Synthesis of new 1, 4-Dihydropyridines by addition-rearrangement process with imine derivatives and β-Ketoester as starting materials in solvent-free conditions

Article abstract of DOI:10.2174/157017809787893082

N-substituted 1, 4-dihydropyridines bearing a carboxyl group at the 4-position were synthesized in solvent-free conditions with Cu²⁺ as the catalyst, imine and β-ketoester as starting materials. The possible mechanism which consists of addition

Full text of DOI:10.2174/157017809787893082

Letters in Organic Chemistry, 2009, 6, 213-218
213
Synthesis of New 1, 4-Dihydropyridines by Addition-Rearrangement
Process with Imine Derivatives and ꢀ-Ketoester as Starting Materials in
Solvent-Free Conditions
Xueming Chen, Xiaoguang Huang, Yunyun Chen, Feng He and Xingshu Li*
School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, China
Received September 18, 2008: Revised February 24, 2009: Accepted February 25, 2008
Abstract: N-substituted 1,4-dihydropyridines bearing a carboxyl group at the 4-position were synthesized in solvent-free
conditions with Cu2+ as the catalyst, imine and ꢀ-ketoester as starting materials. The possible mechanism which consists
of addition-rearrangement process was proposed and examined by the reaction of isolated product of first addition to ꢀ-
ketoester.
Keywords: Dihydropyridines, addition-rearrangement, Cu2+-catalyzed, imines, ꢀ-ketoester, solvent-free.
Dihydropyridines (DHP), first synthesized by Hantzsch
in 1882, have been found versatile in organic synthesis,
pharmacological and biological activities. They have been
used as calcium channel blockers [1] (for example, nifedip-
ine nitrendipine, felodipine, amlodipine) for the treatment of
cardiovascular diseases such as hypertension and angina
pectoris. Other pharmacological activities such as noncom-
petitive inhibition of topoisomerase [2], radioprotection [3],
modulation of cocaine dependence in animals [4], MDR re-
versal [5] and HIV protease inhibition [6] have also been
found in recent years. Besides, used as reducing agent in the
laboratory for several decades, dihydropyridines have also
proven to be very important synthetic intermediates, espe-
cially in preparation of nitrogen alkaloids [7]. Recently, a
great deal of success has been made in asymmetric dihydro-
pyridine-mediated reduction of ꢁ,ꢀ-unsaturated electrophiles
and imines including reductive amination of ketones [8].
to 1,4-dihydropyridines. However, from the practical and
pharmaceutical standpoint, it is very important to expand the
dihydropyridine family members and to develop efficient
synthetic methods for the purpose of the systematic study of
their biological activities. Herein, we report an efficient
method for the synthesis of N-substituted 1,4-dihydro-
pyridines bearing a carboxyl group at the 4-position with
Cu2+ as the catalyst, imine and ꢀ-ketoester as starting materi-
als in solvent-free conditions.
During our study of a Mannich-type reaction with ꢀ-
ketoester and imine in dichloromethane (Scheme 1), we
found a by-product (4a) in the presence of excess ethyl ace-
toacetate, which may formed by one imine molecule reacting
with two equivalent ethyl acetoacetate. Although the yield
was low, the single-crystal of this compound was obtained
and the structure of dihydropyridine conformation was char-
acterized by X-ray diffraction analysis (Fig. 1). As dihydro-
pyridines were very useful compounds in organic synthesis
and pharmaceutical sciences, we decided to study this reac-
tion in detail for developing a new method for the synthesis
of N-substituted 1,4-dihydropyridines.
The classical method for the construction of 1,4-DHP
ring is Hantzsch ester synthesis which uses ammonia, alde-
hyde and dicarbonyl compound as starting materials. Al-
though many improved procedures have been reported [9], it
is still necessary to develop alternative methods for prepar-
ing these useful compounds. Recently, some new strategy,
such as by adding Lewis acids or protonic acids to the reac-
tion system, the use of microwave to promote the reaction
were also reported. For example, Fukuzawa et al. reported
the Scandium(III) triflate catalyzed reaction of imines with
ethyl propiolate for synthesis of 1,4-dihydropyridine deriva-
tives with moderate yields [10]. Palacios et al. described the
use of functionalized enones derived from ꢁ-acylstyryl car-
boxylates or phosphonates affording biologically active
asymmetrical and symmetrical dihydropyridines with car-
boxylate or phosphonate groups [1]. Menendez and coopera-
tors [11] developed a cerium ammonium nitrate catalyzed
three-component domino reaction among aromatic amines,
ethyl acetoacetate and ꢁ,ꢀ-unsaturated aldehydes for an entry
In a preliminary screening study we first chose Cu(OTf)2
as the catalyst for accelerating the reaction and with di-
chloromethane as solvent in ambient temperature. The yield
of dihydropyridines was improved but there was still ap-
peared much Mannich adduct. As solvent-free organic reac-
tion was significant from the view point of green and sus-
tainable chemistry [12], we tried to carry out the reaction in
solvent-free conditions. It was to our delight that the isolated
yield of dihydropyridine was up to 76% and the adduct was
almost disappeared in such a reaction conditions. Other Cu
catalysts such as CuCl2, CuSO4, CuBr and CuBr2 were also
tested and the results were showed in Table 1. The best result
was obtained with CuBr2 as the catalyst (up to 90% yield)
and moderated yields were provided with others (entry 2:
CuCl2, 65% yield; entry 3: CuSO4, 55% yield; entry 4: CuBr,
49% yield.). On the other hand, low yield ( 40%, Table 1,
entry 6 ) was obtained when the reaction was carried out
without the catalyst at the same reaction conditions.
*Address correspondence to this author at the School of Pharmaceutical
Science, Sun Yat-Sen University, Guangzhou 510006, Chinal; Fax: +86-20-
39943050; E-mail: lixsh@mail.sysu.edu.cn
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

214 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Chen et al.
O
O
O
O
CH3
O
O
NH
3a
O
O
O
O
CH2Cl2
RT
+
O
N
+
O
O
O
1a
O
O
2a
O
O
N
O
4a
Scheme 1. The reaction of ꢀ-ketoester and imine.
Fig. (1). ORTEP of the molecule of N-substituted 1,4-dihydropyridines bearing a carboethoxy group at the 4-position with ring numbering at
50% probability (CCDC 679132).
Table 1. The Domino Cu-Catalyzed Synthesis of 1,4-dihydropyridine in Solvent-Free Conditiona
O
O
O
O
O
O
O
O
cat.10%
O
N
O
N
O
+
solvent-free, RT
O
O
4a
1a
2a
Entry
Catalysts
Yield(%)b
1
Cu(OTf)2
76
2
3
4
5
6
CuCl2
CuSO4
CuBr
CuBr2
-
65
55
49
90
40
aimine (1.0mmol), ꢀ-ketoester (2.1mmol), and Catalyst (0.1mmol). bIsolated yields.

Synthesis of New 1, 4-Dihydropyridines
Letters in Organic Chemistry, 2009, Vol. 6, No. 3
215
Various imines derived from ethyl glyoxylate and aro-
matic amines were also treated with three kinds of ꢀ-
ketoesteres in such an optimal condition and the results were
listed in Table 2. Besides the imines derived from 2-
phenylethyl amine and ethyl glyoxylate which gave lower
yields (entry 15: methyl acetoacetate, 40% yield; entry 16:
ethyl acetoacetate, 37% yield; entry 17: t-butyl acetoacetate,
35% yield), the reaction proceeded normally in good yields
distributing from 50% to 90%. It appeared that electron-
donating substituents on the phenyl ring of amine were fa-
vorable to the yields of the product. For example, the imines
derived from aniline and various alkyl acetoacetate gave
moderate to good yields (Table 2, entry 9: methyl acetoace-
tate, 75% yield; entry 10: ethyl acetoacetate, 83% yield, en-
try 11: t-butyl acetoacetate, 56% yield), while 4-
methoxyaniline and 4-methylaniline gave good to excellent
yields (Table 2, entries 1 to 5, from 80% to 90% respec-
tively). On the other hand, electron-withdrawing groups on
the phenyl ring of the amine decreased the yields. When 4-
chloroaniline was used, 55-65% yields were obtained by the
reaction of the corresponding imine with alkyl acetoacetate
(Table 2, entry 6-8).
The steric hindrance effects of the substrates for the
yields of the reaction were also important. Methyl acetoace-
tate or ethyl acetoacetate gave products with higher yields
than that from t-butyl acetoacetate. For example, imine de-
rived from p-methylaniline and ethyl glyoxylate reacted with
methyl acetoacetate and ethyl acetoacetate gave 90% and
88% yield, respectively (Table 2, entry 3-4) while t-butyl
acetoacetate provided 80% yield (Table 2, entry 5).
Different from classic Hantzsch reaction mechanism, the
possible mechanism of the reaction is shown in Scheme 3.
Firstly the imine 1 reacts with ꢀ-ketoester to give ꢀ-amino
ketone 3. Addition of the amino group of compound 3 to the
second ꢀ-ketoester and followed by dehydration provides the
intermediate I. In the presence of Cu2+ as Lewis acid, the
rearrangement of the amino group in I to its carbonyl creates
the intermediate III, which process elimination to afford
intermediate IV. The following Micheal addition and loss of
water gives the targeted 1,4-dihydropyridine 4.
To further examine the feasibility of the addition-
rearrangement mechanism, we carried out the synthesis of
1,4-dihydropyridines with the Mannich-type products 3 and
Table 2. Scope and Yields of the Cu-Catalyzed Synthesis of 1,4-dihydropyridinesa
O
OR2
O
O
O
O
Et
cat.10%
C
OEt
R1
N
+
solvent-free, RT
OR2
R1
N
O
OR2
O
1
2
4
Entry
R1
R2
Product
Yield(%)b
1
2
p-CH3OPh
p-CH3OPh
p-CH3Ph
p-CH3Ph
p-CH3Ph
p-ClPh
p-ClPh
p-ClPh
Ph
Me
t-Bu
Me
Et
4b
4c
4d
4e
4f
85
82
90
88
80
65
60
55
75
83
56
54
50
40
40
37
35
3
4
5
t-Bu
Me
Et
6
4g
4h
4i
7
8
t-Bu
Me
Et
9
4j
10
11
12
13
14
15
16
17
Ph
4k
4l
Ph
t-Bu
Me
Et
Bn
4m
4n
4o
4p
4q
4r
Bn
Bn
t-Bu
Me
Et
2-phenylethyl
2-phenylethyl
2-phenylethyl
t-Bu
aimine (1.0mmol), ꢀ-ketoester (2.1mmol), and Copper(II) bromide (0.1mmol). bIsolated yield.

216 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Chen et al.
O
O
O
O
O
OCH3
C
OEt
CH2Cl2
RT
O
H3CO
N
+
OCH3
C
OEt
H3CO
NH
1a
2b
3b
O
O
O
OCH3
OEt
OR
H3CO
N
O
4b: R = CH3
5a: R = CH2CH3
CuBr2 /RT
OR
O
Scheme 2. The synthesis of 1,4-dihydropyridine with two seperated steps
CH3
O
O
OCH3
O
O
O
O
H
O
O
H
N
H3C
OCH3
RNH2
+
EtO
EtO
R
EtO
NHR
O
1
3
Cu2+
O
OCH3
O
O
O
O
H3CO
O
O
Cu2+
CH3
O
H3C
OCH3
CH3
EtO
H3C
NR
EtO
H3C
NR
-H2O
O
OCH3
II
I
OCH3
OCH3
HO
O
O
O
O
H3CO
OCH3
CH3
R
O
H
Hoffman elimilation
Micheal addition
N
R
N+
O-
EtO
H3CO
CH3
OCH3
O
III
IV
OCH3
HO
OCH3
CH3
OCH3
-O
O
HO
O
O
O
CH3
N+
CH3
O
O
- H2O
R
N
R
N
R
EtO
EtO
EtO
CH3
O
CH3
CH3
O
OCH3
OCH3
OCH3
V
VI
4
Scheme 3. The possible mechanism of imine reacting with ethyl acetoacetate.

Synthesis of New 1, 4-Dihydropyridines
Letters in Organic Chemistry, 2009, Vol. 6, No. 3
217
EXPERIMENTAL SECTION
General Procedure for the Preparation of Imines
To a solution of p-methoxyaniline (1.23g, 10mmol) in
20ml of toluene was added anhydrous sodium sulfate (7.1g,
50 mmol) under stirring. After the mixture was stirred for
several minutes at room temperature, ethyl glyoxalate (1.2g,
12 mmol) was added in dropwise. The mixture was stirred
for another one hour until the disappearance of amine moni-
tored by TLC. Removing of sodium sulfate by filtration and
toluene under vacuum gave the crude imine in almost quanti-
tive yield which was used for the next step without purifica-
tion.
General Procedure for the Synthesis of 1, 4-dihydro-
pyridines
Imine (1.0mmol) and ꢀ-ketoester (2.1mmol) were added
to a round-bottomed flask containing copper (II) bromide
(0.1mmol). The mixture was stirred at room temperature for
18h. After the reaction completed (monitored by TLC), the
crude product was purified by flash column chromatography
(1:10 ethyl acetate/petroleum ether as eluents) to afford the
desired 1,4-dihydropyridine products
Fig. (2). ORTEP of the molecule obtained using imine methyl ace-
toacetate with ring numbering at 50% probability (CCDC 679131).
ꢀ-keto esters as starting materials (Scheme 2). The Mannich-
type products were obtained by reacting of imine with ꢀ-
ketoesteres such as methyl acetoacetate or ethyl acetoacetate
in dichloromethane. Then, reacting with another 1 equivalent
of ꢀ-ketoesteres in solvent-free condition, the desired prod-
ucts were obtained in good yields. The X-ray diffraction
analysis of the compound 4b was shown in Fig. (2). The
results demonstrated that Mannich-type products 3 were the
intermediate of the reaction, and the following addition-
rearrangement domino process generated 1,4-dihydro-
pyridine products.
Triethyl 1-(4-methoxyphenyl)-2, 6-dimethyl-1,4-dihydropy-
ridine-3,4,5-tricarboxylate (4a)
1
Yellow solid. H NMR (CDCl3, 300MHz) ꢁ 1.24-1.32
(m, 9H), 2.05 (s, 6H), 3.83 (s, 3H), 4.11-4.23 (m, 6H),
4.85(s, 1H), 6.88-6.91 (d, 2H), 7.05-7.08 (d, 2H) ppm; 13C
NMR (CDCl3, 75MHz) ꢁ 14.72, 18.55, 40.44, 55.80, 60.40,
60.89, 101.35, 114.63, 131.49, 149.38, 159.55, 167.63,
173.95 ppm. Anal. Calcd for C23H29NO7: C, 64.02; H, 6.77;
N, 3.25. Found: C, 63. 99; H, 6.37; N, 3.01.
The preparation of some other unsymmetrical dihydro-
pyridines via this method was also carried out and the results
were listed in Table 3. The moderate to good yields obtained
in these examples indicated that it was an alternative strategy
for preparing the dihydropyridine family.
4-Ethyl 3,5-dimethyl 1-(4-methoxyphenyl)-2, 6-dimethyl-1,
4-dihydropyridine-3, 4,5-tricarboxylate (4b)
Yellow solid. 1H NMR (CDCl3, 300MHz) ꢁ 1.22-1.27 (t,
3H), 2.06 (s, 6H), 3.75 (s, 6H), 3.83 (s, 3H), 4.12-4.14 (q,
Table 3. The Cu-Catalyzed Synthesis of Unsymmetrical 1,4-dihydropyridinesa
O
O
O
OR2
OEt
O
O
OR2
O
OR3
R1
N
C
OEt
R1
NH
O
CuBr2 /RT
OR3
O
3
5
Entry
R1
R2
R3
Product
Yield ( %)b
1
2
3
4
5
6
CH3O
CH3O
CH3O
CH3
CH3
CH3
Et
Et
5a
5b
5c
5d
5e
5f
65
62
53
70
84
52
t-Bu
t-Bu
Et
CH3
CH3
Et
CH3
t-Bu
CH3
t-Bu
aMannich-type product (3) (1.0mmol), ꢀ-ketoester(1.2mmol), and Copper(II) bromide (0.1mmol). bIsolated yield.

218 Letters in Organic Chemistry, 2009, Vol. 6, No. 3
Chen et al.
2H), 4.85 (s, 1H), 6.89-6.92 (d, 2H), 7.04-7.07 (d, 2H) ppm.
13C NMR (CDCl3, 75MHz) ꢀ 14.62, 18.57, 40.22, 51.78,
55.82, 61.02, 100.88, 114.65, 131.44, 149.87, 159.56,
168.04, 173.70. Anal. Calcd for C21H25NO7: C, 62.52; H,
6.25; N, 3.47. Found: C, 62. 73; H, 6.44; N, 3.40.
ACKNOWLEDGEMENTS
We thank the National Science Foundation of China
(20472116) for the financial support of this study.
SUPPORTING INFORMATION
3,5-Di-tert-butyl 4-ethyl 1-(4-methoxyphenyl)-2, 6-dimeth-
yl-1, 4-dihydropyridine-3, 4,5-tricarboxylate (4c)
Supporting information can be viewed at
www.bentham.org/loc
Colorless oil. 1H NMR (CDCl3, 300MHz) ꢀ 1.21-1.29 (t,
3H), 1.45 (s, 18H), 2.01 (s, 6H), 3.83 (s, 3H), 4.11-4.18 (t,
2H), 4.79 (s, 1H), 6.88-6.91 (d, 2H), 7.06-7.08 (d, 2H) ppm;
13C NMR (CDCl3, 75MHz) ꢀ 14.79, 18.41, 28.60, 41.17,
55.78, 60.80, 80.22, 102.58, 114.50, 131.61, 148.44, 159.38,
167.05, 174.26 ppm. Anal. Calcd for C27H37NO7: C, 66.51;
H, 7.65; N, 2.87. Found: C, 66.23; H, 7.46; N, 2.77.
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2.44 (s,1.5H), 2.48 (s, 1.5H), 3.90-3.93 (m, 6H), 4.30-4.33
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62.01, 115.05, 116.35, 140.65, 153.50, 168.56, 171.64,
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The Synthesis of Compound 5a
3-Acetyl-2-(4-methoxyphenylamino)-butanedioic acid,
ethyl methyl ester (1.0mmol) and ꢁ-ketoester (1.1mmol)
were added to a flask containing copper (II) bromide
(0.1mmol). The mixture was stirred at room temperature for
18h. After the reaction completed (monitored by TLC), the
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[12]
1
less oil. H NMR (CDCl3, 300MHz) ꢀ 1.25-1.31 (m, 6H),
2.06 (s, 6H), 3.75 (s, 3H), 3.84 (s, 3H), 4.12-4.23 (m, 4H),
4.85 (s, 1H), 6.89-6.92 (d, 2H), 7.05-7.08 (d, 2H) ppm; 13C
NMR (CDCl3, 75MHz) ꢀ 14.75, 18.58, 40.28, 51.73, 55.74,
60.95, 100.78, 101.31, 116.60, 131.42, 132.77, 149.85,
159.51, 168.05, 173.80 ppm.