Eco-friendly access to β-ketoamides: One-step catalyst-and solvent-free amidation of β-ketoesters under microwave irradiation

Article abstract of DOI:10.13005/ojc/340117

A highly efficient and facile catalyst- and solvent-free one step amidation of β-ketoesters, without using any additional reagents, is described. Therefore, β-ketoamides are obtained in good to excellent yields by condensation of β-ketoesters with various primary or secondary amines. This eco-friendly protocol has been developed under microwave irradiation.

Full text of DOI:10.13005/ojc/340117

ISSN: 0970-020 X
CODEN: OJCHEG
2018, Vol. 34, No.(1):
Pg. 152-160
ORIENTAL JOURNAL OF CHEMISTRY
An International Open Free Access, Peer Reviewed Research Journal
www.orientjchem.org
Eco-friendly Access to β-ketoamides: One-step
Catalyst-and Solvent-free Amidation of β-ketoesters
Under Microwave Irradiation
KHADIDJA DECHIRA1,2,ASSYATALEB1,AOUICHA BENMAATI1,
SALIH HACINI1 and HADJIRA HABIB ZAHMANI1*
1Laboratoire de Chimie Fine, Faculte des Sciences Exactes et Appliquées,
Universite d’Oran1 Ahmed Benbella, B.P -1524 Menouar, 31000 Oran, Algerie.
2Centre de Recherche Scientifique et Technique en Analyses Physico-Chimiques
(C.R.A.P.C.) B.P 384, Bou-Ismail RP 42004 Tipaza, Algerie.
*Corresponding author E-mail: habibzahmanihadjira@gmail.com
http://dx.doi.org/10.13005/ojc/340117
(Received: September 25, 2017; Accepted: December 20, 2017)
ABSTRACT
A highly efficient and facile catalyst- and solvent-free one step amidation of β-ketoesters,
without using any additional reagents, is described. Therefore, β-ketoamides are obtained in good
to excellent yields by condensation of β-ketoesters with various primary or secondary amines.
This eco-friendly protocol has been developed under microwave irradiation.
Keywords: Amidation, β-ketoesters, β-ketoamides, Catalyst-free, Solvent-free,
Microwave irradiation.
INTRODUCTION
β-ketoamides. These products are very useful
compounds to access to a wide variety of Chemical
structures (heterocycles, natural products) and
targets of pharmaceutical research2. Various
synthetic methods have been reported in the
literature to prepare amides, but the processes of
access to β-ketoamides are rather limited. Among
these, mention may be made of the nucleophilic
amidation of electrophiles such as β-ketoacids3,
β-ketoesters 4, β-thioesters5 and keten dimmers6.
Catalyst-free methodologies for synthesis
of organic compounds are of great interest for the
development of a sustainable chemistry. In addition
to the simplicity of the procedure and the reduced
cost, this also makes it possible to considerably
reduce the chemical waste in our environment1. In
this communication, we report a simple and rapid,
catalyst-free one-step synthesis of various
This is an
Open Access article licensed under a Creative Commons Attribution-NonCommercial-ShareAlike
4.0 International License (https://creativecommons.org/licenses/by-nc-sa/4.0/ ), which permits unrestricted
NonCommercial use, distribution and reproduction in any medium, provided the original work is properly cited.

153
ZAHMANI et al., Orient. J. Chem., Vol. 34(1), 152-160 (2018)
Other methods are based on Dieckmann cyclization 4.81 Hz, 2H), 3.57−3.47 (m, 2H), 3.34 (dd, J= 6.04,
of amidoesters7, treatment of carboxamides with 3.96 Hz, 1H), 2.54(dt, J= 6.04, 3.96, 1H), 2.41− 2.17
phosgene or phosphoryl chloride8, diketenes9, (m, 2H), 2.15−1.96 (m, 3H), 1.92−1.81 (m, 1H),
enzymatic hydrolysis of β-ketonitriles10 and 1.79−1.62 (m, 2H) ppm; 13C NMR (75 MHz, CDCl3):
aminolysis of β-ketoesters11, organocatalytic δ = 207.35(C), 168.06(C), 66.82(CH2), 66.59(CH2),
multicomponent of polyfunctional substrates12. 54.12(C), 46.26(CH2), 42.29 (CH2), 41.98 (CH2),
β-Ketoamides can also be prepared via Wolf 30.17(CH2), 27.09(CH2), 23.64(CH2) ppm.
rearrangement of diazodiketones in the presence
of amines13.
N,N-diallyl-2-oxocyclohexanecarboxamide
(2c). Brown oil; Rf (EtO2/PE: 6/4) = 0.33; IR: ν3082,
1
Among these approaches, the amidation 2983, 1720, 1631, 1190, 924 cm-1; H NMR (300
is the most frequently used reactions. In general MHz, CDCl3): δ = 5.80−5.69 (m, 2H), 5.25−5.08
this process involves specific reaction conditions (m, 4H), 4.28 (dd, J = 15.5, 4.3 Hz, 1H), 3.84−3.79
as the use of a specific catalysts, vigorous reaction (m, 1H), 3.72 (dd, J = 5.0, 1.6 Hz, 1H), 3.68 (d, J =
conditions and prolonged reaction times. These 5.5 Hz, 1H), 3.48 (dd, J = 10.0, 5.3 Hz, 1H), 2.53 (dt,
reactions often lead to unsatisfactory yields of J = 13.3, 4.5 Hz, 1H), 2.33 − 2.14 (m, 2H), 1.99 (dqd,
1,3-ketoamides due to the competitive enaminoester J = 12.4, 5.2, 2.7 Hz, 3H), 1.85−1.73 (m, 1H),
formation, or requires uncommercial starting 1.68−1.57 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3):
materials. In our efforts to develop greener and δ = 207.60(C), 169.95(C), 133.71(CH), 133.08(CH),
simpler amidation method, we focused on the 117.07(CH2), 116.67(CH2), 54.65(CH), 49.50 (CH2),
catalyst-free approach. Therefore, a facile one-pot 48.17(CH2), 42.17(CH2), 30.69(CH2), 27.24 (CH2),
process for the synthesis of N-mono-and 23.85(CH2) ppm.
di-substitued β-ketoamides has been elaborated
from readily available cyclic β-ketoesters in the
2-(4-phenylpiperazine-1-carbonyl)
presence of amines. Amines, amongst the most cyclohexanone (3c). White solid; m.p. = 102.9 °C;
important reagents in organic synthesis by their Rf (EtO2/PE: 6/4) = 0.28; IR: ν 2861, 1692, 1640,
1
basic and nucleophilic characters, are used in our 1596, 1183, 729, 669 cm-1; H NMR (300 MHz,
strategy as reagent and as catalyst. Realizing a CDCl3): δ = 7.34 (t, J = 7.6 Hz, 2H), 7.25−6.93 (m,
combination process of temperature and pressure 3H), 4.17 −3.97 (m, 1H), 3.83−3.75 (m, 1H), 3.58
to activate this reaction was a key contribution.
(ddd, J = 21.9, 10.9, 9.9 Hz, 2H), 3.26(s, 3H),
2.63−2.55 (m, 1H), 2.45−2.35 (m, 1H), 2.30−2.22
(m, 1H), 2.17−1.94 (m, 3H), 1.92−1.66 (m, 3H) ppm;
13C NMR (75 MHz, CDCl3): δ = 207.43(C), 167.97(C),
150.71(C), 129.25(CH), 120.69(CH), 116.75(CH),
54.26(CH2), 49.67(CH2), 45.67(CH2), 41.98(CH2),
41.79(CH2), 30.94(CH2), 30.29(CH2), 27.13(CH2),
23.60(CH2) ppm.
EXPERIMENTAL
General procedure for the synthesis of
β-Ketoamides:
To an open glass tube (G4), were added
β-ketoesters (1.0 mmol) and primary or secondary
amines (1.1 mmol) in solvent - free. The tube was
positioned in the centre of the microwave cavity,
and irradiated (850 W) until the temperature reached
180 °C for 15 to 60 minutes. Purificationof the
resultant product by short column chromatography
over silica gel (40–63 mesh) afforded the pure
products.
2-(morpholine-4-carbonyl) cyclopentanone
(4c). White oil; Rf (EtO2/PE: 6/4) = 0.32; IR: ν 2967,
1
1735, 1623, 1109, 1067 cm-1; H NMR (300 MHz,
CDCl3): δ =3.86 (dd, J = 13.4, 1.8 Hz, 1H),
3.78−3.67 (m, 3H), 3.54 (ddd, J = 11.3, 2.8, 1.4 Hz,
1H), 3.44−3.28 (m, 3H), 2.56−2.44 (m, 1H), 2.24
(dd, J = 8.4, 6.6 Hz, 2H), 2.18−2.07 (m, 2H),
1.90−1.76 (m, 1H),1.28−1.14(m 1H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 214.28(C), 166.79(C),
67.13(CH2), 66.88(CH2), 51.62(CH), 46.68(CH2),
42.75(CH2), 38.72(CH2), 27.14(CH2), 21.08(CH2) ppm.
2-(morpholine-4-carbonyl)cyclohexanone
(1c). Brown solid; mp = 77.7 °C; Rf (EtO2/PE: 4/6) =
0.25; IR: μ 2941, 2859, 1705, 1626, 1186, 1109 cm-1;
1H NMR (300 MHz, CDCl3): δ = 3.82 (dt, J= 13.60,
4.34 Hz, 1H) , 3,71 (t, J= 4.81 Hz, 2H) , 3,67 (t, J=

154
ZAHMANI et al., Orient. J. Chem., Vol. 34(1), 152-160 (2018)
N,N-diallyl-2-oxocyclopentanecarboxamide
54.82(CH2), 48.33(CH2), 38.70(CH), 27.94(CH2),
27.04(CH2), 21.04(CH2) ppm.
(5c).Yellow oil; Rf (EtO2/PE: 4/6) = 0.26; IR: ν 3461,
1
1738, 1632, 1413, 921 cm-1; H NMR (300 MHz,
CDCl3): δ = 5.86−5.64 (m, 2H), 5.14 (dd, J = 13.7,
3.2 Hz, 3H), 5.09 (d, J = 5.8 Hz, 1H), 4.30 (d, J = 3.2
Hz, 1H), 4.25 (d, J = 4.6 Hz, 1H), 3.80 (dd, J = 18.1,
4.5 Hz, 1H), 3.65 (dd, J = 15.5, 5.9 Hz, 1H), 3.35 (t,
J = 8.6 Hz, 1H), 2.55 – 2.39 (m, 1H), 2.26 (dd, J =
8.8, 6.3 Hz, 2H), 2.19– 2.07 (m, 2H), 1.88− 1.72 (m,
1H) ppm; 13C NMR (75 MHz, CDCl3): δ = 214.60 (C),
168.95(C), 133.23(CH), 132.68(CH), 116.85 (CH2),
116.37(CH2), 51.97(CH), 49.22(CH2), 48.18 (CH2),
38.52(CH2), 27.50(CH2), 20.97(CH2) ppm.
2-(morpholine-4-carbonyl)-3,4-dihydrona
phthalen-1(2H)-one (9c). White solid; Rf (EtO2/PE:
5/5) = 0.51; 1H NMR (300 MHz, CDCl3): δ= 8.02 (dd,
J = 7.8, 1.1 Hz, 1H), 7.55 (td, J = 7.5, 1.4 Hz, 1H),
7.36 (d, J = 7.7 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H),
3.95 (dt, J = 3.7, 3.7 Hz, 1H), 3.90−3.82 (m, 1H),
3.80 (d, J = 4.7 Hz, 1H), 3.77 (t, J = 4.2 Hz, 3H),
3.64−3.43 (m, 3H), 3.12 (dt, J = 16.8, 4.5 Hz, 1H),
3.05 (td, J = 11.4, 5.3, 4.5 Hz, 1H), 2.53 (dtd, J =
13.7, 11.5, 4.8 Hz, 1H), 2.31 (dq, J = 13.6, 4.4 Hz,
1H) ppm. 13C NMR (75 MHz, CDCl3): δ = 194.16
(C), 168.39(C), 144.10(C), 133.90(C), 132.00(CH),
128.84(CH), 127.63(CH), 126.86(CH), 66.89(CH2),
51.33(CH), 46.72(CH2), 42.47(CH2), 28.40(CH2),
26.36(CH2) ppm.
2-oxo-N,N-dipropylcyclopentanecarboxamide
(6c). Brawn oil; Rf (EtO2/PE: 6/4) = 0.29; IR: ν 2872,
1
1739, 1630, 1509, 1103, 733 cm-1; H NMR (300
MHz, CDCl3) : δ = δ: 3.55−3.41 (m, 2H), 3.34 (t, J =
8.5 Hz, 1H), 3.18−3.06 (m, 2H), 2.48−2.36 (m, 1H),
2.29−2.23 (m, 2H), 2.19−2.08 (m, 2H), 1.89−1.76
(m, 1H), 1.34−1.20 (m, 4H), 0.93 (dd, J = 15.7, 7.4
Hz, 6H) ppm; 13CNMR (75 MHz, CDCl3) : δ =
214.72(C), 168.72(C), 51.59(CH), 47.86(CH2),
46.04(CH2), 38.48(CH2), 31.36(CH2), 29.76(CH2),
27.68(CH2), 21.01(CH2), 20.03(CH2), 20.00(CH2),
13.76(CH3), 13.72(CH3) ppm.
1-morpholinobutane-1,3-dione (10c).
Yellow oil;Rf (EtO2/PE:5/5) = 0.33;IR:ν 2922, 1716,
1623, 1110, 1067 cm-1; 1H NMR (300 MHz, CDCl3):
δ= 3.65 (dd, J = 8.3, 5.2 Hz, 6H), 3.55 (s, 2H), 3.41 (s, 2H),
2.26 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3): δ
202.19(C), 165.08(C), 66.62 (CH2), 66.51(CH2),
49.66(CH2), 46.73(CH2), 42.09(CH2), 30.30(CH3).
2-(piperidine-1-carbonyl)cyclopentanone
N-tert-butyl-2-oxocyclohexanecarboxamide
and N-tert-butyl-2-hydroxycyclohex-1-ene carboxamide
(11c). White solid; mp = 98-100 °C; Rf (EtO2/PE:
8/2) = 0.7; IR: ν 3336, 1702, 1630, 1424, 914 cm-1;
1H NMR (400 MHz, CDCl3): δ =14.29 (s, 1H), 6.65
(s, 1H), 5.14 (s, 1H), 3.02 (ddd, J = 9.6, 5.6, 1.1 Hz,
1H), 2.41−2.34 (m, 1H), 2.16−2.10 (m, 1H),
2.00−1.98-1.93 (m, 1H), 1.92−1.83 (m, 3H),
1.61−1.57 (m, 2H), 1.32 (s, 9H), 1.27 (s, 9H) ppm;
13CNMR (101 MHz, CDCl3): δ= 210.66(C), 172.58
(C), 169.78(C), 167.87(C), 97.34(C), 56.56 (CH),
51.15(C), 51.01(C), 41.97(CH2), 30.98(CH2),
29.29(CH3), 28.89(CH3), 28.63(CH2), 27.10(CH2),
23.85(CH2), 22.96(CH2), 22.58(CH2), 21.93(CH2) ppm.
(7c). yellow oil; Rf (EtO2/PE: 6/4) = 0.36; IR: ν 2851,
1
1739, 1626, 1433, 1217, 751 cm-1; H NMR (300
MHz, CDCl3) : δ = 3.58 (dddd, J = 16.7, 14.4, 10.8,
5.5 Hz, 4H), 2.86 (t, J = 7.2 Hz, 1H), 2.54−2.41 (m,
1H), 2.34−2.28 (m, 1H), 2.23−2.10 (m, 2H),
2.0−1.80 (m, 2H), 1.72−1.55(m, 6H) ppm; 13C NMR
(75 MHz, CDCl3): δ = 214.07(C), 166.66(C), 66.86
(CH2), 66.60(CH2), 51.37(CH), 46.42(CH2), 42.46
(CH2), 38.23 (CH2), 26.91(CH2), 20.82(CH2) ppm.
2-(isoindoline-2-carbonyl)cyclopentanone
(8c). white solid; m.p. = 91 °C; Rf (EtO2/PE: 4/6) =
0.29; IR: ν 2892, 1731, 1648, 1594, 1196, 725, 704
cm-1; 1H NMR (300 MHz, CDCl3): δ = 8.21 (d, J = 8.1
Hz, 1H), 7.18 (dd, J = 7.1, 5.9 Hz, 2H), 7.03 (t, J =
7.9 Hz, 1H), 4.54 (td, J =10.1, 6.1 Hz, 1H), 4.07 (td,
J = 10.1, 7.3 Hz, 1H), 3.48 (t, J = 10.2, 6.6 Hz, 1H),
3.33−3.07 (m, 2H), 2.67−2.50 (m, 1H), 2.36 (dd, J =
8.2, 2.6 Hz, 1H), 2.33 (s, 1H), 2.31−2.18(m, 2H),
1.99−1.83(m, 1H) ppm; 13CNMR (75 MHz, CDCl3): δ
N-benzyl-2-hydroxycyclohex-1-enecarboxamide
and N-benzyl-2-oxocyclohexanecarboxamde (12c).
White oil; Rf (EtO2/PE: 7/3) = 0.7; 1H NMR (300 MHz,
CDCl3): δ =14.16 (s, 1H),7.28 (s, 1H), 7.27−7.20 (m,
5H), 6.15 (s, 1H), 4.43−4.35 (m, 2H), 3.18−3.12 (m,
1H), 2.36−2.25(m, 1H), 2.20−2.19(m, 2H), 2.09−2.07
(m, 1H), 1.92−1.88 (m, 2H), 1.65−1.60 (m, 2H) ppm;
13C NMR (75 MHz, CDCl3): δ = 208.63(C),
=
214.32(C), 166.81(C), 142.83(C), 131.66(C),
127.49(CH), 124.61(CH), 124.09(CH), 117.32(CH),

155
ZAHMANI et al., Orient. J. Chem., Vol. 34(1), 152-160 (2018)
171.43(C), 169.14(C), 168.36(C), 137.47(C),
137.30(C), 127.57(CH), 127.49(CH), 126.50(CH),
126.42(CH), 126.29(CH), 126.16(CH), 96.05(C),
55.28(C), 42.17(CH2), 41.88(CH2), 40.97(CH2), 30.11
(CH2), 28.21(CH2), 26.12 (CH2), 22.99(CH2),
21.50(CH2), 21.46(CH2), 20.83(CH2) ppm.
2.31−2.22 (m, 4H), 2.19−2.0 (m, 1H), 1.80−1.67
(m, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ = 216.0
(C), 166.9 (C), 133.7 (CH), 115.7 (CH2), 54.2 (CH),
41.4 (CH2), 38.6 (CH2), 25.9 (CH2), 20.1 (CH2) ppm.
N-allyl-1-oxo-1,2,3,4-tetrahydronaphthalene-
2-carboxamide (17c). White solid; Rf (PE/ ACEt2: 8/
2) = 0.75; 1H NMR (300 MHz, CDCl3): δ = 7.95 (dd,
J = 7.8, 1.0 Hz, 1H), 7.43 (td, J = 7.5, 1.4 Hz, 1H),
7.25-7.22 (m, 1H), 7.18 (d, J = 7.6 Hz, 1H), 5.87 –
5.71 (m, 1H), 5.15 (ddd, J = 17.2, 3.1, 1.6 Hz, 1H),
5.05 (ddd, J = 10.3, 2.8, 1.4 Hz, 1H), 3.94 – 3.83 (m,
2H), 3.35 (t, J = 7.2 Hz, 1H), 3.05 (dt, J = 16.7, 5.3
Hz, 1H), 2.83 (ddd, J = 23.2, 14.7, 7.4 Hz, 1H), 2.38
(td, J = 7.4, 5.3 22Hz, 2H) ppm; 13C NMR (75 MHz,
CDCl3): δ = 196.2 (C), 167.7 (C), 144.6 (C), 134.1
(CH), 133.9 (CH), 131, 7 (C), 128.7 (CH), 127.5
(CH), 126.6 (CH), 115.7 (CH2), 52.8 (CH), 42.0
(CH2), 27.8 (CH2), 25.4 (CH2) ppm.
2-oxo-N-phenylcyclopentanecarboxamide
(13c). White solid; mp = 88-90 °C; Rf (EtO2/PE: 5/5) =
0.4; IR: ν 3050, 1951, 1739, 1664, 1533, 1442, 1311,
1146 cm-1; 1H NMR (300 MHZ, CDCl3): δ = 8.74 (s,
1H), 7.56 (d, J = 7.7 Hz, 2H), 7.32 (t, J = 7.9 Hz, 2H),
7.10 (t, J = 7.4 Hz, 1H), 3.15 (t, J = 9.4 Hz, 1H), 2.46−
2.27 (m, 4H), 2.12−2.05 (m, 1H), 1.91−1.84 (m, 1H)
ppm; RMN13C (300 MHZ, CDCl3): δ = 217.06 (C) ,
164.59 (C), 137.83 (C), 129.10 (CH), 124.43 (CH),
119.97 (CH), 54.81(CH), 39.22 (CH2), 25.82 (CH2),
20.35 (CH2) ppm.
N-tert-butyl-2-oxocyclopentanecarboxamide
(14c). White solid; m.p.= 96-98 °C; Rf (EtO2/ PE: 8/
2) = 0.54; IR: μ 3312, 1741, 1663, 1548, 745 cm-1; 1H
NMR (300 MHz, CDCl3): δ = 6.57 (s, 1H), 2.91 (t, J =
9.1 Hz, 1H), 2.43−2.22 (m, 4H), 2.11−1.99 (m, 1H),
1.98−1.73 (m, 1H), 1.36 (s, 9H) ppm; 13C NMR (75
MHz, CDCl3): δ = 217.05(C), 165.66(C), 54.82(CH),
51.24(C), 38.95(CH2), 28.73(CH3), 25.75(CH2),
20.28(CH2) ppm.
N-tert-butyl-3-oxobutanamide (18c). White
oil; Rf (EtO2/PE: 7/3) = 0.75; IR: ν 3316, 1714, 1646,
1544, 791 cm-1; 1H NMR (400 MHz, CDCl3): δ = 6.66
(s, 1H), 3.31 (s, 2H), 2.24 (s, 3H), 1.34 (s, 9H) ppm;
13C NMR (75 MHz, CDCl3): δ = 204.87(C),
164.49(C), 51.33(CH2), 50.92(C), 30.99(CH3),
28.35(CH3) ppm.
MATERIALS AND METHODS
N-(furan-2-ylmethyl)-2-oxocyclopentane-
carboxamide(15c). Brown solid; Rf (AcOEt/PE: 1/1)
= 0.38; IR: ν 3050, 1951, 1739, 1664, 1533, 1442,
Solvents and reagents were purchased
from Sigma-Aldrich and used as received. The
reactions under microwave irradiation were
performed in a microwave apparatus Anton Paar,
Monowave 300 model power 850 W. The reactions
were monitored by TLC visualized by UV (254 nm)
and/or with p-anisaldehyde.The melting points were
determined on an M-560 melting point apparatus
and are uncorrected. Purification of reaction
products was carried out by flash chromatography
using silical-gel (40-63 mm) eluted with AcOEt/PE
or EtO2/PE. NMR data were recorded at 300 or 400
MHz (Bruker Avance spectrometers) in CDCl3 using
1
1311, 1146 cm-1; H NMR (300 MHz, CDCl3): δ =
7.38 (t, J = 1.8 Hz, 1H), 6.34 (dd, J = 3.1, 1.9 Hz, 1H),
6.26 (dd, J = 3.2, 1.7 Hz, 1H), 4.54 (dd, J = 15.5, 5.8
Hz, 1H), 4.43 (dd, J = 15.5, 5.4 Hz, 1H), 3.05 (t, J =
9.4 Hz, 1H), 2.43−2.29 (m, 4H), 2.12−2.08 (m, 1H),
1.90−1.88 (m, 1H) ppm; 13C NMR (75 MHz, CDCl3):
δ = 215.9 (C), 166.7 (C), 151.0 (C), 142.1 (CH),
110.1(CH), 106.9 (CH), 54.1 (CH2), 38.6 (CH2), 36.4
(CH2), 25.8 (CH2), 20.3 (CH2) ppm.
N-allyl-2-oxocyclopentanecarboxamide
(16c). white solid; Rf (EtO2/PE: 7/3) = 0.46; 1H NMR as internal standards the residual CHCl3 signal for
(300 MHz, CDCl3): δ = 6.95 (s, (NH)1H), 5.74 (ddt, 1H NMR (d = 7.26 ppm) and the deuterated solvent
J = 17.1, 10.5, 5.4 Hz, 1H), 5.13 (ddd, J = 17.2, 3.1, signal for 13C NMR (d = 77.16ppm). IR spectra were
1.6 Hz, 1H), 5.04 (ddd, J = 10.3, 2.9, 1.4 Hz, 1H), obtained with a Alpha-p Brucker ATR diamond
3.80 (tt, J = 5.6, 1.6 Hz, 2H), 2.95 (t, J = 9.3 Hz, 1H), FT-IR spectrophotometer.

156
ZAHMANI et al., Orient. J. Chem., Vol. 34(1), 152-160 (2018)
RESULTS AND DISCUSSION
In a second stage, the scope of the reaction
was investigated with variety of secondary amines
1b-6b and cyclic β-ketoesters (five (C5) and six (C6)
membered rings). The solvent-free methodology
appeared to be applicable to prepare a wide range
of N-disubstitued β-ketoamides compounds, as
reported Table. 2.
The environment-friendly methods
developed in our work have now evolved to
microwave-accelerated solvent free aminolysis
procedure. In this context, to appraise the
combination of temperature and pressure effect we
tested the feasibility of amidation at several
temperatures. We initiated our studies of
the amidation of cylohexanone-ester 1a with
morpholine 1b. For the experimental procedure we
simply mixed 1equiv. of ester 1a with 1,1 equiv of
amine 1b and irradiated the reaction mixtures in a
MW oven in the absence of solvent (Schema 1). As
summarized in Table. 1, formation of β-ketoamide
1c generally required high temperatures; at 80 °C,
100 °C and 120 °C the isolated yields of amide just
slightly increased. On the other hand, we observed
that an increased temperature from 160 °C to
180 °C did increase the conversion from 94% to
quantitative and speed up the time of reaction. We
show here that the ester 1a and amine 1b can only
react when they collide by heating the mixture, as
particles move faster and collide more frequently.
A variety of secondary amines were
efficiently converted to the corresponding products
in moderate to excellent yields (52%-quantitative).
The reaction of cyclopentanone-ester 2a with
morpholine and dipropylamine (Table. 2, entries 4
and 6) provide excellent yields of 4c and 6c.
Actually, in most of the cases, aminolysis occurred
to be more efficient under solvent-free conditions
(table 2, entries 1, 4, 6, 7 and 8). Furthermore we
studied the reactivity of morpholine toward ethyl
1-oxo-1,2,3,4-tetrahydronaphtalene-2-carboxylate
3a and acyclic ketoester; ethyl acetoacetate 4a
(Table 2, entries 9 and 10). Aminolysis of 3a gave
the corresponding amide 9c with good yield (90%),
however, only moderate catalytic activity was
observed in the case of ethyl acetoacetate 4a which
product yield 10c do not exceed 52%.
O
O
O
O
O
Microwave irradiation
Solvent- free
N
OEt
+
O
N
H
1a
1b
1c
Scheme 1
Table. 1: Reaction temperatures tested for the
amidation of 1a
Entry
Temp.(°C)
Time (min.)
yield % (1c)
1
2
3
4
5
80
120
120
120
60
Trace
20
37
100
120
160
180
95
30
Quantitative

157
Table. 2: Solvent-free and catalyst-free synthesis of various β-ketoamide under MW irradiation
ZAHMANI et al., Orient. J. Chem., Vol. 34(1), 152-160 (2018)
Entry
β-Ketoester
Amine
β-Ketoamide
Reaction time (min.)
Yield b
%
O
O
O
O
O
N
1
60
Quantitative
OEt
N
H
O
1a
1b
1c
O
O
N
N
N
H
2
3
4
5
6
7
8
9
30
30
30
30
30
30
30
30
73
2b
2c
O
O
N
NH
N
74
O
3b
O
3c
O
O
O
OEt
N
N
H
O
Quantitative
2a
1b
4c
O
O
N
N
H
79
90
64
74
90
2b
5c
O
O
N
H
N
N
4b
6c
O
O
N
H
5b
7c
O
O
N
HN
6b
8c
O
O
O
O
O
N
OEt
N
H
O
3a
1b
9c

158
10
ZAHMANI et al., Orient. J. Chem., Vol. 34(1), 152-160 (2018)
O
O
30
52
70
O
O
O
N
OEt
N
H
O
4a
1a
1b
10c
O
O
O
O
11
30
N
NH2
OEt
H
7b
8b
11c
O
O
NH2
N
H
12
13
14
15
16
45
45
15
30
30
40
12c
O
O
O
O
NH2
N
H
OEt
Quantitative
2a
9b
13c
O
O
NH2
N
H
80
50
67
7b
14c
O
O
O
O
N
H
NH2
10b
15c
O
O
H2N
N
H
11b
16c
O
O
O
O
17c
O
H2N
OEt
N
H
17
18
30
77
85
3a
11b
O
O
O
NH2
OEt
N
H
45
4a
7b
18c

159
ZAHMANI et al., Orient. J. Chem., Vol. 34(1), 152-160 (2018)
In evaluating the amine catalysts effects
we noticed that the aminolysis performance depends
strongly on the amines basicity as shown in Table.
3. It is clear that the yield of the reaction decreased
with increasing pKa.
Following the same protocol, we directed
our attention to the amidation of primary amine
which are known by their low reactivity. All reactions
were performed using 1.1 equiv of amine to form
N-disubstitued ketoamide from Ketoesters
Thus, this new approach allows us to
understand the basic catalytic activity of amine in
aminolysis process. In this method, reactions are
faster, safer and with higher chemical yields, that is
why this method becomes superior to the
conventional method. Furthermore these results
reveal that the present method is useful for aromatic
as well as for aliphatic amines.
and were obtained with moderate to good yield
(40% -quantitative). As is evident from Table. 2,
aniline and tertbutylamine produced the best yields
compared to other amines (Table 2, entries 13, 14
and 18). Benzylamine and furfurylamine, the less
reactive amines, produce slightly low yields (40 and
50%), (Table. 2, entries 12 and 15).
Table. 3: Influence of the pKa of the amine on the yield of the reaction.
Entry
Amine
NH2
pKa
4.6
8.3
Keto-ester
% yield
1
2
2a
1a
Quantitative yield
Quantitative yield
O
N
H
3
4
10.68
11.6
2a
80
NH2
NH2
1a
40
reagents or catalyst and provided the product in
good to excellent yield. The feasibility of activating
reaction by the mean of temperature and pressure
in microwave irradiation has been demonstrated.
This eco-friendly procedure show notable
advantages as: (a) operational simplicity; (b) fast
reaction; (c) ecological advantages; (d) economic
experience and (e) good yield.
CONCLUSION
In conclusion, a highly efficient and facile
one-step synthesis of N-mono-and di-substitued
β-ketoamides has been described. This method
involves the formation of new bond in solvent free
aminolysis without the use of any additional
REFERENCES
1.
(a) Horváth, I. T.; Anastas, P.T. Chem. Rev.
2007, 107, 2169-2173; (b) Liu, S.; Xiao, J. J. 2.
Mol. Catal. A: Chem. 2007, 270, 1-43; (c)
Anastas, P.T. ; Zimmerman, J. B. Environ. Sci.
Technol. 2003, 37, 94A-101A.
(a) Bagley, M. C.; Chapaneri, K., Dale, J. W.;
Xiong, X.; Bower, J. J. Org. Chem. 2005, 70,
1389-1399, (b) Griffin, R. J.; Fontana, G.;

160
ZAHMANI et al., Orient. J. Chem., Vol. 34(1), 152-160 (2018)
Golding, B. T.; Guiard, S.; Hardcastle, I. R.;
7.
8.
Johnson, D.H.J.Chem.Soc. 1958, 0, 1624-1628.
Bredereck, H.; Gompper, R.; Klemm, K. Chem
Ber. 1959, 92, 1456-1460.
Leahy, J. J.; Martin, N.; Richardson, C.;
Rigoreau, L.; Stockley, M.; Smith, G. C. M. J.
Med. Chem. 2005, 48, 569-585; (c)
Takayama, K.; Iwata, M.; Hisamichi, H.;
Okamoto, Y.; Aoki, M.; Niwa, A. Chem. Pharm.
Bull. 2002, 50, 1050-1059; (d)
Szczepankiewicz, B. G.; Heathcock, C. H. J.
Org. Chem. 1994, 59, 3512-3513.
9.
10.
Clemens, R. J. Chem. Rev. 1986, 86, 241-318.
Gotor, V.; Liz, R.; Testera, A. M. Tetrahedron
2004, 60, 607-618.
(a) Garcia, M. J.; Rebolledo, F.; Gotor, V.
Tetrahedron Lett. 1993, 34, 6141-6142; (b)
Ponde, D. E.; Deshpande, V. H.; Bullrile, V.
J.; Sudalai, A.; Gajare, A. S. D. J. Org. Chem.
1998, 63, 1058-1063.
11.
3.
4.
Meyer, C.; Piva, O.; Pete. J-P. Tetrahedron
2000, 56, 4479-4489.
(a) Cossy, J.; Thellend, A. Synthesis 1989,
10, 753-755; (b) Miriyala, B.; Williamson, J.
S. Tetrahedron Lett. 2003, 44, 7957-7959;
(c) Štefane, B.; Polanc, S. Synlett. 2004, 4,
698-702; (d) Štefane, B.; Polanc, S.
Tetrahedron 2007, 63, 10902-10913. (e)
Witzeman, J. S.; Nottingham, W. D. J. Org.
Chem. 1991, 56, 1713-1718.
Ley, S. V.; Woodward, P. R. Tetrahedron Lett.
1987, 28, 3019-3020.
Sung, K.; Wu, S. Y. Synth. Commun. 2001,
31, 3069-3074.
12.
13.
Neo, A. G.; Delgado, J.; Polo, C.; S.
Marcaccini.; Marcos, C. F. Tetrahedron Lett.
2005, 46, 23-26.
(a) Dudognon, Y.; Presset, M.; Rodriguez,
J.; Bugaut, X.; Constantieux, T. Chem.
Commun. 2016, 52, 3010-3013. (b) Presset,
M.; Coquerel, Y.; Rodriguez, J. J. Org. Chem.
2009, 74, 415-418; (c) Leung-Toung, R.;
Wentrup, C. J. Org. Chem, 1992, 57, 4850-
485; (d) Cossy, J.; Leblanc, C. Tetrahedron
Lett. 1991, 32, 3051-3052; (e) Wolff, L. Justus
Liebigs Ann. Chem. 1912, 394, 86-108.
5.
6.