Synthesis of novel tricyclic 4-chloro-7,8,10,11-tetrahydro-5H-benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-ones

Article abstract of DOI:10.1002/jhet.384

(Chemical Equation Presented) A series of tricyclic 7,8,10,11-tetrahydro- 5H-benzo[e]pyrimido[4,5-b][1,4]diazepin-9(6H)-ones were prepared in moderate to high yields using TFA-promoted iminium-cyclization reactions of 3-(6-(butylamino)-4-chloropyrimidin-5-ylamino)cyclohex-2-enones and various aldehydes.

Full text of DOI:10.1002/jhet.384

990
Synthesis of Novel Tricyclic 4-Chloro-7,8,10,11-tetrahydro-5H-
benzo[e]pyrimido[4,5-b][1,4]diazepin-9(6H)-ones
Vol 47
Jinbao Xiang, Lianyou Zheng, Tong Zhu, Qun Dang,* and Xu Bai*
Center for Combinatorial Chemistry and Drug Discovery, School of Pharmaceutical Sciences,
College of Chemistry, Jilin University, Changchun, Jilin, People’s Republic of China
*E-mail: qdang@jlu.edu.cn or xbai@jlu.edu.cn
Received August 9, 2009
DOI 10.1002/jhet.384
Published online 18 June 2010 in Wiley InterScience (www.interscience.wiley.com).
A series of tricyclic 7,8,10,11-tetrahydro-5H-benzo[e]pyrimido[4,5-b][1,4]diazepin-9(6H)-ones were
prepared in moderate to high yields using TFA-promoted iminium-cyclization reactions of 3-(6-(butyla-
mino)-4-chloropyrimidin-5-ylamino)cyclohex-2-enones and various aldehydes.
J. Heterocyclic Chem., 47, 990 (2010).
To identify the optimal reaction conditions, the for-
mation of the pyrimido-benzodiazepine nucleus was ini-
tially studied using benzaldehyde as the substrate, and
results are summarized in Table 1.
INTRODUCTION
Benzodiazepines have long been associated with inter-
esting biological activities. For example, clozapine is
used to treat schizophrenia; pirenzepine acts selectively
as a muscarinic receptor (M1) antagonist; and apafant
acts as the platelet activating factor inhibitors [1]. Con-
sequently, syntheses of benzodiazepine derivatives or
diazepine-containing heterocycles are of interest to or-
ganic and medicinal chemists. Thus, dibenzo[b,e][1,4]-
diazepines and other tricyclic systems with a 1,4-diaze-
pine moiety are well documented in the literature [2–9].
As part of our program to prepare heterocyclic libraries,
we developed a series of methodologies to rapidly access var-
ious heterocyclic scaffolds with benzodiazepine as the core
[10–15]. These methodologies entail Bischler–Napieralski
cyclization reactions and iminium cyclization reactions as the
key transformation steps. To expand the scope of the imi-
nium-cyclization reaction, we envisioned that enaminones 1
could be reacted with various aldehydes to prepare 7,8,10,11-
tetrahydro-5H-benzo[e]pyrimido[4,5-b][1,4]diazepin-9(6H)-
ones [16], as depicted in Scheme 1. Although syntheses of
dibenzo [b,e][1,4]diazepines are frequently reported, there is
few report of aminopyrimidines as substrates for such cycli-
zation reactions [16]. Given the large structural differences
between a pyrimidine and benzene, optimization of the cycli-
zation reaction was investigated. Herein, we reported the de-
velopment of this method to prepare 7,8,10,11-tetrahydro-
5H-benzo[e]pyrimido[4,5-b][1,4]diazepin-9(6H)-ones.
The standard conditions of AcOH-EtOH are often
reported for similar type of cyclization reactions of ani-
lines leading to dibenzo[b,e][1,4]diazepines [2,4]. There-
fore, these conditions were studied initially. No desired
product was detected at room temperature (entry 1,
Table 1) and only trace amount was isolated after pro-
longed heating (entry 2, Table 1). The lower reactivity
of pyrimidines 1 compared to standard anilines is likely
because of the large structural differences between py-
rimidine and benzene. It is possible that the pyrimidine
ring nitrogens are protonated under the acidic reaction
conditions, which decreased the propensity of the n-
butylamino group toward imine formation. It was rea-
soned that a stronger acid, such as TFA might help to
promote the key imine formation step. Thus, switching
the acid from acetic acid to stronger acids, such as TFA
and sulfuric acid led to low yields of desired product 2,
entries 3–5, Table 1. The conditions of TFA-acetonitrile
proved to be productive in other iminium cyclization
reactions, therefore they were investigated next. Treat-
ment of pyrimidine 1 and benzaldehyde in the presence
of TFA at room temperature led to product 2 in 22%
yield (entry 6, Table 1). On the hand, moderate
heating at 60ꢀC produced the desired product 2 in 56%
yield. The reaction temperature to reflux shortened the
reaction time to 18 h, producing compound 2 in 59%
yield (entry 8, Table 1). To test the solvent effect of
acetonitrile, the reaction was repeated using AcOH
with CH3CN (entry 9), and after reflux for 18 h only
11% of the desired product was obtained. Another
RESULTS AND DISCUSSION
The desired enaminones 1 were readily prepared via
condensation of 3 [17] with 1,3-cyclohexandione in ace-
tic acid in 78% yields, as depicted in Scheme 2.
C
V
2010 HeteroCorporation

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Synthesis of Novel Tricyclic 4-Chloro-7,8,10,11-tetrahydro-5H-
benzo[e]pyrimido[4,5-b][1,4]diazepin-9(6H)-ones
991
Scheme 1
Table 1
Cyclization Reactions between 1 and Benzaldehydea
condition investigated was Py/SOCl2-CH2Cl2 [18],
which was reported for aniline cyclization reactions.
Reflux for 78 h, the desired product was isolated in 40%
yield (entry 10). Thus, the TFA-acetonitrile conditions
(entry 8, Table 1) were identified as optimal, which
were applied to other aldehydes and results are summar-
ized in Table 2.
Entry Solvent
Acid
Temp (ꢀC) Time (h) Yield (%)
1
2
EtOH
EtOH
EtOH
AcOH
AcOH
TFA
24
reflux
24
24
43
24
43
95
24
52
18
18
78
NRb
5c
2c
3
4
EtOH
EtOH
TFA
reflux
reflux
24
10
8
5
H2SO4
TFA
TFA
6
CH3CN
CH3CN
CH3CN
CH3CN
22c
56
59
11c
40
7
60
As disclosed in Table 2, both aliphatic and aromatic
aldehydes are compatible for the current reactions, pro-
ducing the expected 7,8,10,11-tetrahydro-5H-benzo[e]-
pyrimido[4,5-b][1,4]diazepin-9(6H)-ones 2 in moderate
to good yields. The reactions with aliphatic aldehydes
(entries 1–3) proceeded at room temperature to generate
the desired products in moderate yields. Various func-
tional groups ranging from electron-donating (methyl or
methoxy; entries 4–6) to electron-withdrawing groups
(halo, cyano, or nitro; entries 8–14) were tolerated under
the reaction conditions. The Results presented in Table
2 seem to suggest that both electronic and steric effects
may affect the yields when benzaldehydes were used.
For example, electron-withdrawing groups tend to give
higher yields (entries 11–14) compared to electron-
donating groups (entries, 4–6). The presence of an ortho
substituent (entries 3 and 8) led to lower yields com-
pared to the corresponding meta- and para-substituted
analogs (entries 4 and 9), which suggests steric hin-
drance may lead to lower yields.
8
9
10
TFA
AcOH
reflux
reflux
reflux
DCM Py/SOCl2
a Yields are isolated products and the reaction was monitored by LC-
MS.
b NR denotes no reaction, all starting materials remained.
c Some starting material 1 was recovered.
chloro-7,8,10,11-tetrahydro-5H-benzo[e]pyrimido[4,5-b]
[1,4]diazepin-9(6H)-ones in moderate to excellent
yields.
EXPERIMENTAL
Acetonitrile (CH3CN) was dried with CaH2 and distilled.
All other commercial reagents were used as received without
purification. Melting points were uncorrected. Mass spectra
and HPLC data were recorded on a LC/MS system with ELSD
1
detection. The H and 13C NMR data were obtained on a Var-
ian 300 (300 and 75 MHz, respectively) spectrometer with
TMS as the internal standard and CDCl3 as the solvent unless
otherwise stated. Multiplicities are indicated as the following:
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd,
doubled doublet; br, broad. Coupling constants (J values) are
quoted in Hertz.
In summary, a novel heterocyclic scaffold entailing
7,8,10,11-tetrahydro-5H-benzo[e]pyrimido[4,5-b][1,4]dia-
zepin-9(6H)-one was prepared efficiently from N-substi-
tuted pyrimidinediamine and aldehydes. The standard
AcOH-EtOH conditions commonly used to prepare
dibenzo[b,e][1,4]diazepines proved to unsuitable for ami-
nopyrimidines. Thus, a new TFA-acetonitrile condition
was successfully developed to produce the desired 4-
3-(6-(Butylamino)-4-chloropyrimidin-5-ylamino)cyclohex-
2-enone (1). A solution of 5-amino-4-chloro-6-(butylamino)-
pyrimidine 3 (1.5 g, 7.5 mmol), 1,3-cyclohexandione (0.84 g,
7.5 mmol), and a catalytic amount of acetic acid (30 lL, 0.52
mmol) in cyclohexane (40 mL) was heated in an azeotropic
distillation apparatus for 2 days. The solvent was removed in
vacuo to give the crude product, which was recrystallized from
acetone to give 1.71 g (78%) of 1, mp 190–192ꢀC.1H NMR:
8.29 (s, 1H), 5.74 (s, 1H), 5.32 (s, 1H), 4.93 (s, 1H), 3.47 (q,
2H, J ¼ 6.9 Hz), 2.51 (t, 2H, J ¼ 5.4 Hz), 2.35 (t, 2H, J ¼
6.3 Hz), 2.10–2.02 (m, 2H), 1.61–1.29 (m, 2H), 1.41–1.29 (m,
2H), 0.92 (t, 3H, J ¼ 7.2 Hz). MS (ESI): m/z 295.3 [MþHþ].
General procedure for the synthesis of 4-chloro-
7,8,10,11-tetrahydro-5H-benzo[e]pyrimido[4,5-b][1,4]diaze-
pin-9(6H)-one (2). To a solution of 3-(6-(butylamino)-4-chlor-
opyrimidin-5-ylamino)cyclohex-2-enone 1 (150 mg, 0.51 mmol)
and an aldehyde (0.612 mmol) in 4 mL acetonitrile was added
TFA (20 lL, 0.27 mmol). The mixture was stirred for corre-
sponding time at ambient temperature or 80ꢀC. After cooling to
Scheme 2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

992
J. Xiang, L. Zheng, T. Zhu, Q. Dang, and X. Bai
Vol 47
Table 2
51.8, 35.9, 31.6, 30.2, 20.8, 20.1, 13.8. MS (ESI): m/z 413.1
[MþHþ].
Synthesis of 4-chloro-7,8,10,11-tetrahydro-SH-benzo[e]pyrimido[4,5-
6][1,4]diazepin 9(6H)-ones.a
11-Butyl-4-chloro-10-(4-methoxyphenyl)-7,8,10,11-tetrahydro-
5H-benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.4). 22%.
1
mp: 167–169ꢀC. H NMR: 8.04 (s, 1H), 7.09 (d, 2H, J ¼ 8.7
Hz), 6.73 (d, 2H, J ¼ 8.7 Hz), 6.30 (s, 1H), 6.09 (s, 1H),
4.50–4.41 (m, 1H), 3.74 (s, 3H), 3.23–3.14 (m, 1H), 2.73–2.59
(m, 1H), 2.55–2.43 (m, 3H), 2.16–1.95 (m, 2H), 1.73–1.53 (m,
2H). 1.38–1.26 (m, 2H), 0.91 (t, 3H, J ¼ 7.5 Hz). 13C NMR:
194.0, 158.4, 156.2, 155.3, 149.8, 145.2, 133.0, 127.2, 119.4,
118.3, 113.9, 57.8, 55.1, 52.4, 35.8, 31.7, 30.1, 20.9, 20.0,
13.8. MS (ESI): m/z 413.1 [MþHþ].
Entry
R
Compd.
Time
Yield (%)
11-Butyl-4-chloro-10-(4-methylphenyl)-7,8,10,11-tetrahydro-5H-
benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.5). 57%. mp:
1
2
3
CH3CH2CH2
CH3CH2CH2
CH3CH2
2.1
2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
2.11
2.12
2.13
7h
34
51
62
13
22
57
59
41
45
65
68
80
87
87
3db
3db
9h
1
144–146ꢀC. H NMR: 8.04 (s, 1H), 7.00 (d, 2H, J ¼ 8.1 Hz),
6.86 (d, 2H, J ¼ 7.8 Hz), 6.29 (s, 1H), 6.11 (s, 1H), 4.50–4.41
(m, 1H), 3.23–3.13 (m, 1H), 2.72–2.56 (m, 1H), 2.54–2.41 (m,
3H), 2.26 (s, 3H), 2.16–1.94 (m, 2H), 1.71–1.50 (m, 2H).
1.38–1.26 (m, 2H), 0.91 (t, 3H, J ¼ 7.2 Hz). 13C NMR: 193.9,
156.3, 155.2, 149.6, 145.1, 137.8, 136.4, 129.1, 125.7, 119.2,
118.3, 57.8, 52.3, 35.7, 31.5, 30.0, 20.70, 20.68, 19.9, 13.7.
MS (ESI): m/z 397.2 [MþHþ].
4
o-MeOC6H4
p-MeOC6H4
p-MeC6H4
Ph
5
6
20h
20h
18h
20h
20
22h
22h
18h
17h
18h
7
8
o-ClC6H4
9
20,40-di-ClC6H3
30,40-di-ClC6H3
p-FC6H4
10
11
12
13
14
11-Butyl-4-chloro-10-phenyl-7,8,10,11-tetrahydro-5H-benzo[e]-
pyrimido [4,5-b][1,4]diazepin-9(6H)-one (2.6). 59%. mp: 154–
155ꢀC. 1H NMR: 8.04 (s, 1H), 7.24–7.17 (m, 3H), 6.98 (dd,
2H, J1 ¼ 7.5 Hz, J2 ¼ 1.8 Hz), 6.28 (s, 1H), 6.15 (s, 1H),
4.52–4.42 (m, 1H), 3.23–3.14 (m, 1H), 2.71–2.42 (m, 4H),
2.16–1.92 (m, 2H), 1.76–1.53 (m, 2H), 1.38–1.25 (m, 2H),
0.91 (t, 3H, J ¼ 7.5 Hz). 13C NMR: 193.9, 156.6, 155.1,
149.5, 145.0, 140.8, 128.4, 126.8, 125.8, 119.1, 118.1, 57.9,
52.3, 35.6, 31.4, 29.9, 20.6, 19.8, 13.6. MS (ESI): m/z 383.2
[MþHþ].
p-CNC6H4
m-NO2C6H4
p-NO2C6H4
a All reactions were conducted at 80ꢀC unless noted, yields are based
on isolated products.
b Reaction was carried out at 25ꢀC.
room temperature, the solvent was removed in vacuo to give the
crude product. Purification by flash chromatography (Petroleum
ether/EtOAc ¼ 5:1 or 2:1) afforded the desired products.
11-Butyl-4-chloro-10-propyl-7,8,10,11-tetrahydro-5H-benzo[e]-
pyrimido[4,5-b] [1,4]diazepin-9(6H)-one (2.1). 51%. mp: 83–
85ꢀC. 1H NMR: 8.05 (s, 1H), 6.45 (s, 1H), 4.87 (t, 1H, J ¼
8.1 Hz), 4.32–4.22 (m, 1H), 3.10–3.01 (m, 1H), 2.72–2.59 (m,
1H), 2.56–2.42 (m, 3H), 2.12–1.91 (m, 2H), 1.65–1.45 (m,
4H), 1.33–1.15 (m, 4H). 0.92–0.83 (m, 6H). 13C NMR: 194.4,
155.5, 154.4, 149.5, 144.3, 119.1, 116.7, 55.2, 51.7, 36.3, 35.5,
31.6, 29.8, 20.9, 19.93, 19.86, 13.8, 13.7. MS (ESI): m/z 349.1
[MþHþ].
11-Butyl-4-chloro-10-(2-chlorophenyl)-7,8,10,11-tetrahydro-5H-
benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.7). 41%. mp:
1
179–181ꢀC. H NMR: 8.04 (s, 1H), 7.34 (d, 1H, J ¼ 7.5 Hz),
7.17–7.05 (m, 3H), 6.27 (s, 1H), 6.24 (s, 1H), 4.33–4.24 (m,
1H), 3.34–3.24 (m, 1H), 2.69–2.35 (m, 4H), 2.09–1.91 (m,
2H), 1.71–1.53 (m, 2H). 1.38–1.26 (m, 2H), 0.91 (t, 3H, J ¼
7.2 Hz). 13C NMR: 193.6, 156.2, 155.2, 150.2, 145.7, 138.6,
133.6, 130.5, 128.5, 127.3, 126.5, 120.2, 117.7, 56.7, 51.8,
35.7, 31.5, 30.0, 20.3, 20.0, 13.8. MS (ESI): m/z 417.1
[MþHþ].
11-Butyl-4-chloro-10-(2,4-dichlorophenyl)-7,8,10,11-tetrahydro-
5H-benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.8). 45%.
mp: 152–154ꢀC. 1H NMR: 8.05 (s, 1H), 7.36 (s, 1H), 7.07–
6.97 (m, 2H), 6.25 (s, 1H), 6.22 (s, 1H), 4.31–4.22 (m, 1H),
3.31–3.22 (m, 1H), 2.65–2.34 (m, 4H), 2.10–1.92 (m, 2H),
1.69–1.49 (m, 2H). 1.37–1.27 (m, 2H), 0.91 (t, 3H, J ¼ 7.2
Hz). 13C NMR: 193.5, 156.2, 155.0, 150.4, 146.0, 137.4,
134.5, 133.7, 130.3, 128.2, 126.8, 120.1, 117.5, 56.4, 51.9,
35.8, 31.6, 30.1, 20.3, 20.0, 13.8. MS (ESI): m/z 451.1
[MþHþ].
11-Butyl-4-chloro-10-ethyl-7,8,10,11-tetrahydro-5H-benzo[e]-
pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.2). 62%. oil. 1H
NMR: 8.03 (s, 1H), 7.29 (s, 1H), 4.78 (t, 1H, J ¼ 8.1 Hz),
4.34–4.25 (m, 1H), 3.09–2.97 (m, 1H), 2.68–2.59 (m, 1H),
2.52 (t, 1H, J ¼ 5.1 Hz), 2.48–2.41 (m, 2H), 2.10–1.94 (m,
2H), 1.74–1.48 (m, 4H), 1.30–1.23 (m, 2H), 0.91–0.80 (m,
6H). 13C NMR: 193.9, 154.8, 154.2, 149.6, 144.8, 119.2,
116.5, 56.7, 51.8, 35.8, 31.6, 29.8, 27.1, 21.0, 19.9, 13.7, 11.1.
MS (ESI): m/z 335.1 [MþHþ].
11-Butyl-4-chloro-10-(2-methoxyphenyl)-7,8,10,11-tetrahydro-
5H-benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.3). 13%.
mp: 168–169ꢀC. 1H NMR: 7.97 (s, 1H), 7.18–7.13 (m, 1H),
6.99 (d, 1H, J ¼ 6.3 Hz), 6.82–6.73 (m, 2H), 6.25 (s, 1H),
6.23 (s, 1H), 4.36–4.26 (m, 1H), 3.78 (s, 3H), 3.33–3.24 (m,
1H), 2.70–2.61 (m, 1H), 2.57–2.42 (m, 3H), 2.12–1.91 (m,
2H), 1.68–1.50 (m, 2H). 1.37–1.24 (m, 2H), 0.90 (t, 3H, J ¼
7.5 Hz). 13C NMR: 193.4, 157.1, 155.7, 155.6, 149.8, 145.1,
128.6, 128.1, 126.8, 120.2, 119.8, 116.7, 111.0, 55.14, 55.11,
11-Butyl-4-chloro-10-(3,4-dichlorophenyl)-7,8,10,11-tetrahydro-
5H-benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.9). 65%.
mp: 132–134ꢀC. 1H NMR: 8.07 (s, 1H), 7.28 (s, 1H), 7.06
(dd, 1H, J1 ¼ 2.1 Hz, J2 ¼ 0.6 Hz), 6.84–6.80 (m, 1H), 6.33
(s, 1H), 6.09 (s, 1H), 4.50–4.41 (m, 1H), 3.21–3.11 (m, 1H),
2.74–2.44 (m, 4H), 2.18–1.94 (m, 2H), 1.71–1.49 (m, 2H).
1.37–1.26 (m, 2H), 0.91 (t, 3H, J ¼ 7.2 Hz). 13C NMR: 193.9,
156.9, 154.9, 150.0, 145.8, 141.5, 132.6, 131.1, 130.4, 128.2,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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Synthesis of Novel Tricyclic 4-Chloro-7,8,10,11-tetrahydro-5H-
benzo[e]pyrimido[4,5-b][1,4]diazepin-9(6H)-ones
993
REFERENCES AND NOTES
125.3, 119.1, 117.6, 57.3, 52.4, 35.6, 31.6, 30.0, 20.7, 19.9,
13.7. MS (ESI): m/z 451.0 [MþHþ].
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Kowalska, M. W.; Głowiak, T. Part II. Arch Pharm Pharm Med Chem
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11-Butyl-4-chloro-10-(4-fluorophenyl)-7,8,10,11-tetrahydro-5H-
benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.10). 68%.
mp: 146–148ꢀC. 1H NMR: 8.05 (s, 1H), 6.97–6.86 (m, 4H),
6.31 (s, 1H), 6.10 (s, 1H), 4.50–4.40 (m, 1H), 3.22–3.13 (m,
1H), 2.73–2.44 (m, 4H), 2.19–1.93 (m, 2H), 1.72–1.49 (m,
2H), 1.42–1.23 (m, 2H), 0.91 (t, 3H, J ¼ 7.2 Hz). 13C NMR:
194.0, 163.3, 160.0, 156.7, 155.2, 149.8, 145.3, 136.7, 127.7,
127.6, 119.3, 118.0, 115.6, 115.3, 57.7, 52.4, 35.7, 31.6, 30.1,
20.8, 20.0, 13.8. MS (ESI): m/z 401.1 [MþHþ].
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[2] Cortes, E. C.; Cornejo, A. L. V.; de Cortes, O. G.-M. J Het-
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11-Butyl-4-chloro-10-(4-cyanophenyl)-7,8,10,11-tetrahydro-5H-
benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.11). 80%.
mp: 51–53ꢀC. 1H NMR: 8.08 (s, 1H), 7.51 (d, 2H, J ¼ 8.4 Hz),
7.10 (d, 2H, J ¼ 8.1 Hz), 6.34 (s, 1H), 6.18 (s, 1H), 4.50–4.40
(m, 1H), 3.23–3.14 (m, 1H), 2.74–2.45 (m, 4H), 2.17–2.00 (m,
2H), 1.70–1.54 (m, 2H). 1.36–1.26 (m, 2H), 0.91 (t, 3H, J ¼ 7.5
Hz). 13C NMR: 193.9, 157.2, 154.7, 149.9, 146.6, 145.7, 132.3,
126.7, 118.9, 118.3, 117.5, 110.7, 57.7, 52.4, 35.5, 31.4, 29.9,
20.5, 19.8, 13.6. MS (ESI): m/z 408.2 [MþHþ].
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11-Butyl-4-chloro-10-(3-nitrophenyl)-7,8,10,11-tetrahydro-5H-
benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.12). 80%.
mp: 51–53ꢀC. 1H NMR: 8.08 (s, 1H), 8.04 (d, 1H, J ¼ 7.8 Hz),
7.84 (s, 1H), 7.43–7.33 (m, 2H), 6.34 (s, 1H), 6.21 (s, 1H), 4.56–
4.47 (m, 1H), 3.21–3.18 (m, 1H), 2.71–2.47 (m, 4H), 2.19–2.04
(m, 2H), 1.75–1.57 (m, 2H). 1.40–1.26 (m, 2H), 0.93 (t, 3H, J ¼
6.9 Hz). 13C NMR: 193.9, 157.2, 154.8, 150.0, 148.4, 145.9,
143.4, 132.2, 129.6, 122.1, 121.2, 119.1, 117.1, 57.6, 52.5, 35.6,
31.5, 30.0, 20.7, 19.9, 13.7. MS (ESI): m/z 428.1 [MþHþ].
11-Butyl-4-chloro-10-(4-nitrophenyl)-7,8,10,11-tetrahydro-5H-
benzo[e] pyrimido[4,5-b][1,4]diazepin-9(6H)-one (2.13). 80%.
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[16] During the preparation of this manuscript, we have noticed
a recent report by Raboisson, P. (McGowan, D.; Nyanguile, O.; Cum-
mings, M. D.; Vendeville, S.; Vandyck, K.; Van den Broeck, W.;
Boutton, C. W.; De Bondt, H.; Quirynen, L.; Amssoms, K.; Bonfanti,
J.-F.; Last, S.; Rombauts, K.; Tahri, A.; Hu, L.; Delouvroy, F.; Ver-
meiren, K.; Vandercruyssen, G.; Van der Helm, L.; Cleiren, E.; Most-
mans, W.; Lory, P.; Pille, G.; Van Emelen, K.; Fanning, G.; Pauwels,
F.; Lin, T.-I.; Simmen, K.; Raboisson, P. Bioorg Med Chem Lett
2009, 19, 2492.)
1
mp: 51–53ꢀC. H NMR: 8.09 (s, 1H), 8.07 (d, 2H, J ¼ 8.4 Hz),
7.16 (d, 2H, J ¼ 8.4 Hz), 6.34 (s, 1H), 6.23 (s, 1H), 4.51–4.41
(m, 1H), 3.26–3.17 (m, 1H), 2.76–2.47 (m, 4H), 2.20–1.93 (m,
2H), 1.74–1.50 (m, 2H). 1.39–1.24 (m, 2H), 0.90 (t, 3H, J ¼ 7.5
Hz). 13C NMR: 193.9, 157.2, 154.7, 150.0, 148.8, 146.7, 145.8,
126.9, 123.7, 119.0, 117.6, 57.7, 52.4, 35.5, 31.5, 29.9, 20.6,
19.9, 13.7. MS (ESI): m/z 428.1 [MþHþ].
Acknowledgments. This work was supported by National Natural
Science Foundation of China grants 90713008, National Key Re-
search Program on Drug Discovery grants of China 2009ZX09501-
010, Ph.D. Programs Foundation of Ministry of Education of China
20070183038, and Changchun Discovery Sciences, Ltd.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet