeOH and 400 µL of TFA was added to the solution. The
reaction took place in a monomode microwave cavity at 150
°C for 20 min. TLC was used to monitor the reaction process.
After completing of reaction, two drops of 1N NaOH in water
was added, and the mixture was extracted between saturated
sodium chloride solution and EtOAc. The organic layer was
dried under reduced pressure, and the residue was purified
by flash column chromatography on silica gel, eluting with
1:2 hexane/EtOAc. The yields for reactions from 1-isocy-
anocyclohexane and methyl 2-isocyanoacetate were 63% and
Synthesis of Methyl 2-(2-(N-(benzo[d][1,3]dioxol-5-
ylmethyl)-2-(tert-butoxycarbonylamino)benzamido)-2-(4-
chlorophenyl)acetamido)acetate 5b. Piperonylamine (15
µL, 0.117 mmol) and 4-chlorobenzaldehyde (17 mg, 0.117
mmol) were dissolved in 1.0 mL of methanol. The mixture
was stirred at room temperature for 1 h, and Boc-protected
anthranilic acid (28 mg, 0.117 mmol) and methyl 2-isocy-
anoacetate (11 µL, 0.117 mmol) were added in sequence.
After reaction completion, the resulting solution was stirred
at room temperature overnight. The reaction mixture was
poured into a saturated sodium chloride solution and
extracted twice with EtOAc. The organic layer was concen-
trated in vacuum, and the residue was purified by flash
column chromatography on silica gel. 65 mg pure product
1
59%, respectively. H NMR (400 MHz, CDCl3) δ 8.99 (s,
1H), 7.67 (d, J ) 7.8, 1H), 7.17 (dd, J ) 12.1, 4.5, 1H),
6.96 (dd, J ) 11.8, 8.0, 4H), 6.80 (dd, J ) 21.7, 7.4, 3H),
6.67 (t, J ) 7.9, 2H), 5.80 (d, J ) 22.6, 2H), 5.28 (s, 1H),
4.86 (d, J ) 14.0, 2H); 13C NMR (101 MHz, CDCl3) δ
171.30, 167.11, 148.20, 147.65, 134.00, 133.73, 132.58,
131.61, 131.16, 130.54, 129.74, 128.67, 127.26, 125.96,
125.23, 122.65, 119.93, 109.31, 108.41, 101.20.
General Procedure for the Synthesis of Compounds
5. Fluorous bezaldehydes 2 (0.4 mmol) and amines 3 (0.5
mmol) were dissolved in methanol and stirred for 1 h at
1
was eluted with 1:1 hexane/EtOAc (yield 91%). H NMR
(400 MHz, CDCl3) δ 8.44-7.90 (m, 2H), 7.55-7.15 (m,
6H), 7.00 (t, J ) 6.8, 1H), 6.56 (d, J ) 8.0, 1H), 6.33 (s,
3H), 5.87 (dd, J ) 8.0, 1.3, 2H), 5.49 (s, 1H), 4.53 (s, 1H),
4.25 (d, J ) 15.8, 1H), 4.14-3.90 (m, 2H), 3.74 (d, J )
12.0, 3H), 1.55 (s, 9H); 13C NMR (101 MHz, CDCl3) δ
171.72, 169.90, 169.38, 158.15, 153.21, 147.71, 146.83,

210 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Zhou et al.
room temperature. Boc-protected anthranilic acids 1 (0.5
mmol) and isocyanides 4 (0.5 mmol) were added to the
mixture in sequence. The reactions were stirred for further
10-24 h until the mixture became clear. TLC and HPLC/
MS were used for monitoring the reaction. The reaction
mixture was directly loaded on a FluoroFlash SPE
cartridge containing 10 g fluorous silica gel. The cartridge
was eluted with 20 mL of MeOH/H2O (v/v 4:1) following
by 20 mL of MeOH. The second fraction was collected
and concentrated to give compound 5 in various yields
from 62% to 97%.
General Procedure for the Synthesis of Compounds
6. Compounds 5 were dissolved in 750 µL of MeOH, and
750 µL of TFA was added to the solution. The reaction
took place in a monomode microwave cavity at 150 °C
for 20 min. HPLC was used to monitor the reaction
process. After completing of reaction, 1N NaOH in water
was added dropwise for neutralization. The mixture was
directly loaded on a FluoroFlash SPE cartridge containing
10 g of fluorous silica gel. The cartridge was eluted with
20 mL of MeOH/H2O (v/v 4:1) following by 20 mL of
MeOH. The second fraction was collected and concen-
trated to give compound 6. The purity was checked by
HPLC/MS/UV214nm. Compounds 6 with lower purity were
further purified by flash chromatography with silica gel
using mixture of hexane and EtOAc as en eluent.
4-(4-Butyl-7,8-dimethoxy-2,5-dioxo-2,3,4,5-tetrahydro-
1H-benzo[e][1,4]diazepin-3-yl)phenyl perfluorooctylsul-
fonate 6{2,1,1}. Yield 31%. 1H NMR (400 MHz, CDCl3) δ
8.22 (s, 1H), 7.25-7.12 (m, 3H), 7.07 (d, J ) 8.2, 2H), 6.12
(s, 1H), 5.33 (s, 1H), 4.07 (s, 1H), 3.78 (d, J ) 11.5, 6H),
3.72-3.61 (m, 1H), 1.90-1.64 (m, 2H), 1.51-1.35 (m, 2H),
0.97 (dd, J ) 14.9, 7.7, 3H); 13C NMR (101 MHz, CDCl3)
δ 170.39, 166.41, 152.33, 148.99, 146.62, 134.55, 128.04,
126.34, 121.57, 120.03, 112.06, 102.57, 66.46, 56.12, 56.10,
51.10, 30.29, 20.07, 13.80; ESI-MS m/z 867(MH+).
4-(4-Benzyl-7,8-dimethoxy-2,5-dioxo-2,3,4,5-tetrahydro-
1H-benzo[e][1,4]diazepin-3-yl)phenyl perfluorooctylsul-
fonate 6{2,1,3}. Yield 36%. 1H NMR (400 MHz, CDCl3) δ
8.51 (s, 1H), 7.49 (d, J ) 5.2, 2H), 7.34 (t, J ) 7.2, 2H),
7.31-7.23 (m, 1H), 7.18 (s, 1H), 6.97 (s, 4H), 6.13 (s, 1H),
5.38 (s, 1H), 5.11 (d, J ) 14.2, 1H), 4.96 (d, J ) 14.3, 1H),
3.78 (d, J ) 19.9, 6H); 13C NMR (101 MHz, CDCl3) δ
170.25, 166.66, 152.51, 148.90, 146.62, 136.06, 134.24,
129.01, 128.39, 126.38, 121.38, 119.56, 112.13, 110.32,
102.67, 65.59, 60.44, 56.16, 56.12, 54.33, 21.08, 14.23; ESI-
MS m/z 901(MH+).
4-(4-Benzyl-7,8-dimethoxy-2,5-dioxo-2,3,4,5-tetrahydro-
1H-benzo[e][1,4]diazepin-3-yl)-2-methoxyphenyl perfluo-
rooctylsulfonate 6{2,2,3}. Yield 48%. 1H NMR (400 MHz,
CDCl3) δ 8.05 (s, 1H), 7.54 (t, J ) 8.4, 2H), 7.34 (dt, J
) 21.9, 7.1, 3H), 7.16 (s, 1H), 6.88 (d, J ) 8.4, 1H),
6.56 (d, J ) 7.3, 1H), 6.33 (s, 1H), 6.13 (s, 1H), 5.45-5.23
(m, 2H), 4.68 (d, J ) 14.2, 1H), 3.77 (t, J ) 12.1, 6H),
3.57 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 169.97,
166.63, 152.55, 151.37, 146.68, 138.04, 136.29, 129.39,
129.13, 128.46, 122.11, 119.59, 112.10, 109.80, 102.67,
65.91, 56.22, 56.18, 54.39; ESI-MS m/z 931(MH+).
4-(4-Butyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-
diazepin-3-yl)phenyl perfluorooctylsulfonate 6{1,1,1}. Yield
1
64%. H NMR (400 MHz, CDCl3) δ 8.36 (s, 1H), 7.69 (d,
J ) 7.6, 1H), 7.20 (t, J ) 11.7, 3H), 7.10-6.90 (m, 3H),
6.70 (d, J ) 7.9, 1H), 5.36 (s, 1H), 4.13 (d, J ) 12.2, 1H),
3.76-3.58 (m, 1H), 1.94-1.65 (m, 2H), 1.54-1.34 (m, 2H),
1.09-0.92 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 170.77,
166.67, 149.02, 134.24, 133.61, 132.29, 131.09, 127.95,
126.53, 125.29, 121.52, 119.83, 66.37, 51.11, 30.28, 20.09,
13.80; ESI-MS m/z 807(MH+).
4-(4-Butyl-7-chloro-2,5-dioxo-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepin-3-yl)phenyl perfluorooctylsulfonate
6{3,1,1}. Yield 87%. 1H NMR (400 MHz, CDCl3) δ 8.50 (s,
1H), 7.69 (s, 1H), 7.13 (dd, J ) 18.2, 9.4, 5H), 6.67 (d, J )
8.4, 1H), 5.36 (s, 1H), 4.08 (s, 1H), 3.75-3.59 (m, 1H), 1.75
(dd, J ) 20.5, 12.9, 2H), 1.44 (dd, J ) 14.4, 7.1, 2H),
1.07-0.83 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 170.42,
165.38, 149.23, 133.91, 132.33, 132.20, 130.96, 130.69,
129.20, 126.47, 121.80, 121.31, 66.29, 51.27, 30.19, 20.07,
13.78; ESI-MS m/z 841(MH+).
4-(4-Benzyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e]-
[1,4]diazepin-3-yl)phenyl perfluorooctylsulfonate 6{1,1,3}.
1
Yield 76%. H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H),
7.73 (d, J ) 7.5, 1H), 7.49 (d, J ) 5.6, 2H), 7.34 (t, J )
6.9, 2H), 7.27 (dd, J ) 7.8, 4.7, 1H), 7.20 (t, J ) 7.1, 1H),
7.10-6.83 (m, 5H), 6.71 (d, J ) 7.8, 1H), 5.40 (s, 1H), 5.14
(d, J ) 14.3, 1H), 4.99 (d, J ) 14.2, 1H); 13C NMR (101
MHz, CDCl3) δ 170.82, 167.00, 148.96, 135.98, 133.99,
132.48, 131.19, 129.12, 129.06, 128.45, 127.56, 126.60,
125.25, 121.35, 120.05, 65.58, 54.25; ESI-MS m/z
841(MH+).
4-(4-Butyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-benzo[e][1,4]-
diazepin-3-yl)-2-methoxyphenyl perfluorooctylsulfonate
1
6{1,2,1}. Yield 79%. H NMR (400 MHz, CDCl3) δ 8.59
(s, 1H), 7.70 (d, J ) 7.7, 1H), 7.22 (t, J ) 7.4, 1H), 7.04 (t,
J ) 7.5, 1H), 6.97 (d, J ) 8.6, 1H), 6.72 (d, J ) 6.7, 3H),
5.35 (s, 1H), 4.10 (dd, J ) 15.4, 8.3, 1H), 3.77 (d, J ) 9.0,
3H), 3.73-3.62 (m, 1H), 1.45 (dd, J ) 14.6, 7.3, 2H),
1.31-1.14 (m, 2H), 0.99 (t, J ) 7.3, 3H); 13C NMR (101
MHz, CDCl3) δ 170.90, 166.87, 151.48, 138.16, 135.22,
133.71, 132.39, 131.00, 127.97, 125.37, 122.45, 119.96,
117.26, 109.70, 66.67, 60.48, 56.37, 51.14, 50.87, 30.30,
21.09, 20.13, 14.23, 13.81; ESI-MS m/z 837(MH+).
4-(4-Butyl-7-chloro-2,5-dioxo-2,3,4,5-tetrahydro-1H-
benzo[e][1,4]diazepin-3-yl)-2-methoxyphenyl perfluorooct-
ylsulfonate 6{3,2,1}. Yield 97%. 1H NMR (400 MHz,
CDCl3) δ 8.63 (s, 1H), 7.70 (s, 1H), 7.18 (d, J ) 8.1, 1H),
7.03 (d, J ) 8.1, 1H), 6.68 (d, J ) 9.2, 3H), 5.35 (s, 1H),
4-(4-Butyl-7,8-dimethoxy-2,5-dioxo-2,3,4,5-tetrahydro-
1H-benzo[e][1,4]diazepin-3-yl)-2-methoxyphenyl perfluo-
rooctylsulfonate 6{2,2,1}. Yield 44%. 1H NMR (400 MHz,
CDCl3) δ 7.97 (s, 1H), 7.18 (s, 1H), 7.05-6.94 (m, 1H),
6.73 (s, 2H), 6.11 (s, 1H), 5.32 (s, 1H), 4.07 (dd, J )
16.1, 9.5, 1H), 3.78 (dd, J ) 15.7, 10.9, 9H), 3.73-3.60
(m, 1H), 1.89-1.63 (m, 2H), 1.44 (dd, J ) 14.7, 7.3, 2H),
1.07-0.89 (m, 3H); 13C NMR (101 MHz, CDCl3) δ
170.26, 166.48, 152.37, 151.49, 146.69, 138.15, 135.48,
127.94, 122.44, 120.05, 117.08, 112.03, 109.57, 102.63,
66.72, 56.35, 56.15, 51.12, 30.30, 20.10, 13.80; ESI-MS
m/z 897(MH+).

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

212 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1
Zhou et al.
(s, 1H), 4.97 (t, J ) 13.5, 2H), 3.72 (d, J ) 18.9, 6H); ESI-
MS m/z 479(MH+).
6.68-6.41 (m, 4H), 5.63 (d, J ) 17.8, 1H), 5.28 (s, 1H),
5.12 (d, J ) 10.4, 1H), 4.00 (s, 1H), 3.56 (s, 4H), 1.64 (s,
2H), 1.35 (d, J ) 7.1, 2H), 0.87 (d, J ) 6.9, 3H); ESI-MS
m/z 441(MH+).
3-(3′-Acetyl-2-methoxybiphenyl-4-yl)-4-butyl-7-chloro-3,4-di-
hydro-1H-benzo[e][1,4]diazepine-2,5-dione 8{3,2,1,5}. Yield
39%. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J ) 4.9, 1H),
7.84-7.78 (m, 1H), 7.69 (d, J ) 3.7, 2H), 7.53 (d, J ) 7.8,
1H), 7.47-7.35 (m, 2H), 7.12 (d, J ) 6.6, 1H), 7.06 (d, J )
7.8, 1H), 6.68 (d, J ) 6.7, 1H), 6.59 (d, J ) 8.1, 1H), 5.34
(s, 1H), 4.03 (s, 1H), 3.74-3.51 (m, 4H), 2.62-2.46 (m,
3H), 1.81-1.62 (m, 2H), 1.38 (dt, J ) 14.8, 7.5, 2H), 0.91
(dt, J ) 11.0, 7.3, 3H); ESI-MS m/z 492(MH+).
4-Butyl-7,8-dimethoxy-3-(3-methoxy-4-(naphthalen-2-
yl)phenyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-di-
1
one 8{2,2,1,2}. Yield 20%. H NMR (400 MHz, CDCl3) δ
7.83-7.72 (m, 3H), 7.54-7.37 (m, 5H), 7.19-7.05 (m, 2H),
6.76 (s, 1H), 6.66 (s, 1H), 6.08 (s, 1H), 5.36 (s, 1H), 4.04
(s, 1H), 3.82-3.72 (m, 6H), 3.66 (s, 4H), 1.70 (s, 2H), 1.42
(d, J ) 7.8, 2H), 0.95 (t, J ) 7.3, 3H); ESI-MS m/z
525(MH+).
3-(4-(Benzo[b]thiophen-2-yl)-3-methoxyphenyl)-4-ben-
zyl-7,8-dimethoxy-3,4-dihydro-1H-benzo[e][1,4]diazepine-
2,5-dione 8{2,2,3,6}. Yield 27%. 1H NMR (400 MHz,
CDCl3) δ 7.69 (d, J ) 7.4, 1H), 7.64 (d, J ) 7.2, 1H),
7.58-7.39 (m, 4H), 7.39-7.20 (m, 7H), 6.56 (s, 1H), 6.27
(s, 1H), 6.05 (s, 1H), 5.37 (s, 1H), 5.23 (d, J ) 14.0, 1H),
4.69 (d, J ) 14.7, 1H), 3.74 (d, J ) 11.0, 6H), 3.56 (s, 3H);
ESI-MS m/z 565(MH+).
3-(3′-Acetylbiphenyl-4-yl)-4-butyl-3,4-dihydro-1H-
benzo[e][1,4]diazepine-2,5-dione 8{1,1,1,5}. Yield 55%. 1H
NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.89 (d, J ) 7.1,
2H), 7.74 (s, 1H), 7.64 (d, J ) 6.1, 1H), 7.50 (dd, J ) 20.9,
13.3, 2H), 7.38 (s, 2H), 7.17 (s, 2H), 7.00 (s, 1H), 6.69 (s,
1H), 5.41 (s, 1H), 4.14 (s, 1H), 3.69 (s, 1H), 2.69-2.57 (m,
3H), 1.81 (s, 1H), 1.46 (d, J ) 6.8, 2H), 1.35-1.12 (m, 1H),
1.08-0.75 (m, 3H); ESI-MS m/z 427(MH+).
3-(4-(Benzo[b]thiophen-2-yl)-3-methoxyphenyl)-4-butyl-
7-chloro-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-di-
1
one 8{3,2,1,6}. Yield 34%. H NMR (400 MHz, CDCl3) δ
7.69 (dd, J ) 20.2, 7.9, 3H), 7.59 (d, J ) 17.1, 2H), 7.43
(d, J ) 8.3, 1H), 7.28-7.20 (m, 2H), 7.09 (d, J ) 7.8, 1H),
6.67 (d, J ) 6.8, 1H), 6.63-6.52 (m, 2H), 5.32 (s, 1H), 4.01
(s, 1H), 3.76 (d, J ) 12.3, 3H), 3.72-3.53 (m, 1H), 1.69
(dd, J ) 19.6, 11.7, 2H), 1.38 (dd, J ) 14.9, 7.2, 2H), 0.92
(t, J ) 7.3, 3H); ESI-MS m/z 505(MH+); HR-MS calcd for
C28H26N2O3S (M+H)+ 505.1353, found 505.1344.
4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(biphenyl-4-yl)-3,4-
dihydro-1H-benzo[e][1,4]diazepine-2,5-dione 8{1,1,2,1}.
1
Yield 59%. H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H),
4-Butyl-3-(4-(naphthalen-2-yl)phenyl)-3,4-dihydro-1H-
benzo[e][1,4]diazepine-2,5-dione 8{1,1,1,2}. Yield 31%. 1H
NMR (400 MHz, CDCl3) δ 7.83 (dd, J ) 46.1, 33.5, 4H),
7.67 (d, J ) 9.6, 2H), 7.59-7.24 (m, 6H), 7.11 (s, 2H), 6.92
(s, 1H), 6.63 (d, J ) 25.1, 1H), 5.36 (s, 1H), 4.08 (s, 1H),
3.67 (d, J ) 30.9, 1H), 1.71 (s, 2H), 1.31 (d, J ) 57.1, 2H),
1.03-0.71 (m, 3H); ESI-MS m/z 435(MH+).
4-Butyl-3-(4-(furan-2-yl)phenyl)-3,4-dihydro-1H-benzo-
[e][1,4]diazepine-2,5-dione 8{1,1,1,4}. Yield 50%. 1H NMR
(400 MHz, CDCl3) δ 7.95-7.49 (m, 3H), 7.35 (d, J ) 35.8,
3H), 7.01 (d, J ) 32.6, 2H), 6.86 (s, 1H), 6.55 (s, 1H), 6.44
(s, 1H), 6.31 (s, 1H), 5.26 (s, 1H), 3.95 (d, J ) 55.9, 1H),
3.56 (s, 1H), 1.33 (s, 3H), 1.14 (d, J ) 14.6, 1H), 0.84 (t, J
) 26.1, 3H); ESI-MS m/z 375(MH+); HR-MS calcd for
C23H23N2O3 (M+H)+ 375.1709, found 375.1703.
4-Benzyl-3-(4-(naphthalen-2-yl)phenyl)-3,4-dihydro-
1H-benzo[e][1,4]diazepine-2,5-dione 8{1,1,3,2}. Yield 47%.
1H NMR (400 MHz, CDCl3) δ 8.05-7.65 (m, 6H), 7.55-7.42
(m, 3H), 7.40 (dd, J ) 9.2, 5.6, 2H), 7.32 (d, J ) 7.0, 3H),
7.18 (d, J ) 4.3, 3H), 7.13 (s, 1H), 6.94 (s, 2H), 6.62 (d, J
) 7.6, 1H), 5.41 (s, 1H), 5.18-4.85 (m, 2H); ESI-MS m/z
469(MH+).
4-Benzyl-3-(4′-vinylbiphenyl-4-yl)-3,4-dihydro-1H-
benzo[e][1,4]diazepine-2,5-dione 8{1,1,3,3}. Yield 35%. 1H
NMR (400 MHz, CDCl3) δ 7.70 (d, J ) 7.3, 1H), 7.64-7.57
(m, 1H), 7.44 (d, J ) 7.5, 3H), 7.38-7.23 (m, 8H), 7.12 (t,
J ) 7.5, 1H), 7.00-6.83 (m, 3H), 6.69-6.53 (m, 2H), 5.68
(d, J ) 17.6, 1H), 5.38 (s, 1H), 5.24-5.11 (m, 1H), 5.00 (t,
J ) 11.9, 2H); ESI-MS m/z 445(MH+).
7.79 (s, 1H), 7.54-7.35 (m, 4H), 7.30 (dd, J ) 12.9, 7.2,
4H), 7.22 (d, J ) 7.0, 1H), 7.02 (t, J ) 22.7, 4H), 6.81 (d,
J ) 7.7, 1H), 6.72 (d, J ) 7.1, 1H), 5.95 (t, J ) 8.7, 2H),
5.47 (d, J ) 6.9, 1H), 5.02 (d, J ) 9.7, 2H); ESI-MS m/z
463(MH+); HR-MS calcd for C29H23N2O4 (M+H)+ 463.1658,
found 463.1648.
4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(4′-vinylbiphenyl-4-yl)-
3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione 8{1,1,2,3}.
1
Yield 59%. H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H),
7.79 (d, J ) 7.8, 1H), 7.46-7.37 (m, 4H), 7.31 (d, J ) 8.3,
2H), 7.21 (t, J ) 7.5, 1H), 7.07 (s, 1H), 7.05-6.93 (m, 4H),
6.84-6.67 (m, 3H), 6.01-5.92 (m, 2H), 5.78 (d, J ) 17.6,
1H), 5.46 (s, 1H), 5.28 (d, J ) 10.9, 1H), 5.09-4.94 (m,
2H); 13C NMR (101 MHz, CDCl3) δ 148.16, 147.59, 139.94,
139.16, 136.90, 136.22, 132.31, 131.31, 130.01, 127.52,
126.89, 126.77, 126.62, 125.00, 122.61, 119.63, 114.16,
109.42, 108.43, 101.17; ESI-MS m/z 489(MH+); HR-MS
calcd for C27H29N2O4 (M+H)+ 489.1814, found 489.1803.
4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(4-(furan-2-yl)phenyl)-
3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione 8{1,1,2,4}.
1
Yield 40%. H NMR (400 MHz, CDCl3) δ 7.84 (s, 1H),
7.75 (s, 1H), 7.42-7.29 (m, 3H), 7.29-7.21 (m, 2H), 7.18
(s, 1H), 7.09-6.84 (m, 4H), 6.78 (d, J ) 8.1, 1H), 6.66 (s,
1H), 6.52 (d, J ) 11.1, 1H), 6.41 (s, 1H), 5.88 (d, J ) 54.9,
2H), 5.36 (d, J ) 31.4, 1H), 4.98 (s, 2H); ESI-MS m/z
453(MH+); HR-MS calcd for C27H29N2O4 (M+H)+ 453.1450,
found 453.1463.
7-Chloro-4-cyclohexyl-3-(4-(furan-2-yl)phenyl)-3,4-dihy-
dro-1H-benzo[e][1,4]diazepine-2,5-dione 8{3,1,4,4}. Yield
44%. 1H NMR (400 MHz, CDCl3) δ 7.75 (d, J ) 18.7, 2H),
7.62-7.37 (m, 4H), 7.14 (t, J ) 19.1, 2H), 6.60 (s, 2H),
6.46 (s, 1H), 5.50 (s, 1H), 5.00 (s, 1H), 2.07 (s, 1H), 1.90
(s, 3H), 1.72 (s, 2H), 1.42 (d, J ) 11.8, 2H), 1.32-1.05 (m,
4-Butyl-3-(2-methoxy-4′-vinylbiphenyl-4-yl)-3,4-dihydro-
1H-benzo[e][1,4]diazepine-2,5-dione 8{1,2,1,3}. Yield 26%.
1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.50 (s, 1H),
7.38-7.17 (m, 4H), 7.09 (s, 1H), 6.93 (d, J ) 12.5, 2H),

Synthesis of 1,4-Benzodiazepine-2,5-dione Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 1 213
2H); ESI-MS m/z 435(MH+); HR-MS calcd for C27H29N2O4
(M+H)+ 435.1475, found 435.1479.
(s, 1H), 6.37 (s, 1H), 6.08 (s, 1H), 5.90 (d, J ) 11.1, 2H),
5.36 (d, J ) 10.6, 1H), 5.19 (s, 1H), 4.57 (s, 1H), 3.74 (t, J
) 14.0, 6H), 3.66 (d, J ) 10.7, 3H); ESI-MS m/z 609(MH+).
3-(3′-Acetylbiphenyl-4-yl)-7-chloro-4-cyclohexyl-3,4-dihy-
dro-1H-benzo[e][1,4]diazepine-2,5-dione 8{3,1,4,5}. Yield
Acknowledgment. This work was supported by National
Cancer Institute (P30CA021765), the American Lebanese
Syrian Associated Charities (ALSAC), and St. Jude Chil-
dren’s Research Hospital.
1
47%. H NMR (400 MHz, CDCl3) δ 8.05 (s, 1H), 7.97 (s,
1H), 7.90 (d, J ) 7.6, 1H), 7.66 (m, 2H), 7.50 (t, J ) 7.7,
1H), 7.41 (d, J ) 8.3, 2H), 7.25 (d, J ) 10.3, 1H), 7.18 (d,
J ) 8.0, 2H), 7.11 (d, J ) 8.5, 1H), 6.62 (d, J ) 8.6, 1H),
5.52 (s, 1H), 5.00 (s, 1H), 2.72-2.52 (m, 3H), 2.05 (s, 1H),
1.89 (s, 3H), 1.72 (d, J ) 10.3, 2H), 1.42 (d, J ) 9.7, 2H),
1.29-1.04 (m, 2H); ESI-MS m/z 487(MH+); HR-MS calcd
for C27H29N2O4 (M+H)+ 487.1788, found 487.1780.
4-(Benzo[d][1,3]dioxol-5-ylmethyl)-3-(biphenyl-4-yl)-8-
chloro-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione
8{4,1,2,1}. Yield 47%. 1H NMR (400 MHz, CDCl3) δ 8.13
(s, 1H), 7.64 (d, J ) 8.4, 1H), 7.26 (ddd, J ) 43.1, 28.5,
13.0, 8H), 6.92 (d, J ) 27.6, 4H), 6.66 (dd, J ) 24.4, 9.9,
2H), 5.85 (d, J ) 7.8, 2H), 5.35 (d, J ) 12.6, 1H), 5.02-4.71
(m, 2H); ESI-MS m/z 497(MH+); HR-MS calcd for
C27H29N2O4 (M+H)+ 497.1268, found 497.1266.
1
Supporting Information Available. Respective H, 13C
NMR and HRMS spectrum of compounds 6 and 8. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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CC900157W