New approach to the synthesis of trans-aconitic acid imides

Article abstract of DOI:10.1007/s11178-005-0232-9

N-arylimides of trans-aconitic acid were prepared by boiling the acid in a glacial acetic acid with N-arylamines. N-Arylamides of the trans-aconitic acid were obtained as intermediates in the course of the synthesis of the corresponding imides. The condensation of the trans-aconitic acid amides with hydrazine afforded arylamides of 1-amino-2,6-dioxo-1,2,3,6-tetrahydropyridine-4- carboxylic acid and proved the cis configuration of the initial amides. 2005 Pleiades Publishing, Inc.

Full text of DOI:10.1007/s11178-005-0232-9

Russian Journal of Organic Chemistry, Vol. 41, No. 5, 2005, pp. 723-726. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 5, 2005,
pp. 730-737.
Original Russian Text Copyright Ó 2005 by Martynov.
New Approach to the Synthesis of trans-Aconitic Acid Imides
A.V. Martynov
Mechnikov Institute of Microbiology and Immunology, Academy of Medical Sciences of the Ukraine,
Kharkov, 61057 Ukraine
Received July 8, 2004
Abstract—N-arylimides of trans-aconitic acid were prepared by boiling the acid in a glacial acetic acid with
N-arylamines. N-Arylamides of the trans-aconitic acid were obtained as intermediates in the course of the synthesis
of the corresponding imides. The condensation of the trans-aconitic acid amides with hydrazine afforded arylamides
of 1-amino-2,6-dioxo-1,2,3,6-tetrahydropyridine-4-carboxylic acid and proved the cis configuration of the initial
amides.
To this end we synthesized a number of the trans-
aconitic acid derivatives by different methods ( also through
anhydride II for comparison of reaction products) and
under versatile conditions (see scheme).
Imides of maleic acid are widely used to prepare poly-
mers in engineering, medicine, and pharmacology [1].
However the characteristics of derivatives obtained de-
pend primarily on the copolymer structure than on the
maleic anhydride proper. This circumstance is due to the
presence of only two reactive groups: the anhydride struc-
ture and the double bond. Unlike the maleic acid the aco-
nitic acid (I) contains in its molecule additionally a free
carboxy group capable to be involved into versatile reac-
tions. The corresponding polymers, aconitic acid deriva-
tives, may have more branched and complex structure
and wider application opportunities.
We failed to obtain imides V in the presence of acetic
anhydride in the reaction medium. The products prepared
did not contain double bonds (did not cause bromine de-
coloration) and could not be isolated in a crystalline state.
Presumably a reaction occurred between the acetic an-
hydride and the double bond of the aconitic acid. The use
of acetic acid instead of sodium acetate also does not
afford imides although both schemes mentioned are
applied to the preparation of maleimides [3, 4].
We formerly reported on preparation of trans-aco-
nitic acid imides [2]. The urgent problem is the develop-
ment of a cheap prepartion procedure for the derivatives
of trans-aconitic acid (I) avoiding the intermediate stage
of the synthesis of unstable anhydride II.
The best results were obtained by boiling the trans-
aconitic acid with arylamines in a glacial acetic acid.
Obviously here forms an anhydride that immediately en-
ters into the reaction with amine. Similar compounds with
Scheme 1.
+22&
&22+
&22+
2
&22+
2
1+
+22&
5
,
+22&
5
2
&+ &22+ꢂ
+1
1
B
ꢀ&+ &2ꢁ 2ꢂꢃꢄꢅꢅ &
B
,,, ꢀꢀꢀ,,,J
ꢄꢆꢅꢃꢃꢃꢄꢇꢅ &
&22+
5
B
B
,9 ꢀꢀꢀ,9J
9 ꢀꢀꢀ9J
2
2
2
,,
R = H (a), p-COOH (b), m-COOH (c), p-COOEt (d), p-SO2NH2 (e), p-Br (f), p-Me (g).
1070-4280/05/4105-0723Ó2005 Pleiades Publishing, Inc.

MARTYNOV et al.
724
Scheme 2.
acid with water, 1:1. Imides precipitated as round crystals
of various color after the solvent crystals melted.
2
The typical analytical feature of imides in the IR
spectra is a bifurcated unsymmetrical absorption band at
+2
–1
2
1700–1720 cm , characteristic of the C=O bond in the
structure of the imide ring, whereas the carbonyl groups
of amides appear as a single absorption band in the region
1700–1710 cm . An analogous bifurcated band is also
observed in the spectra of maleimides. But here both
bands are symmetrical.
+2
2
2
2+
1+
–1
2
2
2
2
5
ꢁ
2+
1+
2+
+1
2
Amides IV were isolated in pure crystalline state only
in reaction of compounds II and III occurring in the cold,
whereas in reaction carried out in the cold between acid
I and amine III amides did not form. This fact evidences
that the aconitic anhydride formed however in the glacial
acetic acid but only at heating.
5
5
FLVꢈ,9
Scheme 3.
WUDQVꢈ,9
1
1
trans-Aconitic acid amides may exist as two isomers
(Scheme 2).
2
2
+2
2
As seen from the structural formula , the trans-isomer
of amide IV cannot build up a pyridine heterocycle in
reaction with hydrazine; this reaction is characteristic of
cis-aconitic acid [the reaction between the cis-aconitic
anhydride and hydrazine gives rise to 4-(3,6-dioxypyrid-
azyl)acetic acid] [5]. In reaction between the trans-
aconitic acid amides and hydrazine formed arylamides
of 1-amino-2,6-dioxo-1,2,3,6-tetrahydropyridine-4-carb-
oxylic acid VIa–g. These bright yellow compounds are
well soluble in water (in contrast to hydrazides, amides,
and imides of the aconitic acid). Inasmuch as the reaction
furnished the products in high yields (60–85%) we
concluded that from anhydride II formed predominantly
the cis-isomer IV of the aconitic acid arylamide
(Scheme 3).
2
+ 1 1+
+2
+1
2
1+
2
&+ &22+ꢀ
KHDWLQJ
5
5
B
B
9, ꢀꢀꢀ9,J
FLVꢁ,9 ꢀꢀꢀ,9J
the same characteristics were obtained by reaction of
aconitic anhydride with amines, but the reaction ended
faster (within 20 min). The attempts to obtain aconitic
acid imides without heating from compounds II and III
both in the glacial acetic acid and in acetic anhydride
were unsuccessful.
For maleimides and aconitic acid imides a reaction
with a sodium hydroxide solution is a characteristic test:
A substance forms of bright red (orange) color that
decolorized in time. This reaction is used for imides
identification on chromatograms and in reaction mixtures
[4]. Amides IV failed to pass this test.
EXPERIMENTAL
IR spectra of imides and amides synthesized were
recorded on a spectrophotometer Specord M-80 from
KBr pellets. H NMR spectra were registered on
spectrometer Bruker WP-200SY at operating frequency
200 MHz b CDCl3.
1
The attempts at recrystallization of imides V from
ethanol and 2-propanol resulted in destruction of imides
and in formation of esters. The attempt at recrystallization
in a mixed solvent (ethanol–water, 2-propanol–water) led
to imides polymerization. In solvents immiscible with water
imides V are well soluble at any temperature.
trans-Aconitic anhydride. To 1.7 g (0.01 mol) of
trans-aconitic acid was added 1.9 ml (0.02 mol) of acetic
anhydride. The reaction mixture was kept at the room
temperature for 15 min. The acetic acid formed and
unreacted acetic anhydride were distilled off in a vacuum
in the cold. The aconitic anhydride precipitated. Yield
0.69 g (44%). The anhydride was recrystallized from the
glacial acetic acid and was stored in a desiccator over
The optimum procedure for imides V purification
proved to be their freezing off from a mixture of acetic
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

NEW APPROACH TO THE SYNTHESIS OF trans-ACONITICACID IMIDES
725
H2SO4 due to its high hydophilism and low stability. mp
46–47°C.
(II) in 10 ml of glacial acetic acid was added at stirring
0.02 mol of N-arylamine IIIa–g, and the mixture was
heated for 20 min. Then the hot mixture was poured into
a porcelain dish that was placed into an ice bath. In the
course of freezing the reaction mixture was carefully
stirred by a glass rod in order to obtain finely crystalline
dispersion (frozen acetic acid and imide).An equal volume
of water was added to the mixture, and the content of
the dish was stirred till the acetic acid melted. The round
crystals of imide remaining in the precipitate were filtered
off. The recrystallization was performed in the same
fashion by freezing imides out of the glacial acetic acid.
Arylamides IVa–IVg of trans-aconitric acid.
To a solution of 3.12 g (0.02 mol) of trans-aconitic
anhydride (II) in 10 ml of glacial acetic acid was added
at stirring 0.02 mol of N-arylamine IIIa–IIIg, and the
mixture was stirred at room temperature till the amine
completely dissolved. Then the reaction mixture was left
standing for 2 h. The separated precipitate was filtered
off and recrystallized from the glacial acetic acid.
Compound IVa, mp 186–187°C, yield 79%. 1H NMR
spectrum, d, ppm: 2.90 s (2H, CH2), 6.91 s (1H, CH),
7.0–7.77 m (Harom), 8.0 s (1H, NH), 12.0 d (2H, COOH).
Found, %: C 58.1; H 4.6; N 5.5. C17H11NO5. Calculated,
%: C 57.8; H 4.4; N 5.6.
Compound IVb, mp 292–293°C, yield 79%. 1H NMR
spectrum, d, ppm: 2.90 s (2H, CH2), 6.91 s (1H, CH),
7.85–8.1 m (Harom), 8.0 s (1H, NH), 12.0 d (2H, COOH).
Found, %: C 53.0; H 3.9; N 4.8. C13H11NO7. Calculated,
%: C 53.2; H 3.8; N 4.8.
Compound IVc, mp 301–302°C, yield 86%. 1H NMR
spectrum, d, ppm: 2.91 s (2H, CH2), 6.91 s (1H, CH),
7.45–8.5 m (Harom), 8.0 s (1H, NH), 12.0 d (2H, COOH).
Found, %: C 53.3; H 3.6; N 4.9. C13H11NO7. Calculated,
%: C 53.2; H 3.8; N 4.8.
b. To a solution of 1.7 g (0.01 mol) of To a solution of
trans-aconitic acid (I) in 10 ml of glacial acetic acid
was added 0.01 mol of N-arylamine III, and the mixture
was heated for 60 min. Then the hot mixture was poured
into a porcelain dish, and the freezing out of the product
was carried out as described in the procedure a. The
recrystallization was performed in the same fashion by
freezing imides out of the glacial acetic acid. IR and
1H NMR spectra of imide prepared by methods a and b
showed the identity of the samples.
1
Compound Va, mp 152–153°C, yield 48%. H NMR
spectrum, d, ppm: 2.95 s (2H, CH2), 6.9 s (1H, CH),
7.0–7.77 m (Harom), 12.0 s (1H, COOH). Found, %:
C 63.2; H 3.6; N 6.0. C12H9NO4. Calculated, %: C 62.3;
H 3.9; N 6.1.
Compound Vb, mp 264–265°C, yield 70%. 1H NMR
spectrum, d, ppm: 2.9 s (2H, CH2), 6.9 s (1H, CH), 7.85–
8.0 m (Harom),12.0 s (1H, COOH). Found, %: C 56.2;
H 3.2; N 5.3. C13H9NO6. Calculated, %: C 56.7; H 3.3;
N 5.1.
Compound IVd, mp 170–171°C, yield 82%. 1H NMR
spectrum, d, ppm: 1.3 t (3H, CH3), 2.9 s (2H, CH2),
4.29 s (2H, CH2), 6.1 s (1H, CH), 7.5–7.95 m (Harom),
8.0 s (1H, NH), 11.0 d (2H, COOH). Found, %: C 56.1;
H 4.9; N 4.3. C15H15NO7. Calculated, %: C 56.1; H 4.7;
N 4.4.
Compound IVe, mp 182–183°C, yield 85%. 1H NMR
spectrum, d, ppm: 2.0 d (2H, NH2), 2.90 s (2H, CH2),
6.90 s (1H, CH), 7.90–7.95 m (Harom), 8.0 s (1H, NH),
11.0 d (2H, COOH). Found, %: C 43.7; H 3.6; N 8.5.
C12H12N2O7S. Calculated, %: C 43.9; H 3.7; N 8.5.
1
Compound Vc, mp 260–262°C, yield 62%. H NMR
spectrum, d, ppm: 2.9 s (2H, CH2), 6.9 s (1H, CH), 7.45–
8.51 m (Harom),12.0 s (1H, COOH). Found, %: C 57.1;
H 3.6; N 5.4. C13H9NO6. Calculated, %: C 56.7; H 3.3;
N 5.1.
1
1
Compound IVf, mp 252–253°C, yield 75%. H NMR
Compound Vd mp 149–150°C, yield 70%. H NMR
spectrum, d, ppm: 2.90 s (2H, CH2), 6.91 s (1H, CH),
7.40–7.53 m (Harom), 8.0 s (1H, NH), 12.0 d (2H, COOH).
Found, %: C 44.1; H 3.0; N 4.2. C12H10BrNO5.
Calculated, %: C 43.9; H 3.1; N 4.3.
spectrum, d, ppm: 1.3 t (3H, CH3), 2.9 s (2H, CH2), 6.85
s (1H, CH), 7.75–7.95 m (Harom), 11.0 s (1H, COOH).
Found, %: C 58.1; H 4.4; N 4.8. C15H13NO6. Calculated,
%: C 59.4; H 4.3; N 4.6.
Compound IVg, mp 210–212°C, yield 92%. 1H NMR
spectrum, d, ppm: 2.30 t (3H, CH3), 6.91 s (1H, CH),
7.0–7.5 m (Harom), 8.0 s (1H, NH), 12.0 d (2H, COOH).
Found, %: C 59.1; H 4.8; N 5.4. C13H13NO5. Calculated,
%: C 59.3; H 5.0; N 5.3.
1
Compound Ve, mp 146–147°C, yield 75%. H NMR
spectrum, d, ppm: 2.90 s (2H, CH2), 6.90 s (1H, CH),
7.75–7.95 m (Harom), 11.0 s (1H, COOH). Found, %:
C 46.0; H 3.2; N 8.8. C12H10N2O6S. Calculated, %:
C 46.4; H 3.2; N 9.0.
1
trans-Aconitic acid arylimides Va–g. a. To a
solution of 3.12 g (0.02 mol) of trans-aconitic anhydride
Compound Vf, mp 211–212°C, yield 70%. H NMR
spectrum, d, ppm: 2.90 s (2H, CH2), 6.85 s (1H, CH),
RUSSIAN JOURNALOF ORGANIC CHEMISTRY Vol. 41 No. 5 2005

MARTYNOV et al.
726
7.85–8.00 m (Harom), 12.0 s (1H, COOH). Found, %:
C 46.6; H 2.2; N 4.2. C12H8BrNO4. Calculated, %:
C 46.5; H 2.6; N 4.5.
Compound Vg, mp 195–196°C, yield 60%. 1H NMR
spectrum, d, ppm: 2.35 t (3H, CH3), 2.85 s (2H, CH2),
6.90 s (1H, CH), 7.0–7.52 m (Harom), 12.0 s(1H, COOH).
Found, %: C 63.5; H 4.0; N 5.7. C13H11NO4. Calculated,
%: C 63.7; H 4.5; N 5.7.
COOH). Found, %: C 54.2; H 3.9; N 14.7. C13H11N3O5.
Calculated, %: C 54.0; H 3.8; N 14.5.
Compound VId, mp 122–123°C, yield 48%. 1H NMR
spectrum, d, ppm: 1.3 t (3H, CH3), 2.0 s (2H, NH2),
2.85 s (2H,CH2), 4.3 (2H, CH2), 7.3 s (1H, CH), 7.8–
8.1 m (Harom), 8.2 s (1H, NH). Found, %: C 56.6; H 4.7;
N 13.4. C15H15N3O5. Calculated, %: C 56.8; H 4.8;
N 13.2.
c. In 10 ml of glacial acetic acid was dissolved
0.01 mol of trans-aconitic acid N-arylamide IVa–IVg,
and the solution was heated for 30 min. Then the hot
mixture was poured into a porcelain dish, and the freezing
out of the product and subsequent recrystallization was
carried out as described in the procedure a. According
to IR and 1H NMR spectra the imides thus obtained were
identical to compounds prepared by procedures a and b.
Compound VIe, mp 105–106° C, yield 70%.
1H NMR spectrum, d, ppm: 2.0 s (4H, NH2), 2.85 s
(2H,CH2), 7.3 s (1H, CH), 7.7–8.0 m (Harom), 8,2 s (1H,
NH), 12.0 s (1H, COOH). Found, %: C 44.2; H 3.9;
N 17.5. C12H12N4O5 S. Calculated, %: C 44.4; H 3.7;
N 17.3.
1
Compound VIf, mp 196–198°C, yield 64%. H NMR
spectrum, d, ppm: 2.0 s (2H, NH2), 2.85 s (2H, CH2),
7.3 s (1H, CH), 7.4–7.6 m (Harom), 8.2 s (1H, NH). Found,
%: C 44.6; H 3.2; N 12.9. C12H10BrN3O3. Calculated,
%: C 44.5; H 3.1; N 13.0.
Compound VIg, mp 154–155°C, yield 55%. 1H NMR
spectrum, d, ppm: 2.0 s (2H, NH2), 2.35 s (3H, Met),
2.8 s (2H, CH2), 7.3 s (1H, CH), 7.0–7.52 m (Harom),
8.2 s (1H, NH). Found, %: C 60.5; H 5.2; N 16.4.
C13H13N3O3. Calculated, %: C 60.2; H 5.0; N 16.2.
1-Amino-2,6-dioxo-1,2,3,6-tetrahydropyridine-4-
carboxylic acid arylamides VIa–VIg. To 0.02 mol of
an appropriate arylamide IVa–IVg in a porcelain dish
was added 0.1 ml (0.02 mol) of hydrazine hydrate, and
the mixture was vigorously stirred with a gless rod till the
mixture turned thick. The formed needle-like crystals of
bright yellow to intensely orange color were ground in
a mortar and recrystallized from 2-propanol.
Compound VIa, mp 116–118°C, yield 45%. 1H NMR
spectrum, d, ppm: 2.0 s (2H, NH2), 2.85 s (2H, CH2),
7.3 s (1H, CH), 7.0–7.64 m (Harom), 8.2 s (1H, NH).
Found, %: C 58.5; H 4.4; N 16.9. C12H11N3O3. Calculat-
ed, %: C 58.8; H 4.5; N 17.1.
Compound VIb, mp 210–211°C, yield 73%. 1H NMR
spectrum, d, ppm: 2.0 s (2H, NH2), 2.85 c (2H, CH2),
7.3 s (1H, CH), 7.45–8.51 m (Harom), 12.0 s (1H,
COOH). Found, %: C 54.1; H 3.9; N 14.7. C13H11N3O5.
Calculated, %: C 54.0; H 3.8; N 14.5.
Compound VIc, mp 215–216°C, yield 52%. 1H NMR
spectrum, d, ppm: 2.0 s (2H, NH2), 2.85 s (2H, CH2),
7.3 s (1H, CH), 7.45–8.51 m (Harom), 12.0 s (1H,
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