A novel, unusual acid catalyzed route to substituted 1,4-dihydropyridine via double decarboxylation

Article abstract of DOI:10.2174/157017811799304278

A simple and high yield route to 3,4,5-trisubstituted 1,4-dihydropyridine systems via an interesting intermolecular condensation and double decarboxylation is described.

Full text of DOI:10.2174/157017811799304278

610
Letters in Organic Chemistry, 2011, 8, 610-613
A Novel, Unusual Acid Catalyzed Route to Substituted 1,4-dihydro-
pyridine via Double Decarboxylation
Jacob Porter, Graham Radomski, Joel Seagren, Benjamin Batura and Samuel David*
Department of Chemistry, The University of Wisconsin, 800 Algoma Blvd., Oshkosh, WI 54901, USA
Received November 13, 2010: Revised June 16, 2011: Accepted June 24, 2011
Abstract: A simple and high yield route to 3,4,5-trisubstituted 1,4-dihydropyridine systems via an interesting
intermolecular condensation and double decarboxylation is described.
Keywords: 3,4,5-trisubstituted 1,4-dihydropyridines, double decarboxylation, enamine, heterocycles, intermolecular
condensation, tandem reaction.
INTRODUCTION
synthesis of the natural product, jasmine [9]. Based on
structure-activity studies, some of these compounds could
also be used as fluorescent calcium channel probes in
studying living systems [8].
Derivatives of 1,4-dihydropyridines are versatile
compounds that have been used as antihypertensive drugs
(e.g. nifedipine) [1], and have also been found to be a
byproduct of ethanol degradation in rat liver [2].
These particular types of 1,4-dihydropyridine derivatives
(I, Fig. 1) have been accessed by heating malonaldehyde
with adenosine at pH 4.6 [4]; by condensing two equivalents
of malondialdehyde with an aldehyde and primary amine at
pH 4.2; [8] by using ꢀ-amino acrylates and TiCl4 [10]; by
using ethyl propiolate and the corresponding imine with
Sc(OTf)3 [1]; or via a domino Michael-aza-cyclization
process with commercial dimethyl-2-ethylidene malonate
and ethyl propiolate with a corresponding amine and
Mg(ClO4)2 [11]. Another approach was a series of reactions
involving the attack of a sulphur stabilized anion on a 3-
substituted alkyl pyridinium ring followed by de-
sulphurization and subsequent acylation to yield the structure
in Fig. (1) [9].
Y
X
O
O
O
Y
X=
R
OR
H
X
may or may not be the same as Y
N
Z
Z = any ring or alkyl group
I
NO2
O
O
H3CO
OCH3
N
H
RESULTS
Nifedipine
In this work, we started by considering a known reaction
wherein three equivalents of 3-(dimethyl amino)-acrolein (II,
Scheme 1) condense in the presence of a weak acid to form a
tri substituted phenyl ring, (III, Scheme 1) [12].
Fig. (1). 3,4,5-trisubstituted 1,4-dihydropyridine systems Structure
of Nifedipine.
CHO
One class of derivatives (3,4,5-trisubstituted 1,4-dihydro-
1-pyridyl systems; I, Fig. 1) has been recently reported in a
variety of applications. Malonaldehyde, which has been
classified as an environmental toxin [3], was found to form
such adducts with bases like adenosine under slightly acidic
conditions and thus was found to be present as a toxic
environmental end product [4]. As a by-product of oxidative
rancidity in foods, malondialdehyde forms 1,4-dihydro-
pyridine derivatives of the type shown in Fig. 1 [5, 6]. This
structure (I, Fig. 1) is also found in compounds that are used
as calcium channel blockers in the treatment of certain
cardiovascular disorders [7] and as an intermediate in the
OHC
Reflux overnight
AcOH
NMe2
OHC
CHO
III
II
Scheme 1. Self-condensation of 3-(Dimethyl amino)-acrolein under
weak-acid reflux.
Based on this, it was expected that the condensation of an
equal number of moles of diethyl (ethoxymethylene)
malonate (V, Scheme 2) and ethyl- 3-N-phenylethylacrylate
(IV, Scheme 2) in acetic acid would result in an
intramolecular condensation making the substituted 2-
pyridone VI (Scheme 2).
*Address correspondence to this author at the Department of Chemistry The
University of Wisconsin 800 Algoma Blvd Oshkosh WI 54901, USA; Tel:
001-(920) 424-1400; Fax: 001-(920) 424-2042; E-mail: davids@uwosh.edu
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© 2011 Bentham Science Publishers

A Novel, Unusual Acid Catalyzed Route to Substituted 1,4-dihydropyridine
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
611
Expected Reaction: Intramolecular condensation
H
COOEt
O
EtOOC
EtOOC
EtOOC
COOEt
COOEt
EtO
+
3 hr reflux
COOEt
EtO
-EtOH
50% AcOH
NH
N
NH
O
V
VI
IV
Ph
Actual reaction: Intermolecular condensation with double decarboxylation
Ph
Ph
H
N
EtOOC
EtOOC
EtOOC
H
H
COOEt
OEt
EtOOC
or
EtOOC
3 hr reflux
COOEt
50% AcOH
+
NH
NMe2
H
H
IV
V
VII
H
H
Ph
VIII
Ph
Scheme 2. Expected versus actual intermolecular condensation of a ꢀ-amino acrylate and an electrophile.
Table 1. Reaction Conditions Attempted to Find the Optimum Yield for the Formation of VIII, Scheme 2. All Reactions Were
Carried Out in 50% Acetic Acid
Ratio of IV to V, Scheme 2
Temperature
Time
Yield
1:2
ambient
reflux
reflux
reflux
reflux
reflux
reflux
reflux
24 hrs
1 hr
0%
1:2
25%
45%
56%
54%
20%
10%
< 5%
1:2
2 hrs
3 hrs
24 hrs
3 hrs
3 hrs
3 hrs
1:2
1:2
1:1
1:0.5
1:0.25
Instead, product VIII, Scheme 2 was obtained upon
refluxing an equimolar quantity of both reactants in mild
acid. In an effort to understand this reaction, it was carried
out under various mole ratios of the reactants, different
reaction times (1 to 24 hours) and varying temperatures
(ambient versus reflux). A 1:2 molar equivalent ratio of IV
to V (Scheme 2) produced the highest yield (56%) with no
unreacted starting material [13]. All other ratios left one of
the starting materials at the end of 24 hours of reflux in 50%
acetic acid. Using this optimal molar ratio, it was found that
the reaction was complete in 3 hours under reflux; on the
other hand, even after 24 hours under ambient temperature,
barely any of the starting materials had reacted. These results
are summarised in Table 1. Also, the use of two mole
equivalents of 3-(N,N-dimethylamino) acrylate (VII, Scheme
2) instead of diethyl (ethoxymethylene) malonate (V,
Scheme 2) resulted in the same product being formed (VIII,
Scheme 2). When the reaction was attempted in refluxing
sodium ethoxide/ethanol, no trace of product VIII, Scheme 2
was found. A likely explanation for the observed product is
that one mole of IV underwent successive intermolecular
addition reactions with two moles of V with the concomitant
loss of 2 moles of CO2, resulting in a rather unexpected
product VIII (Scheme 3).
CONCLUSION
Thus, this interesting reaction cascade shows a simple
and
efficient
route
to
3,4,5-trisubstituted
1,4-
dihydropyridine ring systems and is reminiscent of the
Hantzsch pyridine synthesis [1, 20]. Scheme 3 shows the
hydrolysis and subsequent decarboxylation of selective ester
groups in the presence of refluxing 50% acetic acid. Thus
this scheme suggests that certain ester groups are hydrolyzed
to carboxylic acids which then undergo decarboxylation.
Future work involves the utilization of this cascade to
make highly useful 3,5-disubstituted pyridines by using alkyl
protecting groups on the nitrogen of the starting ꢀ-amino

612 Letters in Organic Chemistry, 2011, Vol. 8, No. 9
Porter et al.
H+
EtO2C
H
EtO2C
CO2Et
OEt
EtO2C
EtO2C
CO2Et
CO2Et
hydrolysis
-EtOH
EtO2C
N
EtO2C
N+
Reflux 3 hrs
+
50% AcOH
-EtOH
H
NH
II
Ph
I
Ph
Ph
H
EtO2C
CO2Et
EtO2C
H+
CO2Et
CO2Et
EtO2C
O
H
H
EtO2C
CO2Et
EtO2C
EtO2C
N+
EtO2C
O
CO2Et
CO2Et
EtO2C
EtO
N
-EtOH
N+
-CO
N
2
Ph
Ph
Ph
Ph
EtO2C
EtO2C
H
H
N
O
H
EtO2C
EtO2C
H
H+
CO2Et
EtO2C
H
CO2Et
H
hydrolysis
-EtOH
O
CO2Et
EtO2C
N
-CO
VIII
2
H
H
N+
C
H NO
23 29
Ph
6
Ph
Ph
Scheme 3. Putative reaction pathway in order to explain the unexpected double decarboxylation product.
malondialdehyde-acetaldehyde adducts using an enzyme-linked
immunosorbent assay. Chem. Res.Toxicol., 1997, 10, 978-986.
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acrylate. After ring formation, the protecting group will be
removed in order to effect aromatization.
[3]
[4]
Also, various electron-donating and withdrawing groups
on N-substituted amino acrylates (like IV, Scheme 2) will be
tried in an effort to understand the importance of basicity of
these N-substituted aminoacrylates [1] in their reactions with
electrophiles like V or VII, Scheme 2.
[5]
[6]
ACKNOWLEDGEMENTS
We are in debt to Brant Kedrowski (Department of
Chemistry, UWisc., Oshkosh, WI) for help with the
manuscript.
[7]
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SUPPLEMENTARY MATERIAL
Supplementary material is available on the publishers
Web site along with the published article.
[9]
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procedure for the preparation of highly functionalized di- and
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dihydropyridines from ꢀ-amino acrylates by using titanium(IV)
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[10]
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A Novel, Unusual Acid Catalyzed Route to Substituted 1,4-dihydropyridine
Letters in Organic Chemistry, 2011, Vol. 8, No. 9
613
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product was an oil; 56% yield.
[15]
[16]
IR: ꢀmax (KCl plates)/cm-1 3019.2 (=C-H), 1723.9 (C=O), 1698.5
(C=O), 1581.1 (C=C), 1215.6, 1183.0, 1078.0, 1029.6, 755.7,
668.8.
1H NMR (270 MHz, CDCl3): ꢁ= 1.18 (3H, t, J=7.2Hz, -CH3) 1.26
(6H, t, J=7.1Hz, -CH3) 2.40 (2H, d, J=5.2Hz, -CH2-) 2.88 (2H, t,
J=7.4Hz, -CH2-) 3.51 (2H, t, J=7.4Hz, -CH2-) 4.00 (2H, q,
J=7.1Hz, -CH2-) 4.15 (4H,q, J=7.1Hz, -CH2-) 4.16 (1H, t,
J=5.2Hz, C-H) 7.03 (2H, s, =C-H) 7.05-7.33 (5H, m, Ar-H);
13C NMR (270 MHz, CDCl3): ꢁ= 14.3, 14.4, 29.4, 36.9, 41.1, 56.4,
60.1, 60.2, 106.1, 127.0, 128.89, 128.91, 137.2, 139.2, 166.9,
171.8.
[13]
[14]
Experimental Procedure and Characterisation Data.
6.05g (0.028 mol) of diethyl (ethoxymethylidene) propanedioate
(V, Scheme 2)was refluxed with 3.0 g (0.014 mol) of ethyl (2E)-3-
[(2-phenylethyl)amino]prop-2-enoate (IV, Scheme 2) in 30 mL of
50% acetic acid. After 3 hours, the reaction was poured over ice
and the mixture was then extracted twice with CH2Cl2, washed with
brine and dried over MgSO4. The solvent was removed under
reduced pressure. Diethyl ether was then added and the solvent was
evaporated again. This process was repeated twice more. Finally,
after removal of all the solvent, the crude product was subjected to
[17]
[18]
TOF-MS ES+(m/z): M=415;[ M+H]+ = 416; [M+Na]+ = 438; [2
M+Na]+=853.
[19]
[20]
HRMS: (C23H29NO6 + H)+, calc. 416.2068; found: 416.2067.
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