One-step, synthesis of Hantzsch esters and polyhydroquinoline derivatives using new organocatalyst

Article abstract of DOI:10.1016/j.cclet.2009.12.011

Herein we report an efficient organocatalyst for the multicomponent Hantzsch reaction under mild condition. The product easily isolated by simple filtration and catalyst can be recovered.

Full text of DOI:10.1016/j.cclet.2009.12.011

Available online at www.sciencedirect.com
Chinese Chemical Letters 21 (2010) 563–567
www.elsevier.com/locate/cclet
One-step, synthesis of Hantzsch esters and polyhydroquinoline
derivatives using new organocatalyst
b
b
Seyed Meysam Baghbanian a, , Samad Khaksar , Seyed Mohammad Vahdat ,
*
Maryam Farhang c, Mahmood Tajbakhsh c
a Chemistry Department, Islamic Azad University, Rasht Branch, Pole-taleshan, PO Box 41325-3516, Rasht, Iran
b Chemistry Department, Islamic Azad University, Ayatollah Amoli Branch, PO Box 678, Amol, Iran
c Department of Chemistry, Mazandaran University, Babolsar 47415, Iran
Received 22 September 2009
Abstract
Herein we report an efficient organocatalyst for the multicomponent Hantzsch reaction under mild condition. The product easily
isolated by simple filtration and catalyst can be recovered.
# 2009 Seyed Meysam Baghbanian. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords: Organocatalyst; Four-component coupling reactions; Polyhydroquinoline
Organocatalysts have gained much importance in recent years due to economic and environmental
considerations [1,2]. These catalysts are generally less expensive, highly reactive, eco-friendly, easy to handle,
reduce reaction times, impart greater selectivity and can be applied in less demanding reaction conditions, such as
rigorously anhydrous or anaerobic conditions. A lot of catalysts have been designed and applied in this area.
However, the design and development of new, effective and easily accessible organic catalysts continues to be a
major challenge. In recent years, the utilization of urea/thiourea derivatives has emerged as a viable strategy in the
design of efficient organocatalysts for organic transformations [3]. Very recently, simple guanidine hydrochloride
was reported as efficient catalysts for the addition of trimethyl phosphite and trimethyl silyl cyanide to aldehydes
and imines [4]. Moreover, it has been demonstrated that guanidine hydrochloride effectively promoted direct
reductive amination and selective 1,2-reduction of a,b-unsaturated carbonyl compounds [5]. Bearing in mind the
usefulness and efficiency of organocatalysts, we decided to explore guanidine hydrochloride as a catalyst for the
synthesis of dihydropyridine and polyhydroquinoline through Hantzsch reaction. In 1882, Hantzsch reported a
cyclocondensation reaction between alkyl acetoacetate, aldehyde and ammonium acetate to obtain a heterocyclic
system of dihydropyrine (DHP), which is known as Hantzsch reaction [6]. The dihydropyrine derivatives have
attracted considerable interest in recent years due to promising activities as calcium channel blockers [7], and as
vasodilators, bronchodilators, antiatherosclerotics, antitumor, heptatoprotective, and antidiabetic agents for the
* Corresponding author.
E-mail address: m.baghbanian@iaurasht.ac.ir (S.M. Baghbanian).
1001-8417/$ – see front matter # 2009 Seyed Meysam Baghbanian. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
doi:10.1016/j.cclet.2009.12.011

564
S.M. Baghbanian et al. / Chinese Chemical Letters 21 (2010) 563–567
treatment of cardiovascular diseases including hypertension [8,9]. Moreover, 1,4-dihydropyridine exhibits several
medicinal applications which include neuroprotectant [10], platelet antiaggregatory activity [11], cerebral
antischemic activity in the treatment of Alzheimer’s disease [12], and chemosensitizer acting in tumor therapy
[13]. In addition, the dihydropyridine unit has been widely employed as a hydride source for reductive amination
[14]. Realizing the importance of dihydropyridine and polyhydroquinoline derivatives in the synthesis of various
drug sources, several new efficient methods have been developed [15–29]. Although most of these processes offer
distinct advantages, they suffer from drawbacks such as unsatisfactory yields, acidic or basic catalysts, extended
reaction times, elevated temperatures, tedious work-up, anhydrous organic solvents and the use of stoichiometric
and/or relatively expensive reagents.
1. Experimental
A mixture of Aldehyde (1 mmol), b-keto ester or 1,3-diketone (2 mmol) and NH4OAc (1 mmol) and
guanidine hydrochloride (0.10 mmol) in ethanol (1 mL) was prepared. The mixture was then stirred at room
temperature until the reaction was completed (monitored by TLC). After evaporation of the solvent, the
crude yellow product was recrystallized from ethanol to give a yellow or white solid and all the products
were known compounds and characterized by physical data (mp, IR, NMR) and comparison with authentic
samples.
2. Results and discussion
The development of efficient and versatile catalytic systems for Hantzsch reaction is an active ongoing research
area and thus, there is scope for further improvement toward milder reaction conditions, variations of substituents and
better yields. Therefore, we have utilized guanidine hydrochloride as an efficient organocatalyst for the Hantzsch
four-component one-pot synthesis in our laboratory. In an initial experiment, using traditional conditions,
benzaldehyde, ethyl acetoacetate, and ammonium acetate in a 1:2:1 ratios were stirred in ethanol. After 10 h, only
50% of product 1a was obtained after recrystallization of the crude product from ethanol. To improve the yield and
optimize the reaction conditions, the same reaction was carried out in the presence of a catalytic amount of 10 mol%
of guanidine hydrochloride under similar conditions. Surprisingly, a significant improvement was observed and the
yield of 1a was dramatically increased to 97% after stirring for only 3 h (entry 1). After this success, various a,b-
unsaturated (entry 3), heteroaromatic (entry 5) and aliphatic (entries 4 and 10) aldehydes were selected to undergo the
Hantzsch reaction in the presence of catalytic amount of guanidine hydrochloride in ethanol at room temperature
(Scheme 1). The study was extended to furnishing the products by a smooth cyclocondensation within 3 h. The yields
in general are high regardless of the structural variations in aldehyde. The results are summarized in Scheme 1
(Table 1).
After successfully synthesizing a series of Hantzsch esters in excellent yields, we turned our attention
towards the synthesis of polyhydroquinoline derivatives via unsymmetrical Hantzsch reaction under similar
conditions. We carried out the four-component coupling reaction of cyclic 1,3-diketone, aldehyde, acetoacetate
ester, and ammonium acetate in ethanol (Scheme 2). Aliphatic, aromatic, heterocyclic and conjugated aldehydes
afforded the desired products in high yields under the same reaction conditions as shown in Table 2.
It is noteworthy to mention that the structural variation of the aldehyde and substituents on the aromatic ring did not
show any obvious effect on this conversion, because the desired products were obtained in high yields in relatively
short reaction times.
Scheme 1.

S.M. Baghbanian et al. / Chinese Chemical Letters 21 (2010) 563–567
565
Table 1
Synthesis of 1,4-dihydropyridine derivatives through Hantzsch reaction using GuHCl as a catalyst.a.
Entry
1
Aldehyde
R1
Et
Yield (%)b
97
Product (Ref.)
Entry
6
Aldehydea
R1
Et
Yield (%)b
98
Product (Ref.)
1a [26,28]
1f [26]
2
3
Et
96
95
1b [28]
1c [28]
7
8
Et
Et
97
95
1g [28]
1h [28]
Me
4
Et
Et
96
98
1d [28]
1e [26]
9
Et
Et
96
97
1i [28]
1j [26]
5
10
a
Reaction condition: aldehyde (1 mmol), acetoacetate ester (2 mmol), NH4OAc (1 mmol), GuHCl (10 mol%), 3 h.
Isolated yield.
b
Scheme 2.
Table 2
Synthesis of octahydroquinoline derivatives through Hantzsch reaction using GuHCl as a catalyst.a.
Entry
1
Aldehyde
R1
Et
Yield (%)b
98
Product (Ref.)
2a [21]
2
3
Et
Et
95
90
2b [21]
2c [21]
4
5
Me
Et
90
78
2d [21]
2e [21]
6
7
Et
Et
98
88
2f [21]
2g [21]
8
9
Et
Et
90
75
2h [26]
2i [21]

566
S.M. Baghbanian et al. / Chinese Chemical Letters 21 (2010) 563–567
Table 2 (Continued )
Entry
Aldehyde
R1
Et
Yield (%)b
95
Product (Ref.)
10
2j [21]
11
Et
90
2k [21]
a
Reaction condition: aldehyde (1 mmol), acetoacetate ester (1 mmol), dimedone (1 mmol), NH4OAc (1 mmol), GuHCl (10 mol%), 3 h.
Isolated yield.
b
3. Conclusions
In summary, we have described herein an efficient methodology for Hantzsch reaction using various electronically
and structurally divergent aldehydes to give the product in good to excellent isolated yields. In contrast to the existing
methods using potentially hazardous catalysts/additives, this new method offers the following competitive advantages:
(i) avoiding the use of any base, metal or Lewis acid catalyst, (ii) short reaction time, (iii) ease of product isolation/
purification by non-aqueous work-up, (iv) high chemoselectivity, (v) no side reaction, and (vi) low costs and simplicity
in process and handling.
References
[1] For selected early examples of organocatalysis, see:
(a) G. Lelais, D.W.C. MacMillan, in: K. Mikami, M. Lautens (Eds.), Frontiers in Asymmetric Catalysis, Wiley, New York, 2007;
(b) S. Connon, J. Org. Biomol. Chem. 5 (2007) 3407;
(c) B. List, Chem. Commun. (2006) 819.
[2] For reviews focused on this topic, see:
(a) P.R. Schreiner, Chem. Soc. Rev. 32 (2003) 289;
(b) Y. Takemoto, Org. Biomol. Chem. 3 (2005) 4299;
(c) S.J. Connon, Chem. Eur. J. 12 (2006) 5418;
(d) P.I. Dalko, L. Moisan, Angew. Chem., Int. Ed. 43 (2004) 5138.
[3] (a) S. Khaksar, A. Heydari, M. Tajbakhsh, et al. Tetrahedron Lett. (2008) 49;
(b) A. Heydari, S. Khaksar, M. Tajbakhsh, Synthesis 19 (2008) 3126;
(c) S.M. Vahdat, R. Baharfar, M. Tajbakhsh, et al. Tetrahedron Lett. 49 (2008) 6501.
[4] (a) A. Heydari, A. Arefi, S. Khaksar, et al. Catal. Commun. 7 (2006) 98;
(b) A. Heydari, A. Arefi, S. Khaksar, et al. J. Mol. Catal. A: Chem. 271 (2007) 142.
[5] A. Heydari, A. Arefi, M. Esfandyari, J. Mol. Catal. A: Chem. 274 (2007) 169.
[6] A. Hantzsch, Ann. Chem. 1 (1882) 215.
[7] R. Mannhold, B. Jablonka, W. Voigdt, et al. Eur. J. Med. Chem. 27 (1992) 229.
[8] F. Bossert, H. Meyer, E. Wehinger, Angew. Chem., Int. Ed. Engl. 20 (1981) 762.
[9] H. Nakayama, Y. Kasoaka, Heterocycles 42 (1996) 901.
[10] V. Klusa, Drugs Future 20 (1995) 135.
[11] R.G. Bretzel, C.C. Bollen, E. Maeser, et al. Am. J. Kidney Dis. 21 (1993) 53.
[12] R.G. Bretzel, C.C. Bollen, E. Maeser, et al. Drugs Future 17 (1992) 465.
[13] R. Boer, V. Gekeler, Drugs Future 20 (1995) 499.
[14] T. Itoh, K. Nagata, M. Miyazaki, et al. Tetrahedron 60 (2004) 6649.
[15] S.J. Tu, J.F. Zhou, X. Deng, et al. Chin. J. Org. Chem. 21 (2001) 313.
[16] G. Sabitha, G.S.K.K. Reddy, C.S. Reddy, et al. Tetrahedron Lett. 44 (2003) 4129.
[17] S.J. Ji, Z.Q. Jiang, J. Lu, et al. Synlett (2004) 831.
[18] N. Tewari, N. Dwivedi, R.P. Tripathi, Tetrahedron Lett. 45 (2004) 9011.
[19] G.V.M. Sharma, K.L. Reddy, P.S. Lakshmi, et al. Synthesis (2006) 55.
[20] M.M. Heravi, K. Bakhtiari, N.M. Javadi, et al. J. Mol. Catal. A: Chem. 264 (2007) 50.
[21] L.M. Wang, J. Sheng, L. Zhang, et al. Tetrahedron 61 (2005) 1539.
[22] S. Ko, M.N.V. Sastry, C. Lin, et al. Tetrahedron Lett. 46 (2005) 5771.
[23] M. Maheswara, V. Siddaiah, Y.K. Rao, et al. J. Mol. Catal. A: Chem. 17 (2006) 179.
[24] R. Gupta, S. Paul, A. Loupy, Synthesis (2007) 2835.
[25] (a) S. KO, C.F. Yao, Tetrahedron Lett. 62 (2006) 7293;
(b) S.C. Reddy, M. Raghu, Chin. Chem. Lett. 19 (2008) 775.

S.M. Baghbanian et al. / Chinese Chemical Letters 21 (2010) 563–567
[26] A. Kumar, R.A. Maurya, Synlett (2008) 883.
567
[27] S. Chandrasekhar, Y.S. Rao, L. Sreelakshmi, et al. Synthesis 1737 (2008).
[28] R. Sridhar, P.T. Perumal, Tetrahedron 61 (2005) 2465.
[29] A. Debache, R. Boulcina, A. Belfaitah, et al. Synlett (2008) 509.