Fe3O4@SiO2-CeCl3 Catalyzed Chemoselective Synthesis of Functionalized 3-Substituted-1,5-Benzodiazepines via One-pot Multicomponent and Domino Reactions

Article abstract of DOI:10.1002/aoc.5707

Fe₃O₄@SiO₂-CeCl₃ catalyzed chemoselective synthesis of functionalized 3-substituted-1,5-benzodiazepines via one-pot multicomponent and domino reactions has been developed. During the one-pot synthesis process, one new cycle and four new bonds (one C–C, two C–N and one C=C) were constructed by the nucleophilic addition and eliminate reaction (dehydration etc.) process, intramolecular proton transfer and cyclization process. The major advantages of the present method are good to excellent yields, shorter reaction time, simple experimental procedure, easy work up, mild reaction conditions, recyclability of the catalyst and ability to tolerate a variety of functional groups which gives economical as well as ecological rewards.

Full text of DOI:10.1002/aoc.5707

Received: 10 February 2020
DOI: 10.1002/aoc.5707
Revised: 12 March 2020
Accepted: 17 March 2020
F U L L P A P E R
Fe3O4@SiO2-CeCl3 Catalyzed Chemoselective Synthesis of
Functionalized 3-Substituted-1,5-Benzodiazepines via One-
pot Multicomponent and Domino Reactions
Laiyun Zhou | Mingliang Wang | Kaixuan Wang | Tiantian Wen |
Lanzhi Wang
Hebei Key Laboratory of Organic
Fe3O4@SiO2-CeCl3 catalyzed chemoselective synthesis of functionalized
3-substituted-1,5-benzodiazepines via one-pot multicomponent and domino
reactions has been developed. During the one-pot synthesis process, one new
cycle and four new bonds (one C–C, two C–N and one C=C) were constructed
by the nucleophilic addition and eliminate reaction (dehydration etc.) process,
intramolecular proton transfer and cyclization process. The major advantages
of the present method are good to excellent yields, shorter reaction time, sim-
ple experimental procedure, easy work up, mild reaction conditions, recyclabil-
ity of the catalyst and ability to tolerate a variety of functional groups which
gives economical as well as ecological rewards.
Functional Molecules, College of
Chemistry and Materials Science, Hebei
Normal University, Shijiazhuang, 050024,
People's Republic of China
Correspondence
Lanzhi Wang, Hebei Key Laboratory of
Organic Functional Molecules, College of
Chemistry and Materials Science, Hebei
Normal University. Shijiazhuang, 050024,
People's Republic of China.
Email: wanglanzhi@126.com
Funding information
National Natural Science Foundation of
China, Grant/Award Number: 21776060;
Natural Science Foundation of Hebei
Province, Grant/Award Number:
B2016205165
K E Y W O R D S
3-substituted-1,5-benzodiazepines, catalysis, domino reaction, Fe3O4@SiO2-CeCl3, one-pot
multicomponent
1 | INTRODUCTION
been carried out by condensation of 1,2-phe-
nylenediamine
with
1,3-dicarbonyl
compounds,
Benzodiazepines are categorized as a heterocyclic system
that is the structural basis of a large number of drugs as
defined by Evans about 30 years ago.[1–4] Heterocyclic
compounds comprising a 1,5-benzodiazepine ring have
been a topic of continued interest as they exhibit a wide
spectrum of drug-like profiles such as good anticonvul-
sant activity against acutely elicited seizure, particularly
for the central nervous system.[5–8] Many biologically
active small molecules with such a core structure have
been marketed for the treatment of various diseases,
mostly as psychotropic substances,[9] such as
Lofendazam, Triflubazam and Clozapine (Figure 1).[10]
Due to the versatile applicability highlights the
importance of accessing efficient synthetic routes to
1,5-benzodiazepines. A number of methods have been
developed for the synthesis of 1,5-benzodiazepines. It has
3-haloalk-2-enones, and alk-2-ynones[11,12] under various
conditions such as oxalic acid in organic solvents, acetic
acid in ethanol under reflux,[13] acetic acid in toluene,[14]
HCl in ethanol,[15] and H2SO4 in ethanol.[16] Most of
these procedures rely on liquid protic acid catalysts,
which pose many drawbacks such as the predicament of
waste disposal. Therefore, the syntheses require tedious
work up procedures for the elimination of liquid catalysts
from the final products. Furthermore, if precious metal
catalysts are used,[17,18] they can be expensive and
unrecyclable, can require harsher reaction conditions
and are also not environmentally benign. Thus, the
development of efficient methods and environment-
friendly catalysts for the construction of the benzodiaze-
pine skeleton still remains a highly desirable yet chal-
lenging task.
Appl Organomet Chem. 2020;e5707.
wileyonlinelibrary.com/journal/aoc
© 2020 John Wiley & Sons, Ltd.
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https://doi.org/10.1002/aoc.5707

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ZHOU ET AL.
FIGURE 1 Example of bioactive
1,5-benzodiazepines
Very recently, an efficient and recoverable heteroge-
support.[20] It was reported that formation of a passive
coating of magnetic nanoparticles could prevent their
aggregation in solutions and thus improve their chemical
stability.[21,22] Owing to its good stability, high surface
area and easy synthesis, silica encapsulated magnetic
nanocrystallities have recently been used as heteroge-
neous catalytic supports.[23]
neous catalyst system constitutes an important aspect of
green organic synthesis.[19] One of the most attractive
alternatives to catalyst supports is magnetic nanoparticles
(MNPs), which has witnessed increasing popularity due
to their high surface areas and improved dispersability in
the reaction medium. Specifically, magnetically
supported catalysts can be recovered using an external
magnet due to the paramagnetic character of the
Previously, we have established a mild method for the
synthesis
of
2-aryl-3-acetyl-1,5-benzodiazepines
SCHEME 1 Design strategy for the synthesis of benzodiazepines

ZHOU ET AL.
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(Scheme 1A).[24] Although this method was proved to be
successful and allowed facile access to 3-acyl-1,5-benzodi-
azepines, it suffered from certain disadvantages, such as
the need for a highly expensive reagent (3-butyn-2-one)
and a limited substrate scope, which makes this strategy
less adaptable for the sustainable synthesis, we wish to
important applications in medicinal and organic
chemistry.
2 | RESULTS AND DISCUSSION
report
a
direct synthesis of highly functionalized
At first, the set of reactions with 1-phenyl-
1,3-butanedione 2 and 1,2-phenylenediamine 1a in pres-
ence of 5 mol% of CeCl3 at room temperature furnished
3-substituted-1,5-benzodiazepines (Scheme 1B) via the
multicomponent[25–27] and domino sequence of a nucleo-
philic
substitution
/nucleophilic
2-methyl-4-phenyl-1,5-benzodiazepine 7 with imine-
addition/dehydration/cyclization/intramolecular proton
transfer in excellent yields under milder reaction condi-
tions by using recyclable catalyst (Fe3O4@SiO2-CeCl3).
This method has a lot of advantages which are atomic
economy, high yield, short time, magnetic recyclable cat-
alyst, one-pot construction of four chemical bonds (one
C–C, two C–N and one C=C) to synthesize multiple
functionalized 1,5-benzodiazepine compounds.[28,29] The
structures of the compound has multiple functional
groups on the seven-membered ring, which will have
enamine structure in 76% yield (Scheme 2, Strategy I).
The results showed that CeCl3 is an effective catalyst for
above two-component domino reaction.
On the basis of the above results, another 2-methyl-
4-phenyl-1,5-benzodiazepine 8 with imine - imine struc-
ture was obtained and the isolated yield of it was 82% by
substituting cesium chloride for acetic acid and changing
the room temperature condition to ice bath conditions
(Scheme 2, Strategy II). Different structures of 1,5-benzo-
diazepine (7 and 8) are synthesized by selecting different
SCHEME 2 The formation mechanism of
1,5-benzodiazepines 7 and 8

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ZHOU ET AL.
catalysts and changing different reaction temperatures.
The formation mechanism was described in Scheme 2.
Inspired by the success of the above domino reactions
of the one-pot synthesis of 1,5-benzodiazepines 7 and 8, a
new synthetic strategy via three-component reaction was
designed for one-pot synthesis of functionalized
3-substituted-1,5-benzodiazepines 6 (Scheme 1B, Strategy
I). However, the expected product 6 wasn't obtained via a
one-pot the condensation reaction of the 1,2-phe-
nylenediamines, 1-phenyl-1,3-butanedione and substituted
benzaldehyde under room temperature. Attempts on vari-
ous reaction conditions were not successful. In the reac-
tion, only the uncyclized product 10 was obtained. The
reason may be due to larger space steric and lower reactiv-
ity of substituted benzaldehyde. In view of this, we were
inspired to try using more active heterocyclic aldehyde (thi-
Therefore, our initial efforts focused on the search of
a catalyst, which is stable enough, efficient and can be
recycled to carry out the synthesis of 1,5-benzodiazepines
in organic solvent at room temperature. In our work, it
was found that CeCl3 is an effective catalyst for this mul-
ticomponent reaction. As an alternative catalyst, the
magnetic nano-particles Fe3O4@SiO2-CeCl3 can be com-
bined with the reaction substrate in a hydrogen bond due
to the presence of a large amount of O-H bonds on the
surface of the carrier Fe3O4@SiO2, so that a certain syn-
ergistic effect is played in the catalysis system. And then,
the Fe3O4@SiO2-CeCl3 catalyst system shows higher cat-
alytic activity than CeCl3 under the same conditions. In
this connection, Fe3O4@SiO2-CeCl3 as a mild heteroge-
neous catalyst was chosen for the synthesis of 1,5-benzo-
diazepines in organic solvent. The route to prepare
Fe3O4@SiO2-CeCl3 is shown in Scheme 3.
azole-2-carboxaldehyde,
pyridine-2-carboxaldehyde)
instead of substituted benzaldehyde as initial material. The
result was satisfactory. The reaction was achieved success-
fully by reacting 1,2-phenylenediamine 1a, 1-phenyl-
1,3-butanedione 2 and thiazole-2-carboxaldehyde 3a in
EtOH at room temperature (Scheme 1B, Strategy II). Mech-
anistically, it is relay catalysis, and the reaction occurred
via successive carbonyl and imine activation processes,
both of which were promoted by the acid catalyst.
Magnetic nanoparticles Fe3O4@SiO2-CeCl3 was pre-
pared by adding CeCl3 with Fe3O4@SiO2 in ethanol solu-
tion. This synthetic process is rather simple, cost-effective
and environmentally-friendly because it uses water and a
small amount of ethanol as a solvent and does not pro-
duce any hazardous waste.
The prepared Fe3O4@SiO2-CeCl3 powder was charac-
terized by various spectral techniques such as FT-IR
SCHEME 3 Pathways for the preparation of Fe3O4@SiO2-CeCl3 (step 3)

ZHOU ET AL.
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spectroscopy (Figure 2A), scanning electron microscopy
(SEM), transmission electron microscopy (TEM), electron
dispersive X-ray spectroscopy (EDX), powder XRD, BET
surface area (BET) and vibrating sample magnetometer
(VSM). Characterization data of Fe3O4@SiO2-CeCl3 are
shown in Figure 3.
To investigate the chemical stability of Fe3O4@SiO2-
CeCl3, we dispersed the samples in different organic sol-
vents such as MeOH, EtOH, CH3CN, DMSO, DMF,
CH2Cl2, THF and toluene for two days at room tempera-
ture. The sample was then collected by filtration, washed
with methanol and dried under vacuum. To our delight,
all samples also showed strong peaks in the XRD pattern
and had similar backbone connections in the FT-IR pro-
file. Therefore, the experimental results clearly show that
Fe3O4@SiO2-CeCl3 has excellent thermal and chemical
stabilities.
Based on the above experimental results, CeCl3 was
successfully loaded in the form of coordination bond or
hydrogen bond. Next, the magnetic nanocatalyst
(Fe3O4@SiO2-CeCl3) will be applied to the one-pot syn-
thesis of 1,5-benzodiazepines with aryl, ester, carboxyl
and acyl groups described above. Initially to optimize the
reaction procedure, 1,2-phenylenediamine 1a, 1-phenyl-
1,3-butanedione 2 and thiazole-2-carboxaldehyde 3a in
EtOH at room temperature and using Fe3O4@SiO2-CeCl3
as the catalyst (Scheme 1B, Strategy II). This reaction
proceeded to completion within 1.2 hr and the product
4aa was isolated in excellent yield (86%). This encourag-
ing result indicated the feasibility of the envisioned three-
component reaction.
in 1,2-phenylenediamines to the carbonyl carbon of the
aromatic aldehyde activated by Fe3O4@SiO2-CeCl3,
which generates intermediate 9 by nucleophilic addition
and dehydration. Then, the other amino group of
1,2-phenylenediamines attack to small steric hindrance
acetyl group of 1-phenyl-1,3-butanedione to give the
intermediate 10. During this step, catalyst Fe3O4@SiO2-
CeCl3 activated the carbonyl carbon of the 1,2-phe-
nylenediamine to promote rapidly reaction. Under the
catalysis of Fe3O4@SiO2-CeCl3, the latter may undergo a
cyclization reaction by the proton transfer to yield the
1
target product. These compounds are determined by H-
NMR, 13C-NMR, MS, and FT-IR. Simple operation, short
reaction time, high yields are the advantages of this syn-
thesis method.
It is worth noting that when we converted thiazole-
2-carboxaldehyde or pyridine-2-carboxaldehyde to
pyruvic aldehyde, ethyl glyoxylate or glyoxylic acid. The
one-pot three-component synthesis methodology of
3-substituted-1,5-benzodiazepines are clearly not applica-
ble. The main reason is that the aldehyde group in
pyruvic aldehyde, glyoxylic acid or ethyl glyoxylate is
more active than benzaldehyde and will react with two
amino groups of 1,2-phenylenediamine to form unneces-
sary by-products. Therefore, the domino reactions were
carried out for synthesis of 3-substituted-1,5-benzodiaze-
pines 5 containing ester, carboxyl and acyl groups
(Scheme 1B, Strategy III). Firstly, intermediate products
11 were achieved by reacting substituted 1,2-phe-
nylenediamine 1a-1f and 1-phenyl-1,3-butanedione 2.
And then, functionalized 3-substituted-1,5-benzodiaze-
pines 5 were obtained by intermediate products 11 with
pyruvic aldehyde 3c, ethyl glyoxylate 3d or glyoxylic acid
3e in EtOH at room temperature and using Fe3O4@SiO2-
CeCl3 as the catalyst.
Then, the scope of the three-component reaction was
explored. The results and the proposed mechanism of
three-component reaction were shown in Table 1. The
first step involves the nucleophilic attack of para-amino
FIGURE 2 (A) IR spectra of CeCl3, Fe3O4@SiO2 and Fe3O4@SiO2-CeCl3. (B) IR spectra of Fe3O4@SiO2-CeCl3

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ZHOU ET AL.
FIGURE 3 (a) SEM image of Fe3O4@SiO2-CeCl3, (b) TEM image of the synthesized Fe3O4@SiO2-CeCl3, (c) Powder XRD spectrum of
prepared Fe3O4@SiO2-CeCl3, (d) EDX spectrum of Fe3O4@SiO2-CeCl3, (e) N2 adsorption–desorption Curve and pore size Distribution Map
of Fe3O4@SiO2-CeCl3 and (f) Fe3O4@SiO2-CeCl3 hysteretic loop diagram
To establish the feasibility of the domino reaction as
well as to optimize the conditions, we started this meth-
odology by subjecting 1,2-phenylenediamine 1a to the
reaction with 1-phenyl-1,3-butanedione 2 and ethyl
glyoxylate 3d as the model substrates. The results of
screening different catalysts are summarized in Table 2.
the effect of catalysts was studied. No appreciable
amount of product 5ad was formed in the absence of
acid-catalysts. To investigate the role of catalysts, we set
up some reactions using different magnetic
nanocatalyst. To our delight, all tested catalysts have
different catalytic effects on this reaction, and the reac-
tion time is greatly shortened. Of the catalysts tested,
Fe3O4@SiO2-CeCl3 emerged as the most effective mag-
netic nanocatalyst. Obviously, Fe3O4@SiO2-CeCl3
afforded the product in maximum yield and needed a
shorter reaction time (Table 2, entry 11). When using
hydrochloric acid as the acid catalyst for the catalytic

ZHOU ET AL.
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TABLE 1
Scope of substrates for the three-component synthesis of benzodiazepines 4a
aReaction conditions: 1,2-phenylenediamine compounds (1.0 mmol), 1-phenyl-1,3-butanedione (1.0 mmol), and heterocyclic aromatic alde-
hydes (1.0 mmol) in EtOH (2.0 ml), Fe3O4@SiO2-CeCl3, r.t.
reaction, the reaction time can be reduced due to the
strong acidity. However, the yield of the target product
5ad is only 39%, which is lower than that of
Fe3O4@SiO2-CeCl3 because of the formation of by-
products (Table 2, entry 2). Similarly, acetic acid only
achieve 47% yield of 5ad (Table 2, entry 3). After exten-
sive screening, Fe3O4@SiO2-CeCl3 (8.0 mg) was found
to be optimal. When the amount of catalyst
Fe3O4@SiO2-CeCl3 was decreased to 5.0 mg, the iso-
lated yield was dropped to 82%.

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ZHOU ET AL.
TABLE 2
Reaction Catalyst variationa
Entry
Catalyst
Timeb (hr)
Yieldc (%)
1
no
5.0
1.2
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
5.0
30
39
47
49
57
52
65
71
35
87
90
82
2f
3g
4
hydrochloric acid
acetic acid
Fe3O4@SiO2-Mandelic acid
Fe3O4@SiO2-PMA
Fe3O4@SiO2-p-TsOH
Fe3O4@SiO2-CoCl2
CeCl3
5
6
7
8
9
Fe3O4@SiO2
10
11d
12e
Fe3O4@SiO2-CeCl3
Fe3O4@SiO2-CeCl3
Fe3O4@SiO2-CeCl3
aReaction conditions: 1,2-phenylenediamine 1a (1.0 mmol), 1-phenyl-1,3-butanedione 2 (1.0 mmol), and ethyl glyoxalate 3d (1.0 mmol), cata-
b
c
lyst (10 mg) in EtOH (2.0 ml) at room temperature unless otherwise mentioned. The time taken for the reaction to complete. Isolated
yield. d Catalyst (8.0 mg). e Catalyst (5.0 mg). f 1 mmol/l (8.0 mg). g glacial acetic acid (8.0 mg).
TABLE 3
Optimization of the reaction conditions for the synthesis of product 5ada
Entry
Solvent
PhMe
THF
Timeb (hr)
Yieldc (%)
1
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.2
47
52
63
54
78
90
87
85
2
3
CH3CN
DMF
4
5
MeOH
EtOH
EtOH
EtOH
6
7d
8e
aReaction conditions: 1,2-phenylenediamine 1a (1.0 mmol), 1-phenyl-1,3-butanedione 2 (1.0 mmol), and ethyl glyoxalate 3d (1.0 mmol),
b
Fe3O4@SiO2-CeCl3 (8.0 mg) in EtOH (2.0 mL) at room temperature, unless otherwise mentioned. The time taken for the reaction to com-
plete. c Isolated yield. d The reaction was performed at 40 ꢀC. e The reaction was performed at 78 ꢀC.

ZHOU ET AL.
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TABLE 4
Scope of substrates for the domino synthesis of benzodiazepines 5a
aReaction conditions: 1,2-phenylenediamine compounds (1.0 mmol), 1-phenyl-1,3-butanedione (1.0 mmol), and pyruvic aldehyde, ethyl
glyoxylate or glyoxylic acid (1.0 mmol) in EtOH (2.0 ml), Fe3O4@SiO2-CeCl3 (8.0 mg), r.t.
Based on the results presented in entry 11 of Table 2,
we subsequently tested the solvent and temperature
effect on the reaction. The screening of different solvents
such as methanol (MeOH), tetrahydrofuran (THF), N,N-
dimethylformamide (DMF), toluene (PhMe) and acetoni-
trile (CH3CN) did not help in improving the yield. Nota-
bly, increasing the reaction temperature has little effect
on the reaction, only the reaction time is shortened. Con-
sequently, the following reaction conditions are rec-
ommended: Fe3O4@SiO2-CeCl3 in ethanol at room
temperature (Table 3).
The scope of the domino reaction was examined in
greater detail after optimum conditions had been reached
(Table 4). The one-pot synthetic methodology exhibits a
high functional group tolerance and a broad substrate
scope. Firstly, the substituted 1,2-phenylenediamine 1a–1f
were tested. Generally, the reaction proceeded smoothly,
regardless of the electron-withdrawing groups and the elec-
tron-donating groups on the aromatic rings of 1,2-phe-
nylenediamine. However, as compared to unsubstituted
1,2-phenylenediamine 1a, 4-methylbenzene-1,2-diamine
1e, or 4,5-dimethylbenzene-1,2-diamine 1f (electron-

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ZHOU ET AL.
FIGURE 4 X-ray structure of compound 4ba
donating group) yielded the corresponding product in bet-
ter yields, because both benzene ring activity and para-
amino reactivity were improved by electron-donating
groups. Whereas the 1,2-phenylenediamine containing a
halide (electron-withdrawing group) on the phenyl ring
furnished the products in relatively lower yields (Table 4).
It is a fact that the yields of fluorine-containing analogues
5BC, 5bd and 5be are higher than those chlorine and bro-
mine-containing analogues. The reason may be that the
fluorine atom on the 1,2-phenylenediamine ring with
small atomic radius and high electronegativity can form
hydrogen bonds with the protic solvent C2H5OH to
cause a solvation effect, which rapidly reduces the elec-
tron-withdrawing performance of fluorine and
increases the nucleophilicity of the amino group on the
1,2-phenylenediamine ring. As a result, series of reac-
tions of 4-fluoro-1,2-phenylenediamine easily occur and
the yields of the target product (5bc, 5bd and 5be) are
higher than chlorine and bromine-containing ana-
logues. Notably, region selectivities were uncovered
when substituents with electron-donating groups were
investigated. But 1,2-phenylenediamine with electron-
withdrawing groups offered a mixture of region-iso-
mers. Fortunately, a single target product can be
obtained by controlling the amount of catalyst and the
reaction time. Furthermore, pyruvic aldehyde 3c, ethyl
glyoxalate 3d and glyoxylic acid 3e were employed
(Table 4). To our delight these reactions proceeded
smoothly to give 3-substituted-1,5-benzodiazepine 5 in
good to excellent yields (Table 4).
Target compound 4ba has been unambiguously deter-
mined by X-ray structural analysis of single crystals [the
CCDC deposition number is 1916521;† formula:
C20H16FN3OS] (Figure 4). It is worth noting that this
result is significant with no literature precedent regarding
the synthesis of highly functionalized benzodiazepines.
To showcase the practical applications of this meth-
odology, we carried out the model reaction on a 10 mmol
scale under the corresponding optimized reaction condi-
tions. We were pleased that 87% yield of the desired prod-
uct 5ad could be obtained, implying that this
methodology is suitable for larger scale synthesis
(Scheme 4).
On the basis of the above results, the plausible mech-
anism to account for the formation of the seven-mem-
bered ring is depicted in Scheme 5. Firstly, the
interaction
of
1-phenyl-1,3-butanedione
with
Fe3O4@SiO2-CeCl3 leads to the activation of the carbonyl
group. Simultaneously, enaminone 11 was obtained by
the first selective nucleophilic addition and the dehydra-
tion reaction of substituted 1,2-phenylenediamine and
1-phenyl-1,3-butanedione. This step has a very high
selectivity. Then, the other amino group of enaminone 11
attacks the electrophilic aldehyde carbonyl carbon of the
SCHEME 4 Gram-scale
synthesis of 5ad

ZHOU ET AL.
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SCHEME 5 A plausible
mechanism for the formation of
benzodiazepines 5
aldehyde derivatives 3 to give the corresponding interme-
diate 12 by loss of a molecule of water. Adduct 12
undergoes intramolecular cyclization enabling cyclic
intermediate 13, which suffers intramolecular proton
transfer to give target product 5. In this process,
enaminone 11 and intermediate 12 were identified by 1H-
NMR and 13C-NMR.
Recently, the reusability of catalysts has been the focus
of most chemists for reasons of economic and environmen-
tal applicability. Therefore the reusability of Fe3O4@SiO2-
CeCl3 was also scrutinized. After completion of the reac-
tion, the crude reaction mass was dissolved in 10 ml of
ethyl acetate then Fe3O4@SiO2-CeCl3 was separated by
centrifugation, washed repeatedly with deionized water,
FIGURE 5 The recyclability of the
catalyst

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ZHOU ET AL.
ethanol and diethyl ether and dried under vacuum. The
catalytic activity of the recycled Fe3O4@SiO2-CeCl3 was
then inspected under the same experimental conditions. To
our delight, it was witnessed that the Fe3O4@SiO2-CeCl3
could be recycled and reused for eight consecutive runs
without any significant depreciation in the catalytic activity
or yield of the reaction (Figure 5). After completion of the
catalyst recyclability experiment, FT-IR analysis of the
recycled Fe3O4@SiO2-CeCl3 (after eight consecutive runs)
was carried out. The FT-IR spectrum of the recycled
Fe3O4@SiO2-CeCl3 exhibited almost insignificant changes
from that of the fresh Fe3O4@SiO2-CeCl3. Therefore all the
functionalities remained relatively unchanged after eight
consecutive runs (Figure 2B).
structure of 4ba was further determined by single-crystal
X-ray diffraction on a Bruker Smart 1000 diffractometer.
Low-resolution mass spectra were recorded on a Thermo
DSQ IImass spectrometer. Synthetic grade chemicals
were purchased from Aladdin and were used as received.
The solvents were commercial products of analytical
grade and dried according to the literature as necessary.
The reactions were monitored by thin-layer chromatogra-
phy (TLC) on pre-coated silica gel GF254 plates.
4.2 | General methods
4.2.1 | Synthesis of magnetic iron
tetroxide
3 | CONCLUSION
Mixing ferric chloride (2.70 g) and ferrous chloride
(0.99 g) in 50 ml of distilled water at a mass ratio of 2:1,
stirring, heating to 80 ꢀC, adding ammonia water,
adjusting the pH value of the solution to 10, cooling after
reacting for 1 hr, stopping stirring, separating and collect-
ing the obtained sample from the magnet.
We
have
disclosed
Fe3O4@SiO2-CeCl3
catalyzed
chemoselective synthesis of functionalized 3-substituted-
1,5-benzodiazepines via one-pot multicomponent and dom-
ino reactions. This protocol simultaneously installs one C–C
bond, two C–N bonds and one C=C bond to form one new
seven-membered ring, which resulted in the one-pot synthe-
sis of highly functionalized 3-substituted-1,5-benzodiaze-
pines containing carboxyl, ester and acyl groups. The
reactions showed a broad substrate scope and readily avail-
able and inexpensive commercial starting materials. Consid-
ering the large number of commercially available aldehydes,
1,2-phenylenediamine and 1,3-dicarbonyls, we recommend
this method as a good choice for functionalized 1,5-benzodi-
azepines synthesis. In addition, the proposed strategy inte-
grating Fe3O4@SiO2-CeCl3 as a catalyst in an acid-driven
system of auto-tandem reaction may also be applied to
establish other synthetic methodologies to heterocycles. This
strategy is currently being investigated by our team.
4.2.2 | Synthesis of Fe3O4@SiO2
Fe3O4 (0.23 g) was dispersed in a mixture of ethanol
(60 ml), deionized water (15 ml), and concentrated
ammonia aqueous solution (1 ml) by ultrasonication for
30 min. Then the tetraethyl orthosilicate (TEOS) with
2 ml was stirred continuously at room temperature for
24 hr. Fe3O4@SiO2 was magnetically separated and
washed with distilled water and ethanol (3 × 10 ml). The
Fe3O4@SiO2 was dried at 100 ꢀC for 4 hr.
4.2.3 | Synthesis of Fe3O4@SiO2-CeCl3
4 | EXPERIMENTAL
Magnetic nanoparticles Fe3O4@SiO2-CeCl3 was prepared
by adding CeCl3 (0.1 g) with Fe3O4@SiO2 (0.1 g) in etha-
nol solution (15 ml). After cooling down to room temper-
ature in air, magnetic nanoparticles obtained by
magnetic separation and finally dried at 45 C overnight
to obtain Fe3O4@SiO2-CeCl3.
4.1 | Materials and methods
ꢀ
Melting points were determined in open capillaries and
1
were uncorrected. The H NMR and 13C NMR spectral
analyses were performed on a 400 MHz (WIPM-NMR-
400) nuclear magnetic resonance spectrometer operating
at 400/500 and 100/125 MHz, respectively, in DMSO-d6
with the chemical shift given in parts per million relative
to tetramethylsilane (TMS) as the internal standard. The
signal multiplicities are represented by s (singlet), d (dou-
blet), t (triplet), m (multiplet), and q (quartet). The IR
spectra were recorded on a Thermo SCIENTIFIC IR spec-
trophotometer in KBr pellets and reported in cm−1. The
4.2.4 | Synthesis of 3-substituted-
1,5-benzodiazepine derivatives 4aa-4fb
In a 50 ml reaction vial, the 1,2-phenylenediamine 1a
(1.0 mmol), 1-phenyl-1,3-butanedione 2 (1.0 mmol), het-
erocyclic aromatic aldehyde 3 (1.0 mmol), and EtOH
(2 ml) were mixed. Subsequently, Fe3O4@SiO2-CeCl3

ZHOU ET AL.
13 of 18
(8 mg) was added to the reaction mixture and stirred at
room temperature. Upon completion, as monitored by
TLC, the solid 4 was crystallized at 0 ꢀC and the resulting
solid was washed with ethanol.
(M + 1); anal. Calcd (%) for C16H16N2O: C 76.16, H 6.39,
N 11.10; found: C 76.43, H 6.37, N 11.11.
3-((4-methyl-2-((−thiazol-2-ylmethylene)amino)phenyl)
amino)-1-phenylbut-2-en-1-one (12)
ꢀ
Yellow solid; 318 mg, 88%; m.p.: 149–150 C; IR (KBr):
1
4.2.5 | Synthesis of 3-substituted-
1,5-benzodiazepine derivatives 5 ac-5fe
3120, 1639, 1607, 1543; H NMR (400 MHz, DMSO-d6,
TMS): δ 2.25 (3H, s, Me), 2.35 (3H, s, Me), 6.08 (1H, s,
CH), 7.16–7.40 (3H, m, Ph), 7.46–7.93 (5H, m, Ph), 8.02–
8.11 (2H, m, thinole ring), 8.90 (1H, s, CH), 13.18 (1H, s,
NH); 13C NMR (100 MHz, DMSO-d6, TMS): δ 21.0, 95.3,
119.6, 124.1, 125.3, 127.3, 128.8, 129.2, 131.4, 131.6, 135.6,
140.1, 141.6, 145.3, 153.8, 161.6, 167.3, 187.3; MS calcd for
C21H19N3OS 361, found 362 (M + 1); anal. Calcd (%) for
C21H19N3OS: C 69.78, H 5.30, N 11.63; found: C 69.92, H
5.31, N 11.65.
In a 50 ml reaction vial, the 1,2-phenylenediamine 1a
(1.0 mmol), 1-phenyl-1,3-butanedione 2 (1.0 mmol) and
EtOH (2 ml) were mixed and then stirred at room tem-
perature. Subsequently, chain aldehyde 3 (1.0 mmol) and
Fe3O4@SiO2-CeCl3 (8 mg) were added to the reaction
mixture. Upon completion, monitored by TLC, the reac-
tion mixture was cooled and filtered to give the crude
product, which was further washed by 96% EtOH to give
pure product 5.
3-benzoyl-1,5-benzodiazepine (4aa)
ꢀ
Light yellow solid; 298 mg, 86%; m.p.: 203–204 C; IR
1
2-methyl-4-phenyl-1,5-benzodiazepine (7)
(KBr): 3301, 3237, 1562, 1497 cm−1; H NMR (400 MHz,
ꢀ
Yellow solid; 178 mg, 76%; m.p.: 178–180 C; IR (KBr):
DMSO-d6, TMS): δ 1.90 (3H, s, Me), 5.82 (1H, d,
J = 4.0 Hz, CH), 6.54 (1H, d, J = 8.0 Hz, NH), 6.57–
6.93(4H, m, Ph), 7.39–7.41 (2H, m, thiazole ring), 7.43–
7.56 (5H, m, Ph), 8.66 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 24.6, 58.4, 113.5, 120.0, 120.4, 120.6,
120.8, 123.2, 128.2, 128.8, 130.9, 138.6, 142.6, 143.4, 153.5,
174.8, 194.8; MS calcd for C20H17N3OS 347, found 348
(M + 1); anal. Calcd (%) for C20H17N3OS: C 69.14, H 4.93,
N 12.09; found: C 68.98, H 4.95, N 12.07.
1
3366, 1639, 1536 cm−1; H NMR (400 MHz, DMSO-d6,
TMS): δ 2.31 (3H, s, Me), 7.05 (1H, s, NH), 7.25–7.28 (2H,
m, Ph), 7.30–7.48 (2H, m, Ph), 7.49–7.52 (2H, m, Ph),
7.53–7.55 (2H, m, Ph), 8.03–8.06 (2H, m, Ph); 13C NMR
(100 MHz, DMSO-d6, TMS): δ 38.3, 125.7, 126.3, 127.4,
128.6, 128.9, 130.6, 132.3, 137.4, 141.1, 144.1, 154.6, 158.6;
MS calcd for C16H14N2 234, found 235 (M + 1); anal.
Calcd (%) for C20H17N3OS: C 82.02, H 6.02, N 11.96;
found: C 82.35, H 6.01, N 11.99.
3-benzoyl-1,5-benzodiazepine (4ba)
ꢀ
2-methyl-4-phenyl-1,5-benzodiazepine (8)
Light yellow solid; 192 mg, 82%; m.p.: 85–87 ꢀC; IR
Bright yellow solid; 310 mg, 85%; m.p.: 176–178 C; IR
(KBr): 3366, 3334, 1633, 1562, 1503 cm−1 1H NMR
;
(KBr): 1581, 1562, 1380 cm−1
;
1H NMR (400 MHz,
(400 MHz, DMSO-d6, TMS): δ 1.93 (3H, s, Me), 5.90 (1H,
d, J = 8.0 Hz, CH), 6.45 (1H, d, J = 4.0 Hz, NH), 6.47–
7.00 (3H, m, Ph), 7.44–7.46 (2H, m, thiazole ring), 7.46–
7.65 (5H, m, Ph), 8.76 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 24.6, 57.9, 106.0, 106.2, 106.3, 106.4,
113.5, 120.5, 122.0, 122.1, 127.4, 128.2, 128.9, 130.9, 140.4,
140.5, 142.7, 143.3, 153.9, 157.3, 159.6, 174.6, 194.6; MS
calcd for C20H16FN3OS 365, found 366 (M + 1); anal.
Calcd (%) for C20H16FN3OS: C 65.74, H 4.41, N 11.50;
found: C 65.89, H 4.43, N 11.46.
DMSO-d6, TMS): δ 2.36 (3H, s, Me), 3.27 (2H, s, CH2),
7.31–7.35 (2H, m, Ph), 7.49–7.51 (1H, m, Ph), 7.53–7.54
(3H, m, Ph), 7.58–7.61 (1H, m, Ph), 8.09–8.12 (2H, m,
Ph); 13C NMR (100 MHz, DMSO-d6, TMS): δ 26.8, 38.4,
125.3, 125.5, 127.8, 128.6, 128.7, 129.3, 131.4, 136.8, 140.6,
140.7, 154.0, 159.1; MS calcd for C16H14N2 234, found 235
(M + 1); anal. Calcd (%) for C16H14N2: C 82.02, H 6.02, N
11.96; found: C 82.31, H 6.01, N 11.97.
3-((2-aminophenyl)amino)-1-phenylbut-2-en-1-one (11)
ꢀ
Light yellow solid; 224 mg, 89%; m.p.: 111–112 C; IR
3-benzoyl-1,5-benzodiazepine (4ca)
(KBr): 3398, 3347, 3237, 1646, 1574 cm−1
;
1H NMR
Cream color solid; 317 mg, 83%; m.p.: 149–150 C; IR
ꢀ
(400 MHz, DMSO-d6, TMS): δ 1.98 (3H, s, Me), 5.02 (2H,
s, NH), 6.06 (1H, s, CH), 6.58–6.62 (1H, m, Ph), 6.80–6.82
(1H, m, Ph), 7.01–7.04 (2H, m, Ph), 7.44–7.50 (3H, m,
Ph), 7.91–7.93 (2H, m, Ph), 12.48 (1H, s, NH); 13C NMR
(100 MHz, DMSO-d6, TMS): δ 20.0, 93.4, 116.0, 116.8,
123.5, 127.2, 127.3, 127.6, 128.2, 128.8, 131.3, 140.1, 144.4,
165.1, 187.2; MS calcd for C16H16N2O 252, found 253
(KBr): 3327, 3249, 1736, 1633, 1555 cm−1 1H NMR
;
(400 MHz, DMSO-d6, TMS): δ 1.89 (3H, s, Me), 5.82 (1H,
d, J = 8.0 Hz, CH), 6.63 (1H, d, J = 8.0 Hz, NH), 6.75–
6.95 (3H, m, Ph), 7.42–7.43 (2H, m, thiazole ring), 7.45–
7.61 (5H, m, Ph), 8.75 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 24.5, 58.0, 114.0, 119.3, 119.5, 120.5,
120.7, 122.1, 126.5, 128.2, 128.4, 128.8, 129.9, 131.1, 140.1,

14 of 18
ZHOU ET AL.
142.6, 142.8, 143.0, 153.3, 174.2, 194.9; MS calcd for
C20H16ClN3OS 381, found 382 (M + 1); anal. Calcd (%)
for C20H16ClN3OS: C 62.90, H 4.22, N 11.00; found: C
62.83, H 4.21, N 11.03.
121.8, 121.9, 123.5, 128.7, 129.0, 131.7, 136.6, 136.7, 138.4,
138.8, 139.7, 146.9, 147.0, 149.2, 163.1, 192.6; MS calcd for
C22H19N3O 341, found 342 (M + 1); anal. Calcd (%) for
C22H19N3O: C 77.40, H 5.61, N 12.31; found: C 77.09, H
5.60, N 12.29.
3-benzoyl-1,5-benzodiazepine (4da)
Earthy solid; 341 mg, 80%; m.p.: 126–127 C; IR (KBr):
ꢀ
3-benzoyl-1,5-benzodiazepine (4bb)
3308, 3223, 1633, 1503 cm−1; 1H NMR (400 MHz, DMSO-
d6, TMS): δ 1.92 (3H, s, Me), 5.84 (1H, d, J = 4.0 Hz, CH),
6.78 (1H, d, J = 8.0 Hz, NH), 6.89–6.91 (3H, m, Ph), 7.47–
7.49 (2H, m, thiazole ring), 7.52–7.65 (5H, m, Ph), 8.77
(1H, s, NH); 13C NMR (100 MHz, DMSO-d6, TMS): δ
24.4, 56.5, 114.1, 114.5, 120.6, 120.7, 122.1, 122.3, 122.4,
128.3, 128.9, 130.3, 131.1, 140.3, 143.0, 153.3, 174.2, 195.0;
MS calcd for C20H16BrN3OS 427, found 428 (M + 1); anal.
Calcd (%) for C20H16BrN3OS: C 56.35, H 3.78, N 9.86;
found: C 56.39, H 3.77, N 9.88.
Light yellow solid; 291 mg, 81%; m.p.: 212–213 C; IR
ꢀ
(KBr): 3282, 3052, 1639, 1548 cm−1; H NMR (400 MHz,
1
DMSO-d6, TMS): δ 1.83 (3H, s, Me), 5.74 (1H, d,
J = 8.0 Hz, CH), 6.40 (1H, d, J = 8.0 Hz, NH), 6.43–6.76
(3H, m, Ph), 7.07–7.21 (4H, m, pyridine ring), 7.23–8.41
(5H, m, Ph), 8.61 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 21.3, 60.4, 113.1, 121.0, 121.1, 121.4,
122.0, 128.2, 128.7, 129.0, 136.8, 136.8, 138.3, 139.7, 140.5,
140.6, 146.6, 149.3, 157.3, 159.7, 162.8, 192.4; MS calcd for
C22H18FN3O 359, found 360 (M + 1); anal. Calcd (%) for
C22H18FN3O: C 73.52, H 5.05, N 11.69; found: C 73.78, H
5.06, N 11.67.
3-benzoyl-1,5-benzodiazepine (4ea)
ꢀ
Light yellow solid; 318 mg, 88%; m.p.: 120–121 C; IR
(KBr): 3301, 3237, 1633, 1517 cm−1; H NMR (400 MHz,
3-benzoyl-1,5-benzodiazepine (4cb)
1
ꢀ
DMSO-d6, TMS): δ 1.88 (3H, s, Me), 2.05 (3H, s, Me), 5.81
(1H, d, J = 4.0 Hz, CH), 6.38 (1H, d, J = 8.0 Hz, NH),
6.46–6.82 (3H, m, Ph), 7.39–7.40 (2H, m, thiazole ring),
7.42–7.55 (5H, m, Ph), 8.63 (1H, s, NH); 13C NMR
(100 MHz, DMSO-d6, TMS): δ 20.7, 24.8, 58.2, 113.3,
120.3, 120.7, 120.9, 128.1, 128.3, 128.8, 130.7, 132.1, 138.4,
142.5, 142.7, 143.6, 153.9, 174.9, 194.5; MS calcd for
C21H19N3OS 361, found 362 (M + 1); anal. Calcd (%) for
C21H19N3OS: C 69.78, H 5.30, N 11.63; found: C 69.85, H
5.29, N 11.59.
Light yellow solid; 290 mg, 77%; m.p.: 180–182 C; IR
(KBr): 3282, 3049, 1639, 1529 cm−1; H NMR (400 MHz,
1
DMSO-d6, TMS): δ 1.84 (3H, s, Me), 5.77 (1H, d,
J = 8.0 Hz, CH), 6.63 (1H, d, J = 8.0 Hz, NH), 6.66–6.78
(3H, m, Ph), 7.09–7.23 (4H, m, pyridine ring), 7.25–8.41
(5H, m, Ph), 8.54 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 21.4, 60.4, 113.8, 119.9, 120.5, 121.3,
121.6, 122.1, 126.7, 128.7, 129.1, 130.8, 136.9, 138.1, 139.8,
140.3, 146.4, 149.3, 162.7, 192.6; MS calcd for
C22H18ClN3O 375, found 376 (M + 1); anal. Calcd (%) for
C22H18ClN3O: C 70.30, H 4.83, N 11.18; found: C 70.51, H
4.84, N 11.21.
3-benzoyl-1,5-benzodiazepine (4fa)
Brick red solid; 338 mg, 90%; m.p.: 182–183 ꢀC; IR (KBr):
1
3249, 1684, 1626 cm−1; H NMR (400 MHz, DMSO-d6,
3-benzoyl-1,5-benzodiazepine (4db)
ꢀ
TMS): δ 1.93 (3H, s, Me), 2.02 (6H, s, Me), 5.82 (1H, d,
J = 8.0 Hz, CH), 6.33 (1H, d, J = 8.0 Hz, NH), 6.46–6.77
(2H, m, Ph), 7.42–7.44 (2H, m, thiazole ring), 7.46–7.60
(5H, m, Ph), 8.69 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 18.8, 19.1, 24.7, 58.3, 113.0, 120.4,
121.4, 121.9, 127.1, 128.1, 128.4, 128.8, 130.6, 130.8, 136.2,
142.5, 143.7, 154.0, 175.1, 194.4; MS calcd for C22H21N3OS
375, found 376 (M + 1); anal. Calcd (%) for C22H21N3OS:
C 70.37, H 5.64, N 11.19; found: C 70.63, H 5.62, N 11.16.
Light yellow solid; 298 mg, 71%; m.p.: 171–173 C; IR
(KBr): 3289, 3036, 1639, 1523 cm−1; H NMR (400 MHz,
1
DMSO-d6, TMS): δ 1.95 (3H, s, Me), 5.69 (1H, d,
J = 4.0 Hz, CH), 6.62 (1H, d, J = 4.0 Hz, NH), 6.70–6.79
(3H, m, Ph), 7.09–7.25 (4H, m, pyridine ring), 7.26–8.41
(5H, m, Ph), 8.65 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 21.5, 60.4, 113.8, 114.7, 121.6, 121.7,
122.1, 122.8, 123.2, 128.7, 129.0, 131.1, 136.9, 138.1, 139.8,
140.5, 146.4, 149.3, 162.7, 192.6; MS calcd for
C22H18BrN3O 421, found 422 (M + 1); anal. Calcd (%) for
C22H18BrN3O: C 62.87, H 4.32, N 10.00; found: C 63.01,
H 4.33, N 10.03.
3-benzoyl-1,5-benzodiazepine (4ab)
ꢀ
Light yellow solid; 283 mg, 83%; m.p.: 178–179 C; IR
(KBr): 3249, 3023, 1626, 1497 cm−1; H NMR (400 MHz,
1
DMSO-d6, TMS): δ 1.98 (3H, s, Me), 5.59 (1H, d,
J = 4.0 Hz, CH), 6.32 (1H, d, J = 4.0 Hz, NH), 6.52–6.90
(4H, m, Ph), 7.01–7.39 (4H, m, pyridine ring), 7.41–8.37
(5H, m, Ph), 8.50 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 21.4, 60.8, 113.5, 120.1, 120.5, 121.3,
3-benzoyl-1,5-benzodiazepine (4eb)
ꢀ
Earthy solid; 302 mg, 85%; m.p.: 143–145 C; IR (KBr):
3282, 3049, 1646, 1517 cm−1; 1H NMR (400 MHz, DMSO-
d6, TMS): δ 1.82 (3H, s, Me), 2.01 (3H, s, Me), 5.75 (1H, d,
J = 8.0 Hz, CH), 6.22 (1H, d, J = 8.0 Hz, NH), 6.39–6.68

ZHOU ET AL.
15 of 18
(3H, m, Ph), 7.05–7.22 (4H, m, pyridine ring), 7.24–8.40
(5H, m, Ph), 8.70 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 20.7, 21.4, 60.5, 113.1, 113.6, 120.1,
121.3, 121.9, 128.7, 129.0, 129.2, 129.3, 131.6, 132.4, 136.3,
136.7, 138.5, 138.6, 139.6, 146.9, 149.2, 163.2, 192.4; MS
calcd for C23H21N3O 355, found 356 (M + 1); anal. Calcd
(%) for C23H21N3O: C 77.72, H 5.96, N 11.82; found: C
77.96, H 5.95, N 11.79.
J = 4.0 Hz, NH), 6.47–6.73 (3H, m, Ph), 7.07–7.56
(5H, m, Ph), 8.71 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 20.7, 28.6, 62.8, 110.1, 120.7, 121.1,
121.1, 127.6, 128.6, 130.4, 133.1, 134.8, 138.3, 139.5,
146.6, 191.3, 205.7; MS calcd for C19H17ClN2O2 340,
found 341 (M + 1); anal. Calcd (%) for C19H17ClN2O2:
C 66.96, H 5.03, N 8.22; found: C 67.12, H 5.04, N
8.20.
3-benzoyl-1,5-benzodiazepine (4fb)
3-benzoyl-1,5-benzodiazepine (5 dc)
ꢀ
ꢀ
Light yellow solid; 325 mg, 88%; m.p.: 154–155 C; IR
Light yellow solid; 281 mg, 73%; m.p.: 231–232 C; IR
(KBr): 3249, 3004, 1633, 1523 cm−1; H NMR (400 MHz,
(KBr): 3340, 3275, 1704, 1639, 1517 cm−1 1H NMR
;
1
DMSO-d6, TMS): δ 1.89 (3H, s, Me), 1.92 (3H, s, Me), 1.98
(3H, s, Me), 5.72 (1H, d, J = 8.0 Hz, CH), 6.06 (1H, d,
J = 8.0 Hz, NH), 6.36 (1H, s, Ph), 6.52 (1H, s, Ph), 7.05–
7.24 (4H, m, pyridine ring), 7.25–8.41 (5H, m, Ph), 8.70
(1H, s, NH); 13C NMR (100 MHz, DMSO-d6, TMS): δ
19.1, 21.4, 60.7, 113.2, 121.0, 121.1 121.2, 121.9, 122.7,
122.7, 127.9, 128.6, 129.0, 129.1, 131.1, 136.3, 136.6, 138.6,
139.5, 146.9, 149.2, 163.3, 192.4; MS calcd for C24H23N3O
369, found 370 (M + 1); anal. Calcd (%) for C24H23N3O: C
78.02, H 6.27, N 11.37; found: C 78.31, H 6.26, N 11.41.
(400 MHz, DMSO-d6, TMS): δ 1.91 (3H, s, Me), 2.13 (3H,
s, Me), 5.20 (1H, d, J = 4.0 Hz, CH), 6.44 (1H, d,
J = 4.0 Hz, NH), 6.53–6.72 (3H, m, Ph), 7.04–7.66 (5H, m,
Ph), 8.70 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6,
TMS): δ 21.0, 28.8, 56.6, 110.1, 120.7, 121.1, 123.5, 127.6,
130.7, 131.5, 133.1, 138.3, 139.9, 146.7, 191.4, 205.7; MS
calcd for C19H17BrN2O2 386, found 387 (M + 1); anal.
Calcd (%) for C19H17BrN2O2: C 59.23, H 4.45, N 7.27;
found: C 59.38, H 4.44, N 7.30.
3-benzoyl-1,5-benzodiazepine (5ec)
ꢀ
3-benzoyl-1,5-benzodiazepine (5 ac)
Brownish yellow solid; 251 mg, 82%; m.p.: 174–176 C; IR
Earthy solid; 272 mg, 85%; m.p.: 209–211 C; IR (KBr):
3353, 3295, 1698, 1633, 1503 cm−1; H NMR (400 MHz,
1
ꢀ
(KBr): 3353, 3269, 1698, 1620, 1510 cm−1; 1H NMR
(400 MHz, DMSO-d6, TMS): δ 1.81 (3H, s, Me), 2.03 (3H, s,
Me), 5.02 (1H, d, J = 8.0 Hz, CH), 6.24 (1H, d, J = 4.0 Hz,
NH), 6.59–6.97 (4H, m, Ph), 7.42–7.52 (5H, m, Ph), 8.53 (1H,
s, NH); 13C NMR (100 MHz, DMSO-d6, TMS): δ 24.6, 27.3,
64.7, 111.4, 118.9, 121.0, 123.1, 128.3, 128.8, 129.5, 130.9,
138.8, 143.4, 154.0, 195.2, 205.5; MS calcd for C19H18N2O2
306, found 307 (M + 1); anal. Calcd (%) for C19H18N2O2: C
74.49, H 5.92, N 9.14; found: C 74.58, H 5.90, N 9.17.
DMSO-d6, TMS): δ 1.83 (3H, s, Me), 2.05 (3H, s, Me),
2.17 (3H, s, Me), 5.06 (1H, d, J = 8.0 Hz, CH), 6.29 (1H,
d, J = 8.0 Hz, NH), 6.44–6.89 (3H, m, Ph), 7.46–7.53
(5H, m, Ph), 8.55 (1H, s, NH); 13C NMR (100 MHz,
DMSO-d6, TMS): δ 20.7, 24.6, 27.3, 64.5, 111.0, 119.1,
119.7, 119.7, 121.0, 127.1, 128.2, 128.3, 128.8, 130.7,
132.1, 138.6, 143.6, 154.4, 194.9, 205.6; MS calcd for
C20H20N2O2 320, found 321 (M + 1); anal. Calcd (%) for
C20H20N2O2: C 74.98, H 6.29, N 8.74; found: C 75.23, H
6.31, N 8.71.
3-benzoyl-1,5-benzodiazepine (5BC)
ꢀ
Light yellow solid; 256 mg, 79%; m.p.: 236–238 C; IR
3-benzoyl-1,5-benzodiazepine (5 fc)
Dark yellow solid; 287 mg, 86%; m.p.: 209–210 ꢀC; IR
(KBr): 3327, 3275, 1698, 1633, 1548 cm−1
;
1H NMR
(400 MHz, DMSO-d6, TMS): δ 1.85 (3H, s, Me), 2.17 (3H,
s, Me), 5.28 (1H, d, J = 4.0 Hz, CH), 6.57 (1H, d,
J = 8.0 Hz, NH), 6.69–6.85 (3H, m, Ph), 7.12–7.41 (5H, m,
Ph), 8.78 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6,
TMS): δ 21.4, 28.8, 56.5, 106.4, 106.6, 109.9, 121.6, 126.5,
128.7, 129.1, 137.8, 134.0, 140.2, 140.3, 157.6, 160.0, 192.6,
205.7; MS calcd for C19H17FN2O2 324, found 325 (M + 1);
anal. Calcd (%) for C19H17FN2O2: C 70.36, H 5.28, N 8.64;
found: C 70.68, H 5.30, N 8.61.
(KBr): 3334, 3282, 1704, 1633, 1543 cm−1 1H NMR
;
(400 MHz, DMSO-d6, TMS): δ 1.78 (3H, s, Me), 2.08 (3H,
s, Me), 2.11 (3H, s, Me), 2.14 (3H, s, Me), 5.18 (1H, d,
J = 4.0 Hz, CH), 6.30 (1H, d, J = 4.0 Hz, NH), 6.58–6.66
(2H, m, Ph), 7.09–7.39 (5H, m, Ph), 8.74 (1H, s, NH); 13C
NMR (100 MHz, DMSO-d6, TMS): δ 19.1, 19.2, 21.4, 28.6,
56.5, 110.4, 121.3, 121.3, 121.9, 127.9, 128.6, 129.0, 131.6,
135.9, 138.0, 139.8, 146.4, 192.6, 205.8; MS calcd for
C21H22N2O2 334, found 335 (M + 1); anal. Calcd (%) for
C21H22N2O2: C 75.42, H 6.63, N 8.38; found: C 75.67, H
6.64, N 8.37.
3-benzoyl-1,5-benzodiazepine (5 cc)
ꢀ
Light yellow solid; 256 mg, 75%; m.p.: 230–232 C; IR
(KBr): 3327, 3282, 1704, 1633, 1536 cm−1
;
1H NMR
3-benzoyl-1,5-benzodiazepine (5ad)
ꢀ
(400 MHz, DMSO-d6, TMS): δ 1.88 (3H, s, Me), 2.16
(3H, s, Me), 5.24 (1H, d, J = 8.0 Hz, CH), 6.44 (1H, d,
Light yellow solid; 289 mg, 90%; m.p.: 166–167 C; IR
(KBr): 3346, 3269, 1717, 1626, 1529 cm−1 1H NMR
;

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ZHOU ET AL.
(400 MHz, DMSO-d6, TMS): δ 0.92 (3H, t, J = 8.0 Hz,
Me), 1.87 (3H, s, Me), 3.89 (2H, q, J = 8.0 Hz, CH2), 5.07
(1H, d, J = 8.0 Hz, CH), 6.25 (1H, d, J = 4.0 Hz, NH),
6.66–7.01 (4H, m, Ph), 7.41–7.51 (5H, m, Ph), 8.58 (1H, s,
NH); 13C NMR (100 MHz, DMSO-d6, TMS): δ 14.5, 24.3,
60.0, 60.6, 110.0, 120.0, 120.1, 120.8, 122.9, 128.2, 128.8,
130.8, 131.0, 138.8, 143.4, 152.6, 171.6, 195.2; MS calcd for
C20H20N2O3 336, found 337 (M + 1); anal. Calcd (%) for
C20H20N2O3: C 71.41, H 5.99, N 8.33; found: C 71.59, H
6.01, N 8.35.
3-benzoyl-1,5-benzodiazepine (5ed)
ꢀ
Light yellow solid; 308 mg, 88%; m.p.: 203–204 C; IR
(KBr): 3353, 3321, 1724, 1639, 1529 cm−1 1H NMR
;
(400 MHz, DMSO-d6, TMS): δ 0.92 (3H, t, J = 4.0 Hz,
Me), 1.86 (3H, s, Me), 2.14 (3H, s, Me), 3.89 (2H, q,
J = 8.0 Hz, CH2), 5.05 (1H, d, J = 8.0 Hz, CH), 6.16 (1H,
d, J = 8.0 Hz, NH), 6.48–6.88 (3H, m, Ph), 7.40–7.48 (5H,
m, Ph), 8.56 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6,
TMS): δ 14.3, 20.7, 24.3, 59.8, 60.5, 109.7, 120.4, 120.7,
120.8, 128.1, 128.5, 128.8, 130.6, 131.8, 138.7, 143.6, 153.0,
171.6, 194.8; MS calcd for C21H22N2O3 350, found 351
(M + 1); anal. Calcd (%) for C21H22N2O3: C 71.98, H 6.33,
N 7.99; found: C 72.23, H 6.31, N 8.02.
3-benzoyl-1,5-benzodiazepine (5bd)
Light yellow solid; 287 mg, 81%; m.p.: 183–185 C; IR
ꢀ
(KBr): 3359, 3263, 1710, 1639, 1517 cm−1 1H NMR
;
(400 MHz, DMSO-d6, TMS): δ 0.95 (3H, t, J = 8.0 Hz,
Me), 1.84 (3H, s, Me), 3.92 (2H, q, J = 8.0 Hz, CH2),
5.08 (1H, d, J = 4.0 Hz, CH), 6.48 (1H, d, J = 4.0 Hz,
NH), 6.51–7.01 (3H, m, Ph), 7.41–7.50 (5H, m, Ph),
8.61 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6,
TMS): δ 14.5, 24.2, 59.3, 60.7, 105.6, 105.8, 106.0, 106.3,
109.9, 127.3, 128.2, 128.8, 130.9, 140.6, 143.3, 152.7,
157.2, 159.5, 171.4, 194.9; MS calcd for C20H19FN2O3
3-benzoyl-1,5-benzodiazepine (5fd)
ꢀ
Light yellow solid; 320 mg, 88%; m.p.: 215–216 C; IR
(KBr): 3366, 3327, 1710, 1633, 1536 cm−1 1H NMR
;
(400 MHz, DMSO-d6, TMS): δ 0.98 (3H, t, J = 8.0 Hz,
Me), 1.90 (3H, s, Me), 2.10 (6H, s, Me), 3.92 (2H, q,
J = 8.0 Hz, CH2), 5.08 (1H, d, J = 8.0 Hz, CH), 6.03 (1H,
d, J = 8.0 Hz, NH), 6.56–6.81 (2H, m, Ph), 7.43–7.51 (5H,
m, Ph), 8.54 (1H, s, NH); 13C NMR (100 MHz, DMSO-d6,
TMS): δ 14.4, 18.9, 19.0, 24.4, 60.1, 60.4, 109.5, 121.2,
121.3, 121.8, 127.3, 128.1, 128.5, 128.7, 130.6, 136.5, 143.7,
152.8, 171.7, 194.9; MS calcd for C22H24N2O3 364, found
365 (M + 1); anal. Calcd (%) for C22H24N2O3: C 72.51, H
6.64, N 7.69; found: C 72.74, H 6.63, N 7.71.
354, found 355 (M
+ 1); anal. Calcd (%) for
C20H19FN2O3: C 67.79, H 5.40, N 7.91; found: C 67.89,
H 5.41, N 7.88.
3-benzoyl-1,5-benzodiazepine (5 cd)
ꢀ
Light yellow solid; 286 mg, 77%; m.p.: 206–208 C; IR
(KBr): 3353, 3314, 1717, 1639, 1543 cm−1
;
1H NMR
3-benzoyl-1,5-benzodiazepine (5ae)
ꢀ
(400 MHz, DMSO-d6, TMS): δ 0.92 (3H, t, J = 4.0 Hz,
Me), 1.87 (3H, s, Me), 3.89 (2H, q, J = 8.0 Hz, CH2), 5.07
(1H, d, J = 8.0 Hz, CH), 6.16 (1H, d, J = 4.0 Hz, NH),
6.48–6.89 (3H, m, Ph), 7.40–7.49 (5H, m, Ph), 8.56 (1H, s,
NH); 13C NMR (100 MHz, DMSO-d6, TMS): δ 14.5, 24.1,
59.5, 60.7, 110.2, 119.0, 119.4, 122.0, 126.3, 128.2, 128.9,
130.0, 131.1, 140.2, 143.0, 151.9, 171.3, 195.2; MS calcd for
C20H19ClN2O3 370, found 371 (M + 1); anal. Calcd (%)
for C20H19ClN2O3: C 64.78, H 5.16, N 7.55; found: C
64.92, H 5.15, N 7.52.
Brown solid; 268 mg, 87%; m.p.: 139–140 C; IR (KBr):
3340, 3056, 1736, 1562, 1503 cm−1; H NMR (400 MHz,
1
DMSO-d6, TMS): δ 1.89 (3H, s, Me), 5.02 (1H, d,
J = 4.0 Hz, CH), 6.17 (1H, d, J = 4.0 Hz, NH), 6.77–7.02
(4H, m, Ph), 7.46–7.54 (5H, m, Ph), 8.56 (1H, s, NH),
12.17 (1H, s, COOH); 13C NMR (100 MHz, DMSO-d6,
TMS): δ 24.3, 59.7, 110.7, 119.6, 120.0, 120.0, 122.8, 128.2,
128.8, 130.6, 130.8, 139.1, 143.4, 152.6, 173.1, 195.4; MS
calcd for C18H16N2O3 308, found 309 (M + 1); anal. Calcd
(%) for C18H16N2O3: C 70.12, H 5.23, N 9.09; found: C
70.42, H 5.21, N 9.12.
3-benzoyl-1,5-benzodiazepine (5dd)
ꢀ
Light yellow solid; 303 mg, 73%; m.p.: 158–159 C; IR
3-benzoyl-1,5-benzodiazepine (5be)
Brownish yellow solid; 267 mg, 82%; m.p.: 179–180 ꢀC; IR
(KBr): 3359, 3314, 1710, 1633, 1523 cm−1
;
1H NMR
(400 MHz, DMSO-d6, TMS): δ 0.98 (3H, t, J = 8.0 Hz,
Me), 1.87 (3H, s, Me), 3.96 (2H, q, J = 8.0 Hz, CH2), 5.07
(1H, d, J = 8.0 Hz, CH), 6.52 (1H, d, J = 8.0 Hz, NH),
6.84–6.97 (3H, m, Ph), 7.45–7.55 (5H, m, Ph), 8.68 (1H, s,
NH); 13C NMR (100 MHz, DMSO-d6, TMS): δ 14.5, 24.1,
59.6, 60.7, 110.2, 114.2, 121.9, 122.3, 128.2, 128.9, 130.4,
131.1, 140.5, 143.0, 151.8, 171.2, 195.2; MS calcd for
C20H19BrN2O3 416, found 417 (M + 1); anal. Calcd (%)
for C20H19BrN2O3: C 57.84, H 4.61, N 6.75; found: C
57.95, H 4.60, N 6.76.
(KBr): 3372, 3327, 1730, 1569, 1510 cm−1 1H NMR
;
(400 MHz, DMSO-d6, TMS): δ 1.86 (3H, s, Me), 5.04 (1H,
d, J = 8.0 Hz, CH), 6.45 (1H, d, J = 8.0 Hz, NH), 6.48–
7.02 (3H, m, Ph), 7.44–7.54 (5H, m, Ph), 8.61 (1H, s, NH),
12.27 (1H, s, COOH); 13C NMR (100 MHz, DMSO-d6,
TMS): δ 24.3, 59.1, 105.4, 105.6, 105.8, 110.6, 121.7, 121.8,
127.0, 128.2, 128.8, 130.9, 140.8, 140.9, 143.3, 152.7, 157.2,
159.5, 173.0, 195.1; MS calcd for C18H15FN2O3 326, found
327 (M + 1); anal. Calcd (%) for C18H15FN2O3: C 66.25, H
4.63, N 8.58; found: C 66.53, H 4.64, N 8.57.

ZHOU ET AL.
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3-benzoyl-1,5-benzodiazepine (5ce)
ACKNOWLEDGMENTS
ꢀ
Earthy solid; 268 mg, 78%; m.p.: 186–188 C; IR (KBr):
We are grateful for financial support from the National
Natural Science Foundation of China (21776060) and the
Natural Science Foundation of Hebei Province
(B2016205165). We also take this opportunity to thank
the Hebei Key Laboratory of Organic Functional Mole-
cules, College of Chemistry and Materials Science, Hebei
Normal University.
3327, 3243, 1639, 1562, 1510 cm−1; H NMR (400 MHz,
1
DMSO-d6, TMS): δ 1.88 (3H, s, Me), 5.02 (1H, d,
J = 4.0 Hz, CH), 6.45 (1H, d, J = 4.0 Hz, NH), 6.71–7.03
(3H, m, Ph), 7.47–7.56 (5H, m, Ph), 8.64 (1H, s, NH),
12.32 (1H, s, COOH); 13C NMR (100 MHz, DMSO-d6,
TMS): δ 24.1, 59.3, 111.0, 118.8, 119.0, 121.9, 126.2, 128.3,
128.9, 129.7, 131.0, 140.6, 143.0, 152.0, 172.9, 195.4; MS
calcd for C18H15ClN2O3 342, found 343 (M + 1); anal.
Calcd (%) for C18H15ClN2O3: C 63.07, H 4.41, N 8.17;
found: C 63.28, H 4.39, N 8.20.
CONFLICT OF INTEREST
There are no conflicts to declare.
ORCID
3-benzoyl-1,5-benzodiazepine (5de)
Lanzhi Wang https://orcid.org/0000-0003-3666-8208
Brownish yellow solid; 294 mg, 76%; m.p.: 187–189 ꢀC; IR
(KBr): 3321, 3243, 1736, 1639, 1555 cm−1
;
1H NMR
REFERENCES
(400 MHz, DMSO-d6, TMS): δ 1.87 (3H, s, Me), 5.00 (1H,
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6.96 (3H, m, Ph), 7.45–7.55 (5H, m, Ph), 8.63 (1H, s, NH),
12.32 (1H, s, COOH); 13C NMR (100 MHz, DMSO-d6,
TMS): δ 24.1, 59.3, 110.0, 114.3, 121.6, 121.9, 122.2, 128.3,
128.9, 130.1, 131.1, 140.8, 142.9, 152.1, 172.8, 195.6; MS
calcd for C18H15BrN2O3 386, found 387 (M + 1); anal.
Calcd (%) for C18H15BrN2O3: C 55.83, H 3.90, N 7.23;
found: C 56.01, H 3.89, N 7.25.
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3-benzoyl-1,5-benzodiazepine (5ee)
Brownish yellow solid; 287 mg, 89%; m.p.: 185–186 ꢀC; IR
(KBr): 3372, 3314, 1736, 1639, 1555 cm−1 1H NMR
;
(400 MHz, DMSO-d6, TMS): δ 1.85 (3H, s, Me), 2.13 (3H,
s, Me), 4.98 (1H, d, J = 4.0 Hz, CH), 6.45 (1H, d,
J = 4.0 Hz, NH), 6.47–6.88 (3H, m, Ph), 7.41–7.48 (5H, m,
Ph), 8.52 (1H, s, NH), 12.17 (1H, s, COOH); 13C NMR
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120.4, 120.8, 128.2, 128.8, 130.7, 131.8, 138.9, 143.6, 153.0,
173.1, 195.0; MS calcd for C19H18N2O3 322, found 323
(M + 1); anal. Calcd (%) for C19H18N2O3: C 70.79, H 5.63,
N 8.69; found: C 71.06, H 5.65, N 8.71.
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3-benzoyl-1,5-benzodiazepine (5fe)
ꢀ
Brownish yellow solid; 302 mg, 90%; m.p.: 179–180 C;
IR (KBr): 3379, 3340, 1730, 1633, 1555 cm−1; H NMR
1
(400 MHz, DMSO-d6, TMS): δ 1.89 (3H, s, Me), 2.09
(6H, s, Me), 4.97 (1H, d, J = 4.0 Hz, CH), 5.94 (1H, d,
J = 8.0 Hz, NH), 6.54–6.79 (2H, m, Ph), 7.43–7.51 (5H,
m, Ph), 8.50 (1H, s, NH), 12.12 (1H, s, COOH); 13C
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128.7, 130.5, 136.8, 143.7, 153.0, 173.2, 195.1; MS calcd
for C20H20N2O3 336, found 337 (M + 1); anal. Calcd (%)
for C20H20N2O3: C 71.41, H 5.99, N 8.33; found: C 71.62,
H 6.01, N 8.32.
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SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of this
article.
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Print
How to cite this article: Zhou L, Wang M,
Wang K, Wen T, Wang L. Fe3O4@SiO2-CeCl3
Catalyzed Chemoselective Synthesis of
Functionalized 3-Substituted-1,5-Benzodiazepines
via One-pot Multicomponent and Domino
Reactions. Appl Organomet Chem. 2020;e5707.
https://doi.org/10.1002/aoc.5707