Catalytic synthesis of 1,4-dihydropyridine derivatives using scandium(III) triflate

Article abstract of DOI:10.1016/j.tetlet.2007.11.003

Scandium(III) triflate smoothly catalyzed the reaction of imines with ethyl propiolate (2.5 equiv) to produce the corresponding N-substituted 1,4-dihydropyridines in good yields in toluene or BTF under reflux conditions. It also catalyzed the reaction of

Full text of DOI:10.1016/j.tetlet.2007.11.003

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Tetrahedron Letters 49 (2008) 114–116
Catalytic synthesis of 1,4-dihydropyridine derivatives
using scandium(III) triflate
Satoshi Kikuchi, Masahiro Iwai, Hiroyuki Murayama and Shin-ichi Fukuzawa*
Department of Applied Chemistry, Institute of Science and Engineering, Chuo University, 1-13-27 Kasuga, Bunkyo-ku, Tokyo, Japan
Received 6 September 2007; revised 29 October 2007; accepted 1 November 2007
Available online 4 November 2007
Abstract—Scandium(III) triflate smoothly catalyzed the reaction of imines with ethyl propiolate (2.5 equiv) to produce the corre-
sponding N-substituted 1,4-dihydropyridines in good yields in toluene or BTF under reflux conditions. It also catalyzed the reaction
of aniline and ethyl propiolate (3.2 equiv) to give another 1,4-dihydropyridine bearing three ester groups in moderate yield under the
same conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
1
Recently, we reported that RE(OTf)3 catalyzed the
reaction of aromatic amines, aldehydes, and ethyl propio-
late in EtOH under reflux conditions to give the several
substituted quinolines.2 When we have optimized the
reaction conditions, we found that, when we used imines
as substrates and toluene as a solvent instead of EtOH,
N-substituted 1,4-dihydropyridine was obtained
predominantly.3
We herein report an expeditious and useful method for
the synthesis of N-substituted 1,4-dihydropyridines in
the presence of a catalytic amount of Sc(OTf)3.
We examined the effect of the RE triflates (RE = Sc, Y,
La, Ce, Pr, Nd, Sm, Yb) and other Lewis acids on the
yield of product in the reaction of imine 1a with ethyl
propiolate 2 in toluene (Table 1). Table 1 shows that
Sc(OTf)3 is the most appropriate Lewis acid for this
reaction (entry 1).8 When we used the trifluoromethane-
sulfonic acid as a typical Brønsted acid, the reaction
hardly proceeded (entry 12).
1,4-Dihydropyridines are versatile compounds because
their derivatives play important roles in medicinal chem-
istry; for example, nifedipine, amlodipine and other
antihypertensive agents.4 Among the numerous methods
developed for the synthesis of 1,4-dihydropyridines,
Hantzsch reaction is one of the most well-accepted
methods and much effort has been made to modify this
reaction.5 However, these classical methods were not
enough to make pyridine libraries.
We next investigated solvents in the reaction using
Sc(OTf)3 (10 mol %) and the results are summarized in
Table 2. Product 3a was hardly obtained in benzene and
THF (entries 1 and 5). When EtOH and 1, 2-dicholoro-
ethane were used as solvents, the reaction could pro-
ceed but the yields of 3a were lower than that in
toluene (entries 4 and 6). The best results were obtained
in toluene and benzotrifluoride (BTF) (entries 1 and 3).
In 2001, Balalaie and Kowsari reported that microwave
irradiation promoted the three-component reaction of
an aromatic amine, an aromatic aldehyde, and ethyl
propiolate to give N-substituted 1,4-dihydropyridine in
a high yield.6 This method may be useful for easily pre-
paring 1,4-dihydropyridine but required expensive
microwave apparatus and severe reaction conditions.7
We usually carried out the reaction of imines 1a–m with
2 in toluene at reflux and the results are shown in Table
3.9 We performed the reaction of the imines, which were
prepared from benzaldehyde and aliphatic amines or
substituted anilines (entries 1–8). When we used imines
1a–d with N-alkyl groups, the yields of the 1,4-dihydro-
pyridines 3a–d were low (entries 1–4). The reaction of
imine 1e gave 1,4-dihydropyridine 3e in moderate yield
(45% yield). In the reaction of imines 1f and 1g, the reac-
tion smoothly proceeded to give 1,4-dihydropyridines 3f
*
Corresponding author. Tel.: +81 338171916; fax: +81 338171985;
e-mail: fukuzawa@chem.chuo-u.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.003

S. Kikuchi et al. / Tetrahedron Letters 49 (2008) 114–116
Table 3. The reaction of imines 1a–m with 2a
115
Table 1. Lewis acids catalyzed reaction of imine 1a with ethyl
propiolate 2a
R1
N
R1
Sc(OTf)3 (10 mol%)
toluene, reflux, 24 h
c-hex
N
R2
N
CO2Et
CO2Et
EtO2C
CO2Et
Ph
R2
1a
2
1a-m
2
3a-m
Entry Imine R1
R2
Product 3 Yieldb
c-hex
N
Acid (10 mol%)
(%)
22c
18
28
35
45c
75c
62c
77
78
54
47
34
0
EtO2C
CO2Et
toluene, reflux, 24 h
1
2
3d
4
5
6
7d
8d
9
1a
1b
1c
1d
1e
1f
c-Hex
t-Bu
Bn
CHPh2
Ph
p-MeOC6H4 Ph
p-MeC6H4 Ph
2,6-MeC6H4 Ph
p-MeOC6H4 p-MeC6H4
p-MeOC6H4 p-ClC6H4
p-MeOC6H4 p-FC6H4
p-MeOC6H4 p-NO2C6H4 3l
p-MeOC6H4 PhCH2CH2 3m
Ph
Ph
Ph
Ph
Ph
3a
3b
3c
3d
3e
3f
Ph
3a
c-hex=cyclohexyl
Yieldb (%)
Entry
Acid
1g
1h
1i
3g
3h
3i
1
2
3
4
5
6
7
8
9
Sc(OTf)3
Y(OTf)3
La(OTf)3
Ce(OTf)3
Pr(OTf)3
Nd(OTf)3
Sm(OTf)3
Yb(OTf)3
InCl3
22
9
Trace
2
4
3
10
1j
3j
3k
11
12
13
1k
1l
1m
Trace
a 1 (0.5 mmol), 2 (1.25 mmol), Sc(OTf)3 (0.05 mmol) in toluene (5 mL)
5
12
6
2
7
at reflux for 24 h.
b Isolated yield.
10
11
12
AlCl3
c GC yield.
TiCl2(OiPr)2
TfOH
d BTF was used as a solvent instead of toluene.
a 1a (0.5 mmol), 2 (1.2 mmol), acid (0.05 mmol) under toluene (5 mL)
reflux conditions for 24 h.
b GC yield.
para-substituted benzaldehyde and p-anisidine to inves-
tigate the substituent effect of the 4-position of R2 on
the reaction (entries 9–12). These reactions smoothly
proceeded to give the corresponding 3 in good and mod-
erate yields. In the case of the methyl group (electron-
donating group), the yield of 3 become high (78%),
and when the imine had an electron-withdrawing group
(Cl, F, NO2), the yields were moderate (34–54%). The
reaction with 1c, 1g, and 1h yielded 3c, 3g, and 3h in
higher yields in BTF than those in toluene (entries 3, 7
and 8).10 The reaction of imine 1m derived from 3-phen-
ylpropanal was performed in the same conditions, how-
ever, the corresponding pyridine was not obtained (entry
13).
Table 2. Sc(OTf)3 catalyzed reaction of imine 1a with ethyl propiolate
2a
c-hex
N
CO2Et
Ph
1a
2
c-hex
N
Sc(OTf)3 (10 mol%)
Solvent, reflux, 24 h
EtO2C
CO2Et
Ph
During our study, we also found that the 1,4-dihydro-
pyridine bearing a carboethoxy methyl group at the 4-
position 511 was obtained in 42% GC yield from the
reaction of aniline 4 with ethyl propiolate 2 in toluene
under reflux conditions (Scheme 1).
3a
c-hex=cyclohexyl
Yieldb (%)
Entry
Solvent
1
2
3
4
5
6
Toluene
Benzene
BTF
EtOH
THF
22
5
29
14
Trace
16
PhNH2
CO2Et
ClCH2CH2Cl
a 1a (0.5 mmol), 2 (1.2 mmol), Sc(OTf)3 (0.05 mmol) under solvent
(5 mL) reflux conditions for 24 h.
b GC yield.
2
4
Ph
N
Sc(OTf)3 (10 mol%)
toluene, reflux, 24 h
EtO2C
CO2Et
CO2Et
and 3g in good yields (75% and 62%, respectively)
(entries 6 and 7). When imine 1h was used, the corres-
ponding 3h was obtained in 77% yield (entry 8). We next
carried out the reaction of the imines derived from the
5; 42%
Scheme 1.

116
S. Kikuchi et al. / Tetrahedron Letters 49 (2008) 114–116
7. A kitchen microwave, which is typically used as the
microwave, is dangerous for the organic syntheses due to
the difficulty in controlling the reaction temperature.
8. When the three-component coupling reaction of cyclo-
hexylamine, benzaldehyde and ethylpropiolate was carried
out in the same conditions, pyridine 3a was obtained in
14% yield.
In conclusion, we developed a useful method for the
synthesis of 1,4-dihydropyridine derivatives from imines
using catalytic amount of scandium(III) triflate. We
could apply this method to the reaction of aniline 4 with
ethyl propiolate 2 and found that the novel 1,4-dihydro-
pyridine was obtained in good yield. Further examina-
tion for the reaction mechanism is in progress.
9. Typical procedures: To a toluene or BTF solution (5 mL)
of Sc(OTf)3 (24.6 mg, 0.05 mmol) and imine (0.5 mmol) in
a round-bottom flask containing a stirring bar was added
the ethyl propiolate (130 lL, 1.28 mmol) using a micro-
syringe. This mixture was heated at reflux for 24 h. After
cooling to rt, the reaction was quenched with brine and
extracted three times with ethyl acetate. This combined
organic layer was dried over Na2SO4. This organic layer
was filtered and evaporated under reduced pressure. The
residue was purified by preparative TLC (SiO2, hexane/
ethyl acetate = 4/1) and/or preparative HPLC (GPC
column, CHCl3 as eluent) to give the desired products.12
10. When we used toluene as a solvent, the yields of 3c, 3g,
and 3h were 19%, 35%, and 27%, respectively.
Acknowledgment
This work was financially supported by Chuo University
Joint Research Grant.
References and notes
1. Reviews, see: (a) Kobayashi, S. Synlett 1994, 689; (b)
Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L.
Chem. Rev. 2002, 102, 2227.
2. Kikuchi, S.; Iwai, M.; Fukuzawa, S. Synlett 2007, 2639.
3. The reviewer comments that our work is an extension of
our previous quinoline synthesis. However, we think that
this is the point of interest of the present work. We could
synthesize quinolines or dihydropyridines preferentially
from the same starting materials by just changing a
solvent.
11. CCDC 655306 contains the supplementary crystallo-
graphic data for compound 5. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif,
or by emailing data_request@ccdc.cam.ac.uk, or by con-
tacting The Cambridge Crystallographic Data Centre, 12,
Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223
336033.
4. (a) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem.,
Int. Ed. Engl. 1981, 20, 762; (b) Goldmann, S.; Stoltefuss,
J. Angew. Chem., Int. Ed. Engl. 1991, 30, 1559; (c)
Nakayama, H.; Kasoaka, Y. Heterocycles 1996, 42, 901.
5. Recent examples, see: (a) Chari, M. A.; Syamasundar, K.
Catal. Commun. 2005, 6, 624; (b) Wang, L.-M.; Sheng, J.;
Zhang, L.; Han, J.-W.; Fan, Z.-Y.; Tian, H.; Qian, C.-T.
Tetrahedron 2005, 61, 1539; (c) Lee, J. H. Tetrahedron
Lett. 2005, 46, 7329; (d) Ko, S.; Sastry, M. N. V.; Lin, C.;
Yao, C.-F. Tetrahedron Lett. 2005, 46, 5771; (e) Vohra, R.
K.; Bruneau, C.; Renaud, J.-L. Adv. Synth. Catal. 2006,
384, 2571; (f) Wang, G.-W.; Xia, J.-J.; Miao, C.-B.; Wu,
X.-L. Bull. Chem. Soc. Jpn. 2006, 79, 454.
12. Data for selected compounds:
1
Compound 3b: H NMR (300 MHz, CDCl3): d = 1.19 (t,
J = 4.2 Hz, 3H), 3.84 (s, 3H), 4.09 (m, 4H), 4.95 (s, 1H),
6.95 (d, J = 12.3 Hz, 2H), 7.19 (m, 5H), 7.37 (d, J =
8.8 Hz, 2H), 7.55 (s, 2H). 13C NMR (CDCl3): d = 14.2,
37.5, 55.6, 60.2, 110.2, 114.9, 122.8, 126.5, 128.0, 128.3,
136.3, 146.3, 158.2, 166.9.
1
Compound 5: H NMR (300 MHz, CDCl3): d = 1.18 (t,
J = 4.2 Hz, 3H), 1.31 (t, J = 4.2 Hz, 6H), 2.60 (d,
J = 2.7 Hz, 2H), 4.03 (q, J = 4.2 Hz, 2H), 4.25 (m, 5H),
7.23 (d, J = 4.2 Hz, 2H), 7.27 (t, J = 4.5 Hz, 1H), 7.42 (t,
J = 4.5 Hz, 2H), 7.58 (s, 2H). 13C NMR (CDCl3):
d = 14.1, 14.3, 29.5, 40.4, 59.9, 60.2, 108.1, 120.7, 126.2,
129.7, 137.5, 142.9, 166.6, 171.3.
6. Balalaie, S.; Kowsari, E. Monatsh. Chem. 2001, 132, 1551.