Reactivity of β-amino alcohols against dialkyl oxalate: Synthesis and mechanism study in the formation of substituted oxalamide and/or morpholine-2,3-dione derivatives

Article abstract of DOI:10.1016/j.tet.2012.09.067

The reactivity of various β-amino alcohols with dialkyl oxalates, in several reaction conditions, has been investigated. Linear disubstituted oxalamides were obtained with primary β-amino alcohols and linear tetrasubstituted oxalamides, or a mixture of linear tetrasubstituted oxalamides and cyclic morpholine-2,3-diones were obtained with N-substituted β-amino alcohols. A DFT study of the possible mechanism has been made. The theoretical results indicate that these reactions are not kinetically controlled, there is an equilibrium between all species and therefore follow a thermodynamic control. The different behavior between the primary β-amino alcohols and N-methyl β-amino alcohols is due to the greater stability of linear disubstituted oxalamides with respect to linear tetrasubstituted oxalamides. The energy of tetrasubstituted oxalamides is closer to the energy of the corresponding morpholine-2,3-diones.

Full text of DOI:10.1016/j.tet.2012.09.067

Tetrahedron 68 (2012) 9583e9591
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Reactivity of
b
-amino alcohols against dialkyl oxalate: synthesis and mechanism
study in the formation of substituted oxalamide and/or morpholine-2,3-dione
derivatives
,
,
*
Maria Luisa Testa a, Elena Zaballos b , Ramon J. Zaragoza
ꢀ b
*
ꢀ
a Istituto per lo Studio dei Materiali Nanostrutturati, CNR, via Ugo La Malfa 153, 90146 Palermo, Italy
Departamento de Química Organica, Universidad de Valencia, Dr. Moliner 50, 46100 Burjassot, Valencia, Spain
b
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 April 2012
Received in revised form 6 September 2012
Accepted 12 September 2012
Available online 20 September 2012
The reactivity of various
investigated. Linear disubstituted oxalamides were obtained with primary
b
-amino alcohols with dialkyl oxalates, in several reaction conditions, has been
-amino alcohols and linear
tetrasubstituted oxalamides, or a mixture of linear tetrasubstituted oxalamides and cyclic morpholine-
2,3-diones were obtained with N-substituted -amino alcohols. A DFT study of the possible mechanism
b
b
has been made. The theoretical results indicate that these reactions are not kinetically controlled, there is
an equilibrium between all species and therefore follow a thermodynamic control. The different behavior
between the primary b-amino alcohols and N-methyl b-amino alcohols is due to the greater stability of
linear disubstituted oxalamides with respect to linear tetrasubstituted oxalamides. The energy of
tetrasubstituted oxalamides is closer to the energy of the corresponding morpholine-2,3-diones.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Amino alcohols
DFT calculations
Reaction mechanism
Oxalamides
Morpholine-diones
1. Introduction
Amino alcohol functional groups are often found in many bio-
active compounds and their stereoselective synthesis and reactions
are of wide interest.1 Among the numerous 1,2-amino alcohols, the
aryl amino alcohols, such as ephedrine 1f, pseudoephedrine
1g, norephedrine 1h, are of particular interest (Fig. 1).2 1,2-Amino
alcohols have an outstanding significance as precursors of oxala-
mides 2 and morpholine-2,3-diones 3. Oxalamides and morpho-
line-2,3-diones are important substructures in compounds that
show biological activity including HIV-1 protease inhibitors,3
cephalosporin bactericides,4 and chemioterapic agents.5
The new retro-bispeptides having the oxalamide moiety located
at the center has become of great interest. The retro-bispeptides
have been used in protein engineering to generate non coded a-
amino acids6 as well as to prepare bioactive peptides with en-
hanced stability toward enzymatic degradation.7 Moreover, oxala-
mide linkages are also of great importance in the material science
field, since they are included in the aliphatic polyamides.8 On the
* Corresponding authors. Tel.: þ34 963543047; fax: þ34 963544328 (E.Z.);
tel.: þ34 963543040; fax: þ34 963544328 (R.J.Z.); e-mail addresses: elena.
ꢀ
zaballos@uv.es (E. Zaballos), ramon.j.zaragoza@uv.es (R.J. Zaragoza).
Fig. 1. Amino alcohols 1, oxalamides 2, and morpholine-2,3-diones 3.
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.09.067

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M.L. Testa et al. / Tetrahedron 68 (2012) 9583e9591
other hand, the bis(amino acid)- and bis(amino alcohol)-oxalamide
gelators represent the class of versatile compounds whose gelation
ability is a consequence of strong and directional intermolecular
hydrogen bonding provided by oxalamide units.9
The synthesis of oxalamide function occurs in a variety of ways,
among them, the reaction of primary amines and dialkyl oxalate to
obtain dialkyl oxalamides.10 Since secondary amines react only
slowly and incompletely with diethyl oxalate, the tetraalkyl oxa-
lamides were prepared from amines and oxalyl chloride in the
presence of a tertiary amine.11 Frequently, in order to afford N-
substituted oxalamides, the synthetic approach involves several
steps, as N-alkylation once oxalamide was formed.12
reactions were initially performed with 2 equiv of amino alcohol
and 1 equiv of oxalate, which are the stoichiometric amounts to
obtain the linear oxalamides 2.
In order to study the influence of the solvent, toluene and eth-
anol are used. The reactions have also been carried out at room
temperature and refluxing of solvents, showing similar results at
both temperatures. The products of these reactions, at room tem-
perature, are shown in Table 1.
Table 1
Reaction of 2 equiv of
toluene or in ethanol
b-amino alcohols 1ae1h with 1 equiv of diethyl oxalate in
The use of b-amino alcohols in the reaction with dialkyl oxalate,
Amino alcohol
Toluene
Ethanol
to obtain oxalamides, it seems very interesting. In this case the
presence of the hydroxyl group can also lead to the production of
cyclic morpholine-2,3-diones.13 It is therefore possible to obtain
both linear oxalamides and cyclic morpholine-2,3-diones. Never-
theless, there are no reports in the literature of a detailed study on
Products
Yield (%)
Products
Yield (%)
1a
1c
1e
1h
2a
2c
2e
2h
4h
2b
94a
2a
2c
2e
2h
4h
2b
3b
2d
2f
76aþ19b
77aþ18b
76aþ19b
13aþ7b
65b
96a
96a
88aþ3b
6b
the reactivity of b-amino alcohols toward dialkyl oxalate in differ-
1b
96b
90b
ent reaction conditions.
4b
Continuing our research in the chemistry of amino alcohols,14
the aim of this paper is the study of the potential influence of the
1d
1f
2d
2f
3f
2g
3g
84aþ5b
90aþ3b
3b
92b
95b
substituents of the b-amino alcohols, as well as the reaction con-
ditions, on the conversion into oxalamides and morpholine-2,3-
diones. To this end, we have carried out a study of the reaction of
3f
2g
3g
Traces
1g
76aþ12b
83b
4b
12b
a
Precipitated product.
some b-amino alcohols with diethyl oxalate. Moreover, a possible
b
Product obtained from the mother liquor (the filtrate liquid), or the crude re-
mechanism of reaction is suggested, which is based on DFT calcu-
lations and additional experimental evidences. The theoretical
study has been carried out in vacuum and in several solvents in
order to study the energy changes in different media.
action mixture. Yield calculated from 1H NMR.
As it can be seen in Table 1, the reaction of primary b-amino
alcohols 1a, 1c, and 1e with diethyl oxalate afforded the corre-
sponding linear disubstituted oxalamides (2a,15 2c, and 2e14b in
Scheme 1), in toluene and also in ethanol. In all cases the yield is
almost quantitative. When toluene is used the product precipitates,
while in ethanol part of product remains in the mother liquor and
we have to proceed with its concentration. In the reaction of nor-
ephedrine 1h with diethyl oxalate in toluene, 88% of the corre-
sponding oxalamide 2h precipitates. An analysis of the mother
liquor reveals the presence of an additional 3% of oxalamide 2h16
with 6% of a product that is identified as the oxamidic ester in-
termediate 4h.17 When the reaction is performed in ethanol, only
13% of the oxalamide 2h precipitates. The presence of the in-
termediate 4h in the mother liquor increases to 65% of the reaction.
These intermediate products 4 had already been observed in the
reaction of primary amino alcohols with dialkyl oxalate to obtain
cyclic morpholine-2,3-diones 3.17 Failure to achieve cyclization to
the cyclic morpholine-diones 3 was attributed to conformational
energy barriers inhibiting rotation around the secondary amide
bond and formation of the cisoid dicarbonyl conformation, neces-
sary for obtaining the final cyclic compound 3.17b However, as we
explain later, there is not a problem of energy barriers (kinetic
control) but energy balance (thermodynamic control), and the
presence of this intermediate is probably due to its stability under
the reaction conditions. When the solvent used is ethanol, the
stability increases considerably. In all reactions, the presence of
cyclic morpholine-2,3-diones was not detected.
2. Results and discussion
This work will be focused on three steps: firstly, the description
of the experimental results from the reaction of b-amino alcohols
1ae1h with diethyl oxalate. Secondly, the study of the possible
reaction mechanisms by theoretical calculations and, finally, addi-
tional experiments were carried out in order to support the pro-
posed mechanism.
2.1. Experimental studies
The b-amino alcohols 1ae1h were subjected to reaction with
diethyl oxalate to afford the linear oxalamides 2ae2h and the
morpholine-2,3-diones 3b, 3d, 3e, and 3g (see Scheme 1). The
Slightly different results were obtained in the reaction of N-
substituted b-amino alcohols (1b,1d,1f, and 1g) with diethyl oxalate.
In the reaction of 1d, 1f, and 1g in toluene, the corresponding linear
oxalamide precipitates (between 76 and 90% yield). An analysis of
the mother liquor revealed the presence of an additional amount of
oxalamide (between 3 and 12% yield) and in some cases (1f, 1g)
a small proportion of cyclic morpholine-2,3-dione (about 4%).
However, into the reaction of amino alcohol 1b with diethyl oxalate
in toluene there is no precipitation. In the crude of reaction the
mayor product is the oxalamide 2b14a (96% yield). When reactions
Scheme 1. Simplified mechanism.

M.L. Testa et al. / Tetrahedron 68 (2012) 9583e9591
9585
were carried out in ethanol, due to the absence of precipitate, the
concentrate is analyzed. The major product is the corresponding
linear tetrasubstituted oxalamide 2, but in some cases there was an
increase in the proportion of cyclic morpholine-2,3-dione (12% in the
case of 3g).
These results indicate that in the reaction of b-amino alcohols
with diethyl oxalate the reaction pathway 1 is favored (see Scheme
1), leading almost exclusively to the oxalamide 2. The result is in-
dependent of the solvent used, toluene or ethanol. However, the
appearance of the morpholine-2,3-dione 3 in the reaction with N-
substituted b-amino alcohols, points to a competition between the
reaction pathway 1 and pathway 2 in Scheme 1. With the use of
ethanol instead of toluene, the formation of cyclic compound is
slightly favored.
The spectroscopic data of compounds 2a,15 2b,14a 2e,14b 2h,16
3b,18 3d,18 3f,19 and 4h17 were in complete agreement with those
reported in the literature. To our knowledge, products 2c, 2d, 2f,20
2g, and 3g are new, and their structures were confirmed by spec-
troscopic data (see Experimental data). As calculated in previous
work,14a in solution linear oxalamides 2b, 2d, 2f, and 2g, can be
found as mixture of three conformers (cc, ct/tc, and tt) due to the
high rotational barrier of the amide bond. The three conformers,
present different signals and the 1H and 13C NMR spectra will be
very complex.
In order to explain the different observed reactivity of the
b-
amino alcohols and N-substituted -amino alcohols with diethyl
oxalate, we have made a complete theoretical study of the possible
mechanisms of reaction.
b
Scheme 2. Mechanism for the conversion of amino alcohols 1a and 1b into the
intermediate 4.
2.2. Theoretical study
Table 2
B3LYP/6-31G** relative free energies (DG, in
The purpose of this section is the study of a possible reaction
mechanism and the evaluation of the kinetic or thermodynamic
control of these reactions.
kcal/mol), in vacuo, of the stationary points
involved in the reaction of dimethyl oxalate
with 1a and 1b
In the Scheme 1, we can see the simplified mechanistic path-
ways (Path 1 and Path 2) which, starting from the b-amino alcohols
D
G
Oxalate-1a
MC1a
TS1a
IN1a
TS2a
MC2a
Oxalate-1b
MC1b
TS1b
IN1b
TS2b
0.0
and reacting with the dialkyl oxalate can lead to the final linear
oxalamides 2 or the cyclic morpholine-2,3-diones 3 .The two paths
share a common intermediate 4. The formation of this intermediate
is produced by intermolecular nucleophilic substitution of an alk-
oxide of the dialkyl oxalate by the amino group of the amino al-
cohol. In the first pathway (Path 1), intermediate 4 is converted into
oxalamide 2 through another intermolecular nucleophilic sub-
stitution of the alkoxide remainder in 4 with a second molecule of
amino alcohol. Cyclic morpholine-2,3-diones 3 arises from the
intramolecular attack of the hydroxyl group of the intermediate 4
to the carbonyl group of the ester moiety with extrusion of alkoxide
group (Path 2).
ꢀ2.6
27.4
8.0
21.5
ꢀ10.2
0.0
ꢀ0.8
30.7
12.8
27.3
ꢀ3.7
MC2b
For the theoretical study we have selected the compounds 1a
and 1b and the dimethyl oxalate. Firstly, we will discuss the for-
mation of the intermediate 4, and later we will study the conver-
sion of 4 into the oxalamide 2 and morpholine-2,3-dione 3.
2.2.1. Kinetic study: formation of the intermediate 4. The complete
suggested mechanism for the conversion of amino alcohols 1a and
1b into the intermediate 4, in a two-steps process, is presented in
Scheme 2. We have also studied the same conversion in a single-
step process (see Scheme 1S, Figs. 1Se4S and Table 1S in
Supplementary data). This single-step process has a higher en-
ergy and only the two-steps mechanism is discussed. The free en-
ergies of the species are in Table 2 and Fig. 2. The geometries of
species involved in the mechanism are in the Supplementary data
(see Figs. 3Se4S).
Initially, the reactants form a molecular complex (MC1), which
is converted into intermediate 4, through transition state TS1 and
TS2. TS1 arises from the intermolecular attack of the amino group
Fig. 2. Free energy profile (
oxalate with 1a (in blue) and with 1b (in red).
DG in kcal/mol), in vacuo, for the reaction of dimethyl

9586
M.L. Testa et al. / Tetrahedron 68 (2012) 9583e9591
of the amino alcohol to the carbonyl group of the oxalate to yield
the tetrahedral intermediate IN1. Extrusion of MeOH in the TS2
leads to the intermediate 4. It should be noted that in all transition
states (TS1 and TS2) there are intramolecular catalysis due to the
hydroxyl group of the amino alcohol (see Fig. 3S in Supplementary
data). Normally, transamination process requires the presence of
a proton donoreacceptor (amine, alcohol or water) that catalyzes
these reactions, through hydrogen bonds (HB), lowering the acti-
vation energy of TSs.21 Without this catalytic effect, the trans-
amination process requires high energy barriers. In this case the
intramolecular catalysis is more favorable than usual in-
termolecular catalysis,21 due to entropic factors.
The conversion of the amino alcohol 1a into the corresponding
intermediate 4a (see Table 2 and Fig. 2) has an activation free en-
ergy of 27.4 kcal/mol (TS1a). The initial intermolecular attack of the
amine (TS1a), to give the tetrahedral intermediate IN1a, is the rate
determining step of the process, being more energetic than the
posterior extrusion of MeOH (21.5 kcal/mol, TS2a). Overall, the
conversion of 1a into 4a is favored by 10.2 kcal/mol (see MC2a). It
should be noted that the intramolecular catalysis, due to the hy-
droxyl group, reduces the activation energy of the process in about
11 kcal/mol. For example, the TS in the reaction of methyl amine
with the dimethyl oxalate (without the catalytic effect of hydroxyl),
has an activation energy (
DE) of 35.1 kcal/mol (see Fig. 5S and Table
1S in Supplementary data).
The energy results for the conversion of 1b in 4b show a signifi-
cant increase in the free energy of all TSs with respect to the
equivalent TSs in the case of the amino alcohol 1a. This maybe due to
steric interaction exerted by the additional methyl group (NeMe).
2.2.2. Kinetic study: conversion of 4 into the oxalamide 2 and mor-
pholinedione 3. The suggested mechanism for the conversion of the
intermediate 4 into the oxalamide 2 and morpholindione 3 is
presented in Scheme 3. All calculations were initially performed in
vacuo. These steps determine the final products to be obtained (2 or
3). Therefore, to obtain more accurate results, calculations were
also performed in toluene and ethanol (single point calculation).22
In this case the study of the possible TSs is very complex due to the
possibility of HB between hydroxyl and amino groups among
themselves and with other functional groups present in the
structures. After a careful research we only show, in order to sim-
plify, the most stable TSs found (see Fig. 6S in Supplementary data).
The free energies of the species are in Table 3, Fig. 3, and Fig. 4.
Conversion of intermediate 4 into linear oxalamide 2 is a trans-
amination process similar to that discussed for the transformation
of amino alcohol 1 into 4. In this reaction pathway (Path 1 in
Scheme 3), after the formation of a molecular complex (MC3), in-
termediate 4 is converted into oxalamide 2 through TS3, the tet-
rahedral intermediate IN2 and TS4. TS3 corresponds to the
intermolecular attack of the amino group of the amino alcohol 1 to
the carbonyl group of the ester moiety of 4 to yield the tetrahedral
intermediate IN2. In this transition state (TS3a and TS3b in Fig. 6S
in Supplementary data) there is intramolecular catalysis due to the
hydroxyl group present in 4 and also an additional HB between this
hydroxyl and the hydroxyl group of the amino alcohol 1. Extrusion
of MeOH in the intermediate IN2 through TS4 leads to the final
oxalamide 2. In this TS (TS4a and TS4b in Fig. 6S in Supplementary
data), intramolecular catalysis is due to the hydroxyl group of the
incoming amino alcohol.
Scheme 3. Mechanism for the conversion of the intermediate 4 into the oxalamide 2
and morpholinedione 3.
of the ester moiety of 4 to yield the tetrahedral intermediate IN3, is
catalyzed by amino group of the amino alcohol 1 yielding the tet-
rahedral intermediate IN3. Similarly, the extrusion of MeOH in the
reaction intermediate IN3, through the TS6 (see TS6a and TS6b in
Fig. 6S in Supplementary data) is also catalyzed by the amino group
of 1 giving the morpholine-2,3-dione 3.
As it can be seen in Table 3 and Fig. 3, the conversion of the
intermediate 4a into oxalamide 2a (Path 1 in Scheme 3), in vacuo,
has an activation free energy of 29.2 kcal/mol (TS3a). In this case,
the initial intermolecular attack of the amine group (TS3a) is the
rate determining step of the process, being more energetic than the
posterior extrusion of MeOH (23.1 kcal/mol, TS4a). The formation of
the oxalamide 2a (actually, the molecular complex MC4 between
2a and MeOH) is an exergonic process in ꢀ9.9 kcal/mol.
For the conversion of intermediate 4 into cyclic morpholine-2,3-
dione 3 we have investigated the reaction pathway 2 (Path 2 in
Scheme 3) through MC5, TS5, IN3 (actually, the molecular complex
between IN3 and 1) and TS6. Throughout this process, the amino
alcohol 1 acts as proton donoreacceptor. In the TS5 (see TS5a and
TS5b in Fig. 6S in Supplementary data) the intramolecular attack of
the hydroxyl group of the amide moiety of 4 to the carbonyl group
On the other hand, the conversion of the intermediate 4a into
cyclic morpholine-2,3-dione 3a (Path 2 in Scheme 3), in vacuo,

M.L. Testa et al. / Tetrahedron 68 (2012) 9583e9591
9587
Table 3
determining step of the process, being more energetic than the
posterior extrusion of MeOH. In this case, the overall process is
slightly endergonic (2.7 kcal/mol, MC7a). Due to the polar nature of
most of the species involved in the conversion of 4a into 2a and 3a,
the inclusion of the solvent (toluene or ethanol) causes a decrease in
the energy of the species. This effect is more pronounced with the
use of a more polar solvent, such as ethanol. The result is a decrease
in the energy profile of the reaction (all overall processes become
exergonic), but the energy difference between TS3a and TS5a does
not substantially change.
The transformation of the intermediate 4b into oxalamide 2b
and morpholine-2,3-dione 3b shows similarities and differences
with respect to the conversion of 4a into 2a and 3a. The most no-
table data is the increase of the free energy barrier through the
pathway 1. It is due to the increased energy of the TS4b, which
becomes the limiting step of this process. This increased energy of
TS4b with respect to TS4a is easily explainable analyzing the ge-
ometry of these transition states (Fig. 6S in Supplementary data).
TS4a is stabilized with two five-membered rings formed by hy-
drogen bonding, NeH/O]C, which allows the flat arrangement of
the oxalamide group.14a In the case of the TS4b the presence of
NeMe prevents this option and produces a considerable increase in
energy. The inclusion of solvent effect causes less variation in the
energy of the species, possibly due to lower polarity of the com-
pounds with the NeMe group. In fact there is very little variation
between toluene and vacuo. Only in ethanol there is a clear de-
crease of the energy profile.
B3LYP/6-31G** relative free energies (DG, in kcal/mol), in vacuo in toluene and in
ethanol, of the stationary points involved in the reaction of 4a and 4b with 1a and
1b, respectively
D
G (vacuo)
D
G (toluene)
D
G (ethanol)
4ae1a
MC3a
TS3a
IN2a
TS4a
MC4a
MC5a
TS5a
MC6a
TS6a
MC7a
4be1b
MC3b
TS3b
0.0
5.0
0.0
2.5
26.6
17.2
20.6
0.0
0.9
24.7
15.7
18.9
29.2
19.6
23.1
ꢀ9.9
2.7
27.7
6.3
ꢀ12.4
ꢀ1.4
22.4
4.6
20.2
ꢀ0.9
0.0
ꢀ1.2
28.9
21.4
30.7
ꢀ3.7
0.5
ꢀ14.1
ꢀ4.1
18.6
2.1
16.5
ꢀ3.1
0.0
ꢀ3.9
26.0
19.5
28.8
ꢀ6.6
ꢀ3.0
18.7
ꢀ0.4
14.3
ꢀ5.5
25.0
2.7
0.0
ꢀ2.9
27.5
19.9
29.6
ꢀ3.9
0.7
21.8
4.4
19.1
ꢀ2.4
IN2b
TS4b
MC4b
MC5b
TS5b
MC6b
TS6b
22.7
4.1
18.1
ꢀ2.3
MC7b
These results (Path 2 lower energy than Path 1) indicate that
if the reaction had a kinetic control, the major product would
be the cyclic morpholine-2,3-dione 3. In the experimental reaction
is obtained mostly the linear oxalamide 2 (see Table 1). This
suggests that these reactions are not kinetically controlled, there
must be an equilibrium between all species and therefore it
must follow a thermodynamic control. To explore the relative
stability of the reaction products, we performed a thermodynamic
study. Experimental studies were also conducted to support this
hypothesis.
2.2.3. Thermodynamic study. For thermodynamic study, we con-
sidered the equilibrium represented in Scheme 4. In this scheme
the linear oxalamide 2 is in equilibrium with the complex formed
between the cyclic morpholine-2,3-dione 3 and the amino alcohol
1 (MC8). For each specie (2a, 2b, MC8a, and MC8b), we conducted
a detailed conformational study, with full minimization at each of
the solvents used (toluene and ethanol). Conformational study of
oxalamides 2 is very complex and has been published previously.14a
Free energies corresponding to the most stable conformers found
for 2 and MC8 are collected in Table 4. The molecular complexes
MC8a and MC8b, are stabilized by a double HB. These HB occur
between the hydroxyl group and amino group of the amino alcohol
1 and the oxygen of the carbonyl groups of the cyclic morpholi-
nedione 3 (see Fig. 9S in Supplementary data).
Fig. 3. Free energy profile (
blue) in toluene (in red) and in ethanol (in green).
DG in kcal/mol), for the reaction of 4a with 1a, in vacuo (in
Fig. 4. Free energy profile (DG in kcal/mol), for the reaction of 4b with 1b, in vacuo (in
blue) in toluene (in red) and in ethanol (in green).
Scheme 4. Equilibrium between 2 and MC8.
going through TS5a (27.7 kcal/mol) and TS6a (25.0 kcal/mol), has
activation free energy of 27.7 kcal/mol (TS5a). The initial in-
termolecular attack of the hydroxyl group of the amide moiety of 4a
to the carbonyl group of the ester moiety of 4a is the rate
The results for the equilibrium 2a/MC8a, show a large differ-
ence in free energy. The oxalamide 2a is much more stable than the

9588
M.L. Testa et al. / Tetrahedron 68 (2012) 9583e9591
Table 4
2.3. Additional experimental evidences
B3LYP/6-31G** relative free energies (DG, in kcal/mol), in toluene and in ethanol, of
the compounds 2 and molecular complexes MC8
With the aim of supporting the suggested thermodynamic
control in the reaction of -amino alcohols with dialkyl oxalates, we
have carried out additional experimental assays. Compound 1a was
selected as an example of primary -amino alcohol and compounds
1b, 1d, 1f, and 1g were selected as examples of N-substituted
amino alcohols. To this end, we have changed the proportions of the
reactants to 1 equiv of amino alcohol and 1 equiv of oxalate. These
proportions are supposed to favor the formation of cyclic mor-
pholine-2,3-diones 3, and therefore it can expect an increase in the
proportion of these compounds. The results are shown in Table 5.
D
G (toluene)
DG (ethanol)
b
2a
0.0
0.0
13.1
MC8a
14.0
b
b
-
2b
MC8b
0.0
5.2
0.0
1.9
MC8a, both in toluene and ethanol, with a value of 14.0 kcal/mol
and 13.1 kcal/mol, respectively. These energy values clearly
indicate that in the equilibrium the only observable product would
be the linear oxalamide 2a, according to experimental results
(see Table 1). The presence of substituents other than hydrogen
on the carbons adjacent to the hydroxyl and amino groups (2c,
2d, and 2h) may vary slightly these energetic results, but hardly
enough to approximate the difference in energy between 2
and MC8.
Table 5
Reaction of 1 equiv of
or in ethanol
b-amino alcohols 1 with 1 equiv of diethyl oxalate in toluene
Amino alcohol (solvent)
Products
Yield (%) a
1a (Ethanol)
1b (Toluene)
2a
2b
3b
2b
3b
2d
3d
2f
93
91
7
We conclude that in the reaction of primary b-amino alcohols
with dialkyl oxalates, linear oxalamides are obtained as the com-
pounds of reaction, regardless of solvent used. With this type of
amino alcohols should not be detected the presence of cyclic
morpholin-2,3-diones.
It should be noted that in the reaction of amino alcohol 1h with
diethyl oxalate, the presence of the intermediate 4h (see Table 1)
may be due to its high stability. In this case the stability of this
intermediate should be similar to that of the final linear oxalamide
2h. In fact, using ethanol as a solvent there is a shift of equilibrium
toward the aforementioned intermediate 4h.
1b (Ethanol)
1d (Ethanol)
1f (Toluene)
1g (Ethanol)
53
43
85
10
86
11
56
40
3f
2g
3g
a
Yield (%) from 1H NMR of the crude of reaction.
In the case of 2b/MC8b equilibrium, the differences in free
energy between 2b and MC8b are significantly reduced. By using
toluene as a solvent, 2b remains as the more stable product in
5.2 kcal/mol, while in ethanol the difference in free energy is only
1.9 kcal/mol. According to these results, the use of ethanol as sol-
vent increases the proportion of the cyclic compound 3b. The en-
ergy difference, in toluene, between 2b and MC8b (5.2 kcal/mol)
does not allow a sufficient concentration of MC8b in the equilib-
rium and therefore there is no observable morpholine-2,3-diones
3b in the reaction between amino alcohol 1b and diethyl oxalate.
However, this difference in ethanol is only 1.9 kcal/mol, this allows
obtaining a small amount of 3b in the reaction between amino
alcohol 1b and diethyl oxalate, according to experimental results
(see Table 1). In this situation, changes in the substituents of the N-
As expected, in the reaction of the primary amino alcohol 1a
with oxalate in ethanol (the most favorable reaction conditions),
we obtained only the linear compound 2a without the presence of
cyclic compound 3a. However, in the reaction of N-substituted
amino alcohols (1b, 1d, 1f, and 1g), both in toluene and ethanol, it
was observed an increase toward the cyclic morpholine-2,3-diones
3 with respect to the corresponding reaction carried out in pro-
portion 2:1 (see Table 1). In reactions that previously showed no
cyclic compounds, for example,1b in toluene or 1d in ethanol, it can
see now these compounds. Again, the use of ethanol instead of
toluene favors the formation of cyclic morpholine-2,3-diones 3.
These results clearly confirm the thermodynamic control of these
reactions.
As previously noted, in the transamination process of dialkyl
oxalate into oxamidic ester intermediate 4, there is intramolecular
catalysis due to the hydroxyl group of the amino alcohol 1 (see
Scheme 2). Also, in the conversion of the intermediate 4 into the
oxalamide 2 (see Scheme 3) there is intramolecular catalysis due
to the hydroxyl group present in 4 (see TS3) or due to the hydroxyl
group of the incoming amino alcohol (see TS4). Finally, in the
conversion of the intermediate 4 into the morpholinedione 3 (see
Scheme 3, TS5 and TS6) the amino alcohol 1 acts as a catalyst. As
a result, the energy barriers for the reactions and also for the
interconversion between species are quite low. We have already
established that the reaction follows a thermodynamic control and
therefore these energy barriers do not influence the proportion of
the final products of reaction, but in the overall speed of all
processes. In view of the energy values calculated, the rate of re-
action should occur much more quickly than expected. At exper-
imental level, it is known that secondary amines (without the
hydroxyl group) react only slowly and incompletely with diethyl
oxalate.11 Also experimental conditions, commonly used, include
long reaction time, at room temperature, or reflux in the solvents
used.
alkyl
b-amino alcohols 1, as well as the reaction conditions, can lead
to different results depending on the relative stability between the
linear oxalamide 2 and the MC8. For example (see Table 1), in tol-
uene, there is a 3% and 4% of the corresponding cyclic compounds
3f and 3g, while in ethanol there is a 4% and 12% of 3b and 3g,
respectively.
The different behavior between the primary
b-amino alcohols
and N-methyl -amino alcohols is due to the difference in stability
b
of linear disubstituted oxalamides (2a, 2c, 2e, and 2h) with respect
to linear tetrasubstituted oxalamides (2b, 2d, 2f, and 2g). In fact, by
observing the MC8a and MC8b (Fig. 9S in Supplementary data), the
presence of the N-methyl group in the MC8b almost does not affect
this MC with respect to the MC8a neither by steric interaction nor
electronic factors. However, as mentioned above for TS4a and TS4b,
the linear disubstituted oxalamides (see 2a in Fig. 9S in
Supplementary data) are stabilized with two five-membered
rings formed by hydrogen bonding, NeH/O]C, which allows
the flat arrangement of the oxalamide group.14a In the linear tet-
rasubstituted oxalamides (see 2b in Fig. 9S in Supplementary data)
the presence of NeMe prevent this option and produces a consid-
erable increase in energy. In consequence, the energy of 2b is closer
to the energy of MC8b.
In order to verify the acceleration of the reactions, which in-
volves an amino alcohol, the reaction of dimethyl oxalate with

M.L. Testa et al. / Tetrahedron 68 (2012) 9583e9591
9589
the amino alcohol 1b (1:1 ratio) was carried out in a NMR tube.
4. Experimental section
Deuterated methanol was used as solvent at 25 ꢁC. 1H and 13C
spectra were recorded after 30 min and after 24 h. The spectra
recorded at 30 min showed a 6:4 ratio of compounds 2b and 3b,
respectively (similar to the corresponding reaction in Table 5), as
well as unreacted dimethyl oxalate. To obtain the linear com-
pound 2b, the consumption of 2 equiv of amino alcohol is re-
quired, thus leaving an excess of oxalate. As traces, are noted
another product that could be the intermediate 4b. The presence
of starting amino alcohol 1b was not detected. The spectra at 24 h
were almost identical, demonstrating that the reaction had been
completed in those 30 min. The addition of a new equivalent
of amino alcohol 1b, has produced a disturbance of equilibrium
and therefore a change in the ratio of the products. In this
case the major product of the reaction was linear compound 2b
with a ratio above 95% (similar to the corresponding reaction in
Table 1).
4.1. Computational methods
All calculations were carried out with the Gaussian 03 suite of
programs.23 Density functional theory24 calculations (DFT) have
carried out using the B3LYP25 exchange-correlation functionals,
together with the standard 6-31G** basis set.26 In the previous
conformational study on this type of molecules, this basis set led
to us concordant results between theoretical calculations and ex-
perimental results.14a Due to the large amount of calculations
carried out, a higher level of calculation (e.g., 6-311þþG**) is not
considered necessary. Since the mechanism involves polar species
the inclusion of solvent effects have been considered by using
a relatively simple self-consistent reaction field (SCRF) method27
based on the polarizable continuum model (PCM) of Tomasi’s
group.28 As indicated in the text, calculations have been made with
single point or total minimization in the solvents used (toluene
and ethanol).
3. Conclusions
The reaction of
the production of linear oxalamides and cyclic morpholine-2,3-
diones. Reaction of primary -amino alcohols with dialkyl oxalate
afforded the corresponding linear disubstituted oxalamides re-
gardless of the solvent used (toluene or ethanol), the ratio of amino
alcohol and dialkyl oxalate (2:1 or 1:1), and the presence of sub-
stituents other than hydrogen on the carbons adjacent to the hy-
b
-amino alcohols with dialkyl oxalate can lead to
4.2. General
b
Unless otherwise specified, materials were purchased from
commercial suppliers and used without further purification. Sol-
vents were distilled prior to use. Thin layer chromatography
was performed on plates precoated with silica gel Si60-F254 (Merck,
Darmstadt, Germany). Column chromatography was carried out with
silica gel Si60, mesh size 0.040e0.063 mm (Merck, Darmstadt, Ger-
many). Melting points were determined with a SanyoeGallencamp
capillary apparatus and are uncorrected. IR spectra were recorded on
a Jasco FTIR 5300 spectrometer. 1H NMR and 13C NMR spectra were
recorded with a Bruker Avance DRX 300 MHz (300 and 75 MHz,
respectively) spectrometer, in DMSO-d6 and in CDCl3 solutions.
Chemical shifts were recorded in parts per million (ppm), downfield
from internal Me4Si. The coupling constants J are given in Hz. The
one-bond multiplicity of carbon atoms was determined by DEPT
experiments. High-resolution mass spectral data were obtained on
a VG Autospec, TRIO 1000 (Fisons) instrument. Electron impact (EI)
or Fast Atom Bombardment (FAB) at 70 eV were used as ionization
mode in mass spectra. The structure of all the compounds was de-
termined by analytical and spectroscopic methods, and by compar-
ison with data of the compounds reported in literature.
droxyl and amino groups. When using N-substituted
b-amino
alcohols in a 2:1 ratio amino alcohol:oxalate the major product is
the corresponding linear tetrasubstituted oxalamide, but in some
cases there is a small amount of cyclic morpholine-2,3-dione. In
a 1:1 ratio the cyclic morpholine-2,3-dione product increases, be-
ing greater with the use of ethanol as a solvent.
The possible mechanism for the reaction of b-amino alcohols
with the dialkyl oxalate to yield the final linear oxalamides or
the cyclic morpholine-2,3-diones, has been investigated in vacuo
and in solvent (toluene and ethanol), using DFT methods at the
B3LYP/6-31G** computational level. Formation of linear oxala-
mides or cyclic morpholinediones shares a common oxamidic es-
ter intermediate. The formation of this intermediate is produced
by intermolecular nucleophilic substitution of an alkoxide of the
dialkyl oxalate by the amino group of the amino alcohol in a two-
steps process. This intermediate is converted into oxalamide
through another two-steps intermolecular nucleophilic sub-
stitution of the alkoxide remainder with a second molecule of
amino alcohol. Cyclic morpholine-2,3-diones arises from the
intramolecular attack of the hydroxyl group of the intermediate to
the carbonyl group of the ester moiety with extrusion of alkoxide
group. In all steps, there is a strong catalytic effect produced
by amino or hydroxyl group of the amino alcohol and thus the
energy barriers are quite low. These theoretical results indicate
that these reactions are not kinetically controlled, there is an
equilibrium between all species and therefore follow a thermody-
namic control.
4.3. General procedures for the preparation of oxalamides (2),
morpholine-2,3-diones (3)
Method A: Diethyl oxalate (0.5 mmol) was added dropwise to
a stirred solution of the appropriate amino alcohol 1 (1 mmol) in
toluene or ethanol (4 ml). The mixture was stirred at rt for 24 h. If
a solid appears was filtered under reduced pressure and analyzed;
the filtrate liquid was concentrated to dryness and analyzed by 1H
NMR. When not precipitated, the crude reaction mixture was
concentrated to dryness and analyzed by 1H NMR. To obtain ana-
lytical information the products were purified by column
chromatography.
The different behavior between the primary
b-amino alcohols
and N-methyl -amino alcohols is due to the difference in stability
b
Method B: Diethyl oxalate (1 mmol) was added dropwise to
a solution of the appropriate amino alcohol 1 (1 mmol) in toluene
or ethanol (4 ml). The mixture was stirred at rt for 24 h, concen-
trated to dryness, and the crude reaction mixture was analyzed by
1H NMR.
of linear disubstituted oxalamides with respect to linear tetrasub-
stituted oxalamides. The linear disubstituted oxalamides are sta-
bilized with two five-membered rings formed by hydrogen
bonding, NeH/O]C, which allows the flat arrangement of the
oxalamide group, and are much more stable than their corre-
sponding morpholine-2,3-diones. In the linear tetrasubstituted
oxalamides the presence of NeMe prevent this option and produce
a considerable increase in energy. In consequence, the energy of
tetrasubstituted oxalamides is closer to the energy of the corre-
sponding morpholine-2,3-diones.
4.3.1. Starting
b-amino alcohol: 2-aminoethanol (1a). Method A
(Toluene): N,N’-bis-(2-hydroxy-ethyl)-oxalamide (2a)14a,15 pre-
cipitated (94%). Method A (Ethanol): 2a precipitated (76%)þ2a (19%)
in the filtrate liquid.
Method B (Ethanol): 2a (93%).

9590
M.L. Testa et al. / Tetrahedron 68 (2012) 9583e9591
4.3.2. Starting
(1b). Method
b
-amino
alcohol:
N-methylethanolamine
oxalamide (2g) (76%) precipitatedþa mixture of 2g (12%): (5S,6S)-
A
(Toluene): N, N’-bis-(2-hydroxy-ethyl)-N,N’-di-
4,5-dimethyl-6-phenylmorpholine-2,3-dione (3g) (4%) in the filtrate
liquid.
methyl-oxalamide (2b)14a (96%) in the crude reaction mixture.
Method A (Ethanol): a mixture of 2b (90%) and 4-methyl-
morpholine-2,3-dione (3b)19 (4%) in the crude reaction mixture.
Method B (Toluene): a mixture of 2b (91%) and 3b (7%).
Method B (Ethanol): a mixture of 2b (53%) and 3b (43%).
Method B (Ethanol): a mixture of 2g (56%) and 3g (40%).
2g: White solid; mp 174e175 ꢁC. IR (KBr) nmax: 3472, 3377, 1643,
1620 cmꢀ1 1H NMR (300 MHz, CD3OD):
d
¼0.85e1.00 (several d,
CH3eC), 2.65e3.00 (several s, CH3eN), 3.66, 4.45 (2 m, CHeN),
4.40e4.60 (m, CHeO), 7.10e7.40 (m,C6H5) ppm 13C NMR (75.4 MHz,
4.3.3. Starting
(1c). Method
oxalamide (2c) precipitated (96%).
b
-amino alcohol: 2-amino-1-phenylethanol
CD3OD):
d
¼14.68, 16.18 (CH3eC), 26.68, 31.69 (CH3eN), 61.92
A
(Toluene): N,N’-bis-(2-hydroxy-2-phenyl-ethyl)-
(CHeN), 75.85, 76.03 (CHeO), 128.35, 128.56, 129.38, 129.86,
129.96, 143.97 (C6H5), 166.26, 166.87 (C]O) ppm. HMRS (EI) calcd
for C22H29N2O4 [MþH]þ 385.2127; found 385.2130.
Method A (Ethanol): 2c precipitated (77%)þ2c (18%) in the
filtrate liquid.
3g: White solid; mp 94e96 ꢁC. IR (KBr) nmax: 3456, 1765,
2c: White solid; mp 186e187 ꢁC. IR (KBr) nmax: 3302; 1649;
1689 cmꢀ1 1H NMR (300 MHz, CDCl3):
d
¼1.41 (d, 3J¼6.8 Hz, 3H,
1537 cmꢀ1 1H NMR (300 MHz, DMSO-d6):
d
¼3.23e3.34 (m, 4H,
CH3eC), 2.92 (s, 3H, CH3eN), 3.89 (m,1H, CHeN), 5.30 (d, 3J¼4.0 Hz,
2ꢂ CH2eN), 4.73 (m, 2H, 2ꢂ CHeO), 5.58 (bs, 2H, 2ꢂ OH,
exchangeable with D2O), 7.23e7.34 (m, 10H, 2ꢂ C6H5), 8.51 (t,
3J¼6.0 Hz, 2H, 2ꢂ NH, exchangeable with D2O) ppm 13C NMR
1H, CHeO), 7.20e7.32 (m, 5H, C6H5) ppm 13C NMR (75.4 MHz,
CDCl3):
d
¼17.77 (q, CH3eC), 32.98 (q, CH3eN), 57.46 (d, CHeN),
81.82 (d, CHeO), 126.11, 129.37, 129.46, 136.12 (C6H5), 153.89 (s,
NeC]O), 156.70 (s, OeC]O) ppm. HMRS (EI) calcd for C12H13NO3
[M]þ 219.0895; found 219.0898.
(75.4 MHz, DMSO-d6):
d
¼47.23 (t), 70.99(d), 126.31 (d), 127.51 (d),
128.42 (d), 143.54 (s), 160.07 (s) ppm. HMRS (FAB) calcd for
C18H19N2O3 [MꢀOH]þ 311.1395; found: 311.1387.
4.3.8. Starting
b
-amino
alcohol:
(1R,2S)-(ꢀ)-norephedrine
4.3.4. Starting
b
-amino alcohol: 2-(methylamino)-1-phenylethanol
(Toluene): N,N’-bis-(2-hydroxy-2-phenyl-ethyl)-
(1h). Method A (Toluene): N,N’-bis-[(1R,2S)-(ꢀ)-norephedrine]oxa-
lamide (2h)16 precipitated (88%)þa mixture of 2h (3%) and N-
[(1R,2S)-(2-Hydroxy-1-methyl-2-phenyl-ethyl)]oxalamic acid ethyl
ester (4h)17 (6%).
(1d). Method
A
N,N’-dimethyl-oxalamide (2d) precipitated (84%)þ2d (5%) in the
filtrate liquid.
Method A (Ethanol): oxalamide 2d (92%) in the crude reaction
mixture.
Method A (Ethanol): 2h precipitated (13%)þa mixture of 2h (7%):
4h (65%) in the filtrate liquid.
Method B (Ethanol): a mixture of 2d (85%) and 4-methyl-6-
phenylmorpholine-2,3-dione (3d).19
Acknowledgements
2d: White solid; mp 132e133 ꢁC. IR (KBr) nmax: 3476, 3369, 1651,
1631 cmꢀ1 1H NMR (300 MHz, CDCl3):
d
¼2.80e3.00 (several s,
NeCH3), 3.10e5.30 (several bs, OH), 3.15e3.75 (m, CH2eN), 4.7e5.30
(m, CHeO), 7.29 (m, C6H5) ppm 13C NMR (75.4 MHz, Cl3CD):
This work was supported by research funds provided by the
Ministerio de Ciencia e Innovacion of the Spanish Government
(project CTQ2009-11027/BQU and CTQ2008-06777-CO2-01/BQU).
ꢀ
d¼32.71,
32.82, 33.15, 37.0. 37.1, 37.9 (CH3eN), 54.84, 55.40, 57.46, 57.53, 57.57,
57.62, (CH2eN), 70.26, 70.66, 70.96, 71.10, 71.61, 71.84, 72.13 (CHeO),
125.86, 125.93, 125.94, 126.02, 126.09, 128.05, 128.69, 128.72, 128.78,
128.84, 141.46, 141.47, 141.74, 141.81, 141.86, 142.01, 142.13 (C6H5),
165.22,165.48,165.78,166.11,166.25,166.41 (C]O) ppm. HRMS (FAB)
calcd for C20H25N2O4 [MþH]þ 357.1814; found 357.1811.
Supplementary data
Figs. 1Se10S, Tables 1Se4S, and Scheme 1S. 1H NMR and 13C
NMR spectra of 2c, 2d, 2f, 2g, and 3g. Supplementary data associ-
ated with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2012.09.067. These data include MOL files
and InChiKeys of the most important compounds described in this
article.
4.3.5. Starting b-amino alcohol: (2R,3R)-3-amino-3-phenylpropane-
1,2-diol (1e). Method A (Toluene): N,N’-bis-[(1R, 2R)2,3-dihydroxy-
1-phenylpropyl]oxalamide (2e),14b precipitated (96%).
Method A (Ethanol): 2e precipitated (76%)þ2e (19%) in the fil-
trate liquid.
References and notes
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b
-amino alcohol: (1S,2R)-(þ)-ephedrine (1f). Method
A (Toluene): N,N’-bis-[(1S,2R)-(þ)-ephedrine]oxalamide (2f) (90%)
precipitatedþa mixture of (2f) (3%): (5R,6S)-4,5-dimethyl-6-phe-
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d
¼0.91,1.00 (2d, CH3eC),
2.62, 2.71, 2.86 (3s, CH3eN), 3.33, 3.98, 4.37 (m, CHeN), 4.70, 4.88,
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125.88, 126.03, 126.24, 127.35, 127.86, 127.98, 128.25, 141.36, 143.78,
143.90 (C6H5), 168.77, 169.08, 169.98, 170.32 (C]O) ppm. HMRS
(FAB) calcd for C22H29N2O4 [MþH]þ 385.2127; found 385.2137.
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b
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M.L. Testa et al. / Tetrahedron 68 (2012) 9583e9591
9591
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