Direct synthesis of imides from dicarboxylic acids using microwaves

Article abstract of DOI:10.1039/a901520e

1,4- and 1,5-dicarboxylic acids, when treated with amines in a domestic microwave oven, afford good yields of the corresponding imides.

Full text of DOI:10.1039/a901520e

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420 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
1999, 420^421y
Direct Synthesis of Imides from Dicarboxylic
Acids using Microwavesy
Julio A. Seijas,* M. Pilar Vazquez-Tato,*
M. Montserrat Mart|nez and Gonzalo Nunez-Corredoira
Departamento de Qu|mica Organica, Facultad de Ciencias, Universidad de Santiago de
Compostela, Aptdo, 280, 27080-Lugo, Spain
1,4- and 1,5-dicarboxylic acids, when treated with amines in a domestic microwave oven, afford good yields of
the corresponding imides.
Imide derivatives are associated with a variety of uses due
to their biological properties,1;2 synthetic applications3;4
and industrial uses.5;6 Thus, N-arylsuccinimides have been
examined as potential fungicides,7 especially N-(3,5-
dichlorophenyl)succinimide.8 The 3-hydroxy derivatives
are involved in their metabolic pathways,9;10 2-aryl-
1,3(2H,4H)-dioxoisoquinolines are known as herbicides
and plant growth regulators11 and some show activities
hydroxy compound. Our question was how to overcome
its formation. First we tried to reduce the reaction time;
however the NMR of the crude mixture showed a singlet
at d 6.89 corresponding to the vinyl proton in the pyrroline
ring. As a second idea, we tried to lead the reaction to
a complete dehydration; however longer heating times
(45 min) did not change the ratio malimide:maleimide.
We think the dehydration occurs in the ¢rst stages of
the synthesis, prior to the cyclization, and may be helped
by the presence of a free carboxylic acid function.
as aminopeptidase
N
inhibitors.12 Despite their wide
applicability, routes available for the synthesis of imide
derivatives are limited. These syntheses usually start from
the anhydride and give the corresponding amic acid,
O
R1
R2
NH2
n
16
followed by cyclization under acidic conditions.13
OH
+
HO
In recent years the use of microwaves to `emulate' classic
R
O
R3
3a–d
1 R = H
2 R = OH
organic reactions has become very popular amongst
23
synthetic organic chemists17
because microwave heating
n
R1
R2
R3
3, 4, 5, 6, 8
a
b
c
d
0
H
Cl
H
H
H
H
H
Cl
H
H
often leads to higher yields, cleaner reactions and shorter
reaction times. These procedures are seriously limited
because of the use of solvents in microwave ovens which
gives rise to elevated temperatures and consequently high
pressures, and in some cases may lead to dangerous
explosions. Here we describe a microwave-induced synthesis
of imides from dicarboxylic acids and amines in a one-pot
reaction in the absence of solvents. One of us24 already
had used microwaves to prepare amides by pyrolysis of
carboxylic acid salts of amines and we thought that this
could be extended to the synthesis of imides. Recently a
paper was published25 where microwave irradiation is used
to prepare cyclic imides from anhydrides in the presence
of TaCl5^SiO2. Our method consists of heating the acid
and amine mixture (molar ratio 1 : 1) until the starting
material disappears in a domestic microwave oven. Thus,
succinic acid 1 was heated with aniline for 20 min yielding
N-phenylsuccinimide 4a in 76% yield. When the amine
employed was 3,5-dichloroaniline 3b the required reaction
time was 15 min to a¡ord fungicide 4b in 78% yield; with
benzylamine a similar yield (78%) of compound 4c was
obtained after 15 min. To check the behaviour of a typical
aliphatic amine the succinimide of homoveratryl amine
3d was also prepared; after 15 min irradiation we obtained
an 84% yield of the desired imide 4d, showing the viability
of our synthesis for the derivatization of b-phenethylamines
as imides.
µw
0
1
2
OMe OMe
R
O
O
O
O
N
N
R1
R2
R1
+
n
n
R2
R3
R3
4a–d R = H
5a–d R = OH
6a–d
R2
R1
R3
CO2H
CO2H
R1
NH2
µw
n
+
O
R2
R3
3a–d
n
N
7
O
8a–d
Scheme 1
Finally, we studied the extension of our procedure to the
formation of six-membered imide rings by using
homophthalic acid 7 with amines 3a^d and obtaining imides
8a^d 73^84% (Table 1) in 15 min. 8d has been used as a
precursor for protoberberine type alkaloids.28
Typical Procedure.öA mixture of succinic acid 1 (400 mg,
3.39 mmol) and aniline (315 mg, 3.39 mmol) in a test tube
was heated in a domestic microwave oven (1000 W, 70%
of total power) until no starting materials were observed
by TLC (20 min). The crude reaction was puri¢ed by £ash
chromatography (ethyl acetate:hexane, 1 : 1) to a¡ord
N-phenylsuccinimide 4a (448 mg, 76%) as a white solid.
In conclusion, we have demonstrated the validity of this
procedure for the synthesis of imides from 1,4- and
1,5-dicarboxylic acids. Our method can be considered as
an improvement over those previously described25 since it
does not use anhydrides, which are always more expensive
than acids and sometimes not easily synthesized. The use
of heavy metals was also avoided, which is really a matter
of environmental concern when trying to extend a method
to a multigram scale synthesis. Our work constitutes a good
example of the better performance of microwaves versus
The synthesis of 3-hydroxy-2,5-pyrrolidinediones was also
attempted. There has been several reports on their synthesis,
all with several steps.26;27 We started with malic acid 2 and
the amines 3a^d. In all four cases, together with the
expected products 5a^d in 59^72% yield, we found 14^19%
of the corresponding maleimides 6a^d (Scheme 1); this
product obviously comes from the dehydration of the
* To receive any correspondence (e-mail: qoseijas@lugo.usc.es;
pilarvt@lugo.usc.es).
y This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).

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J. CHEM. RESEARCH (S), 1999 421
Table 1 Synthesis of imides from dicarboxylic acids and amines by microwave heating
Yield
nmax
cm
/
m/z
M
1
‡
Acid Amine Prod. t/min (%)
du(300 MHz)
dc(CˆO)
176.3
(%)
Mp (lit.)/8C
1
1
3a
3b
4a
4b
20
15
76
78
2.88 (s, 4H)
1705
175(100)
153^155
(153^15429
135^136
)
2.92 (s, 4H), 7.29 (s, 2H),
7.41 (s, 1H)
175.3
1700^
1720
247(11)
245(65)
243(100)
189(100)
(136.5^137.58)
1
1
2
3c
3d
3a
4c
15
15
15
78
84
62
2.72 (s, 4H), 4.67 (s, 2H),
176.9
1695
1705
98^99/
(98-9930
125^127
)
4d
2.72 (s, 4H), 2.84 (t, 2H),
3.73 (t, 2H)
2.90 (dd 1H), 3.26 (dd,
177.1
263(20)
191(50)
173(100)
(126.5^127.531
178^180
)
5a
179.2, 176.0
169.6
3430,
1700
1710
1H), 4.83 (m, 1H)
(179^18032
88^89
)
(+6a)
5b
(‡19) 6.88 (s, 2H)
60 2.88 (dd 1H), 3.26 (dd,
(89ö9033
131^132
)
2
3b
10
176.6, 172.2,
3530
1695^
1730
1720
263(6)
1H), 4.82 (dd, 1H)
261(37)
259(55)
245(11)
243(67)
241(100)
205(71)
(144^14527
)
(+6b)
(‡19) 6.89 (s, 2H), 7.36 (s, 3H)
168.5
132^133
(141^1428)
105^106
2
2
3c
3d
5c
10
15
72
2.69 (dd, 1H), 3.07 (dd,
1H), 4.58^4.66 (m, 3H)
178.2, 173.8
170.5
3360,
1700
1700
(101^10326
69^70
)
(‡6c)
5d
(‡14) 4.67 (s, 2H), 6.69 (s, 2H)
187(100)
279(16)
(68.5^7034
)
59
2.64 (dd, 1H), 2.85 (t, 2H),
3.03 (dd, 1H), 3.75 (t, 2H),
4.58 (dd, 1H)
178.4, 174.1,
3365,
1690^
1715
1705
131.3^133.2a
(+6d)
8a
(‡16) 2.86 (t, 2H), 3.76 (t, 2H),
170.6
261(24)
237(61)
139.4^140.6b
186.5^188.2
6.68 (s, 2H)
4.23 (s, 2H)
7
7
3a
3b
15
15
74
170.0, 163.9
169.5, 164.6
1715,
1670
1720,
1675
(188^18935
)
8b
75
4.24 (s, 2H)
309(3),
307(16)
305(25)
251(79)
228.0^228.7
(230.5^232.535
)
7
7
3c
3d
8c
8d
15
15
84
73
4.04 (s, 2H), 5.18 (s, 2H)
169.9, 164.9
169.8, 164.8
1705,
1665
1710,
1665
126.9^128.4
(12736
)
2.88 (t, 2H), 4.04 (s, 2H),
4.21 (t, 2H)
325(5)
143.3^144.6c
aFound: C, 59.98; H, 6.64; N, 4.96. C14H17NO5 requires C, 60.21; H, 6.14; N 5.01%. bFound: C, 64.22; H, 6.14; N, 5.48. C14H15NO4 requires C,
64.36; H, 5.79; N, 5.36%. cFound: C, 70.46; H, 5.74; N, 3.94. C19H19NO4 requires C, 70.14; H, 5.89; N, 4.30%.
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