An effcient protocol for accessing β-Amino dicarbonyl compounds through aza-Michael reaction

Article abstract of DOI:10.1590/S0103-50532010000600025

β-Amino dicarbonyl compounds comprise a class of useful ligands on the coordination chemistry. In view of their importance, an effcient and facile method for the synthesis of β-amino dicarbonyl compounds has been developed, exploring the aza-Michael addition reactions in an aqueous medium. It was possible to achieve good to excellent yields, along with regioselectivity, the substituted diethyl 2-(phenylmethyl)malonates that were easily isolated without any chromatographic purifcation. The correct confguration of two of these β-amino dicarbonyl compounds were confrmed by X-ray crystallography. A complementary mechanism of this aza-Michael protocol is proposed to explain the results obtained.

Full text of DOI:10.1590/S0103-50532010000600025

J. Braz. Chem. Soc., Vol. 21, No. 6, 1129-1135, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
through aza-Michael Reaction
Ihssan Meskini,a Loïc Toupet,b Maria Daoudi,a Abdelali Kerbal,a Brahim Bennani,a
Pierre H. Dixneuf,c Zahid H. Chohan,d Ana Cristina Lima Leite*,e
and Taibi Ben Hadda*,f
aLaboratoire de Chimie Organique, Faculté des Sciences Dhar Mehraz, Fès, Morocco
bInstitut de Physique - IPR - UMR 6251, CNRS, Université de Rennes, 1, Rennes, France
cLaboratoire Catalyse et Organométalliques, Institut Sciences Chimiques de Rennes, UMR 6226,
CNRS, University of Rennes, Av. Géneral Leclec, 35042 Rennes, France
dDepartment of Chemistry, Bahauddin Zakariya University, Multan 60800, Pakistan
eDepartment of Pharmaceutical Science, Centre for Health Science, Federal University of
Pernambuco, 50740-520 Recife-PE, Brazil
fLaboratoire Chimie des Matériaux, Faculté des Sciences, 60000 Oujda, Morocco
Compostos b-amino-dicarbonilados constituem uma classe de ligantes promissores para
a química de coordenação. Diante desta perspectiva, um método eficiente e fácil visando à
síntese de compostos b-amino-dicarbonilados foi desenvolvido, explorando a reação de adição
do tipo azo-Michael em meio aquoso. Com isso, uma série de dez dietil 2-(feniletil)malonatos
dissubstituídos foram obtidos de uma maneira regiosseletiva e facilmente purificados, levando
à rendimentos satisfatórios. As análises cristalográficas de dois destes compostos forneceram
as informações apropriadas sobre a conformação e configuração dos mesmos. Por último, uma
proposta complementar do mecanismo reacional para as reações de adição de Michael em meio
aquoso foi também descrito.
b-Amino dicarbonyl compounds comprise a class of useful ligands on the coordination
chemistry. In view of their importance, an efficient and facile method for the synthesis of b-amino
dicarbonyl compounds has been developed, exploring the aza-Michael addition reactions in an
aqueous medium. It was possible to achieve good to excellent yields, along with regioselectivity,
the substituted diethyl 2-(phenylmethyl)malonates that were easily isolated without any
chromatographic purification. The correct configuration of two of these b-amino dicarbonyl
compounds were confirmed by X-ray crystallography. A complementary mechanism of this aza-
Michael protocol is proposed to explain the results obtained.
Keywords: polydentate ligands, b-amino dicarbonyl compounds, Michael addition, aqueous
medium
Introduction
co-factors of the HI), leading to the formation of bimetallic
complexes.2,3 A number of bimetallic metal complexes,
in many cases exploring the well-known polydentate
ligands, appear therefore in this context to be the most
promising drug candidates to HI inhibitors.4,5 Another
interesting application for such polydentate ligands involves
the synergic water activation that occurs by way of the
so-called ‘remote metallic atoms’. Such organometallic
The rational design of new HIV-1 Integrase (HI)
inhibitors, a valid target for chemotherapeutic intervention,1
is primarily based on intermolecular coordination
between HI / chemical inhibitor / metals (Mg2+ and Mn2+,
*e-mail: tbenhadda@yahoo.fr or ana.leite@pq.cnpq.br

1130
An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
compounds are considered in structural terms to block the
intramolecular electron transfer on the HI structure.6 This
explanation clearly demonstrates that polydentate ligands
are of special interest in the field of bioorganometallic
chemistry.7 In view of our interest in designing novel
bimetallic coordinating ligands8 endowed with potential
action to inhibit the HI enzyme, the object of this study is
the synthesis of polydentate ligands with the same topology,
as drawn in Figure 1.9
For preparation of such polydentate ligands, the
aza-Michael reactions appear to be the key-step leading
the expected b-amino esters adducts.10 In fact, this
kind of reaction has been widely employed to generate
structurally diverse b-amino dicarbonyl compounds,
where the undoubted importance of the aza-Michael step
can be seen from the large number of unconventional
methodologies, as well as the broad range of applications.11
Most of these unconventional methodologies have used
Lewis acids, which although leading to satisfactory yields,
require to remove the Lewis acids through tediously
chromatography.12 Moreover, the use of an aqueous medium
also has been successful achieved.13 As a drawback, the
use of substituted alkenes, such as benzylidene-malonic
acid diethyl ester, is rarely reported in the literature. These
substrates are expected to be less reactive or conversely
more resistant to undergo the Michael condensation,
resulting in low conversion of the desired adducts.14 For a
synthetic point of view, this is a considerable limitation on
the aza-Michael reaction process and poses a significant
challenge.
To this end, we decided to investigate the feasibility of
applying the aza-Michael reactions to the more challenging
substituted alkene derivatives. Our plan also included the
application of this key-step to the synthesis of a novel set of
polydentate ligands, in order to highlight the versatility of
the procedure as well as to generate some insights regarding
the reaction mechanism.
Results and Discussion
Firstly, diethyl 2-benzylidenemalonates (4a-d) were
prepared from the classical condensation of benzaldehydes
with diethyl malonate under ethanol reflux, using piperidine
and glacial acetic acid as a catalyst system. This procedure
furnished the intermediates, 2-arylidene-malonic acid
diethyl esters (4a-d), very quickly and in excellent yields
(Scheme 1).
To understand the scope and limitations of the aza-
Michael reactions, compound 6 was chosen as the model
reaction because of its thermostability and also because
piperidinyl is considerably less reactive when employing
the traditional Michael protocols. Some of these conditions
are presented in Table 1. During the investigation of
experimental conditions, it was possible to observe that the
acid catalyst (HOAc, 0.1 mL) accelerates such reactions.
Interestingly, only a short reaction time (3 h) was required
to furnish product 6 on very good yields with no detected
by-products (Table 1, entries 4 and 5). In contrast, neither
the presence of co-solvent (EtOH) nor the heating were
crucial, the yields remaining similar to or lower than
those expected when using pure water (entries 2 and 3).
Boric acid also well works, but it was necessary additional
purification by chromatography. Apart from the aqueous
medium, the use of dichloromethane as solvent at catalyst-
free condition led to low conversion (yield < 20%) of the
desired product 6, in agreement with the previous results
by Shou and colleagues.15
Figure 1. (a) Structures of representative HI inhibitors that act through the
sequestration of enzyme’s co-factors; 5 (b) Expected coordination mode
for the ligands (6-15) after metallic complexation.

Vol. 21, No. 6, 2010
Meskini et al.
1131
R2
R2
N
O
O
O
CHO
O
O
OEt
OEt
OEt
OEt
a
b
R1
R1
+
R1
OEt OEt
O
4a: R1 = H
compounds 6-15
4b: R1 = p-Cl
4c: R1 = m-OCH3
4d: R1 = p-OCH3
Scheme 1. General synthesis of the polydentate ligands (6-15). Reagents and conditions: a) piperidine, HOAc, EtOH, reflux, 12 h; b) secondary amine,
water, r.t., catalyst.
Table 1. Investigation of the aza-Michael condensation promoted by aqueous medium for the synthesis of compound 6
Entry
Catalyst
None
Co-solvent
None
Temp (°C)
time (h)
Yield a (%)
1
2
3
4
5
6
30
100
30
120
3
80
30b
61
78
75
63
None
None
None
EtOHc
120
3
HOAcd
None
30
HOAcd
None
60
3
Boric acid (10% mol)e
None
30
4
a Determined as isolated products after recrystallization; b The starting materials were recovered and at the same time, by-products were observed; c Using
only EtOH, as reported in reference 9; d 0.1 mL of HOAc (pH = 4.5); eSimilar to reported by Chaudhuri.12
Having determined the best conditions, it was identified
that precursors 4a-d reacted satisfactorily, albeit slowly,
with various secondary amines under catalyst-free
conditions to provide the desired adducts 6-15 in good to
excellent yields, along with regioselectivity and without
needs of column chromatography (Table 2). Moreover, the
reactions proceeded normally even when the methoxy group
was attached on aromatic ring (14 and 15), in contrast with
the protocol described by Shou and colleagues.15 It is worth
noting that the yields were found to be essentially the same
as those obtained when the reactions were performed under
either the presence or absence of the acid catalyst (HOAc).
These results suggest that the acid catalyst accelerates the
aza-Michael reactions under these substrates.
These products were characterized using spectroscopic
and micro-analytical data. Compounds 8 and 9 were
crystallized from ethanol solutions and gave single
crystals suitable for X-ray analysis. These single crystals
displayed centrosymmetric space groups for both
compounds, indicative that each crystalline structure was
composed of both enantiomers. An ORTEP view of the
polydentate ligands 8 and 9 are shown in Figures 2 and 3,
while the crystal data for these are reported in Table 3
and the bond lengths and angles of compound 9 are
summarized in supplementary material. In the molecular
structure of 9, the nitrogen (N2) and the two oxygen (O1
and O3) of the carbonyl groups are in cisoidal / transoidal
conformations, with respective dihedral angles of the
0.04(1),145.7(2)and88.3(1)fortheplanesO1–C3–C6–O2,
O1–C3–C1–N1 and O3–C6–C1–N1. We have note that
after the trans addition around the C1=C2 double bond;
the observed angles were quite different from 180°
[H1–C1–C2–H2 = 176.9(2), C3–C2–C1–C9 = 56.9(1) and
N1–C1–C2–C6 = 60.6(9)]. In fact, these untypical values
were confirmed by the angle of atoms in trans positions,
which was again different of 180°, as the example the
[N1–C1–C2–H2 = −60.3(5)]. More unexpected, it was
possible to observe that, in contrast with the polydentate
ligand 8, the crystal structure of the ligand 9 was stabilized
by one unusual intramolecular type-H bonding within the
C–Cl+d…-dN=C, resulting in an interesting 3D network, as
depicted in Figure 4.
In light of this interesting finding, we decided to
apply several primary amines (arylamines, benzylamines,
1,4-phenylenediamine and unprotected amino acids)
using this same synthetic protocol, but the presence of the
desired products was no longer observed in all the cases
using either prolonged reaction times or a large excess of
amines. In contrast to secondary amines, which enabled
functionalized polydentate compounds 6-15 to be obtained
in good to excellent yields, the reaction of 4a-d with the
primary amines (arylamines, benzylamine and para-
phenylenediamine) in water did not furnish the expected
polydentate ligands bearing the central RN-H group, either

1132
An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Table 2. Aqueous medium-promoted aza-Michael condensation
At HOAc-catalyst a
At Catalyst-freeb
R2
R2
N
Starting Compound
Products
time
Yieldc (%)
time
Yieldc (%)
N
4a
4b
6
7
3
3
78
168
80
N
O
80
168
168
96
76
N
H3C
N
4a
4b
8
9
Nd
Nd
Nd
CH3
N
H3C
N
Nd
168
73
CH3
N
4b
4b
10
11
5
3
68
70
168
168
71
67
N
N
N
4b
4b
12
13
Nd
Nd
168
168
73
83
N
5
70
N
4c
14
15
5
5
63
78
168
168
75
77
N
4d
a See the entry 4 on Table 1; b See the entry 1 on Table 1; c Isolated yields, when Nd is not determined.

Vol. 21, No. 6, 2010
Meskini et al.
1133
Figure 4. View of the H-bonding interactions of the ligand 9 in the unit
cell.
Figure 2. ORTEP drawing of compound 8 in its correct configuration
with thermal ellipsoid plot (50% probability). Critical distances
[O1—O3 = 3.5(2) Å, O3—N2 = 3.9(3) Å and O1—N2 = 5.0(6) Å].
the nucleophilic character of the nitrogen atom of the
amine. This proposed mechanism would seem to present
a plausible and satisfactory explanation of the formation
of enol intermediates. To complement this, we would like
to address the issue of why this protocol did not work
well with primary amines. Since the chemical behaviour
of primary and secondary amines undergoing these aza-
Michael reactions is quite different, it is plausible to suggest
that secondary amines in an aqueous medium probably
give rise to the formation of ammonium species, which
easily attacks the electrophilic alkene, thereby furnishing
the unstable intermediate of addition with subsequent
proton abstraction from protonated water by way of the
enolate. On the other hand, using primary amines under
aqueous medium probably results in the formation of
ammonium salts. This implies that these ammonium
salts are catalytically deactivated species or, conversely,
less nucleophilic and thus less susceptible to attack from
the respective alkenes (Scheme 2). Furthermore, the
Figure 3. ORTEP view of the compound 9 with the atom numbering
scheme. Displacement ellipsoids for non-H atoms are drawn at the 50%
probabilitylevel. Criticaldistances[O1—O3=3.3(3)Å, O3—N2=3.8(2)Å
and O1—N2 = 5.0(3) Å].
in the presence of the acid catalyst (HOAc) or with the
addition of more than one equivalent of aniline.
Moreover, the mechanism for formation of the aza-
Michael adducts should be mentioned. This is different
from the Lewis acid-promoted aza-Michael reactions, in
that such Lewis acids function by activating the unsaturated
double bond, generating a nucleophilic attack by way of
chelation of the 1,3-dicarbonyl core. More recently, Ranu
and Banerjee13 have argued that the aqueous medium
creates a dual action through the H-bonds, increasing
Scheme 2. Possible paths of equilibrium of the reactions of amines in
aqueous medium.

1134
An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Table 3. Crystal data and structure refinement for the compounds 8 and 9
X-ray data
8
9
Empirical formula
Formula weight
Temperature
C19H24N2O4
344.40
C19H23N2O4Cl
378.13
110(2) K
0.71073Å
Monoclinic, P21/a
110(2) K
0.71073 Å
Monoclinic, P21/c
Wavelength
Crystal system, space group
Unit cell dimensions
A = 8.65020(10) Å
B = 16.7029(2) Å
C = 13.5938(2) Å
Volume
alpha = 90 deg.
beta = 90.220(2) deg.
gamma = 90 deg.
1826.25(9)Å3
4
alpha = 90 deg.
beta = 92.147(2) deg.
gamma = 90 deg.
1962.70(6) Å3
4
Z
Calculated density
F(000)
1.253 g cm−3
1.282 g cm−3
736
800
Absorption coefficient
Theta range for data collection
Limiting indices
0.218 mm−1
2.65 to 27.00 deg.
0.220 mm−1
2.65 to 27.00 deg.
−11<=h<=10, −21<=k<=21,
−16<=l<=17
−11<=h<=10, −21<=k<=21,
−16<=l<=17
Reflections collected / unique
Completeness to theta = 27.00
CCDC number
17406 / 4274 [R(int) = 0.0479]
17406 / 4274 [R(int) = 0.0316]
99.8 %
734198
99.8 %
734197
equilibrium steps occurring in the course of the aza-Michael
reactions are probably the slowest, and are, consequently,
speeded up when an acid catalyst is used. Additionally, a
referee commented that the water effect in reactions with
amines is more complex than dual activation. This statement
is genuine and we agree with him. For instance, the nature
of species generated from mixture of primary / secondary
amines and water depends on the nucleophilicity of the
employed amine.16 Likewise, solubilization of reactants and
products in water is usually of relevancy to get desirable
yields in such aza-Michael reactions.14
Experimental
General methods
Synthesis of intermediates 4a-d
To a solution of ethyl malonate (15 g, 93 mmol) in 40 mL
of ethanol, were added the respective aldehyde (100 mmol),
1.5 mL of piperidine and 1 mL of glacial acetic acid. Then,
themixturewasstirredatrefluxingtemperatureofethanolfor
12 h, until thin-layer chromatography indicated the complete
consume of the starting material. After removing solvent,
the crude product was washed with a saturated solution of
sodium bisulfite (20 mL). The product was extracted by
diethyl ether (2 × 20 mL), dried with sodium sulphate and
evaporated to give the respective pure oil.
Conclusions
One important result of this study was a straightforward
synthesis of ten novel 2-(aryl-disubstituted amino-1-yl-
methyl)-malonic acid diethyl esters (6-15), which constitute
a functionalized class of polydentate ligands. Despite
prolonged reaction times, this aza-Michael protocol led to
higher yields in an aqueous medium at room temperature,
and consequently, would appear to be a simple and useful
synthetic protocol. Considering their high efficiency on
the gram-scale synthesis, in addition to the especially high
purity of the final products, this protocol appears to be of
use for synthesis and pharmacological screening of drug
candidates.
General procedure for the synthesis of compounds 6-15
To a solution of the intermediate 4a-d (8.1 mmol) in
water (25 mL) was added the respective secondary amine
(6 mmol) at the presence or absence of acetic acid (0.1 mL)
and the mixture was stirred at room temperature until the
complete consume of the starting material.After removing
solvent, the crude products were dissolved in diethyl ether
(2 × 40 mL) and washed with water until the pH became
neutral. The organic solvent was dried with sodium sulphate
and then evaporated to give the respective pure compound.

Vol. 21, No. 6, 2010
Meskini et al.
1135
Supplementary Information
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2001, 25, 391; Daoudi, M.; Larbi, N. B.; Bonvoisin, J.; Kerbal,
A.; Ben-Hadda, T.; Bennani, B.; Launay, J. B.; Dixneuf, P.
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Benjelloun, D.; Kerbal, A.; Launay, J. P.; Bonvoisin, J.; Jaud,
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Ben-Hadda, T.; Buyukgungorc, O.; Acta Crystallogr., Sect. E:
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1
Detailed experimental procedures, full set of H and
13C NMR spectra and X-ray data are available free of charge
at http://jbcs.sbq.org.br, as a PDF file.
Acknowledgements
This work was funded by Project Global de Recherche
de l’Université Mohamed Premier (PGR-UMP-BHT-2005,
Morocco), Centre National de la Recherche Scientifique
(CNRS, France), Brazilian Research National Council
(CNPq, grant 479982/2008-2), National Institute of
Research and Technology in Dengue (INCT-Dengue, grant
573876/2008-8, Brazil) and FACEPE PRONEX (grant
APQ-0981-1.06/08). Authors acknowledge the referees
and the editor of JBCS for their helpful comments and
corrections.
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Received: August 27, 2009
Web Release Date: February 1, 2010

J. Braz. Chem. Soc., Vol. 21, No. 6, S1-S18, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
through aza-Michael Reaction
Ihssan Meskini,a Loïc Toupet,b Maria Daoudi,a Abdelali Kerbal,a Brahim Bennani,a
Pierre H. Dixneuf,c Zahid H. Chohan,d Ana Cristina Lima Leite*,e
and Taibi Ben Hadda*,f
aLaboratoire de Chimie Organique, Faculté des Sciences Dhar Mehraz, Fès, Morocco
bInstitut de Physique - IPR - UMR 6251, CNRS, Université de Rennes, 1, Rennes, France
cLaboratoire Catalyse et Organométalliques, Institut Sciences Chimiques de Rennes, UMR 6226,
CNRS, University of Rennes, Av. Géneral Leclec, 35042 Rennes, France
dDepartment of Chemistry, Bahauddin Zakariya University, Multan 60800, Pakistan
eDepartment of Pharmaceutical Science, Centre for Health Science, Federal University of
Pernambuco, 50740-520 Recife-PE, Brazil
fLaboratoire Chimie des Matériaux, Faculté des Sciences, 60000 Oujda, Morocco
General remarks
sodium bisulfite (20 mL). The product was extracted by
diethyl ether (2 x 20 mL), dried with sodium sulphate and
evaporated to give the respective pure oil.
All common laboratory chemicals were purchased from
commercial sources and used without further purification.
Melting points were determined using a Thomas Hoover
apparatus and are uncorrected. Infrared spectra were
recorded on a Beckman 310 spectrometer as KBr pellets.
Diethyl 2-benzylidenemalonate (4a): Yellow oil, 71%
of yield, Rf 0.7 (ether/n-hexane, 1/1). IR (KBr): nmax/cm−1
2875-2982 (CH), 1722 (C=O), 1629 and1497 (C=C), 1294-
1
1
The H and 13C NMR spectra were recorded on Bruker
1254 (C-O). H NMR (300 MHz, CDCl3) d: 1.25 (t, 3H,
3
AC 300 spectrometer and TMS as an internal standard.
Coupling constants (J) are given in hertz. The FAB mass
spectra were obtained on a Hewlett-Packard 5989A Mass
Spectrometer (70 eV). Elemental analyses (C, N and H)
were performed by the Service Central Analyses (CURI,
Université Sidi Mohamed BenAbdellah, Fès, Morocco) and
the results lay within the acceptable range ( 0.4%). CCD
Saphire 3 Xcalibur diffractometer (Oxford Diffraction)
with graphite monochromatized MoKa radiation was used
to record the X-ray analysis.
H2C-CH3, 3J 7.1 Hz), 1.31 (t, 3 H, CH2-CH3, J 7.1 Hz),
4.28 (q, H, CH2-CH3, 3J 7.2 Hz), 4.32 (q, 2H, CH2-CH3, 3J
7.2 Hz), 7.45–7.32 (m, 5H, Ph), 7.72 (s, 1H, C=CH-Ph).
13C NMR (75.5 MHz, CDCl3) d: 61.6/61.6 (2C, 2CH2-CH3),
14.1/13.8 (2C, 2CH2-CH3), 126.1 (Cquat, =C-), 128.7 (2Ctert,
ortho), 129.4 (Ctert, para), 130.5 (2Ctert, meta), 132.8 (Cquat
,
Ph), 142.0 (Ph-CH), 166.6 and 166.2 (2C=O). MS (IE):
Calc. for [M]+ C14H16O4: 248, [M+H]+ (m/z) = 249 (100%).
Diethyl 2-(4-chlorobenzylidene)malonate (4b): Yellow
oil, 77% yield, Rf 0.73 (ether/hexane, 1/1). IR (KBr):
General procedure
n
max/cm−1 2906-2982 (CH), 1724 (CO) 1591/1631 (C=C),
1
To a solution of ethyl malonate (15 g, 93 mmol) in 40 mL
of ethanol, were added the respective aldehyde (100 mmol),
1.5 mL of piperidine and 1 mL of glacial acetic acid. Then
themixturewasstirredatrefluxingtemperatureofethanolfor
12 h, until thin-layer chromatography indicated the complete
consume of the starting material. After removing solvent,
the crude product was washed with a saturated solution of
1254/1308 (C-O). H NMR (300 MHz, CDCl3) d: 1.31-
1.25 (2 t, 6H, 2H2C-CH3, J 7.11 Hz), 4.31-4.4 (2 q, 4H,
3
2CH2-CH3, 3J 7.12 Hz), 7.45-7.30 (m, 4H, Ph), 7.7 (s, 1H,
C=CH-ph). 13C NMR (75.5 MHz, CDCl3) d: 13.7 and 13.8
(2CH3-CH2), 61.4 and 61.7 (2CH2-CH3), 125.4 (C=C-
(CO2Et)2), 129.0 (2Cortho), 130.3 (2Cmeta), 130.4 (Cquat, para/
Cl), 132.9 (Cquat, C-Cl-Ph), 140.0 (ClPh-CH=), 166.3 and
163.8 (2C=O). MS (IE): Calc. for [M]+ C14H15ClO4: 282.07;
[M+H]+. = 283 (100%).
*e-mail: tbenhadda@yahoo.fr or ana.leite@pq.cnpq.br

S2
An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Diethyl 2-(3-methoxybenzylidene)malonate (4c):
CDCl3) d: 1.06 (t, 3H, OCH2CH3, 3J 7.1 Hz), 2.30 (s, 2H,
C1’H2), 2.53 (s, 2H, C1’H2), 3.93 (s, 4H, C2’H2OC2’H2),
3.90-4.07 (m, 2H, OCH2CH3), 4.20 (d, 1H, C2H (CO2Et)2,
3J 10.3 Hz), 4.25-4.39 (m, 3H, OCH2CH3 + PhC3H), 7.12
(d, 2H, meta, 3J 8.30 Hz), 7.35 (d, 2H, ortho, 3J 8.30 Hz).
13C NMR (75.5 MHz, CDCl3) d: 13.8 (C, OCH2CH3, ester),
14.3 (C, OCH2CH3, ester), 49.5 (2C, 2 C1’H2N, morph),
54.6 (Ctert, C2H(CO2Et)2), 61.5 (C, CH2OCH3, ester),
61.6 (C, CH2OCH3, ester), 67.1 (2C, 2C2’H2O, morph),
68.0 (Ctert, C3H-Ph), 128.4 (Ctert, 2C-meta, Ph), 130 (Ctert,
2C-ortho, Ph), 131.8 (Cquat, Ph, para/Cl), 134.8 (Cquat, CCl,
Ph), 167.6 (2 C=O). 2D NMR experiments have confirmed
the signals observed and the different correlations of homo
and heteronuclear. MS (IE): Calc. for [M]+ C18H24ClNO5:
369.13, [M+H]+ (m/z) = 370 (15%), [M-CH(CO2Et)2]+ (m/z)
= 210 (100%). Elemental analysis for C18H24NO5Cl Calc.
(Found): C 58.53 (58.60), H 6.50 (6.71), N 3.79 (4.03)%.
Yellow oil, 70% yield, Rf 0.53 (ether/hexane, 2/1). IR
(KBr): nmax/cm−1 2906-2982 (CH), 1754 (C=O), 1254/1308
(C-O). 1H NMR (300 MHz, CDCl3) d: 1.31-1.25 (2 t, 6H,
2H2C-CH3, 3J 7.11 Hz), 4.31-4.4 (m, 4H, 2CH2-CH3), 4.01
(s, 3H, CH3O), 7.30 -7.45 (m, 4H, Ph), 7.4 (s, 1H, C=CH-
Ph). 13C NMR (75.5 MHz, CDCl3) d: 13.7 and 14.0 (2CH3-
CH2), 61.4 and 60.1 (2CH2-CH3), 125.4 (C=C-(CO2Et)2),
125.4 (C=C-(CO2Et)2), 129.0 (2Cortho), 130.3 (2Cmeta), 130.4
(Cquat, para/CH3O), 132.9 (Cquat, Ph-OMe), 140.0 (Ph-CH=),
166.3 and 163.8 (2C=O). Elemental analysis for C15H18O5
Calc. (Found): C 64.74 (65.03) H 6.52 (6.32)%.
General procedure for the synthesis of 6-15
To a solution of the intermediate 4a-d (8.1 mmol) in
water (25 mL) was added the respective secondary amine
(6 mmol) at the presence or absence of acetic acid (0.1 mL)
and the mixture was stirred at room temperature until the
complete consume of the starting materials.After removing
solvent, the crude products were dissolved in diethyl ether
(2 × 40 mL) and washed with water until the pH became
neutral. The organic solvent was dried with sodium sulphate
and then evaporated to give the respective pure compound.
Diethyl 2-((3,5-dimethyl-pyrazol-1-yl)(phenyl)methyl)
malonate (8): White powder, mp 86-88 °C. Rf = 0.69
(ether/hexane: 1/1). IR (KBr): nmax/cm−1 2868-2974 (C-H),
1747/1719 (C=O), 1586/1554 (C=C), 1460/1419 (C=N),
1269/1264 (C-O). 1H NMR (300 MHz, CDCl3) d: 0.98 (t,
3H, CH2CH3, 3J 7.1 Hz), 1.17 (t, 3H, CH2CH3, 3J 7.1 Hz),
2.21 (s, 1H, C3’H, pyrazol), 2.25 (s, 1H, C1’H, pyrazol),
Diethyl 2-(phenyl(piperidin-1-yl)methyl)malonate (6):
White powder, mp 67-68 °C. Rf = 0.72 (ether/hexane,
1/1). IR (KBr): nmax/cm−1 2848-2974 (C-H, Ph), 2754/2800
(C-H, aliph), 1750/1740 (C=O), 1514/1450 (C=C),
3
3.97(q, 2H, OCH2CH3, J 7.1 Hz), 4.16-3.99 (2q, 2H,
OCH2CH3, 3J 7.3 Hz), 4.9 (d, 1H, PhC3HC2H, 3J 11.4 Hz),
5.74 (s, 1H, H2’, pyrazol), 7.45-7.25 (m, 5H, Ph), 7.78 (d,
1
3
1313/1257 (C-O). H NMR (300 MHz, CDCl3) d: 1.00
1H, ph-C3H, J 11.2 Hz). 13C NMR (75.5 MHz, CDCl3)
(t, 3H, H2C-CH3, 3J 7.1 Hz); 1.26 (m, 2H, -C3’H2-, piper),
1.35 (t, 3H, H2C-CH3, 3J 7.1 Hz), 1.50 (m, 4H, 2C2’H2,
piper), 2.20 (s large, 2H, C1’H2, piper), 2.59 (s large, 2H,
C1’H2 , piper), 4.02 (dq, 2HAB, O-CH2 –CH3, 2JA-B 10.7 Hz,
d: 13.67 (C, C3’H3, pyrazol), 13.64/10.06 (2C, 2CH2CH3),
13.87 (C, C1’H3, pyrazol), 57.52 (Ctert, Ph-C3HC2H),
60.35 (Ctert, PhC3HC2H), 61.57 (2C, 2CH2CH3), 105 (Ctert,
C2’H, pyrazol), 128.50/128.3/127.93 (5C, Ph), 137.30
(Cquat, C3’, pyrazol), 139.30 (Cquat, Ph), 147.3 (Cquat, C1’,
pyrazol), 166.90/166.85 (2C=O). MS (IE): Calc. for [M]+
C19H24N2O4: 344.17, [M+H]+ (m/z) = 345 (11%), 83 (100%).
Elemental analysis for C19H24N2O4 Calc. (Found): C 66.27
(65.71), H 6.97 (5.80), N 8.13 (8.78)%.
3
3J 6.9 Hz), 4.23 (d, 1H, C2H-(CO2Et)2, J 12.1 Hz), 4.33
(dq, 2H, O-CH2 –CH3,JA-B 0.2 Hz, 3J 7.1 Hz), 4.43 (d, 1H,
ph-C3H, 3J 12 Hz), 7.15-7.34 (m, 5H, Ph). 13C NMR (75.5
MHz, CDCl3) d: 14.30/13.75 (2C, 2OCH2CH3), 24.40
(C, C3’H2, piper), 26.50 (2C, 2C2’H2, piper), 50.55 (2C,
2C1’H2, piper), 54.96 (Ctert, C2H(CO2Et)2), 61.30/ 61.15 (2C,
2OCH2CH3), 69.15 (Ctert, PhC2H), 127.53 (2Ctert, meta, Ph),
127.80 (Ctert, para, Ph), 128.69 (2Ctert, ortho, Ph), 133.93
(Cquat, Ph), 167.22/168.04 (2C=O). MS (IE): Calc. for [M]+
C19H27NO4: 333.19, [M+H]+ (m/z) = 334 (35%), 174 (100%).
Elemental analysis for C19H27NO4 Calc. (Found): C 68.46
(67.89), H 8.40 (7.89), N 4.20 (4.22)%.
Diethyl 2-((4-chlorophenyl)(3,5-dimethyl-pyrazol-
1-yl)methyl)malonate (9): White powder, mp 77-79 °C.
Rf = 0.68 (ether/hexane: 1/1). IR (KBr): nmax/cm−1 2969
(C-H , Ph), 2674/2806 (C-H), 1747/1720 (C=O), 1592/1464
1
(C=C), 1329/ 1256 (C-O). H NMR (300 MHz, CDCl3)
d: 7.32-7.29 (m, 2H, aromatic), 7.14-7.18 (m, 2H, Ph),
4.5 (d, 1H, PhC3H, 3J 11.40 Hz), 4.25 (q, 2H, CH2OCH3,
3J 7.1 Hz), 4.09 (d, 1H, C2H(CO2Et)2, 3J 11.40 Hz), 3.95 (m,
2H, CH2OCH3), 2.49 (m, 2H, N-C1’H2, pyrazole), 2.35 (m,
2H, NC1’H2, pyrazole), 1.59 (m, 4H, 2C1’H2C2’H2, pyrazole),
1.30 (t, 3H, OCH2CH3, 3J 7.1 Hz), 1.03 (t, 3H, OCH2CH3,
3J 7.1 Hz). 13C NMR (75.5 MHz, CDCl3) d: 166.97/167.88
Diethyl 2-((4-chlorophenyl)(morpholino)methyl)
malonate (7): White crystals, mp 68-69 °C. Rf = 0.55
(ether/ hexane: 1/1). IR (KBr): nmax/cm−1 2935-2985 (C-H,
4-Cl-Ph), 2826-2887 (C-H), 1747 (C=O), 1712 (C=O),
1590-1489 (C=C), 1306-1258 (C-O). 1H NMR (300 MHz,

Vol. 21, No. 6, 2010
Meskini et al.
S3
(2C=O), 133.35 (Cquat, CCl, Ph), 133.22 (Cquat, Ph, para/
Cl), 130.35 (Ctert, 2C ortho, Ph), 128.05 (Ctert, 2C meta, Ph),
64.05 (Ctert, C3HPh), 61.40 (C, OCH2CH3, ester), 61.30 (C,
OCH2CH3, ester), 56.50 (Ctert, C2H(CO2Et)2), 48.41/46.88
(2C, 2C1’H2N, pyrazole), 22.84 (2C, 2C1’H2C2’H2),
pyrazole), 13.91/14.12 (2C, 2OCH2CH3). MS (IE): Calc.
for [M]+ C18H24ClNO4: 353.14, [M+H]+ (m/z)=354 (18%),
[M-CH(CO2Et)2]+ (m/z)=194 (100%), [M-pyrol]+ (m/z) =
283. Elemental analysis for C18H24NO4Cl Calc. (Found): C
62.12 (62.10), H 7.08 (7.28), N 3.18 (4.04)%.
50.51 (2C, 2C1’H2N), 54.95 (Ctert, C2H(CO2Et), 61.4 and
61.3 (2C, 2CH2CH3, ester), 69.5 (Ctert, C3HPh), 129.9
(Ctert, 2C meta/Ar), 128.04 (Ctert, 2C ortho/Ar), 132.6
(Cquat, para/Cl), 133.4 (Cquat, ClC), 167.03 (C=O), 167.71
(C=O). MS (IE): Calc. for [M]+ C19H26ClNO4: 367.16,
[M+H]+ (m/z) = 368 (16%), [M-CH(CO2Et)2]+ (m/z) = 208
(100%), [M-PhCl]+ (m/z) = 256. Elemental analysis for
C19H26NO4Cl Calc. (Found): C 62.12 (62.10), H 7.08 (7.28),
N 3.18 (3.14)%.
Diethyl 2-((benzyl(ethyl)amino)(4-chlorophenyl)
methyl)malonate(12):Whitecrystals,mp70-72°C.Rf=0.56
(ether/hexane: 1/1). IR (KBr): nmax/cm−1 2808/2985 (CH);
1732 (C=O), 1594/1595 (C=C), 1248/1291 (C-O). 1H NMR
(300 MHz, CDCl3) d: 1.30 (t, 3H, OCH2CH3 , 3J 7.07 Hz);
2.1 (m, 1H, CHCH3,3J 12.90 Hz), 1.01 (t, 3H, OCH2CH3 ,
3J 7.07 Hz), 2.55 (m, 1H, CHCH3,3J 12.90 Hz), 2.9 (d, 1H,
CH-Ph, 3J 13.80 Hz ), 3.9 (d, 1H, CH-Ph, 3J 13.80 Hz), 4.01
(dq, 2HA-B, OCH2CH3, JAB 14.10 Hz, 3J 7.07 Hz), 4.24 (d, 1H,
C2H(CO2Et)2, 3J 12.30 Hz), 4.30 (dq, 2HAB, OCH2CH3, JAB
14.10 Hz, 3J 7.07 Hz), 4.62 (d, 1H, ClPhC3H, 3J 12.30 Hz),
7.23-7.1 (m, 5H, aromatic, 3J 4.42 Hz), 7.24-7.37 (m, 4H,
PhCl, 3J 8.43 Hz). 13C NMR (75.5 MHz, CDCl3) d: 13.41
(C, NCH2CH3), 13.79 (C, OCH2CH3, ester), 14.07 (C,
2OCH2CH3, ester), 54.21 (Csec, NCH2CH3), 55.47 (Ctert,
C2H(CO2Et)2), 61.75 (Ctert, C3HPhCl), 61.75/61.70 (Csec,
2CH2, ester), 126.91 (Ctert, 2C para, Ph), 167.84 (C-O),
128.15 (Ctert, 2C ortho, Ph), 128.15 (Ctert, 2C ortho, Ph-Cl),
128.28 (Ctert, 2C meta, Ph), 130.81 (Ctert, 2C meta, Ph-Cl),
133.54 (Cquat, Ph, para/Cl), 139.41 (Cquat, CCl, Ph), 166.93
(C=O). MS (IE): Calc. for [M]+ C23H28ClNO4: 417.5,
[M+H]+ (m/z)= 418 (12%), [M-CH(CO2Et)2]+ (m/z) = 258
(100%), [M- N(CH2Ph,C2H5)]+ (m/z) = 283. Elemental
analysis for C23H28ClNO4 Calc. (Found): C 66.18 (65.53),
H 6.71 (6.66), N 3.35 (3.55)%.
Diethyl 2-((4-chlorophenyl)(pyrazol-1-yl)methyl)
malonate (10): White crystals, mp 87-89 °C. Rf = 0.65
(ether/hexane; 1/1). IR (KBr): nmax/cm−1 2896/2985 (CH),
1748 (C=O), 1514/1595 (C=C), 1292/1308 (C-O). 1H NMR
(300 MHz, CDCl3) d: 7.5 (d, 2H, C3’H, C5H, pyrazol,
3
3J 14.27 Hz), 7.28-7.44 (m, 4H, Ph, J 8.68 Hz), 6.20 (t,
1H, pyrazol,3J 2.08 Hz), 5.85 (d, 1H, PhC3H, 3J 11.33 Hz),
4.80 (d, 1 H, C2H(CO2Et)2, 3J 11.33 Hz), 4.10 (dq, 2HAB,
3
OCH2CH3, JAB 14.32 Hz, J 7.11 Hz), 4.01 (dq, 2HAB,
3
OCH2CH3, JAB 14.32 Hz, J 7.11 Hz), 2.25 (s, 3H, CH3,
pyrazol), 2.20 (s, 3H, CH3, pyrazol), 1,13 (t, 3H, OCH2CH3,
3J 7.11 Hz), 1.04 (t, 3H, OCH2CH3, 3J 7.11 Hz). 13C NMR
(75.5 MHz, CDCl3) d: 166.36 (C=O), 166.26 (C=O), 147.65
(Cquat, pyrazol), 139.3 (Cquat, pyrazol), 135.7 (Cquat, CCl,
Ph), 134.62 (Cquat, Ph, para/Cl), 129.83 (Ctert, 2C meta, Ph),
128.7 (Ctert, 2C ortho, Ph), 129.27 (Ctert, C3’C4’, pyrazol),
105.45 (Ctert, C4H, pyrazol), 61.75/ 61.70 (Csec, 2CH2, ester),
59.55 (Ctert, C3HPh), 57.45 (Ctert, C2H(CO2Et)2), 13.87 (C,
OCH2CH3, ester), 13.75 (C, OCH2CH3, ester), 13.66 (C,
CH3, pyrazol), 10.95 (CH3, pyrazol). MS (IE): Calc. for
[M]+ C17H19N2O4Cl: 350.5, [M+H]+ (m/z) = 351 (15%),
[M-CH(CO2Et)2]+ (m/z)=191(100%),[M-pyrol]+(m/z)=283
(21%). Elemental analysis for C18H24ClNO4 Calc. (Found):
C 64.55 (64.46), H 6.32 (6.62), N 8.86 (9.06)%.
Diethyl 2-((4-chlorophenyl)(piperidin-1-yl)methyl)
malonate (11): White powder, mp 63-65 °C. Rf = 0.65
(ether/hexane: 1/1). IR (KBr): nmax/cm−1 2973/2930
(aromatic C-H, Ph), 2797/2848 (aliphatic C-H), 1755
(C=O), 1737 (C=O), 1493/1452 (C=C), 1312/1257 (C-O).
1H NMR (300 MHz, CDCl3) d: 1.05 (t, 3H, OCH2CH3,
3J 7.10 Hz), 1.26 (m, 2H, 2N(CH2)2C 3’H2,3J 5.9 Hz), 1.35
(t, 3H, OCH2CH3, 3J 7.10 Hz), 1.48 (m, 4 H, NC 1’H2C2’H2),
2.16 (m, 2H, NC1’H2), 2.46 (m, 2H, NC 1’H2), 4.16* (d, H,
C2H(CO2Et)2,3J12.10Hz),4.35*(d,H,PhC3H,3J12.20Hz);
4.02 (dq, 2HAB, OCH2CH3, JAB 11.3 Hz); 4.30 (dq, 2HAB,
OCH2CH3, JAB 10.7 Hz); 7.1 (d, 2H, aromatic-ortho,
Diethyl 2-((4-chlorophenyl)(pyrrolidin-1-yl)methyl)
malonate (13): White crystals, mp 81-83 °C. Rf = 0.67
(ether/hexane: 1/1). IR (KBr): nmax/cm−1 2981/2935
(CH); 1764 (C=O), 1594/1554 (C=C), 1490/1463 (C=N),
1
1300/1257 (C-O). H NMR (300 MHz, CDCl3) d: 1.04
3
(t, 3H, OCH2CH3, J 7.1 Hz), 1.16 (t, 3H, OCH2CH3,
3J 7.1 Hz), 2.20 (s, 3H, CH3, pyrazol), 2.25 (s, 3H, CH3,
pyrazol), 4.0 (dq, 2HAB, OCH2CH3, JAB 14.3 Hz, 3J 7.2 Hz);
3
4.12 (dq, 2HAB, OCH2CH3, JAB 14.3 Hz, J 7.2 Hz), 4.84
3
(d, 1H, C2H(CO2Et)2, J 11,3 Hz), 5.70 (d, 1H, PhC3H,
3J 11.3 Hz), 5.74 (s, 1H, pyrazol), 7.25-7.44 (m, 4H, Ph,
3J 8.25 Hz). 13C NMR (75.5 MHz, CDCl3) d: 10.95 (CH3,
pyrazol), 13.66 (CH3-pyrazol), 13.75 (OCH2CH3, ester),
13.87 (OCH2CH3, ester), 57.45 (Ctert, C2H(CO2Et)2), 59.55
(Ctert, C3HPh), 61.75/61.70 (Csec, 2CH2, ester), 105.45
3
3J 10.7 Hz), 7.32 (d, 2H, aromatic-meta, J 10.9 Hz).
13C NMR (75.5 MHz, CDCl3) d: 14.3 and 13.8 (2C, 2CH3,
esters), 24.40 (C, N(CH2)2C3’H2), 26.4 (2C, 2C2’H2CH2N),

S4
An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
(Ctert, CH, pyrazol), 128.7 (Ctert,2C ortho, Ph), 129.4 (Ctert,
2C meta, Ph), 134.25 (Cquat, Ph, para/Cl), 138.9 (Cquat
for [M]+ C20H29NO5: 363.56, [M+H]+ (m/z) = 364 (10%),
[M-CH(CO2Et)2]+ (m/z) = 204 (100%). Elemental analysis
for C20H29NO5 Calc. (Found): C 66.09 (66.12), H 8.04
(8.14), N 3.85 (3.89)%.
,
CCl, Ph), 139.3 (Cquat, pyrazol), 147.65 (Cquat, pyrazol),
166.60 (C=O), 166.75 (C=O). MS (IE): Calc. for [M]+
C19H23ClN2O4: 378.13, [M+H]+ (m/z) = 379 (17%),
[M-CH(CO2Et)2]+ (m/z) = 219 (100%), [M-pyrazol)]+
(m/z) = 283. Elemental analysis for C19H23N2O4Cl Calc.
(Found): C 60.31 (60.43), H 6.08 (6.05), N 7.40 (7.69)%.
Diethyl 2-((4-methoxyphenyl)(piperidin-1-yl)methyl)
malonate (15): White crystals, mp 101 °C. Rf = 0.71
(ether/hexane: 2/1). IR (KBr): nmax/cm−1 2981/2935 (CH);
1
1764 (C=O), 1280/1277 (C-O). H NMR (300 MHz,
Diethyl 2-((3-methoxyphenyl)(piperidin-1-yl)methyl)
malonate (14): White crystals, mp 98 °C. Rf = 0.70
(ether/hexane: 2/1). IR (KBr): nmax/cm−1 1760 (C=O),
CDCl3) d: 1.35 (t, 3H, OCH2CH3, 3J 7.0 Hz), 1.51 (t, 3H,
OCH2CH3, 3J 7.0 Hz), 2.45 (m, 2H, NC1’H2), 2.76 (m, 2H,
NC1’H2), 4.05 (s, 1H, CH3O), 4.35 (dq, 2HAB, OCH2CH3,
JAB 10 Hz), 4.48 (dq, 2HAB, OCH2CH3, JAB 11.3 Hz), 4.81
(d, H, PhC3H, 3J 10 Hz); 7.58-7.69 (m, 4H, Ph). 13C NMR
(75.5 MHz, CDCl3) d: 15.0 and 14.8 (2C, 2CH3, ester),
22.10 (C, N(CH2)2C3’H2), 25.2 (2C, 2C2’H2CH2N), 48.61
(2C, 2C1’H2N), 56.15 (Ctert, C2H(CO2Et), 58.3 (Ctert, C3HPh),
61.4 and 61.3 (2C, 2CH2CH3, ester), 113.10 (Ctert), 129.9
(Ctert), 132.6 (Cquat), 153.1 (Cquat, CH3OC), 172.71 (C=O),
171.00 (C=O), MS (IE): Calc. for [M]+ C20H29NO5: 363.57,
[M+H]+ (m/z) = 364 (19%), [M-CH(CO2Et)2]+ (m/z) = 204
(100%). Elemental analysis for C20H29NO5 Calc. (Found):
C 66.09 (65.92), H 8.04 (8.02), N 3.85 (3.68)%.
1
1320/1277 (C-O). H NMR (300 MHz, CDCl3) d: 1.30
3
(t, 3H, OCH2CH3, J 9.0 Hz), 1.58 (t, 3H, OCH2CH3,
3J 9.0 Hz), 2.45-2.30 (m, 2H, NC1’H2), 2.58-2.66 (m, 2H,
NC1’H2), 4.19 (dq, 2HAB, OCH2CH3, JAB 10 Hz), 4.07 (s,
3H, CH3OPh), 4.38 (dq, 2HAB, OCH2CH3, JAB 10 Hz); 4.73
(d, H, PhC3H, 3J 10 Hz); 7.03 (d, 2H, Ph), 7.25 (d, 2H, Ph).
13C NMR (75.5 MHz, CDCl3) d: 14.3 and 14.5 (2C, 2CH3,
ester), 22.10 (C, N(CH2)2C3’H2), 24.8 (2C, 2C2’H2CH2N),
50.1 (2C, 2C1’H2N), 54.1 (Ctert, C2H(CO2Et), 58.3 (Ctert,
C3HPh), 60.5 (CH3OPh), 61.9 and 62.3 (2C, 2CH2CH3,
ester), 119.6 (Ctert), 130.5 (Ctert), 159.3 (Cquat, CH3OC),
137.2 (Cquat), 175.1 (C=O), 176.7 (C=O). MS (IE): Calc.
Table S1. Bond lengths (Å) and angles (deg) for 9
O(1)-C(3)
1.201(2)
O(4)-C(7)
1.458(2)
O(2)-C(3)
1.331(2)
N(1)-C(15)
1.356(2)
O(2)-C(4)
1.459(2)
N(1)-N(2)
1.366(2)
O(3)-C(6)
1.202(2)
N(1)-C(1)
1.463(2)
O(4)-C(6)
1.335(2)
N(2)-C(17)
1.331(2)
O(1)-C(3)-O(2)
O(1)-C(3)-C(2)
O(2)-C(3)-C(2)
O(2)-C(4)-C(5)
O(3)-C(6)-O(4)
O(3)-C(6)-C(2)
O(4)-C(6)-C(2)
124.78(15)
124.24(16)
110.97(14)
106.59(14)
124.97(17)
124.02(17)
110.99(15)
N(1)-C(1)-C(9)
N(1)-C(1)-C(2)
N(1)-C(15)-C(16)
N(1)-C(15)-C(18)
N(2)-C(17)-C(16)
N(2)-C(17)-C(19)
N(2)-N(1)-C(1)
112.43(13)
108.00(14)
105.73(16)
122.59(15)
110.85(15)
119.80(16)
119.57(13)

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Table S2. Torsion angles [deg] for (9)
N(1)-C(1)-C(2)-C(3)
N(1)-C(1)-C(2)-C(6)
N(1)-N(2)-C(17)-C(16)
N(1)-N(2)-C(17)-C(19)
N(1)-C(1)-C(9)-C(14)
N(1)-C(1)-C(9)-C(10)
N(1)-C(15)-C(16)-C(17)
N(2)-N(1)-C(1)-C(2)
N(2)-N(1)-C(1)-C(9)
N(2)-N(1)-C(15)-C(16)
N(2)-N(1)-C(15)-C(18)
178.59(12)
60.69(16)
−0.37(18)
−179.40(15)
−128.96(16)
51.2(2)
C(1)-C(2)-C(6)-O(3)
39.9(2)
C(1)-N(1)-C(15)-C(16)
C(1)-N(1)-N(2)-C(17)
C(1)-N(1)-C(15)-C(18)
C(1)-C(2)-C(6)-O(4)
C(3)-O(2)-C(4)-C(5)
C(3)-C(2)-C(6)-O(3)
C(3)-C(2)-C(6)-O(4)
C(6)-O(4)-C(7)-C(8)
C(7)-O(4)-C(6)-O(3)
C(7)-O(4)-C(6)-C(2)
−175.55(16)
175.98(14)
5.4(3)
−141.76(14)
174.73(15)
−79.0(2)
0.49(19)
41.34(19)
−83.05(18)
−0.77(19)
−179.86(16)
99.30(16)
−81.9(2)
−1.1(3)
−179.43(14)
Table S3. Electrostatic-bond parameters for 9 (Å, °)
D-X...A
d(D-X)
1.74(2)
d(X...A)
3.11(4)
d(D...A)
4.84(7)
<(D-X…A)
118.5(4)
C12 Cl1 N2
Figure S1. 1H NMR (300 MHz) spectrum of compound 6 in CDCl3.

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An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Figure S2. 1H NMR (300 MHz) spectrum of compound 6 in CDCl3 expanded at 4.5-1.0ppm.
Figure S3. 13C NMR (75 MHz) spectrum of compound 6 in CDCl3.

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Figure S4. HETCOR of compound 6 in CDCl3.
Figure S5. COSY of compound 6 in CDCl3.

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An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Figure S6. 1H NMR (300 MHz) spectrum of compound 7 in CDCl3.
Figure S7. 13C NMR (75 MHz) spectrum of compound 7 in CDCl3.

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Figure S8. COSY of compound 7 in CDCl3.
Figure S9. HETCOSY of compound 7 in CDCl3.

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An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Figure S10. COSY of compound 7 in CDCl3.
Figure S11. 1H NMR (300 MHz) spectrum of compound 9 in CDCl3.

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Figure S12. 13C NMR (75.5 MHz) spectrum of compound 9 in CDCl3.
Figure S13. COSY of compound 9 in CDCl3.

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An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Figure S14. 1H NMR (300 MHz) spectrum of compound 9 in CDCl3 expanded at 4.5-1.0ppm.
Figure S15. 1H NMR (300 MHz) spectrum of compound 10 in CDCl3.

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Figure S16. 13C NMR (75.5 MHz) spectrum of compound 10 in CDCl3.
Figure S17. COSY of compound 10 in CDCl3.

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An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Figure S18. HETCOSY of compound 10 in CDCl3.
Figure S19. 1H NMR (300 MHz) spectrum of compound 11 in CDCl3.

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Figure S20. 13C NMR (75.5 MHz) spectrum of compound 11 in CDCl3.
Figure S21. COSY of compound 11 in CDCl3.

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An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Figure S22. HETCOSY of compound 11 in CDCl3.
Figure S23. 1H NMR (300 MHz) spectrum of compound 12 in CDCl3.

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Figure S24. 13C NMR (75.5 MHz) spectrum of compound 12 in CDCl3.
Figure S25. COSY of compound 12 in CDCl3.

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An Efficient Protocol for Accessing b-Amino Dicarbonyl Compounds
J. Braz. Chem. Soc.
Figure S26. COSY of compound 12 in CDCl3.