Lewis acid-catalyzed sequential transformations: Straightforward preparation of functional dihydropyridines

Article abstract of DOI:10.1002/adsc.200600343

Lewis acids catalyze the addition of β-enaminoacrylates or β-enaminones to α,β-unsaturated aldehydes leading to substituted dihydropyridines in high yields under mild reaction conditions.

Full text of DOI:10.1002/adsc.200600343

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DOI: 10.1002/adsc.200600343
Lewis Acid-Catalyzed Sequential Transformations: Straightfor-
ward Preparation of Functional Dihydropyridines
Ramandeep Kaur Vohra,a Christian Bruneau,a and Jean-Luc Renauda,*
a
Sciences Chimiques de Rennes, Catalyse et OrganomØtalliques, UMR 6226, CNRS, UniversitØ de Rennes 1, Campus de
Beaulieu, 35042 Rennes Cedex, France
Fax : (+33)-2–2323–6939; e-mail: jean-luc.renaud@univ-rennes1.fr
Received: July 11, 2006; Accepted: October 18, 2006
Abstract: Lewis acids catalyze the addition of b-en-
aminoacrylates or b-enaminones to a,b-unsaturated
aldehydes leading to substituted dihydropyridines
in high yields under mild reaction conditions.
intermediates in a domino-cascade 1,4-Michael addi-
tion/enamine formation to lead to substituted and
non-symmetrical 1,4-dihydropyridines (Scheme 1).[21]
Keywords: domino reactions; homogeneous cataly-
sis; iron; Lewis acids; nitrogen heterocycles; scandi-
um
Scheme 1.
4-Substituted Hantzsch-type 1,4-dihydropyridines are
analogues of NADH coenzymes and represent an im-
portant class of drugs.[1] Current literature reveals that
We report here our preliminary results on the prep-
1,4-dihydropyridines exhibit neuroprotectant and pla- aration of this type of compound by a cascade reac-
telet anti-aggregratory activity, and show efficient bio- tion involving b-enaminocarbonyl derivatives and
logical properties as cerebral anti-ischemic agents in conjugated enals in the presence of a catalytic
the treatment of Alzheimerꢀs disease and as chemo- amount of a Lewis acid under mild conditions.
sensitizers in tumour therapy.[2–5] Dihydropyridines
In our continuing work on Lewis acid-catalyzed
are usually subsequently oxidized to pyridines.[6] synthesis of functionalized b-enamino esters and b-en-
Many classical methods for the synthesis of symmetri- aminones,[22] we anticipated that a Lewis acid could
cal 1,4-dihydropyridines have been reported[7–11] based activate the unsaturated aldehyde, then favour the
on conventional heating of a b-keto ester, an ammoni- conjugated addition and the final amine condensa-
um salt and an aldehyde in organic solvents, but most tion/isomerization (Scheme 1).
of these methods involve long reaction times, harsh
A blank reaction carried out at room temperature
reaction conditions and generally lead to low yields. in dichloromethane overnight from ethyl N-benzyl-
Therefore, it is necessary to develop more efficient aminobut-2-enoate (2a) and 3-methylbut-2-enal (3a),
and versatile methods for the preparation of 1,4-dihy- without any Lewis acid, did not lead to the desired di-
dropyridines and the progress in this field has been hydropyridine and only the starting substrates were
recently achieved by the use of promoters such as mi- isolated. Zinc(II) acetate, which was shown to be
crowaves,[6b,12] TMSCl,[5] ionic liquids,[13,14] poly- active in the synthesis of compound 2a from ethyl 3-
mers[15,16] and Yb(OTf)3.[17] A synthesis of N-benzyl- oxobutanoate and benzylamine,[22] was first tested as
G
1,4-dihydropyridines was also disclosed from 1-aza- Lewis acid but no catalytic activity was found. By
1,3-butadiene via a Diels–Alder reaction.[18] However, contrast, cerium
AHCTREUNG
to the best of our knowledge, few reports have been of 1a at room temperature in a moderate 15% yield.
made so far about an efficient, versatile and mild pro- The structure of 1a was assigned on the basis of
cedure for the synthesis of unsymmetrical 1,4-dihy- 1H NMR, 13C NMR, and mass spectra. NMR analysis
dropyridines. b-Enamino ketones and esters are (1H, 13C, HMBC and HMQC) revealed that the prod-
useful precursors in synthesis as they combine nucleo- uct formed during this catalysis is the 4,4-dimethyldi-
philicity of the enamine[19,20] and electrophilicity[20] of hydropyridine. By comparison with the thermal reac-
the enone moieties. They are subsequently potential tion involving a cyclic enamino ester and an a,b-unsa-
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Ramandeep Kaur Vohra et al.
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turated aldehyde, it is worthy of note that this reac- triflate as catalyst, the dihydropyridine was isolated in
tion leads to the other regioisomer and thus comple- a satisfying yield (54%, Table 1). It is worthy of note
ments the former process.[23] Encouraged by this ini- that sodium sulfate was used to ensure an efficient
tial result, we investigated the activity of other Lewis elimination of water. Molecular sieves were also used
acids. Iron
A
ACHTREUNG
peared to be good candidates to promote the forma-
tion of the dihydropyridine 1a (Table 1). The reaction lytic reaction, we extended it to various b-enamino
esters and b-enaminones with a,b-unsaturated carbon-
Table 1. Lewis acid-catalyzed cascade cyclization.[a]
yl compounds (Table 2). Thus N-benzyl- (2a) and N-
phenyl-b-aminoacrylates (2b) reacted with cinnamal-
dehyde for 16 h to give the dihydropyridines 1b and
1c in high yields (entries 1–4, Table 2) at room tem-
perature in the presence of 5 mol% of Lewis acid.
The 1,4-dihydropyridines 1b–d were obtained in very
high yields from cinnamaldehyde and b-enamino
esters (75–93%) and b-enaminones (90–99%)
(Table 2). More substituted enals, such as citral and
2,3-dimethylbut-2-enal, were also reactive and the
corresponding dihydropyridines (1e, f) were isolated
in 40% and 87% yield, respectively (entries 7 and 8,
Lewis Acid
Zn(OAc)2·6H2O
CeCl3·7H2O
FeCl3·6H2O
Temperature
Yield [%]
A
reflux
r.t.
reflux
r.t.
N.R.
15
53
Table 2). Both iron
N
N
Sc
A
54
triflate reacted smoothly and revealed good efficien-
cies.
After demonstrating that Lewis acids are effective
catalysts for this ring formation reaction and, because
we had previously described that such Lewis acids
could also promote the synthesis of b-enamino esters
[a]
Reaction conditions: 0.75 mmol of aldehyde, 0.5 mmol of
b-enamino ester 1, 0.025 mmol of Lewis acid (5 mol%)
in 5 mL of CH2Cl2, 150 mg of Na2SO4 (1.5 mmol).
of 0.5 mmol of ethyl 3-N-benzylaminobut-2-enoate and b-enamino ketones from the corresponding dicar-
(2a) with 0.75 mmol of 3-methylbut-2-enal (3a) in the bonyl compounds,[22] we envisioned to develop a one-
presence of 0.025 mmol (5 mol%) of Lewis acid and pot process. Then, via a sequential reaction,[24] we
1.5 mmol of sodium sulfate in dichloromethane led to could directly provide a one-pot access to the substi-
the desired dihydropyridine in good yields under mild tuted dihydropyridines from b-keto esters or b-dike-
conditions. Even at room temperature, with scandium tones, an amine and a conjugated aldehyde.
Table 2. Lewis acid-catalyzed synthesis of substituted dihydropyridines.[a]
Entry
R1
R2
R3
R4
R5
Lewis Acid
FeCl3·6H2O
Compound
Yield [%]
1
2
3
4
PhCH2
PhCH2
Ph
OEt
OEt
OEt
OEt
CH3
CH3
OEt
OEt
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
H
CH3
1b
1b
1c
1c
1d
1d
1e
1f
90
75
93
80
99
90
40
87
Sc
FeCl3·6H2O
Sc(OTf)3
FeCl3·6H2O
Sc(OTf)3
FeCl3·6H2O
Sc(OTf)3
A
Ph
ACHTREUNG
5[b]
6[b]
7
PhCH2
PhCH2
PhCH2
PhCH2
ACHTREUNG
A
(CH2)2
8
ACHTREUNG
[a]
Reaction conditions: 0.75 mmol of aldehyde, 0.5 mmol of b-enamino esters 2a, b, 0.025 mmol of Lewis acid (5 mol%) in
5 mL of CH2Cl2, 150 mg (1.5 mmol) of Na2SO4, 16 h.
0.5 mmol of b-enamino ketone 2c was used.
[b]
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Straightforward Preparation of Functional Dihydropyridines
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equivs.). The solution was stirred at room temperature until
completion by TLC analysis. The solution was then filtered
through Celite, and concentrated under vacuum. The crude
oily mixture was purified on silica gel by flash chromatogra-
phy (eluent: heptane/ethyl ether, 9/1).
The b-keto esters or b-diketones (1 equiv.) were
first treated with the amine (1.1 equivs.) in the pres-
ence of a catalytic amount of a Lewis acid (5 mol%)
in dichloromethane. This first step was followed by
TLC analysis and after completion, the a,b-unsaturat-
ed aldehyde (1.5 equivs.) was added. After 16 h, the
reaction was quenched by filtration over Celite. The
dihydropyridines 1b, g–l were isolated after purifica-
tion on silica gel in high yields, comparable to those
obtained starting directly from isolated b-enamino
esters. Whatever the substituent on the ester or the
nature of the Lewis acid (iron or scandium), the reac-
tion proceeded with very good efficiency (Table 3).
In conclusion, we have demonstrated that iron and
scandium salts are efficient catalysts for the transfor-
mation of enamino esters and enaminones with conju-
gated enals to give functional dihydropyridine deriva-
tives via a formal Michael addition/enamine forma-
tion cascade reaction. A tremendous advantage of
these salts lies in the fact that they also catalyze the
enamine formation from b-diketo compounds and pri-
mary amines, and thus make possible the sequential
Lewis acid-catalyzed enamino derivatives/1,4-dihydro-
pyridines synthesis. Further efforts will be devoted to
the development of an asymmetric version for this
cascade transformation.
General Procedure for the One-Pot Sequential
Transformation
To previously dried sodium sulfate (300 mg) were succes-
sively added under argon, ferric chloride or scandium tri-
flate (5 mol%), dichloromethane (10 mLmmolÀ1), the dicar-
bonyl derivative (1 equiv.), and finally a primary amine (1.1
equivs.). The reaction mixture was stirred at room tempera-
ture until completion as detected by TLC analysis. Then, the
unsaturated aldehyde (1 equiv.) was added and the solution
stirred at room temperature or under reflux for 16 h. The
solution was then filtered through Celite, and concentrated
under vacuum. The crude oily mixture was purified on silica
gel by flash chromatography (eluent: heptane/ethyl ether,
9/1).
Data for Product 1g: 1H NMR (300.802 MHz, CDCl3):
d=1.30 [s, C(CH3)3], 2.42 (s, CH3), 4.58 (AB, J=17.1 Hz,
G
Experimental Section
Preparation of 1,4-Dihydropyridines from Enamino
Esters and Enals
1H, CHHPh), 4.66 (AB, J=17.1 Hz, 1H, CHHPh), 4.68 (d,
J=5.0 Hz, Ha, CHPh), 4.96 (dd, J=7.7, 5.0 Hz, Hb), 5.94 (d,
J=7.7 Hz, Hc), 7.27–7.40 (m, 10H, CHAr); 13C NMR
To previously dried sodium sulfate (300 mg) were succes-
sively added under argon, ferric chloride or scandium tri-
flate (5 mol%), dichloromethane (10 mLmmolÀ1), the en-
amino ester (1 equiv.) and the unsaturated aldehyde (1.5
(75.455 MHz, CDCl3): d=15.8 (CH3), 28.1 [C(CH3)3], 41.1
A
Table 3. Lewis acid-catalyzed one-pot cascade reaction.[a]
Lewis Acid
R1
R2
R3
R4
Temperature
Compound
Yield [%]
FeCl3·6H2O
FeCl3·6H2O
FeCl3·6H2O
EtO
t-BuO
BnO
EtO
EtO
EtO
Me
Bn
Bn
Bn
Bn
n-Bu
n-Bu
n-Bu
n-Bu
Ph
Ph
Ph
Ph
Ph
Me
Ph
Me
H
H
H
H
H
Me
H
r.t.
1b
1g
1h
1b
1i
1j
1k
1l
98
96
98
75
80
63
80
86
reflux
reflux
r.t.
r.t.
r.t.
Sc
Sc
Sc
Sc
Sc
A
G
U
E
r.t.
r.t.
C
Me
Me
[a]
Reaction conditions: 1) 0.55 mmol of amine, 0.5 mmol of keto ester or b-diketone, 0.025 mmol of Lewis acid (5 mol%) in
5 mL of CH2Cl2, 150 mg (1.5 mmol) of Na2SO4; 2) 0.5 mmol of unsaturated aldehyde.
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Ramandeep Kaur Vohra et al.
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(CHPh), 53.6 (NCH2Ph), 78.9 [Cq, C
N
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Acknowledgements
The authors are grateful to the European Union COST Pro-
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Adv. Synth. Catal. 2006, 348, 2571 – 2574