Chapter 2
Chapter-2
One-Pot, Solvent Free Synthesis of Hantzsch
1, 4-Dihydropyridines Using β-Cyclodextrin as a
Supramolecular Catalyst
2.1 Introduction
2.2 Review of Literature
2.3 Present Work
2.4 Conclusion
2.5 Experimental Section
2.6 Spectral Data
2.7 References
Lett. Org. Chem. 2011, 8 (7), 477-483.
21
Chapter 2
2.1 Introduction
1,4-Dihydropyridines (DHPs) belongs to the class of nitrogen containing
heterocycles having a six member ring. The parent 1,4-DHP was prepared as a
unstable substance by Cook and Lyons in 1965.1 Every 3,5-disubstitution at the
skeleton of 1,4-DHP ‘a’ by electron withdrawing substituents X and Y such as COR,
COOR, CN and NO2 enhances their chemical stability, where as electron donating
groups like SC6H5 and OC6H5 have destabilising effect. 1,4-DHP-3,5-dicarboxylates
are called Hantzsch dihydropyridines or Hantzsch esters.
H
H
H
X
4
H
3
Y
R2OOC
5
N
H
1,4-DHP
6
H
4
R3
3
COOR2
5
1
N
H
a
1
2
R1
6
N
H
2
R1
Hantzsch 1,4-DHP
R1 = Me, R2 = Et
R3 = H or Ph
There is always something new on the old topic of Hantzsch reaction. This is
mainly due to fact that it offers an efficient way to prepare 1,4-dihydropyridines
(1,4-DHPs) which exhibits significant biological activities2 in the treatment of
cardiovascular diseases (as calcium channel blockers). They have been also used as
antidepressive,
antionaxeity,
analgesic,
antitumoral,
hypnotic,
vascodilator,
bronchodilator and anti-inflammatory agent.3 Some clinically important drugs such as
Amlodipine, Nifedipine, Felodipine, Isradipine (Figure 2.1) and Nicardipine
containing the 1,4-dihydropyridine parent nucleus have been manufacture and use
worldwide.4 In addition, the dihydropyridine unit has been widely employed as
hydride source for reductive amination.5 They are also useful as cognition enhancer,
neuroprotectance and platelet anti-aggrigatory agent.6 Some of 1,4-DHPs act as
NADH mimics for the reduction carbonyl compounds and their derivatives.7 Some
Hantzsch esters serve as biomimetic reducing agents (NADPH model8).
1,4-Dihydropyridines are also good precursors of the corresponding substituted
pyridine derivatives.9 Some 1,4-DHP moieties are also reported as drug-resistance
modifiers,10 antioxidants and a drug for the treatment of urinary urge incontinence.11
1,4-Dihydro-4-pyrazolylpyridines and 4-pyrazolylpyridines obtained from parent
22
Chapter 2
1,4-DHP skeleton act as good antimicrobial agent.12 Recent literature reveals that the
1,4-dihydropyridine derivatives act as glycoprotein inhibitor,13 calcium channel
blockers,14 antimitotic agent,15 anticancer16 and antitubercular agents.17 Hantzsch
diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate also act as a good source
of hydride for reduction purpose.18
NO2
COOMe
MeOOC
Me
N
H
Me
Nifedipine
Cl
COOEt
MeOOC
Me
N
H
CH2OCH2CH2NH2
Amlodipine
Cl
N
O
N
Me
OOC
COOMe
MeOOC
Cl
COOEt
Me
Me
N
Me
H
Isradipine
Me
N
Me
H
Feldopine
Figure 2.1: Biologically active dihydropyridines.
2.2 Review of Literature
The author Hantzsch first reported the synthesis of 1,4-dihydropyridines via
the condensation of aldehyde, ethyl acetoacetate with ammonia in refluxing alcohol or
acetic acid19 which requires longer reaction time and low to moderate yield of
product. Up till now numerous literature citations exist relating to various attempts to
improve the Hantzsch reaction using alternative catalyst and greener methods.20
Owing to the modest yield reported, numerous improvements on this method have
since been developed including the use of catalyst such as boronic acid,21 metal
triflates,22 molecular iodine,23 TMS iodide,24 Bu4NHSO4,25 bakers’ yeast,26 cerric
ammonium nitrate,27 in situ generated HCl28 and silica supported acids.29 Some
solvent free methods for synthesis of 1,4-DHP includes use of ultrasound
irradiation,30 sulfonic acid functionalized silica,31 iron(III) trifluroacetate and
trifluromethanesulfonate,32 silica sulfuric acid,33 Ba(NO3)234 and PPA-SiO2.35 Some
23
Chapter 2
other methods include microwave assisted synthesis,36 use of catalyst like
CsCl3.7H2O,37 thiamine hydrochloride.38 The some latest methods involving the
improvements in the synthesis of Hantzsch 1,4-DHPs are given bellow.
Yadav J. S. et al. (2003)39
Yadav et al. reported 1-n-butyl-3-methylimidazolium tetrafluoroborate
([bmim]BF4) or 1-n-butyl-3-methylimidazolium hexafluorophosphate ([bmim]PF6)
ionic liquids for the synthesis of 1,4-dihydropyridine derivatives in good yields by the
condensation of aldehyde, β-ketoester and methyl 3-aminocrotonate. The recovered
activated ionic liquids were recycled for four to five runs with no loss in activity
(Scheme 2.1).
O
O
R
H
O
+
NH2 O
+
O
[bmim]BF4 or
O
OMe
[bmim]PF6
R
O
MeO
O
N
H
R = alkyl, aryl, heteroaryl
Scheme 2.1
Bridgwood K. L. et al. (2008)
40
Bridgwood et al. investigated magnesium nitride as a source of ammonia for
the preparation of dihydropyridines (Scheme 2.2). Magnesium nitride (Mg3N2) is a
commercially available, bench-stable solid that generate ammonia on treatment with
protic solvents.
O
O
R2
OR1
+
O
R2
Mg3N2, EtOH, H2O
R1OOC
COOR1
N
H
H
R1 = Et, Me
R2 = alkyl, aryl, vinyl
Scheme 2.2
24
Chapter 2
Debache A. et al. (2009)41
Debache
et
al.
described
an
efficient
one
step
synthesis
of
1,4-dihydropyridines (Scheme 2.3) in good to excellent yields via triphenylphosphine
catalyzed Hantzsch three component reaction of an aromatic aldehyde, ethyl
acetoacetate and ammonium acetate in ethanol under reflux condition for 2-5 h.
O
O
H +
Ar
O
O
Me
PPh3 (20 mol %)
OEt
+ AcONH4
Ar
O
EtO
OEt
EtOH, reflux, 2-5 h
Me
N
H
Me
Scheme 2.3
Tamaddon F. et al. (2010)42
Tamaddon et al. prepared efficiently 1,4-dihydropyridines using ammonium
carbonate in water (Scheme 2.4). Competition between Biginelli and Hantzsch
reaction was observed with pyridine carbaldehydes. Using this methodology,
Hantzsch esters were synthesized in higher yields and purities than with other
procedures without the use of a catalyst or an organic solvent.
O
R1
O
H +
O
O
Me
OR
+ (NH4)2CO3
H2O, 55-60 0C
R1
O
RO
OR
Me
N
H
Me
Scheme 2.4
Yadav D. K. et al. (2011)43
Yadav et al. described a simple, inexpensive and efficient one-pot synthesis of
1,4-dihydropyridines has been accomplished via lithium bromide-catalyzed Hantzsch
three-component condensation reaction of an aldehyde, β-ketoester and ammonium
acetate in acetonitrile at room temperature in good to excellent yields (Scheme 2.5).
The present protocol is applicable to wide range of substrates including aliphatic,
aromatic and heterocyclic aldehydes affording 1,4-dihydropyridines.
O
O
R2
OR1
+
O
R2
NH4OAc, LiBr (10 mol %)
Acetonitrile, rt, 3 - 6 h
H
R1OOC
COOR1
N
H
R1 = Et, Me
R2 = alkyl, aryl, heteroaryl
Scheme 2.5
25
Chapter 2
Bandyopadhyay D. et al. (2012)44
Bandyopadhyay et al. investigated bismuth nitrate pentahydrate as a very
efficient catalyst under microwave irradiation for a one-pot, three-component
synthesis of 1,4-dihydropyridines in excellent yields from diverse amines/ammonium
acetate, aldehydes and 1,3-dicarbonyl compounds under solvent-free conditions
(Scheme 2.6). The excellent yield and extreme rapidity of the method is due to a
concurrent effect of the catalyst and microwave irradiation.
O
O
R1
O
H +
NH4OAc
O
Me
R2
+
or
R3 NH2
MWI
R1
O
R2
Bi(NO3)3.5H2O
R2
Me
(5 mol %)
R1 = alkyl, aryl, heteroaryl
R2 = Me, OEt, OMe
R3 = aryl, heteroaryl
N
Me
H/ R3
Scheme 2.6
Xiao Yun Wu (2012)45
Xiao Yun Wu synthesized l,4-Dihydropyridine derivatives from the one-pot
condensation of aldehydes, acetoacetates, and ammonium acetate in ionic liquid
n-Butyl pyridinium tetrafluoroborate ([BPy][BF4 ]) (Scheme 2.7).
The recovered
ionic liquid could be recycled for at least five runs without losing its activity.
O
0
100 - 110 C
ArCHO + CH3COCH2CO2R +
NH4OAc
[BPy] [BF4]
R = Me, Et
Ar
RO
Me
O
OR
N
H
Me
Scheme 2.7
2.3 Present Work
In synthetic organic chemistry, a one-pot synthesis has become a blue print to
improve the efficiency of a reaction wherein a reactant is subjected to successive
chemical reactions in one vessel.46 A number of the reported protocols to synthesize
DHPs requiring solvents and catalysts are not acceptable in the context of green
synthesis; utilize reagents and catalysts which are either toxic or expensive and
stoichiometric use of reagents with respect to reactant. Additionally, the clean
handling of some anhydrous metal halides is not easy enough in the laboratory apart
from their hygroscopic nature due to strong tendency for hydrolysis. However, the
developments in this area demand further searches for better catalysts that could be
26
Chapter 2
superior to the existing ones with regard to toxicity, handling, and recyclability. In
this respect, we planned to introduce potential catalyst to overcome these limitations.
By looking towards the development
of biomimetic approaches through
supramolecular catalysis involving cyclodextrin herein, we have attempted the
Hantzsch reaction involving synthesis of 1,4-dihydropyridine using β-CD as catalyst
under solvent free condition.
For initial studies, ethyl acetoacetate 1, para-nitrobenzaldehyde 2, ammonium
acetate 3 (2 : 1 : 1.5) as representative reactants and 1 mmol of β-CD catalyst were
selected (Scheme 2.8) for optimization of reaction. We found that at the given ratio
the ethyl acetoacetate was not totally consume (monitored by TLC, Hexane : Ethyl
acetate 9:1) affording low yield of 1, 4-DHP, so we use excess of ammonium acetate
(2 : 1 : 3) showing total consumption of ethyl acetoacetate with better yield of
product, this may due to the increase in concentration of liberating ammonia. The
effects of temperature on the reaction were examined under solvent free condition.
The yield of the product 4e was strongly depends on temperature. The formation of
product at low temperature does not fever even after exposure to long reaction time.
We found that the reaction time decreases and yield of product get increases with
increase in temperature. This might be because of increase in temperature fevers the
liberation of ammonia from ammonium acetate and promoting the condensation. The
results were summarized in Table 2.1 and graphically shown in Figure 2.2.
NO2
O
O
Me
OEt
1
CHO
+
-CD
O2N
+
2
O
EtO
Me
AcONH4
3
O
OEt
N
H
Me
4e
Scheme 2.8
27
Chapter 2
Table 2.1: To study effect of temperature using 1 mmol of catalyst under solvent
free condition.a
Entry
a
Yieldb
p-NO2 Benzaldehyde
Temp.
Time
(mmol)
(0C)
1
10
0-5
6h
-
2
10
30
4.5 h
50
3
10
40
4h
52
4
10
60
2h
60
5
10
80
20 min
87
6
10
100
30 min
72
7
10
120
25 min
(%)
73
b
Ethyl acetoacetate (20 mmol), Ammonium acetate (30 mmol), Isolated yield.
Figure 2.2: Effect of temperature for 1 mmol of catalyst in synthesis of 1,4-DHP (4e)
under solvent free condition.
After the preliminary investigation, our efforts were directed toward the
evaluation of catalytic activity by using para-nitrobenzaldehyde (10 mmol), ethyl
acetoacetate (20 mmol), ammonium acetate (30 mmol) and β-CD ranging from 0.1
mmol to 10 mmol at 80 0C with vigorous stirring (Scheme 2.9). We found that the
better yield (87%) was obtained at 1 mmol of catalyst for 10 mmol of substrate. When
amount of catalyst was greater than 1 mmol, little decrease in the yield of product (4e)
28
Chapter 2
occurs. Higher amount of β-CD did not improve the result to the greater extent. The
results were summarized in Table 2.2.
NO2
O
O
Me
OEt
1
CHO
+
+
O
-CD
O2N
2
80 0C
AcONH4
3
O
EtO
OEt
Me
N
H
Me
4e
Scheme 2.9
Table 2.2: To study effect of catalyst at 80 0C under different catalytic amount.
Entry p-NO2
Benzaldehyde
Catalyst
Time
(mmol)
Yield
(%)
(mmol)
a
b
1
10a
Nil
3.5 h
60
2
10a
0.125
2.08 h
68
3
10a
0.25
50 min
77
4
10a
0.5
42 min
83
5
10a
1
20 min
87
6
10a
1.5
2.0 h
66
7
10a
2
3.0 h
73
8
10b
2.5
3.5 h
61
9
10b
3
4.5 h
56
10
10b
3.5
4.15 h
58
11
10b
4
4.5 h
67
12
10b
4.5
4.45 h
65
13
10b
5
4.55 h
66
14
10b
10
7.0 h
63
Under solvent free condition.
In 10 ml of ethanol.
Furthermore the effect of various solvents from non-polar to polar on catalytic
activity were examined by using 0.1 mmol of catalyst for 1 mmol of substrate under
various reaction condition. The various solvent afforded the desired product in the
lower to moderate yield (46-75 %, Table 2.3). Better yield obtained in ethanol
29
Chapter 2
(75 %). The reaction also performed in pure water at 80 0C but it require long reaction
time (8 h, entry 11, Table 2.3) with moderate yield of 4e (68 %). Whereas the neat
condition furnished the DHP 4e in 87% (entry 5, Table 2.2).
Table 2.3: To study effect of various solvent for catalytic activity.a
Entry
Solvent
Temperature (0C)
Time (h)
Yield (%)b
1
Hexane
reflux
8
46
2
CCl4
reflux
6.15
45
3
Chloroform
reflux
4.5
48
4
Acetic acid
80
1.5
61
5
THF
reflux
7
51
6
DCM
reflux
8.5
57
7
Methanol
reflux
3
68
8
Acetonitrile
80
4.15
46
9
Ethanol
80
3.15
75
10
DMSO c
80
1
38
11
Water
80
8
68
12
Ethanol:
7.5
70
Water 80
(50:50)
a
Reaction was carried out with p-NO2 benzaldehyde (1 mmol), ethyl acetoacetate
(2 mmol), ammonium acetate (3 mmol) and catalytic amount of β-CD (0.1 mmol)
b
Isolated yield
c
Catalyst not recovered
In view of these results, then we selected the optimized reaction condition to
determine the scope of β-CD catalyzed reaction under solvent free condition. A range
of structurally diverse aldehydes 2 (1 mmol), ethylacetoacetate 1 (2 mmol),
ammonium acetate 3 (3 mmol) and catalytic amount of β-CD (0.1 mmol) were
subjected for stirring under solvent free condition at 80 0C (Scheme 2.10) to produced
corresponding 1,4-DHPs (4a – 4k) in short time. The results were presented in Table
2.4. In all cases, the crude products were obtained by extracting reaction mixture in
ethyl acetate and the purified by recrystalization in ethanol and/or column
chromatography. Aliphatic, aromatic and heterocyclic aldehydes have been studied
and give the corresponding products in good to excellent yields. It has been found that
the aliphatic aldehyde requires shorter reaction time than aromatic ones. The electron
donor and electron withdrawer group also affect the reaction time (as shown in Table
30
Chapter 2
2.4). The role of catalyst has been confirmed when the similar reaction carried
without addition of catalyst under similar condition, it require long reaction time and
lower yield of desired product. The recovered β-CD was recrystallized twice from
deionized water and then dried at temperature of 110 0C and reused. Figure 2.3 shows
the FT-IR spectra of pure β-CD and recovered β-CD after successive reactions. All
FT-IR spectra are found to be similar. No new peaks appear in the spectra of recycled
β-CD indicates that no chemical reaction occurred with β-CD.
O
O
Me
+
O
R CHO
OEt
1
+
-CD
EtO
0
80 C
2
R
O
OEt
Me
AcONH4
N
H
Me
4 a-k
3
Scheme 2.10
Table 2.4: Beta-Cyclodextrin catalyzed Hantzsch synthesis of 1,4-dihydropyridine
under solvent free condition at 80 0C.a
Entry
a
b
R
Time
Yield b
Melting point (0C)
(%)
Measured
Reported
4a
H
10 min
95
176
178-18048
4b
CH3
20 min
86
122
118-12048
4c
C6H5
60 min
90
158-160
156-15821b
4d
m-NO2C6H4
35 min
92
166
164-16621b
4e
p-NO2C6H4
20 min
87
130
130-13221b
4f
p-FC6H4
1.5 h
90
146-148
-
4g
p-ClC6H4
30 min
88
143
144-14648
4h
3,4-(OCH3)2 C6H3
2.15 h
89
137
-
4i
3,4,5-(OCH3)3 C6H2 2.5 h
91
142
140-14248
4j
2-Furyl
10 min
93
163
160-16241
4k
2-Pyridil
30 min
88
196-198
-
All the reactions were performed using 0.1 mmol of catalyst.
Isolated yield.
31
Chapter 2
FT-IR spectrum of pure β-CD
where a, b and c are FT-IR of first, second and third recycled β-CD
Figure 2.3: FTIR spectra of pure and recycled β-CD
From a mechanistic point of view, β-CD may favors the knoevenogel
condensation through activation of carbonyl group of aldehyde via hydrogen bonding
(supramolecular interaction)47 by providing microenvironment inside the cavity of
β-CD with one equivalent of ethyl acetoacetate to afford 5 or β-CD may favors the
condensation of second equivalent of beta ketoester with ammonia affording 6.
Condensation of these two fragments (Michael type addition) gives intermediate 7,
which
subsequently
cyclizes
followed
by
dehydration
to
corresponding
1,4-dihydropyridine (Figure 2.4).
32
Chapter 2
Figure 2.4: Proposed mechanism for synthesis of 1,4-dihydropyridine.
2.4 Conclusion
In conclusion, we have developed a simple and highly efficient method for
one pot three component synthesis of 1,4-dihydropyridins in good to excellent yields
from various aliphatic, aromatic and heterocyclic aldehydes, ethyl acetoacetate,
ammonium acetate in presence of β-CD as a supramolecular catalyst under solvent
free condition at 80 0C. The catalyst has been quantitatively recovered and reused.
The experimental protocol is simple, mild, affording high yields and represents an
attractive alternative to existing methods.
2.5 Experimental Section
Chemicals required for synthesis were obtained from Aldrich and
Spectrochem. Melting points were uncorrected and IR spectra were recorded
Shimadzu FT-IR (Model IRAffinity-1) using KBr. 1H NMR spectra were recorded at
33
Chapter 2
300 MHz (Varian-NMR-Mercury 300) in CDCl3 using TMS as an internal standard.
Mass spectra were under ESI mode on Thermo Finnigan (Model- LCQ Advantage
MAX) mass spectrometer.
General procedure for the preparation of Hantzsch 1, 4-Dihydropyridines
A mixture of aldehyde (1 mmol), ethyl acetoacetate (2 mmol), ammonium
acetate (3 mmol) and catalytic amount of beta-cyclodextrin (0.1 mmol) were heated at
80
0
C with constant stirring for appropriate time till the reaction completed
(monitored by TLC). The reaction mixture after being cool to room temperature was
poured into cold water and extracted three times with ethyl acetate (3 x 5 mL). The
organic layer washed with 10% NaHCO3 solution, dried over anhydrous Na2SO4,
filtered and concentrate in rota evaporator to leave crude product which was purified
by recrystalization in ethanol and/or column chromatography over silica gel using
hexane: ethyl acetate (9:1) as eluent. The aqueous layer was freeze at lower
temperature (0-10 0C) to recovered precipitated cyclodextrin by filtration, allows
drying and reused.
2.6 Spectral Data
Diethyl 2,6-dimethyl-1,4dihydropyridine-3,5-dicarboxylate:
O
O
EtO
Molecular formula: C13H19NO4
Molecular weight : 253
Mp
: 176 0C
-1
IR (KBr, cm ) ν
:
1
H NMR (CDCl3, 300 MHz, ppm) δ :
Diethyl 2,4,6-trimethyl-1,4dihydropyridine-3,5-dicarboxylate:
Molecular formula: C14H21NO4
Molecular weight : 267
Mp
: 122 0C
IR (KBr, cm-1) ν
:
1
H NMR (CDCl3, 300 MHz, ppm) δ :
OEt
Me
N
H
Me
3350, 2987, 1693, 1654, 1116
5.15 (s, 1H, NH), 4.17 (q, 4H, 2 x OCH2),
3.26 (s, 2H, CH2), 2.19 (s, 6H, 2 x CH3),
1.28 (t, 6H, 2 x CH3)
O
Me
EtO
Me
O
OEt
N
H
Me
3344, 2983, 1697, 1645, 1136
5.51 (s, 1H, NH), 4.2 (q, 4H, 2 x OCH2),
3.82 (q, 1H, CH), 2.26 (s, 6H, 2 x CH3),
1.31 (t, 6H, 2 x CH3), 0.96 (d, 3H, CH3)
34
Chapter 2
Diethyl 4-(phenyl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarboxylate:
O
Molecular formula: C19H23NO4
Molecular weight : 329
Mp
: 158-160 0C
EtO
OEt
Me
IR (KBr, cm-1) ν
:
1
H NMR (CDCl3, 300 MHz, ppm) δ :
MS (m/e)
O
:
N
H
3341, 2925, 1687, 1650, 1123, 738
7.29 - 7.11 (m, 5H, Aromatic), 5.61
(s, 1H, NH), 4.98 (s, 1H, CH), 4.08
(q, 4H, 2 x OCH2), 2.33 (s, 6H, 2 x CH3),
1.22 (t, 6H, 2 x CH3)
330 [M+1], 352 [M+ Na]
Diethyl 4-(3-nitrophenyl)-2,6-dimethyl1,4-dihydropyridine-3,5-dicarboxylate:
IR (KBr, cm-1) ν
1
OEt
Me
:
:
Molecular formula: C19H22N2O6
Molecular weight : 375
Mp
: 130 0C
O
O
EtO
:
H NMR (CDCl3, 300 MHz, ppm) δ :
Me
NO2
Me
1
N
H
3323, 2923, 1698, 1672, 1459, 1376,
1117, 786
8.12 (s, 1H, Aromatic), 8.02 (d, 1H,
Aromatic), 7.99 (d, 1H, Aromatic), 7.37
(t, 1H, Aromatic), 5.82 (s, 1H, NH), 5.09
(s, 1H, CH), 4.08 (q, 4H, 2 x OCH2), 2.36
(s, 6H, 2 x CH3), 1.22 (t, 6H, 2 x CH3)
375 [M+1], 397 [M +Na]
Diethyl 4-(4-nitrophenyl)-2,6-dimethyl1,4-dihydropyridine-3,5-dicarboxylate:
IR (KBr, cm-1) ν
O
EtO
H NMR (CDCl3, 300 MHz, ppm) δ :
MS (m/e)
NO2
O
Molecular formula: C19H22N2O6
Molecular weight : 374
Mp
: 166 0C
Me
OEt
N
H
Me
3318, 2924, 1701, 1648, 1459, 1348,
1120, 863
8.08 (d, 2H, Aromatic), 7.45 (d, 2H,
Aromatic), 5.70 (brs, 1H, NH), 5.09
(s, 1H, CH), 4.09 (q, 4H, 2 x OCH2), 2.35
35
Chapter 2
MS (m/e)
:
(s, 6H, 2 x CH3), 1.21 (t, 6H, 2 x CH3)
375 [M+1], 397 [M +Na]
Diethyl 4-(4-flurophenyl)-2,6-dimethyl1,4-dihydropyridine-3,5-dicarboxylate:
Molecular formula: C19H22FNO4
Molecular weight : 347
Mp
: 146-148 0C
F
O
EtO
OEt
Me
IR (KBr, cm-1) ν
:
1
H NMR (CDCl3, 300 MHz, ppm) δ :
MS (m/e)
:
Molecular formula: C19H22ClNO4
Molecular weight : 363
Mp
: 143 0C
Me
Cl
O
O
EtO
OEt
Me
IR (KBr, cm-1) ν :
1
H NMR (CDCl3, 300 MHz, ppm) δ :
:
Diethyl 4-(3,4-dimethoxyphenyl)-2,6dimethyl-1,4-dihydropyridine-3,5dicarboxylate:
Molecular formula: C21H27NO6
Molecular weight : 389
Mp
: 137 0C
:
N
H
Me
3358, 2987, 1695, 1651, 1118, 831
7.23 – 7.15 (m, 4H, Aromatic), 5.58
(brs, 1H, NH), 4.95 (s, 1H, CH), 4.09
(q, 4H, 2 x OCH2), 2.32 (s, 6H, 2 x CH3),
1.21 (t, 6H, 2 x CH3)
362 [M-1], 364 [M+1]
OMe
OMe
O
O
EtO
Me
IR (KBr, cm-1) ν
N
H
3341, 2924, 1686, 1650, 1123, 856
7.26 – 6.85 (m, 4H, Aromatic), 5.65 (brs,
1H, NH), 4.96 (s, 1H, CH), 4.09 (q, 4H,
2 x OCH2), 2.32 (s, 6H, 2 x CH3), 1.21
(t, 6H, 2 x CH3)
348 [M+1], 370 [M+ Na]
Diethyl 4-(4-clorophenyl)-2,6-dimethyl1,4-dihydropyridine-3,5-dicarboxylate:
MS (m/e)
O
OEt
N
H
Me
3344, 3093, 2981, 1687, 1651, 1209,
36
Chapter 2
1
H NMR (CDCl3, 300 MHz, ppm) δ :
MS (m/e)
:
Diethyl 4-(3,4,5-trimethoxyphenyl)-2,6dimethyl-1,4-dihydropyridine-3,5dicarboxylate:
OMe
MeO
O
EtO
OEt
Me
IR (KBr, cm-1) ν
:
1
H NMR (CDCl3, 300 MHz, ppm) δ :
:
Molecular formula: C17H21NO5
Molecular weight : 319
Mp
: 163 0C
IR (KBr, cm-1) ν
:
1
H NMR (CDCl3, 300 MHz, ppm) δ :
N
H
Me
3356, 2980, 1695, 1647, 1205, 1130
6.51 (s, 2H, Aromatic), 5.54 (s, 1H, NH),
4.97 (s, 1H, CH), 4.12 (q, 4H, 2 x OCH2),
3.79 (s, 9H, OCH3), 2.34 (s, 6H, 2 x
CH3), 1.25 (t, 6H, 2 x CH3),
418 [M-1], 419 [M]+, 420 [M+1]
Diethyl 4-(furan-2-yl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarboxylate:
O
O
O
EtO
OEt
Me
N
H
Me
3345, 2980, 1707, 1149
5.93 – 7.21 (m, 3H, Aromatic), 5.77
(s, 1H, NH), 5.20 (s, 1H, CH), 4.15
(q, 4H, 2 x OCH2), 2.32 (s, 6H, 2 x
CH3), 1.25 (t, 6H, 2 x CH3)
Diethyl 4-(pyridin-2-yl)-2,6-dimethyl1,4-dihydropyridine-3,5dicarboxylate:
Molecular formula: C18H22N2O4
Molecular weight : 330
Mp
: 196-198 0C
OMe
O
Molecular formula: C22H29NO7
Molecular weight : 419
Mp
: 142 0C
MS (m/e)
1120
6.87 – 6.70 (m, 3H, Aromatic), 5.52
(s, 1H, NH), 4.94 (s, 1H, CH), 4.10
(q, 4H, 2 x OCH2), 3.83 (s, 3H, OCH3),
3.81 (s, 3H, OCH3), 2.33 (s, 6H, 2 x
CH3), 1.23 (t, 6H, 2 x CH3)
389 [M]+, 388 [M-1]
N
O
EtO
Me
O
OEt
N
H
Me
37
Chapter 2
IR (KBr, cm-1) ν
:
1
H NMR (CDCl3, 300 MHz, ppm) δ :
MS (m/e)
:
3273, 3172, 2929, 1689, 1643, 1116
8.48 (d, 1H, Aromatic), 8.37 (brs, 1H,
NH), 7.57 (t, 1H, Aromatic), 7.46 (d, 1H,
Aromatic), 7.12 (t, 1H, Aromatic), 5.17
(s, 1H, CH), 4.08 (q, 4H, 2 x OCH2), 2.25
(s, 6H, 2 x CH3), 1.20 (t, 6H, 2 x CH3)
331 [M]+
2.6.1 Spectra
Table 2.5: FTIR, 1H NMR and Mass spectra of selected compounds.
Sr. Spectra
No.
1.
FTIR of Diethyl 4-(phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate.
1
2.
H NMR of Diethyl 4-(phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate.
3.
Mass of Diethyl 4-(phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate
4.
FTIR of Diethyl 4-(4-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate.
1
5.
H NMR of Diethyl 4-(4-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine3,5-dicarboxylate.
6.
Mass of Diethyl 4-(4-nitrophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate.
7.
FTIR of Diethyl 4-(pyridin-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate.
1
8.
H NMR of Diethyl 4-(pyridin-2-yl)-2,6-dimethyl-1,4-dihydropyridine3,5-dicarboxylate.
9.
Mass of Diethyl 4-(pyridin-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5dicarboxylate.
38
Chapter 2
39
Chapter 2
40
Chapter 2
41
Chapter 2
42
Chapter 2
43
Chapter 2
44
Chapter 2
45
Chapter 2
46
Chapter 2
47
Chapter 2
2.7 References
1.
Cook, N. C.; Lyons, J. E. J. Am. Chem. Soc. 1965, 87, 3283.
2.
(a) Stout, D. M.; Meyers, A. I. Chem. Rev. 1982, 82, 223. (b) Wie, X. Y.;
Rulledge, A.; Triggle, D. I. J. Mol. Pharmacol. 1989, 35, 541. (c) Bossert, F.;
Vater, W. Med. Res. Rev. 1989, 9, 291. (d) Mauzerat, D.; Westheimer, H. F.
J. Am. Chem. Soc. 1955, 77, 2261.
3.
(a) Saunsins, A.; Duburs, G. Heterocycles 1988, 27, 269. (b) Mager, P. P.;
Coborn, R. A.; Solo, A. J.; Triggle, D. J.; Rothe, H. Drug Des. Discovery
1992, 8, 273. (c) Mannhold, R.; Joblonca, B.; Voigt, W.; K. Schonafinger.;
Schraven, E. Eur. J. Med. Chem. 1992, 27(3), 229.
4.
(a) Bossert, F.; Meyer, H.; Wehinger, E. Angew. Chem. Ind. Ed. Engl. 1981,
20, 762. (b) Love, B.; Godman, M. M.; Snader, K. M.; Tedeschi, R.; Macko,
E. J. Med. Chem. 1974, 17, 956. (c) Gilpin, P. K.; Pachla, L. A. Anal. Chem.
1999, 71, 217. (d) Cosconati, S.; Marinelli, L.; Lavecchia , A.; Novellino, E.
J. Med. Chem. 2007, 50, 1504.
5.
Itoh, T.; Nagata, K.; Miyazoki, M.; Ishkawa, H.; Kurihara, A.; Ohsawa A.
Tetrahedron 2004, 60, 6649.
6.
Cooper, K.; Fray, M. J.; Parry, M. J.; Richardson, K. K.; Steele, J. J. Med.
Chem. 1992, 35, 3115.
7.
(a) Sambongi, Y.; Nitta, H.; Ichihasi, K.; Futai M.; Ueda, I. J. Org. Chem.
2002, 67, 3499. (b) Itoh, T.; Nagata, Miyazoki, K. M.; Ishkawa, H.; Kurihara,
A.; Ohsawa, A. Tetrahedron Letter 2002, 43, 3105.
8.
Lavilla, R. J. Chem. Soc. Perkin Trans.1 2002, 1141.
9.
(a) Heravi, M. M.; Behbahani, F. K.; Oskooic, H. A.; Shoer, R. H.
Tetrahedron Letter, 2005, 46, 2775. (b) Bagley, M. C.; Lubinu, M. C.
Synthesis 2006, 1283. (c) Adibi, H.; Hajipour, A. R. Bioorg. Med. Chem.
Lett. 2007, 17, 1008.
10. Shridhar, R.; Perumal, P. Tetrahedron, 2005, 61, 2465.
11. Moseley, J. D. Tetrahedron Lett. 2005, 46, 3179.
12. Prakash, O.; Hussain, K.; Kumar, R.; Wadhva, D.; Sharma, C.; Aneja, K. R.
Org. Med. Chem. Lett. 2011, 1, 5.
13. Zhou, X-F.; Zhang, L.; Tseng, E.; Ramsy, E. S.; Schentag, J. J.; Coburn, R.
A.; Morris, M. E. Drug Metab. Dispos. 2005, 33, 321.
48
Chapter 2
14. (a) Mojarrad, J. S.; Zamani, Z.; Nazimihey, H.; Ghasemi, S.; Asgari, D. Adv.
Pharm. Bull. 2011, 1, 1. (b) Chang, C-C.; Cao, S.; Kang, S.; Silverman, R. B.
Bioorg. Med. Chem. 2010, 18, 3147.
15. Lavanay, T.; Manjula, S.; Ellandala, R.; Kumar, T. P.; Madhavi, K. Int. J.
Res. Pharm. Chem. 2011, 1(4), 1203.
16. Kumar, R. S.; Idhayadhula, A.; Nasser, A. J. A.; Murali, K. Indian J. Chem.
2011, 50B, 1140.
17. Trivedi, A.; Dodiya, D.; Dholariya, B.; Kataria, V.; Bhuva, V.; Shah, V.
Chem. Biol. Drug. Des. 2011, 78, 881.
18. (a) Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem.
Soc. 2009, 131, 8756. (b) Xing, R.-G.; Li, Y.-N.; Liu, Q.; Han, Y.-F.; Wei,
X.; Li, J.; Zhou, B. Synthesis 2011, 2066. (c) Li, G.; Antilla, J. C. Org. Lett.
2009, 11, 1075. (d) Pelletier, G.; Bechara, W. S.; Charette, A. B. J. Am.
Chem. Soc. 2010, 132, 12817. (e) Rueping, M.; Brinkmann, C.; Antonchick,
A. P.; Atoresei, I. Org. Lett. 2010, 12, 4604.
19. (a) Hantzch A. Justus Leibigs Ann. Chem. 1882, 215, 1. (b) Love, B.; Snader,
K. M.; J. Org. Chem. 1965, 30, 1914.
20. (a) Correa, W. H.; Scott, J. L. Green Chem. 2001, 3, 296. (b) Sapkal, S. B.;
Shelke, K. F.; Shingate, B. B.; Shingare, M. S. Tetrahedron Lett. 2009, 50,
1754. (c) Kumar, A.; Mourya, R. A. Synlett 2008, 883.
21. (a) Sridhar, R.; Perumal, P. T.; Tetrahedron 2005, 61, 2465. (b) Debache, A.;
Boulcina, R.; Belfaithah, A.; Rhouhati, S.; Carboni, B. Synlett 2008, 4, 509.
22. Wang, L. M.; Sheng, J.; Zhang, L.; Hang, J-W.; Fan, Z. Y.; Tian, H.; Quian,
C. T. Tetrahedron 2005, 61, 1539.
23. Ko, S.; Sastry, M. N. V.; Lin, C.; Yao, C. F. Tetrahedron Lett. 2005, 46,
5771.
24. Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadhav, J. S. Tetrahedron
Lett. 2003, 44, 4129.
25. Tewari, N.; Dwivedi, N.; Tripathi, R. P.; Tetrahedron Lett. 2004, 45, 9011.
26. Lee, J. H. Tetrahedron Lett. 2005, 46, 7329.
27. Ko, S.; Yao, C. F. Tetrahedron 2006, 62, 7293.
28. Sharma G. V. M.; Reddy, K. L.; Lakshmi, P. S.; Krishna, P. R. Synthesis
2006, 55.
49
Chapter 2
29. (a) Maheswara, M.; Siddaiah, V.; Rao, Y. K.; Tzeng, Y.; Sridhar, C. J. Mol.
Cat. A: Chem. 2006, 260(1-2), 179. (b) Gupta, R.; Paul, S.; Loupy, A.
Synthesis 2007, 2835.
30. Wang, X-S.; Li, Z. Y.; Zhang, J. C.; Li, J-T Ultrasonics Sonochem. 2008, 15,
677.
31. Biswanath, D.; Kanaparthy, S.; Katta, V.; Bomenna, R. Chem. Pharm. Bull.
2008, 56 (3), 366.
32. Adibi, H.; Samimi, H. A.; Beygzadeh, M. Catal. Commun. 2007, 8, 2119.
33. Datta, B.; Pasha, M. A. Chin. J. Catal. 2011, 32(7), 1180.
34. Rao, C. V. N.; Rao, P. V.; Prasad, S. R.; Subhani, S.; Gopi, Y. Der
Pharmacia Lett. 2012, 4(2), 620.
35. Khojastehnezhad, A.; Moenpour, F.; Shams, A. Synthesis and Reactivity in
Inorganic, Metal-organic and Nano-Metal Chemistry 2012, 42, 273.
36. (a) Ohberg, L.; Westman, J. Synlett 2001, 1296. (b) Agarwal, A.; Chauhan, P.
M. S. Tetrahedron Lett. 2005, 46, 1345. (c) Tu, S.; Zhang, J.; Zhu, X.;
Zhang, Y.; Wang, Q.; Xu, J.; Jiang, B.; Jia, R.; Zhang, J.; Shi, F. J.
Heterocycl. Chem. 2006, 43, 985. (d) Khrustalev, D. P.; Suleinemova, A. A.;
Fazyelov, S. D.; Gazaliev, A. M.; Ayapbergenov , K. A. Russ. J. Gen. Chem.
2010, 80 (2), 376.
37. Sabitha G.; Arundhati, K.; Sudhakar, K.; Sastry, B. S.; Yadhav, J. S. Synth.
Commun. 2009, 39, 2843.
38. Lei, M.; Ma, L.; Hu, L.; Synth. Commun. 2011, 41, 1969.
39. Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. Green Chem.
2003, 5, 60.
40. Brigwood, K. L.; Veitch, E. G.; Ley, S. V. Org. Lett. 2008, 10(16), 3627.
41. Debache, A.; Ghalem, W.; Boulcina, R.; Bailfaitah, A.; Rhouti, S.; Carboni,
B. Tetrahedron Lett. 2009, 50, 5248.
42. Tamaddon, F.; Razmi, Z.; Jafari, A. A. Tetrahedron Lett. 2010, 51, 1187.
43. Yadav, D. K.; Patel, R.; Srivastava, V. P.; Watal, G.; Yadav, L. D. S. Chin. J.
Chem. 2011, 29, 118.
44. Bandyopadhyay, D.; Maldonado, S.; Banik, B. K.; Molecules 2012, 17, 2643.
45. Wu, X. Y. Synth. Commun. 2012, 42, 454.
46. Shaabani, A.; Samadi, S.; Rahmati, A. Synth. Commun. 2007, 37, 491.
50
Chapter 2
47. (a) Reddy, L. R.; Rao, K. R. Organic Preparations and Procedures Int. 2000,
32(2), 185. (b) Krishnaveni, N, S.; Surendra, K.; Kumar, V. P.; Srinivas, B.;
Reddy, C. S.; Rao, K. R. Tetrahedron Lett. 2005, 46, 4299.
48. Nayak, A. S.; Achaiah, G.; Malla Reddy, V. Indian J. Heterocycl. Chem.
2009, 18, 413.
51