Ammonolysis of morpholine-2,5-diones: Participation of the primary amide group. Part 2

Article abstract of DOI:10.1002/poc.1884

The ammonolysis of three morpholine-2,5-dione derivatives was investigated and the mechanism ascertained by kinetic studies and theoretical calculations. The kinetics, followed by high-performance liquid chromatography analysis, evidenced the presence of two intermediates, which were isolated and characterized. The ammonolysis occurs with a complex mechanism involving two consecutive reactions followed by two parallel ones. The second step of the whole reaction involves an anchimeric assistance of the primary amide group. The pseudo-first-order rate constants were calculated by appropriate equations, which describe the single steps of the process. Computational density functional theory investigations of vicinal primary amide group participation were performed using a model compound, and the transition states were generated. The theoretical calculations evidenced the essential role exerted by ammonia, which acts as a proton transfer.

Full text of DOI:10.1002/poc.1884

Research Article
Received: 23 February 2011,
Revised: 19 April 2011,
Accepted: 9 May 2011,
Published online in Wiley Online Library: 10 July 2011
(wileyonlinelibrary.com) DOI 10.1002/poc.1884
Ammonolysis of morpholine‐2,5‐diones:
participation of the primary amide group.
Part 2
Antonio Arcellia*, Alessandro Bonginia, Gianni Porzia and Samuele Rinaldib
The ammonolysis of three morpholine‐2,5‐dione derivatives was investigated and the mechanism ascertained by
kinetic studies and theoretical calculations. The kinetics, followed by high‐performance liquid chromatography
analysis, evidenced the presence of two intermediates, which were isolated and characterized. The ammonolysis
occurs with a complex mechanism involving two consecutive reactions followed by two parallel ones. The second
step of the whole reaction involves an anchimeric assistance of the primary amide group. The pseudo‐first‐order rate
constants were calculated by appropriate equations, which describe the single steps of the process. Computational
density functional theory investigations of vicinal primary amide group participation were performed using a model
compound, and the transition states were generated. The theoretical calculations evidenced the essential role
exerted by ammonia, which acts as a proton transfer. Copyright © 2011 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: ammonolysis; anchimeric assistance; computational investigations; kinetic investigations; morpholine‐2,5‐diones;
primary amide group participation
INTRODUCTION
RESULTS AND DISCUSSION
In the last decades, the intramolecular participation of vicinal
groups represents an interesting topic in organic chemistry be-
cause it could be involved in the catalytic process of enzymes.[1,2]
However, the intramolecular participation of amide group was
ignored in proposed mechanisms of many enzymatic reactions.
This is mainly because the intramolecular involvement of amide
function has not been enough investigated in simple model of
organic reactions, and in any case, high effective intramolecular
catalysis has not been observed. A significant example in bio-
chemistry of the intramolecular amide group participation has
been shown to involve anchimeric assistance from the aceta-
mido group that promotes glycosidic bond breaking.[3–5]
Various works have been focused on the participation of amide
group in the hydrolysis of esters,[6–8] but, to the best of our
knowledge, only the example previously reported by us takes
into account the tertiary amide ammonolysis assisted by a vicinal
primary amide group.[9] In the present paper, our aim is to exam-
ine thoroughly the mechanism previously hypothesized by inves-
tigating other morpholine‐2,5‐dione derivatives.[9] Really, in recent
experiments, we isolated a reaction intermediate not previously
detected. Thus, we synthesized and submitted to kinetic studies
the racemate of 3,6‐trans morpholine‐2,5‐dione derivatives 1, 2
and 3 in order to ascertain the structure of the intermediate
and verify the possible influence of the alkyl substituent at N‐4
(Scheme 1) on the efficiency of intramolecular catalysis, that is,
the anchimerically assisted process. In fact, in previous kinetic
studies concerning the acid hydrolysis of the ether linkage
assisted by the vicinal secondary amide group, we observed a
remarkable reaction rate change with the bulkiness of the alkyl
substituent at the carbonyl group.[10]
In the previous work,[9] the kinetics were spectrophotometrically
monitored, and the dependence of optical density versus time
evidenced two step consecutive reactions. In the present study,
we followed the ammonolysis of morpholine‐2,5‐dione deriva-
tives 1, 2 and 3 by high‐performance liquid chromatography
(HPLC) analysis because by this technique, it was possible to ev-
idence two consecutive reactions (first‐order rate constants k1
and k2) and two parallel ones (first‐order rate constants k3
and k4) (Scheme 1). The first step is the opening of the morpho-
line‐2,5‐dione derivative A by ammonia to give the first interme-
diate B. The second step, that is, the conversion of the first
intermediate B into the second one C, is the process, which
involves the intramolecular participation of the secondary amide
group induced by ammonia. Subsequently, intermediate C suf-
fers two parallel reactions by means of the nucleophilic attack
of ammonia or ethanol giving the 2‐hydroxy‐propionamide
and D or E, respectively (Scheme 1).
The rate constants of the three steps were evaluated monitor-
ing the concentration changes of A, B, C, D and E versus time by
HPLC analysis. Because the rate constant k1 >> k2 (Table 1), the
* Correspondence to: Antonio Arcelli, Dipartimento di Chimica “G. Ciamician”,
University of Bologna, Via Selmi 2, 40126 Bologna, Italy.
E‐mail: antonio.arcelli@unibo.it
a A. Arcelli, A. Bongini, G. Porzi
Dipartimento di Chimica “G. Ciamician”, Via Selmi 2, 40126 Bologna, Italy
b S. Rinaldi
Dipartimento I.S.A.C., Università Politecnica delle Marche, Via Brecce Bianche,
60131 Ancona, Italy
J. Phys. Org. Chem. 2012, 25 132–141
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AMMONOLYSIS OF MORPHOLINE‐2,5‐DIONES
O
O
where k1, k2, k3 and k4 are the first‐order rate constants of various
reaction steps (Table 1).
PhH2C
R
PhH2C
R
NH2
OH
5 M NH3/EtOH, r.t.
O
N
Figures 1–6 show the concentration versus time dependence
of the various compounds. The experimental curves are fitted
by the appropriate Eqns 1–5, which describe the single steps of
the overall process (Scheme 1). The curves in Figs 1, 3 and 5 de-
scribe the disappearance of the starting lactones investigated 1,
2 and 3. The curves in Figs 2, 4 and 6 show the disappearance
of B (solid circle) and the formation and disappearance of C
(open square), and finally the formations of D and E are dis-
played by solid triangle and star, respectively.
The k2 value, obtained by Eqn 2, was introduced in Eqn 3 in or-
der to calculate the rate constant of the disappearance of C, that
is, k3 + k4 (Scheme 1). Then, the values of k3 and k4 were obtained
by Eqns 4 and 5, respectively, taking into account that the de-
composition of intermediate C occurs through two parallel reac-
tions, and therefore the ratio k3/k4 = [D]/[E] is constant within the
experimental error (Table 1).
The curves (Figs 1–6) are plotted by using an iterative
nonlinear least square procedure[13] and the pseudo‐fist‐order
rate constants (k1–k4) were calculated according to Eqns 1–4.
The best fit of the experimental points gives a correlation coeffi-
cient R ≥ 0.98.
As it results from data reported in Table 1, the first step (k1),
that is, the lactone opening, is fast and is not significantly influ-
enced by the substituent at N‐4, in agreement with the Taft
values σI, which are small and similar.[14] Also, the steric effect
of the substituent at N‐4, measured by ν or Es constants,[15] does
not exert a relevant effect on the reaction rate.
Conversely, the second step B → C, in which the anchimeric
assistance is involved, appears sensible to both the steric and po-
lar effect. Really, the k2 increases 7–10‐fold on going from sub-
strate 1 to 3 according to the increase of both the steric and
polar parameters of the substituents.[14,15]
In order to determine the rate enhancement induced by the
neighbouring primary amide group, we take into account the
reference substrate already used[9], which, subjected to ammo-
nolysis, displayed an estimated rate constant k = 3 × 10−9/s.
Therefore, the rate accelerations, k2/k, measured for the sub-
strates investigated are about 5 × 103 for 1, 4 × 104 for 2 and
5 × 104 for 3.
N
k1
CH3
CH3
O
A
O
B
k2
1. R = benzyl
2. R = cyclohexyl
3. R = isopropyl
O
PhH2C
NH
OH
NH
R
O
CH3
C
NH3
EtOH
k3
k4
OH
O
O
OH
H2N
PhH2C
PhH2C
R
H2N
+
+
NH2
OEt
O
NH
NH
O
R
D
E
Scheme 1. Pathway of morpholine‐2,5‐diones ammonolysis
second step is not affected by the first one, and the overall ki-
netic process becomes less complex. Then, the process can be
considered constituted by an independent first step, that is,
the decomposition of A, followed by the decomposition of inter-
mediate B and the conversion of C in D and E through two par-
allel reactions (Scheme 1).
Because k1 >> k2, we assumed the initial concentration
[B0] = [A0], that is, the starting concentration. The first‐rate
constants were calculated according to the following equa-
tions[11,12], which describe the dependence of the concentration
of A, B, C, D and E versus time:
½Aꢀ ¼ ½A0ꢀe−k t
(1)
(2)
1
½Bꢀ ¼ ½B0ꢀe−k t
2
h
i
½Cꢀ ¼ ½B0ꢀ ½k2=ðk3 þ k4−k2Þꢀe−k t−½k2=ðk3 þ k4−k2Þꢀe−ðk þk Þt (3)
3
4
2
h
i
½Dꢀ ¼ ½B0ꢀ k3=ðk3 þk4Þ−½k3=ðk3 þ k4−k2Þꢀe−k t−½k2k3=ðk3 þ k4Þðk2−k3−k4Þꢀe−ðk
3þk4Þt
2
(4)
CHARACTERIZATION OF INTERMEDIATE C
h
i
½Eꢀ ¼ ½B0ꢀ k4=ðk3 þk4Þ−½k4=ðk3 þ k4−k2Þꢀe−k t−½k2k4=ðk3 þ k4Þðk2−k3−k4Þꢀe−ðk
3þk4Þt
2
The chemical structure of intermediate C was ascertained by exam-
ining the product obtained from the ammonolysis of the starting
(5)
Table 1. Pseudo‐first‐order rate constants measured at 25 °C 0.1a
Substrates
10−3 × k1/sb
10−5 × k2/sc
10−5 × k3/sd
10−5 × k4/se
[D]/[E]f
1
2
3
5.83 0.5
6.66 0.5
2.83 0.33
1.56 0.66
12.0 0.33
16.0 1.16
0.9 0.66
10 1.0
4.33 0.5
0.53 0.07
1.33 0.18
1.55 0.20
1.7
7.8
2.7
aStandard errors are reported.
bDecomposition rate constant of A calculated by the Eqn 1.
cDecomposition rate constant of B calculated by Eqn 2.
dFormation rate constant of D calculated by Eqn 4.
eFormation rate constant of E calculated by Eqn 5.
fProducts ratio determined by HPLC analysis.
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A. ARCELLI ET AL.
Figure 4. Dependence of the concentration of 2B (●), 2C (□), 2D (▲)
and 2E (⋆) versus time. Points are experimental; the curves are calculated
by Eqns 2–4 and 5, respectively
Figure 1. Dependence of the concentration of 1A versus time. Points
are experimental; the curve is calculated by Eqn 1
Figure 2. Dependence of the concentration of 1B (●), 1C (□), 1D (▲)
and 1E (⋆) versus time. Points are experimental; curves are calculated
by Eqns 2–4 and 5, respectively
Figure 5. Dependence of the concentration of 3A versus time. Points
are experimental; the curve is calculated by Eqn 1
Figure 6. Dependence of the concentration of 3B (●), 3C (□), 3D (▲)
and 3E (⋆) versus time. Points are experimental; curves are calculated
by Eqns 2–4 and 5, respectively
Figure 3. Dependence of the concentration of 2A versus time. Points
are experimental; the curve is calculated by Eqn 1
lactone 2. The investigation was performed on this substrate be-
cause the chromatographic separation of intermediate 2C is
easier than that of intermediates 1C or 3C. The ammonolysis
was stopped after about 2 h, and the reaction mixture was
worked up following the general procedure reported in the Gen-
eral section.
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Copyright © 2011 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2012, 25 132–141

AMMONOLYSIS OF MORPHOLINE‐2,5‐DIONES
We wish to point out that, in addition to the intermediate de-
scribed in Scheme 1, it is possible that the alternative intermedi-
ate isomer is 2Ciso (Fig. 7), derived from the attack of the
primary amide carbonyl oxygen (instead of nitrogen) on the ter-
tiary amide carbonyl carbon. Nevertheless, 2Ciso can be ex-
cluded because it is an imino ester, that is, the same very
reactive intermediate hypothesized in the esters and amides
synthesis from carboxylic acids in the presence of N,N′‐dicyclo-
hexylcarbodiimide.[16] On the contrary, the intermediate recov-
ered is stable, being isolated by chromatographic elution.
Besides, although the 1H and 13C spectra are consistent with
both the structures 2C and 2Ciso, we observed a coupling be-
tween the imidic proton Hy and the carbon Ce by 2D experi-
ments (refer to the EXPERIMENTAL section) and a very fast
exchange in D2O, which is consistent with the presence of an
acid proton such as the imidic NH group. These findings, par-
ticularly the last two, substantiate the proposed structure of
intermediate 2C, which is strengthened by the theoretical calcu-
lations (refer to the THEORETICAL CALCULATIONS section).
TS1
TS2
TSpi
Int
12.7
Int'
10.0
34.0
25.4
Cm
13.1
HBC
2.4
0.0
r.c.
Figure 8. Free‐energy profile for the formation of intermediate Cm
assisted by ammonia. The barriers are referred to the hydrogen‐bonded
complex HBC
The calculations show the preliminary formation of a hydro-
gen‐bonded complex HBC between Bm and NH3, in which am-
monia is placed at 0.1937 n/m from one of the hydrogen atoms
of the primary amidic group. The free energy of this complex
(−666.958216 hartrees) is taken as the zero point for the further
steps. Then, a transition state (TS), TS1, is generated (Fig. 9A),
in which we note the incipient formation of a N–C bond between
the primary amide nitrogen and the tertiary amide carbonyl car-
bon (0.1977 n/m, 0.39 e−). Ammonia acts as a proton transfer,
taking a proton from the amidic group and giving a proton to
the oxygen carbonyl group with the formation of an incipient
O–H bond (0.1492 n/m, 0.17 e−), which facilitates the contempo-
rary nucleophilic attack of nitrogen on the carbonyl. The theoret-
ical studies demonstrate the essential role of NH3 in the
neighbouring participation of the primary amide: in fact, in the
absence of ammonia, we find a TS at very high energy,
65.3 kcal/mol in comparison with 34.0 kcal/mol (Supplementary
material). Therefore, as observed in the experimental conditions
employed, the reaction cannot occur in the absence of ammo-
nia. The simultaneous formation of the C–N and O–H bonds
leads to the cyclic intermediate Int, which, through the fast pyra-
midal inversion at the tertiary nitrogen in TSpi (0.4 kcal/mol
above Int), gives the intermediate Int′ that is the species really
prone to the next step. The further breaking of the bond be-
tween the tertiary nitrogen and the ex‐carbonyl carbon gives rise
to the imide Cm. As we see in TS2 (Fig. 9B), also this step is
THEORETICAL CALCULATIONS
In order to determine the pathway of the anchimerically assisted
ammonolysis of intermediates B to C, density functional theory
theoretical calculations were performed using a model com-
pound Bm in which the N‐alkyl and the benzyl groups in B were
substituted with two methyl groups in order to simplify the cal-
culations (refer to the Computational methods section for com-
putational details). The reaction mechanism and the free
energy profile for the formation of intermediate Cm are reported
in Scheme 2 and Fig. 8, respectively.
Figure 7. Structural isomers of intermediate C
O
H
O
O
H
N
N
H3C
H3C
H3C
NH
H
H3C
H3C
H
H
OH
OH
N
H
N
HO
N
NH2
N
H
OH
H3C
CH3
H
CH3
O
O
CH3
Int
TS1
+
NH3
HBC (Bm.NH3)
O
H3C
N
O
O
H3C
H3C
O
O
+
NH
O
OH
H3C
H3C
H3C
H3C
H
NH
H3C
NH
OH
N
OH
O
N
HO
N
HO
CH3
N
H
H
H3C
CH3
CH3
Cm
H
H
Int'
H2N
TSpi
NH3
TS2
Scheme 2. Reaction mechanism for the Cm intermediate
J. Phys. Org. Chem. 2012, 25 132–141
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A. ARCELLI ET AL.
Figure 9. Transition states TS1 (A) and TS2 (B) with relevant interatomic distances (Å)
Scheme 3. (i) CH2Cl2/Et3N/r.t.; (ii) NaOH/EtOH/H2O; (iii) HCl; (iv) NaH (60% dispersion in mineral oil) in dry tetrahydrofuran (THF)/dimethylformamide at
reflux; (v) 1 M lithium hexamethyldisilazide/THF at −78 °C
Figure 10. Expanded section of HMBC spectrum of intermediate 2C
catalyzed by ammonia, which favours the contemporary transfer
of the proton from oxygen to nitrogen. The low value of the ac-
SYNTHESIS OF THE SUBSTRATES 1–3
tivation energy of TS2 (15.4 kcal/mol) makes the second step
very fast and, consequently, this intermediate very unstable
and not isolable in the course of the experimental work.
Two considerations deserve a brief comment. The first is that
in TS1, we have the formation of a new chiral centre at C‐5, giv-
ing rise to two diastereomeric intermediates. However, because
the energies involved are very similar and the chiral centre is
destroyed in the subsequent step, we consider only one path
for simplicity. We have intensively investigated also the possible
attack by the carbonyl oxygen of the primary amide on the ter-
tiary amide carbonyl carbon (Fig. 9), but no corresponding TS
was found.
The substrates submitted to the kinetic investigations 1, 2 and
3 were synthesized by following our procedure[17] outlined
in Scheme 3, that is, based on the alkylation of the synthones
4‐N‐alkyl‐1,4‐morpholin‐2,5‐diones 7–9. The products 1, 2 and
3 were obtained with a total regioselection and with a practi-
cally total 1,4‐trans induction, with respect to the methyl
group at C‐6, as previously observed for analogous morpholin‐
2,5‐diones.[17–22] The trans isomers were isolated as racemates
in good overall yield (after purification by silica gel chroma-
tography), and the trans configuration was deter mined on the
1
basis of H NMR data and making use of our experience previ-
ously acquired on the morpholin‐2,5‐dione derivatives.[17–22]
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AMMONOLYSIS OF MORPHOLINE‐2,5‐DIONES
was added by a dropping funnel, in an inert atmosphere, to give
a total volume of 100 mL in a volumetric flask. The final concen-
trations of the starting lactones 1–3 are the same as reported
earlier. The glass flask was quickly stopped with a latex septum
and kept at 25 °C. At fixed times, 2 mL of the solution were re-
moved by means of 2.5 mL Hamilton TLL syringe (Bonaduz, GR,
Switzerland), and the reaction was stopped by dissolving the
sample in 2 mL of cold 4.9 M HCl and diluting to 25 mL, as previ-
ously described.
CONCLUSIONS
In this paper, we describe the mechanism of the anchimerically
assisted ammonolysis of three lactones (1–3). The kinetics, fol-
lowed by HPLC analysis, evidenced a complex process involving
two consecutive reactions and two parallel ones. We emphasize
that all the compounds involved in the process have been iso-
lated and characterized, and the first‐order rate constants of
the four steps have been calculated by the appropriate kinetic
equations. The conversion of intermediate B into the C one is
anchimerically assisted, and it appears sensible to both the steric
and polar effect. Interestingly, the high rate enhancement
caused by the assistance of the neighbouring primary amide
group on the tertiary amide one is in the range 5 × 103–5 × 104.
Besides, on the basis of the theoretical calculations, we dem-
onstrated that the highly effective intramolecular catalysis needs
the presence of ammonia, which acts as proton transfer. In fact,
on the basis of the theoretical calculations, the anchimerically
assisted process cannot occur in the absence of ammonia (at
least in the experimental conditions employed) because the
corresponding TS is too high in energy to be competitive. In ad-
dition, the alternative pathway, involving the attack of oxygen of
the primary amide group instead of nitrogen, can be excluded
because the corresponding TS was not detected.
High‐performance liquid chromatography analysis
The separation of the compounds A, B, C, D and E was per-
formed by Hewlett Packard 1090 (Palo Alto, CA, USA) coupled
with 5 µ C18 Luna column by using the mobile phase CH3CN/
phosphate buffer (0.03 M) at pH = 4.2 for the substrate 2 and at
pH = 7 for 1 and 3. The concentrations of A, B, C, D and E were
calculated by the calibration line built with authentic samples
at various concentrations (mol/L) and the area measured by
HPLC. Retention times of various compounds and the elution
conditions are reported in the Supplementary material.
Computational methods
In this work, we have isolated intermediate C not previously
noticed:[9] in fact, on the basis of the NMR analysis and the the-
oretical calculations, we ascertained the structure of the second
intermediate C, which is different from that hypothesized in a
previous study.[9]
All calculations were performed with the Gaussian 03W suite
of programmes (Gaussian, Inc., Pittsburgh, PA, USA).[23] All the
molecular geometries were optimized at the density functional
theory level by using the Becke’s three‐parameter exchange
functional in conjunction with the Lee‐Yang‐Carr correlation
functional (B3LYP).[24] For all the atoms, the 6‐311G (d, p) basis
set was used. To take into account bulk solvent effects, full ge-
ometry optimizations within a continuum solvent model (with
ethanol as solvent) were carried out via the self‐consistent reac-
tion field approach using the polarizable continuum model
method.[25–27] Additional spheres were placed on hydrogen
atoms that are transferred in the investigated TSs and were co-
herently used in all the calculations.
Finally, we underline that examples of such a type of participa-
tion are not found in the literature.
EXPERIMENTAL
Kinetics
Kinetics of the ammonolysis of lactones 1–3 were followed by
HPLC.
Preliminary experiments, performed by 1H NMR and HPLC
analysis, evidenced the complexity of the lactone ammonolysis,
which give rise to two intermediates. Because the disappearance
of the starting lactone A is meaningfully faster than the subse-
quent steps (Table 1), the kinetics were carried out in single tiny
glass bottles (5 mL) sealed by a screw plug with Teflon septa. Ki-
netic runs were initiated by adding 100 μL of the stock solution
of lactone (0.46 M for 1 and 0.31 M for 2 and 3) in ethanol to each
tiny bottle containing 3 mL of 5 M NH3 solution in ethanol, pre‐
thermostatted at 25 0.1 °C. Then, the lactone concentrations
employed for the kinetic measurements were 0.015 M for 1
and 0.01 M for 2 and 3. The tiny bottles were kept in a thermo-
stat, and the reaction was stopped by cooling each sample, re-
moved at fixed times, in crushed ice and by adding 2 mL of
cold 4.9 M HCl. The solution was then diluted with ethanol and
water (enough to dissolve the NH4Cl) to give a total volume of
25 mL in order to obtain an appropriate concentration to be ana-
lysed by using HPLC, according to the calibration straight line.
The steps subsequent to the decomposition of the starting
lactone A were followed on one single suitable solution, and
the concentrations versus time of B, C, D and E (Scheme 1) were
monitored by using the HPLC analysis. Kinetic measurements
were carried by using a solution of the starting lactone in 3 mL
of ethanol, and 5 M NH3 in ethanol (thermostatted at 25 0.1 °C)
Calculations of the harmonic vibrational frequencies were car-
ried out to determine the nature of each optimized critical point.
For all the TSs, inspection of the negative frequency was suffi-
cient to specify the corresponding reaction path. Gibbs free
energies, taken as the sum of the electronic and thermal free en-
ergies at 298.15 K, are always used for discussing the energetics.
Geometries and energies of all calculated structures are
reported in the Supplementary material.
Synthesis of the substrates (1–3)
General
1H and 13C NMR spectra were recorded on a Varian MR 400 spec-
trometer (Palo Alto, CA, USA) equipped with an indirect probe at
400 MHz and at 100 MHz, respectively, using CDCl3 as the solvent
at 25 °C, unless otherwise stated. Chemical shift was reported in
ppm relative to tetramethylsilane, and the coupling constants (J)
are in hertz. Melting points (m.p.) were measured on an Electro-
thermal IA 9000 apparatus (Thermo Fisher Scientific, Rochford,
Essex, UK) and were uncorrected. Dry tetrahydrofuran (THF) was
distilled from sodium benzophenone ketyl and dry dimethylforma-
mide (DMF) from calcium hydride. Chromatographic separations
were performed with silica gel 60 (230–400 mesh).
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A. ARCELLI ET AL.
General procedure to the N‐alkyl‐ethylglycinates (4–6)
phase was dried on MgSO4 and evaporated under vacuum,
and the residue was dissolved in a mixture of anhydrous THF
(50 mL) and anhydrous DMF (20 mL) under inert atmosphere.
NaH (4.0 g of 60% dispersion in mineral oil, 100 mmol) was slowly
added to the stirred solution, and when hydrogen evolution
ceased, the reaction was refluxed and monitored by TLC (the
sample was acidified and extracted with ethyl acetate). When
the starting material disappeared (1–2 h), the reaction mixture
was cooled at 0 °C and acidified with concentrated HCl. After
evaporation under vacuum of the most part of solvent, the product
was extracted with ethyl acetate and the organic phase washed
with 0.1 M HCl, then with water. The organic phase was dried on
MgSO4 and evaporated under vacuum, and the residue was sub-
mitted to silica gel chromatography, eluting with hexane/ethyl
acetate. The pure product was isolated in 55–74% yield.
To a stirred solution of the alkyl amine (100 mmol) and triethyla-
mine (16.9 mL, 120 mmol) in CH2Cl2 (50 mL), cooled at 0 °C, ethyl-
bromoacetate (13.2 mL, 120 mmol), diluted in 10 mL of CH2Cl2,
was slowly added dropwise. The cooling bath was removed,
allowing the reaction to warm up to room temperature (r.t.).
The reaction mixture was then stirred at r.t. and followed by
thin‐layer chromatography (TLC) (extracting a basified aliquot
with ethyl acetate and eluting with cyclohexane/ethyl acetate
40/60). After about 24 h, the organic solvent was evaporated un-
der vacuum and the residue dissolved in diethyl ether (300 mL)
and water (100 mL). After separation, the organic phase was
washed with water and dried on MgSO4, and the organic solvent
was evaporated, being careful to the product 6, which is volatile.
The residue was submitted to silica gel chromatography, eluting
with hexane/ethyl acetate, except the product 6, which was
eluted with petroleum ether/diethyl ether. The oily product
was isolated pure in 72–83% yield.
4‐N‐Benzyl‐6‐methyl‐1,4‐morpholin‐2,5‐dione 7. The title pure
product was obtained in 74% yield, as a colourless oil, by using
intermediate 4. 1H NMR δ: 1.66 (d, 3H, J = 6.8), 3.97 (d, 1H,
J = 18.0), 4.04 (d, 1H, J = 18.0), 4.58 (d, 1H, J = 14.8), 4.65 (d, 1H,
J = 14.8), 4.95 (q, 1H, J = 6.8), 7.23–7.26 (m, 2ArH), 7.31–7.39 (m,
3ArH). 13C NMR δ: 17.4, 47.4, 49.4, 75.0, 128.3, 128.4, 129.1,
134.7, 165.3, 166.2. Anal. Calcd for C12H13NO3: C, 65.74; H, 5.98;
N, 6.39. Found: C, 66.12; H, 5.98; N, 6.38.
N‐Benzyl‐ethylglycinate 4. The title product was obtained in
1
83% yield by using benzylamine. H NMR δ: 1.27 (t, 3H, J = 7.2),
1.89 (bs, 1H), 3.41 (s, 2H), 3.81 (s, 2H), 4.19 (q, 2H, J = 7.2), 7.24–
7.29 (m, 1ArH), 7.30–7.36 (m, 4ArH). 13C NMR δ: 14.2, 50.1, 53.3,
60.7, 127.2, 128.3, 128.5, 139.6, 172.4. Anal. Calcd for
C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.52; H, 7.82; N,
7.25.
4‐N‐Cyclohexyl‐6‐methyl‐1,4‐morpholin‐2,5‐dione 8. The title
pure product was obtained in 65% yield, as a white solid (m.p.
1
94–95 °C), by using intermediate 5. H NMR δ: 1.03–1.14 (m, 1H),
N‐Cyclohexyl‐ethylglycinate 5. The title product was obtained in
1.26–1.46 (m, 4H), 1.61 (d, 3H, J = 6.8), 1.66–1.73 (m, 3H), 1.81–
1.87 (m, 2H), 4.03 (s, 2H), 4.32–4.39 (m, 1H), 4.86 (q, 1H, J = 6.8).
13C NMR δ: 16.8, 25.0, 25.1, 25.2, 29.3, 29.4, 43.0, 52.2, 74.8,
165.6, 166.1. Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N,
6.63. Found: C, 62.64; H, 8.13; N, 6.66.
1
80% yield by using the cyclohexylamine. H NMR δ: 1.03–1.27
(m, 5H), 1.27 (t, 3H, J = 7.2), 1.57–1.65 (m, 1H), 1.63 (bs, 1H),
1.69–1.76 (m, 2H), 1.82–1.87 (m, 2H), 2.36–2.44 (m, 1H), 3.42
(s,2H), 4.18 (q, 2H, J = 7.2). 13C NMR δ: 14.1, 24.7, 25.9, 33.2,
48.2, 56.3, 60.6, 172.7. Anal. Calcd for C10H19NO2: C, 64.83;
H,10.34; N, 7.56. Found: C, 64.92; H, 10.31; N, 7.55.
4‐N‐Isopropyl‐6‐methyl‐1,4‐morpholin‐2,5‐dione 9. The title pure
product was obtained in 55% yield, as colourless crystals (m.p.
74–76 °C), by using intermediate 6. 1H NMR δ: 1.15 (d, 3H,
J = 6.8), 1.16 (d, 3H, J = 6.8), 1.61 (d, 3H, J = 6.8), 4.01 (s, 2H),
4.73–4.84 (m, 1H), 4.85 (q, 1H, J = 6.8). 13C NMR δ: 17.0, 17.1,
19.2, 42.1, 44.4, 75.1, 165.7, 166.1. Anal. Calcd for C8H13NO3: C,
56.13; H, 7.65; N, 8.18. Found: C, 56.21; H, 7.64; N, 8.20.
N‐Isopropyl‐ethylglycinate 6. The title product was obtained in
1
72% yield by using the isopropylamine. H NMR δ: 1.06 (d, 6H,
J = 6.4), 1.27 (t, 3H, J = 7.2), 1.67 (bs, 1H), 2.74–2.84 (m, 1H), 3.40
(s, 2H), 4.18 (q, 2H, J = 7.2). 13C NMR δ: 14.2, 22.7, 48.3, 48.7,
60.7, 172.7. Anal. Calcd for C7H15NO2: C, 57.9; H, 10.41; N, 9.65.
Found: C, 57.91; H, 10.39; N, 9.68.
General procedure of the alkylation of morpholin‐2,5‐diones (7–9)
General procedure to 4‐N‐alkyl‐6‐methyl‐1,4‐morpholin‐2,5‐diones
(7–9)
Intermediates 7, 8 or 9 (20 mmol) in dry THF (40 mL) were met-
alled with a 1 M solution of lithium hexamethyldisilazide (22 mL)
at −78 °C under an inert atmosphere. After about 1h, benzylbro-
mide (2.6 mL, 22 mmol) was added, and the reaction mixture, un-
der stirring, was monitored by TLC. When the starting reagent
practically disappeared, the cooling bath was removed, allowing
the reaction to warm up to r.t. The reaction was then quenched
with 1 M HCl (20 mL), and the organic solvent was evaporated
under vacuum. After extraction with ethyl acetate (2 × 50 mL),
the organic phase was washed with water (10 mL), dried (MgSO4)
and evaporated under vacuum. The residue was then submitted
to silica gel chromatography, eluting with hexane/ethylacetate,
and the product was isolated in 76–85% yield.
To a solution of 4, 5 or 6 (50 mmol) and triethylamine (7.1 mL,
51 mmol) in CH2Cl2 (50 mL) stirred at 0 °C, (R,S)‐bromopropionyl-
bromide (5.4 mL, 51 mmol) in 10 mL of CH2Cl2 was slowly
dropped. Then, the cooling bath was removed allowing the reac-
tion to warm up to r.t., and the reaction mixture was stirred at r.t.
monitored by TLC. After about 1 h, the organic solvent was evap-
orated under vacuum, the residue dissolved in ethyl acetate
(200 mL) and the organic phase washed with diluted HCl, then
with water. The organic extract, dried on MgSO4, was evaporated
in vacuo, and NaOH (4.0 g, 100 mmol) dissolved in 60 mL of 50%
ethanol/water was added to the crude product. The reaction
mixture was stirred at r.t. and monitored by TLC; after about
1 h, the starting material disappeared. The reaction mixture was
then cooled at 0 °C and acidified with concentrated HCl
(10 mL). After evaporation under vacuum of the most part of eth-
anol, the product was extracted with diethyl ether. The organic
3‐Benzyl‐4‐N‐benzyl‐6‐methyl‐1,4‐morpholin‐2,5‐dione 1. The title
pure product was obtained in 85% yield, as a colourless oil
that solidifies on standing to white crystals (m.p. 100–102 °C),
by using intermediate 7. 1H NMR δ: 1.41 (d, 3H, J = 6.8), 3.18
wileyonlinelibrary.com/journal/poc
Copyright © 2011 John Wiley & Sons, Ltd.
J. Phys. Org. Chem. 2012, 25 132–141

AMMONOLYSIS OF MORPHOLINE‐2,5‐DIONES
(dd, 1H, J = 4.8, 14.0), 3.22 (dd, 1H, J = 4.8, 14.0), 3.45 (q, 1H,
J = 6.8), 3.85 (d, 1H, J = 14.8), 4.35 (t, 1H, J = 4.8), 5.39 (d, 1H,
J = 14.8), 7.12–7.14 (m, 2ArH), 7.20–7.23 (m, 2ArH), 7.31–7.39
(m, 6ArH). 13C NMR δ: 17.3, 36.8, 47.3, 59.8, 73.4, 128.2, 128.4, 129.1,
129.3, 129.7, 134.4, 134.9, 166.6, 167.3. Anal. Calcd for C19H19NO3:
C, 73.77; H, 6.19; N, 4.53. Found: C, 73.57; H, 6.20; N, 4.54.
3.64 (dd, 1H, J = 6.8, 7.6), 3.73 (d, 1H, J = 13.2), 3.87 (d, 1H,
J = 13.2), 5.14 (q, 1H, J = 6.8), 5.28 (bs, 1H), 5.85 (bs, 1H), 7.17–
7.19 (m, 2ArH), 7.23–7.33 (m, 8ArH). 13C NMR (40 °C) δ: 17.6,
39.2, 51.9, 61.7, 71.0, 127.3, 127.9, 128.5, 128.8, 128.9, 129.4,
136.4, 136.6, 172.3, 172. Anal. Calcd for C19H22N2O3: C, 69.92; H,
6.79; N, 8.58. Found: C, 69.69; H, 6.77; N, 8.55.
3‐Benzyl‐4‐N‐cyclohexyl‐6‐methyl‐1,4‐morpholin‐2,5‐dione 2. The
title pure product was obtained in 79% yield, as a white amor-
phous solid (m.p. 109–111 °C), by using intermediate 8.
2‐(Benzylamino)‐3‐phenylpropanamide 1D. The title pure prod-
uct was isolated as a white amorphous solid (m.p. 123–125 °C)
from the ammonolysis of lactone 1. 1H NMR δ: 1.66 (bs, 1H),
2.77 (dd, 1H, J = 9.6, 13.6), 3.22 (dd, 1H, J = 4.4, 13.6), 3.38 (dd,
1H, J = 4.4, 9.6), 3.56 (d, 1H, J = 13.2), 3.75 (d, 1H, J = 13.2), 5.46
(bs, 2H), 7.05–7.07 (m, 2ArH), 7.16–7.19 (m, 3ArH), 7.21–7.32 (m,
5ArH). 13C NMR δ: 39.3, 52.7, 63.2, 127.1, 127.3, 128.0, 128.6,
128.9, 129.2, 137.4, 139.2, 176.9. Anal. Calcd for C16H18N2O: C,
75.56; H, 7.13; N, 11.01. Found: C, 75.65; H, 7.15; N, 10.98.
1H NMR δ: 1.09–1.22 (m, 1H), 1.31–1.46 (m, 2H), 1.33 (d, 3H,
J = 6.8), 1.50–1.72 (m, 4H), 1.82–1.92 (m, 2H), 2.01–2.07 (m, 1H),
3.15 (dd, 1H, J = 6.0, 14.0), 3.29 (dd, 1H, J = 4.0, 14.0), 3.50
(q, 1H, J = 6.8), 4.11–4.19 (m, 1H), 4.50 (dd, 1H, J = 4.0, 6.0), 7.20–
7.23 (m, 2ArH), 7.31–7.35 (m, 3ArH). 13C NMR δ: 16.6, 25.1, 25.6,
25.9, 30.2, 31.4, 39.5, 55.7, 58.3, 73.3, 127.9, 129.0, 129.6, 134.5,
166.3, 167.7. Anal. Calcd for C18H23NO3: C, 71.73; H, 7.69;
N, 4.65. Found: C, 71.47; H, 7.67; N, 4.66.
Ethyl‐2‐(benzylamino)‐3‐phenylpropanoate 1E. The title pure
product was isolated as a colourless oil from the ammonolysis
of lactone 1. H NMR δ: 1.16 (t, 3H, J = 7.2), 1.68 (bs, 1H), 2.94
3‐Benzyl‐4‐N‐isopropyl‐6‐methyl‐1,4‐morpholin‐2,5‐dione 3. The
1
title pure product was obtained in 76% yield, as a colourless
(dd, 1H, J = 7.2, 14.0), 2.98 (dd, 1H, J = 7.2, 14.0), 3.52 (t, 1H,
J = 7.2), 3.64 (d, 1H, J = 13.2), 3.81 (d, 1H, J = 13.2), 4.10 (q, 2H,
J = 7.2), 7.16–7.18 (m, 2ArH), 7.21–7.30 (m, 8ArH). 13C NMR δ:
14.3, 39.9, 52.1, 60.8, 62.2, 126.8, 127.2, 128.3, 128.5, 129.4,
137.5, 139.7, 174.8. Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47;
N, 4.94. Found: C, 76.56; H, 7.44; N, 4.95.
1
oil, by using intermediate 9. H NMR δ: 1.29 (d, 3H, J = 6.8), 1.35
(d, 3H, J = 6.8), 1.36 (d, 3H, J = 6.8), 3.15 (dd, 1H, J = 6.0, 14.0),
3.30 (dd, 1H, J = 4.4, 14.0), 3.58 (q, 1H, J = 6.8), 4.40–4.50 (m, 1H),
4.47 (dd, 1H, J = 4.4, 6.0), 7.20–7.23 (m, 2ArH), 7.32–7.36
(m, 3ArH). 13C NMR δ: 16.7, 20.2, 21.0, 39.5, 48.3, 58.5, 73.6, 128.1,
129.3, 129.7, 134.7, 166.5, 167.9. Anal. Calcd for C15H19NO3: C,
68.94; H, 7.33; N, 5.36. Found: C, 68.62; H, 7.35; N, 5.35.
2‐Benzyl‐3‐N‐(cyclohexyl)‐4‐oxa‐5‐hydroxyhexanamide 2B. The title
pure product was isolated as a waxy solid from the ammonolysis
of lactone 2. 1H NMR δ: 0.60–0.65 (m, 1H), 0.81–0.91 (m, 1H),
0.95–1.10 (m, 2H), 1.13–1.27 (m, 1H), 1.34 (d, 3H, J = 6.8), 1.52–
1.62 (m, 3H), 1.65–1.70 (m, 1H), 1.77–1.83 (m, 1H), 3.16–3.24 (m,
1H), 3.30 (dd, 1H, J = 5.6, 13.6), 3.74 (dd, 1H, J = 10.0, 13.6), 3.87–
3.92 (m, 2H), 4.31 (dq, 1H, J = 1.6, 6.8), 5.40 (bs, 1H), 7.15–7.31
(m, 5ArH), 7.44 (bs, 1H). 13C NMR δ: 21.8, 24.8, 25.6, 25.8, 30.1,
30.8, 35.4, 57.9, 63.7, 65.4, 127.0, 128.7, 129.5, 137.7, 174.5,
176.6. Anal. Calcd for C18H26N2O3: C, 67.90; H, 8.23; N, 8.80.
Found: C, 68.14; H, 8.21; N, 8.82.
Separation and characterization of the intermediates and reaction
products
Five millimoles of lactone (1, 2 or 3) was dissolved in dry ethanol
(50 mL) at 0 °C; then, gaseous ammonia was bubbled for 30min.
The flask was tightly capped and the cooling bath removed, allow-
ing the reaction to warm up to r.t. At suitable times (Figs 1–6),
ethanol and the excess of ammonia were evaporated under re-
duced pressure, and the residue was dissolved in ethyl acetate
(50 mL) and extracted with 1 M HCl. The organic phase, dried
on MgSO4, was concentrated under vacuum, and from the residue,
submitted to silica gel chromatography, eluting with hexane/ethyl
acetate, the pure intermediate B was isolated. The aqueous phase
was neutralized with 1 M NaOH and extracted with ethyl acetate.
The organic phase was dried on MgSO4 and concentrated under
vacuum, and the residue was submitted to silica gel chromatog-
raphy, eluting with hexane/ethyl acetate to separate the pure
compounds C, D, E and lactamide.
N‐(2‐Hydroxypropionyl)‐3‐phenyl‐2‐(cyclohexylamino)propiona-
mide 2C. The title pure product was isolated as white crystals
(m.p. 105–107 °C) from the ammonolysis of lactone 2. In this
case, the sample was prepared by dissolving the compound in
DMSO‐d6 under inert atmosphere, and about 30 mg of activated
powdered 4 Å molecular sieves was then added. After stirring for
1 day, the solution was rapidly taken in an NMR tube and tightly
capped. The tube was maintained vertical until the residual mo-
lecular sieves precipitated on the bottom. The complete signal
assignment was then executed, except for those belonging to
the aromatic ring and to the cyclohexyl ring, unnecessary to
the purpose. The 1H, 13C and heteronuclear multiple‐bond corre-
lation (HMBC) spectra were acquired at various temperatures in
order to determine the optimal condition for evidencing the
Hy–Ce crosspeak (Fig. 10). Then, the decisive HMBC experiment
was executed at 19 °C using 400 increments (13C spectral win-
dow from −10 to 190 ppm) and 640 scans per increment, obtain-
ing the expected crosspeak. Chemical shifts are reported in ppm
relative to the solvent residual peak (2.50 ppm) and to the sol-
vent peak (39.52 ppm) as the references for the 1H and 13C
NMR experiments, respectively. The internally stored gHSQC
and gHMBC sequences were used for the single and multiple
2‐Benzyl‐3‐N‐(benzyl)‐4‐oxa‐5‐hydroxyhexanamide 1B. The title
pure product was isolated as a colourless oil from the ammono-
lysis of lactone 1. 1H NMR δ: 1.08 (d, 3H, J = 6.8), 3.21–3.32
(m, 2H), 3.38 (d, 1H, J = 8.4), 4.20 (d, 1H, J = 16.8), 4.34 (dq, 1H,
J= 6.8, 8.4), 4.51 (d, 1H, J = 16.8), 5.21 (bs, 1H), 6.30 (bs, 1H),
7.12–7.17 (m, 4ArH), 7.23–7.32 (m, 6ArH). 13C NMR δ: 21.1, 34.5,
49.0, 59.5, 65.5, 126.8, 127.0, 128.0, 128.8, 129.0, 129.1, 135.8,
136.8, 171.9, 177.7. Anal. Calcd for C19H22N2O3: C, 69.92; H, 6.79;
N, 8.58. Found: C, 70.22; H, 6.82; N, 8.55.
N‐(2‐Hydroxypropionyl)‐3‐phenyl‐2‐(benzylamino)propionamide 1C.
The title pure product was isolated as a colourless wax from the
ammonolysis of lactone 1. 1H NMR (40 °C) δ: 1.31 (d, 3H, J = 6.8),
2.05 (bs, 1H), 2.97 (dd, 1H, J = 7.6, 13.6), 3.08 (dd, 1H, J = 6.8, 13.6),
J. Phys. Org. Chem. 2012, 25 132–141
Copyright © 2011 John Wiley & Sons, Ltd.
wileyonlinelibrary.com/journal/poc

A. ARCELLI ET AL.
bond 1H–13C correlation experiments, respectively, using 400
increments (13C spectral window from −10 to 190 ppm) and
640 scans per increment in the gHMBC experiment for evidenc-
ing the crosspeak between the imidic proton Hy and the
oxydrilated carbon Ce (Fig. 10). The splitting of some signals in
the 13C NMR spectra is due to the presence of two rotamers.
1H NMR δ: 0.84–0.93 (m, 1H), 0.98–1.16 (m, 4H), 1.14 (d, 3H,
J = 6.8), 1.47–1.51 (m, 1H), 1.56–1.67 (m, 3H), 1.75–1.78 (m, 1H),
1.91 (bs, 1H), 2.32–2.37 (m, 1H), 2.80 (dd, 1H, J = 7.6, 13.2), 2.86
(dd, 1H, J = 6.8, 13.2), 3.65 (dd, 1H, J = 6.8, 7.6), 4.77 (q, 1H,
J = 6.8), 7.19 (bs, 1H), 7.17–7.28 (m, 5ArH), 7.41 (bs, 1H). 13C
NMR δ: 17.4, 17.5, 24.0, 24.3, 25.7, 32.2, 33.6, 39.3, 54.1, 59.4,
59.5, 69.4, 69.5, 126.2, 126.3, 127.9, 128.0, 129.1, 129.2, 137.9,
171.8, 173.9. Anal. Calcd for C18H26N2O3: C, 67.9; H, 8.23;
N, 8.80. Found: C, 67.85; H, 8.22; N, 8.81.
the ammonolysis of lactone 3. 1H NMR δ: 0.79 (d, 3H, J = 6.0),
0.95 (d, 3H, J = 6.4), 1.45 (bs, 1H), 2.48–2.57 (m, 1H), 2.64
(dd, 1H, J = 9.6, 14.0), 3.16 (dd, 1H, J = 4.4, 14.0), 3.28 (dd, 1H,
J = 4.4, 9.6), 5.75 (bs, 2H), 7.20–7.33 (m, 5ArH). 13C NMR δ: 22.5,
23.6, 39.5, 48.5, 61.9, 127.0, 128.8, 129.3, 137.7, 178.1. Anal. Calcd
for C12H18N2O: C, 69.87; H, 8.80; N, 13.58. Found: C, 69.98; H, 8.78;
N, 13.54.
Ethyl‐2‐(isopropylamino)‐3‐phenylpropanoate 3E. The title pure
product was isolated as a colourless wax from the ammonolysis
1
of lactone 3. H NMR δ: 0.98 (d, 3H, J = 6.4), 1.04 (d, 3H, J = 6.4),
1.11 (t, 3H, J = 7.2), 1.60 (bs, 1H), 2.69–2.78 (m, 1H), 2.86 (dd, 1H,
J = 7.6, 13.2), 2.97 (dd, 1H, J = 6.4, 13.2), 3.59 (dd, 1H, J = 6.4, 7.6),
4.06 (q, 2H, J = 7.2), 7.17–7.30 (m, 5ArH). 13C NMR δ: 14.3, 22.2,
23.9, 40.4, 47.2, 60.6, 60.9, 126.8, 128.5, 129.3, 137.5, 175.3. Anal.
Calcd for C14H21NO2: C, 71.46; H, 8.99; N, 5.95. Found: C, 71.72;
H, 9.01; N, 5.93.
2‐(Cyclohexylamino)‐3‐phenylpropanamide 2D. The title pure
product was isolated as a white amorphous solid (m.p. 129–131 °C)
1
from the ammonolysis of lactone 2. H NMR δ: 0.61–0.71 (m, 1H),
0.93–1.24 (m, 4H), 1.48–1.52 (m, 2H), 1.57–1.65 (m, 3H), 1.72–
1.76 (m, 1H), 2.17–2.25 (m, 1H), 2.69 (dd, 1H, J = 9.6, 13.6), 3.23
(dd, 1H, J = 4.0, 13.6), 3.41 (dd, 1H, J = 4.0, 9.6), 5.40 (bs, 2H),
7.21–7.34 (m, 5ArH). 13C NMR δ: 24.8, 25.0, 25.9, 32.9, 34.5, 39.6,
56.1, 61.5, 127.0, 128.8, 129.2, 137.7, 178.3. Anal. Calcd for
C15H22N2O: C, 73.13; H, 9.0; N, 11.37. Found: C, 73.23; H, 9.02; N,
11.35.
Acknowledgements
The authors thank Prof. S. Sandri for useful discussions regarding
the experimental work. Thanks are due to the University of Bolo-
gna for financial support (funds for selected research topics).
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product was isolated as a colourless wax from the ammonolysis
1
of lactone 2. H NMR δ: 0.94–1.03 (m, 1H), 1.11 (t, 3H, J = 7.2),
1.09–1.34 (m, 4H), 1.54–1.75 (m, 5H), 1.80–1.85 (m, 1H), 2.32–
2.39 (m, 1H), 2.88 (dd, 1H, J = 7.6, 13.6), 2.96 (dd, 1H, J = 6.8,
13.6), 3.64 (dd, 1H, J = 6.8, 7.6), 4.06 (q, 2H, J = 7.2), 7.17–7.23
(m, 3ArH), 7.25–7.29 (m, 2ArH). 13C NMR δ: 14.3, 24.8, 25.1, 26.1,
32.8, 34.2, 40.4, 55.3, 60.3, 60.6, 126.8, 128.5, 129.3, 137.6, 175.3.
Anal. Calcd for C17H25NO2: C, 74.14; H, 9.15; N, 5.09. Found: C,
74.47; H, 9.11; N, 5.07.
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(UK) 1993.
2‐Benzyl‐3‐N‐(cyclohexyl)‐4‐oxa‐5‐hydroxyhexanamide 3B. The
title pure product was isolated as a white amorphous solid (m.
1
p. 164–165 °C) from the ammonolysis of lactone 3. H NMR δ:
0.48 (d, 3H, J = 6.4), 1.19 (d, 3H, J = 6.8), 1.35 (d, 3H, J = 6.4), 3.30
(dd, 1H, J = 5.2, 13.2), 3.71–3.77 (m, 2H), 3.81–3.85 (m, 2H), 3.74
(dq, 1H, J = 1.6, 6.4), 5.37 (bs, 1H), 7.16–7.31 (m, 5ArH), 7.40 (bs,
1H). 13C NMR δ: 19.8, 20.4, 21.8, 35.3, 49.0, 62.7, 65.4, 127.1,
128.7, 129.6, 137.8, 174.4, 176.6. Anal. Calcd for C15H22N2O3: C,
64.73; H, 7.97; N, 10.06. Found: C, 64.84; H, 7.95; N, 10.04.
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N‐(2‐Hydroxypropionyl)‐3‐phenyl‐2‐(isopropylamino)propionamide
3C. The title pure product was isolated as a colourless wax from
the ammonolysis of lactone 3. 1H NMR (40 °C) δ: 1.02 (d, 3H,
J = 6.4), 1.06 (d, 3H, J = 6.4), 1.24 (d, 3H, J = 6.8), 1.64 (bs, 1H),
2.73–2.83 (m, 1H), 2.90 (dd, 1H, J = 8.4, 13.2), 3.05 (dd, 1H,
J = 6.0, 13.2), 3.68 (dd, 1H, J = 6.0, 8.4), 5.40 (bs, 1H), 6.00 (bs,
1H), 7.16–7.32 (m, 5ArH). 13C NMR (40 °C) δ: 17.5, 22.3, 23.7,
40.0, 47.4, 60.7, 70.6, 127.1, 128.7, 129.4, 137.1, 172.8, 173.7. Anal.
Calcd for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C, 65.11;
H, 7.92; N, 10.10.
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Burant, J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P. Hratchian, J.
2‐(Isopropylamino)‐3‐phenylpropanamide 3D. The title pure
product was isolated as white crystals (m.p. 121–123 °C) from
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