Synthesis of 1,4-Benzodiazepine-2,5-diones using an ionic liquid as a Soluble Support

Article abstract of DOI:10.1055/s-0028-1083289

The first report of the use of an ionic liquid as a soluble support for the synthesis of 1,4-benzodiazepine-2,5-diones is reported in this paper. This synthetic method is simple and efficient and the products are obtained in good yields. All of the produc

Full text of DOI:10.1055/s-0028-1083289

PAPER
205
Synthesis of 1,4-Benzodiazepine-2,5-diones Using an Ionic Liquid as a Soluble
Support
S
ynthesis of 1,4-B
o
enzodiazepin
n
e-2,5-dionesgwei Xie, Cuifen Lu, Guichun Yang,* Zuxing Chen
Ministry-of-Education Key Laboratory for the Synthesis and Application of Organic Functional Molecules,
School of Chemistry and Chemical Engineering, Hubei University, Wuhan, Hubei, 430062, P. R. of China
E-mail: yangguichun@hubu.edu.cn
Received 31 July 2008
miliar reaction conditions of classical organic chemistry
Abstract: The first report of the use of an ionic liquid as a soluble
support for the synthesis of 1,4-benzodiazepine-2,5-diones is re-
ported in this paper. This synthetic method is simple and efficient
and the products are obtained in good yields. All of the products
were characterized by IR, 1H NMR, and 13C NMR.
are reinstated and, yet, product purification is still facili-
tated due to their macromolecular properties.4 Non-
crosslinked polystyrene and poly(ethylene glycol) (PEG)
are the most common and useful soluble polymers for liq-
uid-phase organic synthesis,5 however, the main limita-
tion of soluble polymer supports is low loading capacity.
Hence, the idea of searching for alternative soluble sup-
ports for high-throughput organic synthesis has been ad-
vocated.
Key words: ionic liquid, synthesis, 1,4-benzodiazepine-2,5-di-
ones, soluble support
1,4-Benzodiazepine-2,5-dione and its analogues represent
an important class of bioactive molecules. These com-
pounds show remarkable potency in various biological
targets, including antithrombotic, antibiotic, and antitu-
mor activity.1 Much effort has been exerted in the synthe-
sis of this class of bioactive compounds.1,2 The
combinatorial or parallel synthetic approaches are espe-
cially noted.2
Recently, more attention within the realm of room tem-
perature ionic liquid research has been paid to ionic liq-
uids with special tasks.6 Ionic liquids have been
introduced as soluble supports in liquid-phase organic
synthesis;7 they have the advantages of retaining the na-
ture of a homogeneous reaction, high loading capacity, a
wide range of solvents, simple monitoring technology,
and low cost.
Using a polymer as a support in combinatorial chemistry
has become an efficient tool to build small molecule li-
braries to accelerate the drug discovery process. In the
field of combinatorial chemistry, solid-phase organic syn-
thesis (SPOS) has been accepted as an efficient method
for high-throughput synthesis.3 Despite its great success,
solid-phase synthesis still exhibits several shortcomings
such as the nature of the heterogeneous reaction and diffi-
culties in reaction monitoring. By replacing insoluble
cross-linked resins with soluble polymer supports, the fa-
Having the above facts in mind and, as a part of our con-
tinuing efforts to develop liquid-phase methods on soluble
supports for the synthesis of heterocyclic compounds,8 we
herein report a new synthetic approach to 1,4-benzodiaz-
epine-2,5-diones using an ionic liquid as a soluble support
(Scheme 1).
As shown in Scheme 1, ionic liquid 1-(2-hydroxyethyl)-
3-methylimidazolium tetrafluoroborate ([2-hydemim]
COO
COO
COOH
Cl
H
Cl
R1NH2
DCC, DMAP
N
+
R1
OH
CH2Cl2
Cu, K2CO3, MeCN
O2N
O2N
O
O2N
1
3
2
R2
COO
O
O2N
N
Br
N
R2NH2
Br
Et3N, CH2Cl2
Br
R1
O
Et3N, CH2Cl2
O2N
N
N
4
O
R1
5
OH
• BF4
N
OH
Scheme 1
SYNTHESIS 2009, No. 2, pp 0205–0210
x
x
.
x
x
.2
0
0
8
Advanced online publication: 19.12.2008
DOI: 10.1055/s-0028-1083289; Art ID: F17408SS
© Georg Thieme Verlag Stuttgart · New York

206
H. Xie et al.
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Table 1 Synthesis of 1,4-Benzodiazepine-2,5-diones Using an Ionic
Liquid as a Soluble Support
[BF4], 1) was reacted with 2-chloro-5-nitrobenzoic acid in
the presence of N,N¢-dicyclohexylcarbodiimide and a cat-
alytic amount of 4-(dimethylamino)pyridine in dry
dichloromethane to offer ionic-liquid-supported carboxy-
lic ester 2. The appearance of the ester carbonyl at 1715
cm–1 in the IR spectrum is a clear evidence for the forma-
tion of 2. The intermediate 2 was treated with a series of
aliphatic amines to afford ionic-liquid-supported amino
esters 3. An array of experiments carried out with differ-
ent reaction temperatures and times, the optimal results
were obtained by refluxing in acetonitrile at 80 °C for five
hours. Amino esters 3 were treated with bromoacetyl bro-
mide in the presence of triethylamine to afford ionic-
liquid-supported amide esters 4. Subsequently, consistent
cyclization/cleavage of 4 to give 5 was achieved by treat-
ment of 4 with a variety of aliphatic amines in the pres-
ence of triethylamine. On completion of the reaction, the
crude products were purified by flash chromatography on
silica gel to afford 1,4-benzodiazepine-2,5-diones 5. The
purified products were characterized by conventional
techniques (1H and 13C NMR and IR). As shown in
Table 1, our method was found to be generally applicable,
all the products were obtained in good overall yields. It is
worthy of note that, in each step of the sequence, the ionic-
liquid-supported intermediates were purified by washing
with diethyl ether. The excess reaction reagents and the
byproducts were removed by simple decantation. More-
over, the ionic liquid [2-hydemim][BF4] (1) could be typ-
Product
R1
Pr
R2
Overall yield (%)
from 1
5a
5b
5c
5d
5e
Pr
Bu
(CH2)4Me
(CH2)5Me
(CH2)2Ph
71
69
71
71
68
5f
5g
5h
5i
Bu
Pr
Bu
(CH2)4Me
(CH2)5Me
(CH2)2Ph
67
66
69
68
70
5j
5k
5l
5m
5n
5o
(CH2)4Me
(CH2)5Me
(CH2)2Ph
Pr
Bu
(CH2)4Me
(CH2)5Me
(CH2)2Ph
67
67
66
64
62
5p
5q
5r
5s
5t
Pr
Bu
(CH2)4Me
(CH2)5Me
(CH2)2Ph
63
62
65
64
61
5u
5v
5w
5x
Pr
Bu
(CH2)4Me
(CH2)5Me
(CH2)2Ph
62
68
67
64
66
ically recovered (the yield of recovered 1 was ≥92%) and 5y
reused with no appreciable decrease in yields and reaction
rates.
Ionic-Liquid-Supported Carboxylic Ester 2
In summary, we report an efficient and new route for the
synthesis of 1,4-benzodiazepine-2,5-diones using an ionic
liquid as a soluble support. The use of this novel ionic liq-
2-Chloro-5-nitrobenzoic acid (3.5 g, 17.5 mmol), DCC (3.09 g, 15
mmol), and DMAP (0.09 g, 0.75 mmol) were added to a soln of [2-
hydemim][BF4] 1 (3.2 g, 15 mmol) in CH2Cl2 (70 mL). After vigor-
uid support offers many advantages compared to previ- ous stirring at r.t. for 12 h, insoluble N,N¢-dicyclohexylurea was re-
moved by filtration. The filtrate was concentrated under reduced
ously reported methods including environmental
pressure and the resulting crude mixture was washed with anhyd
friendliness, much higher loading capacity, easy isolation
Et2O (3 × 20 mL) and dried under vacuum to give 2 as a yellow vis-
and purification of the products, shorter reaction times,
cous oil in 97% yield.
higher yields, no need for use of large excess of reagents,
compatibility with automatic manipulation, use of stan-
dard analytical methods (IR, NMR, TLC) to monitor reac-
tion progress, and recyclability of the soluble support. To
our knowledge, this methodology has not previously been
reported for the preparation of these 1,4-benzodiazepine-
IR (NaCl): 1715 cm–1.
1H NMR (600 MHz, CD3Cl): d = 3.89 (t, 2 H, NCH2), 4.06 (s, 3 H,
NCH3), 4.39 (t, 2 H, NCCH2), 7.63 (t, J = 1.6 Hz, 1 H, H4), 7.67 (d,
1 H, Ph-H3), 7.70 (t, J = 1.6 Hz, 1 H, H5), 8.35 (d, 1 H, Ph-H4), 8.82
(s, 1 H, Ph-H6), 8.88 (s, 1 H, NCHN).
2,5-diones and may complement existing methods in the
Ionic-Liquid-Supported Amino Esters 3; General Procedure
literature. We are currently exploring the scope and poten-
tial of the ionic liquid by extending this methodology to
other heterocyclic targets.
To a soln of 2 (2.0 g, 5 mmol), K2CO3 (0.96 g, 7 mmol), and Cu
powder (0.02 g, 0.25 mmol) in MeCN (20 mL) was added dropwise
a soln of aliphatic amine (7 mmol) in MeCN (5 mL). The mixture
was stirred at 80 °C for 5 h and then cooled to r.t. and filtered. The
filtrate was concentrated under reduced pressure and the resulting
crude mixture was washed with anhyd Et2O (3 × 20 mL) and dried
under vacuum to give 3.
All organic solvents and bases were dried by standard methods.
TLCs were performed on precoated plates of silica gel HF254 (0.5
mm, Yantai, China). Flash column chromatography was performed
on silica gel H (Yantai, China). Melting points were measured on a
WRS-1A digital melting point apparatus and uncorrected. IR spec-
tra were recorded on an IR spectrum one (PE) spectrophotometer,
1H NMR (600 MHz) and 13C NMR (150 MHz) spectra were record-
ed on a Varian Unity Inova 600 spectrometer in CDCl3 using TMS
as internal standard. Element analysis was determined by a Vario
EL III (Germany) analyzer.
3a
IR (NaCl): 3279, 1711 cm–1.
1H NMR (600 MHz, CD3Cl): d = 0.94 (t, 3 H, CH3), 1.58 (m, 2 H,
CH2), 3.09 (m, 2 H, CH2), 3.63 (s, 3 H, NCH3), 3.92 (t, 2 H, CH2),
4.01 (t, 1 H, NH), 4.38 (t, 2 H, CH2), 6.80 (d, J = 1.6 Hz, 1 H, Ph-
H3), 7.66–7.69 (d, 2 H, H4, H5), 8.23 (d, 1 H, Ph-H4), 8.78 (s, 1 H,
Ph-H6), 8.93 (s, 1 H, NCHN).
Synthesis 2009, No. 2, 205–210 © Thieme Stuttgart · New York

PAPER
Synthesis of 1,4-Benzodiazepine-2,5-diones
IR (NaCl): 1688, 1652, 1527, 1346 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.95 (t, 6 H, CH3), 1.30–1.60 (m,
8 H, CH2), 3.21 (t, J = 7.2 Hz, 2 H, CH2), 3.39 (t, J = 7.2 Hz, 2 H,
CH2), 4.28 (s, 2 H, H3), 7.40 (d, J = 7.8 Hz, 1 H, H9), 8.34 (d,
J = 7.8 Hz, 1 H, H8), 8.79 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 11.10, 13.97, 19.77, 22.32, 27.24,
28.77, 46.90, 48.92, 51.41, 122.43, 126.44, 127.16, 130.93, 144.49,
144.48, 164.88, 167.75.
207
13C NMR (150 MHz, CDCl3): d = 11.53, 23.32, 37.91, 47.33, 55.52,
62.11, 108.32, 114.32, 122.81, 123.03, 125.62, 126.21, 136.73,
137.32, 155.81, 166.13.
Ionic-Liquid-Supported Amide Esters 4; General Procedure
To a vigorously stirred soln of 3 (3.0 mmol) and Et3N (0.7 mL, 5
mmol) in anhyd CH2Cl2 (20 mL) was added dropwise a soln of
freshly distilled 2-bromoacetyl bromide (0.45 mL, 5 mmol) in an-
hyd CH2Cl2 (10 mL) over 15 min at ice-bath temperature; the mix-
ture was then refluxed at 40 °C for 12 h. The solvent was evaporated
and the crude mixture was washed with anhyd Et2O (3 × 10 mL)
and dried under vacuum to afford 4.
Anal. Calcd for C17H23N3O4: C, 61.25; H, 6.95; N, 12.60. Found: C,
61.12; H, 6.92; N, 12.58.
4-Hexyl-7-nitro-1-propyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5d)
Mp 98.5–99.1 °C.
4a
IR (NaCl): 3374, 1712 cm–1.
1H NMR (600 MHz, CD3Cl): d = 0.96 (t, 3 H, CH3), 1.48 (m, 2 H,
CH2), 3.36 (t, 2 H, CH2), 3.63 (s, 3 H, NCH3), 3.91 (t, 2 H, CH2),
4.24 (s, 1 H, COCHBr), 4.36 (t, 2 H, CH2), 7.47 (d, 1 H, Ph-H3),
7.63–7.68 (d, 2 H, H4, H5), 8.44 (d, 1 H, Ph-H4), 8.81 (s, 1 H,
NCHN), 8.95 (s, 1 H, Ph-H6).
13C NMR (150 MHz, CDCl3): d = 11.52, 20.41, 26.43, 37.92, 41.91,
55.73, 62.32, 116.61, 122.63, 122.82, 123.21, 125.23, 125.62,
137.21, 143.93, 147.62, 166.21, 166.53.
IR (NaCl): 1688, 1653, 1526, 1344 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.96 (t, 6 H, CH3), 1.2–1.69 (m,
10 H, CH2), 3.21 (t, J = 7.2 Hz, 2 H, CH2), 3.39 (t, J = 7.2 Hz, 2 H,
CH2), 4.18 (s, 2 H, H3), 7.40 (d, J = 7.8 Hz, 1 H, H9), 8.34 (d,
J = 7.8 Hz, 1 H, H8), 8.79 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 11.12, 13.56, 19.98, 22.41, 27.34,
28.78, 29.76, 46.93, 48.91, 51.38, 122.39, 126.41, 127.20, 130.90,
144.43, 144.47, 164.87, 167.71.
Anal. Calcd for C18H25N3O4: C, 62.23; H, 7.25; N, 12.10. Found: C,
62.12; H, 7.31; N, 12.05.
1,4-Benzodiazepine-2,5-diones 5; General Procedure
To a soln of 4 (5 mmol) and Et3N (1.2 mL, 8.6 mmol) in CH2Cl2 (10
mL) was added dropwise a soln of aliphatic amine (10 mmol) in
CH2Cl2 (5 mL). Then the liquid mixture was stirred mechanically
and refluxed at 40 °C for 12 h. The resulting soln was concentrated
and the crude soln was purified by flash chromatography (silica gel,
n-hexane–EtOAc, 4:1) to give the products 5a–y.
7-Nitro-4-phenethyl-1-propyl-3,4-dihydro-1H-1,4-benzodiaz-
epine-2,5-dione (5e)
Mp 54.4–55.3 °C.
IR (NaCl): 1689, 1655, 1527, 1344 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.90 (t, 3 H, CH3), 1.48 (t, 2 H,
CH2), 3.0 (t, J = 7.2 Hz, 2 H, CH2), 3.65 (t, J = 7.2 Hz, 2 H), 3.91 (t,
J = 7.2 Hz, 2 H, CH2), 4.20 (s, 2 H, H3), 7.21–7.31 (m, 5 H), 7.38
(d, J = 7.8 Hz, 1 H, H9), 8.33 (d, J = 7.8 Hz, 1 H, H8), 8.74 (s, 1 H,
H6).
13C NMR (150 MHz, CDCl3): d = 11.21, 21.32, 29.93, 34.21, 49.03,
50.81, 122.32, 122.61, 122.81, 126.73, 126.91, 127.32, 128.23,
128.31, 128.52, 137.92, 144.53, 144.71, 165.12, 167.83.
7-Nitro-1,4-dipropyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-
dione (5a)
Mp 121.3–122.5 °C.
IR (NaCl): 1689, 1654, 1526, 1344 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.95 (t, 6 H, CH3), 1.41–1.65 (m,
4 H, CH2), 3.18 (t, J = 7.2 Hz, 2 H, CH2), 3.30 (t, J = 7.2 Hz, 2 H,
CH2), 4.12 (s, 2 H, H3), 7.36 (d, J = 7.8 Hz, 1 H, H9), 8.34 (d,
J = 7.8 Hz, 1 H, H8), 8.81 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 11.12, 11.14, 20.25, 20.51, 46.34,
48.91, 51.38, 122.42, 126.44, 127.16, 130.93, 144.46, 144.48,
164.84, 167.72.
Anal. Calcd for C20H21N3O4: C, 65.38; H, 5.76; N, 11.44. Found: C,
65.29; H, 5.80; N, 11.46.
1-Butyl-7-nitro-4-propyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5f)
Mp 123.1–124.2 °C.
Anal. Calcd for C15H19N3O4: C, 59.01; H, 6.27; N, 13.76. Found: C,
58.92; H, 6.32; N, 13.65.
IR (NaCl): 1688, 1653, 1527, 1345 cm–1.
4-Butyl-7-nitro-1-propyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5b)
Mp 120.5–121.6 °C.
IR (NaCl): 1688, 1653, 1526, 1343 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.95 (t, 6 H, CH3), 1.33–1.60 (m,
6 H, CH2), 3.21 (t, J = 7.2 Hz, 2 H, CH2), 3.39 (t, J = 7.2 Hz, 2 H,
CH2), 4.14 (s, 2 H, H3), 7.55 (d, J = 7.8 Hz, 1 H, H9), 8.50 (d,
J = 7.8 Hz, 1 H, H8), 8.92 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 11.13, 13.56, 20.23, 20.50, 28.61,
46.35, 48.91, 51.36, 122.41, 126.45, 127.17, 130.92, 144.46,
144.49, 164.85, 167.74.
1H NMR (600 MHz, CDCl3): d = 0.96 (t, 6 H, CH3), 1.33–1.63 (m,
6 H, CH2), 3.27 (t, J = 7.2 Hz, 2 H, CH2), 3.49 (t, J = 7.2 Hz, 2 H,
CH2), 4.16 (s, 2 H, H3), 7.46 (d, J = 7.8 Hz, 1 H, H9), 8.38 (d,
J = 7.8 Hz, 1 H, H8), 8.81 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 11.10, 13.87, 19.78, 20.01, 28.76,
46.89, 48.92, 51.34, 122.39, 126.40, 127.15, 130.89, 144.42,
144.50, 164.85, 167.71.
Anal. Calcd for C16H21N3O4: C, 60.17; H, 6.63; N, 13.16. Found: C,
60.11; H, 6.72; N, 13.20.
1,4-Dibutyl-7-nitro-3,4-dihydro-1H-1,4-benzodiazepine-2,5-di-
one (5g)
Mp 102.1–104.2 °C.
Anal. Calcd for C16H21N3O4: C, 60.17; H, 6.63; N, 13.16. Found: C,
60.04; H, 6.67; N, 13.12.
IR (NaCl): 1689, 1651, 1525, 1340 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.95 (t, 6 H, CH3), 1.32–1.59 (m,
8 H, CH2), 3.25 (t, J = 7.2 Hz, 2 H, CH2), 3.42 (t, J = 7.2 Hz, 2 H,
7-Nitro-4-pentyl-1-propyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5c)
Mp 114.3–116.5 °C.
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208
H. Xie et al.
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CH2), 4.16 (s, 2 H, H3), 7.58 (d, J = 7.8 Hz, 1 H, H9), 8.53 (d,
J = 7.8 Hz, 1 H, H8), 8.91 (s, 1 H, H6).
Anal. Calcd for C17H23N3O4: C, 61.25; H, 6.95; N, 12.60, found: C
61.12; H, 7.01; N, 12.63.
13C NMR (150 MHz, CDCl3): d = 13.51, 13.67, 19.75, 19.90, 29.58,
29.73, 46.92, 48.71, 51.40, 122.41, 126.40, 127.12, 130.92, 144.49,
144.69, 164.86, 167.73.
4-Butyl-7-nitro-1-pentyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5l)
Mp 94.1–95.2 °C.
IR (NaCl): 1689, 1654, 1526, 1345 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.92 (t, 6 H, CH3), 1.26–1.61 (m,
10 H, CH2), 3.25 (t, J = 7.2 Hz, 2 H, CH2), 3.38 (t, J = 7.2 Hz, 2 H,
CH2), 4.14 (s, 2 H, H3), 7.44 (d, J = 7.8 Hz, 1 H, H9), 8.53 (d,
J = 7.8 Hz, 1 H, H8), 8.91 (s, 1 H, H6).
Anal. Calcd for C17H23N3O4: C, 61.25; H, 6.95; N, 12.60. Found: C,
61.12; H, 7.07; N, 12.57.
1-Butyl-7-nitro-4-pentyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5h)
Mp 102.1–104.2 °C.
IR (NaCl): 1689, 1652, 1525, 1344 cm–1.
13C NMR (150 MHz, CDCl3): d = 13.57, 13.92, 20.15, 22.34, 27.13,
29.38, 29.66, 43.87, 46.90, 49.99, 122.43, 126.44, 127.15, 130.92,
144.48, 144.49, 164.87, 167.74.
1H NMR (600 MHz, CDCl3): d = 0.96 (t, 6 H, CH3), 1.24–1.69 (m,
10 H, CH2), 3.25 (t, J = 7.2 Hz, 2 H, CH2), 3.50 (t, J = 7.2 Hz, 2 H,
CH2), 4.14 (s, 2 H, H3), 7.40 (d, J = 7.8 Hz, 1 H, H9), 8.44 (d,
J = 7.8 Hz, 1 H, H8), 8.83 (s, 1 H, H6).
Anal. Calcd for C18H25N3O4: C, 62.23; H, 7.25; N, 12.10. Found: C,
62.15; H, 7.29; N, 12.14.
13C NMR (150 MHz, CDCl3): d = 13.55, 13.97, 19.78, 22.31, 27.24,
28.76, 29.74, 46.91, 48.90, 51.39, 122.41, 126.41, 127.14, 130.99,
144.43, 144.46, 164.86, 167.73.
7-Nitro-1,4-dipentyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-
dione (5m)
Mp 104.2–105.1 °C.
IR (NaCl): 1693, 1654, 1529, 1325 cm–1.
1H NMR(600 MHz, CDCl3): d = 0.96 (t, 6 H, CH3), 1.25–1.60 (m,
12 H, CH2), 3.33 (t, J = 7.2 Hz, 2 H, CH2), 3.56 (t, J = 7.2 Hz, 2 H,
CH2), 4.16 (s, 2 H, H3), 7.41 (d, J = 7.8 Hz, 1 H, H9), 8.34 (d,
J = 7.8 Hz, 1 H, H8), 8.77 (s, 1 H, H6).
Anal. Calcd for C18H25N3O4: C, 62.23; H, 7.25; N, 12.10. Found: C,
62.06; H, 7.34; N, 12.06.
1-Butyl-4-hexyl-7-nitro-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5i)
Mp 75.1–76.1 °C.
IR (NaCl): 1687, 1652, 1525, 1343 cm–1.
13C NMR (150 MHz, CDCl3): d = 13.58, 13.73, 22.15, 22.41, 27.14,
27.25, 29.31, 29.46, 40.74, 46.94, 49.88, 122.41, 126.42, 127.11,
130.94, 144.44, 144.48, 164.84, 167.71.
1H NMR (600 MHz, CDCl3): d = 0.96 (t, 6 H, CH3), 1.28–1.60 (m,
12 H, CH2), 3.25 (t, J = 7.2 Hz, 2 H, CH2), 3.50 (t, J = 7.2 Hz, 2 H,
CH2), 4.15 (s, 2 H, H3), 7.42 (d, J = 7.8 Hz, 1 H, H9), 8.54 (d,
J = 7.8 Hz. 1 H, H8), 8.89 (s, 1 H, H6).
Anal. Calcd for C19H27N3O4: C, 63.14; H, 7.53; N, 11.63. Found: C,
63.07; H, 7.58; N, 11.58.
13C NMR (150 MHz, CDCl3): d = 13.55, 13.97, 19.86, 22.32, 26.84,
27.24, 28.76, 31.34, 46.89, 48.88, 51.37, 122.40, 126.41, 127.12,
130.90, 144.45, 144.45, 164.86, 167.74.
4-Hexyl-7-nitro-1-pentyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5n)
Mp 111.1–112.6 °C.
IR (NaCl): 1690, 1655, 1525, 1345 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.96 (t, 6 H, CH3), 1.25–1.61 (m,
14 H, CH2), 3.78 (t, J = 7.2 Hz, 2 H, CH2), 3.96 (t, J = 7.2 Hz, 2 H,
CH2), 4.14 (s, 2 H, H3), 7.42 (d, J = 7.8 Hz, 1 H, H9), 8.35 (d,
J = 7.8 Hz, 1 H, H8), 8.77 (s, 1 H, H6).
Anal. Calcd for C19H27N3O4: C, 63.14; H, 7.53; N, 11.63. Found: C,
63.08; H, 7.55; N, 11.60.
1-Butyl-7-nitro-4-phenethyl-3,4-dihydro-1H-1,4-benzodiaz-
epine-2,5-dione (5j)
IR (NaCl): 1688, 1653, 1526, 1344 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.95 (t, 3 H, CH3), 1.21–1.57 (m,
4 H, CH2), 2.98 (t, J = 7.2 Hz, 2 H, CH2), 3.42 (t, J = 7.2 Hz, 2 H,
CH2), 3.66 (t, J = 7.2 Hz, 2 H, CH2), 4.23 (s, 2 H, H3), 7.21–7.34
(m, 5 H), 7.38 (d, J = 7.8 Hz, 1 H, H9), 8.32 (d, J = 7.8 Hz, 1 H, H8),
8.84 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 13.52, 19.83, 29.71, 33.92, 46.93,
50.51, 51.92, 126.52, 126.73, 127.11, 128.22, 128.33, 128.51,
128.62, 128.83, 130.71, 137.82, 144.53, 144.71, 164.82, 167.53.
13C NMR (150 MHz, CDCl3): d = 13.53, 13.71, 22.18, 22.51, 27.04,
27.15, 27.17, 29.31, 31.71, 31.56, 46.89, 49.48, 122.42, 126.43,
127.14, 130.95, 144.14, 144.42, 164.85, 167.72.
Anal. Calcd for C20H29N3O4: C, 63.98; H, 7.79; N, 11.19. Found: C,
63.85; H, 7.82; N, 11.22.
7-Nitro-1-pentyl-4-phenethyl-3,4-dihydro-1H-1,4-benzodiaz-
epine-2,5-dione (5o)
IR (NaCl): 1690, 1654, 1535, 1345 cm–1.
Anal. Calcd for C21H23N3O4: C, 66.13; H, 6.08; N, 11.02. Found: C,
66.05; H, 6.21; N, 10.98.
1H NMR (600 MHz, CDCl3): d = 0.90 (t, 3 H, CH3), 1.20–1.60 (m,
6 H, CH2), 3.01 (t, J = 7.2 Hz, 2 H, CH2), 3.65 (t, J = 7.2 Hz, 2 H,
CH2), 3.90 (t, J = 7.2 Hz, 2 H, CH2), 4.22 (s, 2 H, H3), 7.20–7.38
(m, 5 H), 7.39 (d, J = 7.8 Hz, 1 H, H9), 8.32 (d, J = 7.8 Hz, 1 H, H8),
8.73 (s, 1 H, H6).
7-Nitro-1-pentyl-4-propyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5k)
Mp 87.2–88.6 °C.
IR (NaCl): 1689, 1655, 1527, 1344 cm–1.
13C NMR (150 MHz, CDCl3): d = 14.13, 22.31, 27.62, 28.93, 34.21,
47.42, 50.83, 52.21, 126.73, 126.91, 127.32, 128.25, 128.35,
128.56, 128.67, 128.93, 129.01, 130.92, 144.03, 144.71, 165.12,
167.73.
1H NMR (600 MHz, CDCl3): d = 0.95 (t, 6 H, CH3), 1.25–1.63 (m,
8 H, CH2), 3.26 (t, J = 7.2 Hz, 2 H, CH2), 3.39 (t, J = 7.2 Hz, 2 H,
CH2), 4.13 (s, 2 H, H3), 7.43 (d, J = 7.8 Hz, 1 H, H9), 8.51 (d,
J = 7.8 Hz, 1 H, H8), 8.90 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 11.12, 13.98, 20.12, 22.42, 27.25,
28.87, 42.93, 48.92, 49.88, 122.44, 126.45, 127.17, 130.94, 144.48,
144.49, 164.87, 167.76.
Anal. Calcd for C22H25N3O4: C, 66.82; H, 6.37; N, 10.63. Found: C,
66.79; H, 6.42; N, 10.65.
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Synthesis of 1,4-Benzodiazepine-2,5-diones
209
1-Hexyl-7-nitro-4-propyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5p)
Mp 100.5–102.5 °C.
CH2), 3.87 (t, J = 7.2 Hz, 2 H, CH2), 4.22 (s, 2 H, H3), 7.22–7.38
(m, 5 H), 7.40 (d, J = 7.8 Hz, 1 H, H9), 8.33 (d, J = 7.8 Hz, 1 H, H8),
8.74 (s, 1 H, H6).
IR (NaCl): 1689, 1651, 1527, 1343 cm–1.
13C NMR (150 MHz, CDCl3): d = 14.11, 22.82, 26.80, 27.50, 31.61,
32.82, 39.81, 48.02, 49.81, 122.32, 123.32, 126.30, 127.21, 128.02,
128.39, 128.70, 128.71, 128.83, 139.52, 143.82, 144.80, 161.31,
166.52.
1H NMR (600 MHz, CDCl3): d = 0.90 (t, 6 H, CH3), 1.20–1.63 (m,
10 H, CH2), 3.24 (t, J = 7.2 Hz, 2 H, CH2), 3.37 (t, J = 7.2 Hz, 2 H,
CH2), 4.15 (s, 2 H, H3), 7.46 (d, J = 7.8 Hz, 1 H, H9), 8.57 (d,
J = 7.8 Hz, 1 H, H8), 8.91 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 11.6, 13.66, 20.14, 22.46, 26.54,
27.58, 31.86, 40.92, 48.93, 49.77, 122.36, 126.43, 127.24, 130.92,
144.43, 144.57, 164.82, 167.74.
Anal. Calcd for C23H27N3O4: C, 67.46; H, 6.65; N, 10.26. Found: C,
67.42; H, 6.67; N, 10.25.
7-Nitro-1-phenethyl-4-propyl-3,4-dihydro-1H-1,4-benzodiaz-
epine-2,5-dione (5u)
Mp 42.6–43.4 °C.
IR (NaCl): 1688, 1649, 1525, 1341 cm–1.
Anal. Calcd for C18H25N3O4: C, 62.23; H, 7.25; N, 12.10. Found: C,
62.18; H, 7.29; N, 11.07.
4-Butyl-1-hexyl-7-nitro-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5q)
Mp 92.5–94.1 °C.
IR (NaCl): 1688, 1653, 1527, 1343 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.90 (t, 6 H, CH3), 1.09–1.61 (m,
12 H, CH2), 3.35 (t, J = 7.2 Hz, 2 H, CH2), 3.66 (t, J = 7.2 Hz, 2 H,
CH2), 4.14 (s, 2 H, H3), 7.47 (d, J = 7.8 Hz, 1 H, H9), 8.34 (d,
J = 7.8 Hz, 1 H, H8), 8.90 (s, 1 H, H6).
1H NMR (600 MHz, CDCl3): d = 0.93 (t, 3 H, CH3), 1.63 (t, J = 7.2
Hz, 2 H, CH2), 2.88 (t, J = 7.2 Hz, 2 H, CH2), 3.52 (t, J = 7.2 Hz, 2
H, CH2), 3.84 (t, J = 7.8 Hz, 2 H, CH2), 4.58 s, 2 H, H3), 7.07–7.33
(m, 5 H), 7.35 (d, J = 7.8 Hz, 1 H, H9), 8.31 (d, J = 7.8 Hz, 1 H, H8),
8.75 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 11.51, 20.32, 33.10, 48.91, 49.82,
52.21, 122.31, 123.30, 126.31, 126.52, 127.80, 128.22, 128.35,
128.56, 128.81, 139.52, 143.82, 144.80, 161.31, 166.12.
Anal. Calcd for C20H21N3O4: C, 65.38; H, 5.76; N, 11.44. Found: C,
65.45; H, 5.80; N, 11.42.
13C NMR (150 MHz, CDCl3): d = 13.57, 13.96, 20.11, 22.62, 26.44,
27.35, 28.86, 31.55, 39.35, 46.39, 48.88, 122.42, 126.44, 127.16,
130.94, 144.48, 144.55, 164.76, 167.76.
4-Butyl-7-nitro-1-phenethyl-3,4-dihydro-1H-1,4-benzodiaz-
epine-2,5-dione (5v)
Anal. Calcd for C19H27N3O4: C, 63.14; H, 7.53; N, 11.63. Found: C,
63.05; H, 7.60; N, 11.59.
IR (NaCl): 1689, 1651, 1526, 1342 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.96 (t, 3 H, CH3), 1.33 (m, 2 H,
CH2), 1.59 (m, 2 H, CH2), 2.88 (t, J = 7.2 Hz, 2 H, CH2), 3.56 (t,
J = 7.2 Hz, 2 H, CH2), 3.89 (t, J = 7.2 Hz, 2 H, CH2), 4.32 (s, 2 H,
H3), 7.10–7.33 (m, 5 H), 7.34 (d, J = 7.8 Hz, 1 H, H9), 8.31 (d,
J = 7.8 Hz, 1 H, H8), 8.75 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 13.80, 20.21, 29.42, 33.10, 46.41,
49.82, 50.20, 122.31, 126.22, 126.30, 127.21, 128.56, 128.78,
129.02, 129.52, 129.71, 139.50, 143.82, 144.81, 161.30, 166.42.
1-Hexyl-7-nitro-4-pentyl-3,4-dihydro-1H-1,4-benzodiazepine-
2,5-dione (5r)
Mp 94.5–96.2 °C.
IR (NaCl): 1687, 1653, 1527, 1335 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.94 (t, 6 H, CH3), 1.26–1.66 (m,
14 H, CH2), 3.23 (t, J = 7.2 Hz, 2 H, CH2), 3.37 (t, J = 7.8 Hz, 2 H,
CH2), 4.15 (s, 2 H, H3), 7.48 (d, J = 7.8 Hz, 1 H, H9), 8.60 (d,
J = 7.8 Hz, 1 H, H8), 8.90 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 13.57, 13.76, 22.48, 22.62, 26.54,
27.10, 27.34, 29.34, 31.52, 40.86, 46.68, 49.78, 122.42, 126.47,
127.15, 130.91, 144.17, 144.43, 164.88, 167.74.
Anal. Calcd for C21H23N3O4: C, 66.13; H, 6.08; N, 11.02. Found: C,
66.08; H, 6.14; N, 10.95.
7-Nitro-4-pentyl-1-phenethyl-3,4-dihydro-1H-1,4-benzodiaz-
epine-2,5-dione (5w)
Anal. Calcd for C20H29N3O4: C, 63.98; H, 7.79; N, 11.19. Found: C,
63.86; H, 7.82; N, 11.15.
IR (NaCl): 1689, 1650, 1528, 1342 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.90 (t, 3 H, CH3), 1.14–1.60 (m,
6 H, CH2), 2.88 (t, J = 7.2 Hz, 2 H, CH2), 3.55 (t, J = 7.2 Hz, 2 H,
CH2), 3.75 (t, J = 7.2 Hz, 2 H, CH2), 4.03 (s, 2 H, H3), 7.06–7.34
(m, 5 H), 7.41 (d, J = 7.8 Hz, 1 H, H9), 8.30 (d, J = 7.8 Hz, 1 H, H8),
8.75 (s, 1 H, H6).
1,4-Dihexyl-7-nitro-3,4-dihydro-1H-1,4-benzodiazepine-2,5-di-
one (5s)
Mp 90.5–91.8 °C.
IR (NaCl): 1688, 1654, 1526, 1344 cm–1.
13C NMR (150 MHz, CDCl3): d = 14.12, 22.50, 26.90, 29.33, 33.12,
46.72, 49.81, 50.22, 122.32, 126.31, 127.31, 127.52, 128.58,
128.73, 129.02, 129.51, 129.92, 139.53, 143.82, 144.81, 161.50,
167.40.
1H NMR (600 MHz, CDCl3): d = 0.92 (t, 6 H, CH3), 1.28–1.61 (m,
16 H, CH2), 3.23 (t, J = 7.2 Hz, 2 H, CH2), 3.38 (t, J = 7.2 Hz, 2 H,
CH2), 4.14 (s, 2 H, H3), 7.47 (d, J = 7.8 Hz, 1 H, H9), 8.59 (d,
J = 7.8 Hz, 1 H, H8), 8.89 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 13.55, 13.71, 22.63, 22.72, 26.56,
26.71, 27.17, 27.44, 31.43, 31.62, 40.89, 46.56, 49.72, 122.40,
126.43, 127.13, 130.90, 144.37, 144.51, 164.84, 167.71.
Anal. Calcd for C22H25N3O4: C, 66.82; H, 6.37; N, 10.63. Found: C,
66.75; H, 6.45; N, 10.66.
4-Hexyl-7-nitro-1-phenethyl-3,4-dihydro-1H-1,4-benzodiaz-
epine-2,5-dione (5x)
Anal. Calcd for C21H31N3O4: C, 64.76; H, 8.02; N, 10.79. Found: C,
64.82; H, 7.95; N, 10.75.
IR (NaCl): 1689, 1654, 1526, 1345 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.96 (t, 3 H, CH3), 1.29–1.60 (m,
8 H, CH2), 2.70 (t, J = 7.2 Hz, 2 H, CH2), 3.20 (t, J = 7.2 Hz, 2 H,
CH2), 3.71 (t, J = 7.2 Hz, 2 H, CH2), 4.14 (s, 2 H, H3), 7.08–7.21
(m, 5 H), 7.54 (d, J = 7.8 Hz, 1 H, H9), 8.49 (d, J = 7.8 Hz, 1 H, H8),
8.93 (s, 1 H, H6).
1-Hexyl-7-nitro-4-phenethyl-3,4-dihydro-1H-1,4-benzodiaz-
epine-2,5-dione (5t)
IR (NaCl): 1686, 1654, 1527, 1343 cm–1.
1H NMR (600 MHz, CDCl3): d = 0.90 (t, 3 H, CH3), 1.29–1.42 (m,
8 H, CH2), 2.98 (t, J = 7.2 Hz, 2 H, CH2), 3.66 (t, J = 7.2 Hz, 2 H,
Synthesis 2009, No. 2, 205–210 © Thieme Stuttgart · New York

210
H. Xie et al.
PAPER
13C NMR (150 MHz, CDCl3): d = 14.11, 22.81, 26.82, 31.60, 33.10,
46.71, 49.82, 50.21, 122.32, 125.3, 126.32, 127.21, 127.52, 128.58,
128.73, 129.02, 129.51, 129.92, 139.51, 143.81, 144.81, 161.30,
166.40.
(2) For solid-phase synthesis of 1,4-benzodiazepine-2,5-diones,
see: (a) Boojamra, C. G.; Burow, K. M.; Thompson, L. A.;
Ellman, J. A. J. Org. Chem. 1997, 62, 1240. (b) Mayer, J.
P.; Zhang, J.; Bjergarde, K.; Lenz, D. M.; Gaudino, J. J.
Tetrahedron Lett. 1996, 37, 8081. (c) Hulme, C.; Peng, J.;
Morton, G.; Salvino, J. M.; Herpin, T.; Labaudiniere, R.
Tetrahedron Lett. 1998, 39, 7227. (d) Kennedy, A. L.;
Fryer, A. M.; Josey, J. A. Org. Lett. 2002, 4, 1167.
(3) For recent reviews, see: (a) Hermkens, P. H. H.; Ottenheijm,
H. C. J.; Rees, D. Tetrahedron 1996, 52, 4527. (b) Booth,
S.; Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D. C.
Tetrahedron 1998, 54, 15385. (c) Lorsbach, B. A.; Kurth,
M. J. Chem. Rev. 1999, 99, 1549. (d) Guillier, F.; Orain, D.;
Bradley, M. Chem. Rev. 2000, 100, 2091. (e) Sammelson,
R.; Kurth, M. J. Chem. Rev. 2001, 101, 137. (f) Krchòák,
V.; Holladay, W. Chem. Rev. 2002, 102, 61. (g) Blaney, P.;
Grigg, R.; Sridharan, V. Chem. Rev. 2002, 102, 2607.
(4) (a) Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489.
(b) Wentworth, P. J.; Janda, K. D. Chem. Commun. 1999,
1917.
Anal. Calcd for C23H27N3O4: C, 67.46; H, 6.65; N, 10.26. Found: C,
67.52; H, 6.67; N, 10.28.
7-Nitro-1,4-bis(phenethyl)-3,4-dihydro-1H-1,4-benzodiaz-
epine-2,5-dione (5y)
IR (NaCl): 1689, 1654, 1526, 1345 cm–1.
1H NMR (600 MHz, CDCl3): d = 2.70 (t, 2 H, CH2), 2.85 (t, 2 H,
CH2), 3.53 (t, 2 H, CH2), 3.74 (t, 2 H, CH2), 4.21 (s, 2 H, H3), 7.04–
7.21 (m, 10 H), 7.54 (d, J = 7.8 Hz, 1 H, H9), 8.49 (d, J = 7.8 Hz, 1
H, H8), 8.93 (s, 1 H, H6).
13C NMR (150 MHz, CDCl3): d = 32.82, 33.12, 48.01, 49.80, 50.21,
122.32, 123.52, 126.32, 126.71, 126.80, 127.20, 127.31, 127.58,
127.73, 128.02, 128.41, 128.62, 128.73, 128.86, 139.51, 139.59,
143.82, 144.81, 161.31, 167.41
Anal. Calcd for C25H23N3O4: C, 69.92; H, 5.40; N, 9.78. Found: C,
69.98; H, 5.42; N, 9.82.
(5) (a) Toy, P. H.; Janda, K. M. Acc. Chem. Res. 2000, 33, 546.
(b) Fishman, A.; Farrah, M. E.; Zhong, J. H.;
Paramanantham, S.; Carrera, C.; Lee-Ruff, E. J. Org.Chem.
2003, 68, 9843. (c) Sauvagnat, B.; Kulig, K.; Lamaty, F.;
Lazaro, R.; Martinez, J. J. Comb. Chem. 2000, 2, 134.
(d) Chen, S.; Janda, K. D. J. Am. Chem. Soc. 1997, 119,
8724. (e) Lin, X. F.; Zhang, J.; Wang, Y. G. Tetrahedron
Lett. 2003, 44, 4113. (f) Wang, Y. G.; Lin, X. F.; Cui, S. L.
Synlett 2004, 1175.
Acknowledgment
This work is supported by the National Natural Sciences Founda-
tion of China (No. 20772026) and the Natural Sciences Foundation
of Hubei province in China (No. 2007ABA031).
(6) For a recent review, see: Davis, J. H. J. Chem. Lett. 2004, 33,
References
1072.
(7) (a) Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett.
2001, 42, 6097. (b) Miao, W.; Chan, T. H. Org. Lett. 2003,
5, 5003. (c) Fraga-Dubreuil, J.; Famelart, M. H.; Bazureau,
J. P. Org. Process Res. Dev. 2002, 6, 374. (d) Fraga-
Dubreuil, J.; Bazureau, J. P. Tetrahedron 2003, 59, 6121.
(8) (a) Peng, H. D.; Huang, Y. L.; Yang, J. H.; Chen, Z. X.;
Yang, G. C. Comb. Chem. High Throughput Screening
2007, 10, 257. (b) Zhang, H. Q.; Yang, G. C.; Chen, J. N.;
Chen, Z. X. Synthesis 2004, 3055. (c) Rao, Z.; Peng, H. D.;
Yang, G. C.; Chen, Z. X. Comb. Chem. High Throughput
Screening 2006, 9, 1743. (d) Chen, Z. X.; Yue, G. Z.; Lu, C.
F.; Yang, G. C. Synlett 2004, 1231. (e) Yue, G. Z.; Wan, Y.
D.; Song, S. J.; Yang, G. C.; Chen, Z. X. Bioorg. Med. Chem.
Lett. 2005, 15, 453.
(1) For recent articles on the syntheses and bioactivities of 1,4-
benzodiazepine-2,5-diones, see: (a) Kamal, A.; Reddy, K.
L.; Devaiah, V. Synlett 2004, 2533. (b) Kamal, A.; Ramana,
A. V.; Reddy, K. S. Tetrahedron Lett. 2004, 45, 818.
(c) Sabb, A. L.; Vogel, R. L.; Welmaker, G. S.; Sabalski, J.
E.; Coupet, J.; Dunlop, J.; Rosenzweig-Lipson, S.; Harrison,
B. Bioorg. Med. Chem. Lett. 2004, 14, 2603. (d) Li, X. Y.;
Cao, H.; Zhang, C. C.; Fuchs, K. J. Med. Chem. 2003, 46,
5567. (e) Parks, D. J.; LaFrance, L. V.; Calvo, R. R.;
Milkiewicz, K. L.; Gupta, V.; Lattanze, J.; Ramachandren,
K.; Carver, T. E.; Petrella, E. C.; Cummings, M. D.;
Maguire, D.; Grasberger, B. L.; Lu, T. B. Bioorg. Med.
Chem. Lett. 2005, 15, 765.
Synthesis 2009, No. 2, 205–210 © Thieme Stuttgart · New York