Deep eutectic solvent as a highly efficient reaction media for the one-pot synthesis of benzo-fused seven-membered heterocycles

Article abstract of DOI:10.1016/j.tetlet.2016.07.005

The combination of choline chloride and urea as a deep eutectic solvent has been applied to the synthesis of benzo-fused seven-membered heterocycles, including tricyclic 1,4-benzodiazepines and 1,4-benzoxazepines, via a one-pot, three-component reaction. The reaction conditions are relatively mild and do not require additional metals, acid catalysts, or organic solvents. The protocol has the advantages of excellent yields in short reaction times, an easy workup procedure, and being environmentally friendly.

Full text of DOI:10.1016/j.tetlet.2016.07.005

Accepted Manuscript
Deep eutectic solvent as a highly efficient reaction media for the one-pot syn-
thesis of benzo-fused seven-membered heterocycles
Ahmad Shaabani, Seyyed Emad Hooshmand, Mohammad Taghi Nazeri, Ronak
Afshari, Shima Ghasemi
PII:
S0040-4039(16)30826-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.07.005
TETL 47867
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 May 2016
17 June 2016
1 July 2016
Please cite this article as: Shaabani, A., Hooshmand, S.E., Nazeri, M.T., Afshari, R., Ghasemi, S., Deep eutectic
solvent as a highly efficient reaction media for the one-pot synthesis of benzo-fused seven-membered heterocycles,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.07.005
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1
Tetrahedron Letters
Deep eutectic solvent as a highly efficient reaction media for the one-pot synthesis of
benzo-fused seven-membered heterocycles
Ahmad Shaabani*, Seyyed Emad Hooshmand, Mohammad Taghi Nazeri, Ronak Afshari and Shima
Ghasemi
Faculty of Chemistry, Shahid Beheshti University, G. C., P. O. Box 19396-4716, Tehran, Iran
Corresponding author: a-shaabani@sbu.ac.ir; Tel.: +98-212-990-2800
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The combination of choline chloride and urea as a deep eutectic solvent has been applied to the
synthesis of benzo-fused seven-membered heterocycles, including tricyclic 1,4-benzodiazepines
and 1,4-benzoxazepines, via a one-pot, three-component reaction. The reaction conditions are
relatively mild and do not require additional metals, acid catalysts or organic solvents. The
protocol has the advantages of excellent yields in short reaction times, an easy workup
procedure and being environmentally friendly.
Available online
Keywords:
Deep Eutectic Solvent
Benzodiazepines
Benzoxazepines
2009 Elsevier Ltd. All rights reserved.
Multicomponent reactions
Green chemistry
1 and 4, such as 1,4-benzodiazepine and 1,4-benzoxazepine
derivatives, are used in medicinal chemistry due to their wide
1. Introduction
spectrum of biological activities (Fig. 1).16-21 Biologically active
1,4-benzodiazepines have demonstrated considerable utility in
central nervous system (CNS)-drug design, and as key
intermediates for the preparation of fused ring compounds.22
Some examples are diazepam and chlorodiazepoxide that act as
anti-anxiety drugs. Amongst the examples of 1,4-benzoxazepines
of medicinal interest are a non-nucleoside HIV-1 reverse
transcriptase inhibitor,23 a histamine receptor agonist19 and
calcium antagonists,24 as well as antidepressants and analgesics.25
Deep Eutectic Solvents (DESs) as a solvent/organocatalyst
have gained widespread attention in the last decade. DESs are
simple and inexpensive to prepare, generate no waste, require no
purification, and possess high atom economy aspects thus
embrace the principles of Green Chemistry.1 DESs are prepared
by mixing high melting-point precursors which in liquid form
possess strong hydrogen-bonding interactions that reduce the
ability of the components to crystallize.2, The most studied
3
series of DESs are those prepared using choline chloride as a
donor compound with components including urea, sugars,
carboxylic acids and ethylene glycol or M2+ ions such as Sn2+.2
One of the most notable properties of DESs is their high
viscosity. This may result from many factors including the
presence of an extensive hydrogen-bonding network, relatively
large ion sizes and electrostatic forces within the liquid.
Furthermore, they possess a very low volatility, a wider liquid
temperature range than molecular solvents and are generally
inflammable. DESs can be used to create alloys,4 and metal
nanoparticles.1,5 In addition, these systems have been investigated
for utilization in pharmaceutical applications,6 extraction,7
surfactant chemistry8 and various organic reactions.9, 10
Figure 1. Representative examples of biologically active compounds
containing the benzo-fused seven-membered heterocycle scaffold
2. Results and Discussion
Multicomponent coupling reactions (MCCRs) are highly
efficient strategies to achieve the rapid assembly of complex
products, especially carbon–carbon and carbon–heteroatom
bond-forming reactions in the synthesis of heterocycles11-13 and
natural products.14 Seven-membered heterocyclic systems hold a
prominent position as they constitute an integral part of natural
alkaloids, antibiotics and synthetic drugs.15 Benzo-fused seven-
membered heterocycles containing two heteroatoms at positions
As part of our continued interest in developing new methods
for the synthesis of heterocyclic compounds26-30 using green
chemistry,31, 32 ionic liquids33 and DESs,34-36 herein, we describe a
highly efficient protocol for the synthesis of tricyclic 1,4-
benzodiazepines and 1,4-benzoxazepines 4 via a one-pot, three-
component reaction in a choline chloride and urea based DES at
80 °C without using metal or acid catalysts nor organic solvents.
This protocol involves the reaction of an o-phenylenediamine or

2
Tetrahedron
2-aminophenol 1, dimedone 2, and various aromatic aldehydes
Previous methods for the synthesis of 1,4-benzoxazepines
3 (Scheme 1).
involved performing the condensation reaction in dichloroethane,
a toxic organic solvent, in the presence of trifluoroacetic acid
with longer reaction times at high temperatures.37 However, in
the presented methodology, the target 1,4-benzoxazepines were
synthesized without acid catalysts, organic solvents or harsh
reaction conditions. The results of the presented protocol were
compared to that of recent reports.38-42 As shown in Table 2, the
presented methodology has several advantages over the reported
Scheme 1. Synthesis of benzo-fused seven-membered heterocycles
via a three-component reaction in DES
methodologies, such as
a
green chemical approach,
straightforward and rapid procedure, without the need of any
metals and a simple work-up protocol.
The scope and limitations of this reaction were explored by
utilizing various o-phenylenediamines or 2-aminophenols (1),
dimedone (2) and various benzaldehyde derivatives (3) (Table 1).
As indicated in Table 1, the benzodiazepines were synthesized in
higher yields (80-94%) with shorter reaction times (20-30 min)
relative to the benzoxazepines (68-88%, 30-40 min).
Table 2. Comparison of the results for the synthesis of 1,4-
benzodiazepine 4b using DES with reported methods.
Entry Conditions
T
Time Yield
(oC)
(min)
(%)
7038
8538
8539
9140
9641
9542
1
2
3
4
5
6
CF3COOH-EtOH
reflux 45
reflux 10
Table 1. Synthesis of tricyclic 1,4-benzodiazepines and 1,4-
benzoxazepines
ZnS NPs-EtOH
ZnS NPs-grinding
Fe3O4@chitosan-EtOH
Fe(OTs)3/SiO2-S.F.
Cu/GA/Fe3O4@SiO2 NPs-
EtOH
Entry R1
R2
H
R3
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
X
Product Yielda
70
r.t.
80
60
19
120
5
1
4-NO2
NH
NH
NH
NH
NH
NH
NH
NH
O
4a
4b
4c
4d
4e
4f
94%
92%
82%
85%
92%
80%
88%
86%
80%
86%
83%
75%
88%
74%
85%
68%
80%
76%
82%
84%
80%
2
4-Cl
H
40
3
4-Me
4-MeO
3-NO2
2-NO2
2,4-Cl
3-NO2
H
H
4
H
7
DES
80
20
92
5
H
6
H
A possible mechanism for the formation of benzodiazepine
derivatives is shown in Scheme 2. Firstly, the DES can activate
the carbonyl group of dimedone 2 which then undergoes facile
condensation with o-phenylenediamine 1 to form an intermediate
imine [A]. The NH2 group of [A] condenses with the DES
activated carbonyl group of benzaldehyde derivatives 3 to form
[B], which then undergoes an intramolecular cyclization to afford
the products 4. Benzoxazepine derivatives may undergo an
analogous mechanism in which intermediate [B] is replaced by
the corresponding oxonium intermediate. DES can play a dual
role in this reaction: (i) as a solvent and (ii) as an organocatalyst
which activates the carbonyl and imine functional groups via
hydrogen bonding.
7
H
4g
4h
4i
8
Me
H
9
10
11
12
13
14
15
16
17
18
19
20
21
4-Cl
H
O
4j
4-Br
H
O
4k
4l
4-Me
4-NO2
4-Ph
H
O
H
O
4m
4n
4o
4p
4q
4r
4s
H
O
3-NO2
3-OH
2-Cl
H
O
H
O
H
O
2-Br
H
O
2,4-Cl
4-NO2
4-Cl
H
O
Me
Me
O
4t
O
4u
aIsolated yield bA mixture of o-phenylenediamine or 2-aminophenol (0.25
mmol), dimedone (0.25 mmol) a benzaldehyde derivative (0.25 mmol) and
the DES (choline chloride/urea 1:2) were stirred vigorously at 80 °C.
Various benzaldehydes containing electron-donating, electron-
withdrawing and halogen substituents were successfully applied
to the reaction and afforded the benzo-fused seven-membered
heterocycles in good to excellent yields. Electron-withdrawing
groups on benzaldehyde showed increased yields in comparison
to electron-donating groups.
Scheme 2. Proposed pathway for the synthesis of benzo-fused seven-
membered heterocycles in choline chloride/urea

3
Another advantage of using DESs is their ability to act as a
recyclable reaction media. The reaction mixture, including the
DES and 4b, was dissolved in water and the insoluble crude
product was filtered off. The DES was recovered from water by
evaporation at 80 °C under vacuum, recycled and reused for four
reaction runs without significant loss of catalytic activity (Fig. 2).
References
1
2
3
Wagle, D. V.; Zhao, H.; Baker, G. A. Acc. Chem. Res. 2014, 47, 2299.
Smith, E. L.; Abbott, A. P.; Ryder, K. S. Chem. Rev. 2014, 114, 11060.
Yusof, R.; Abdulmalek, E.; Sirat, K.; Rahman, M. B. A. Molecules
2014, 19, 8011.
Malaquias, J. C.; Steichen, M.; Thomassey, M.; Dale, P. J. Electrochim.
Acta. 2013, 103, 15.
Liao, H. G.; Jiang, Y. X.; Zhou, Z. Y.; Chen, S. P.; Sun, S. G. Angew.
Chem. 2008, 120, 9240.
Weaver, K. D.; Kim, H. J.; Sun, J.; MacFarlane, D. R.; Elliott, G. D.
Green Chem. 2010, 12, 507.
Dai, Y.; van Spronsen, J.; Witkamp, G.-J.; Verpoorte, R.; Choi, Y. H. J.
Nat. Prod. 2013, 76, 2162.
Arnold, T.; Jackson, A. J.; Sanchez-Fernandez, A.; Magnone, D.; Terry,
A. E.; Edler, K. J. Langmuir. 2015, 31, 12894.
Liu, P.; Hao, J.-W.; Mo, L.-P.; Zhang, Z.-H. RSC Adv. 2015, 5, 48675.
4
5
6
7
8
9
100
80
60
40
20
0
10 Alonso, D. A.; Baeza, A.; Chinchilla, R.; Guillena, G.; Pastor, I. M.;
Ramón, D. J. Eur. J. Org. Chem. 2016, DOI: 10.1002/ejoc.201501197.
11 Halimehjani, A. Z.; Namboothiri, I. N.; Hooshmand, S. E. RSC Adv.
2014, 4, 48022.
12 Halimehjani, A. Z.; Namboothiri, I. N.; Hooshmand, S. E. RSC Adv.
2014, 4, 51794.
1
2
3
4
13 Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc. Rev. 2014,
43, 4633.
Run
14 Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083.
15 Sternbach, L. H. The Benzodiazepine Story; Springer, 1978.
16 Bremner, J. B.; Samosorn, S. Azepines and their Fused-Ring
Derivatives. 2008.
17 Cepanec, I.; Litvic, M.; Pogorelic, I. Org. Process Res. Dev. 2006, 10,
1192.
Figure 2. Reusability of DES for the synthesis of 4b
3. Conclusions
In summary, we have developed a convenient and highly
efficient method for the synthesis of benzo-fused seven-
membered heterocycles, including tricyclic 1,4-benzodiazepines
18 Miki, T.; Kori, M.; Mabuchi, H.; Tozawa, R.-i.; Nishimoto, T.;
Sugiyama, Y.; Teshima, K.; Yukimasa, H. J. Med. Chem. 2002, 45,
4571.
19 Smits, R. A.; Lim, H. D.; Stegink, B.; Bakker, R. A.; de Esch, I. J.;
Leurs, R. J. Med. Chem. 2006, 49, 4512.
20 Ursini, A.; Capelli, A. M.; Carr, R. A.; Cassarà, P.; Corsi, M.;
Curcuruto, O.; Curotto, G.; Dal Cin, M.; Davalli, S.; Donati, D. J. Med.
Chem. 2000, 43, 3596.
21 Bihel, F.; Kraus, J.-L. Org. Biomol. Chem. 2003, 1, 793.
22 Essaber, M.; Baouid, A.; Hasnaoui, A.; Benharref, A.; Lavergne, J.-P.
Synth. Commun. 1998, 28, 4097.
and
1,4-benzoxazepines,
using
a
DES
as
a
solvent/organocatalyst.
The mild reaction
conditions,
experimental simplicity, straightforward purification procedures,
excellent yields with short reaction times, as well as the
application of green chemistry principles, are the advantages of
this methodology. This protocol may find use in synthetic and
medicinal chemistry since the products contain structural and
functional groups present in biologically active molecules.
23 Klunder, J. M.; Hargrave, K. D.; West, M.; Cullen, E.; Pal, K.; Behnke,
M. L.; Kapadia, S. R.; McNeil, D. W.; Wu, J. C.; Chow, G. C. J. Med.
Chem. 1992, 35, 1887.
24 Li, R.; Farmer, P. S.; Wang, J.; Boyd, R. J.; Cameron, T. S.; Quilliam,
M. A.; Walter, J. A.; Howlett, S. E. Drug Des. Discov. 1995, 12, 337.
25 Nagarajan, K.; David, J.; Kulkarni, Y.; Hendi, S.; Shenoy, S.;
Upadhyaya, P. Eur. J. Med. Chem. 1986, 21, 21.
26 Hajishaabanha, F.; Shaabani, A. RSC Adv. 2014, 4, 46844.
27 Shaabani, A.; Mofakham, H.; Maleki, A.; Hajishaabanha, F. J. Comb.
Chem. 2010, 12, 630.
Acknowledgments
We gratefully acknowledge financial support from the Iran
National Science Foundation (INSF), the Research Council of
Shahid Beheshti University and Catalyst Center of Excellence
(CCE) at Shahid Beheshti University.
28 Shaabani, A.; Rezayan, A. H.; Keshipour, S.; Sarvary, A.; Ng, S. W.
Org. Lett. 2009, 11, 3342.
29 Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi, H.
R. Org. Lett. 2008, 10, 2581.
30 Shaabani, A.; Ghadari, R.; Sarvary, A.; Rezayan, A. H. J. Org. Chem.
2009, 74, 4372.
31 Shaabani, A.; Sarvary, A.; Ghasemi, S.; Rezayan, A. H.; Ghadari, R.;
Ng, S. W. Green Chem. 2011, 13, 582.
32 Halimehjani, A. Z.; Hooshmand, S. E.; Shamiri, E. V. Tetrahedron Lett.
2014, 55, 5454.
33 Shaabani, A.; Soleimani, E.; Maleki, A. Tetrahedron Lett. 2006, 47,
3031.
34 Shaabani, A.; Hooshmand, S. E.; Tabatabaei, A. T. Tetrahedron Lett.
2016, 57, 351.
35 Shaabani, A.; Hooshmand, S. E. Tetrahedron Lett. 2016, 57, 310.
36 Shaabani, A.; Afshari, R.; Hooshmand, S. Res. Chem. Intermed. 2016,
42, 5607.
37 Ghandi, M.; Momeni, T.; Nazeri, M. T.; Zarezadeh, N.; Kubicki, M.
Tetrahedron Lett. 2013, 54, 2983.
38 Naeimi, H.; Foroughi, H. New J. Chem. 2015, 39, 1228.
39 Naeimi, H.; Foroughi, H. Res. Chem. Intermed. 2016, 42, 3999.
40 Maleki, A.; Kamalzare, M. Tetrahedron Lett. 2014, 55, 6931.
41 Elwahy, A. H.; Shaaban, M. R. RSC Adv. 2015, 5, 75659.
42 Shaabani, A.; Sepahvand, H.; Hooshmand, S. E.; Borjian Boroujeni, M.
Appl. Organomet. Chem. 2016, 30, 414.

Graphical Abstract
Deep eutectic solvent as a highly efficient
reaction media for the one-pot synthesis of
benzo-fused seven-membered heterocycles
Leave this area blank for abstract info.
Ahmad Shaabani,* Seyyed Emad Hooshmand, Mohammad Taghi Nazeri, Ronak Afshari and Shima Ghasemi

4
Tetrahedron
Highlights



Use of a deep eutectic solvent for the synthesis of benzo-fused seven-membered heterocycles
Mild reaction conditions with good to excellent yields in short reaction times
Potential applications in synthetic and medicinal chemistry