Synthesis instructions as PDF file for printing - kriemhild

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5013 Synthesis of 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-
3,5-dicarboxylic acid diethyl ester
NH 4 HCO 3
+
+ 2
O
OC 2 H 5
1
H 5 C 2 O
O O
OC 2 H 5
H O O CH3 H3C N
H
CH3 + 4 H2O CH5NO3 C7H6O C6H10O3 C19H23O4N + CO2 (79.1) (106.1) (130.1)
(329.4)
Literature
Hinkel, L. E., Ayling, E. E. Morgan, W. H., J. Chem. Soc., 1931, 1835
Classification
Reaction types and substance classes
reaction of the carbonyl group in aldehydes, reaction of the carbonyl group in ketones,
Hantzsch synthesis, ring closure reaction
carboxylic acid ester, aldehyde, ketone, heterocycle, aromatics
Work methods
microwave-assisted reaction, heating under reflux, filtering, evaporating with rotary
evaporator, stirring with magnetic stir bar, draining of gases
Instruction (batch scale 100 mmol)
Equipment
Microwave system ETHOS 1600, 500 mL two-neck flask, 50 mL round bottom flask,
magnetic stirrer, magnetic stir bar, reflux condenser, glass tube (40 cm, NS 29), adapter with
ground glass joint and hose coupling, suction flask, 2 wash bottles, Buechner funnel (diameter
6 cm), rotary evaporator, desiccator
Substances
benzaldehyde (bp 179 °C) 10.6 g (10.1 mL, 100 mmol)
acetoacetic acid ethyl ester (bp 180 °C) 28.6 g (27.8 ml, 220 mmol)
ammonium hydrogen carbonate 9.88 g (125 mmol)
ethanol (bp 78 °C) 100 mL
tert-butyl methyl ether (bp 55 °C) 40 mL
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Reaction
The reaction apparatus consists of a 500 mL two-neck flask with magnetic stir bar, electronic
temperature control and reflux condenser. The reflux condenser is connected with an adapter
with ground glass joint and hose coupling and a hose for draining of the gases forming during
reaction. The hose is connected with an empty safety wash bottle which is connected with a
wash bottle, filled with about 300 mL of water.
10.6 g (10.1 mL, 100 mol) benzaldehyde, 28.6 g (27.8 mL, 220 mmol) acetoacetic acid ethyl
ester, 9.88 g (125 mmol) ammonium hydrogen carbonate and 40 mL ethanol are filled in the
reaction flask. The reaction apparatus is installed with the glass tube in the micro wave system
(see "Technical instructions: Standard refluxing apparatus for micro wave systems") and
treated for 40 minutes: The mixture is heated with 900 W in 2 minutes to 80 °C and this
temperature is kept for 20 minutes with 400 W, then with 700 W with a temperature ramp in
3 minutes from 80 °C to 88 °C until continuously refluxing and this temperature is kept for
15 minutes with 500 W. Afterwards the reaction mixture is further stirred for 30 minutes
without additional energy supply.
Work up
Until its complete crystallization the cooled reaction mixture is kept in the cooler overnight
where the crude product crystallizes as light-yellow solid material. The crude product is finely
chopped in the flask and sucked off over a Buechner funnel. On the Buechner funnel it is
washed with 10 mL, 20 mL and 10 mL ethanol and sucked off.
A second product fraction can be gained from the filtrate:
The solvent is evaporated from the filtrate at the rotary evaporator and the remaining oily
crystalline paste is stirred with 30 mL tert-butyl methyl ether for 15 minutes. The solid
material is filtered over a folded filter paper and washed repeatedly with 10 mL tert-butyl
methyl ether. The yellowish residue is transferred in a 50 mL flask and stirred with 20 mL
ethanol for 15 minutes, then sucked off over a Buechner funnel, washed with less ethanol and
sucked off again.
The two product fractions are dried in the desiccator at reduced pressure.
Yield (total): 21.1 g (64.1 mmol, 64%); mp 156-158 °C; GC-purity of both fractions 100%.
The first product fraction is colourless and finely crystalline, the second pale-yellow.
Comments
An aquaeous solution of ammonia was not used for the reaction since a high water
concentration in the system is disadvantageous for the reaction. From the used ammonium
hydrogen carbonate in the temperature area of 80 °C the ammonia necessary for the reaction
is released. A larger excess of ammonia does not lead to an increase in yield.
2
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Waste management
Recycling
The evaporated ethanol is collected and redistilled.
Waste disposal
Waste Disposal
tert-butyl methyl ether filtrate organic solvents, halogen free
ethanol filtrates and washing solutions organic solvents, halogen free
Time
2 - 3 hours (without drying time)
Break
Before work-up
After isolation of the first product fraction
Degree of difficulty
Easy
Analytics
GC
Sample preparation:
50 mg of a sample are dissolved in 1 mL dichlormethane from which 3 µL are injected.
GC-conditions:
column: HP-5; length 30 m, internal diameter 0.32 mm, film 0.25 µm
inlet: split injection 194:1
carrier gas: H2, pre-column pressure 31 kPa
oven: 3 min isotherm at 50 °C, afterwards with 8 °C/min to 320 °C
detector: 300 °C
Percent concentration was calculated from peak areas.
GC of the pure product
Retention time of the product = 29 min. No impurities were detected.
3
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1 H NMR spectrum of the product (300 MHz, CDCl3)
7.3
7.0
7.2
(ppm)
7.1
6.0
5.0
H 5 C 2 O
9
8
4.1
(ppm)
4.0
(ppm)
δ (ppm) Multiplicity Number of H Assignment
1.22 t 6 CH2-CH3
2.32 s 6 CH3 (at the ring)
4.08 m 4 CH2-CH3
4.99 s 1 4-H
5.72 s 1 NH
7.07-7.30 m 5 CH arene
4.0
O O
3
10
7
4
1
H C 2
3 N 6 CH3 H
11
12
5
3.0
OC 2 H 5
4
2.0
1.0
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13 C NMR spectrum of the product (300 MHz, CDCl3)
160
140
120
100
(ppm)
δ (ppm) Assignment
167.65 C=O
147.76 C-7
143.87 C-2, C-6
127.99, 127.82 C-8, C-12, C-9, C11
126.09 C-10
104.14 C-3, C-5
59.72 O-CH2-
39.62 C-4
19.55 CH3 at the ring
14.24 CH3-CH2-
76.5-77.5 solvent
80
5
60
40
H 5 C 2 O
20
9
8
O O
3
10
7
4
1
H3C 2 N 6 CH3 H
11
12
5
OC 2 H 5
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IR-spectrum of the product (KBr)
%T
16,6
16
15
14
13
12
11
10
9
8
7
6,4
3340,57
3057,97
2898,55
3239,13 2985,50
Hantzsch-Synthese
Zielprodukt
1689,27
4000,0 3000 2000 1500 1000 450,0
cm-1
1653,14
1486,94
6
1454,42
(cm -1 ) Assignment
3340 N-H- valence
3080, 3060 C-H-valence, arene
2985, 2900 C-H-valence, alkane
1690 C=O-valence, ester
1655 C=C-valence, alkene
1490 C=C-valence, arene
1324,35
1371,32
1248,48
1299,06
1165,38
1208,74
1122,02
1049,76
1020,86
1089,51
829,37
735,43
771,56
702,91
500,58
637,87
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