One-pot, multi-component synthesis of ethyl (E)-1-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-aryl-2,5-dihydro-1H-benzo[b][1,4]diazepine-3-carboxylate derivatives

Article abstract of DOI:10.1016/j.tetlet.2020.151604

A new methodology for the synthesis of novel benzo[b][1,4]diazepine derivatives via a one-pot, multi-component reaction of benzaldehyde, o-phenylenediamine, and ethyl propiolate has been developed. Readily available starting materials, operationally simpl

Full text of DOI:10.1016/j.tetlet.2020.151604

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One-pot, multi-component synthesis of ethyl (E)-1-(3-ethoxy-3-oxoprop-1-
en-1-yl)-2-aryl-2,5-dihydro-1H-benzo[b][1,4]diazepine-3-carboxylate deriva-
tives
Hong-bo Tan, Yin-feng Wang, Jia Xu, Chun-sheng Hu
PII:
S0040-4039(20)30013-7
DOI:
https://doi.org/10.1016/j.tetlet.2020.151604
TETL 151604
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
23 October 2019
19 December 2019
8 January 2020
Please cite this article as: Tan, H-b., Wang, Y-f., Xu, J., Hu, C-s., One-pot, multi-component synthesis of ethyl
(
E)-1-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-aryl-2,5-dihydro-1H-benzo[b][1,4]diazepine-3-carboxylate derivatives,
Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.2020.151604
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One-pot, multi-component synthesis of ethyl
E)-1-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-aryl-
,5-dihydro-1H-benzo[b][1,4]diazepine-3-
Leave this area blank for abstract info.
(
2
carboxylate derivatives
Hong-bo Tan*, Yin-feng Wang, Jia Xu, Chun-sheng Hu*
R2
O
OEt
N
H2N
NH2
R1
EtO
AcOH
2
O
R2
+
EtOH, reflux, 3h
O
H
R1
OEt
NH
O
3
1
4a-l
Yield 68-91%
R1 = H, Me, OMe, tBu, Br, Cl, F, NO2; R2 = H, Me, Bz

1
Tetrahedron Letters
journal homepage: www.elsevier.com
One-pot, multi-component synthesis of ethyl (E)-1-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-
aryl-2,5-dihydro-1H-benzo[b][1,4]diazepine-3-carboxylate derivatives
Hong-bo Tan*, Yin-feng Wang, Jia Xu, Chun-sheng Hu*
Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI,
Chongqing University of Arts and Sciences, 319 Honghe Ave., Yongchuan, Chongqing, 402160, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new methodology for the synthesis of novel benzo[b][1,4]diazepine derivatives via a one-pot,
multi-component reaction of benzaldehyde, o-phenylenediamine, and ethyl propiolate has been
developed. Readily available starting materials, operationally simple, metal-free reaction
conditions, simplicity of product isolation and good yields are key advantages of this
methodology. The structure of the benzo[b][1,4]diazepines were confirmed by NMR, HRMS
and XRD.
Available online
Keywords:
2
009 Elsevier Ltd. All rights reserved.
Multi-component reaction
One-pot condensation
Metal-free
Benzo[b][1,4]diazepines
agents, anticonvulsants, and antimicrobial agents.11 Therefore,
the development of synthetic routes toward novel analogs of
benzo[b][1,4]diazepines is a highly rewarding challenge for
bioorganic chemists. Several general synthetic methods have
been described in the literature for the synthesis of
9
10
Introduction
Multi-component
reactions
(MCRs)
are
powerful
transformations used to condense three or more partners to
deliver novel scaffolds with inherent molecular complexity.1,2
The advantages of MCRs include the preservation of atom and
step economies and the ability to access highly diverse chemical
space rapidly and efficiently. MCRs are widely used synthetic
12-19
benzo[b][1,4]diazepine derivatives.
Due to our current interest in the development of efficient and
straightforward methods to prepare benzo[b][1,4]diazepine
derivatives from readily available building blocks, herein we
report a simple and efficient method for the synthesis of
benzo[b][1,4]diazepines via
benzaldehyde 1, o-phenylenediamine 2, and ethyl propiolate 3 in
ethanol to afford the title compounds 4a-l in good yields (Scheme 1).
3
-5
protocols in the drug discovery process as well as in a variety
of other useful endeavors.6, 7
MeO
OH
a
one-pot MCR involving
H
Cl
N
O
H
N
Bn
H
N
O
O
N
H
NH
R2
N
H
O O
Ph
O
OEt
N
HIV protease inhibitor
anticancer agent
H2N
NH2
R1
EtO
AcOH
2
O
R2
+
EtOH, reflux
O
H
F
S
H
R1
OEt
NH
4a-l
H
O
O
O
N
N
N
Br
N
O
3
1
O
N
H
Scheme 1. Synthesis of novel benzo[b][1,4]diazepines 4.
Results and Discussion
anticonvulsant
antimicrobial agent
Figure 1. Structures of selected medicinally and biologically
important benzo[b][1,4]diazepines.
The reaction conditions were studied using 3-
bromobenzaldehyde 1f (2 mmol), o-phenylenediamine 2 (2
mmol), and ethyl propiolate 3 (4 mmol) as the model substrates
(Table 1). For entries 1-4, the effect of the acid catalysts was
examined, including methanesulfonic acid (MSA), p-
toluenesulfonic acid (p-TsOH), trifluoroacetic acid (TFA) and
acetic acid (AcOH). Among these acids, AcOH was the most
effective and produced 4f in moderate yield (78%, entry 4). For
Benzo[b][1,4]diazepines are important scaffolds which are
found in pharmaceuticals, natural products and many other
applications.
As
shown
in
Figure
1,
substituted
benzo[b][1,4]diazepines and their analogs have received
8
significant attention as HIV Protease inhibitors, anticancer

2
Tetrahedron Letters
entries 4-7, the effect of the reaction solvent was investigated in
the presence of AcOH (0.2 equiv.). Varying the solvent from
EtOH to MeCN, CH Cl and THF gave low yields of 4f (Table 1,
O
N
OEt
N
EtO
O
H2N
NH2
2
AcOH (0.2 eq)
O
2
2
H
+
EtO
+
O
EtOH, reflux, 3h
entries 4-7). The use of excess ethyl propiolate 3 gave better
results, with higher yields and less byproduct 5f formation (Table
H
(
CH2O)n
NH
OEt
EtO
NH
6
EtO
3
O
1
, entry 8). We therefore determined the conditions in entry 8 of
O
7
8
Table 1 as the optimized conditions.
Scheme 3. Synthesis of novel benzo[b][1,4]diazepines 7 and 8.
Table 1. Optimization of the reaction conditions.
Furthermore, under the same optimized conditions, varying
O
OEt
the aldehyde from benzaldehydes to paraformaldehyde gave the
H2N
NH2
corresponding benzo[b][1,4]diazepine
benzo[b][1,4]diazepine 8 (Scheme 3).
7
and unexpectedly
2
Acid (0.2 eq)
N
O
Br
N
+
Solvent, reflux
+
N
H
O
EtO
H
Br
OEt
NH
A
plausible mechanism for the one-pot reaction of
benzaldehyde (1), o-phenylenediamine (2) and ethyl propiolate
Yield 4f (%)a (3) is illustrated in Scheme 4. Presumably, the initial
O
5f
(byproduct)
1f
3
Br
4f
Entry
Solvent
EtOH
EtOH
EtOH
EtOH
MeCN
Acid
Time
6 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
3 h
1
2
3
4
5
6
MSA
p-TsOH
TFA
31%
39%
52%
78%
57%
46%
41%
87%
85%
condensation of o-phenylenediamine 2 with benzaldehyde 1
forms imine intermediate 9, which would undergo aza-Michael
addition to ethyl propiolate
3 to give β-enamino ester
1
9
intermediate 10. Cyclization then takes place (here the β-
enamino ester behaves as a carbon nucleophile and adds to the
imine carbon), producing intermediate 11, which, in turn,
undergoes another aza-Michael addition to ethyl propiolate 3 to
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
CH
2 2
Cl
7
8b
9c
THF
2
0-22
give benzo[b][1,4]diazepines 4 (Scheme 4).
EtOH
CHO
EtOH
O
R1
a
Isolated yield. b Ratio of 1f/2/3 = 1/1/2.25. c Ratio of 1f/2/3 = 1/1/2.5.
OEt
R1
H
N
NH2
NH2
1
R1
3
N
With the optimized reaction conditions in hand, an
R2
R2
NH
O
R2
NH2
investigation into the versatility of this process was performed.
As shown in Scheme 2, the reaction proceeded smoothly with
electron-withdrawing group and electron-donating group
substituted benzaldehydes. The reaction conditions were
compatible with a variety of substituents, including methyl,
methoxy, t-butyl, bromo, fluoro, and 3,4-difluoro groups.
2
OEt
9
10
O
R2
OEt
O
EtO
3
R1
R1
O
OEt
N
R1
H2N
NH2
R1
H
N
H
N
2
AcOH (0.2 eq)
OEt
H
OEt
O
R2
N
OEt
+
O
EtOH, reflux, 3h
EtO
O
O
H
R2
N
H
N
H
R1
NH
4a-l
O
R2
OEt
O
R2
N
H
1
3
4
11
O
OEt
N
O
OEt
N
O
OEt
N
MeO
Scheme 4. Proposed mechanism for the formation of
benzo[b][1,4]diazepines 4.
EtO
OEt
EtO
NH
NH
4b (76%)
NH
4c (79%)
O
O
O
4a (85%)
O
O
OEt
OEt
OEt
O
O
OEt
O
N
O
N
NH2
NH2
3
3
H
O
OEt
EtO
EtO
H
N
N
O
Br
OEt
N
NH2
N
H
2
EtO
NH
NH
EtO
EtO
12
13
NH
O
4d (82%)
O
4e (74%)
O
4f (87%)
O
N
O
OEt
N
EtO
O
OEt
Br
O2N
Cl
Cl
N
O
EtO
EtO
NH
EtO
NH
O
NH
O
OEt
OEt
O
EtO
OEt
OEt
4g (84%)
O
O
4h (88%)
4i (91%)
3
O
O
O
H
H
N
O
N
N
O
O
O
N
O
O
EtO
EtO
EtO
OEt
N
H
H
OEt
OEt
N
H
N
F
H
N
Cl
N
Cl
8
NH
NH
NH
14
EtO
EtO
EtO
O
4j (83%)
O
4k (68%)
O
4l (81%)
Scheme 5. Proposed mechanism for the formation of
benzo[b][1,4]diazepine 8.
Scheme 2. Structures of novel benzo[b][1,4]diazepines 4a-l.
A plausible mechanism for the formation of 8 is illustrated in
Scheme 5. Presumably, o-phenylenediamine 2 undergoes aza-

3
Michael addition twice with two moles of ethyl propiolate 3 to
give bis-β-enaminoester intermediate 13. Cyclization then takes
place (one of the β-enamino ester acts as a carbon nucleophile
and adds to another β-enamino ester via a Michael addition),
producing intermediate 14, which, in turn, undergoes another
Further studies to extend the scope and synthetic utility of this
MCR are in progress.
Declarations of interest
None.
aza-Michael addition to ethyl propiolate
3
to give
benzo[b][1,4]diazepines 8 (Scheme 5).
Acknowledgments
1
The structures of the products were confirmed by H NMR,
C NMR, 2D-NMR and HRMS. Single-crystal X-ray analysis of
1
3
This work was financially supported by the Science &
Technology Research Program of Chongqing Municipal
Education Commission (No. KJQN201901305) and Science &
Technology Research Program of Chongqing University of Arts
and Sciences (No. 2017RBX10).
4
i and 8 conclusively confirmed their structures and, by analogy,
those of the other isolated products. The ORTEP diagrams of 4i
CCDC-1887918) and 8 (CCDC-1900108) are shown in Figure 2
and Figure 3, respectively.
(
References and notes
1
2
3
4
5
.
.
.
.
.
Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chemical
reviews 2014, 114, 8323.
Yi, J.; Badir, S. O.; Alam, R.; Molander, G. A. Organic letters
2
019.
Ruijter, E.; Orru, R. V. Drug Discovery Today: Technologies
013, 10, e15.
2
Bourgault, J. P.; Maddirala, A. R.; Andreana, P. R. Organic &
biomolecular chemistry 2014, 12, 8125.
Lamberth, C.; Jeanguenat, A.; Cederbaum, F.; De Mesmaeker, A.;
Zeller, M.; Kempf, H.-J.; Zeun, R. Bioorganic & medicinal
chemistry 2008, 16, 1531.
6
7
.
.
Boukis, A. C.; Reiter, K.; Frölich, M.; Hofheinz, D.; Meier, M. A.
Nature communications 2018, 9, 1439.
Ghorbani, M.; Mohammadi, B.; Saraii, M.; Masoumi, B.;
Abbasian, M.; Ramazani, A.; Slepokura, K.; Lis, T. Organic
letters 2016, 18, 4759.
8
.
Schimer, J.; Cígler, P.; Veselý, J.; Grantz Šašková, K. r.; Lepsik,
M.; Brynda, J.; Rezacova, P.; Kozisek, M.; Cisarova, I.;
Oberwinkler, H.; Kraeusslich, H.-G.; Konvalinka, J. Journal of
medicinal chemistry 2012, 55, 10130.
Figure 2. ORTEP diagram of crystal structure of 4i.
9
1
1
1
.
Chen, Y.; Le, V.; Xu, X.; Shao, X.; Liu, J.; Li, Z. Bioorganic &
medicinal chemistry letters 2014, 24, 3948.
0. Shao, Y.-P.; Han, R.-B.; Wu, H.-F.; Piao, F.-Y. Medicinal
Chemistry Research 2018, 27, 642.
1. Wang, L.-Z.; Li, X.-Q.; An, Y.-S. Organic & biomolecular
chemistry 2015, 13, 5497.
2. Maiti, G.; Kayal, U.; Karmakar, R.; Bhattacharya, R. N.
Tetrahedron Letters 2012, 53, 1460.
1
1
3. Maleki, A.; Kamalzare, M. Tetrahedron letters 2014, 55, 6931.
4. Jeganathan, M.; Pitchumani, K. ACS Sustainable Chemistry &
Engineering 2014, 2, 1169.
1
5. Solan, A.; Nişanci, B.; Belcher, M.; Young, J.; Schaefer, C.;
Wheeler, K. A.; Toeroek, B.; Dembinski, R. Green Chemistry
2
014, 16, 1120.
1
1
6. Jiang, B.; Rajale, T.; Wever, W.; Tu, S. J.; Li, G. G. Chemistry-an
Asian Journal 2010, 5, 2318.
7. Singha, R. K.; Sharmaa, S.; Kaura, A.; Sainia, M.; Kumarb, S.
Iranian Journal of Catalysis 2016, 6, 1.
1
1
2
8. Yin, L. Y.; Wang, L. Z. Tetrahedron Letters 2016, 57, 5935.
9. Yaragorla, S.; Pareek, A. Tetrahedron Letters 2018, 59, 909.
0. Kilic, H.; Bayindir, S.; Erdogan, E.; Saracoglu, N. Tetrahedron
2
012, 68, 5619.
2
2
1. Kohrt, S.; Santschi, N.; Cvengroš, J. Chemistry–A European
Journal 2016, 22, 390.
2. Garg, V.; Kumar, P.; Verma, A. K. The Journal of organic
chemistry 2018, 83, 11686.
Figure 3. ORTEP diagram of crystal structure of 8.
In conclusion, we have developed a simple and efficient
protocol for the preparation of new benzo[b][1,4]diazepine
derivatives via a novel MCR. The method has several advantages
over previously reported methods: readily available starting
materials, operationally simple, metal-free reaction conditions,
simplicity of product isolation and good yields. Furthermore, the
benzo[b][1,4]diazepines have NH and carbonyl groups, which
enable further modifications leading to molecular diversity.
Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/XXXXXX.
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Graphical Abstract

4
Tetrahedron Letters
To create your abstract, type over the instructions in the
template box below.
One-pot, multi-component synthesis of ethyl
E)-1-(3-ethoxy-3-oxoprop-1-en-1-yl)-2-aryl-
,5-dihydro-1H-benzo[b][1,4]diazepine-3-
Leave this area blank for abstract info.
(
2
carboxylate derivatives
Hong-bo Tan*, Yin-feng Wang, Jia Xu, Chun-sheng Hu*
R2
O
OEt
H2N
NH2
R1
EtO
AcOH
2
O
N
R2
+
EtOH, reflux, 3h
O
H
R1
OEt
NH
O
3
1
4a-l
Yield 68-91%
R1 = H, Me, OMe, tBu, Br, Cl, F, NO2; R2 = H, Me, Bz
Fonts or abstract dimensions should not be changed or altered.
Novel benzo[b][1,4]diazepines were synthesized by
Declaration of interests
The authors declare that they have no known
a new multi-component reaction.
☒
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
Highlights-2:
The title compounds were characterized by NMR,
HRMS and XRD analysis.
☐
The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
Highlights-3:
The products enable further structural modifications
leading to molecular diversity.
Highlights
Highlights-4:
Highlights-1:

5
The potential of this reaction is high for use in
medicinal & synthetic chemistry.