Facile Yb(OTf)3 promoted one-pot synthesis of polyhydroquinoline derivatives through Hantzsch reaction

Article abstract of DOI:10.1016/j.tet.2004.11.079

Yb(OTf)₃ catalyzed efficient Hantzsch reaction via four-component coupling reactions of aldehydes, dimedone, ethyl acetoacetate and ammonium acetate at ambient temperature was described as the preparation of polyhydroquinoline derivatives. The

Full text of DOI:10.1016/j.tet.2004.11.079

Tetrahedron 61 (2005) 1539–1543
Facile Yb(OTf) promoted one-pot synthesis of
3
polyhydroquinoline derivatives through Hantzsch reaction
a,*
a
Li-Min Wang, Jia Sheng, Liang Zhang, Jian-Wei Han, Zhao-Yu Fan, He Tian
a
a
a
a
b
and Chang-Tao Qian
a
Laboratory for Advanced Materials, Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Lu,
Shanghai 200237, People’s Republic of China
b
Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, People’s Republic of China
Received 2 September 2004; revised 21 November 2004; accepted 25 November 2004
Available online 16 December 2004
3
Abstract—Yb(OTf) catalyzed efficient Hantzsch reaction via four-component coupling reactions of aldehydes, dimedone, ethyl
acetoacetate and ammonium acetate at ambient temperature was described as the preparation of polyhydroquinoline derivatives. The process
presented here is operationally simple, environmentally benign and has excellent yield. Furthermore, the catalyst can be recovered
conveniently and reused efficiently.
q 2004 Elsevier Ltd. All rights reserved.
1
. Introduction
developing rare earth metal triflates especially Yb(OTf)3
and Sc(OTf) catalyzed organic synthesis. As a new type of
Lewis acid, they have been applied in a variety of
3
4-Substituted 1,4-dihydropyridines (1,4-DHPs) are
analogues of NADH coenzymes and an important class of
1
4
reactions. The most characteristic feature of these rare
earth metal triflates is that they act as water-compatible
strong Lewis acids in aqueous solvents. Only catalytic
amount of the catalysts is enough to complete reactions in
most cases. Moreover, they can be easily recovered after
reactions and reused without any loss of activity. As a part
of our program aiming at developing selective and
environmental friendly methodologies for the preparation
of fine chemicals and in continuation of our interest in
1
drugs. Current literature reveals that these compounds
possess a variety of biological activities. For example, they
can cure the disordered heart ratio as the chain-cutting agent
of factor IV channel and also have the calcium channel
2
–6
agonist–antagonist modulation activities.
the hydrogenation methods of these compounds to pyridines
Furthermore,
7
are intensively investigated. Classical method for the
synthesis of 1,4-dihydropyridines is one-pot condensation
of aldehydes with ethyl acetoacetate, and ammonia either in
1
5
lanthanide triflates catalyzed organic reactions, in this
paper, we wish to highlight our finding about the Yb(OTf)3
catalyzed four-component Hantzsch reaction using ethanol
as a solvent at ambient temperature. In this study, Yb(OTf)3
has been employed as a mild and efficient catalyst for
Hantzsch condensation.
8
acetic acid or by refluxing in alcohol. This method,
however, involves long reaction time, harsh reaction
conditions, the use of a large quantity of volatile organic
solvents and generally gives low yields. Therefore, it is
necessary to develop an efficient and versatile method for
the preparation of 1,4-DHPs and the progress in this field is
remarkable including recently the promotion of micro-
9
10
11
12,13
2. Results and discussion
wave, TMSCl, ionic liquid and polymer.
them finished the reaction at ambient temperature.
But few of
Firstly, the mixture of benzaldehyde, dimedone, ethyl
acetoacetate and ammonium acetate was chosen as the
model reaction (Scheme 1) to detect whether the use of
ytterbium triflate was efficient and investigate the optimized
conditions. The results were summarized in Table 1.
Over the past few years, much effort has gone into
3
Keywords: Yb(OTf) ; Four-component coupling reactions; Dimedone;
Polyhydroquinoline.
*
Corresponding author. Fax: C86 21 64252288/64252758;
e-mail: wanglimin@ecust.edu.cn
It was found that the conventional Lewis acids such as AlCl3
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.079

1540
L.-M. Wang et al. / Tetrahedron 61 (2005) 1539–1543
Scheme 1.
a
Table 1. The reaction of benzaldehyde, ethyl acetoacetate, dimedone and ammonium acetate: effect of catalysts
b
Entry
Catalyst
Amount
of catalyst
Time
(h)
Yield
(
mol%)
1
2
3
4
5
6
7
8
9
None
ZnCl
24
12
12
12
12
12
5
5
5
5
5
36
42
43
48
76
84
75
80
82
90
90
89
2
150
200
200
25
15
0.5
1
2
5
7.5
10
5
AlCl
FeCl
3
3
NdCl
La(OTf)
3
3
Yb(OTf)
Yb(OTf)
Yb(OTf)
Yb(OTf)
Yb(OTf)
Yb(OTf)
Yb(OTf)
3
3
3
3
3
3
3
1
1
1
1
0
1
2
3
5
5
c
90,91,90,89
a
b
c
All reactions were carried out in ethanol at room temperature.
Isolated yields.
Catalyst was reused four times.
and FeCl , as well as the condition of no catalyst showed
3
it showed almost no loss of activity after four successive
runs. The yields obtained were from 91 to 89% (with yields
of product 4a being 90, 91, 90, 89% in the first, second, third
and fourth run, respectively). In view of environmental
friendly methodologies, recovery and reuse of the catalyst is
highly preferable.
poor effect to the yield of the product, which was probably
due to their poor water tolerance. Even large amount of
catalysts was used, the results were still unsatisfactory and
many side reactions could be observed (entry 1–4). When
using the rare earth metal compounds (entry 5–6), the results
seemed to be better. While adding 0.5 mol% of Yb(OTf)3
into the system under similar reaction conditions, the speed
of reaction was obviously accelerated, but the yield was not
yet satisfactory (entry 7). Further studies showed that
increasing the amount of Yb(OTf)3 could improve the
reaction significantly. Inspired by the results, we have
changed the amount from 0.5 to 10 mol%, finding that
We then continued to optimize the model process
mentioned above by detecting the efficiency of several
classic solvents chosen as the medium for comparison
(
Table 2). In each case, the substrates were mixed together
with 5 mol% Yb(OTf)3 agitated with 3–5 ml solvent.
Obviously, the polar solvents such as ethanol and aceto-
nitrile (entry 1, 2) were much better than non-polar solvents
5
mol% of Yb(OTf) was good enough (entry 7–12). After
3
(entry 4–6). The results could be interpreted with the much
the reaction was completed, the product was filtered directly
and the catalyst can be extracted by water from the residue.
Lanthanide triflates are more soluble in water than that in
organic solvents. The catalyst could be recovered almost
quantitatively from the aqueous layer, which could be
subsequently reused several times. As indicated in Table 1,
better solubility of the catalyst and the reagents in the polar
solvents. When acetone was applied (entry 3), it was found
that the reaction proceeded quickly but the obtained yellow
solid contained many other by-products which were
probably due to the fast self-assembling of reagents or
some competitive reactions promoted by Yb(OTf)3 in
acetone.
Table 2. The reaction of benzaldehyde, ethyl acetoacetate, dimedone and
ammonium acetate: effect of solvents
a
b
Thus, we selected the optimized reaction condition to exam
the universality of this catalyst’s application. Various
aromatic, aliphatic and heterocyclic aldehydes were selected
to undergo the Hantzsch reaction in the presence of catalytic
amount of Yb(OTf)3 in ethanol at room temperature
(Scheme 2). The results of this study are summarized in
Table 3. It was indicated that both electron-rich and
electron-deficient aldehydes as well as heterocyclic
ones such as furfural, thiophene-2-carboxaldehyde and
Entry
Solvent
OH
CH CN
Acetone
Toluene
Time (h)
Yield (%)
1
2
3
4
5
6
C
2
H
5
5
5
5
24
24
24
90
83
54
26
35
17
3
2 2
CH Cl
Cyclohexane
a
All reactions were carried out using Yb(OTf)
Isolated yields.
3
at room temperature.
b

L.-M. Wang et al. / Tetrahedron 61 (2005) 1539–1543
1541
Scheme 2.
a
3
Table 3. Yb(OTf) Catalyzed Hantzsch synthesis of polyhydroquinoline derivatives
b
Entry
R
C
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
6
H
5
5
2
4
8
7
2
4
4
6
8
2
3
2
2
8
5
8
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
90
94
94
90
90
95
91
95
92
90
94
94
95
95
90
86
85
p-MeC
p-MeOC
p-HOC
p-(Me)
p-(Ph)
p-FC
p-BrC
2,4-Cl
6
H
4
6
H
4
6 4
H
2
NC
NC
6 4
H
2
6
H
4
6
H
4
6
H
4
2
C
6
H
3
10
11
12
13
14
15
16
17
C
6
H
2-furyl
5
CH]CH
3-Me-2-thienyl
5-Me-2-thienyl
2-thienyl
3-pyridyl
2 5
C H
3 7
n-C H
a
All reactions were carried out using Yb(OTf)
Isolated yields.
3
at room temperature in EtOH.
b
pyridine-3-carboxaldehyde worked well, giving high yields
of products with little difference. However, aliphatic
aldehydes afforded relevant lower yields (entry 16–17).
4.2. General experiment
To a stirred mixture of dimedone (2 mmol), ethyl aceto-
acetate (2 mmol) and Yb(OTf) (0.06 g, 5 mol%) in ethanol
3
(
(
5 mL), aldehyde (2 mmol) and ammonium acetate
2 mmol) were added at room temperature. The reaction
3
. Conclusions
mixture was stirred at room temperature for 5 h. The
resulting yellow solid was filtered and recrystallized to give
the pure product. The filtrate was concentrated diluted with
ethyl acetate, washed with water and the aqueous layer
containing the catalyst could be evaporated under reduced
pressure to give a white solid, which could be reused
without losing catalytic activity.
In conclusion, we have demonstrated that four-component
Hantzsch reaction can effectively be performed with the
promotion of Yb(OTf) , which provides a simple and
efficient method for the synthesis of polyhydroquinoline
derivatives. The present method has many obvious
advantages compared to those reported in the previous
literatures, including the avoidance of discharging harmful
organic solvents, the generality, the simplicity of the
methodology and the recycling of the catalyst.
3
1
.2.1. Compound 4a. Mp: 202–204 8C. H NMR
4
(
500 MHz, CDCl ): dZ0.94 (s, 3H), 1.08 (s, 3H), 1.19 (t,
3
JZ7.1 Hz, 3H), 2.14–2.33 (m, 4H), 2.38 (s, 3H), 4.05 (q,
JZ7.1 Hz, 2H), 5.05 (s, 1H), 5.78 (s, 1H), 7.08–7.31 (m,
K1
H). IR (KBr): 3290, 1698, 1612 cm . Anal. Calcd for
5
C H NO : C, 74.31; H, 7.42; N, 4.13. Found: C, 74.57; H,
2
1
25
3
7.51; N, 4.06.
4. Experimental
1
.2.2. Compound 4b. Mp: 260–261 8C. H NMR
4
(
4
.1. Methods and apparatus
500 MHz, CDCl ): dZ0.95 (s, 3H), 1.07 (s, 3H), 1.21 (t,
3
JZ7.1 Hz, 3H), 2.12–2.22 (m, 4H), 2.25 (s, 3H), 2.36 (s,
H), 4.03–4.09 (m, 2H), 5.01 (s, 1H), 5.73 (s, 1H), 7.00 (d,
1
Melting points were determined on a Kofler hot plate. H
NMR spectra were recorded at Bruker WP-500SY
(
3
JZ7.9 Hz, 2H), 7.18 (d, JZ7.9 Hz, 2H). IR (KBr): 3275,
K1
1702, 1647 cm . Anal. Calcd for C H NO : C, 74.76; H,
7.70; N, 3.96. Found: C, 74.92; H, 7.79; N, 3.90.
500 MHz) in CDCl3 using TMS as internal standard.
22
27
3
FT-IR spectra were obtained as KBr discs on Nicolet 5SXC
spectrometer. Mass spectra were determined on a Micro-
mass GCT spectrometer.
1
4.2.3. Compound 4c. Mp: 257–259 8C. H NMR

1542
L.-M. Wang et al. / Tetrahedron 61 (2005) 1539–1543
1
4.2.14. Compound 4n. Mp: 238–240 8C. H NMR
(
500 MHz, CDCl ): dZ0.95 (s, 3H), 1.08 (s, 3H), 1.20 (t,
3
JZ7.2 Hz, 3H), 2.16–2.26 (m, 3H), 2.33–2.38 (m, 4H), 3.74
s, 3H), 4.06 (q, JZ7.1 Hz, 2H), 5.00 (s, 1H), 5.81 (s, 1H),
(500 MHz, CDCl ): dZ1.03 (s, 3H), 1.10 (s, 3H), 1.26 (t,
JZ7.1 Hz 3H), 2.26 (t, JZ3.1 Hz, 3H), 2.34–2.38 (m, 4H),
4.10–4.14 (m, 2H), 5.42 (s, 1H), 5.89 (s, 1H), 6.82–6.84 (m,
3
(
6
.72–6.75 (m, 2H), 7.20–7.22 (m, 2H).
2
H), 7.03 (q, 1H).
1
.2.4. Compound 4d. Mp: 232–234 8C. H NMR
4
1
4.2.15. Compound 4o. Mp: 66–67 8C. H NMR (500 MHz,
(
500 MHz, CDCl ): dZ0.94 (s, 3H), 1.08 (s, 3H), 1.20 (t,
3
JZ7.2 Hz, 3H), 2.08–2.18 (m, 3H), 2.20–2.35 (m, 4H), 4.07
q, JZ7.6 Hz, 2H), 4.98 (s, 1H), 5.62 (s, 1H), 6.65 (d, JZ
CDCl ): dZ0.93 (s, 3H), 1.08 (s, 3H), 1.18 (t, JZ7.0 Hz,
3H), 2.14–2.36 (m, 4H), 2.39 (s, 1H), 4.05 (q, JZ7.0 Hz,
2H), 5.03 (s, 1H), 5.71 (s, 1H), 6.87 (t, JZ8.7 Hz, 2H),
3
(
8
.9 Hz, 2H), 7.16 (d, JZ8.4 Hz, 2H).
7
.24–7.27 (m, 2H).
1
.2.5. Compound 4e. Mp: 229–231 8C. H NMR
4
1
(
500 MHz, CDCl ): dZ0.96 (s, 3H), 1.07 (s, 3H), 1.22 (t,
3
4.2.16. Compound 4p. Mp: 145–146 8C. H NMR
500 MHz, CDCl ): dZ0.75 (t, JZ7.5 Hz, 3H), 1.10 (s,
6
JZ7.1 Hz, 3H), 2.12–2.23 (m, 3H), 2.28–2.35 (m, 4H), 2.86
s, 6H), 4.07 (q, JZ7.4 Hz, 2H), 4.95 (s,1H), 5.87 (s, 1H),
(
3
(
H), 1.29 (t, JZ7.1 Hz, 3H), 1.40–1.46 (m, 2H), 2.16 (d,
JZ7.2 Hz, 1H), 2.27 (d, JZ3.1 Hz, 2H), 2.31 (t, JZ7.5 Hz,
6
.60 (d, JZ8.4 Hz, 2H), 7.16 (d, JZ8.6 Hz, 2H).
4
1
H), 4.02 (t, JZ5.1 Hz, 1H), 4.17–4.20 (m, 2H), 5.55 (s,
H).
1
.2.6. Compound 4f. Mp: 260–262 8C. H NMR (500 MHz,
4
CDCl ): dZ0.98 (s, 3H), 1.09 (s, 3H), 1.21 (t, JZ7.1 Hz,
3
3
2
H), 2.19–2.36 (m, 4H), 2.38 (s, 3H), 4.08 (q, JZ7.1 Hz,
H), 5.00 (s, 1H), 5.66 (s, 1H), 6.89–7.21 (m, 4H).
1
.2.17. Compound 4q. Mp: 147–148 8C. H NMR
4
(500 MHz, CDCl ): dZ0.78 (t, JZ7.2 Hz, 3H), 1.08 (s,
3
6
6
H), 1.10–1.37 (m, 6H), 2.13–2.32 (m, 7H), 4.01 (t, JZ
.1 Hz, 1H), 4.10–4.23 (m, 2H), 5.59 (s, 1H).
1
.2.7. Compound 4g. Mp: 184–186 8C. H NMR
4
(
500 MHz, CDCl ): dZ0.93 (s, 3H), 1.08 (s, 3H), 1.18 (t,
3
JZ7.2 Hz, 3H), 2.19–2.37 (m, 4H), 2.39 (s, 3H), 4.05 (q,
JZ7.2 Hz, 2H), 5.03 (s, 1H), 5.67 (s, 1H), 6.88 (t, JZ
Acknowledgements
8
.8 Hz, 2H), 7.26 (t, JZ7.2 Hz, 2H).
1
.2.8. Compound 4h. Mp: 253–255 8C. H NMR
We thank the National Nature Science Foundation of China
and the Science Foundation of East China University of
Science and Technology for their financial support.
4
(
500 MHz, CDCl ): dZ0.93 (s, 3H), 1.08 (s, 3H), 1.19 (t,
3
JZ7.1 Hz, 3H), 2.19–2.25 (m, 3H), 2.33–2.40 (m, 4H), 4.05
q, JZ7.1 Hz, 2H), 5.01 (s, 1H), 5.71 (s, 1H), 7.19 (d, JZ
(
8
.2 Hz, 2H), 7.32 (d, JZ8.1 Hz, 2H).
1
.2.9. Compound 4i. Mp: 241–244 8C. H NMR (500 MHz,
4
References and notes
CDCl ): dZ0.95 (s, 3H), 1.07 (s, 3H), 1.18 (t, JZ7.0 Hz,
3
3
2
H), 2.10–2.22 (m, 4H), 2.32 (s, 3H), 4.05 (q, JZ7.0 Hz,
H), 5.34 (s, 1H), 6.04 (s, 1H), 7.09–7.34 (m, 3H).
1. Mauzeral, D.; Westheimer, F. H. J. Am. Chem. Soc. 1955, 77,
2261–2264.
2
. Kawase, M.; Shah, A.; Gaveriya, H.; Motohashi, N.;
Sakagami, H.; Varga, A.; Molnar, J. Bioorg. Med. Chem.
2002, 10, 1051–1055.
1
.2.10. Compound 4j. Mp: 204–206 8C. H NMR
4
(
500 MHz, CDCl ): dZ1.08 (s, 3H), 1.10 (s, 3H), 1.25–
3
1
4
6
.31 (m, 3H), 2.29 (t, JZ7.3 Hz, 3H), 2.33–2.38 (m, 4H),
.12–4.21 (m, 2H), 4.71 (d, JZ7.0 Hz, 1H), 5.76 (s, 1H),
.22 (d, JZ7.1 Hz, 2H), 7.22–7.30 (m, 5H).
3. Suarez, M.; Verdecia, Y.; Illescas, B.; Martinez-Alvarez, R.;
Avarez, A.; Ochoa, E.; Seoane, C.; Kayali, N.; Martin, N.
Tetrahedron 2003, 59, 9179–9186.
4
. Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.
Tetrahedron Lett. 2003, 44, 4129–4131.
1
.2.11. Compound 4k. Mp: 246–248 8C. H NMR
4
(
500 MHz, CDCl ): dZ1.02 (s, 3H), 1.11 (s, 3H), 1.26 (t,
5. Sawada, Y.; Kayakiri, H.; Abe, Y.; Mizutani, T.; Inamura, N.;
Asano, M.; Hatori, C.; Aramori, I.; Oku, T.; Tanaka, H. J. Med.
Chem. 2004, 47, 2853–2863.
3
JZ6.9 Hz, 3H), 2.20–2.26 (m, 3H), 2.35–2.37 (m, 4H),
4
6
.10–4.18 (m, 2H), 5.25 (s, 1H), 5.80 (s, 1H), 6.02 (s, 1H),
.20 (s, 1H), 7.18 (s, 1H).
6. Shan, R.; Velazquez, C.; Knaus, E. E. J. Med. Chem. 2004, 47,
2
54–261.
1
.2.12. Compound 4l. Mp: 220–222 8C. H NMR
4
7. Zhang, D.; Wu, L. Z.; Zhou, L.; Han, X.; Yang, Q. Z.; Zhang,
L. P.; Tung, C. H. J. Am. Chem. Soc. 2004, 126, 3440–3441.
8. Loev, B.; Snader, K. M. J. Org. Chem. 1965, 30, 1914–1916.
9. Tu, S.-J.; Zhou, J.-F.; Deng, X.; Cai, P.-J.; Wang, H.; Feng,
J.-C. Chin. J. Org. Chem. 2001, 21, 313–316.
(
500 MHz, CDCl ): dZ1.05 (s, 3H), 1.09 (s, 3H), 1.27 (t,
3
JZ7.2 Hz, 3H), 2.22–2.36 (m, 4H), 4.15 (q, JZ7.2 Hz, 2H),
.31 (s, 1H), 5.93 (s, 1H), 6.46 (q, JZ3.2 Hz, 1H), 6.60 (d,
JZ1.1 Hz, 1H).
5
1
0. Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S.
Tetrahedron Lett. 2003, 44, 4129–4131.
1
.2.13. Compound 4m. Mp: 226–229 8C. H NMR
4
(
500 MHz, CDCl ): dZ0.99 (s, 3H), 1.09 (d, JZ7.8 Hz,
11. Ji, S. J.; Jiang, Z. Q.; Lu, J.; Loh, T. P. Synlett 2004, 831–835.
12. Breitenbucher, J. G.; Figliozzi, G. Tetrahedron Lett. 2000, 41,
4311–4315.
3
3
H), 1.23 (t, JZ7.1 Hz, 3H), 2.21 (q, JZ7.0 Hz, 3H), 2.37
d, JZ3.0 Hz, 4H), 2.40 (s, 3H), 4.06–4.15 (m, 2H), 5.35 (d,
JZ4.1 Hz, 1H), 5.84 (s, 1H), 6.62 (q, JZ9.5 Hz, 1H), 6.90
d, JZ5.1 Hz, 1H).
(
13. Dondoni, A.; Massi, A.; Minghini, E.; Bertolasi, V.
Tetrahedron 2004, 60, 2311–2326.
(

L.-M. Wang et al. / Tetrahedron 61 (2005) 1539–1543
1543
1
1
4. (a) Kobayashi, S. Synlett 1994, 689–701. (b) Kobayashi, S.;
Sugiura, M.; Kitagawa, H.; Lam, W. W.-L. Chem. Rev. 2002,
2000, 65, 3864–3868. (b) Sun, P. P.; Qian, C.; Wang, L. M.;
Chen, R. Synth. Commun. 2002, 32, 2973–2978. (c) Wang,
L. M.; Qian, C.; Tian, H.; Ma, Y. Synth. Commun. 2003, 33,
1459–1468. (d) Wang, L. M.; Xia, J. J.; Tian, H.; Qin, F.; Qian,
C.; Sun, J. Synthesis 2003, 1241–1247. (e) Wang, L.; Liu, J.;
Tian, H.; Qian, C. Synth. Commun. 2004, 34, 1349–1358.
102, 2227–2302. (c) Kanta De, S. Tetrahedron Lett. 2004, 45,
339–2341. (d) Nakamura, I.; Kamada, M.; Yamamoto, Y.
2
Tetrahedron Lett. 2004, 45, 2903–2906.
5. (a) Ma, Y.; Qian, C.; Wang, L. M.; Yang, M. J. Org. Chem.