Expedient green-chemistry approaches for a one-pot synthesis of two series of novel 1,5-benzodiazepines: Via domino reactions

Article abstract of DOI:10.1039/c9nj06332c

Unique green-chemistry approaches have been developed for the one-pot synthesis of two series of novel 1,5-benzodiazepines 4 and 5. The CeCl3-KI promoted two-component domino reaction of 1,2-phenylenediamines with 1,3-acetonedicarboxylate in ethanol affor

Full text of DOI:10.1039/c9nj06332c

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Expedient green-chemistry approaches for one-pot
synthesis of two series of novel 1,5-benzodiazepines via
domino reactions
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Hai-tao Wu, Lan-zhi Wang*
www.rsc.org/
Unique green-chemistry approaches have been developed for the one-pot synthesis of two series of novel 1,5-
benzodiazepines 4 and 5. The CeCl3-KI promoted two-component domino reaction of 1,2-phenylenediamines with 1,3-
acetonedicarboxylate in ethanol afforded novel 1,5-benzodiazepin-2-ones 4. An expedient approach to 1,5-
benzodiazepines 5 has also been developed via three-component domino reactions using 1,2-phenylenediamines, 1,3-
acetonedicarboxylate and aldehydes in the presence of a catalytic amount of magnetic nanoparticles (γ-Fe2O3@SiO2/CeCl3)
in ethanol at ambient temperature. During the above one-pot synthesis process, one new seven-membered nitrogen
heterocycle (diazepin) and four new bonds (one C–C, two C–N and one C=C) were constructed by the nucleophilic addition,
elimination reaction (dehydration etc.), hydride transfer and cyclization process. Structures of all 48 products were fully
confirmed by spectroscopic techniques and by single-crystal X-ray analysis of 5db. Moreover, plausible synthesis reaction
mechanisms of two series of novel 1,5-benzodiazepines 4 and 5 have been proposed. The methods have advantages such
as operational simplicity, mild reaction conditions, short reaction time, easy recovery and reusability of the catalyst, high
yields of products, and non-toxic EtOH as the solvent.
H
N
O
N
H
O
O
Introduction
N
N
N
Cl
1,5-benzodiazepines derivatives with unique seven-membered
heterocycles1 are broadly used as analgesic,2 sedative,3
anticonvulsant,4 antidepressive,5 antianxiety and hypnotic6, 7
agents due to their extensive pharmacological and biological
activities (Fig. 1).8, 9 Recently, the results of medical research
indicated that 1,5-benzodiazepines could be used as antibiotic,
anticancer,10 and antiviral (HIV) agents.11 For this reason, a
great deal of attention has been dedicated to the
development of synthetic routes to the construction of the
1,5-benzodiazepines.
N
N
N
Cl
O
N
N
N
N
Gastrozepin
Clobazam
Clozapine
Fig. 1 Representative examples of benzodiazepines scaffolds found in some drugs.
The most conventional strategies for the synthesis of 1,5-
benzodiazepines include cyclocondensation reactions of 1,2-
phenylenediamines
with
α,β-unsaturated
carbonyl
compounds, β-haloketones, or ketones in the presence of
varieties reagents and catalysts.12 Unfortunately, many of
these processes suffer from one or more limitations, such as
harsh reaction conditions, long reaction times, low product
yields, co-occurrence of several side reactions, and
environmental unfriendliness. Owing to this reason, these
processes have a limited scope and application in synthesis. In
this regard, multicomponent or domino reactions allow the
formation of several bonds in a single operation and provide
certain advantages such as simplicity in extraction, purification
processes and high degree of atom economy. The design of
new multicomponent or domino reactions for synthesis of 1,5-
benzodiazepines via greener procedures for C-C and C-N bond
a. AdCollege of Chemistry & Material Science, Hebei Normal University,
Shijiazhuang 050024, China.
b. E-mail address: wanglanzhi@126.com
† Electronic Supplementary Information (ESI) available: IR, MS/MS and NMR
spectra See DOI: 10.1039/x0xx00000x
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formation has attracted great attention, particularly in the bond, which improved the yield of product 4 up tVoie9w5A%rtic.leInOntlhinee
areas of drug discovery and organic chemistry.13, 14
initial experiment, the two-component domino reaction of
DOI: 10.1039/C9NJ06332C
As part of our ongoing interest in the efficient synthesis of 1,2-phenylenediamine 1a, 1,3-acetonedicarboxylate 2 was
new 1,5-benzodiazepines derivatives, we herein report the considered as a model reaction. The results are listed in Table
unique green-chemistry approaches for one-pot synthesis of 1.
two series of rare contractual 1,5-benzodiazepines 4 and 5 via
Temperature played a vital role in the synthesis of 1,5-
domino condensations (Scheme 1). The CeCl3-KI promoted benzodiazepines 4. At lower temperature (0 oC or r.t), only the
two-component domino reaction of 1,2-phenylenediamines intermediate 7 was formed, and the product 4a was still not
1a-d with 1,3-acetonedicarboxylate 2 in ethanol afforded obtained for a long time (10 hours, Table 1 entries 1-2).
novel 1,5-benzodiazepin-2-ones 4a-d (Scheme 1, Strategy I). Howerver, when the reaction was heated to reflux, the target
An expedient approach to 1,5-benzodiazepines 5aa-dk has compound 4a was obtained in 30% yield, which indicated the
also been developed via three-component domino reactions product 4a was generated from intermediate 7 at higher
using 1,2-phenylenediamines 1a-d, 1,3-acetonedicarboxylate 2 temperature (reflux) (Table 1 entry 3). The result showed that
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and aldehydes 3a-k in the presence of
a magnetic the reaction of the nucleophilic addition and elimination of
nanoparticles (γ-Fe2O3@SiO2/CeCl3) in ethanol at ambient amino groups to ester groups of intermediate 7 to form target
temperature (Scheme 1, Strategy II). To the best of our products 4 required a higher temperature (reflux). Therefore,
knowledge, this is only one paper that describes the synthesis room temperature-reflux were chosen as optimum
of benzodiazepines 4 and 5. The reports on such molecular temperature.
structure are few in number.
When no catalyst was added during the reaction, only small
amount of product was formed (Table 1, entry 3). This shows
that the reaction was greatly affected by the catalyst. Next,
the catalyst was examined. We investigated several catalysts
for this reaction, including solid organic acid (p-TsOH),
heteropoly acids [PMA(H3PMo12O40)], protic acid (HOAc),
Lewis acid (CeThe yield of product 5ab was not the highest
when p-TsOH, HOAc, CeCl3 and PMA were used for the
reaction (Table 1, entries 4-6). With CeCl3-KI as the catalyst,
the product 5ab yield can be as high as 92% (Table 1, entry
8).Cl3 and CeCl3-KI). The results substantiated the catalytic
role of CeCl3-KI over other acids. Previous research results
showed that the activity of CeCl3·7H2O increases in the
presence of an iodide source such as KI or NaI owing to the
formation of the CeClnI3-n·7H2O (n=0,1,2) complex that exhibits
stronger Lewis acid character than CeCl3·7H2O,15,16 according
to the following equation.
I
H
N
O
COOC2H5
R1
NH2
NH2
R1
1) EtOH r.t.
O
2) CeCl3-KI
EtOH reflux
N
H
1a-d
4a-d
COOC2H5
C2H5OOC
2
two-component domino reaction
II
R2
H
COOC2H5
O
R1
R1
NH2
NH2
N
1) EtOH r.t.
R2
3a-k
H
COOC2H5
O
2) EtOH r.t.
N
H
γ-Fe2O3@SiO2/CeCl3
5aa-dk
1a-d
COOC2H5
C2H5OOC
2
three-component domino reaction
R1=H, CH3, Cl, Br
Br
H3C
Cl
Cl
O2N
Cl
R2=
H3CO
N
N
O
OC2H5
S
S
-Rare construction of seven membered ring
-Domino reactions
CeCl3·7H2O + (3-n)KI
CeClnI3-n·7H2O + (3-n)KCl (n=0,1,2).
-Mild conditions and fast reaction
-Green-chemistry approaches
-An intramolecular 1,5-hydride transfer
Scheme 1. Design strategy for the synthesis of benzodiazepines.
Results and discussion
Initially, a two-component domino reaction (Scheme 1,
Strategy I) for the synthesis of the novel 1,5-benzodiazepines 4
was investigated. The reactions were carried out by taking a
mixture of substituted 1,2-phenylenediamines 1 and 1,3-
acetonedicarboxylate 2 in ethanol in a round bottom flask
with stirring at room temperature. In this step, without any
catalyst, the yield of intermediate compound 7 can be up to
1
98%. Structure of compound 7 was determined by H NMR.
Then, the CeCl3-KI was added as a catalyst to the mixed
solution of the resulted compound 7 under reflux temperature
to obtain the product 4 by a domino sequence of nucleophilic
addition and elimination reaction of enamine ester 7 with the
removal of the ethanol molecules. In this step, CeCl3-KI was
used as a multifunctional catalyst for selective activation of
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Table 1. Optimization of domino reaction conditionsa.
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DOI: 10.1039/C9NJ06332C
O
H
N
COOC2H5
NH2
O
NH2
N
H
4a
1a
COOC2H5
C2H5OOC
2
Entry
1
2
3
4
5
6
7
8
Temp.
0 oC
r.t.
Solvent
Catalysts
-
-
Time
10h
10h
Yieldb/%
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
MeOH
PhMe
EtOAc
MeCN
-
-
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Fig. 2 Optimized molecular structure shows intra molecular hydrogen bond
(light blue colour) between NH and ester C=O group in compound 4b and
exhibits Z configuration of product 4b.
r.t.-ref.c
r.t.-ref.c
r.t.-ref.c
r.t.-ref.c
r.t.-ref.c
r.t.-ref.c
r.t.-ref.c
r.t.-ref.c
r.t.-ref.c
r.t.-ref.c
-
10h
30
70
72
78
75
92
92
89
80
82
p-TsOH
HOAc
CeCl3
PMA
CeCl3-KI
CeCl3-KI
CeCl3-KI
CeCl3-KI
CeCl3-KI
50min
45min
55min
65min
40min
40min
45min
55min
55min
Table 2. Scope of 1,2-phenylenediamin for domino synthesis of benzodiazepines 4a, b
.
H
O
COOC2H5
9
N
R
R
NH2
R
NH2
EtOH reflux
CeCl3-KI
r.t.
10
11
12
+
NH2
O
EtOH
N
H
N
H
C CH2COOC2H5
1a-d
1a
4a-d
COOC2H5
2
7a-d
CHCOOC2H5
C2H5OOC
a
Reaction condition: 1,2-benzenediamine (1 mmol), and 1,3-
Br
NH2
NH2
NH2
H3C
NH2
NH2
Cl
NH2
NH2
b
acetonedicarboxylate (1 mmol), catalyst (5 mol %), solvent (2 mL). Isolated
yield. c From 7a to 4a at reflux temperature.
NH2
O
1b
1c
1d
Finally, the effect of various solvents on time and yield of
the reaction was ascertained. The yield of the target product
4a was not high by using PhMe, EtOAc and MeCN as solvents
(Table 1, entries 10-12). The similar yield of the target product
4a can be obtained both by using methanol and ethanol as a
solvent (Table 1, entries 8-9). However, ethanol is deemed to
be the preferred solvent for this transformation considering
the requirements of green chemistry. Therefore, ethanol was
selected as the reaction solvent in this study.
For compound 4 configuration, geometry optimizations and
frequency calculations for the product 4b were carried out at
B3LYP/6-31(G) level using Gaussian 09 program package, and
optimized configuration was obtained and shown in Fig. 2.
From Fig. 2, it was noted that we have obtained exclusively (Z)
configuration of product 4b due to intermolecular hydrogen
bonding. The intra-molecular hydrogen bonding of compound
4b exist between N2 H2···O3 (N2 O3 = 2.689 Å; O3 H2 = 1.850
Å, ∠N2 H2···O3 = 136.60) (Fig. 2).17
O
H
N
H
N
O
H
N
H3C
Cl
N
H
N
H
N
H
C2H5OOC
C2H5OOC
C2H5OOC
4a, 40min, 92%
H
4b, 35min, 95%
4c, 43min, 89%
O
N
Br
N
H
C2H5OOC
4d, 45min, 90%
a
Reaction condition: 1,2-benzenediamine (1 mmol) and 1,3-
b
acetonedicarboxylate (1 mmol), catalyst (5 mol %), solvent (2 mL).
Isolated yield.
good to excellent yields. From Table 2, it was also observed
that 1,2-phenylenediamines with electron-donating groups (-
CH3) gave much better results than those with electron-withd
groups.
With this optimized procedure in hand, the substrate scope
of this reaction was evaluated.
On the basis of the above results, the plausible mechanism
is depicted in Scheme 2. The reaction sequence proceeds with
the formation of intermediate enamine ester 7 by selective
nucleophilic addition and dehydration reaction of substituted
1,2-phenylenediamines 1 and 1,3-acetonedicarboxylate 2.
Then, the other amino group of enamine ester 7 attacks on
the carbonyl carbon of the ester to give the intermediate 8. In
this step, catalyst CeClnI3-n activated the carbonyl carbon of
the ester and also promoted ethoxy removal reaction.
Subsequently, the possible product 4 was obtained by loss of
the ethanol molecules.
In order to explore how the reaction mechanism works,
some controlled experiments were carried out. As shown in
Scheme 3 (C and D). The reactions were performed by reacting
1,2-phenylenediamines with ethyl acetoacetate and ethyl
propiolate respectively. Compounds 13 and 14 with similar
partial structure of compound 7 were obtained by the
A novel series 1,5-
benzodiazepines 4a-d has been obtained as shown in Table 2.
We evaluated different substituted 1,2-phenylenediamines
1a-d. Fortunately, in the case of substituted 1,2-
phenylenediamines, these reactions exhibit high chemo- and
regio-selectivity. Therefore, no undesired isomers were
obtained under these reaction conditions. The 1H NMR and 13
C
NMR spectra were consistent with the presence of only one
isomer. Significantly, 1,2-phenylenediamines bearing various
electron-donating or electron-withdrawing functional groups
on the phenyl ring afforded the 1,5-benzodiazepines 4a-d in
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reaction. However, the further reaction products 15 and 16 example, refluxing in EtOH, led to a significantVidewecArrteicalesOenlionef
were not found, which means that compounds 13 and 14 did yield of aim
DOI: 10.1039/C9NJ06332C
not yield 15 and 16 continually, that is, the reaction of amino
attack ester group (CH=COOC2H5) cannot occurred. The results
Table 3. Optimization of the domino reaction conditionsa.
show that the above mechanism (Scheme 2) is correct for this
Cl
reaction. Structure of compound 13 and 14 was determined
by 1H NMR.
COOC2H5
O
O
H
N
NH2
NH2
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11
12
13
14
15
16
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CeClnI3-n
OC2H5
H
COOC2H5
OH
-CH3CH2OH
H
N
Cl
R
N
H
COOC2H5
1a
3b
5ab
2
C2H5OOC
N
H
Yieldb/%
10
65
61
70
83
83
92
92
8
O
CHCOOC2H5
H
N
Entry
Catalysts
Catalyst free
p-TsOH
HOAc
PMA
CeCl3
CeCl3-KI
CeCl3/SiO2
γ-Fe2O3@SiO2/CeCl3
Time
4h
R
1
2
3
4
5
6
7
8
30min
25min
45min
40min
40min
40min
40min
N
4
H
CeClnI3-n
C2H5OOC
R
NH2
O
H2
H2N
H2N
R
N
C
C
C
OC2H5
7
H
CHCOOC2H5
C2H5OOC
O
1
-H2O
a Reaction condition: 1,2-benzenediamine (1 mmol), 1,3-acetonedicarboxylate
(1 mmol) and aromatic aldehyde (1 mmol), catalyst (5 mol %), EtOH (2 mL), r.t..
b Isolated yield.
C2H5OOC
2
product. The reason is that this condition (reflux) will
contribute to side reactions, while a certain extent, reduce the
reaction time. The reaction medium is one of the most
important factors influencing any process, several solvents
including methanol, ethanol, toluene, acetonitrile and ethyl
acetate were tested. The same high yield of the target product
5ab can be obtained both by using methanol and ethanol as a
solvent. However, ethanol is deemed to be the preferred
solvent for one-pot transformation considering the
requirements of green chemistry. Among the existing
methods, the synthesis of 1,5-benzodiazepine was an acid-
catalyzed reaction. Therefore, acid catalyst plays an important
Scheme 2. A plausible mechanism for the formation of products 4.
Inspired by the success of the above domino reactions of
the one-pot synthesis of 1,5-benzodiazepines 4, another one-
pot synthesis of 1,5-benzodiazepines
5 was achieved
successfully via three-component domino reaction (Scheme 1,
Strategy II). The aldehydes 3a-k and the catalyst (γ-
Fe2O3@SiO2/CeCl3) were added to the mixed solution of the
resulted compound 7a-d under room temperature to obtain
the product 5aa-dk in 69-96% yields. The whole process takes
40-50 min. The products were isolated from the solution by
19
role.18, We investigated several catalysts for this reaction,
H
N
O
including solid organic acid (p-TsOH), heteropoly acids
[PMA(H3PMo12O40)], protic acid (HOAc) and Lewis acid (CeCl3).
To our delight, all tested catalysts have different catalytic
effects on the reaction. The yield of product 5ab was not the
highest when p-TsOH and HOAc were used for the reaction,
but can be completed within the shortest time. It may be due
to higher acidity of these catalysts (Table 3, entries 2-3),
whereas side reaction was increased. Of the catalysts tested,
CeCl3 emerged as the most effective acid (Table 3, entry 5). As
alternate acids, the use of CeCl3/SiO2 and γ-Fe2O3@SiO2/CeCl3
under the same conditions afforded compound 5ab in 92%
yield (Table 3, entries 7-8). These two catalysts both exhibited
high catalytic activity, but γ-Fe2O3@SiO2/CeCl3 (Fig. 3) can be
easily magnetically separated and exhibits significant
recyclability, with no significant loss of activity after many
consecutive runs. The specific surface area of the catalyst is an
important parameter for its practical application. Fig. 3 (c) is a
graph of the N2 adsorption-desorption isothermal curve and
the BJH pore size distribution of the γ-Fe2O3@SiO2/CeCl3 at
the temperature of liquid nitrogen. It can be seen that the N2
O
NH2
C
D
N
H
O
15
EtOH r.t.
N C CHCOOC2H5
H H
NH2
NH2
13
14
EtOH r.t.
O
NH2
H
N
O
O
N C
CHCOOC2H5
CH3
O
H
N
H
CH3
16
Scheme 3. Controlled experiments.
vacuum filtration. Initially to optimize the reaction procedure
a model reaction was performed using 1,2-phenylenediamine
1a, 1,3-acetonedicarboxylate 2 and p-chlorobenzaldehyde 3b
under various conditions. The results are summarized in Table
3. In some ways, the yields and the time of reaction closely
depended on temperature. The reaction was effectively
completed upon room temperature. Lower temperature can
also be applied but results in a longer reaction time. It was
also observed that
a higher reaction temperature, for
4 | J. Name., 2012, 00, 1-3
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adsorption-desorption isothermal curve shows
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DOI: 10.1039/C9NJ06332C
hysteresis loop, which belongs to the field of the mesoporous
material. The pore diameter is mostly in the range of 3.8 nm
and the pore volume is 0.129 nm. The specific surface area of
γ-Fe2O3@SiO2/CeCl3 is 83.422m2/g, which makes the catalyst
have a wide contact surface with reactants in the reaction
system. Thus γ-Fe2O3@SiO2/CeCl3 played a better catalytic role
in reactions. The VSM magnetization curves of magnetic
nanoparticles, before and after functionalization, exhibit a
superparamagnetic character (Fig.3(d)). The magnetic
saturation (Msat) values are 27.45 emu/g, 50.56 emu/g and
55.81 emu/g for γ-Fe2O3@SiO2/CeCl3, γ-Fe2O3@SiO2 and γ-
Fe2O3. The decrease in Msat for γ-Fe2O3@SiO2/CeCl3 is
probably due to the existence of the large amount of
nonmagnetic material [SiO2/CeCl3] on the surface of the γ-
Fe2O3 particles. Even with this reduction in the saturation
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(a)
(b)
Fig. 4 X-ray single crystal structure shows intra molecular hydrogen bond
(red and white) between NH and ester C=O group in compound 5db and
exhibits (Z) configuration of product 5db (CCDC No. 1887505).
(c)
(d)
Fig. 3 TEM , SEM, BET and VSM images of γ-Fe2O3@SiO2/CeCl3 nanoparticles
(a), (b), (c) and (d).
Fig 5. Optimized molecular structure of 5db shows intra molecular hydrogen
bond (light blue color) between NH and ester C=O groupand exhibits （Z）
configuration of product 5db.
magnetization, the prepared catalyst could still be efficiently
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separated from the reaction mixtures with the help of an exclusively (Z) configuration of compounds 5db due to
View Article Online
DOI: 10.1039/C9NJ06332C
external magnetic force.
intermolecular hydrogen bonding between N2 H2···O4 (N2 O4
To study the synthetic utility and scope, optimized reaction = 2.728 Å; O4 H2 = 2.066 Å, ∠N2 H2···O4 = 133.230) (Fig.4).
condition was applied to aldehydes 3a-k, 1,3- On the basis of the above results, the plausible mechanism
acetonedicarboxylate and substituted 1,2- is depicted in Scheme 4. First of all, enamine ester 7 was
2
phenylenediamines 1a-d. All these reactions proceeded obtained by the first selective nucleophilic addition and
efficiently to offer the products in excellent yields (69-96%) in dehydration reaction of substituted 1,2-phenylenediamines 1
shorter reaction time (Table 4), moreover the reaction and 1,3-acetonedicarboxylate 2. Then, the other amino group
promotes the formation of one C-C, two C-N and one C=C of enamine ester 7 attack to the carbxonyl carbon of aldehyde
bonds in one-pot. Firstly, the substituted 1,2- to give the intermediate 9 by loss of a molecule of water. In
phenylenediamines 1a-d were examined. These reactions this step, catalyst γ-Fe2O3@SiO2/CeCl3 activated the carbonyl
exhibit high chemo- and regio-selectivity, and the single carbon of the aldehyde to promote rapidly reaction.
isomer can be obtained in excellent yield. Significantly, we Subsequently, the intermediate 9 may undergo a cyclization
observed that 1,2-phenylenediamines with electron-donating reaction enabling the cyclic intermediate 10. At last, the cyclic
(-CH3) were more reactive. Furthermore, we chose a variety of intermediate 10 suffers intramolecular proton transfer to give
aromatic aldehydes 3a-j to investigate the reaction. It was the product 5.
found that the nature of substitutions on aromatic aldehydes
has no significant effect on the reaction time and yields. The
substrates smoothly underwent the domino reaction to afford
the corresponding products in good yields. Similarly, ethyl
glyoxylate 3k were employed. Interestingly, aromatic aldehyde
showed better results than ethyl glyoxylate (Table 4). This
result can be attributed to higher reactivity of ethyl glyoxylate
3k than that of aromatic aldehydes 3a-j and led to more side
reactions and difficult product separation.
8
9
10
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42
43
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45
46
47
48
49
50
51
52
53
54
55
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59
60
The structure of 5db was characterized by X-ray analysis of
single crystals (Fig. 4). [the CCDC deposition number is
1887505;† formula: C22H22BrClN2O4 ] (Fig. 4).
From the optimized configuration (Fig.5) and X-ray single
crystal structure (Fig.4), it was noted that we have obtained
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DOI: 10.1039/C9NJ06332C
NJC
PAPER
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Scope of substrates for the domino synthesis of benzodiazepines 5a, b
.
R2
H
N
COOC2H5
R1
R1
NH2
NH2
O
EtOH r.t.
H
CeCl3
COOC2H5
O
R2
N
H
5aa-dk
COOC2H5
1a-d
3a-k
C2H5OOC
2
Cl
NH2
NH2
NH2
NH2
H3C
NH2
NH2
Cl
Br
NH2
O2N
CHO
NH2
Cl
CHO
CHO
1c
1a
3b
1b
1d
3a
3c
H3CO
Br
H
H3C
Cl
N
CHO
CHO
S
S
CHO
N
CHO
CHO
CHO
CHO
3d
3f
3e
3g
3i
3j
3h
O
OC2H5
O
3k
Cl
H
N
H
N
H
N
H
N
H
N
Cl
Br
H3C
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
N
H
N
H
N
H
N
H
N
H
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
(Z) 5ab, 40min, 90%
(Z) 5da, 43min, 88%
(Z) 5ca, 45min, 86%
(Z) 5aa, 40min, 90%
(Z) 5ba, 39min, 92%
Cl
NO2
Cl
Cl
NO2
H
N
H
N
H
N
H
N
H
N
Br
H3C
H3C
Cl
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
N
H
N
H
N
H
N
H
N
H
C2H5OOC
C2H5OOC
(Z) 5bc, 39min, 96%
Br
C2H5OOC
C2H5OOC
C2H5OOC
(Z) 5db, 46min, 89%
(Z) 5cb, 47min, 87%
(Z) 5bb, 37min, 94%
(Z) 5ac, 41min, 92%
Br
NO2
NO2
Br
H
N
H
N
H
N
H
N
H
N
Cl
Br
H3C
Cl
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
N
H
N
H
N
H
N
H
N
H
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
(Z) 5cc, 43min, 89%
(Z) 5bd, 37min, 94%
(Z) 5dc, 44min, 90%
(Z) 5ad, 43min, 91%
(Z) 5cd, 45min, 88%
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5
CH3
CH3
CH3
CH3
Br
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DOI: 10.1039/C9NJ06332C
H
N
H
N
H
N
H
N
H
N
Cl
Br
H3C
Br
6
7
8
9
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
N
H
N
H
N
H
N
H
N
H
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
(Z) 5dd, 45min, 87%
OCH3
(Z) 5be, 39min, 94%
(Z) 5ce, 45min, 89%
(Z) 5ae, 45min, 92%
(Z) 5de, 46min, 87%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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59
60
OCH3
OCH3
Cl
OCH3
Cl
H
N
H
N
H
N
H
N
H
N
Cl
Br
H3C
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
N
H
N
H
N
H
N
H
N
H
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
(Z) 5af, 45min, 91%
(Z) 5ag, 38min, 94%
(Z) 5df, 47min, 89%
(Z) 5bf, 40min, 94%
(Z) 5cf, 47min, 88%
Cl
Cl
Cl
Cl
Cl
Cl
H
H
N
H
N
H
N
H
N
N
N
N
Br
Cl
H3C
H3C
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
N
H
N
H
N
H
N
H
N
H
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
(Z) 5dg, 43min, 91%
(Z) 5ah, 42min, 90%
(Z) 5bh, 40min, 93%
(Z) 5bg 35min, 95%
(Z) 5cg 42min, 88%
H
S
H
N
H
S
H
N
H
N
S
N
N
N
N
Br
H3C
Cl
Cl
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
N
H
N
H
N
H
N
H
N
H
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
(Z) 5dh, 45min, 87%
(Z) 5ai, 45min, 89%
(Z) 5ci, 48min, 84%
(Z) 5ch, 47min, 87%
(Z) 5bi, 41min, 91%
N
N
N
N
H
N
S
H
N
S
H
N
H
N
S
S
H
N
S
H3C
Cl
Br
Br
COOC2H5
COOC2H5
COOC2H5
COOC2H5
COOC2H5
N
H
N
H
N
H
N
H
N
H
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
(Z) 5di, 47min, 96%
(Z) 5aj, 40min, 90%
(Z) 5bj, 37min, 94%
(Z) 5dj, 42min, 89%
(Z) 5cj, 43min, 89%
H
N
H
H
COOC2H5
COOC2H5
COOC2H5
H
N
COOC2H5
COOC2H5
N
N
H3C
Cl
Br
COOC2H5
COOC2H5
COOC2H5
N
H
N
H
N
H
N
H
C2H5OOC
C2H5OOC
C2H5OOC
C2H5OOC
(Z) 5dk, 7h, 71%
(Z) 5ak, 6.5h, 78%
(Z) 5bk, 6h, 82%
(Z) 5ck, 7h, 69%
a
Reaction conditions: 1,2-benzenediamine compounds (1 mmol), 1,3-acetonedicarboxylate (1mmol) and aldehyde (1 mmol) in EtOH (2 mL), γ-
Fe2O3@SiO2/CeCl3, r.t.. b Isolated yield.
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DOI: 10.1039/C9NJ06332C
CH2COOCH2CH3
H
COOC2H5
O
R1
NH2
CHCOOCH2CH3
N
C
R1
NH2
NH2
-H2O
OHH
N
C
CHCOOCH2CH3
R1
NH2
O
7
CeCl3
H
1
COOC2H5
CH2COOCH2CH3
6
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
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-H2O
H
R2
3
CeCl3
CeCl3
CeCl3
R2
R2
H
N
R1
N
C
H
R2
R1
R1
N
COOCH2CH3
H+ shift
COOCH2CH3
COOCH2CH3
N
C
CHCOOCH2CH3
N
H
N
5
H
CH
H
CH2COOCH2CH3
C2H5OOC
9
10
H
Scheme 4. A plausible mechanism for the formation of products 5.
Analyser. The structure of 5db was further determined by single-
crystal X-ray diffraction on a Bruker Smart 1000 diffractometer.
Commercially available chemicals and solvents were purchased
from Aladdin and were used as received. The reactions were
monitored by thin-layer chromatography (TLC) on pre-coated silica
gel GF254 plates.
Conclusions
In summary, we have successfully developed unprecedented
approaches to one-pot synthesis of two series of novel 1,5-
benzodiazepines 4 and 5 with rare extracyclic enamine
structure through the two-component and three-component
domino reactions respectively.
A cascade nucleophilic
Synthesis of 1,5-benzodiazepin-2-ones 4a-d
addition, eliminate (dehydration etc.), hydride transfer and
cyclization reactions occur to yield the novel 1,5-
benzodiazepines as single isomers. The pure products were
In a 50 mL reaction vial, the 1,2-benzenediamines 1a (1 mmol), 1,3-
acetonedicarboxylate 2 (1 mmol) and EtOH (2 mL) were mixed and
obtained in high yields and short reaction times with then stirred at room temperature for 20 minutes. Subsequently,
CeCl3-KI (0.1 mmol) were added to the reaction mixture at reflux
temperature and reacted for 20 minutes. Upon completion,
monitored by TLC, the reaction mixture was cooled and filtered to
give the crude product, which was further washed and recrystallize
by EtOH to give pure product 4a.
recyclability of the catalyst (γ- Fe2O3@SiO2/CeCl3). Mechanistic
insight was obtained in detail. The benefits of these methods
are their simplicity of operation, simplicity of purification, mild
reaction conditions, short reaction time and the good product
yields. Products of type 4 or 5 present interesting skeleton and
geometries that ought to be tested in medicinal chemistry, and
their preparation is difficult to imagine by other routes.
Synthesis of 1,5-benzodiazepines 5aa-5dk
In a 50 mL reaction vial, the 1,2-benzenediamines 1a (1 mmol), 1,3-
acetonedicarboxylate 2 (1 mmol) and EtOH (2 mL) were mixed and
then stirred at room temperature. Subsequently, p-
chlorobenzaldehyde 3b (1 mmol) and γ-Fe2O3@SiO2/CeCl3 (0.1
mmol) were added to the reaction mixture. Upon completion,
monitored by TLC, the reaction mixture filtered to give the crude
product, which was further washed and recrystallize by EtOH to
give pure product 5ab. The anoparticle catalysts can be separated
from the mixture by an external magnet.
Experimental section
General
Melting points of these products were determined in open
capillaries. The H NMR and 13C NMR spectra were recorded on a
1
400 MHz (WIPM-NMR-400) nuclear magnetic resonance
spectrometer operating at 400 and 100 MHz, using DMSO-d6 as the
solvent with TMS as internal standard. The signal multiplicities are
represented by s (singlet), d (doublet), t (triplet), m (multiplet), and
q (quartet). Low-resolution mass spectra were recorded on a
Thermo DSQ II mass spectrometer. The IR spectra were recorded on
a Thermo Scientific IR spectrophotometer in KBr pellets. The
elemental analysis was performed using a Vario ELIII Elemental
Compound 4a
92% yield (227 mg); Pale yellow solid; mp 232-234 °C; 1H NMR (400
MHz, DMSO-d6, TMS): δ=1.21 (t, J=7.1Hz, 3H), 3.12 (s, 2H), 4.09 (q,
J=7.1 Hz, 2H), 4.78 (s, 1H), 7.09-7.27 (m, 4H), 10.26 (s, 1H), 10.40 (s,
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1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS): δ=14.89, 41.72, 6.90%; M+1 (mass spectrum), 395.0. C23H26N2O4 requires C, 70.03;
59.08, 84.95, 122.89, 125.09, 125.44, 130.36, 131.43, 155.50, H, 6.64; N, 7.10%; M, 394.46.
168.14, 169.88 ppm; IR (KBr): v=3211, 1690, 1620, 1503 cm-1; Found
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DOI: 10.1039/C9NJ06332C
C, 63.26; H, 5.57; N, 11.48%; M+1 (mass spectrum), 247.3.
C13H14N2O3 requires C, 63.40; H, 5.73; N, 11.38%; M, 246.26.
Compound 5ca
86% yield (357 mg); White solid; mp 132-134 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.94 (t, J=7.0 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H), 3.89-
3.97 (m, 2H), 3.99-4.07 (m, 2H), 4.18 (d, J=4.6 Hz, 1H), 4.44 (s, 1H),
Compound 4b
95% yield (247 mg); White solid; mp 244-246 °C; 1H NMR (400 MHz, 5.23 (t, J=5.0 Hz, 1H), 6.60 (d, J=5.6 Hz, 1H), 6.64-6.85 (m, 3H), 7.22-
DMSO-d6, TMS): δ=1.20 (t, J=7.1Hz, 3H), 2.26 (s, 3H), 3.12 (s, 2H), 7.37 (m, 5H), 10.24 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
4.08 (q, J=7.1 Hz, 2H), 4.74 (s, 1H), 6.89-7.15 (m, 3H), 10.20 (s, 1H), δ=14.12, 14.76, 55.79, 58.93, 61.07, 61.35, 87.49, 118.00, 118.40,
10.34 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS): δ=14.90, 123.65, 126.50, 126.75, 127.56, 128.21, 128.53, 140.52, 142.04,
20.74, 41.75, 59.01, 84.41, 122.84, 122.93, 126.19, 129.03, 130.20, 155.90, 168.87, 169.50 ppm; IR (KBr): v=3347, 1731, 1621, 1513 cm-
134.48, 155.60, 168.12, 169.91 ppm; IR (KBr): v=3210, 1693, 1621, 1; Found C, 64.10; H, 6.11; N, 6.62%; M+1 (mass spectrum), 415.1.
1502 cm-1; Found C, 64.49; H, 5.97; N, 10.84%; M+1 (mass C22H23ClN2O4 requires C, 63.69; H, 5.59; N, 6.75%; M, 414.88.
spectrum), 261.2. C14H16N2O3 requires C, 64.60; H, 6.20; N, 10.76%;
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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34
35
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47
48
49
50
51
52
53
54
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57
58
59
60
M, 260.29.
Compound 5da
88% yield (404 mg); White solid; mp 133-135 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.94 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.1 Hz, 3H), 3.89-
Compound 4c
1
89% yield (250 mg); Pale gray solid; mp 258-260 °C; H NMR (400 3.97 (m, 2H), 3.99-4.07 (m, 2H), 4.19 (d, J=4.7 Hz, 1H), 4.45 (s, 1H),
MHz, DMSO-d6, TMS): δ=1.20 (t, J=7.1Hz, 3H), 3.19 (s, 2H), 4.09 (q, 5.23 (t, J=4.9 Hz, 1H), 6.60 (d, J=5.6 Hz, 1H), 6.72-6.99 (m, 3H), 7.20-
J=7.1 Hz, 2H), 4.80 (s, 1H), 7.12-7.33 (m, 3H), 10.33 (s, 1H), 10.36 (s, 7.37 (m, 5H), 10.24 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS): δ=14.86, 41.66, δ=14.13, 14.76, 55.80, 58.94, 60.96, 61.36, 87.67, 116.19, 128.80,
59.15, 85.60, 112.66, 124.65, 125.03, 128.44, 130.59, 131.60, 121.24, 123.93, 126.73, 126.87, 127.57, 128.53, 140.79, 141.99,
154.93, 168.12, 169.72 ppm; IR (KBr): v=3212, 1691, 1629, 1500 cm- 155.86, 168.87, 169.49 ppm; IR (KBr): v=3356, 1732, 1625, 1522 cm-
1; Found C, 55.70; H, 4.83; N, 9.87%; M+1 (mass spectrum), 281.1. 1; Found C, 57.48; H, 4.93; N, 6.24%; M+1 (mass spectrum), 460.9.
C13H13ClN2O3 requires C, 55.62; H, 4.67; N, 9.98%; M, 280.71.
C22H23BrN2O4 requires C, 57.53; H, 5.05; N, 6.10%; M, 459.33.
Compound 4d
Compound 5ab
90% yield (293 mg); Pale gray solid; mp 252-254 °C; H NMR (400 90% yield (373 mg); Pale yellow solid; mp 150-152 °C; 1H NMR (400
MHz, DMSO-d6, TMS): δ=1.20 (t, J=7.1Hz, 3H), 3.19 (s, 2H), 4.09 (q, MHz, DMSO-d6, TMS): δ=0.89 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H),
J=7.1 Hz, 2H), 4.81 (s, 1H), 7.21-7.31 (m, 3H), 10.32 (s, 1H), 10.36 (s, 3.83-3.96 (m, 2H), 3.97-4.05 (m, 2H), 4.09 (d, J=4.6 Hz, 1H), 4.41 (s,
1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS): δ=14.86, 41.66, 1H), 5.26 (t, J=5.1 Hz, 1H), 6.27 (d, J=5.7 Hz, 1H), 6.65-6.88 (m, 4H),
59.16, 85.67, 116.30, 124.92, 127.75, 130.99, 131.87, 154.89, 7.35-7.42 (m, 4H), 10.21 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6,
168.12, 169.71 ppm; IR (KBr): v=3211, 1694, 1621, 1503 cm-1; Found TMS): δ=14.06, 14.76, 55.57, 58.88, 61.28, 86.84, 119.42, 119.57,
C, 48.09; H, 4.17; N, 8.48%; M+1 (mass spectrum), 327.1. 122.30, 124.91, 127.66, 128.41, 128.80, 131.96, 139.01, 141.69,
1
C12H13BrN2O3 requires C, 48.02; H, 4.03; N, 8.62%; M, 325.1.
156.20, 168.76, 169.51 ppm; IR (KBr): v=3374, 1730, 1630, 1503 cm-
1; Found C, 63.73; H, 5.65; N, 6.67%; M+1 (mass spectrum), 415.4.
C22H23ClN2O4 requires C, 63.69; H, 5.59; N, 6.75%; M, 414.88.
Compound 5aa
1
90% yield (342 mg); Pale yellow solid; mp 96-98 °C; H NMR (400
MHz, DMSO-d6, TMS): δ 0.89 (t, J=7.0 Hz, 3H), 1.13(t, J=7.1 Hz, 3H),
Compound 5bb
3.84-3.96 (m, 2H), 3.96-4.06 (m, 2H), 4.10 (d, J=4.7 Hz, 1H), 4.42 (s, 94% yield (403 mg); Pale yellow solid; mp 116-118 °C; 1H NMR (400
1H), 5.24 (t, J=5.0 Hz, 1H), 6.26 (d, J=5.3 Hz, 1H), 6.64-6.88 (m, 4H), MHz, DMSO-d6, TMS): δ=0.91 (t, J=7.1 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H),
7.21-7.38 (m, 5H), 10.26 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, 2.16 (s, 3H), 3.85-3.96 (m, 2H), 3.96-4.05 (m, 2H), 4.09 (d, J=4.6 Hz,
TMS): δ 14.04, 14.82, 55.79, 58.83, 61.23, 61.79, 86.55, 119.28, 1H), 4.37 (s, 1H), 5.23 (t, J=5.0 Hz, 1H), 6.21 (d, J=5.4 Hz, 1H), 6.46-
119.58, 112.20, 124.81, 126.85, 127.49, 127.69, 128.46, 139.11, 6.67 (3H, m), 7.35-7.40 (m, 4H), 10.19 (s, 1H) ppm; 13C NMR (100
142.58, 156.42, 168.95, 169.57 ppm; IR (KBr): v=3329, 1733, 1632, MHz, DMSO-d6, TMS): δ=14.11, 14.78, 20.89, 55.57, 58.78, 60.96,
1502 cm-1; Found C, 69.49; H, 6.31; N, 7.33%; M+1 (mass spectrum), 61.25, 86.30, 119.65, 120.15, 122.24, 125.16, 128.40, 128.77,
381.1. C22H24N2O4 requires C, 69.46; H, 6.36; N, 7.36%; M, 380.44.
131.91, 133.87, 138.68, 141.66, 156.26, 168.76, 169.54 ppm; IR
(KBr): v=3383, 1721, 1621, 1501 cm-1; Found C, 64.35; H, 6.01; N,
6.37%; M+1 (mass spectrum), 429.1. C23H25ClN2O4 requires C, 64.41;
H, 5.88; N, 6.53%; M, 428.91.
Compound 5ba
92% yield (363 mg); Pale yellow solid; mp 132-134 °C; 1H NMR (400
MHz, DMSO-d6, TMS): δ=0.92 (t, J=7.1 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H),
2.16 (s, 3H), 3.86-3.95 (m, 2H), 3.98-4.04 (m, 2H), 4.09 (d, J=5.4 Hz,
Compound 5cb
1H), 4.39 (s, 1H), 5.21 (t, J=4.8 Hz, 1H), 6.19 (d, J=5.1 Hz, 1H), 6.46- 87% yield (391 mg); White solid; mp 138-140 °C; 1H NMR (400 MHz,
6.67 (m, 3H), 7.19-7.37 (m, 5H), 10.23 (s, 1H) ppm; 13C NMR (100 DMSO-d6, TMS): δ=0.93 (t, J=7.0 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H), 3.89-
MHz, DMSO-d6, TMS): δ=14.12, 14.81, 20.85, 55.90, 58.74, 61.20, 3.98 (m, 2H), 4.00-4.06 (m, 2H), 4.17 (d, J=4.3 Hz, 1H), 4.43 (s, 1H),
61.55, 86.09, 119.71, 120.04, 122.14, 125.25, 126.83, 127.44, 5.25 (t, J=5.0 Hz, 1H), 6.60 (d, J=5.8 Hz, 1H), 6.64-6.85 (m, 3H), 7.36-
128.45, 133.78, 138.82, 142.58, 156.48, 168.95, 169.60 ppm; IR 7.41 (m, 4H), 10.20 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
(KBr): v=3356, 1741, 1635, 1501 cm-1; Found C, 70.17; H, 6.73; N, δ=14.10, 14.73, 55.52, 58.99, 60.55, 61.41, 87.73, 118.01, 118.57,
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123.78, 126.46, 128.28, 128.49, 128.71, 132.07, 140.40, 141.12, 7.67-8.21 (m, 4H), 10.14 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6,
View Article Online
155.68, 168.68, 169.43 ppm; IR (KBr): v=3356, 1739, 1630, 1494 cm- TMS): δ=14.04, 14.64, 55.11, 59.06, 60.90, 61.60, 88.06, 116.47,
DOI: 10.1039/C9NJ06332C
1; Found C, 58.67; H, 4.81; N, 6.37%; M+1 (mass spectrum),451.0. 120.93, 121.70, 123.67, 124.26, 126.79, 128.23, 140.58, 147.04,
C22H22Cl2N2O4 requires C, 58.81; H, 4.94; N, 6.23%; M, 449.33.
149.87, 155.29, 168.44, 169.35 ppm; IR (KBr): v=3411, 1733, 1639,
1512 cm-1; Found C, 52.25; H, 4.24; N, 8.43%; M+1 (mass spectrum),
506.0. C22H22BrN3O6 requires C, 52.39; H, 4.40; N, 8.33%; M, 504.33.
Compound 5db
89% yield (439 mg); White solid; mp 122-124 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.93 (t, J=7.1 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H), 3.89-
Compound 5ad
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3.97 (m, 2H), 3.98-4.06 (m, 2H), 4.18 (d, J=4.3 Hz, 1H), 4.44 (s, 1H), 91% yield (418 mg); White solid; mp 148-150 °C; 1H NMR (400 MHz,
5.24 (t, J=5.1 Hz, 1H), 6.60 (d, J=5.7 Hz, 1H), 6.73-6.98 (m, 3H), 7.36- DMSO-d6, TMS): δ=0.88 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H), 3.83-
7.41 (m, 4H), 10.20 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS): 3.96 (m, 2H), 3.97-4.05 (m, 2H), 4.09 (d, J=4.7 Hz, 1H), 4.41 (s, 1H),
δ=14.11, 14.73, 55.50, 59.00, 60.48, 61.42, 87.82, 116.28, 120.84, 5.23 (t, J=5.1 Hz, 1H), 6.27 (d, J=5.7 Hz, 1H), 6.65-6.88 (m, 4H), 7.33-
121.42, 124.07, 126.84, 128.49, 128.70, 132.07, 140.67, 141.09, 7.51 (m, 4H), 10.21 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
155.65, 168.68, 169.43 ppm; Found C, 53.40; H, 4.34; N, 5.80%; IR δ=14.04, 14.75, 55.52, 58.88, 61.29, 86.91, 119.43, 119.57, 120.54,
(KBr): v=3374, 1731, 1621, 1495 cm-1; M+1 (mass spectrum), 494.1. 122.30, 124.91, 127.66, 129.18, 131.32, 139.00, 142.11, 156.18,
C22H22BrClN2O4 requires C, 53.51; H, 4.49; N, 5.67%; M, 493.78.
168.75, 169.51 ppm; IR (KBr): v=3383, 1739, 1621, 1504 cm-1; Found
C, 57.48; H, 5.01; N, 6.14%; M+1 (mass spectrum), 461.0.
C22H23BrN2O4 requires C, 57.53; H, 5.05; N, 6.10%; M, 459.33.
Compound 5ac
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92% yield (391 mg); Tangerine solid; mp 180-182 °C; H NMR (400
MHz, DMSO-d6, TMS): δ=0.88 (t, J=7.1 Hz, 3H), 1.11 (t, J=7.1 Hz, 3H),
Compound 5bd
3.83-3.95 (m, 2H), 3.96-4.04 (m, 2H), 4.19 (d, J=4.3 Hz, 1H), 4.38 (s, 94% yield (445 mg); Yellow solid; mp 118-120 °C; 1H NMR (400 MHz,
1H), 5.42 (t, J=5.1 Hz, 1H), 6.37 (d, J=6.0 Hz, 1H), 6.66-6.90 (m, 4H), DMSO-d6, TMS): δ=0.94 (t, J=7.1 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H), 2.18
7.69-7.20 (m, 4H), 10.16 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, (s, 3H), 3.90-3.99 (m, 2H), 4.00-4.08 (m, 2H), 4.11 (d, J=4.6 Hz, 1H),
TMS): δ=14.05, 14.72, 55.16, 58.89, 61.42, 61.64, 87.13, 119.60, 4.41 (s, 1H), 5.24 (t, J=5.0 Hz, 1H), 6.22 (d, J=5.6 Hz, 1H), 6.50-6.70
122.48, 123.63, 125.05, 127.61, 128.35, 138.97, 147.01, 150.53, (m, 3H), 7.35-7.53 (m, 4H), 10.23 (s, 1H) ppm; 13C NMR (100 MHz,
155.85, 168.53, 169.41 ppm; IR (KBr): 3410, 1730, 1633, 1512 cm-1; DMSO-d6, TMS): δ=14.13, 14.82, 20.94, 55.58, 58.81, 61.05, 61.27,
Found C, 62.05; H, 5.59; N, 9.75%; M+1 (mass spectrum), 426.1. 86.27, 119.68, 120.18, 120.51, 122.24, 125.18, 129.16, 131.31,
C22H23N3O6 requires C, 62.11; H, 5.45; N, 9.88%; M, 425.43.
133.89, 138.67, 142.09, 156.26, 168.75, 169.55 ppm; IR (KBr):
v=3356, 1731, 1630, 1501 cm-1; Found C, 58.50; H, 5.46; N, 5.79%;
M+1 (mass spectrum), 475.0. C22H23BrN2O4 requires C, 58.36; H,
5.32; N, 5.92%; M, 473.36.
Compound 5bc
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96% yield (422 mg); Tangerine solid; mp 160-162 °C; H NMR (400
MHz, DMSO-d6, TMS): δ=0.91 (t, J=7.1 Hz, 3H=), 1.11 (t, J=7.1 Hz,
3H), 2.17 (s, 3H), 3.85-3.94 (m, 2H), 3.95-4.03 (m, 2H), 4.18 (d, J=4.6
Compound 5cd
Hz, 1H), 4.35 (s, 1H), 5.39 (t, J=5.2 Hz, 1H), 6.30 (d, J=6.0 Hz, 1H), 88% yield (435 mg); White solid; mp 130-132 °C; 1H NMR (400 MHz,
6.48-6.69 (m, 3H), 7.67-8.20 (m, 4H), 10.13 (s, 1H) ppm; 13C NMR DMSO-d6, TMS): δ=0.93 (t, J=6.9 Hz, 3H), 1.14 (t, J=6.9 Hz, 3H), 3.90-
(100 MHz, DMSO-d6, TMS): δ=14.08, 14.73, 20.85, 55.21, 58.81, 3.97 (m, 2H), 4.00-4.10 (m, 2H), 4.17 (d, J=3.7 Hz, 1H), 4.44 (s, 1H),
61.39, 86.61, 119.69, 120.36, 122.42, 123.63, 125.13, 128.32, 5.23 (t, J=4.5 Hz, 1H), 6.59 (d, J=5.6 Hz, 1H), 6.64-6.85 (m, 3H), 7.33-
134.06, 138.66, 146.99, 150.53, 155.94, 168.53, 169.45 ppm; IR 7.52 (m, 4H), 10.20 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
(KBr): 3409, 1731, 1630, 1508 cm-1; Found C, 62.99; H, 5.78; N, δ=14.09, 14.72, 55.49, 59.00, 60.63, 61.42, 87.74, 118.04, 118.58,
9.41%; M+1 (mass spectrum), 440.1. C23H25N3O6 requires C, 62.86; 120.67, 123.77, 126.48, 128.30, 129.09, 131.40, 140.39, 141.56,
H, 5.73; N, 9.56%; M, 439.46.
155.67, 168.67, 169.44 ppm; IR (KBr): v=3352, 1740, 1630, 1512 cm-
1; Found C, 53.55; H, 4.98; N, 5.59%; M+1 (mass spectrum), 495.0.
C22H22BrClN2O4 requires C, 53.51; H, 4.49; N, 5.67%; M, 493.78.
Compound 5cc
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89% yield (409 mg); Tangerine solid; mp 184-186 °C; H NMR (400
MHz, DMSO-d6, TMS): δ=0.93 (t, J=7.0 Hz, 3H), 1.11 (t, J=7.1 Hz, 3H),
Compound 5dd
3.88-3.95 (m, 2H), 3.98-4.07 (m, 2H), 4.27 (d, J=4.1 Hz, 1H), 4.42 (s, 87% yield (468 mg); White solid; mp 132-134 °C; 1H NMR (400 MHz,
1H), 5.41 (t, J=5.0 Hz, 1H), 6.67 (d, J=4.1 Hz, 1H), 6.67-6.87 (m, 3H), DMSO-d6, TMS): δ=0.93 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H), 3.89-
7.68-8.21 (m, 4H), 10.14 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, 3.98 (m, 2H), 3.99-4.06 (m, 2H), 4.18 (d, J=4.7 Hz, 1H), 4.45 (s, 1H),
TMS): δ=14.06, 14.66, 55.13, 59.00, 60.96, 61.55, 87.97, 118.14, 5.22 (t, J=5.2 Hz, 1H), 6.60 (d, J=5.9 Hz, 1H), 6.73-6.98 (m, 3H), 7.32-
118.81, 123.68, 123.95, 126.47, 128.28, 128.46, 140.35, 147.07, 7.52 (m, 4H), 10.20 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
149.92, 155.32, 168.45, 169.33 ppm; IR (KBr): v=3410, 1739, 1632, δ=14.09, 14.71, 55.44, 59.01, 60.55, 61.43, 87.86, 116.29, 120.67,
1515 cm-1; Found C, 57.63; H, 5.06; N, 9.03%; M+1 (mass spectrum), 120.86, 121.43, 124.06, 126.85, 129.07, 131.41, 140.66, 141.51,
460.0. C22H22ClN3O6 requires C, 57.46; H, 4.82; N, 9.14%; M, 459.88.
155.63, 168.67, 169.43 ppm; IR (KBr): v=3356, 1738, 1623, 1503 cm-
1; Found C, 49.11; H, 4.21; N, 5.12%; M+1 (mass spectrum), 539.0.
C22H22BrClN2O4 requires C, 49.09; H, 4.12; N, 5.20%; M, 538.23.
Compound 5dc
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90% yield (454 mg); Tangerine solid; mp 172-174 °C; H NMR (400
MHz, DMSO-d6, TMS): δ=0.93 (t, J=7.0 Hz, 3H), 1.11 (t, J=7.1 Hz, 3H),
Compound 5ae
3.88-3.96 (m, 2H), 3.98-4.07 (m, 2H), 4.28 (d, J=4.2 Hz, 1H), 4.42 (s, 92% yield (363 mg); White solid; mp 130-132 °C; 1H NMR (400 MHz,
1H), 5.41 (t, J=5.2 Hz, 1H), 6.69 (d, J=6.0 Hz, 1H), 6.75-7.01 (m, 3H), DMSO-d6, TMS): δ=0.91 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H), 2.25
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(s, 3H), 3.85-3.96 (m, 2H), 3.97-4.07 (m, 2H), 4.09 (d, J=5.0 Hz, 1H), 1; Found C, 67.19; H, 6.15; N, 6.90%; M+1 (mass speVciterwumArt)ic,le4O1n1l.in1e.
4.45 (s, 1H), 5.17 (t, J=5.2 Hz, 1H), 6.23 (d, J=5.4 Hz, 1H), 6.63-6.87 C23H26N2O5 requires C, 67.30; H, 6.38; N, 6.82%; M, 410.46.
(m, 4H), 7.08-7.25 (m, 4H), 10.29 (s, 1H) ppm; 13C NMR (100 MHz,
DOI: 10.1039/C9NJ06332C
DMSO-d6, TMS): δ=14.10, 14.83, 21.03, 55.83, 58.83, 61.20, 61.41,
86.49, 119.25, 119.60, 122.10, 124.74, 126.73, 127.72, 129.06,
136.44, 139.00, 139.53, 156.55, 169.01, 169.60 ppm; IR (KBr):
v=3375, 1713, 1630, 1512 cm-1; Found C, 69.94; H, 6.49; N, 7.25%;
M+1 (mass spectrum), 395.2. C23H26N2O4 requires C,70.03; H, 6.64;
N, 7.10%; M, 394.46.
Compound 5bf
94% yield (399 mg); Pale yellow solid; mp 114-116 °C; 1H NMR (400
MHz, DMSO-d6, TMS): δ=0.93 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H),
2.15 (s, 3H), 3.71 (s, 3H), 3.86-3.96 (m, 2H), 3.97-4.02 (m, 2H), 4.04
(d, J=5.3 Hz, 1H), 4.42 (s, 1H), 5.14 (t, J=5.2 Hz, 1H), 6.13 (d, J=5.3 Hz,
1H), 6.46-6.67 (m, 3H), 6.83-7.27 (m, 4H), 10.26 (s, 1H) ppm; 13C
NMR (100 MHz, DMSO-d6, TMS): δ=14.13, 14.80, 20.91, 55.38,
55.97, 58.75, 60.09, 61.15, 85.91, 113.79, 119.80, 120.07, 122.07,
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Compound 5be
94% yield (384 mg); White solid; mp 114-116 °C; 1H NMR (400 MHz, 125.36, 127.93, 131.41, 133.74, 138.76, 156.64, 158.61, 168.99,
DMSO-d6, TMS): δ=0.94 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H), 2.16 169.64 ppm; IR (KBr): v=3348, 1732, 1625, 1515 cm-1; Found C,
(s, 3H), 2.25 (s, 3H), 3.86-3.96 (m, 2H), 3.97-4.04 (m, 2H), 4.08 (d, 67.99; H, 6.81; N, 6.49%; M+1 (mass spectrum), 425.1. C24H28N2O5
J=4.9 Hz, 1H), 4.42 (s, 1H), 5.14 (t, J=5.3 Hz, 1H), 6.16 (d, J=5.4 Hz, requires C, 67.91; H, 6.65; N, 6.60%; M, 424.49.
1H), 6.45-6.66 (m, 3H), 7.08-7.23 (m, 4H), 10.26 (s, 1H) ppm; 13C
NMR (100 MHz, DMSO-d6, TMS): δ=14.13, 14.83, 20.84, 21.12,
55.93, 58.74, 61.18, 85.97, 119.75, 120.02, 122.06, 125.31, 126.72,
129.06, 133.71, 136.41, 138.72, 139.54, 156.61, 169.00, 169.64 ppm;
IR (KBr): v=3356, 1733, 1625, 1501 cm-1; Found C, 70.71; H, 7.08; N,
6.64%; M+1 (mass spectrum), 409.1. C24H28N2O4 requires C,70.57; H,
6.91; N, 6.86%; M, 408.49.
Compound 5cf
88% yield (392 mg); White solid; mp 146-148 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.94 (t, J=7.0 Hz, 3H), 1.14 (t, J=7.0 Hz, 3H), 3.71
(s, 3H), 3.89-3.97 (m, 2H), 3.98-4.06 (m, 2H), 4.13 (d, J=4.3 Hz, 1H),
4.47 (s, 1H), 5.16 (t, J=5.0 Hz, 1H), 6.55 (d, J=5.4 Hz, 1H), 6.63-6.85
(m, 3H), 6.85-7.28 (m, 4H), 10.27 (s, 1H) ppm; 13C NMR (100 MHz,
DMSO-d6, TMS): δ=14.10, 14.74, 55.39, 55.96, 58.95, 60.56, 61.30,
87.39, 113.86, 118.06, 118.41, 123.57, 126.59, 128.06, 128.15,
Compound 5ce
89% yield (382 mg); White solid; mp 138-140 °C; 1H NMR (400 MHz, 133.97, 140.47, 156.07, 158.69, 168.92, 169.54 ppm; IR (KBr):
DMSO-d6, TMS): δ=0.95 (t, J=6.9 Hz, 3H), 1.14 (t, J=7.0 Hz, 3H), 2.25 v=3339, 1741, 1630, 1513 cm-1; Found C, 62.16; H, 5.79; N, 6.16%;
(s, 3H), 3.89-3.96 (m, 2H), 3.99-4.07 (m, 2H), 4.17 (d, J=4.6 Hz, 1H), M+1 (mass spectrum), 445.0. C23H25ClN2O5 requires C, 62.09; H,
4.48 (s, 1H), 5.17 (t, J=4.4 Hz, 1H), 6.57 (d, J=5.4 Hz, 1H), 6.58-6.87 5.66; N, 6.30%; M, 444.91.
(m, 3H), 7.09-7.24 (m, 4H), 10.27 (s, 1H) ppm; 13C NMR (100 MHz,
DMSO-d6, TMS): δ=14.12, 14.74, 21.09, 55.87, 58.94, 60.67, 61.33,
87.53, 117.99, 118.34, 123.54, 126.52, 126.64, 128.13, 129.13,
136.56, 138.99, 140.42, 156.05, 168.93, 169.54 ppm; IR (KBr):
v=3392, 1721, 1639, 1512 cm-1; Found C, 64.34; H, 5.70; N, 6.62%;
M+1 (mass spectrum), 429.1. C23H25ClN2O4 requires C,64.41; H, 5.88;
N, 6.53%; M, 428.91.
Compound 5df
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89% yield (436 mg); Pale gray solid; mp 148-150 °C; H NMR (400
MHz, DMSO-d6, TMS): δ=0.95 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H),
3.71 (s, 3H), 3.89-3.97 (m, 2H), 3.98-4.06 (m, 2H), 4.13 (d, J=4.9 Hz,
1H), 4.48 (s, 1H), 5.16 (t, J=5.2 Hz, 1H), 6.54 (d, J=5.7 Hz, 1H), 6.72-
6.98 (m, 3H), 6.85-7.27 (m, 4H), 10.27 (s, 1H) ppm; 13C NMR (100
MHz, DMSO-d6, TMS): δ=14.11, 14.73, 55.38, 56.01, 58.96, 60.56,
61.32, 87.52, 113.87, 116.17, 120.93, 121.29, 123.84, 127.00,
Compound 5de
87% yield (412 mg); White solid; mp 110-112 °C; 1H NMR (400 MHz, 127.87, 133.96, 140.75, 156.03, 158.70, 168.90, 169.55 ppm; IR
DMSO-d6, TMS): δ=0.95 (t, J=6.9 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H), 2.25 (KBr): v=3338, 1745, 1628, 1503 cm-1; Found C, 56.36; H, 4.97; N,
(s, 3H), 3.90-3.99 (m, 2H), 4.00-4.07 (m, 2H), 4.18 (d, J=4.8 Hz, 1H), 5.86%; M+1 (mass spectrum), 491.0. C23H25BrN2O5 requires C, 56.45;
4.48 (s, 1H), 5.16 (t, J=5.0 Hz, 1H), 6.58 (d, J=5.6 Hz, 1H), 6.70-6.98 H, 5.15; N, 5.72%; M, 489.36.
(m, 3H), 7.09-7.24 (m, 4H), 10.27 (s, 1H) ppm; 13C NMR (100 MHz,
DMSO-d6, TMS): δ=14.13, 14.75, 21.10, 55.87, 58.96, 60.55, 61.33,
87.57, 116.10, 120.79, 121.18, 123.84, 126.62, 126.88, 129.14,
136.55, 138.94, 140.83, 156.01, 168.92, 169.52 ppm; IR (KBr):
v=3365, 1739, 1632, 1503 cm-1; Found C, 58.29; H, 5.18; N, 6.15%;
M+1 (mass spectrum), 475.0. C23H25BrN2O4 requires C, 58.36; H,
5.32; N, 5.92%; M, 473.36.
Compound 5ag
94% yield (422 mg); Pale yellow solid; mp 122-124 °C; 1H NMR (400
MHz, DMSO-d6, TMS): δ=0.84 (t, J=7.1 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H),
3.75 (d, J=3.4 Hz, 1H), 3.79-3.93 (m, 2H), 3.95-4.06 (m, 2H), 4.30 (s,
1H), 5.66 (m, 1H), 6.14 (d, J=6.0 Hz, 1H), 6.70-6.91 (m, 4H), 7.42-
7.70 (m, 3H), 10.11 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
δ=14.03, 14.76, 53.11, 58.91, 60.43, 61.50, 87.11, 119.90, 120.07,
122.66, 125.29, 127.69, 128.03, 128.83, 130.99, 132.08, 133.03,
Compound 5af
91% yield (374 mg); Yellow solid; mp 140-142 °C; 1H NMR (400 MHz, 139.56, 139.62, 155.44, 168.22, 169.34 ppm; IR (KBr): v=3383, 1731,
DMSO-d6, TMS): δ=0.90 (t, J=7.1 Hz, 3H), 1.15 (t, J=7.1 Hz, 3H), 3.84- 1634, 1512 cm-1; Found C, 58.84; H, 4.89; N, 6.19%; M+1 (mass
3.96 (m, 2H), 3.98-4.07 (m, 2H), 4.05 (d, J=4.8 Hz, 1H), 4.45 (s, 1H), spectrum), 451.0. C22H22Cl2N2O4 requires C, 58.81; H, 4.94; N, 6.23%;
5.17 (t, J=5.1 Hz, 1H), 6.19 (d, J=5.3 Hz, 1H), 6.64-6.84 (m, 4H), 6.86- M, 449.33.
7.28 (m 4H), 10.29 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
δ=14.09, 14.75, 55.35, 55.96, 58.84, 61.18, 61.39, 86.42, 119.35,
119.71, 122.13, 124.78, 127.86, 127.95, 134.57, 139.07, 156.59,
158.65, 168.99, 169.63 ppm; IR (KBr): v=3357, 1722, 1648, 1512 cm-
Compound 5bg
95% yield (440 mg); White solid; mp 156-158 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.86 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.1 Hz, 3H), 2.16
(s, 3H), 3.74 (d, J=3.5 Hz, 1H), 3.81-3.93 (m, 2H), 3.93-4.05 (m, 2H),
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4.25 (s, 1H), 5.63 (m, 1H), 6.07 (d, J=6.1 Hz, 1H), 6.53-6.76 (m, 3H),
Compound 5ch
View Article Online
DOI: 10.1039/C9NJ06332C
7.41-7.67 (m, 3H), 10.08 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, 87% yield (362 mg); White solid; mp 140-142 °C; H NMR (400 MHz,
TMS): δ=14.03, 14.73, 20.91, 53.09, 58.84, 60.23, 61.48, 86.53, DMSO-d6, TMS): δ=0.94 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.1 Hz, 3H), 3.88-
120.02, 120.77, 122.61, 125.49, 127.71, 128.82, 131.00, 132.04, 3.97 (m, 2H), 3.99-4.06 (m, 2H), 4.23 (d, J=4.7 Hz, 1H), 4.35 (s, 1H),
133.02, 134.34, 139.36, 139.61, 155.57, 168.22, 169.37 ppm; IR 5.25 (t, J=5.2 Hz, 1H), 6.58 (d, J=5.7 Hz, 1H), 6.77-6.98 (m, 3H), 7.24-
(KBr): v=3338, 1732, 1626, 1502 cm-1; Found C, 59.76; H, 5.31; N, 8.52 (m, 4H), 10.18(s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
5.85%; M+1 (mass spectrum), 465.0. C23H24Cl2N2O4 requires C, δ=14.08, 14.76, 54.54, 58.97, 61.44, 63.69, 87.28, 116.31, 121.35,
1
59.62; H, 5.22; N, 6.05%; M, 463.35.
121.84, 122.83, 124.13, 127.33, 137.34, 140.71, 149.14, 155.82,
160.86, 168.95, 169.42 ppm; IR (KBr): v=3392, 1741, 1630, 1518 cm-
1; Found C, 61.77; H, 5.45; N, 9.94%; M+1 (mass spectrum), 416.0.
C21H22ClN3O4 requires C, 61.65; H, 5.33; N, 10.10%; M, 415.87.
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Compound 5cg
88% yield (426 mg); White solid; mp 152-154 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.89 (t, J=6.9 Hz, 3H), 1.12 (t, J=7.0 Hz, 3H), 3.83
(d, J=2.7 Hz, 1H), 3.87-3.95 (m, 2H), 3.97-4.10 (m, 2H), 4.34 (s, 1H),
Compound 5dh
5.62 (m, 1H), 6.45 (d, J=5.6 Hz, 1H), 6.72-6.93 (m, 3H), 7.42-7.65 (m, 87% yield (400 mg); White solid; mp 142-144 °C; 1H NMR (400 MHz,
3H), 10.10 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS): DMSO-d6, TMS): δ=0.94 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.1 Hz, 3H), 3.88-
δ=14.01, 14.67, 52.96, 59.03, 59.92, 61.65, 87.86, 118.55, 119.34, 3.97 (m, 2H), 3.97-4.06 (m, 2H), 4.23 (d, J=4.7 Hz, 1H), 4.35 (s, 1H),
124.17, 126.91, 127.79, 128.71, 128.90, 130.91, 132.05, 133.23, 5.25 (t, J=5.2 Hz, 1H), 6.58 (d, J=5.7 Hz, 1H), 6.77-6.99 (m, 3H), 7.24-
139.00, 140.97, 154.83, 168.17, 169.24 ppm; IR (KBr): v=3384, 1732, 8.52 (m, 4H), 10.18(s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
1648, 1514 cm-1; Found C, 54.76; H, 4.51; N, 5.66%; M+1 (mass δ=14.08, 14.76, 54.57, 58.97, 61.44, 63.69, 87.22, 116.31, 121.35,
spectrum), 485.0. C22H21Cl3N2O4 requires C, 54.62; H, 4.38; N, 5.79%; 121.84, 122.83, 124.13, 127.33, 137.34, 140.71, 149.14, 155.82,
M, 483.77.
160.86, 168.95, 169.42 ppm; IR (KBr): v=3292, 1721, 1630, 1504 cm-
1; Found C, 54.65; H, 4.69; N, 9.27%; M+1 (mass spectrum), 461.9.
C21H22BrN3O4 requires C, 54.79; H, 4.82; N, 9.13%; M, 460.32.
Compound 5dg
91% yield (481 mg); White solid; mp 158-160 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.89 (t, J=7.1 Hz, 3H), 1.13 (t, J=7.0 Hz, 3H), 3.83
Compound 5ai
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(d, J=3.5 Hz, 1H), 3.86-3.96 (m, 2H), 3.97-4.06 (m, 2H), 4.34 (s, 1H), 89% yield (344 mg); Yellow solid; mp 96-98 °C; H NMR (400 MHz,
5.62 (m, 1H), 6.43 (d, J=5.9 Hz, 1H), 6.85-6.97 (m, 3H), 7.42-7.65 (m, DMSO-d6, TMS): δ=0.91 (t, J=7.1 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H), 3.84-
3H), 10.09 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS): 3.97 (m, 2H), 3.98-4.10 (m, 2H), 4.03 (d, J=4.0 Hz, 1H), 4.54 (s, 1H),
δ=14.01, 14.70, 52.99, 59.04, 59.87, 61.66, 87.94, 121.37, 122.22, 5.47 (t, J=5.0 Hz, 1H), 6.38 (d, J=5.5 Hz, 1H), 6.70-6.89 (m, 4H), 6.96-
124.47, 127.33, 127.81, 128.91, 130.90, 132.06, 133.21, 138.99, 7.36 (m, 3H), 10.27 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
141.23, 154.79, 168.16, 169.23 ppm; IR (KBr): v=3385, 1735, 1631, δ=14.12, 14.82, 56.29, 58.94, 61.38, 87.02, 120.32, 122.20, 124.10,
1506 cm-1; Found C, 49.97; H, 3.89; N, 5.44%; M+1 (mass spectrum), 124.83, 125.21, 127.27, 128.64, 138.38, 147.43, 156.08, 168.59,
529.0. C22H21BrCl2N2O4 requires C, 50.02; H, 4.01; N, 5.30%; M, 169.59 ppm; IR (KBr): v=3292, 1721, 1630, 1504 cm-1; Found C,
528.22.
62.05; H, 5.59; N, 7.38%; M+1 (mass spectrum), 387.1. C20H22N2O4S
requires C, 62.16; H, 5.74; N, 7.25%; M, 386.46.
Compound 5ah
90% yield (343 mg); Pale yellow solid; mp 112-114 °C; 1H NMR (400
Compound 5bi
MHz, DMSO-d6, TMS): δ=0.90 (t, J=7.1 Hz, 3H), 1.13 (t, J=7.1 Hz, 3H), 91% yield (364 mg); Yellow solid; mp 116-118 °C; 1H NMR (400 MHz,
3.84-3.95 (m, 2H), 3.95-4.05 (m, 2H), 4.17 (d, J=4.8 Hz, 1H), 4.30 (s, DMSO-d6, TMS): δ=0.93 (t, J=7.1 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H), 2.16
1H), 5.28 (t, J=5.2 Hz, 1H), 6.24 (d, J=5.6 Hz, 1H), 6.68-6.89 (m, 4H), (s, 3H), 3.86-3.96 (m, 2H), 3.98-4.08 (m, 2H), 4.01 (d, J=5.9 Hz, 1H),
7.23-8.51 (m, 4H), 10.18(s, 1H); 13C NMR (100 MHz, DMSO-d6, TMS): 4.51 (s, 1H), 5.44 (t, J=5.1 Hz, 1H), 6.30 (d, J=5.5 Hz, 1H), 6.52-6.71
δ=14.07, 14.77, 54.41, 58.85, 61.30, 64.55, 86.30, 119.88, 120.06, (m, 3H), 6.95-7.35 (m, 3H), 10.25 (s, 1H) ppm; 13C NMR (100 MHz,
121.49, 122.38, 122.69, 124.97, 128.21, 137.21, 139.08, 149.02, DMSO-d6, TMS): δ=14.08, 14.86, 20.81, 56.24, 58.75, 58.84, 61.34,
156.48, 161.42, 169.08, 169.52; IR (KBr): v=3292, 1739, 1638, 1512 86.41, 120.46, 121.01, 122.13, 124.07, 125.15, 126.13, 127.24,
cm-1; Found C, 66.02; H, 5.94; N, 11.06%; M+1 (mass spectrum), 133.83, 138.09, 147.41, 156.15, 168.58, 169.62 ppm; IR (KBr):
382.2. C21H23N3O4 requires C, 66.13; H, 6.08; N, 11.02%; M, 381.43.
v=3356, 1739, 1622, 1506 cm-1; Found C, 63.12; H, 6.19; N, 6.86%;
M+1 (mass spectrum), 401.0. C21H24N2O4S requires C, 62.98; H, 6.04;
N, 6.99%; M, 400.49.
Compound 5bh
93% yield (368 mg); Pale yellow solid; mp 116-118 °C; 1H NMR (400
MHz, DMSO-d6, TMS): δ=0.92 (t, J=7.1 Hz, 3H), 1.12 (t, J=7.1 Hz, 3H),
Compound 5ci
2.16 (s, 3H), 3.86-3.94 (m, 2H), 3.95-4.04 (m, 2H), 4.15 (d, J=4.7 Hz, 84% yield (354 mg); Yellow solid; mp 106-108 °C; 1H NMR (400 MHz,
1H), 4.27 (s, 1H), 5.26 (t, J=5.2 Hz, 1H), 6.18 (d, J=5.5 Hz, 1H), 6.50- DMSO-d6, TMS): δ=0.94 (t, J=7.0 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H), 3.89-
6.71 (m, 3H), 7.23-8.50 (m, 4H), 10.16(s, 1H) ppm; 13C NMR (100 3.98 (m, 2H), 4.00-4.07 (m, 2H), 4.12 (d, J=4.3 Hz, 1H), 4.58 (s, 1H),
MHz, DMSO-d6, TMS): δ=14.09, 14.82, 20.93, 54.42, 58.77, 61.27, 5.46 (t, J=5.0 Hz, 1H), 6.70 (d, J=5.6 Hz, 1H), 6.72-6.85 (m, 3H), 6.97-
64.36, 85.80, 120.20, 120.60, 121.47, 122.32, 122.68, 125.71, 7.37 (m, 3H), 10.28 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS):
133.99, 137.21, 138.80, 149.02, 156.56, 161.44, 169.08, 169.54 ppm; δ=14.08, 14.81, 56.14, 58.15, 59.03, 61.48, 88.04, 118.74, 119.41,
IR (KBr): v=3301, 1732, 1639, 1516 cm-1; Found C, 66.86; H, 6.43; N, 123.65, 124.26, 125.33, 127.35, 128.13, 139.72, 146.78, 155.54,
10.55%; M+1 (mass spectrum), 396.1. C22H25N3O4 requires C, 66.82; 168.48, 169.50 ppm; IR (KBr): v=3348, 1730, 1621, 1503 cm-1; Found
H, 6.37; N, 10.63%; M, 395.45.
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C, 57.21; H, 5.08; N, 6.51%; M+1 (mass spectrum), 421.0. MHz, DMSO-d6, TMS): δ=14.04, 14.74, 54.50, 59.07,V6ie1w.A5r8tic,le6O1n.6lin8e,
DOI: 10.1039/C9NJ06332C
C20H21ClN2O4S requires C, 57.07; H, 5.03; N, 6.66%; M, 420.91.
88.28, 116.48, 121.02, 121.93, 123.12, 124.45, 128.22, 140.17,
143.56, 154.84, 168.16, 169.29, 174.01 ppm; IR (KBr): v=3301, 1732,
1625, 1506 cm-1; Found C, 54.13; H, 4.86; N, 9.88%; M+1 (mass
spectrum), 467.9. C19H20BrN3O4S requires C, 54.09; H, 4.78; N,
9.96%; M, 466.35.
Compound 5di
96% yield (447 mg); Yellow solid; mp 128-130 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.95 (t, J=7.1 Hz, 3H), 1.16 (t, J=7.1 Hz, 3H), 3.89-
3.98 (m, 2H), 4.00-4.09 (m, 2H), 4.13 (d, J=4.6 Hz, 1H), 4.59 (s, 1H),
5.45 (t, J=5.0 Hz, 1H), 6.72 (d, J=5.6 Hz, 1H), 6.76-6.98 (m, 3H), 6.98-
Compound 5ak
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7.37 (m, 3H), 10.28 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, TMS): 78% yield (294 mg); Light yellow solid; mp 96-98 °C; H NMR (400
δ=14.12, 14.81, 56.17, 58.13, 59.05, 61.50, 88.12, 116.12, 121.59, MHz, DMSO-d6, TMS): δ=0.87 (t, J=7.1 Hz, 3H), 1.22 (t, J=7.2 Hz, 3H),
122.27, 123.93, 124.27, 125.34, 127.38, 127.74, 139.98, 146.74, 1.25 (t, J=7.2 Hz, 3H), 3.75-3.90 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 4.18-
155.51, 168.48, 169.51 ppm; IR (KBr): v=3347, 1721, 1612, 1499 cm- 4.28 (m, 2H), 4.26 (s, 1H), 4.48 (s, 1H), 4.95 (s, 1H), 5.47 (s, 1H),
1; Found C, 51.79; H, 4.79; N, 5.91%; M+1 (mass spectrum), 467.0. 6.67-6.99 (m, 4H), 10.42 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6,
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C20H21BrN2O4S requires C, 51.62; H, 4.55; N, 6.02%; M, 465.36.
TMS): δ=13.95, 14.39, 14.92, 52.85, 59.07, 59.51, 61.43, 62.01,
86.60, 120.00, 120.43, 122.29, 124.65, 127.13, 136.81, 156.43,
167.69, 169.99, 170.67 ppm; IR (KBr): v=3357, 1748, 1658, 1513 cm-
1; Found C, 60.65; H, 6.52; N, 7.36%; M+1 (mass spectrum), 377.1.
C19H24N2O6 requires C, 60.63; H, 6.43; N, 7.44%; M, 376.40.
Compound 5aj
90% yield (349 mg); White solid; mp 152-154 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.85 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H), 3.79-
3.92 (m, 2H), 3.93-4.04 (m, 2H), 4.05 (d, J=3.8 Hz, 1H), 4.36 (s, 1H),
5.57 (dd, J=6.3, 3.8 Hz, 1H), 6.57 (d, J=6.3 Hz, 1H), 6.75-6.93 (m, 4H),
Compound 5bk
7.59-7.81 (m, 2H), 10.07 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6, Light yellow solid; 82% yield (320 mg); mp 86-88 °C; H NMR (400
TMS): δ=14.11, 14.86, 54.67, 59.03, 61.62, 62.43, 87.48, 120.48, MHz, DMSO-d6, TMS): δ=0.88 (t, J=7.1 Hz, 3H), 1.21 (t, J=7.4 Hz, 3H),
120.94, 121.11, 122.74, 125.28, 129.11, 138.72, 143.54, 155.54, 1.25 (t, J=7.5 Hz, 3H), 2.15 (s, 3H), 3.74-3.89 (m, 2H), 4.09 (q, J=7.0
168.31, 169.47, 174.99 ppm; IR (KBr): v=3311, 1739, 1648, 1505 cm- Hz, 2H), 4.17-4.28 (m, 2H), 4.23 (s, 1H), 4.44 (s, 1H), 4.91 (s, 1H),
1; Found C, 58.76; H, 5.25; N, 10.95%; M+1 (mass spectrum), 388.1. 5.34 (s, 1H), 6.50-6.78 (m, 3H), 10.35 (s, 1H) ppm; 13C NMR (100
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C19H21N3O4S requires C, 58.90; H, 5.41; N, 10.85%; M, 387.45.
MHz, DMSO-d6, TMS): δ=13.93, 14.36, 14.95, 20.80, 52.63, 58.99,
59.63, 61.42, 61.99, 86.02, 120.65, 120.87, 122.29, 124.82, 133.83,
136.61, 156.49, 167.67, 170.01, 170.74 ppm; IR (KBr): 3374, 1740,
1641, 1517 cm-1; Found C, 61.44; H, 6.56; N, 7.33%; M+1 (mass
spectrum), 391.1. C20H26N2O6 requires C, 61.53; H, 6.71; N, 7.18%;
M, 390.43.
Compound 5bj
94% yield (377 mg); Yellow solid; mp 172-174 °C; 1H NMR (400 MHz,
DMSO-d6, TMS): δ=0.89 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H), 2.17
(s, 3H), 3.81-3.92 (m, 2H), 3.93-4.00 (m, 2H), 4.03 (d, J=3.8 Hz, 1H),
4.32 (s, 1H), 5.54 (dd, J=6.3, 3.8 Hz, 1H), 6.49 (d, J=6.3 Hz, 1H), 6.57-
6.75 (m, 3H), 7.59-7.81 (m, 2H), 10.03 (s, 1H) ppm; 13C NMR (100
Compound 5ck
MHz, DMSO-d6, TMS): δ=14.06, 14.75, 20.89, 54.60, 58.86, 61.50, 69% yield (283 mg); Light yellow solid; mp 120-122 °C; 1H NMR (400
62.24, 86.79, 120.58, 120.83, 121.69, 122.59, 126.49, 134.30, MHz, DMSO-d6, TMS): δ=0.91 (t, J=7.0 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H),
138.40, 143.42, 155.60, 168.23, 169.42, 174.95 ppm; IR (KBr): 1.25 (t, J=7.1 Hz, 3H), 3.75-3.93 (m, 2H), 4.10 (q, J=7.0 Hz, 2H), 4.18-
v=3315, 1733, 1621, 1503 cm-1; Found C, 59.78; H, 5.73; N, 10.51%; 4.27 (m, 2H), 4.29 (s, 1H), 4.52 (s, 1H), 4.98 (s, 1H), 5.87 (s, 1H),
M+1 (mass spectrum), 402.1. C20H23N3O4S requires C, 59.83; H, 5.77; 6.67-7.15 (m, 3H), 10.39 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6,
N, 10.47%; M, 401.48.
TMS): δ=14.03, 14.34, 14.94, 52.91, 59.11, 59.17, 61.55, 62.06,
87.19, 119.24, 119.37, 123.73, 126.21, 128.10, 138.27, 156.07,
167.68, 169.91, 170.31 ppm; IR (KBr): v=3358, 1739, 1646, 1503 cm-
1; Found C, 55.68; H, 5.81; N, 6.63%; M+1 (mass spectrum), 411.0.
C19H23ClN2O6 requires C, 55.54; H, 5.64; N, 6.82%; M, 410.85.
Compound 5cj
89% yield (376 mg); Pale yellow solid; mp 178-180 °C; 1H NMR (400
MHz, DMSO-d6, TMS): δ=0.90 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H),
3.85-3.95 (m, 2H), 3.96-4.08 (m, 2H), 4.14 (d, J=3.5 Hz, 1H), 4.41 (s,
1H), 5.54 (dd, J=6.1, 3.9 Hz, 1H), 6.78 (dd, J=8.4, 2.1 Hz, 1H), 6.86-
Compound 5dk
6.91 (m, 3H), 7.61-7.82 (m, 2H), 10.07 (s, 1H) ppm; 13C NMR (100 71% yield (323 mg); Light yellow solid; mp 110-112 °C; 1H NMR (400
MHz, DMSO-d6, TMS): δ=14.05, 14.73, 54.51, 59.05, 61.61, 61.67, MHz, DMSO-d6, TMS): δ=0.91 (t, J=6.9 Hz, 3H), 1.21 (t, J=7.1 Hz, 3H),
88.17, 119.07, 120.24, 120.98, 124.16, 127.81, 128.51, 139.91, 1.25 (t, J=7.1 Hz, 3H), 3.78-3.93 (m, 2H), 4.09-4.14 (m, 2H), 4.17-
143.54, 154.87, 168.16, 169.28, 174.05 ppm; IR (KBr): v=3305, 1730, 4.26 (m, 2H), 4.29 (s, 1H), 4.52 (s, 1H), 4.99 (s, 1H), 5.86 (s, 1H),
1625, 1513 cm-1; Found C, 54.23; H, 4.92; N, 9.83%; M+1 (mass 6.80-7.28 (m, 3H), 10.38 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6,
spectrum), 422.0. C19H20ClN3O4S requires C, 54.09; H, 4.78; N, 9.96%; TMS): δ=13.88, 14.43, 14.81, 52.92, 59.14, 59.19, 61.57, 62.06,
M, 421.9.
87.30, 116.12, 122.14, 122.21, 123.99, 126.66, 138.55, 155.99,
167.66, 169.91, 170.29 ppm; IR (KBr): v=3366, 1739, 1651, 1512 cm-
1; Found C, 50.05; H, 4.91; N, 6.24%; M+1 (mass spectrum), 457.1.
C19H23BrN2O6 requires C, 50.12; H, 5.09; N, 6.15%; M, 455.30.
Compound 5dj
1
89% yield (415 mg);mp 182-184 °C; Pale yellow solid; H NMR (400
MHz, DMSO-d6, TMS): δ=0.90 (t, J=7.1 Hz, 3H), 1.14 (t, J=7.1 Hz, 3H),
3.85-3.95 (m, 2H), 3.96-4.08 (m, 2H), 4.14 (d, J=3.7 Hz, 1H), 4.42 (s,
1H), 5.53 (dd, J=6.3, 4.0 Hz, 1H), 6.83-7.02 (m, 3H), 6.90 (dd, J=8.4,
2.1 Hz, 1H), 7.61-7.82 (m, 2H), 10.07 (s, 1H) ppm; 13C NMR (100
Conflicts of interest
There are no conflicts to declare.
14 | J. Name., 2012, 00, 1-3
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ARTICLE
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M. Lang, J. Wang, Eur. J. Org. Chem. 2018, (23),V2ie9w5A8rt-ic2le9O62nl.ine
B. Nagaraju, J. Kovvuri, K. S. Babu, P. R. Adiyala, V. L. Nayak,
A. Alarifi, A. Kamal, Tetrahedron 2017,D7O3I:(4109.1),06399/6C99-N6J907663.32C
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (21776060), the Natural Science
Foundation of Hebei Province (B2016205165).
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View Article Online
DOI: 10.1039/C9NJ06332C
Graphical Abstract
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Expedient green-chemistry approaches for one-pot synthesis of two series of
novel 1,5-benzodiazepines via domino reactions
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Hai-tao Wu, Lan-zhi Wang*
College of Chemistry and Material Science, Hebei Normal University, Shijiazhuang, 050024, P. R.
China; Phone: 13933001162; E-mail: wanglanzhi@126.com
R2
O
H
N
H
N
R1
R1
NH2
NH2
R1
O
COOC2H5
C2H5OOC
COOC2H5
N
H
N
H
2
1
C2H5OOC
C2H5OOC
4: yields 90-95%
5: yields 69-96%
two-component domino reaction
three-component domino reaction
O
R2
H
3
R1
COOC2H5
COOC2H5
N
H
NH2
Unique green-chemistry approaches have been developed for the one-pot synthesis of two
Series of novel 1,5-benzodiazepines 4 and 5. The CeCl3-KI promoted two-component domino
reaction of 1,2-phenylenediamines with 1,3-acetonedicarboxylate in ethanol afforded novel
1,5-benzodiazepin-2-ones 4. An expedient approach to 1,5-benzodiazepines 5 has also been
developed via three-component domino reactions using 1,2-phenylenediamines,
1,3-acetonedicarboxylate and aldehydes in the presence of a catalytic amount of magnetic
nanoparticles (γ-Fe2O3@SiO2/CeCl3) in ethanol at ambient temperature. During the one-pot
synthesis process, one new seven-membered nitrogen heterocycle (diazepin) and four new
bonds (one C–C, two C–N and one C=C) were constructed by the nucleophilic addition,
eliminate reaction (dehydration etc.), hydride transfer and cyclization process. Moreover, the
methods have advantages such as operational simplicity, mild reaction conditions, short
reaction time, easy recovery and reusability of the catalyst, high yields of products, and
non-toxic EtOH as the solvent.