Uncatalyzed, green aza-Michael addition of amines to dimethyl maleate

Article abstract of DOI:10.1016/j.tet.2014.06.124

Dimethyl maleate was found to be a very reactive and selective acceptor for the aza-Michael addition in comparison to other commonly used electron-deficient alkenes. It reacts efficiently with a variety of aliphatic amines in complete absence of any catalyst and solvent at room temperature. Under these environmentally-friendly conditions, high yields of selectively mono-adducts were obtained within short reaction times.

Full text of DOI:10.1016/j.tet.2014.06.124

Tetrahedron 70 (2014) 6607e6612
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Uncatalyzed, green aza-Michael addition of amines to dimethyl
maleate
*
Giovanna Bosica , Anthony John Debono
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:
Dimethyl maleate was found to be a very reactive and selective acceptor for the aza-Michael addition in
comparison to other commonly used electron-deficient alkenes. It reacts efficiently with a variety of
aliphatic amines in complete absence of any catalyst and solvent at room temperature. Under these
environmentally-friendly conditions, high yields of selectively mono-adducts were obtained within short
reaction times.
Received 15 March 2014
Received in revised form 17 June 2014
Accepted 30 June 2014
Available online 4 July 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Dimethyl maleate
aza-Michael reaction
Mono-adduct
Solvent-free
Catalyst-free
1. Introduction
stereoselective manner as well as applied to the total synthesis of
natural products.4g,5
In recent years significant attention has been given to the de-
velopment of efficient and operationally simple protocols for car-
bonecarbon and carboneheteroatom bonds formation, aimed at
the construction of valuable molecules. Elimination of volatile and
harmful organic solvents is an important target of green chemistry
to prevent solvent wastes, hazards and toxicity and to make syn-
theses simpler, saving energy.1 Uncatalyzed reactions can offer
a step forward in this direction being interesting ways of carrying
on more eco-sustainable synthetic methodologies.2 Thus, the de-
velopment of efficient procedures for useful chemical trans-
formations without any solvent and any catalyst is highly
appreciated.
Typical procedures for aza-Michael reactions require strong acid
or base catalysts, which are harmful to the environment and pro-
duce undesirable by-products.6 Much work has been carried out on
the aza-Michael addition and a variety of novel catalytic systems
and conditions have been reported in the literature, mainly aiming
at further improving the green credentials of this reaction class.7
Such innovations include, among others, the use of lanthanide
derivatives,8 silica-supported acids,9 resins,10 clay-supported Lewis
acids,11 organic polymers,12 task-specific ionic liquids,13 and re-
actions in water14 or solvent-free.15 Although some improvements,
many of the above procedures still require harsh reaction condi-
tions, expensive catalysts, long reaction times, use of hazardous
organic solvents and excess amount of Michael acceptors, with
poor selectivity, all features, which are not desirable from a green
chemistry point of view. Most of the reported methods have fo-
cussed on the addition of secondary aliphatic amines or, at times,
aromatic amines and the few non-catalytic aza-Michael reactions
are restricted to electron-poor acceptors with terminal double
bonds or very active double bonds, or else highly nucleophilic ali-
phatic amines.16,3a
The aza-Michael reaction is considered a very efficient and
versatile method of creating new CeN bond3 and one of the
shortest routes to b-amino carbonyl derivatives, which have be-
come increasingly important to the natural product and pharma-
ceutical areas. In fact, it is one of the most widely used reactions in
modern organic synthesis of biologically active compounds and
being a conjugate addition it benefits from good atom economy.4
Moreover aza-Michael addition is of remarkable significance in
asymmetric synthesis as documented by the various asymmetric
aza-Michael protocols available to perform this reaction in highly
Dimethyl maleate (2) is a high versatile Michael acceptor, having
two electron withdrawing groups in a- and b-position, which easily
allow to access multi-functionalized final adducts.17 To the best of
our knowledge only a very limited number of aza-Michael addi-
tions using dimethyl maleate have previously been reported,
which, whereas has previously been shown to be suitable acceptor
* Corresponding author. E-mail address: giovanna.bosica@um.edu.mt (G. Bosica).
http://dx.doi.org/10.1016/j.tet.2014.06.124
0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

6608
G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e6612
for Michael addition with nitro compounds, under different basic
catalysts.18 Among the few examples of aza-Michael additions with
dimethyl maleate, and mainly different alkyl fumarates, there are
procedures, which require the prior preparation of an ionic liquid
catalyst using harsh chemicals and an excess of Michael acceptor,19
or organic solvents like ethanol at 0 ꢀC and pyridine and triethyl-
amine at 100 ꢀC, to overcome the insolubility in organic solvents of
methylamine hydrochloride, used as nucleophile in excess;20 while
neat conditions for 24 h at room temperature or for 10 h under
refluxing are reported with a few amines only.21 Whereas some
other procedures refer to regioselective additions to unsymmetrical
alkyl fumarates under high temperatures and with long reaction
times22 or require an additional inert atmosphere.23 Overall mostly
of these have a finite scope of substrates since their main target is
the synthesis of specific compounds like aminoacids, poly-
carboxylates with surfactant proprieties and unsaturated polyester
resins.20,23
selective towards the mono-adduct, with no bis-adduct detected
under any of the conditions. Much to our surprise, the neat reaction
carried out in absence of both catalyst and solvent at room tem-
perature also resulted in an excellent yield of 96%, within 4 h (entry
12, Table 1).
One notable observation was that when the reaction was carried
out in absence of solvent and catalyst, the isomeric dimethyl fu-
marate precipitated out of the reaction after a few minutes. How-
ever it was not found to hinder the aza-Michael addition in any way
since the reaction between dimethyl fumarate and the amine
proceeds efficiently to result in the same mono-adduct.
On recognising that such mild conditions resulted in high yields
of solely mono-adduct, we decided to explore whether they would
have been suitable for other amines, and a variety of different
amines (1bep) were reacted with 2 (Table 2). Other linear aliphatic
primary amines gave similar results, with yields ranging from 87%
to 97% (entries 1, 3, 10, Table 2), as well as the secondary aliphatic
amine tested, dibutylamine (entry 7, Table 2), with 72% yield within
7 h of reaction. The cyclic (entries 9 and 11, Table 2) and branched
(entries 2, 4, 5, 6 and 8, Table 2) aliphatic primary amines also
resulted in good yields within relatively short reaction times. One
anomaly was the low yield obtained using isopropyl amine (entry 2,
Table 2)dthis was probably due to the volatility of the amine. No
reaction was observed with the aromatic amines (entries 13e15,
Table 2) used, after 24 h of stirring at room temperature in absence
of solvent and catalyst. Although the reaction with aniline (entry
13, Table 2) was warmed to 50 ꢀC for two extra hours and later
mixed with 1 equiv of DBU in acetonitrile, none of these conditions
elicited any observable reaction.
Following our previous studies on solvent-free and uncatalyzed
aza-Michael additions,24,16c herein we report a green aza-Michael
reaction between dimethyl maleate and different amines (1aep)
under neat conditions, without any catalyst and solvent, at room
temperature (Scheme 1).
R1
N
O
O
H
N
OMe
OMe
R
OMe
OMe
+
R
R1
O
O
1a-p
2
3a-p
Scheme 1. aza-Michael addition of amines to dimethyl maleate.
Table 2
aza-Michael addition of various amines (1bep) to dimethyl maleate (2)
2. Results and discussion
A series of screening reactions using 1-pentylamine (1a), as the
nucleophile, and 2, as the Michael acceptor, were used in order to
determine the most efficient conditions for reaction. All reactions
were performed on a 0.01 mol scale of the reagents in stoichio-
metric ratio. A variety of catalysts were tested with both acetoni-
trile and THF as solvent. All of the reactions resulted in excellent
yield of mono-adduct (3a) within a relatively short reaction time
(Table 1). It is also of note that the reaction was, in all cases,
Entry
R1
R2
Time (h)
Yieldb 3 (%)
1
2
3
4
5
6
7
8
n-C3H7 (1b)
(CH3)2CH (1c)
n-C4H9 (1d)
C2H5CH(CH3) (1e)
(CH3)2CHCH2 (1f)
(CH3)3C (1g)
n-C4H9 (1h)
(CH3)2CHC2H4 (1i)
c-C5H9 (1j)
n-C6H13 (1k)
cy-C6H11 (1l)
C6H5CH2 (1m)
C6H5 (1n)
C6H5 (1o)
p-(C2H5)C6H4 (1p)
H
H
H
H
H
H
4
6
5
5
6
7
7
4
5.5
4
5
6
24
24
24
97
52
87
85
68
65
72
70
67
94
78
62
NR
NR
NR
Table 1
Model reaction between 1-pentylamine (1a) and dimethyl maleate (2)
n-C4H9
H
H
H
H
H
H
CH3
H
9
10
11
12
13a
14
15
Entry Catalyst
Solvent
Temp Time Yieldb
(h)
3a (%)
1
2
3
4
5
6
7
8
DBU (1 equiv)
DBU (1 equiv)
DBU (0.1 equiv)
K2CO3 (1 equiv)
K2CO3 (0.1 equiv)
[DBU][Ac] (1 equiv)
[DBU][Ac] (0.1 equiv)
Al2O3 (acidic, 1 equiv)
Al2O3 (weakly acidic, 1 equiv) THF
Amberlyst A-21 (1 equiv)
Acetonitrile rt
5
5
5
6
6
7
7
8
10
6
6
4
4
4
6
5.5
95
96
95
90
88
72
75
80
83
97
96
96
95
97
88
92
NR¼‘no reaction’.
THF
rt
a
After 24 h, the reaction was heated to 50 ꢀC for 2 h and then 1 equiv of DBU in
acetonitrile was added.
Acetonitrile rt
Acetonitrile rt
Acetonitrile rt
b
Yield of pure isolated product.
/
rt
/
rt
Under the same neat reaction conditions other typical Michael
acceptors (4) were then tested with hexylamine (1k), to compare
the results with those obtained using dimethyl maleate. As can be
seen in Table 3, they performed very differently to dimethyl mal-
eate and the results were highly dependent on the structure of the
acceptor. Methyl acrylate (4a) and acrylonitrile (4b) resulted in
a high percentage conversion of starting material with a much
longer reaction time (20 h). In both cases, the result was a mixture
of both mono- (5) and bis-adduct (6). Other acceptors tested were
much less reactive: trans-methyl crotonate (4c) gave a yield of 60%
THF
rt
9
rt
10
11
12
13a
14
15
16
THF
rt
Amberlyst 15 (1 equiv)
THF
rt
/
/
/
/
/
/
rt
/
/
rt
50 ꢀC
rt
THF
Acetonitrile rt
a
Ratio of amine:acceptor was 1.2:1.
Yield of pure isolated product.
b

G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e6612
6609
Table 3
Reaction between 1-hexylamine (1k) and various Michael acceptors (4)
Entry
1
Acceptor (4)
Time (h)
20
Yielda 5 (%)
Yielda 6 (%)
4a
70
12
2
3
4b
4c
20
96
80
60
8
NR
4
5
4d
4e
96
96
NR
NR
NR
NR
6
7
4f
96
96
NR
NR
NR
NR
4g
mono-adduct after 96 h while trans-4-phenyl buten-2-one (4d),
2-cyclopentenone (4e), 2-cyclohexenone (4f) and trans-2-hexenal
(4g) resulted in no observable reaction, under these conditions.
Michael acceptors with terminal double bonds are typically
more reactive than those with non-terminal double bonds.3a This
would explain the higher reactivity of methyl acrylate and acrylo-
nitrile compared to the other acceptors tested. It would also explain
the non-selectivity of these acceptors, which leads to the formation
of some bis-adduct.24 However, dimethyl maleate is clearly an ex-
ception to this rule. The presence of two electron-withdrawing
groups alpha to the double bond make it highly electron-
deficient, thus a very reactive acceptor despite possessing a non-
terminal double bond. The fact that the double bond is non-
terminal and so sterically hindered may be the reason behind the
selectivity towards a mono-adduct when compared to methyl ac-
rylate and acrylonitrile.
It was found that in comparison to other common Michael ac-
ceptors, dimethyl maleate is quite particular. It is more reactive
than acceptors with terminal double bonds, such as methyl acrylate
and acrylonitrile, which are considered to be some of the most
reactive Michael acceptors. Furthermore, dimethyl maleate is also
highly selective towards the mono-adduct in contrast to these
acceptors.
4. Experimental
4.1. General
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,
pHw6.0) alumina 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 either 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 frequencies of 250 MHz and 62.9 MHz for 1H and 13C NMR,
respectively. An Aspect 3000 computer using 16 K complex points
for 1H NMR and 64 K complex points for 13C NMR was used for
processing. Samples were dissolved in deuterated chloroform (with
TMS); 5 mg in 0.8 mL CDCl3 for 1H NMR and between 35 mg and
50 mg in 0.8 mL CDCl3 for 13C NMR. 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. Microanalyses were performed with a CHNS-O
analyzer Model EA 1108 from Fisons Instruments. Reaction moni-
toring was done by TLC and GC analysis. Ready-purchased silica on
PET sheets with fluorescent indicator, 254 nm, were used as sta-
tionary phase for TLC. Gas chromatography was carried out on
3. Conclusions
It has been shown that the use of catalysts, solvents and heating
are not necessary for the efficient addition of 1-pentylamine to
dimethyl maleate. The reaction proceeds efficiently resulting in
high yields of solely mono-adduct after 4 h of reaction time. The use
of DBU, potassium carbonate, alumina, Amberlyst resins and ionic
liquid [DBU][Ac] did not improve the yield or reaction time when
screened as catalysts.
Several novel aza-Michael mono-adducts were prepared in ab-
sence of catalyst and solvent, under ambient conditions by using
dimethyl maleate as acceptor. It can thus be concluded that the aza-
Michael addition of linear, cyclic and branched aliphatic primary
and secondary amines to dimethyl maleate can be carried out ef-
fectively with remarkable advantages, such as the simple experi-
mental procedure, mild reaction conditions, short reaction
time and high product yields, and more importantly avoiding
hazardous organic solvents and any excess of reagents, so with
100% of atom economy.

6610
G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e6612
a Shimadzu GC-2010 plus gas chromatograph equipped with
a flame ionisation detector and HiCap 5 GC column with di-
(14), 71 (16), 43 (12). Anal. Calcd for C11H21NO4 (231.289): C, 57.12;
H, 9.15; N, 6.06; O, 27.67. Found: C, 57.35; H, 9.31; N, 6.21; O, 27.50.
mensions of 0.32 mm (internal diameter)ꢂ30 m (length)ꢂ0.25
mm
(film thickness), using nitrogen as carrier gas. Many of the syn-
thesised compounds are known and their spectroscopic data are in
agreement with those reported in the literature.
4.5.2. Dimethyl 2-(propylamino)succinate (3b).21 Clear, colourless
oil. IR (neat, cmꢁ1):
n
¼3325, 2961, 2872, 1732, 1437, 1370. 1H NMR
(250 MHz, CDCl3):
d
3.75 (3H, s), 3.70 (3H, s), 3.65 (1H, t, J¼6.5 Hz),
2.80e2.55 (2H, m), 2.70e2.40 (2H, m), 1.65 (1H, s), 1.55e1.40 (2H,
m), 0.90 (3H, t, J¼7.3 Hz). 13C NMR (62.9 MHz, CDCl3):
d 174.5, 172.0,
4.2. Procedure A: general procedure followed for the prepa-
ration of 3a during screening reactions (Table 1)
58.0, 52.2, 51.8, 50.0, 38.0, 23.2, 11.6.
4.5.3. Dimethyl 2-(iso-propylamino)succinate (3c).21 Clear, colour-
less oil. IR (neat, cmꢁ1):
¼3325, 2963, 2873, 2845,1734, 1436, 1370.
1H NMR (250 MHz, CDCl3):
3.75 (3H, s), 3.70 (3H, s), 3.75e3.70
To a stirred solution of dimethyl maleate (2) (10 mmol) in the
chosen solvent (10 mL), 1-pentylamine (1a) (10 mmol) was added,
followed by the chosen catalyst (10 mmol) (see Table 1). The re-
action was left stirring and monitored by TLC and GC. The
resulting diester (3a) was purified by gravity column chromatog-
raphy on silica gel (using mixtures of n-hexane and ethyl acetate)
and dried by rotary evaporation. The yield was obtained and the
product was then analysed by NMR and IR spectroscopy. When no
catalyst and solvent were used the same procedure was followed
except that the reactants were mixed together immediately. When
solid catalysts were used the crude mixture was filtered through
a filter paper and the catalyst rinsed with diethyl ether, then the
filtrate was concentrated by rotary evaporation before purification.
When the reaction was not carried out at room temperature an oil
bath and a reflux condenser were used. In some cases the quan-
tities of reagents or catalyst were varied from the general pro-
cedure, as indicated in table. When [DBU][Ac] was used as reaction
medium (Table 1, entries 6 and 7) the reaction components were
extracted from the mixture using three 5 mL portions of diethyl
ether.
n
d
(1H, m), 2.90e2.70 (1H, sep, J¼6.1 Hz), 2.75e2.60 (2H, m), 1.75 (1H,
s),1.05 (6H, m). 13C NMR (62.9 MHz, CDCl3):
51.8, 47.2, 38.7, 23.6, 22.2.
d 174.8,171.3, 55.5, 52.1,
4.5.4. Dimethyl 2-(butylamino)succinate (3d). Clear, colourless oil.
IR (neat, cmꢁ1):
(250 MHz, CDCl3):
n
¼3328, 2954, 2932, 2862,1730,1436,1366.1H NMR
d
3.75 (3H, s, OMe), 3.70 (3H, s, OMe), 3.65 (1H, t,
J¼6.4 Hz, CHN), 2.80e2.55 (2H, m, CH2N), 2.60e2.45 (2H, m, CH2CO),
1.70 (1H, s, NH),1.55e1.20 (4H, m), 0.90 (3H, t, J¼7.3 Hz, Me).13C NMR
(62.9 MHz, CDCl3): d 174.3,171.4, 57.9, 52.3, 52.1, 47.8, 37.9, 32.2, 20.3,
13.9. MS (EI): m/z (%)¼217 (5) [M]þ, 174 (18), 158 (100), 144 (15), 114
(22), 84 (16), 57 (12). Anal. Calcd for C10H19NO4 (217.262): C, 55.28; H,
8.81; N, 6.45; O, 29.46. Found: C, 55.39; H, 9.01; N, 6.28; O, 29.53.
4.5.5. Dimethyl 2-(sec-butylamino)succinate (3e). Clear, colourless
oil. IR (neat, cmꢁ1):
n
¼3332, 2960, 2936, 2878, 1748, 1732, 1435,
1373. 1H NMR (250 MHz, CDCl3):
d
3.75 (3H, s, OMe), 3.70 (3H, s,
OMe), 3.75e3.65 (1H, m, CHN), 2.80e2.60 (1H, m, CHN), 2.60e2.45
(2H, m, CH2CO), 1.75 (1H, s, NH), 1.55e1.20 (2H, m), 1.00 (3H, m,
4.3. Procedure B: general procedure followed for the prepa-
ration of adducts 3, 5 and 6
Me), 0.85 (3H, m, Me). 13C NMR (62.9 MHz, CDCl3):
d 174.9, 174.8,
171.4, 171.1, 55.7, 55.3, 53.2, 53.1, 52.1, 52.0, 51.8, 38.8, 38.76, 30.3,
29.0, 20.3, 19.5, 10.3, 9.8. MS (EI): m/z (%)¼217 (5) [M]þ, 202 (8), 188
(87), 158 (100), 144 (25), 128 (59), 102 (30), 70 (19). Anal. Calcd for
Amine (1) (10 mmol) was added to dimethyl maleate (2)
(10 mmol), under stirring in a round bottomed flask equipped with
a magnetic bar. The reaction was left stirring at ambient conditions
and monitored by TLC and GC analysis. The resulting adduct (3) was
purified by gravity column chromatography on silica gel, using
mixtures of n-hexane and ethyl acetate, and dried by rotary evap-
oration. The yield was obtained and the product was then analysed
by IR and NMR spectroscopy. For adducts 5 and 6 Procedure B was
followed with the difference being that the Michael acceptor 4 was
used instead of 2 together with 1-hexylamine (1k), while keeping
all of the other conditions the same.
C10H19NO4 (217.262): C, 55.28; H, 8.81; N, 6.45; O, 29.46. Found: C,
55.40; H, 8.95; N, 6.29; O, 29.50.
4.5.6. Dimethyl 2-(iso-butylamino)succinate (3f).25 Clear, colourless
oil. IR (neat, cmꢁ1):
NMR (250 MHz, CDCl3):
n
¼3332, 2954, 2872, 1745, 1732, 1437, 1366. 1H
d 3.75 (3H, s), 3.70 (3H, s), 3.65 (1H, t,
J¼6.1 Hz), 2.70 (2H, m), 2.50e2.25 (2H, m), 1.65 (2H, m), 0.90 (6H, d,
J¼6.7 Hz). 13C NMR (62.9 MHz, CDCl3)
d 174.4, 171.5, 58.1, 56.1, 52.1,
51.9, 38.0, 28.7, 20.6, 20.5.
4.5.7. Dimethyl 2-(tert-butylamino)succinate (3g).26 Clear, colour-
less oil. IR (neat, cmꢁ1):
¼3333, 2959, 2870, 1735, 1645, 1635, 1437,
1390. 1H NMR (250 MHz, CDCl3):
3.80 (1H, m), 3.75 (3H, s), 3.70
(3H, s), 2.60 (2H, m), 1.05 (9H, s). 13C NMR (62.9 MHz, CDCl3):
176.1, 171.3, 52.4, 52.3, 51.7, 50.7, 40.6, 29.2.
n
4.4. Preparation of ionic liquid [DBU][Ac]
d
The ionic liquid [DBU][Ac], used during the initial screening
reactions, was prepared, as described in the literature,13c by care-
fully mixing equimolar portions of DBU and glacial acetic acid in
a round-bottomed flask at room temperature and stirring for 6 h.
The resulting mixture was then dried by rotary-evaporation for 6 h.
d
4.5.8. Dimethyl 2-(dibutylamino)succinate (3h). Clear, colourless oil.
IR (neat, cmꢁ1):
(250 MHz, CDCl3):
n
¼3325, 2958, 2928, 2871, 1734, 1437, 1368. 1H NMR
d
3.90 (1H, m, CHN), 3.72 (3H, s, OMe), 3.68 (3H, s,
OMe), 2.90e2.65 (2H, m, CH2CO), 2.60e2.45 (4H, m, CH2N),1.50e1.20
(8H, m), 0.90 (6H, t, J¼7.2Hz, Me).13C NMR (62.9 MHz, CDCl3):
d 172.7,
4.5. Product identification
172.1, 59.8, 51.6, 51.3, 35.0, 31.0, 29.7, 20.3,14.0. MS (EI): m/z (%)¼273
(5) [M]þ, 230 (32), 214 (100), 200 (18),158 (16),114 (14), 84 (6), 57 (6),
32(10). Anal. Calcd for C14H27NO4 (273.369): C, 61.51; H, 9.96; N, 5.12;
O, 23.41. Found: C, 61.39; H, 9.81; N, 5.26; O, 23.49.
4.5.1. Dimethyl 2-(pentylamino)succinate (3a). Clear, colourless oil.
IR (neat, cmꢁ1):
n
¼3335, 2955, 2930, 2858, 1730, 1456, 1437, 1364.
1H NMR (250 MHz, CDCl3):
d
3.75 (3H, s, OMe), 3.70 (3H, s, OMe),
3.65 (1H, t, J¼6.4 Hz, CHN), 2.80e2.55 (2H, m, CH2N), 2.70e2.45
(2H, m, CH2CO), 1.80 (1H, s, NH), 1.55e1.40 (3H, m), 1.40e1.20 (3H,
4.5.9. Dimethyl 2-(iso-pentylamino)succinate (3i). Clear, colourless
oil. IR (neat, cmꢁ1):
n
¼3336, 2955, 2928, 2870, 1740, 1466, 1437,
1366. 1H NMR (250 MHz, CDCl3):
3.75 (3H, s, OMe), 3.70 (3H, s,
OMe), 3.65 (1H, t, J¼6.7 Hz, CHN), 2.80e2.60 (2H, m, CH2N),
m), 0.90 (3H, t, J¼6.8 Hz, Me). 13C NMR (62.9 MHz, CDCl3):
d 174.0,
d
171.5, 58.0, 57.8, 52.0, 48.0, 38.0, 30.0, 29.9, 22.5, 15.0. MS (EI): m/z
(%)¼231 (5) [M]þ, 216 (3), 200 (4), 172 (100), 158 (15), 114 (25), 98

G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e6612
6611
2.60e2.45 (2H, m, CH2CO), 1.70e1.55 (2H, m, CH2), 1.65 (1H, s, NH),
1.40e1.25 (1H, m, CH), 0.90 (6H, d, J¼6.5 Hz, Me). 13C NMR
2.55e2.40 (2H, m), 1.80e1.55 (2H, m), 1.5e1.20 (8H, m), 0.90 (3H, t,
J¼6.7 Hz, Me). 13C NMR (62.9 MHz, CDCl3):
d 172.0, 52.0, 50.6, 45.5,
(62.9 MHz, CDCl3):
d
174.3, 171.4, 57.9, 52.1, 51.8, 46.3, 39.1, 37.9,
38.0, 31.3, 26.7, 26.6, 22.5, 17.1, 14.0. MS (EI): m/z (%)¼201 (8) [M]þ,
186 (16), 172 (3), 130 (100), 128 (84), 98 (50), 56 (28), 43 (12). Anal.
Calcd for C11H23NO2 (201.306): C, 65.63; H, 11.52; N, 6.96; O, 15.90.
Found: C, 65.79; H, 11.41; N, 6.78; O, 15.79.
25.9, 22.7, 22.5. MS (EI): m/z (%)¼231 (5) [M]þ, 216 (3), 200 (4), 172
(100), 158 (15), 116 (55), 114 (16), 84 (18), 43 (20). Anal. Calcd for
C
11H21NO4 (231.289): C, 57.12; H, 9.15; N, 6.06; O, 27.67. Found: C,
57.30; H, 9.26; N, 6.11; O, 27.49.
4.5.17. Methyl 3-[hexyl(3-methoxy-3-oxopropyl)amino]propanoate
(6a).4d,24 Clear, yellow oil. IR (neat, cmꢁ1):
n
¼2954, 2930, 2857,
4.5.10. Dimethyl 2-(cyclopentylamino)succinate (3j). Clear, colour-
less oil. IR (neat, cmꢁ1):
NMR (250 MHz, CDCl3):
n
¼3325, 2953, 2868, 1748, 1435, 1360. 1H
1740, 1456, 1437, 1356. 1H NMR (250 MHz, CDCl3):
d
3.65 (6H, s),
d
3.75 (3H, s, OMe), 3.70 (3H, s, OMe),
2.75 (4H, t, J¼7.3 Hz), 2.50e2.35 (6H, m), 1.50e1.35 (2H, m),
1.30e1.20 (6H, m), 0.85 (3H, t, J¼6.7 Hz). 13C NMR (62.9 MHz,
3.70e3.65 (1H, t, J¼6.7 Hz CHN), 3.10e3.00 (1H, quin, J¼6.1 Hz, CHN),
2.80e2.60 (2H, m, CH2CO), 1.90e1.30 (9H, m). 13C NMR (62.9 MHz,
CDCl3):
d 173.1, 53.9, 51.5, 49.4, 32.6, 31.8, 27.2, 27.1, 22.7, 14.1.
CDCl3): d 174.8, 171.3, 58.1, 56.6, 52.1, 51.8, 38.5, 33.7, 32.6, 23.9, 23.9.
MS (EI): m/z (%)¼229 (5) [M]þ, 214 (3), 200 (6), 170 (100), 156 (13),
102 (25), 70 (8). Anal. Calcd for C11H19NO4 (229.273): C, 57.62; H,
8.35; N, 6.11; O, 27.91. Found: C, 57.73; H, 8.16; N, 6.34; O, 27.76.
4.5.18. 3-[(2-Cyanoethyl)(hexyl)amino]propanenitrile (6b).30 Clear,
yellow oil. IR (neat, cmꢁ1):
¼2955, 2932, 2857, 2255, 1732, 1456,
1437, 1201, 1177. 1H NMR (250 MHz, CDCl3):
n
d
2.75 (4H, t, J¼6.7 Hz),
2.45 (4H, t, J¼7.3 Hz), 2.40 (2H, t, J¼7.9 Hz), 1.50e1.35 (2H, m),
4.5.11. Dimethyl 2-(hexylamino)succinate (3k). Clear, colourless oil.
1.30e1.20 (6H, m), 0.87 (3H, t, J¼6.7 Hz). 13C NMR (62.9 MHz,
IR (neat, cmꢁ1):
n
¼3335, 2993, 2953, 2927, 2856, 1747, 1732, 1435,
CDCl3):
d 118.6, 53.6, 49.8, 31.7, 27.4, 26.8, 22.6, 17.0, 14.03.
1362. 1H NMR (250 MHz, CDCl3):
d
3.75 (3H, s, OMe), 3.70 (3H, s,
OMe), 3.65 (1H, t, J¼6.7 Hz, CHN), 2.80e2.60 (2H, m, CH2N),
2.70e2.40 (2H, m, CH2CO), 1.60 (1H, s, NH), 1.55e1.40 (2H, m, CH2),
1.35e1.20 (6H, m, CH2), 0.90 (3H, t, J¼6.7 Hz, Me). 13C NMR
Acknowledgements
The authors thank the University of Malta and the Strategic
Educational Pathways ScholarshipdMalta (European Social Fund
(ESF) under Operational Programme IIdCohesion Policy
2007e2013, ‘Empowering People for More Jobs and a Better Quality
Of Life’) for financial support.
(62.9 MHz, CDCl3): d 174.3,171.4, 57.8, 52.1, 51.8, 48.2, 37.9, 31.7, 30.1,
26.9, 22.6, 14.0. MS (EI): m/z (%)¼245 (6) [M]þ, 230 (3), 213 (4), 186
(100), 172 (16), 114 (14), 85 (9), 43 (8). Anal. Calcd for C12H23NO4
(245.315): C, 58.75; H, 9.45; N, 5.71; O, 26.09. Found: C, 58.69; H,
9.40; N, 5.56; O, 26.19.
4.5.12. Dimethyl 2-(cyclohexylamino)succinate (3l). Clear, colour-
References and notes
1
less oil. IR (neat, cmꢁ1):
n
¼3327, 2928, 2853, 1730, 1437, 1368. H
NMR (250 MHz, CDCl3):
(3H, s, OMe), 2.80e2.55 (2H, m, CH2CO), 2.40 (1H, m, CHN),1.90e1.60
(5H, m), 1.30e0.90 (6H, m). 13C NMR (62.9 MHz, CDCl3):
174.8,
d 3.80 (1H, m, CHN), 3.75 (3H, s, OMe), 3.70
1. (a) Tanaka, K. Solvent-free Organic Synthesis; Wiley-VCH: Weinheim, Germany,
2003; (b) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025e1074; (c) Ranu, B. C.;
Dey, S. S.; Hajra, A. ARKIVOC 2002, 7, 76e81.
2. (a) Chemistry of Waste Minimisation; Clark, J. H., Ed.; Chapman and Hall: Lon-
don, UK, 1995; (b) Poliakoff, M.; Fitzpatrick, J. M.; Farren, T. R.; Anastas, P. T.
Science 2002, 297, 807e810.
d
171.2, 55.1, 54.9, 52.0, 51.7, 38.7, 33.8, 32.8, 25.9, 24.8, 24.5. MS (EI):
m/z (%)¼243 (6) [M]þ, 200 (17),184 (100),170 (15),140 (11),102 (21),
70 (6), 55 (8). Anal. Calcd for C12H21NO4 (243.299): C, 59.24; H, 8.70;
N, 5.76; O, 26.30. Found: C, 59.36; H, 8.59; N, 5.68; O, 26.19.
3. (a) Rulev, A. Y. Russ. Chem. Rev. 2011, 80, 197e218; (b) Jung, M. E. In Compre-
hensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, UK,
1991; Vol. 4, p 1; (c) Perlmutter, P. Conjugate Addition Reactions in Organic
Synthesis; Pergamon: Oxford, UK, 1992; p 114; (d) Harrison-Marchand, A.;
Chataigner, I.; Maddaluno, J. In Science of Synthesis; Georg Thieme: New York,
NY, 2005; Vol. 26, p 1225.
4. (a) Cardillo, G.; Tomassini, C. Chem. Soc. Rev. 1996, 25, 117e128; (b) Carey, J. S.;
Laffan, D.; Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337e2347;
(c) Dugger, R. W.; Ragan, J. A.; Brown Ripin, D. H. Org. Process Res. Dev. 2005, 9,
253e258; (d) Denmark, S. E.; Forbes, D. C.; Hays, D. S.; De Pue, J. S.; Wilde, R. G.
J. Org. Chem. 1995, 60, 1391e1407; (e) Rulev, A. Y.; Yenil, N.; Pesquet, A.; Oulyadi,
H.; Maddaluno, J. Tetrahedron 2006, 62, 5411e5416; (f) Mather, B. D.; Viswa-
nathan, K.; Miller, K. M.; Long, T. E. Prog. Polym. Sci. 2006, 31, 487e531; (g)
Krishna, P. R.; Sreeshailam, A.; Srinivas, R. Tetrahedron 2009, 65, 9657e9672; (h)
Pletsas, D.; Garelnabi, E. A. E.; Li, L.; Phillips, R. M.; Wheelhouse, R. T. J. Med.
Chem. 2013, 56, 7120e7132; (i) Georgiev, N. I.; Bojinov, V. B. Dyes Pigm. 2010, 89,
249e256.
5. For recent reviews see: (a) Amara, Z.; Caron, J.; Joseph, D. Nat. Prod. Rep. 2013,
30, 1211e1225; (b) Reyes, E.; Fernandez, M.; Uria, U.; Vicario, J. L.; Badia, D.;
Carillo, L. Curr. Org. Chem. 2012, 16, 521e546; (c) Moyano, A.; Rios, R. Chem. Rev.
2011, 111, 4703e4832; (d) Enders, D.; Wang, C.; Liebich, J. X. Chem.dEur. J. 2009,
15, 11058e11076; (e) Hamashima, Y. Chem. Pharm. Bull. 2006, 54, 1351e1364; (f)
Xu, L.-W.; Xia, C.-G. Eur. J. Org. Chem. 2005, 4, 633e639; (g) Sibi, M. P.; Manyem,
S. Tetrahedron 2000, 56, 8033e8061.
4.5.13. Dimethyl 2-(benzylamino)succinate (3m).27 Clear, colourless
oil. IR (neat, cmꢁ1):
NMR (250 MHz, CDCl3):
n
¼3337, 3028, 3001, 2953, 2845, 1728, 1494. 1H
d 7.30e7.25 (5H, m), 3.92e3.81 (2H, m),
3.75 (3H, s), 3.70e3.64 (1H, m), 3.68 (3H, s), 2.70 (2H, m), 2.0 (1H, s).
13C NMR (62.9 MHz, CDCl3):
57.0, 52.1, 52.0, 51.8, 38.0.
d 174.1, 171.3, 139.6, 128.4, 128.3, 127.2,
4.5.14. Methyl 3-(hexylamino)propanoate (5a).28,24 Clear, yellow
oil. IR (neat, cmꢁ1):
¼3320, 2957, 2937, 2857, 1746, 1663, 1558,
1437, 1364. 1H NMR (250 MHz, CDCl3):
3.70 (3H, s), 2.90 (2H, t,
n
d
J¼6.7 Hz), 2.60 (2H, t, J¼7.3 Hz), 2.50 (2H, t, J¼6.30 Hz), 1.70 (1H, s),
1.55e1.40 (2H, m),1.35e1.20 (6H, m), 0.90 (3H, t, J¼6.7 Hz). 13C NMR
(62.9 MHz, CDCl3):
22.6, 14.1.
d 173.3, 51.6, 49.8, 45.1, 34.5, 31.8, 30.0, 27.0,
6. (a) Azizi, N.; Saidi, M. R. Tetrahedron 2004, 60, 383e387; (b) Chan, P. W. H.;
Cottrel, I. F.; Moloney, M. G. Tetrahedron Lett. 1997, 38, 5891e5894; (c) Shaikh,
N. S.; Deshpande, V. H.; Bedekar, A. V. Tetrahedron 2001, 57, 9045e9048; (d)
Jenner, G. Tetrahedron Lett. 1995, 36, 233e236; (e) Kobayashi, S.; Karumoto, K.;
Sugiura, M. Org. Lett. 2002, 4, 1319e1322; (f) Reboule, I.; Gil, R.; Collin, J. Tet-
rahedron Lett. 2005, 46, 7761e7764.
7. (a) Hou, X.; Hemit, H.; Yong, J.; Nie, L.; Aisa, H. Synth. Commun. 2010, 40,
973e979; (b) Wei, T.; Hua, M.; Shi, H.; Liu, Y.; Zhang, Y. J. Chem. Res. 2010,
452e454; (c) Yadav, J. S.; Reddy, A. R.; Rao, Y. G.; Narsaiah, A. V.; Reddy, B. V. S.
Synthesis 2007, 3447e3450; (d) Khan, A. T.; Parvin, T.; Gazi, S.; Choudhury, L.
Tetrahedron Lett. 2007, 48, 3805e3808.
4.5.15. 3-(Hexylamino)propanenitrile (5b).29 Clear, yellow oil. IR
(neat):
¼3313, 2953, 2940, 2913, 2855, 2247, 1468, 1422, 1377,
1341, 1128 cmꢁ1. 1H NMR (250 MHz, CDCl3):
n
d
2.93 (2H, t, J¼6.7 Hz),
2.62 (2H, t, J¼7.3 Hz), 2.52 (2H, t, J¼6.1 Hz), 1.55e1.40 (3H, m),
1.40e1.22 (6H, m), 0.87 (3H, t, J¼6.7 Hz). 13C NMR (62.9 MHz,
CDCl3):
d 118.8, 49.3, 45.1, 31.7, 29.9, 26.9, 22.6, 18.7, 14.0.
4.5.16. Methyl 3-(hexylamino)butanoate (5c). Brown solid: IR
(Nujol mull, cmꢁ1):
¼2963, 2944, 2893, 2862, 2847, 1717, 1456,
1377. 1H NMR (250 MHz, CDCl3):
3.70 (3H, s, OMe), 3.40e3.20 (1H,
m, CHN), 3.10e2.95 (2H, m, CH2N), 2.85e2.60 (2H, m, CH2CO),
8. (a) Duan, Z.; Xuan, X.; Li, T.; Yang, C.; Wu, Y. Tetrahedron Lett. 2006, 47,
5433e5436; (b) Varala, R.; Sreelatha, N.; Adapa, S. R. Synlett 2006, 1549e1553;
(c) Bartoli, G.; Bartolacci, M.; Giuliani, A.; Marcantoni, E.; Massacesi, M.; Tor-
regiani, E. J. Org. Chem. 2005, 70, 169e174.
n
d

6612
G. Bosica, A.J. Debono / Tetrahedron 70 (2014) 6607e6612
9. (a) Mukherjee, C.; Misra, A. Lett. Org. Chem. 2007, 4, 54e59; (b) Wang, Y.; Yuan,
Y.-Q.; Guo, S.-R. Molecules 2009, 14, 4779e4789; (c) Saidi, M. R.; Pourshojaei, Y.;
Aryanasab, F. Synth. Commun. 2009, 39, 1109e1119.
10. (a) Pal, R.; Sarkar, T.; Khasnobis, S. ARKIVOC 2012, i, 570e609; (b) Das, B.;
Chowdhury, N. J. Mol. Catal. A Chem. 2007, 263, 212e215.
17. See, for example: (a) Ballini, R.; Bosica, G. Liebigs Ann. Chem. 1996, 2087e2089;
(b) Ballini, R.; Bosica, G.; Fiorini, D.; Righi, P. Synthesis 2002, 681e685; (c)
Ballini, R.; Bosica, G.; Palmieri, A.; Petrini, M.; Pierantozzi, C. Tetrahedron 2003,
ꢁ
59, 7283e7289; (d) Ballini, R.; Bosica, G.; Mase, A.; Petrini, M. Eur. J. Org. Chem.
2000, 2927e2931.
11. (a) Choudhary, V. R.; Dumbre, D. K.; Patil, S. K. RSC Adv. 2012, 2, 7061e7065; (b)
Mao, X.-X.; Shen, Y.-M.; Wang, J.; Xia, Q.-H. Kinet. Catal. 2011, 52, 525e528; (c)
Vijender, M.; Kishore, P.; Satyanarayana, B. Synth. Commun. 2007, 37, 589e592.
12. (a) Beletskaya, I. P.; Tarasenko, E. A.; Khokhlov, A. R.; Tyurin, V. S. Russ. J. Org.
Chem. 2010, 46, 461e467; (b) Polshettiwar, V.; Varma, R. S. Tetrahedron Lett.
2007, 48, 8735e8738; (c) Kumar, D.; Patel, G.; Mishra, B. G.; Varma, R. S. Tet-
rahedron Lett. 2008, 49, 6974e6976.
18. (a) Ballini, R.; Bosica, G. Tetrahedron 1995, 51, 4213e4222; (b) Ballini, R.; Bosica,
G.; Damiani, M.; Righi, P. Tetrahedron 1999, 55, 13451e13456; (c) Ballini, R.;
Barboni, L.; Bosica, G.; Fiorini, D.; Palmieri, A. Pure Appl. Chem. 2006, 78,
1857e1866; (d) Ballini, R.; Palmieri, A. Adv. Synth. Catal. 2006, 348, 1154e1156.
19. Liang, X.; Wang, Y.; Gong, G.; Yang, J. Catal. Commun. 2008, 10, 281e284.
€
€
ꢀ
€
ꢀ
20. Boros, M.; Kokosi, J.; Vamos, J.; Kovesdi, I.; Noszal, B. Amino Acids 2007, 33,
709e717.
13. (a) Xu, J.-M.; Wu, Q.; Zhang, Q.-Y.; Zhang, F.; Lin, X.-F. Eur. J. Org. Chem. 2007,
1798e1802; (b) Ying, A.; Zheng, M.; Xu, H.; Qiu, F.; Ge, C. Res. Chem. Intermed.
2011, 37, 883e890; (c) Ying, A.-G.; Wang, L.-M.; Deng, H.-X.; Chen, J.-H.; Chen,
X.-Z.; Ye, W.-D. ARKIVOC 2009, xi, 288e298; (d) Chen, X.; Li, X.; Song, H.; Qian,
Y.; Wang, F. Tetrahedron Lett. 2011, 52, 3588e3591.
14. (a) Ranu, B. C.; Banerjee, S. Tetrahedron Lett. 2007, 48, 141e143; (b) Labade, V. B.;
Pawar, S. S.; Shingare, M. S. Monatsh. Chem. 2011, 142, 1055e1059; (c) Matveeva,
E. V.; Petrovskii, P. V.; Klemenkova, Z. S.; Bondarenko, N. A.; Odinets, I. L. C. R.
Chim. 2010, 13, 964e970.
15. (a) Saikia, M.; Kakati, D.; Joseph, M. S.; Sarma, J. C. Lett. Org. Chem. 2009, 6,
654e658; (b) Ai, X.; Wang, X.; Liu, J.-M.; Ge, Z.-M.; Cheng, T.-M.; Li, R.-T. Tet-
rahedron 2010, 66, 5373e5377; (c) Nath, J.; Chaudhuri, M. K. Catal. Lett. 2009,
133, 388e393.
21. Pfau, M. Bull. Soc. Chim. Fr. 1967, 1117e1125.
22. Zaderenko, P.; Lopez, M. C.; Ballesteros, P. J. Org. Chem. 1996, 61, 6825e6828.
ꢀ
23. (a) Okada, Y.; Banno, T.; Toshima, K.; Matsumura, S. J. Oleo Sci. 2009, 58,
519e528; (b) Straub, T.; Koskinen, A. M. P. Polym. Prepr. 2005, 46, 687.
24. Bosica, G.; Spiteri, J.; Borg, C. Tetrahedron 2014, 70, 2449e2454.
25. Davis, J. W.; Furst, A. Anal. Chem. 1968, 40, 1910e1912.
26. Faderl, C.; Kachkovskyi, G.; Reiser, O.; Kachkovskyi, G. Adv. Synth. Catal. 2013,
355, 2240e2248.
27. Nakajima, Y.; Oda, J.; Inouye, Y. Agric. Biol. Chem. 1975, 39, 2065e2068.
28. (a) Coutts, R. T.; Hubbard, J. W.; Midha, K. K.; Prasad, K. J. Pharm. Sci. 1971, 60,
28e33; (b) Yadav, J. S.; Reddy, B. V. S.; Basak, A. K.; Narsaiah, A. V. Chem. Lett.
2003, 32, 988e989.
29. Gay, M. L.; Molton, P.; Ponnamperuma, C. Org. Mass Spectrom. 1974, 9,
16. (a) Medina, F.; Michon, C.; Agbossou-Niedercorn, F. C. R. Chim. 2013, 16,
311e317; (b) Ballini, R.; Gabrielli, S.; Palmieri, A. Curr. Org. Chem. 2010, 14,
1124e1126.
30. Denton, T. T.; Joyce, A. S.; Kiely, D. E. J. Org. Chem. 2007, 72, 4997e5000.
ꢀ
65e83; (c) Ballini, R.; Bazan, N. A.; Bosica, G.; Plamieri, A. Tetrahedron Lett.
2008, 49, 3865e3867.