Zn(L -proline)2 as a powerful and reusable organometallic catalyst for the very fast synthesis of 2-amino-4H-benzo[g]chromene derivatives under solvent-free conditions

Article abstract of DOI:10.1002/aoc.3306

An efficient route for the synthesis of 2-amino-4H-benzo[g]chromenes via a three-component coupling reaction of aldehydes, malononitrile and 2-hydroxy-1,4-naphthaquinone in the presence of Zn(L-proline)₂ is reported. High yields, short reaction

Full text of DOI:10.1002/aoc.3306

Full Paper
Received: 2 January 2015
Revised: 15 January 2015
Accepted: 2 February 2015
Published online in Wiley Online Library: 16 March 2015
(wileyonlinelibrary.com) DOI 10.1002/aoc.3306
Zn(L-proline)2 as a powerful and reusable
organometallic catalyst for the very fast
synthesis of 2-amino-4H-benzo[g]chromene
derivatives under solvent-free conditions
Behrooz Maleki*, Saeed Babaee and Reza Tayebee
An efficient route for the synthesis of 2-amino-4H-benzo[g]chromenes via a three-component coupling reaction of aldehydes,
malononitrile and 2-hydroxy-1,4-naphthaquinone in the presence of Zn(L-proline)2 is reported. High yields, short reaction times,
non-toxicity and recyclability of the catalyst, and easy work-up are the main merits of this protocol. Copyright © 2015 John Wiley &
Sons, Ltd.
Keywords: Zn(L-proline)2; 2-amino-4H-benzo[g]chromenes; aldehydes; malononitrile; 2-hydroxy-1,4-naphthaquinone; recyclable catalyst
phthalimide-N-oxyl.[16] However, several of these methods suffer
from certain drawbacks such as prolonged reactions times, use
Introduction
The development of methodologies that involve the use of inex-
pensive and reusable catalysts under mild and environmentally
friendly reaction conditions is one of the major goals in green and
sustainable chemistry. Methodologies leading to various heterocy-
clic structures are in high demand for both academic and industrial
applications.[1]
of volatile or hazardous organic solvents, tedious work-up condi-
tions, use of extra energy sources and employment of large
amount of catalyst, which lead to difficulty in product separation
and non-recyclability of the catalyst. Therefore, it is desirable to
develop a more efficient and a general method for the synthesis
of 2-amino-4H-benzo[g]chromene derivatives.
2-Hydroxy-1,4-naphthoquinone has been known for the past
4000 years, is found in many natural products and has been
employed as a synthetic intermediate for the preparation of numer-
ous heterocyclic compounds. Molecules containing the heterocy-
clic quinone group constitute one of the most important classes
of compounds in organic chemistry because of their biological
properties such as antitumor, antibacterial, antifungal and anti-
inflammatory activities.[2–8]
Multicomponent reactions (MCRs) have emerged as a powerful
synthetic strategy because of their efficiency, atom economy,
high selectivity and convenience in the construction of diverse
chemical libraries of ‘drug-like’ molecules.[9] MCRs are convergent
reactions, in which three or more starting materials react to give a
highly complex product in one pot. Typically, purification of
products resulting from MCRs is also simple because all the organic
reagents employed are consumed and incorporated into the tar-
get compound.
Experimental
General
All chemicals were obtained from Merck and Sigma-Aldrich and
used as received. Infrared (IR) spectra were recorded with a
Shimadzu 435-U-04 spectrophotometer (KBr pellets). H NMR and
1
13C NMR spectra were recorded with a Bruker DRX-300 Avance
spectrometer in DMSO-d6 or CDCl3, and shifts are given in parts
per million (ppm) downfield from tetramethylsilane as an internal
standard. Melting points were determined using an Electrothermal
9200 instrument.
General Procedure for Synthesis of 2-Amino-4H-benzo[g]
chromene Derivatives
A mixture of aldehydes (1 mmol), malononitrile (1 mmol) and
2-hydroxy-1,4-naphthaquinone (1 mmol) was stirred with Zn(L-
proline)2 (20 mol%) at 60°C for the required period of time (for
solid aldehydes, 0.1 ml of ethanol was added). Upon completion
of the reaction as indicated using TLC (hexane–ethyl acetate,
Zn(L-proline)2 is an efficient, inexpensive, non-toxic, stable and re-
usable catalyst which is not dissociated under reaction conditions.
Also, many advantages such as higher solubility in water, insolubil-
ity in organic solvents, eco-friendly nature and convenient work-up
make Zn(L-proline)2 a green catalyst in organic synthesis.[10]
To the best of our knowledge, only a few methods are available
for the preparation of 4-aryl-5,10-dihydro-4H-benzo[g]chromene-
5,10-dione derivatives. Recently, many catalysts have been used
for this preparation such as triethylbenzylammonium chloride
(TEBA),[11] DMF/AcOH under microwave irradiation,[12] Et3N,[13] 1,8-
diazabicyclo[5.4.0]undec-7-ene,[14] ionic liquids[15] and potassium
*
Correspondence to: Behrooz Maleki, Department of Chemistry, Hakim Sabzevari
University, Sabzevar 96179-76487, Iran. E-mail: b.maleki@hsu.ac.ir
Department of Chemistry, Hakim Sabzevari University, Sabzevar 96179-76487, Iran
Appl. Organometal. Chem. 2015, 29, 408–411
Copyright © 2015 John Wiley & Sons, Ltd.

Zn(L-proline)2 for the synthesis of 2-amino-4H-benzo[g]chromenes
4:1), an appropriate amount of hot EtOH (96%, 2 ml) was added
and the mixture stirred for 2 min. The resulting crude product
was poured into crushed ice and the solid product that separated
was filtered and recrystallized from ethanol (96%, 2 ml) to afford
pure 2-amino-4H-benzo[g]chromene derivatives.
in the presence of Zn(L-proline)2 (30 mol%) under solvent-free
conditions at room temperature and after 5 min, 32% of product
is observed, and the yield of the reaction increases as the reaction
temperature increases (entries 3–6). As evident from entries 3 and
5, the temperature is necessary for the synthesis of 4a. Using
30 mol% of Zn(L-proline)2 at 70°C, the yield unexpectedly decreases
to 85% (entry 6). A possible explanation for the trace product yield
is that the starting material or the product may be destroyed during
the reaction. The best results are obtained at 60°C (entry 5). To de-
termine the optimal amount of Zn(L-proline)2, the model reaction
was carried out using various amounts (entries 7 and 8). The results
show that 20 mol% of Zn(L-proline)2 is sufficient to obtain the best
yield (entry 7).
Encouraged by this success, a study of the substrate scope was
carried out. The results are summarized in Table 2. It can be seen
from the results that a wide range of aromatic aldehydes are
suitable for this MCR. Aromatic aldehydes tethered with both
electron-donating and electron-withdrawing substituents afford
the desired products in very good yields.
Results and Discussion
In continuation of our efforts towards the development of greener
methodologies,[17] we report herein a simple, clean and environ-
mentally friendly process for the synthesis of 2-amino-4H-benzo
[g]chromene derivatives by reaction of various aldehydes,
malononitrile and 2-hydroxy-1,4-naphthaquinone in the presence
of Zn(L-proline)2 under solvent-free conditions (Scheme 1).
For the present study, the catalyst Zn(L-proline)2 was prepared
following a literature procedure.[9i] Initially, benzaldehyde (1 mmol),
malononitrile (1 mmol) and 2-hydroxy-1,4-naphthaquinone
(1 mmol) were selected as representative substrates to investigate
the reaction conditions. The catalyst plays an important role in
the formation of 2-amino-4-(phenyl)-5,10-dihydro-5,10-dioxo-4H-
benzo[g]chromene-3-carbonitrile (4a). Without the catalyst, it is ob-
served that there is no conversion to product even after 2 h (Table 1,
entries 1 and 2). Then, we focused our attention on using Zn(L-pro-
line)2 catalyst, which might help to reduce the reaction time and
improve the yields of the target compounds. Our studies show that
There is no effect on the reaction time and the yield of the
corresponding products when electron-donating groups and
electron-withdrawing groups on benzaldehydes are used. Further-
more, we examined aliphatic aldehydes such as butanal instead
of benzaldehydes in the reaction. All the starting materials in the
Table 2. Three-component synthesis of 2-amino-4H-benzo[g]chromene
derivatives from the reaction of 2-hydroxynaphthalene-1,4-dione (1 mmol),
malononitrile (1 mmol) and aldehydes (1 mmol) in the presence of Zn(L-
proline)2 (20 mol%)
Scheme 1. Synthesis of 2-amino-4H-benzo[g]chromene derivatives catalysed
by Zn(L-proline)2.
Products (4a–q) RCHO (3a–q)
Time (min) Yield (%)a
Ref.
Table 1. Screening of reaction conditions for synthesis of 2-amino-4-
(phenyl)-5,10-dihydro-5,10-dioxo-4H-benzo[g]chromene-3-carbonitrile (4a)
4a
4b
4c
4d
4e
4f
C6H5
4
5
91
90
90
92
93
86
89
82
78
93
89
90
80
87
94
90
86
[15b)]
[15b)]
[15b)]
[15b)]
[15b)]
[15b)]
[15b)]
[15c)]
[11]
4-OCH3C6H4
3-OCH3C6H4
3,4-OCH3C6H3
4-ClC6H4
9
5
6
2-ClC6H4
10
8
4g
4h
4i
4-BrC6H4
Entry
Zn(L-proline)2
(mol%)
Temp. (°C)
Time (min)
Yield (%)a
4-FC6H4
12
15
4
4-CH3C6H4
3-NO2C6H4
2-NO2C6H4
2,4-ClC6H3
4-OHC6H4
2,3,4-OCH3C6H3
4-NO2C6H4
2-Thienyl
4j
[10]
1
2
3
4
5
6
7
8
None
None
30
r.t.b
60
120
120
5
No reaction
4k
4l
6
[15b)]
[15b)]
[15b)]
[15b)]
[15b)]
[12]
No reaction
8
r.t.b
22
76
90
85
91
82
4m
4n
4o
4p
4q
14
6
30
50
5
30
60
5
5
30
70
5
7
20
60
5
4-Pyridyl
7
[16]
10
60
5
aAll known products have been reported previously in the literature
and were characterized by comparison of IR and NMR spectra with
those of authentic samples.
aIsolated yield.
bRoom temperature.
Appl. Organometal. Chem. 2015, 29, 408–411
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc

B. Maleki et al.
Figure 1. Reusability of Zn(L-proline)2 for the synthesis of 2-amino-4-
(phenyl)-5,10-dihydro-5,10-dioxo-4H-benzo [g]chromene-3-carbonitrile (4a).
Scheme 2. Reactionbetweenbenzaldehyde, 2-hydroxy-1,4-naphthaquinone
and ethyl cyanoacetate in the presence of Zn(L-proline)2 (20 mol%).
reaction are intact without formation of any desired product and
side products after 1 h. In addition to the aromatic aldehydes, the
reaction also proceeds smoothly using heterocyclic aldehydes in
high yield.
The applicability of the catalyst was further extended by reaction
between benzaldehyde (1 mmol), 2-hydroxy-1,4-naphthaquinone
(1 mmol) and ethyl cyanoacetate (1 mmol) under solvent-free
conditions at 60°C. The reaction is complete in 30 min and 69% of
13-phenyl-5H-dibenzo[b,i]xanthene-5,7,12,14(13H)-tetraone (5a) is
obtained after work-up (Scheme 2).[18] Subsequently, reactions of
other aromatic aldehydes (such as with 4-methoxy, 4-nitro substit-
uents) with ethyl cyanoacetate also give the corresponding deriva-
tives of 5a in good yields.
To show the merit of the present work, we summarize the results
for the synthesis of 2-amino-4H-benzo[g]chromenes obtained by
other workers in Table 3. In contrast to other existing methods,
the present methodology offers several advantages such as excel-
lent yields, simple procedure, short reaction times, easy synthesis,
simple work-up and greener conditions using Zn(L-proline)2 as an
efficient catalyst (Table 3).
Finally, the recycling of Zn(L-proline)2 was investigated during
the synthesis of 4a. After completion of the reaction, the solid prod-
uct was collected by filtration. Then, water was removed under re-
duced pressure, and diethyl ether was added to the solidified
mixture in order to separate the catalyst from the mixture, being in-
soluble in organic solvents. Then the catalyst was filtered, washed
with diethyl ether and dried at 80°C for 2 h to afford Zn(L-proline)2
Scheme 3. Proposed mechanism.
Table 3. Comparison of the efficiencies of various catalysts used in the
synthesis of 2-amino-4H-benzo[g]chromenes
which was reused directly for the next run. It is found that Zn
(L-proline)2 can be used for the reactions for up to three runs
without any appreciable loss of efficiency (Fig. 1).
A plausible mechanism of the reaction is presented Scheme 3.
We believe that Zn(L-proline)2 facilitates cyanoolefin formation
and synthesis of 2-amino-4H-benzo[g]chromenes. The reaction
occurs via initial formation cyanoolefin [A] from condensation of al-
dehydesand malononitrile, whichreactswith2-hydroxynaphthalene-
1,4-dione to give intermediate [B] which subsequently undergoes
cyclization to afford the desired products (4a–q).
Entry 2-Amino-4H-
benzo[g]chromene
Conditions
Time Yield
(min) (%)
4b
4e
4o
4-OCH3C6H4
4-ClC6H4
DMF/AcOH/MWI[12]
Et3N/rt/CH3CN13a)
6
81
1440 70
120 80
[bmim]OH/rt/EtOH15c)
This work
5
90
TEBA/85°C/solvent free[11]
Pyrr[CH3COO]/rt/solvent free15a)
[bmim]OH/rt/EtOH15c)
This work
190 93
12 90
50 92
6
93
Conclusions
4-NO2C6H4
TEBA/85°C/solvent free[11]
Et3N/rt/CH3CN13a)
[bmim]OH/rt/EtOH15c)
[Et3NH][HSO4]/rt/solvent free15d)
This work
180 94
1440 75
40 93
We have developed an efficient and environmentally friendly
method for the synthesis of 2-amino-4H-benzo[g]chromenes in ex-
cellent yield within short reaction times. This procedure provides
several advantages such as cleaner reactions, easier work-up and
being an eco-friendly and promising strategy. It is expected that
12 91
4
94
wileyonlinelibrary.com/journal/aoc
Copyright © 2015 John Wiley & Sons, Ltd.
Appl. Organometal. Chem. 2015, 29, 408–411

Zn(L-proline)2 for the synthesis of 2-amino-4H-benzo[g]chromenes
[10] a) M. Kidwai, A. Jain, Appl. Organometal. Chem. 2012, 26, 528; b)
M. M. Heravi, M. H. Tehrani, K. Bakhtiari, H. A. Oskooei, Catal.
Commun. 2007, 8, 1341; c) A. Manvar, P. Bochiya, V. Virsodla,
R. Khunt, A. Shah, J. Mol. Catal. A 2007, 275, 148; d) M. Kidwai, A. Jain,
R. Poddar, J. Organometal. Chem. 2011, 696, 1939; e) Z. N. Siddiqui,
T. N. M. Musthafa, Tetrahedron Lett. 2011, 52, 4008; f) V. Sivamurugan,
R. Suresh Kumar, M. Palanichamy, V. Murugesan, J. Heterocycl. Chem.
2005, 42, 969; g) M. M. Heravi, A. Ghods, K. Bakhtiari, F. Derikvand,
Synth. Commun. 2010, 40, 1927; h) C. R. Winck, M. P. Darbem,
R. S. Gomes, A. W. Rinaldi, N. L. C. Domingues, Tetrahedron Lett. 2014,
55, 4123; i) Z. N. Siddiqui, F. Farooq, Catal. Sci. Technol. 2011, 1, 810.
[11] Y. Changsheng, Y. Chenxia, L. Tuanjie, T. Shujiang, Chin. J. Chem. 2009,
27, 1989.
the present methodology will find application in organic synthesis.
In addition, it is easy to separate and recover the catalyst for an-
other catalytic cycle.
Acknowledgments
This research work was supported by the University of Hakim
Sabzevari. The authors thank the University of Hakim Sabzevari
for financial support to carry out this research.
[12] X. H. Wang, X. H. Zhang, S. J. Tu, F. Shi, X. Zou, S. Yan, Z. G. Han, W. J. Hao,
X. D. Cao, S. S. Wu, J. Heterocycl. Chem. 2009, 46, 832.
References
[13] a) A. Shaabani, R. Ghadari, S. Ghasemi, M. Pedarpour, A. H. Rezayan,
A. Sarvary, S. W. Ng, J. Comb. Chem. 2009, 11, 956; b) I. V. Magedov,
A. S. Kireev, A. R. Jenkins, N. M. Evdokimov, D. T. Lima, P. Tongwa,
J. Altig, W. F. A. Steelant, S. V. Slambrouck, M. Y. Antipin, A. Kornienko,
Bioorg. Med. Chem. Lett. 2012, 22, 5195.
[14] J. M. Khurana, B. Nand, P. Saluja, Tetrahedron 2010, 66, 5637.
[15] a) H. R. Shaterian, K. Kangani, Sci. Iran. 2013, 20, 571; b) H. R. Shaterian,
M. Mohammadnia, J. Mol. Liq. 2013, 177, 353; c) Y. Yu, H. Guo, X. Li,
J. Heterocycl. Chem. 2011, 48, 1264; d) F. Khorami, H. R. Shaterian, Res.
Chem. Intermed. 2013. doi:10.1007/s11164-013-1423-6.
[1] a) H. Veisi, P. Mohammadi, J. Gholami, Appl. Organometal. Chem. 2014,
28, 868; b) H. Veisi, R. Ghorbani-Vaghei, S. Hemmati, M. Haji Aliani,
T. Ozturk, Appl. Organometal. Chem. 2015, 29, 26; c)
R. Ghorbani-Vaghei, S. Hemmati, H. Veisi, Appl. Organometal. Chem.
(in press), doi:10.1002/aoc.3264; d) K. Karami, N. Haghighat Naeini, Appl.
Organometal. Chem. 2015, 29, 33; e) M. Riahi Farsani, F. Jalilian,
B. Yadollahi, H. Amiri Rudbari, Appl. Organometal. Chem. 2015, 29, 7; f)
H. A. Patel, A. L. Patel, A. V. Bedekar, Appl. Organometal. Chem. 2015,
29, 1.
[2] M. F. Sartori, Chem. Rev. 1963, 63, 279.
[16] M. G. Dekamin, M. Eslami, A. Maleki, Tetrahedron 2013, 69, 1074.
[17] a) B. Maleki, S. Hemmati, A. Sedrpoushan, S. Sedigh Ashrafi, H. Veisi, RSC
Adv. 2014, 4, 40505; b) B. Maleki, S. Sedigh Ashrafi, J. Mex. Chem. Soc.
2014, 58, 74; c) B. Maleki, S. Hemmati, R. Tayebee, S. Salemi,
Y. Farokhzad, M. Baghayeri, F. Mohammadi Zonoz, E. Akbarzadeh,
R. Moradi, A. Entezari, M. R. Abdi, S. Sedigh Ashrafi, F. Taimazi,
M. Hashemi, Helv. Chim. Acta 2013, 96, 2147; d) B. Maleki, S. Barzegar,
Z. Sepehr, M. Kermanian, R. Tayebee, J. Iran. Chem. Soc. 2012, 9, 757;
e) B. Maleki, F. Taimazi, Org. Prep. Proced. Int. 2014, 46, 252; f)
B. Maleki, S. Sedigh Ashrafi, R. Tayebee, RSC Adv. 2014, 4, 41521; g)
B. Maleki, S. Sedigh Ashrafi, J. Mex. Chem. Soc. 2014, 58, 159; h)
H. Veisi, B. Maleki, F. Hosseini Eshbala, H. Veisi, R. Masti,
S. Sedigh Ashrafi, M. Baghayeri, RSC Adv. 2014, 4, 30683; i) B. Maleki,
S. Sedigh Ashrafi, RSC Adv. 2014, 4, 42873; j) M. Baghayeri, H. Veisi,
H. Veisi, B. Maleki, H. Karimi-Maleh, H. Beitollahi, RSC Adv. 2014, 4,
49595; k) M. Gholizadeh, M. Ebrahimpour, S. F. Hojati, B. Maleki, Arab.
J. Chem. 2014, 7, 267; l) H. Veisi, B. Maleki, M. Hamelian,
S. Sedigh Ashrafi, RSC Adv. 2015, 5, 6365.
[3] M. Behforouz, J. Haddad, W. Cai, Z. Gu, J. Org. Chem. 1998, 63, 343.
[4] A. S. Hammam, M. S. K. Youssef, M. Radwansh, M. A. Abdel-Rahman,
Bull. Korean Chem. Soc. 2004, 25, 779.
[5] M. Ough, A. Lewis, E. A. Bey, J. Gao, J. M. Ritchie, W. Bornmann,
D. A. Boothman, L. W. Oberley, J. J. Cullen, Cancer Biol. Ther. 2005,
4, 95.
[6] D. O. Moon, Y. H. Choi, N. D. Kim, Y. M. Park, G. Y. Kim, Int.
Immunopharmacol. 2007, 7, 506.
[7] V. F. De Andrade-Neto, M. O. F. Goulart, J. F. Da Silva Filho, M. J. Da Silva,
M. D. C. F. R. Pinto, A. V. Pinto, M. G. Zalis, L. H. Carvalho, A. U. Krettli,
Bioorg. Med. Chem. Lett. 2004, 14, 1145.
[8] P. S. Elisa, E. B. Ana, A. G. Ravelo, D. J. Yapu, A. G. Turba, Chem. Biodivers.
2005, 2, 264.
[9] a) A. Domling, I. Ugi, Angew. Chem. Int. Ed. Engl. 2000, 39, 3168;
b) J. Zhu, H. Bienayme (Eds), Multicomponent Reactions,
Wiley-VCH, Weinheim, 2005; c) M. S. R. Murty, M. R. Katiki,
B. Ramalingeswara Rao, K. R. Ram, Synth. Commun. 2014, 44,
1664; d) B. Kodicherla, P. C. Perumgani, M. R. Mandapati, Appl.
Organometal. Chem. 2014, 28, 756.
[18] Z. Noroozi Tisseh, S. C. Azimi, P. Mirzaei, A. Bazgir, Dyes Pigm. 2008,
79, 273.
Appl. Organometal. Chem. 2015, 29, 408–411
Copyright © 2015 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/aoc