Choline chloride catalyzed eco-friend and effective one-pot synthesis of 9-arylacridine-1,8-dione and hexahydroquinoline via Hantzsch type reaction

Article abstract of DOI:10.3987/COM-17-13760

Choline chloride was utilized to efficiently catalyzed Hantzsch type reaction for the synthesis of 9-arylacridine-1,8-dione and hexahydroquinoline derivatives. The optimized catalytic system benefits from facile operation and separation procedures, in goo

Full text of DOI:10.3987/COM-17-13760

HETEROCYCLES, Vol. 94, No. 10, 2017, pp. -. © 2017 The Japan Institute of Heterocyclic Chemistry
Received, 3rd June, 2017, Accepted, 27th July, 2017, Published online, 9th August, 2017
DOI: 10.3987/COM-17-13760
CHOLINE CHLORIDE CATALYZED ECO-FRIEND AND EFFECTIVE
ONE-POT SYNTHESIS OF 9-ARYLACRIDINE-1,8-DIONE AND
HEXAHYDROQUINOLINE VIA HANTZSCH TYPE REACTION
Shengxue Mao, Fei Li, Yue Lv, Chengwei Lv,* and Shijun Yu*
School of Chemistry and Chemical Engineering, Liaoning Normal University,
Dalian 116029, PR China; E-mail: chengweilv@126.com; sjyu@lnnu.edu.cn
Abstract – Choline chloride was utilized to efficiently catalyzed Hantzsch type
reaction for the synthesis of 9-arylacridine-1,8-dione and hexahydroquinoline
derivatives. The optimized catalytic system benefits from facile operation and
separation procedures, in good to excellent yields, and for wide substrate
tolerance. This methodology is of interest also due to employing simple and
inexpensive choline chloride as catalyst and environmentally benign ethanol as
solvent without the use of any harmful organic solvent and toxic metal catalyst.
Nowadays, developing chemical processes using more eco-friendly acceptable catalysts, reagents,
solvents and efficient processes have appeared as subjects of innovation in green chemistry.1
Deep-eutectic solvents (DES) have drawn increasing attention in recent years due to their less toxic,
stable, biocompatible properties and been widely applied as sustainable reaction medium or catalyst in
organic synthesis.2 The formation of DESs results from strong hydrogen bond interactions between
hydrogen bond acceptors and hydrogen bond donors such as urea, carboxylic acids, or glycerol.3 Choline
chloride which is simple, non-toxic, and readily available has been utilized as a versatile hydrogen bond
acceptor.4 It is well known that environmentally-friendly ethanol was protic polar solvent5 and we
speculate that it could also play the role of hydrogen bond donor. The combination of choline chloride
and protic polar solvent would generate catalytic active species too. Expanding environmentally benign,
efficient and economical strategy that employing ethanol as solvent and choline chloride as promoter for
the synthesis of important compounds is attractive to our group.
Multi-component reaction (MCR) is a powerful and ideal bond-forming technique in organic,
combinatorial, and medicinal chemistry.6-8 This strategy has greater efficiency with respect to structural
complexity and atom economy for the synthesis of diverse chemical libraries in one-pot reactions.9,10
Development or improvement of the unknown and known MCRs for the synthesis of privileged scaffolds

has received significant attention in recent years.11-13 Hantzsch type condensation is one of the most
prominent MCRs that produces important 1,4-dihydropyridine derivatives. This class of compounds is the
key building blocks of numerous nitrogen-containing heterocyclic natural products and represents a
“drug-like” structural motif with a broad spectrum of applications in organic synthesis and medicinal
chemistry.14 In view of these useful properties, a good number of methods have been developed to
synthesize polyfunctionalized 1,4-dihydropyridine heterocycles by the one-pot multi-component strategy
of aromatic aldehyde with 1,3-dicarbonyl compounds and ammonium acetate.15 However, the catalysts
employed in most of these reactions are not always cheap, simple, and eco-friendly. Thus, the
development of more green, general, efficient, feasible, high yielding, and cost effective methods for the
synthesis of this class of compounds is highly desirable.16 As a continuation of our research devoted to
the development of green organic transformations and one-pot multi-component reactions for the
synthesis of various heterocyclic compounds,17 herein, we wish to demonstrate that the combination of
ethanol and catalytic amount of choline chloride is an effective and environmentally friendly reacted
system in the synthesis of 1,4-dihydropyridine derivatives acridine-1,8-diones and hexahydroquinolines
via Hantzsch type reaction.
Scheme 1. The approach for the preparation of acridine-1,8-diones and hexahydroquinolines
In our initial endeavours, ammonium aetate, dimedone and benzaldehyde (mole ratio 1.5:2:1) were
selected as model substrates to investigate the feasibility of this reaction system (Table 1). As we
expected, the product 4a was furnished in a satisfactory yield in protic polar solvents such as MeOH,
EtOH and i-PrOH (Table 1, Entries 1~3). But we were surprised to note that glycerol gave a poor
outcome for this reaction (Table 1, Entry 4) and reaction in water afforded xanthenedione as the main
product (Table 1, Entry 5). Therefore, EtOH was used as the most appropriate reaction medium with its
low toxicity and higher yield. Next, two comparison experiments were tested with
triethylbenzylammonium chloride (TEBAC) or tetrabutylammonium bromide (TBAB) as promoter
(Table 1, Entries 6, 7). It was found that the catalytic ability of choline chloride was superior to other
quaternary ammonium salt. To achieve the best reaction conditions, the model reaction was carried out in
different temperature, time and molar ratio of ammonium acetate. As shown in Table 1, increasing or
decreasing the molar ratio of ammonium acetate failed to improve the result (Table 1, Entries 8, 9) and

o
reaction at 120 C for 3 h could offer the target molecule with 92% yield (Entry 12). Further screening
showed that decreasing the catalyst amount to 10 mol% could lead to a slightly higher yield of 93%
(Table 1, Entry 13). However, the product yield dropped to 89% by further decreasing the catalyst to 5
mol% (Table 1, Entry 14). Thus, the reaction was optimized using cheap, safe, and environmentally
benign reaction medium and catalyst.
Table 1. Optimization of the reaction conditions for the synthesis of 4a
Entrya
1
Catalyst/mol%
choline chloride 30%
choline chloride 30%
choline chloride 30%
choline chloride 30%
choline chloride 30%
TEBAC 30%
Solvent
MeOH
i-PrOH
EtOH
glycerol
H2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
Temp./oC
120
Time/h
Yieldb/%
85
5
5
5
5
5
5
5
5
5
5
2
3
3
3
2
3
4
5
6
7
120
120
120
120
120
120
120
120
110
120
120
120
88
92
76
19
84
89
91
84
91
90
92
93
TBAB 30%
8c
9d
10
11
12
13
14
choline chloride 30%
choline chloride 30%
choline chloride 30%
choline chloride 30%
choline chloride 30%
choline chloride 10%
choline chloride 5%
120
89
a Reaction condition: 0.5 mmol benzaldehyde, 0.75 mmol ammonium acetate, and 1.0 mmol dimedone.
b Isolated yields. c 0.85 mmol ammonium acetate. d 0.5 mmol ammonium acetate.
Table 2. Scope of substrate for the synthesis of 4
Entrya
1
R
C6H5
Product
4a
Yieldb/%
93
Mp/oC
287-294 (277-27915c)
>300 (>30017d)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
isopropyl
94
92
92
93
90
87
98
93
95
96
93
97
83
96
79
86
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
>300 (303-30517d)
>300 (>299-30217d)
299-300 (278-28015c)
>300 (>30017d)
296-298 (>30015e)
296-299 (>30015e)
>300 (283-28515e)
300-303 (263-26415e)
>300 (>30017d)
>300 (294-29715e)
>300 (>30017d)
270-288 (302-30417d)
305-313 (293-29517d)
293-295 (297-29917d)
285-286 (283-28415a)
4p
4q
a Reaction condition: 0.5 mmol benzaldehyde, 0.75 mmol ammonium acetate, 1.0 mmol dimedone and
0.05 mmol choline chloride, 120 oC, 3 h. b Isolated yields.

With the optimized conditions in hand, we turned our attention to check the generality as well as the
effectiveness of our newly developed protocol. Various aromatic aldehydes having different substituent
were employed, and the reaction proceeded smoothly to give the desired products 4a-4p in good to
excellent yields (Table 2). The presence of electron donating substituent or weakly electron withdrawing
group in the ortho, meta or para positions on the ring of aromatic aldehyde seemed to have little influence
on the yield values. Unfortunately, poor yields were obtained when nitro group was present in ortho or
para positions of phenyl ring (Table 2, Entries 14, 16). However, employing 3-nitrobenzaldehyde as
substrate gave a satisfactory result (Table 2, Entry 15). This outcome showed that introducing strongly
electron-withdrawing group in ortho or para positions of phenyl ring would decrease the yield. In other
words, the electron deficient benzaldehyde which containing an overactive carbonyl group was disfavored
to the reaction.
Inspired by the catalytic potential of choline chloride, we replaced the substrate from dimedone to ethyl
acetoacetate and repeated the reaction with the same substituted aldehydes (Scheme 1). Compared with
the initial reaction utilizing dimedone, the reactions produced the corresponding hexahydroquinoline in
slightly high yields at 90 oC for 3.5 h. The nature of the aldehyde substituents also showed no significant
effect on the yields (Table 3). However, aliphatic aldehydes afforded moderate yields in this two reaction
system.
Table 3. Scope of substrate for the synthesis of product 5
Entrya
1
R
C6H5
Product
5a
Yieldb/%
96
Mp/oC
229-234 (218-22017d)
282-286 (260-26215f)
246-253 (230-23117d)
218-232 (203-20517d)
264-271 (255-25715d)
223-226 (199-20015b)
265-269 (247-24817d)
261-264 (243-24515b)
218-220 (205-20717d)
215-217 (207-21015b)
269-271 (252-25415f)
209-211 (196-19817d)
225-227 (192-19415f)
243-256 (240-24215d)
188-189 (182-18415d)
183-187 (207-20915d)
159-162 (157-15816b)
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
isopropyl
93
94
95
91
90
95
93
95
96
96
97
97
81
91
94
72
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
a Reaction condition: 0.5 mmol benzaldehyde, 0.75 mmol ammonium acetate, 0.5 mmol dimedone, 0.5
mmol ethyl acetoacetate and 0.05 mmol choline chloride, 90 oC, 3.5 h. b Isolated yields.

To expand the reaction scope, we also tried the reaction by replacing ethyl acetoacetate with
malononitrile. As some literature reported,18 the corresponding tetrahydrobenzo[b]pyrans were obtained
instead of polyhydroquinolines in anhydrous ethanol (Scheme 2). We also found that adding a little water
could improve the reaction and afford high yields.
Scheme 2. The four component approach for replacing ethyl acetoacetate with malononitrile
The plausible mechanism of this reaction was proposed in Scheme 3. Initially, the benzylidenedimedone
formed via Knoevenagel condensation of aldehyde and dimedone which were facilitated through
hydrogen bonding between choline chloride and the oxygen of carbonyl groups. Then, Michael addition
of another dimedone to benzylidenedimedone gave tetraketone. Finally, the nucleophilic attack of
nitrogen to carbon group led to the desired product with the elimination of water.
Scheme 3. The possible mechanism for the formation of acridine-1,8-dione

In summary, we have studied the catalytic ability of choline chloride as a mild, environmentally benign,
economical and efficient catalyst for the multi-component synthesis of 9-arylacridine-1,8-dione and
hexahydroquinoline derivatives with good to excellent yields in ethanol. Broad substrate scope, non-toxic
and widely available catalyst, environmentally benign solvent and easy purification are the most attractive
merits of this methodology.
EXPERIMENTAL
Commercial solvents and reagents were used directly as received materials, except for benzaldehyde,
which was used as freshly distilled sample. Melting points were measured on Beijing Tech X-5 melting
point detector and were uncorrected. FT-IR spectra were determined on a Bruker Shimadzu IR-460
spectrometer. 1H and 13C NMR spectra were recorded on a Bruker Avance 500 MHz.
General procedure for synthesis of 9-arylacridine-1,8-diones 4a-q.
o
0.05 mmol Choline chloride and 1 mL EtOH were added to a 10 mL pressure tube and stirred at 120 C
for 10 min. Then aldehyde (0.5 mmol), dimedone (1 mmol), and ammonium acetate (0.75 mmol) were
added. This mixture was heated at 120 oC for 3 h. After completion of the reaction, 1 mL water was added
o
and continuously stirred for a moment at 120 C. Finally, the mixture was left to cool in ice bath and
filtered to afford the desired 9-arylacridine-1,8-dione without further purification.
General procedure for the synthesis of hexahydroquinolines 5a-q.
0.05 mmol Choline chloride and 1 mL EtOH were added to a 10 mL pressure tube and stirred at 90 oC for
10 min. Then the corresponding aldehyde (0.5 mmol), dimedone (0.5 mmol), ethyl acetoacetate (0.5
mmol), and ammonium acetate (0.75 mmol) were added. This mixture was heated at 90 oC for 3.5 h and 1
mL water was added upon completion of the reaction. Finally, the mixture was left to cool in ice bath and
was filtered to afford the desired hexahydroquinoline without further purification.
ACKNOWLEDGEMENTS
We are grateful for financial support from the National Natural Science Foundation of China (21403100)
and Liaoning Province, the Doctoral Scientific Research Foundation (20141100).
REFERENCES AND NOTES
1. (a) A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725; (b) A. Kumar, M. S. Rao, and V. K.
Rao, Aust. J. Chem., 2010, 63, 1538; (c) R. A. Sheldon, Chem. Soc. Rev., 2012, 41, 1437; (d) S. K.
Kundu, J. Mondal, and A. Bhaumik, Dalton Trans., 2013, 42, 10515; (e) P. Gupta and S. Paul, Catal.
Today, 2014, 236, 153; (f) M. A. Bodaghifard, M. Solimannejad, S. Asadbegi, and S.
Dolatabadifarahani, Res. Chem. Intermed., 2016, 42, 1165.

2. (a) A. P. Abbott, D. Boothby, G. Capper, D. L. Davies, and R. K. Rasheed, J. Am. Chem. Soc., 2004,
126, 9142; (b) X. Lian, S. Guo, G. Wang, L. Lin, X. Liu, and X. Feng, J. Org. Chem., 2014, 16,
7703; (c) P. Liu, J. W. Hao, L. P. Mo, and Z. H. Zhang, RSC Adv., 2015, 5, 48675; (d) X. Xiong, Q.
Han, L. Shi, S. Xiao, and C. Bi, Chin. J. Org. Chem., 2016, 36, 480.
3. (a) J. M. Pérez and D. J. Ramón, ACS Sustainable Chem. Eng., 2015, 3, 2343; (b) N. Azizi and M.
Edrisi, Res. Chem. Intermed., 2017, 43, 379.
4. (a) Q. Zhang, K. D. O. Vigier, S. Royer, and F. Jerome, Chem. Soc. Rev., 2012, 41, 7108; (b) C. Ruß
and B. König, Green Chem., 2012, 14, 2969; (c) D. A. Alonso, A. Baeza, R. Chinchilla, G. Guillena,
I. M. Pastor, and D. J. Ramón, Eur. J. Org. Chem., 2016, 4, 612.
5. (a) F. Huang, H. Wu, J. Peng, W. Yang, and Y. Cao, Curr. Org. Chem., 2007, 11, 1207; (b) F. Tache,
S. Udrescu, F. Albu, F. Mičale, and A. Medvedovici, J. Pharm. Biomed. Anal., 2013, 75, 230; (c) S.
S. Sajadikhah, M. T. Maghsoodlou, N. Hazeri, M. Norouzi, and M. Moein, Res. Chem. Intermed.,
2015, 41, 8665; (d) C. F. Zhou, J. J. Li, and W. K. Su, Chin. Chem. Lett., 2016, 27, 1686.
6. S. Anvar, I. Mohammadpoor-Baltork, S. Tangestaninejad, M. Moghadam, V. Mirkhani, A. R.
Khosropour, A. L. Isfahani, and R. Kia, ACS Comb. Sci., 2014, 16, 93.
7. K. Aswin, S. S. Mansoor, K. Logaiya, S. P. N. Sudhan, V. S. Malik, and H. Ramadoss, Res. Chem.
Intermed., 2014, 40, 2583.
8. S. Zheng, S. Zhong, Z. Chen, W. Chen, and Q. Zhu, ACS Comb. Sci., 2016, 18, 475.
9. X. Feng, J. J. Wang, J. J. Zhang, C. P. Cao, Z. B. Huang, and D. Q. Shi, Green Chem., 2015, 17,
973.
10. L. Aguirre-Diaz, F. Gandara, M. Iglesias, N. Snejko, E. Gutierrez-Puebla, and M. Monge, J. Am.
Chem. Soc., 2015, 137, 6132.
11. Y. Gu, Green Chem., 2012, 14, 2091.
12. G. Brahmachari and B. Banerjee, ACS Sustainable Chem. Eng., 2014, 2, 411.
13. M. V. Reddy, G. C. S. Reddy, and Y. T. Jeong, Tetrahedron Lett., 2016, 57, 1289.
14. (a) L. Nagarapu, M. D. Kumari, N. V. Kumari, and S. Kantevari, Catal. Commun., 2007, 8, 1871; (b)
R. A. Mekheimer, A. A. Hameed, and K. U. Sadek, Green Chem., 2008, 10, 592; (c) P. Mahajabeen
and A. Chadha, RSC Adv., 2013, 3, 21972; (d) D. Patil, D. Chandam, A. Mulik, P. Patil, S. Jagadale,
R. Kant, V. Gupta, and M. Deshmukh, Catal. Lett., 2014, 144, 949; (e) A. V. Borhade, B. K. Uphade,
and A. G. Gadhave, Res. Chem. Intermed., 2015, 41, 1447; (f) A. Amoozadeh, S. Rahmani, M.
Bitaraf, F. B. Abadi, and E. Tabrizian, New J. Chem., 2016, 40, 770.
15. (a) D. Q. Shi, S. N. Ni, F. Yang, J. W. Shi, G. L. Dou, X. Y. Li, and X. S. Wang, J. Heterocycl.
Chem., 2008, 45, 653; (b) B. Maleki, R. Tayebee, M. Kermanian, and S. S. Ashrafi, J. Mex. Chem.
Soc., 2013, 57, 290; (c) G. M. Ziarani, A. Badiei, M. Hassanzadeh, and S. Mousavi, Arab. J. Chem.,

2014, 7, 335; (d) N. G. Khaligh, Chin. J. Catal., 2014, 35, 1497; (e) D. Patil, D. Chandam, A. Mulik,
P. Patil, S. Jagadale, R. Kant, V. Gupta, and M. Deshmukh, Catal. Lett., 2014, 144, 949; (f) S. Igder,
A. R. Kiasat, and M. R. Shushizadeh, Res. Chem. Intermed., 2015, 41, 7227; (g) M. Ghorbani, S.
Noura, M. Oftadeh, M. Narimani, and K. Behbodi, J. Mol. Liq., 2015, 209, 224; (h) M.
Nasr-Esfahani, D. Elhamifar, T. Amadeh, and B. Karimi, RSC Adv., 2015, 5, 13087; (i) Z. Zarnegar,
J. Safari, and Z. M. Kafroudi, New J. Chem., 2015, 39, 1445.
16. (a) R. H. Nia, M. Mamaghani, F. Shirini, K. Tabatabaeian, and M. Heidary, Org. Prep. Proced. Int.,
2014, 46, 152; (b) B. L. Li, A. G. Zhong, and A. G. Ying, J. Heterocycl. Chem., 2015, 52, 445; (c) A.
Ghorbani-Choghamarani and G. Azadi, RSC Adv., 2015, 5, 9752; (d) H. R. Safaei, M. Safaei, and M.
Shekouhy, RSC Adv., 2015, 5, 6797; (e) Z. Nasresfahani and M. Z. Kassaee, Catal. Commun., 2015,
60, 100; (f) A. Ghorbani-Choghamarani and B. Tahmasbi, New J. Chem., 2016, 40, 1205; (g) S. D.
Guggilapu, S. K. Prajapti, A. Nagarsenkar, G. Lalita, G. M. N. Vegi, and B. N. Babu, New J. Chem.,
2016, 40, 838.
17. (a) C. Lyu, Y. Liu, J. Wang, and X. Zhou, Chin. J. Appl. Chem., 2015, 32, 1371; (b) S. Gao, D. Xiao,
Y. Yang, X. Wei, S. Sun, J. Lang, and C. Lv, Heterocycles, 2016, 92, 1698; (c) W. Y. Pan, Y. M.
Xiao, H. Q. Xiong, and C. W. Lü, Res. Chem. Intermed., 2016, 42, 7057; (d) S. J. Yü, S. Wu, X. M.
Zhao, and C. W. Lü, Res. Chem. Intermed., 2017, 43, 3121.
18. (a) K. A. Undale, Y. Park, K. Park, D. H. Dagade, and D. M. Pore, Synlett, 2011, 791; (b) A. M.
Zonouz, S. Okhravi, and D. Moghani, Monatsh. Chem., 2016, 147, 1819.