One-pot isocyanide-based five-component reaction: Synthesis of highly functionalized N-cyclohexyl-2-(2,4-dioxo-2,3,4,5 tetrahydro-1H-benzo[b][1,5]diazepin-3-yl)-2-phenylacetamides

Article abstract of DOI:10.1080/00397911.2016.1271894

A new protocol has been developed for the efficient synthesis of structurally diverse N-cyclohexyl-2-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,5]diazepin-3-yl)-2-phenylacetamides through a one-pot, five-component condensation reaction of an aromatic diamine, an aromatic aldehyde, an isocyanide, ethyl malonyl chloride, and water in dichloromethane with good yields, at ambient temperature, in the presence of MgCl₂ as a catalyst.

Full text of DOI:10.1080/00397911.2016.1271894

A One-Pot Isocyanide-Based Five-Component Reaction: Synthesis of Highly
Functionalized N-Cyclohexyl-2-(2,4-Dioxo-2,3,4,5 Tetrahydro-1H-
Benzo[b][1,5]Diazepin-3-yl)-2-Phenylacetamides
Sajjad Mousavi Faraz1, Abbas Rahmati1, Valiollah Mirkhani1
1Department of Chemistry, University of Isfahan, Isfahan, Iran
Corresponding author: Abbas Rahmati E-mail: a.rahmati@sci.ui.ac.ir.
Abstract
A new protocol has been developed for the efficient synthesis of structurally diverse N-
cyclohexyl-2-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,5]diazepin-3-yl)-2-
phenylacetamides via a one-pot, five-component condensation reaction of an aromatic
diamine, an aromatic aldehyde, an isocyanide, ethyl malonyl chloride, and water in
dichloromethane with good yields, at ambient temperature, in the presence of MgCl2 as a
catalyst.
Graphical Abstract
KEYWORDS: Diazepine, Multi-component reaction, Isocyanide.
INTRODUCTION
One of the most important challenges in pharmaceutical chemistry is the design and
synthesis of biologically active molecules. Multi-component reactions (MCRs) are potent
transformations and very effective synthetic routes in which three or more starting
1

materials are combined in a one-pot fashion to reach highly garnished products. These
methods have considerable advantages over the classical stepwise procedure permitting
some chemical bonds formation and making complex molecular structures from routinely
and in particular simple precursors in an only one synthetic workup without isolation of
intermediates from the reaction mixture [1–3]. MCRs, specially isocyanide based multi-
component reactions (IMCRs) are considered as potent ones in drug discovery and high-
throughput synthesis of organic compounds [4]. The pharmaceutical industry has focused
on diversity-oriented and biased combinatorial libraries [5]. Recently, design of multi-
component reactions (MCRs) with high atom economy, high conversion character, and
facility in a one-pot form has achieved noticeable interest because of their capability to
produce more molecular variety and complexity [6–8]
.
Synthesis and use of different types of benzodiazepines as an important class of
heterocycles have been reported in the literature [9–12]. Recently, the area of biological
interest of benzodiazepines has been extended to antibiotics [13–17]. Also, they are
extensively investigated for therapeutic applications such as development of anxiolytic
and antipsychotics agents [18, 19], antiarrhythmics [20], drags to treat viral infection (HIV)
[21, 22], cholecystokinin-B receptor antagonists [23, 24] and cardiovascular disorders [25]. In
addition, these heterocycles have prominent anticonvulsant properties which are
considered in epilepsy treatment [26, 27]. Benzodiazepines have the privilege to be
privileged the scaffold [28–37] certainly in the core of many compounds, including peptide
hormones such as Cholecystokinin(A) [38] potassium blockers (B) [36, 39] and interleukin-
1B converting enzyme (ICE) inhibitor (C) [40] (Fig. 1). In addition, Ursini and co-workers
2

reported that 3-(aryloxycarbonyl)amino-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-1H-1,5-
benzodiazepine D acts as a cholecystokinin-B receptor antagonists [41]. A literature survey
shows that there is a large number of reports on the synthesis of benzodiazepine
derivatives [42]. Lately, Shaabani et al. reported a synthetic pathway for
benzo[b][1,5]diazepine-2,4-diones whose structures are nearly similar to the compounds
in this work [24]. Li group using this method reported a new type of anticancer agent [43]
In addition, Bazgir using Meldrum’s acid via a two different multi-component reactions
synthesized the title compound [44, 45]
.
.
In line of our previous studies on IMCRs [46–49], we wish to highlight our findings about
synthesis of highly functionalized N-cyclohexyl-2-(2,4-dioxo-2,3,4,5-tetrahydro-1H-
benzo[b][1,5]diazepin-3-yl)-2-phenylacetamides 5a-n via a one-pot five-IMCR of
benzene-1,2-diamine 1, ethyl malonyl chloride 2, benzaldehyde 3, isocyanide 4 and water
in dichloromethane at room temperature, in the presence of MgCl2 as catalyst (Scheme
1).One of the drawbacks of the previously described methods for the synthesis of
diazepins was the long reaction times [44]. Using 2 instead of Meldrum’s acid and MgCl2
as catalyst, high number of different chemicals was synthesized.
DISCUSSION
To optimize the conditions for the synthesis of N-cyclohexyl-2-(2,4-dioxo-2,3,4,5-
tetrahydro-1H-benzo[b][1,5]diazepin-3-yl)-2-phenylacetamides, 1, 2, 4-
fluorobenzaldehyde, cyclohexyl isocyanide and water were selected as model reactants.
Firstly, the effect of various solvents were evaluated (Table1). As can be seen in Table 1,
3

the results showed that the efficiency and the yield of the reaction in CH2Cl2 was higher
than those obtained using other solvents.
As indicated in Table 2, the reaction of 1, 2, 4-fluorobenzaldehyde, cyclohexyl
isocyanide and water was also carried out in the presence of various acidic and basic
catalysts (40 mol%). Results showed that reaction proceeds in the presence of both series
of catalysts and higher reaction yield was reached using MgCl2. Subsequently, testing the
effect of catalyst loading with values of 10, 20, 30, and 40 mol % was carried out. The
results indicated that 20 mol % of catalyst was optimal. Higher amounts of catalyst did
not lead to a significant change in yield. We continued to focus on the optimization of
reaction conditions. Initially, this transformation was carried out in dichloromethane at
room temperature in the absence of catalyst. It was found that the yield of product was
low even after 24 h (entry 1, Table 2). To increase yield of reaction, 40 mol % of catalyst
was added to the reaction system. The results are summarized in Table 2. Among them,
MgCl2 was proven superior to other catalyst, and the yield of the desired product 5a
could be increased to 93% (entry 1, Table 3). As shown in Table 3, the both electron-
withdrawing and electron-donating benzaldehydes were examined and the reaction
proceeded with both of them.
In the next step, this promising reaction was further synthesized through varying the
structure of the isocyanide component (Table 3). The reaction proceeds under mild
conditions at room temperature in a manner that no undesirable side reaction and
products were observed.
4

A possible mechanism for the formation of product 5a is shown in Scheme 2. It is
conceivable that the initial event is the formation of intermediate 6 through nucleophilic
attack of benzene-1,2-diamine 1 to acyl portion of ethyl malonyl chloride 2. Then, an
intermolecular cyclization of 6 affords seven-membered ring 7 in the presence of a
catalytic amount MgCl2. Knoevenagel condensation reaction of 3 and 7 in the presence of
MgCl2 after passing some steps leads to α,β-unsaturated molecule 10 [44, 45]. On the basis
of the well-established chemistry of reaction of Michael-type addition reaction of an
isocyanides 4 with α,β-unsaturated compound 10 [50, 51], intermediate 11 was produced by
nucleophilic attack of isocyanide 4 to α,β-unsaturated compound 10 using catalyst
followed by nucleophilic attack of a H2O molecule on the nitrilium moiety and
production of compound 13. Finally, after two tautomerizations of intermediate 13 the
diazepine- amide 5a is produced.
CONCLUSIONS
In summary, an impressive and simple procedure to construct the highly functionalized
benzo[b][1,5]diazepin scaffolds from readily available starting materials was developed.
This effective strategy for the preparation of synthetically, pharmaceutically and
biologically interesting benzodiazepine derivatives includes some important features like
the mild reaction conditions, excellent yields, high atom economy, and easy workup
procedure.
EXPERIMENTAL
5

General
All chemicals and reagents were purchased from Across, Alfa Aesar, Daejung or Merck
chemical companies and were used without purification. The identify of previously
known organic products were confirmed through comparison of their melting points and
1H NMR spectral data with those reported in the literature [44, 45]. Structure of other
synthetic compounds were elucidated using IR, 1H NMR, 13C NMR spectroscopy and
the elemental analysis. Melting points were determined on a Buchi B-545 apparatus using
open capillary tubes. The reactions was monitored by TLC using silica gel SIL G/UV 254
plates. FT-IR spectra were recorded as KBr pellets using a Shimadzu Corporation
spectrometer at 400–4000 cm-1. The 1H NMR and 13C NMR spectra were recorded on a
Bruker Avance DPX FT-NMR spectrometer at 400 and 100 MHz, respectively (δ in
ppm). EI-MS (70 eV): Finningan-MAT-8430 mass spectrometer; in m/z. Elemental
analyses were performed using a Heraeus CHNS Rapid analyzer.
General Procedure For The Synthesis (5a-N) Using One-Pot Five Component
Method
A solution containing 1 (1 mmol), 2 (1 mmol), benzaldehyde (1 mmol), isocyanide (1
mmol), H2O (0.5 mL) and MgCl2 (0.2 mmol) in CH2Cl2 (5 mL) was stirred for 5 h at
room temperature. After completion of the reaction, as indicated by TLC (ethyl acetate/n-
hexane, 1/1), the reaction solution was filtered off and the residue was washed several
time with EtOH to receive 5a-n.
6

Spectral Data Of N-Cyclohexyl-2-(2,4-Dioxo-2,3,4,5-Tetrahydro-1H-
Benzo[B][1,5]Diazepin-3-Yl)-2-(4-Fluorophenyl)Acetamide (5a):
Yield 93%. White powder; mp 261-263°C; IR (KBr, cm-1) 3323, 3176, 3071, 2983, 2930,
2855,1700, 1641, 1590, 1546, 1509, 1427, 1327, 1256, 1146, 1084. 1H NMR (300.13
MHz, DMSO-d6) δ=0.97 – 1.77 (m, 5CH2 of cyclohexyl); 3.39 (br. s, CH of cyclohexyl,
overlap with solvent); 3.76 (d, J=11.2, CH); 4.38 (d, J=11.2, CH); 6.99 – 7.24 (m, 8
arom. H); 8.10 (d, J=7.2, NH_ cyclohexyl); 10.36 (s, NH); 10.55 (s, NH).13C NMR (100
MHz, DMSO-d6) δ:24.28, 24.34, 25.14, 31.82, 32.25, 47.35, 51.38, 113.20, 113.41,
114.92, 115.14, 122.33, 123.62, 125.19, 125.27, 129.79, 141.80, 160.40, 162.81, 164.20
ppm.
-
).Anal. calc. for C23H24FN3O3(409.18): C 67.47, H 5.91, N 10.26;
found: C 67.81, H 5.97, N 9.99.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Research Council of the
University of Isfahan.
“Supporting Information: Full experimental detail, spectra data and copies of 1H NMR
and 13C NMR spectra of 5a, 5f and 5h and Copies of 1H NMR spectra of known
compounds can be found via the “Supplementary Material” section of this article’s
webpage.”
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Table 1. Effect of solvent on the model reactiona
Entry
Solvent
MeCN
EtOAc
Toluene
EtOH
Time(h)
Yieldb(%)
1
2
3
4
5
10
15
12
12
8
65
52
27
15
93
CH2Cl2
aBenzene-1,2-diamine (1 mmol), ethyl malonyl chloride (1 mmol), 4-fluorobenzaldehyde
(1 mmol), cyclohexyl isocyanide (1 mmol) and water(1 mmol) at room temperature, in
the presence of MgCl2 (20 mol %).
bIsolated yield
13

Table 2. Monitoring of the catalyst effect and catalyst amount on the model reactiona
Entry
Catalyst
-
Time(h)
24
Yieldb(%)
Catalyst amount (mol%)
1
2
3
4
5
6
7
8
9
9
10
18
25
27
22
65
25
30
21
20
72
93
40
40
40
40
40
40
40
40
40
40
20
Na2CO3
NaHCO3
Pyridine
NaH
12
12
12
12
Et3N
12
NiCl2
12
[bmim]5[PW11ZnO39].3H2O 12
H6[P2W18O62].18H2O
MgBr2
12
12
6
MgCl2
aBenzene-1,2-diamine (1 mmol) , ethyl malonyl chloride (1 mmol), 4-fluorobenzaldehyde
(1 mmol), cyclohexyl isocyanide (1 mmol) and water(1 mmol) at room temperature, in
the presence of catalyst
b Isolated yield
14

Table 3. Synthesis of diazepine in the presence of MgCl2
Entry Aryl
aldehyde
Isocyanide
Product
Time(h) Yieldb(%)
1
4-F-C6H4 Cyclohexyl
5
4
93
89
2
4-Cl-C6H4 cyclohexyl
2-Cl-C6H4 cyclohexyl
3
4
5
6
6
5
5
6
91
95
89
87
3-NO2-
C6H4
Cyclohexyl
Cyclohexyl
Cyclohexyl
3-MeO-
C6H4
2,4-
diMeO-
C6H4
7
3-Br-C6H4 Cyclohexyl
5
91
15

8
9
2-OH-
C6H4
1,1,3,3-
5
6
93
85
tetramethylbutyl
4-Me-
C6H4
Cyclohexyl
Cyclohexyl
10
11
Ph
6
6
84
86
4-Cl-C6H4 2,6-Me2C6H3
12
13
14
3-MeO-
C6H4
2,6-Me2C6H3
2,6-Me2C6H3
4
6
6
92
88
80
Ph
Ph
4-Me-C6H4-
SO2CH2
aIsolated yield.
16

Scheme 1. Synthesis of diazepine in the presence of MgCl2 as catalyst
17

Scheme 2. Possible mechanism for the formation of product 5a.
18

Fig. 1. The structure of some medicinally and biologically important diazepines
19