A simple and fast synthetic pathway of β-Enamino-esters by condensation of β-Keto ester with aliphatic and aromatic amines in ethanol

Article abstract of DOI:10.14233/ajchem.2015.18324

The β-keto ester undergoes condensation reactions with aliphatic and aromatic amines in ethanol to give high-yielding β-enamino ester. The method is simple, cost-effective and environmentally benign. Structural characterization of the synthesized compound

Full text of DOI:10.14233/ajchem.2015.18324

Asian Journal of Chemistry; Vol. 27, No. 7 (2015), 2575-2578
A
SIAN
J
OURNAL OF HEMISTRY
C
http://dx.doi.org/10.14233/ajchem.2015.18324
A Simple and Fast Synthetic Pathway of β-Enamino-Esters by Condensation of
β-Keto Ester with Aliphatic and Aromatic Amines in Ethanol
1,2
1,2
3
4
Y. KOUADRI1,2,*, M.R. OUAHRANI , B.E. MISSAOUI , F. CHEBROUK and N. GHERRAF
1Laboratoire de Chimie Organique, Université KASDI Merbah, Ouargla, Algéria
2Laboratoire VPRS Université KASDI Merbah, Ouargla, Algéria
3Centre de Recherche Scientifique et Technique en Analyses Physico-Chimiques (CRAPC), BP 248, Alger 16004, Algéria
4Laboratoire des Ressources Naturelles et Aménagement des Milieux Sensibles, Université Larbi ben M'hidi, Oum Elbouaghi, Algeria
*Corresponding authors: Fax: +213 32424213; Tel: +213 559103485; E-mail: hadadberini@yahoo.com; ngherraf@yahoo.com
Received: 14 June 2014;
Accepted: 14 October 2014;
Published online: 30 March 2015;
AJC-17082
The β-keto ester undergoes condensation reactions with aliphatic and aromatic amines in ethanol to give high-yielding β-enamino ester.
The method is simple, cost-effective and environmentally benign. Structural characterization of the synthesized compounds was carried
out by spectroscopic methods (1H NMR, 13C NMR and DEPT).
Keywords: β-Keto esters, β-Enamin oesters.
However, these methods suffer from one or more drawbacks
such as the use of expensive or less readily available reagents,
vigorous reaction conditions, longer reaction times, unsatis-
factory yields, low selectivity or the use of toxic solvents that
limit these methods to small scale synthesis.
Due to the importance of these compounds in organic
synthesis, the development of facile and efficient synthetic
methods to the β-enamino esters is of prime necessity. It invol-
ves the condensation of amines on β-keto esters (Scheme-II).
INTRODUCTION
The β-enamino esters are useful synthones for the synthesis
of various pharmaceuticals1 and bioactive heterocycles2,3 such
as 1,4-dihydropyridines4 pyrazoles, oxazoles, quinolines, dibenzo-
diazepines, tetrahydrobenzoxazines, tetronic acids and tetra-
hydro phenanthridines5. They have been utilized for the prepa-
ration of different important antibacterial, anti-inflammatory,
anticonvulsant and antitumour agents6. Moreover, they are
useful intermediates for the preparation of α,β-aminoacids7,
azocompounds8 and alkaloids9. Given their importance in the
field of chemical synthesis, research continues to grow to develop
a variety of more effective methods in terms of reduction of
time, yield and selectivity.
Different synthetic ways are used, we can cite as examples:
(1) The condensation of β-keto esters with amines in the
presence of catalysts, such as: NaAu-ClO4·2H2O10; Bi(TFA)311;
Zn(ClO4)2·6H2O12; CeCl3·7H2O13; SiO2/HClO414; (AlPO4)15; (2)
Addition of amines to alkylpropiolates or dialkylacetylendi-
carboxylates a solvent-free16; (3) Hydroamidation of electron-
deficient terminal alkynes by amides in the presence of a Pd-
catalyst17; (4) Addition of anilines to alkyl-propiolates in the
presence of catalyzed by Au(I)18; AgNTf219; (5) Treatment of
aliphatic or aromatic nitriles with an excess of α-bromo esters
in the presence of activated zinc dust20; (6) Reaction of aryl
nitriles with potassium ethyl malonate in the presence of zinc
chloride21; (Scheme-I).
EXPERIMENTAL
1H, 13C, DEPT spectra were recorded on a Bruker Avance
300. Chemical shifts are given in parts per million (ppm) with
respect to internal TMS for all recorded NMR spectra and J
values are quoted in hertz (Hz). The nuclear magnetic resonances
were recorded on a Bruker AC-300 device.
General procedure
Operating mode of β-keto esters with aliphatic primary
amines: In a three-necked 100 mL flask equipped with a
magnetic stirrer with heating and cooling, the β-keto ester
(1 eq) was placed in 10 mL of ethanol and then we add an
equivalent of primary amine in 10 mL of EtOH. The mixture
is subjected to stirring and heated under reflux. The reaction
was followed by thin layer chromatography TLC. The solvent
was evaporated under reduced pressure.
Ethyl 2-(allylamino)cyclohex-1-ene carboxylate (1):
Yield: 82 %; 1H NMR (CDCl3) δ ppm: 1.20 (t, J = 7 Hz, 3H,

2576 Kouadri et al.
Asian J. Chem.
O
O
R1
OR4
O
O
O
KO
OR4
OR4
R2R3NH (1)
R1
R2R3NH
(2)
R1CN
(6)
for
for
R1=H,CO2R
R2=H,alkyl
R3=Ar,alkyl
R4=Et,Me
R1
O
R1=Ar,alkyl
R2=H,R3=H
R4=Et
R2
N
OR4
R3
(4)
R2R3NH
R1CN
for
(3)
(5)
R1=alkyl,Ar
R2=H
R3=Ar
R4=Et,Me
O
for
for
O
R2R3NH
Br
R1=H
R1=Ar,alkyl
R2=H
R3=H
OR4
OR4
R2=H,alkyl
R3=COEt
R4=Et
R4=Et
O
OR4
R1
Scheme-I: Synthesis of b-enamino esters
R
O
O
(Z)-methyl 3-(allylamino)but-2-enoate (4): Yield: 80 %;
1H (CDCl3) δ ppm: 1.83 (s, 3H, CH3); 3.54 (s, 3H, CH3); 3.75
(t, 2H, -CH2); 4.41 (s, 1H, =CH); 5 (dd, J = 10.4 Hz, J = 1.1
Hz, 1H, =CH); 5.1 (dd, J = 17.2 Hz, J = 1.1 Hz, 1H, =CH); 5.8
(ddt, J = 15.2 Hz, J = 10.1 Hz, J = 5 Hz, 1H, =CH); 8.57 (s,
1H, NH); 13C NMR (CDCl3) δ ppm: 29,69 (CH3); 45,15
(-CH2-); 49,69 (CH3); 82,39 (=CH); 115,91 (=CH); 134,73
(=CH); 162,02 (Cq); 170,88 (C=O).
(Z)-Méthyl 3-(2,2-dimethoxyethylamino)but-2-enoate
(5): Yield: 75 %; 1H NMR (CDCl3) δ ppm: 2.45 (s, 3H, CH3);
3.81-3.89 (m, 7H); 4.02 (s, 3H, CH3); 4.91-4,98 (m, 2H); 8.57
(s,1H, NH); NMR DEPT (CDCl3) δ ppm: 29,08 (CH3); 45,10
(-CH2-); 50,25 (CH3); 82,44 (=CH); 103,73 (-CH).
NH
O
R2
+
R NH2
R2
O
R1
R1
O
R3
R3
Scheme-II: Synthesis of β-enamino esters
CH3); 1.46-1.64 (m, 4H); 2.20-2.30 (q, J = 5.85 Hz, 4H); 3.76
(t, 2H, -CH2); 4.08 (q, J = 7 Hz, 2H, -CH2); 5.1 (dd, J = 10.5
Hz, J = 1.3 Hz, 1H, =CH); 5.2 (dd, J = 17 Hz, J = 1.3 Hz, 1H,
=CH); 5.7 (ddt, J = 15.3 Hz, J = 10.2 Hz, J = 5.1 Hz, 1H,
=CH); 9.01 (s, 1H, NH); 13C NMR (CDCl3) δ ppm: 14,65
(CH3); 22,25 (CH2); 22,69 (-CH2-); 23,82 (-CH2-); 26,01
(-CH2-); 44,44 (-CH2-); 58,64 (-CH2-); 90,14 (=C); 115,54
(=CH); 135,49 ( =C); 159,40 (=CH); 170,88 (C=O).
(Z)-Diméthyl 3-(2,2-dimethoxyethylamino)pent-2-
enedioate (6): Yield: 74 %; 1H NMR (CDCl3) δ ppm: 3.16-
3,30 (m, 4H); 3.32 (s, 6H, CH3); 3.53 (s, 3H, CH3); 3.63 (s,
3H, CH3); 4.30 (t, J = 5.5Hz, 1H, -CH) 4.44 (s, 1H, =CH);
8.51 (s, 1H, NH); NMR DEPT (CDCl3) δ ppm: 38,94 (-CH2-);
45,95 (-CH2-); 50,52 (CH3); 52,78 (CH3); 54,90 (2CH3); 85,36
(=CH); 103,80 (-CH).
Condensation with aniline: In a test tube is placed the
phenyl with β-keto cyclic. The obtained product was washed
with ethyl ether.
Ethyl 2-(phenylamino)cyclohex-1-ene carboxylate (7):
Yield: 85 %; 1H NMR (CDCl3) δ ppm: 1.25 (t, J = 7 Hz, 3H,
CH3); 1.69 (d, J = 6.61, 4H); 2.27-2.44 (dt, J = 5.86 Hz, 22.66
Hz, 4H); 4.14 (q, J = 7 Hz, 2H, -CH2); 7.10-7.20 (m, 3H, Harom);
7.30-7.40 (m, 2H, Harom) 10.81 (s, 1H, NH); 13C NMR (CDCl3)
δ ppm: 14,62 (CH3); 21,93 (-CH2-); 22,24 (-CH2-); 23,75
Ethyl 2-(2,2-dimethoxyethylamino)-cyclohex-1-ene
carboxylate (2): Yield: 87 %; H NMR (CDCl3) δ ppm: 1.20
1
(t, J = 7 Hz, 3H, CH3); 1.43-1.64 (m, 4H); 2.14-2.29 (q, J =
5.85 Hz, 4H); 3.24 (t, 2H, -CH2-); 3.34 (s, 6H, CH3) 4.08 (q, J
= 7 Hz, 2H,-CH2); 4.35 (t, J = 5 Hz, 1H, -CH-); 8.90 (s, 1H,
NH); 13C NMR (CDCl3) δ ppm: 14,60 (CH3); 22,28 (-CH2-);
22,63 (-CH2-); 23,85 (-CH2-); 26,58 (-CH2-); 44,03
(-CH2-); 54,13 (CH3); 58,65 (-CH2-); 90,66 (=C); 103,53
(-CH); 158,66 (=C); 170,73 (C=O).
Méthyl 2-(2,2-dimethoxyethylamino)cyclopent-1-ene
carboxylate (3):Yield: 84 %; 1H NMR (CDCl3) δ ppm: 1.47-
1,87 (m, 2H); 2.43-2,60 (m, 4H); 3.27 (t, J = 5.5 Hz, 2H,
-CH2-); 3.65 (s, 6H, CH3); 4.35 (t, J = 5 Hz, 1H, -CH-); 7,42
(s, 1H, NH); 13C NMR (CDCl3) δ ppm: 20,85 (CH2-); 29,13
(-CH2-); 32,20 (-CH2-); 46,75 (-CH2-); 50,14 (CH3); 54,49
(CH3); 94,15 (=C); 103,76 (CH) 155,33 (C=O); 168,60 (=C).

Vol. 27, No. 7 (2015)
A Simple and Fast Synthetic Pathway of β-Enamino-Esters 2577
(-CH2-); 27,65 (-CH2-); 58,90 (-CH2-); 92,43 (C); 124,20
(Carom); 129,22 (Carom) 139,37(C); 156,51 (Carom); 170,00
(C=O).
Methyl 2-(2-aminophenylamino) cyclopent-1-ene
carboxylate (8): Yield: 83 %; 1H NMR (CDCl3) δ ppm: 1.76-
1,91 (m, 2H); 2.44-2,66 (dt, 4H); 3.76 (s, 3H, CH3); 6.68-6,81
(m, 2H, Harom); 6.97-6,10 (m, 2H, Harom); 8,71 (s, 1H, NH).
Spectroscopic (1H NMR,13C NMR) characteristics data,
confirming the presence of β-enamino esters: The 1H NMR
spectra analysis of the compounds obtained in Table-1, shows
that the compounds 2, 3, 5 and 6 exhibit, characteristic signals:
a high field singlet signal between 3.43 and 3.45 ppm corres-
ponding to 2(OCH3) and a second signal in the form of a triplet
in the range 4.30-4.35 ppm corresponding to proton CH
(OMe)2 of acetyl, while a massive characterizing proton
CH2CH(OMe)2 resonates in the range 3.24-3.27 ppm.
The 1H NMR spectra of compounds 1and 4exhibit a doublet
split triplet signal in the range 5.60-5.90 ppm corresponding
to the proton HC=CH2, the chemical shifts of the protons of
the double bond Hcis and Htrans appear almost superimposed in
the form of a split doublet in the range 5-5.40 ppm, followed
by an apparent signal in the range 3.7-3.8 ppm corresponding
to the protons of CH2-CH=CH2.
RESULTS AND DISCUSSION
The results of the condensation of these β-keto esters with
amines are recorded on Table-1.As has already been discussed,
β-enamino esters are obtained via condensation reactions of
β-keto esters with primary amines in ethanol under reflux, or
at room temperature under solvent free conditions. The reaction
yields vary from 70 to 87 %.
The method averred to be very selective, since the ketonic
carbonyl group is more electrophilic than ester, (Alternatively,
the ketone loses no resonance when it accepts a nucleophile,
while ester loses the minor contributor of resonance), according
to the following mechanism:
We also noted that a singlet signal is observed in the range
4.41-4.44 ppm for compounds 4, 5 and 6 corresponding to the
ethylene protons.
In case of 13C NMR it is suggested that on the one hand,
the disappearance of the function C=O of the ketone β-keto
esters and on the other hand the appearance of two ethylenic
carbons in α and β of the ester function.
R
OH
O
O
O
NH
O
H
H
-H20
R N
R NH2
R2
R2
R2
+
In conclusion, we have prepared eight enaminos derived
from β-keto esters, in simple terms and with very good yields.
O
O
R1
O
R1
R1
R3
R3
R3
TABLE-1
RESULTS OF THE CONDENSATION OF THESE β-KETO ESTERS WITH AMINES
Entry
01
Amine
Operating conditions
Resulting products
Yield (%)
82
β-keto ester
NH
O
O
O
Ethanol,
5h under reflux
OEt
NH2
OEt
1
MeO
OMe
O
O
O
MeO
MeO
NH2
NH2
HN
Ethanol,
4h under reflux
02
03
87
84
OEt
OEt
2
MeO OMe
O
O
MeO
MeO
HN
O
Ethanol,
3h under reflux
OMe
OMe
3
NH
O
O
O
O
O
Ethanol,
5h under reflux
NH2
NH2
04
05
80
75
OMe
MeO OMe
HN
OMe
OMe
4
MeO
MeO
Ethanol,
4h under reflux
O
OMe
5
MeO OMe
MeO
MeO
NH2
O
Ethanol,
6h under reflux
HN
06
74
MeO2C
CO2Me
MeO2C
Ph
CO2Me
6
NH
O
O
O
O
O
Ethanol,
6h under reflux
OEt
NH2
NH2
07
08
85
83
OEt
7
Ph
NH
O
Ethanol,
6h under reflux
OMe
OMe
8

2578 Kouadri et al.
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