Aza-Michael reaction: Selective mono- versus bis-addition under environmentally-friendly conditions

Article abstract of DOI:10.1016/j.tet.2014.02.021

Aza-Michael reactions between primary amines and methyl propenoate have been investigated under environmentally-friendly solventless heterogeneous catalysis in order to obtain the mono- or the bis-adduct. The reaction conditions can be altered so as to maximise the yields of the required product with high selectivity.

Full text of DOI:10.1016/j.tet.2014.02.021

Tetrahedron 70 (2014) 2449e2454
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Aza-Michael reaction: selective mono- versus bis-addition under
environmentally-friendly conditions
*
Giovanna Bosica , Jonathan Spiteri, Caroline Borg
Department of Chemistry, University of Malta, Msida MSD 2080, Malta
a r t i c l e i n f o
a b s t r a c t
Article history:
Aza-Michael reactions between primary amines and methyl propenoate have been investigated under
environmentally-friendly solventless heterogeneous catalysis in order to obtain the mono- or the bis-
adduct. The reaction conditions can be altered so as to maximise the yields of the required product
with high selectivity.
Received 28 October 2013
Received in revised form 28 January 2014
Accepted 10 February 2014
Available online 18 February 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Aza-Michael reaction
Primary amines
Mono-addition
Bis-addition
Solvent-free
Acidic alumina
1. Introduction
products.5 To efficiently catalyse the aza-Michael addition, in the
past few years alternative methods6 have been developed, such as
The aza-Michael reaction is one of the most important reactions
in modern organic synthesis since a new carbonenitrogen bond is
formed.1 It is characterized by 100% atom efficiency, uses cheap and
microwave or ultrasound accelerated reactions,7 use of Lewis
acids,8 ionic liquids,9 silica-supported catalysts10 and reactions in
water.11,7c,3d However, despite some advantages, many of these
methods use hazardous organic solvents, which is not desirable
from a green chemistry point of view, require long reaction times,
large excesses of reagents, the prior preparation of the task specific
ionic liquid catalytic medium and of the alumina or silica-sup-
ported catalysts, and in many cases the catalyst has not been re-
coverable, which has limited industrial applications. Among
heterogeneous catalysts, neutral and basic aluminas12,7b,4d were
mostly reported as other catalysts’ supports as well as silica, which
often require a further work-up of the filtrate at the end of the
reaction.10b While acidic alumina was reported as useful hetero-
geneous catalyst for classical CeC bond forming Michael additions
only,13 not for hetero-Michael reactions. Moreover several of these
alternative methods have a finite scope of substrates and the re-
ported yields were mainly observed for the mono-adducts only of
secondary amines, whereas the reactions with primary amines
were mostly not selective, affording mixtures of mono- and bis-
adducts in almost equal amounts, or giving only bis-adducts
when using a very large excess of Michael acceptors.
easily available starting materials and provides an easy route to b-
amino carbonyl derivatives, which are valuable building blocks for
the synthesis of various nitrogen-containing biologically active
compounds, antibiotics and other drugs.2 Primary amines add to
electron poor alkenes that are susceptible to nucleophilic attack to
give secondary and tertiary derivatives. The first product formed,
the mono-adduct, can react further to give the tertiary derivative,
or bis-adduct, and to control the reaction’s selectivity obtaining the
desired product when using primary amines is not always an easy
to achieve target. In fact most of the amines used in the literature
were secondary amines, where there is no possibility of second
addition, or primary aromatic amines, usually much less reactive
nucleophiles,3 and to the best of our knowledge no emphasis has
been put on the production of either the mono-adduct or the bis-
adduct when using primary amines, in spite of the great impor-
tance of this reaction.4
The most common methodologies to perform aza-Michael re-
actions require activation by harsh bases or strong acids, which are
harmful to the environment and also give rise to undesirable by-
An important target of green chemistry is represented by
elimination of volatile organic solvents making the syntheses
simpler, saving energy and preventing solvent wastes, hazards, and
toxicity.14 The use of heterogeneous catalysts for organic reactions
* Corresponding author. E-mail address: giovanna.bosica@um.edu.mt (G. Bosica).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.02.021

2450
G. Bosica et al. / Tetrahedron 70 (2014) 2449e2454
Table 2
is rapidly growing over homogeneous catalytic systems because of
their several advantages like relative ease of extraction from the
products, high stability and tolerance to harsh reaction conditions,
ease of handling, reuse and environmental friendliness.15 Thus
heterogeneous catalysis and solventless conditions both show great
potential for environmental pollution control and their combina-
tion represents a good way toward ideal synthesis.16 In this context
the development of efficient and operationally simple procedures
for increasing selectivity of the aza-Michael mono- or bis-additions
under environmentally-friendly conditions is highly appreciated.
In this study, the aza-Michael reactions between primary
amines (1) and methyl propenoate (2) were investigated under
solvent-free conditions and heterogeneous solid catalysis in order
to efficiently obtain the mono-adduct (3) or the bis-adduct, (4)
(Scheme 1).
Improving the yield of the mono-adduct, C5H11NH(CH2CH2COOCH3), 3a
Entry C5H11NH2:
Catalyst
Reaction Product
time (h)
Yielda (%)
C4H6O2 1a:2
1
2
3
4
5
6
7
2.2:1.0
2.2:1.0
3.0:1.0
2.2:1.0
3.0:1.0
1.0:1.0
1.0:1.0
24
Bis-Adduct
12
Mono-adduct 54
Bis-adduct 18
Mono-adduct 53
Bis-adduct 11
Mono-adduct 70
Bis-adduct
Mono-adduct 62
Bis-adduct
Mono-adduct 59
Bis-adduct 18
Mono-adduct 63
Bis-adduct 14
Mono-adduct 53
6
24
6
1 g basic Al2O3
8
1 g basic Al2O3 24
9
2 g acid Al2O3
2 g basic Al2O3
24
4
a
Yield of pure isolated products.
amine:methyl propenoate was 1.0:1.2. According to the stoi-
chiometric equation this ratio should yield the mono-addition
product, while 40% of the bis-adduct and 14% of the mono-
adduct were obtained. This can be attributed to the fact that
the initially produced mono-adduct is a secondary amine. Sec-
ondary amines are more basic than primary amines and thus the
mono-adduct reacts faster than pentan-1-amine with methyl
propenoate. A good yield was expected for bis-adduct when the
ratio used was that of 1.0:2.2 (entry 2, Table 1) since two moles of
methyl propenoate are required for its formation. However,
a good yield was only obtained when the ratio used was that of
1.0:3.0 (entry 5, Table 1). In this latter scenario, the concentration
of methyl propenoate present in the reaction mixture was rela-
tively high and this favoured the formation of the bis-adduct. On
the other side, in order to maximise the yield of the mono-
addition product the amount of pentan-1-amine was then
gradually increased in relation to the amount of methyl prope-
noate, and the yield of the mono-adduct increased from 14%
(entry 1, Table 1) to 54% and 70% (entries 1 and 3, Table 2). This
result was as expected since pentan-1-amine was present in
a greater concentration than the mono-adduct in the reaction
mixture.
Scheme 1. Mono- versus bis-addition product in aza-Michael reaction.
2. Results and discussion
In a preliminary study the aza-Michael reaction between pen-
tan-1-amine (1a, R¼C5H11) and methyl propenoate (2) was in-
vestigated as model reaction. The reaction was carried out at room
temperature in the absence of any solvent and the conditions were
initially altered using different ratios of reactants under no external
catalysis and later testing two different heterogeneous solid cata-
lysts, respectively, basic and acidic Al2O3, so as to maximise the
yields of the required product. Tables 1 and 2 show the results of
these preliminary studies.
From this initial study summarized in Tables 1 and 2, it was
observed that under neat conditions and without any catalyst
added 70% yield for the bis-adduct was obtained when the ratio
of 1a:2 was 1:3 (entry 5, Table 1), while the same good yield for
the mono-adduct was obtained when this ratio was the oppo-
site, 3:1 (entry 3, Table 2). Whereas under Al2O3 heterogeneous
solid catalysis, the best results with nearly stoichiometric ratio
of reactants were obtained when acidic Al2O3 (2 g, 200 mol %)
was added as catalyst (respectively, 87% for the bis- and 63%
for the mono-adduct, entry 7, Table 1 and entry 6, Table 2). The
use of basic alumina had no significant effect on the yields
obtained.
On the basis of these preliminary results we selected acidic
alumina as the catalyst of choice. In a second series of experiments
different amounts of the acidic and weakly acidic catalyst
(100e300 mol %) were employed and increasing reaction temper-
atures were applied to further improve the selectivity obtained for
the mono- or bis-addition reaction between hexan-1-amine (1b,
R¼C6H13) and methyl propenoate (2), chosen as second model re-
action (Tables 3 and 4).
Table 1
Improving the yield of the bis-adduct, C5H11N(CH2CH2COOCH3)2, 4a
Entry C5H11NH2:
Catalyst
Reaction Product
time (h)
Yielda (%)
40
C4H6O2 1a:2
1
2
3
4
5
6
7
8
1.0:1.2
1.0:2.2
1.0:2.2
1.0:2.2
1.0:3.0
1.0:3.0
1.0:2.2
1:2
48
Bis-adduct
Mono-adduct 14
Bis-adduct 31
Mono-adduct 28
24
10 g basic Al2O3 24
Bis-adduct
60
/
54
/
Mono-adduct
Bis-adduct
Mono-adduct
Bis-adduct
Mono-adduct 24
Bis-adduct
Mono-adduct
Bis-adduct
Mono-adduct
Bis-adduct
1 g basic Al2O3
24
24
24
24
48
70
2 g basic Al2O3
2 g acid Al2O3
2 g basic Al2O3
68
/
87
/
79
Mono-adduct 14
/ not collected.
a
Yield of pure isolated products.
In order to maximize the yield for the mono-product 3b the
amount of 1b:2 was increased to 1.5:1 and 2:1, no major effect was
evident although the reaction was complete in only 2.5 h (entry 2,
Table 3). However in all the reactions conducted for improvement
of the mono-adduct, the bis-adduct was also apparent. Although
All reactions were performed on a 0.01 mol scale of the lim-
iting reagent, mixing together the two starting materials without
any solvent and adding the solid catalyst when required. In the
first reaction (entry 1, Table 1) the ratio of pentan-1-

G. Bosica et al. / Tetrahedron 70 (2014) 2449e2454
2451
Table 3
different aliphatic and aromatic amines were reacted with methyl
propenoate, under the corresponding best reaction conditions
found. When using other aliphatic amines (Tables 5 and 6) the re-
sults were similar to those obtained with the model reactions with
high selectivities, high yields and no side reactions. Whereas cy-
clohexylamine produced mono-adduct in high yields but bis-
adduct in substantially lower yields, which can be associated
with the increased steric hindrance of the product. On the other
hand aromatic amines are very weak nucleophile, and hence ad-
dition is much more difficult to occur. Furthermore, the following
bis-addition is even more difficult for steric reasons, and thus the
capability of forming any bis-adduct is even smaller.3 Under our
conditions the mono-adducts of the primary aromatic amines were
produced in quantitative yields, except for 4-nitroaniline (1h), in
which the bis-adducts were formed in low yields, even with an
excess of 2. A secondary aromatic amine (1i), which can only pro-
duce the mono-adduct, was also tested, and it was not produced in
high yields as obtained with the primary aromatic amines, this
result can again be attributed to the increased steric hindrance.
Optimization of the mono-adduct C6H13NH(CH2CH2COOCH3), 3b
Entry Ratio 1b:2 Alumina
Reaction Temperature Yielda (%)
catalyst (g)
time (h)
(ꢀC)
3b:4b
1
2
3
4
5
6
7
8
1.5:1
2:1
1:1
1:1
2:1
1:1
1:1
1.5:1
Acidic (2)
Acidic (2)
Acidic (2)
Weakly acidic (2)
Weakly acidic (2)
Acidic (1)
Acidic (3)
Acidic (2)
48
2.5
3
5
5
RT
RT
RT
RT
62:20
65:11
72:17
70:15
51:7
RT
26
4
2.5
RT
RT
63:22
73:18
84:10
50e60(2.5)b
a
Yield of pure isolated products.
Heating time (h).
b
Table 4
Optimization of the bis-adduct C6H13N(CH2CH2COOCH3)2, 4b
Entry Ratio 1b:2 Alumina
Reaction Temperature (ꢀC)b Yielda (%)
catalyst (g) time (h)
3b:4b
1
2
3
4
5
6
1:2.2
1:2
1:2.2
1:2
1:2
1:2
Acidic (2)
Acidic (2)
Acidic (2)
Acidic (2)
Acidic (2)
Acidic (2)
97
144
23
48
48
RT
RT
RT
RT
/:84
/:80
/:88
5:90
/:84
/:73
Table 5
50e60(8)
70e80(15)
;
Mono-addition of aliphatic and aromatic amines, 1cei, and 2
51
Entry
R
Reaction
time (h)
Temperature (ꢀC)
Yieldsa
(%) 3:4
100e110(3)
100e110(5.5)
100e110(6)
7
8
1:2
1:2
Acidic (2)
Acidic (1)
5.5
6
/:90
/:80
1
2
3
4
5
6
7
n-C3H7 1c
n-C4H9 1d
2
3
1.5
3
3
40e45
70e80
79:11
80:11
95:3
/ not collected.
c-C6H11 1e
Ph 1f
p-C2H5eC6H4 1g
p-NO2eC6H4 1h
PhNHCH3 1ic
100e110
100e110
100e110
100e110
100e110
a
Yield of pure isolated products.
Heating time (h).
97:1
b
87:5
3
3.5
Traceb
81d
a
Yield of pure isolated products.
Approximate GC yield 1.7:0.7 (of 3:4).
Secondary amine used.
weakly acidic alumina catalyst produced similar results to that of
acidic alumina, a difference in the reaction times was evident, those
of acidic alumina being much shorter. Also, a change in the amount
of catalyst used was done and it was found that an increase in the
amount of catalyst does not significantly affect the yield of the
product, whereas a decrease affects the rate and the yield of the
reaction in a negative way (entries 7, and 6, Table 3). A great im-
provement was finally observed for the mono-product 3b when
heating at 50e60 ꢀC was applied, recording increased yield and
greatly reduced reaction time (84%, entry 8, Table 3). According to
the results shown in Table 3 the best conditions for production of
the mono-adduct were using the 1.5:1 mol ratio of amine to ac-
ceptor, with 0.2 g of acidic alumina per mmol of substrate as the
catalyst, and increasing the temperature to reflux values.
Following the initial promising results obtained for the bis-
product the mole ratio of 1b:2 was only slightly decreased to 1:2,
obtaining the same good results and showing that the slight excess
of 2 in the mixture did not affect the yield of product 4b as well as
longer reaction time. In this case weakly acidic alumina was not
utilized as it had shown that for the mono-adduct no improvement
was observed. Monitoring the temperature effect on the bis-
product 4b it was determined that heating the reaction at
50e60 ꢀC increased the rate of reaction (entry 5, Table 4) as ob-
served through GC analysis, as after 8 h of heating the reaction
proceeded much faster than without heating; however the reaction
still reached finalization after 48 overall hours. Furthermore (entry
6, Table 4) heating at 70e80 ꢀC for 15 h did not make a significant
difference and only increasing the temperature up to 100e110 ꢀC
greatly affected the rate of reaction (entry 7, Table 4), reducing the
reaction time to only 5.5 h. It was concluded that the best condi-
tions observed in bis-addition optimization were the 1:2 stoichio-
metric ratio of amine to acceptor, the use of 0.2 g of acidic alumina
per mmol of substrate and heating to reflux.
b
c
d
Mono-adduct 3i only possible product.
Table 6
Bis-addition of aliphatic and aromatic amines, 1ceh, and 2
Entry
R
Reaction
time (h)
Temperature
Yieldsa
(%) 3:4
(ꢀC)(heating
time,h)
1
2
3
n-C3H7 1c
n-C4H9 1d
c-C6H11 1e
Ph 1f
p-C2H5eC6H4
1g
6
6.5
27
22.5
27
40e45(6)
/:88
/:93
42:51
98:1
98:1
70e80(6.5)
100e110(8.5)
100e110(9)
100e110(8)
4
5b
6b
p-NO2eC6H4 1h
4
100e110(9)
Tracec
a
Yield of pure isolated products.
2.5 equiv acceptor was used.
Approximate GC yield 3.2:1.2 (of 3:4).
b
c
Finally the catalyst recycling was examined. One of the funda-
mentals in green chemistry is the decrease in use of the catalyst. It
is dependent on the recycling of the catalyst and its reuse for sev-
eral cycles. During our study the catalyst from entry 4 Table 4,
which was used in the production of the bis-adduct 4b, was re-
covered by simple filtration, washed with diethyl ether and then
dried under vacuum in a desiccator. It was reused, under same
conditions, without any special activation for two consecutive cy-
cles (entries 2 and 3, Table 7) producing a yield of 83% and 74% of
4b, respectively.
3. Conclusions
To explore the efficiency and more general validity of this
procedure for the selective mono- or bis-aza-Michael addition,
The aza-Michael reaction is one of the most widely used re-
actions in modern organic synthesis and a powerful tool for

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G. Bosica et al. / Tetrahedron 70 (2014) 2449e2454
Table 7
4.2. Procedure A: general procedure followed for the prepa-
ration of mono-adducts, 3
The % yields obtained for 4b using recycled acidic alumina catalyst
Entry
Ratio 1b:2
Acidic alumina
catalyst (mol %)
Reaction
time (h)
Yielda (%) 4b
The amine 1 (15 mmol) and methyl propenoate 2 (10 mmol) were
pipetted into a round bottomed flask equipped with a magnetic bar
and a reflux condenser. Acidic alumina (2 g, 200 mol %) was then
introduced in the flask at room temperature by means of a plastic
funnel. The mixture was heated to reflux by using an oil bath. The
reaction was followed by TLC and GC analysis. On completion the
mixture was allowed to cool to room temperature. The mixture was
then filtered through a filter paper and the catalyst rinsed with
diethyl ether. The filtrate was concentrated by rotary evaporation
and then purification of the mono-adduct was done using gravity
column chromatography on silica gel. For aliphatic amines, the bis-
adduct side product was primarily eluted using 75:25 of hexane
and ethyl acetate. As soon as the bis-adduct was eluted, the eluent’s
polarity was increased to 50:50 of hexane and ethyl acetate to elute
the remaining mono-adduct. On the other hand, for aromatic
amines, the mono-adduct was the first to elute out of the column,
and was eluted using only 80:20 of hexane and ethyl acetate, re-
spectively. The yields of the purified adducts 3 were finally recorded
and characterisation was done using IR and NMR spectroscopy.
1
2
3
1:2
1:2
1:2
200
200b
200c
48
68
72
90%
83%
74%
a
Yield of pure isolated products.
Catalyst recycled from entry 1.
Catalyst recycled from entry 2.
b
c
building CeN bonds following green chemistry principles. Our
results show that aza-Michael reactions between primary amines
and methyl propenoate can be controlled in order to obtain in
high yields the required product, which is the secondary or the
tertiary derivative, as result of a selective mono- or a double-
addition. Moreover the reaction can be performed under green
environmentally-friendly conditions, using nearly stoichiometric
ratio of reactants and with a simple work-up procedure. In fact
the best results for both adducts were obtained under solvent-
free conditions and heterogeneous acidic catalysis, so acidic
Al2O3 could be proposed as an alternative efficient solid het-
erogeneous catalyst for selective aza-Michael reactions, with the
advantage of no need of catalyst preparation or activation, as
required by mostly of the supported solid catalysts, no pro-
motions of side reactions like the polymerization of the starting
electron poor alkene, and small amounts required (only 0.2 g per
mmol of substrate). It shows a high catalytic activity in solvent-
free green conditions, can be easily separated minimizing prod-
uct losses and can be easily recycled at least two times, without
re-activation and any significant loss of activity; in addition, the
catalyst is easily commercially available. More applications of
aza-Michael reactions promoted by acidic alumina are under
development in our laboratories.
4.3. Procedure B: general procedure followed for the prepa-
ration of bis-adducts, 4
Procedure A was followed with the difference being that
20 mmol of the Michael acceptor 2 and 10 mmol of the amine 1
were utilized, while keeping all of the other conditions the same. At
the end of the reaction the products in the mixture were then
separated by column chromatography on silica gel. The bis-adducts
produced from aliphatic amines were eluted using 75:25 of hex-
anes and ethyl acetate, respectively. In the case of aromatic amines,
the mono-adduct and the amine were first eluted using 80:20 of
hexanes and ethyl acetate, and then the bis-adduct was eluted
using ethyl acetate only. The product 4 was weighed and charac-
terized by IR and NMR analysis.
4. Experimental
4.1. General
4.4. Product identification
All commercially available chemicals and reagents were pur-
chased from Aldrich and used without further purification. Acidic
(Scharlau, grain size: 0.05e0.2 mm, 70e290 mesh ASTM, pH 4.5,
activity degree 1), weakly acidic (SigmaeAldrich, w150 mesh, pH
4.4.1. Methyl 3-(pentylamino)propanoate (3a).17 Colourless oil. IR
(neat, cmꢁ1):
n
¼3323, 2954, 2927, 2858, 1732, 1436,1460,1363,1128,
1064, 1014, 839. 1H NMR (CDCl3, 250 MHz):
d
0.90 (t, J¼6.7 Hz, 3H),
1.23e1.34 (m, 4H), 1.42e1.53 (m, 2H), 1.60 (br s, 1H), 2.58 (dt, J¼6.7
w6.0) and basic (Acros, Brockmann I, 50e200 mm, pH 9e10) alu-
and 7.3 Hz, 4H), 2.89 (t, J¼6.7 Hz, 2H), 3.68 (s, 3H). 13C NMR (CDCl3,
mina were used without any activation. IR spectra were recorded
on a Shimadzu IRAffinity-1 FTIR Spectrometer, calibrated against
a 1602 cmꢁ1 polystyrene absorbance spectrum. Samples were ei-
ther analysed as a thin film or in a NujolÔ mull, between sodium
chloride discs. The 1H and 13C NMR spectra were recorded on
Bruker AM250 NMR spectrometer fitted with a dual probe at fre-
quencies of 250 MHz and 62.9 MHz for 1H and 13C NMR, re-
spectively. Samples were dissolved in deuterated chloroform (with
TMS). Mass spectra (EI) were recorded with a Thermo Finnigan
Trace DSQ quadropole mass spectrometer together with a Thermo
Finnigan Trace GC Ultra equipped with a 25 m by 0.22 mm BP1
(100% dimethlypolysiloxane stationary phase) column. Microanal-
yses were performed with a CHNS-O analyzer Model EA 1108 from
Fisons Instruments. Reaction monitoring was done by TLC and GC
analysis. Gas chromatography was carried out on a Shimadzu GC-
2010 plus gas chromatograph equipped with a flame ionisation
detector and HiCap 5 GC column with dimensions of 0.32 mm
62.9 MHz) d (ppm) 14.0, 22.6, 29.5, 29.8, 34.0, 45.0, 50.0, 52.0, 173.2.
4.4.2. Methyl 3-[(3-methoxy-3-oxopropyl)(pentyl)amino]propanoate
(4a). Colourless oil. IR (neat, cmꢁ1):
¼2953, 2858, 1750, 1436, 1355,
1128, 1093, 1049, 840. 1H NMR (CDCl3, 250 MHz):
n
d
0.88 (t, J¼6.7 Hz,
3H, Me), 1.18e1.48 (m, 6H, (CH2)3Me), 2.36e2.47 (m, 6H, CH2CO,
CH2N), 2.76 (t, J¼7.3 Hz, 4H, CH2N), 3.68 (s, 6H, OMe). 13C NMR
(CDCl3, 62.9 MHz) d (ppm) 14.1, 22.6, 27.0, 29.7, 32.8, 49.2, 52.0, 53.8,
173.2. MS (EI): m/z (%)¼259 (6) [M]þ, 202 (100), 186 (62), 160 (26),
130 (44), 84 (26). Anal. Calcd for C13H25NO4 (259.343): C, 60.21; H,
9.72; N, 5.4; O, 24.68. Found: C, 60.37; H, 9.51; N, 5.31; O, 24.89.
4.4.3. Methyl 3-(hexylamino)propanoate (3b).18,2e Yellow oil. IR
(neat, cmꢁ1):
n
¼3325, 2922, 1734, 1436, 1363, 1174, 1016, 840, 725.
1H NMR (CDCl3, 250 MHz)
d
0.88 (t, J¼6.7 Hz, 3H), 1.22e1.38 (m,
6H), 1.41e1.57 (m, 3H), 2.53 (t, J¼6.1 Hz, 2H), 2.60 (t, J¼7.3 Hz, 2H),
2.88 (t, J¼6.1 Hz, 2H), 3.70 (s, 3H). 13C NMR (CDCl3, 62.9 MHz)
(internal diameter)ꢂ30 m (length)ꢂ0.25
m
m (film thickness), using
d (ppm) 14.1, 22.6, 27.0, 30.1, 31.8, 34.6, 45.1, 49.9, 51.6, 173.3.
nitrogen as carrier gas. Most of the synthesised compounds are
known and their spectroscopic data are in agreement with those
reported in the literature.
4.4.4. Methyl
3-[hexyl(3-methoxy-3-oxopropyl)amino]propanoate
¼2929, 1735, 1436, 1355,
(4b).2g Colourless oil. IR (neat, cmꢁ1):
n

G. Bosica et al. / Tetrahedron 70 (2014) 2449e2454
2453
1174, 1041, 842. 1H NMR (CDCl3, 250 MHz):
d
0.88 (t, J¼6.7 Hz,
(30). Anal. Calcd for C12H17NO2 (207.269): C, 69.54; H, 8.27; N, 6.76;
O, 15.44. Found: C, 69.72; H, 8.11; N, 6.88; O, 15.31.
3H), 1.18e1.48 (m, 8H), 2.40 (t, J¼7.3 Hz, 2H), 2.44 (t, J¼7.3 Hz,
4H), 2.76 (t, J¼7.3 Hz, 4H), 3.68 (s, 6H). 13C NMR (CDCl3,
62.9 MHz)
173.1.
d
(ppm) 14.1, 22.7, 27.0, 27.1, 31.8, 32.6, 49.3, 51.5, 53.9,
4.4.14. Methyl
anoate (4g). Brown oil. IR (neat, cmꢁ1):
1456, 1375, 1172, 1076, 819. 1H NMR (CDCl3, 250 MHz):
3-[4-ethyl(3-methoxy-3-oxopropyl)anilino]prop-
¼2960, 1737, 1610, 1516,
1.21 (t,
n
d
4.4.5. Methyl 3-(propylamino)propanoate (3c).18 Pale yellow oil. IR
(neat, cmꢁ1):
¼3325, 2956, 1735, 1436, 1363, 1178, 1012, 839, 750.
1H NMR (CDCl3, 250 MHz):
J¼7.3 Hz, 3H, Me), 2.5e2.7 (m, 2H, CH2Me), 2.57 (t, J¼7.3 Hz, 4H,
CH2CO), 3.5e3.6 (m, 4H, CH2N), 3.67 (s, 6H, OMe), 6.82 (d, J¼8.5 Hz,
2H, Ph), 7.14 (d, J¼8.5 Hz, 2H, Ph). 13C NMR (CDCl3, 62.9 MHz)
n
d
0.92 (t, J¼7.3 Hz, 3H), 1.50 (sextet,
J¼7.3 Hz, 2H), 1.50 (s, 1H, NeH), 2.53 (t, J¼6.1 Hz, 2H), 2.58 (t,
d (ppm) 15.9, 27.8, 32.4, 47.2, 51.7, 113.3, 128.8, 133.2, 144.9, 172.6.
J¼7.3 Hz, 2H), 2.89 (t, J¼6.1 Hz, 2H), 3.69 (s, 3H).
MS (EI): m/z (%)¼293 (38) [M]þ, 262 (10), 220 (100), 178 (16) 148
(16), 118 (14). Anal. Calcd for C16H23NO4 (293.360): C, 65.51; H, 7.90;
N, 4.77; O, 21.81. Found: C, 65.36; H, 7.61; N, 4.90; O, 21.69.
4.4.6. Methyl 3-[(3-methoxy-3-oxopropyl)(propyl)amino]propanoate
(4c).19 Colourless oil. IR (neat, cmꢁ1):
n
¼2954, 1737, 1436, 1373,
1174, 1047, 842. 1H NMR (CDCl3, 250 MHz):
d
0.85 (t, J¼7.3 Hz, 3H),
4.4.15. Methyl 3-(methylanilino)propanoate (3i).3d Brown-yellow
1.44 (sextet, J¼7.3 Hz, 2H), 2.37 (t, J¼7.3 Hz, 2H), 2.45 (t, J¼7.3 Hz,
4H), 2.77 (t, J¼7.3 Hz, 4H), 3.68 (s, 6H).
oil. IR (neat, cmꢁ1):
n
¼3026, 2949, 1734, 1600, 1502, 1435, 1363,
1172, 1045, 837. 1H NMR (CDCl3, 25 MHz):
d
2.58 (t, J¼7.3 Hz, 2H),
2.93 (s, 3H), 3.67 (s, 3H), 3.68 (t, J¼7.3 Hz, 2H), 6.73 (t, J¼6.7 Hz, 1H),
6.74 (d, J¼8.5 Hz, 2H), 7.25 (t, J¼7.9 Hz, 2H).
4.4.7. Methyl 3-(butylamino)propanoate (3d).18,11a Pale yellow oil.
IR (neat, cmꢁ1):
NMR (CDCl3, 250 MHz):
J¼7.3 Hz, 2H), 1.47 (quintet, J¼7.3 Hz, 2H), 1.58 (s, 1H, NeH), 2.53 (t,
J¼6.7 Hz, 2H), 2.61 (t, J¼7.3 Hz, 2H), 2.89 (t, J¼6.7 Hz, 2H), 3.69 (s,
3H).
n
¼3325, 2954, 1735, 1436, 1361, 1176, 1058, 734. 1H
d
0.92 (t, J¼7.3 Hz, 3H), 1.34 (sextet,
Acknowledgements
The Authors thank the University of Malta for financial support.
References and notes
4.4.8. Methyl
(4d).20 Colourless oil. IR (neat, cmꢁ1):
1174, 1045, 842. 1H NMR (CDCl3, 250 MHz):
1.28 (sextet, J¼6.1 Hz, 2H), 1.40 (quintet, J¼6.7 Hz, 2H), 2.40 (t,
J¼7.3 Hz, 2H), 2.45 (t, J¼7.3 Hz, 4H), 2.77 (t, J¼7.3 Hz, 4H), 3.68 (s,
6H).
3-[butyl(3-methoxy-3-oxopropyl)amino]propanoate
¼2954, 1728, 1436, 1373,
0.90 (t, J¼7.3 Hz, 3H),
n
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4.4.9. Methyl 3-(cyclohexylamino)propanoate (3e).17,11a Yellow oil.
IR (neat, cmꢁ1):
n
¼3319, 2926, 1735, 1436, 1363, 1170, 1045, 846,
750. 1H NMR (CDCl3, 250 MHz):
d
0.95e1.22 (m, 4H), 1.42 (s, 1H),
1.54e1.95 (m, 6H), 2.42 (dt, J¼3.7 Hz, J¼2.4 Hz, 1H), 2.52 (t,
J¼6.7 Hz, 2H), 2.91 (t, J¼6.7 Hz, 2H), 3.69 (s, 3H).
4.4.10. Methyl 3-[cyclohexyl(3-methoxy-3-oxopropyl)amino]prop-
anoate (4e).5c,8c Pale pink oil. IR (neat, cmꢁ1):
n
¼2927, 1730, 1435,
1357, 1174, 1047, 840. 1H NMR (CDCl3, 250 MHz):
d
1.0e1.30 (m, 4H),
1.85e1.55 (m, 6H), 2.38e2.30 (m, 1H), 2.42 (t, J¼7.3 Hz, 4H), 2.78 (t,
J¼7.3 Hz, 4H), 3.65 (s, 6H).
4.4.11. Methyl 3-anilinopropanoate (3f).3d White solid. IR (Nujol,
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cmꢁ1):
n
¼3396, 1741, 1602, 1506, 1174, 746. 1H NMR (CDCl3,
250 MHz):
d
2.63 (t, J¼6.7 Hz, 2H), 3.46 (t, J¼6.7 Hz, 2H), 3.70 (s,
3H), 4.02 (broad s, 1H), 6.63 (d, J¼7.9 Hz, 2H), 6.73 (t, J¼7.3 Hz, 1H),
7.20 (t, J¼8.5 Hz, 2H). 13C NMR (CDCl3, 62.9 MHz)
d (ppm) 33.7, 39.4,
51.7, 113.0, 117.7, 129.3, 147.6, 172.8.
4.4.12. Methyl
(4f).3d White solid. IR (Nujol, cmꢁ1):
1506, 1373, 1199, 908, 734. 1H NMR (CDCl3, 250 MHz):
3-[(3-methoxy-3-oxopropyl)anilino]propanoate
¼3030, 2954, 1734, 1600,
2.59 (t,
n
d
J¼7.3 Hz, 2H), 2.63 (t, J¼7.3 Hz, 2H), 3.64 (t, J¼7.3 Hz, 2H), 3.65 (t,
J¼7.3 Hz, 2H), 3.68 (s, 6H), 6.77 (d, J¼8.6, 2H), 6.80 (t, J¼7.3 Hz, 1H),
7.26 (t, J¼6.7 Hz, 2H).
4.4.13. Methyl 3-(4-ethylanilino)propanoate (3g). Brown oil. IR
(neat, cmꢁ1):
n
¼3396, 3016, 2958, 1732, 1616, 1517, 1436, 1367, 1174,
1047, 823. 1H NMR (CDCl3, 250 MHz):
d
1.19 (t, J¼7.3 Hz, 3H, Me),
2.54 (q, J¼7.3 Hz, 2H, CH2Me), 2.62 (t, J¼6.7 Hz, 2H, CH2CO), 3.44 (t,
J¼6.7 Hz, 2H, CH2N), 3.70 (s, 3H, OMe), 3.91 (broad s, 1H, NH), 6.58
(d, J¼8.5 Hz, 2H, Ph), 7.03 (d, J¼8.5 Hz, 2H, Ph). 13C NMR (CDCl3,
62.9 MHz)
d (ppm) 15.9, 27.9, 33.8, 39.8, 51.7, 113.3, 128.6, 133.7,
145.5,172.9. MS (EI): m/z (%)¼207 (54) [M]þ, 192 (27), 134 (100),118

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G. Bosica et al. / Tetrahedron 70 (2014) 2449e2454
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