Cyclization of the reaction products of p-phenylenediamine with maleic acid

Article abstract of DOI:10.1023/B:COHC.0000040777.58344.5a

Treatment of p-phenylenediamine with maleic acid and its diethyl ester gave di- and tetracarboxylic amino acids and their esters. A benzene derivative having an α-alanine and an aspartic acid residue has been prepared. The cyclization of aminocarboxylic a

Full text of DOI:10.1023/B:COHC.0000040777.58344.5a

Chemistry of Heterocyclic Compounds, Vol. 40, No. 6, 2004
CYCLIZATION OF THE REACTION
PRODUCTS OF p-PHENYLENEDIAMINE
WITH MALEIC ACID
K. Rutkauskas and Z.-I. Beresnevicius
Treatment of p-phenylenediamine with maleic acid and its diethyl ester gave di- and tetracarboxylic
amino acids and their esters. A benzene derivative having an α-alanine and an aspartic acid residue has
been prepared. The cyclization of aminocarboxylic acids to imidazole and pyrimidine derivatives has
been carried out.
Keywords: acrylic acid, hydropyrimidinedione, carboxymethylimidazolidinedione, carboxymethyl-
imidazolidinethione, maleic acid, p-phenylenediamine.
N-Substituted amino acids are convenient compounds for the preparation of heterocyclic systems. The
action of urea, cyanates, or thiocyanates on N-aryl-α-alanine gives substituted hydropyrimidinediones or their
thio analogs [1] but N-arylaspartic acids give imidazolidinedione derivatives under these conditions [2].
In this work we have carried out the reaction of p-phenylenediamine with maleic acid and its ester and
studied the cyclization reactions of the aminocarboxylic acids obtained with urea and potassium thiocyanate.
Depending on reaction time, heating p-phenylenediamine with diethyl maleate gives the products of mono- or
diaddition. The sole product obtained in modest yield (33%) after heating for 6 h was diethyl
N-(4-aminophenyl)aspartate (2), but after 16 h the tetraethyl ester 3 could also be obtained via column
chromatography along with compound 2. The 1H NMR spectra of compounds 2 and 3 show singlets at 1.07 and
2.7 ppm corresponding to the methyl and methylene fragments of the ester groups. The overlapping signals for
the aliphatic CHCH2 part of the aspartic acids were observed at 3.9-4.3 ppm.
Basic hydrolysis of the esters 2 and 3 and subsequent acidification of the hydrolysate with acetic acid
gave the di- (4) and tetracarboxylic (5) acids.
The N-(4-aminophenyl)aspartic acid (4) was also prepared by the reduction of N-(4-nitrophenyl)aspartic
acid which was synthesized by treating p-nitroaniline with maleic acid and by a direct synthesis from
p-phenylenediamine and maleic acid. The patent [3] reports that p-phenylenediamine forms the corresponding
amide with maleic acid and undergoes hydrolysis to give the acid 4. When the amine 1 was heated with maleic
acid in water for 6 h we were unable to observe formation of the amide but the acid 4 was separated from the
reaction mixture upon cooling.
N-[4-(2-Carboxyethylamino)phenyl]aspartic acid (6) was synthesized from the amino acid 4 by heating
1
with acrylic acid in dilute acetic acid. The H NMR spectrum of the tricarboxylic acid 6, when compared with
the spectrum of compound 4, shows additional signals for the methylene groups of the aliphatic part of
__________________________________________________________________________________________
Kaunas Technological University, Kaunas 3028, Lithuania; e-mail: zigmuntas.beresnevicius@ktu.lt.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 923-927, June, 2004. Original article
submitted December 4, 2002; revision submitted April 14, 2003.
792
0009-3122/04/4006-0792©2004 Plenum Publishing Corporation

α-alanine. Heating of the tricarboxylic acid 6 with urea in acetic acid and subsequent addition of HCl gives the
1,4-bis[2,4-(1H,3H))-dioxohexahydropyrimidin-1-yl]benzene (7), i.e. the α-alanine and the aspartic acid
residues form the same heterocyclic system. This is explained by the fact that N-substituted β-alanine with urea
in acid medium forms N-carbamoyl β-alanine which is cyclized to the dihydropyrimidinedione. Under the same
conditions, N-substituted aspartic acid forms a ureidosuccinic acid derivative [4] which cyclises to the
corresponding 5-carboxymethylhydantoin derivative or an orotic acid derivative which undergoes
decarboxylation in these conditions to give the dihydropyrimidinedione.
Scheme 1
O
O
O
O
O
O
O
O
O
O
O
O
H2N
N
H
N
H
N
H
3
2
NH2
HO
O
OH
H2N
N
H
O
NH2
OH
HO
1
4
O
O
HO
O
OH
O
HO
O
O
N
H
N
H
HO
OH
O
5
N
H
N
H
6
Compound 7 was also obtained along with compound 10 from the aspartic acid dimer 5 by heating the
latter with urea. The bisdihydrouracil derivative is difficultly soluble whereas the 1,4-bis(2,4-dioxo-5-
carboxymethylimidazolidin-1-yl)benzene (10) is soluble in water.
Heating the tricarboxylic acid 6 with potassium thiocyanate in acetic acid and subsequent addition of
hydrochloric acid gave compound 8 which has thiohydantoin and thiodihydrouracil residues in its structure.
Under analogous conditions, the tetracarboxylic acid 5 and thiocyanate give the derivative 9 which has two
carboxymethylthiohydantoin substituents (Scheme 2).
The 1H NMR spectrum of compound 7 shows triplets at 2.7 and 3.6 ppm characteristic of
dihydropyrimidinediones, corresponding to the two methylene groups. The spectra of the imidazole derivatives 9
and 10 show multiplets for the methylene groups at 3.1-3.6 and triplets for the methine groups near 5 ppm.
793

Scheme 2
S
S
S
S
H
N
HN
HN
NH
N
N
O
N
N
O
O
O
O
O
O
8
OH
OH
HO
9
O
N
O
H
N
H
N
5
6
O
N
O
7
O
O
O
O
N
H
N
HN
NH
HN
N
N
N
O
O
O
O
O
O
O
OH
HO
OH
11
10
EXPERIMENTAL
1H NMR spectra were recorded on Bruker AW-80 (80 MHz) and JEOL FX-100 (100 MHz) instruments
with HMDS as internal standard. Monitoring of the reaction course and the purity of the compounds obtained
was carried out by TLC on Silufol 254 and Silufol UV-254 plates.
Diethyl N-(4-Aminophenyl)aspartate (2) and Diethyl N-[4-(1,2-Bisethoxycarbonylethylamino)-
phenyl]aspartate (3). A mixture of amine 1 (10.8 g, 100 mmol), diethyl maleate (34.4 g, 200 mmol), and acetic
acid (50 ml) was refluxed for 16 h. The liquid fractions were distilled in vacuo to give an oily mass (21.2 g).
Passage of 1 g of this mass through a 100/250 grade silica gel column, eluting with acetone and hexane (1:1),
gave fractions with Rf 0.64 and 0.47. The solvent was distilled off and the fraction with Rf 0.64 was crystallized
from hexane to give the diethyl ester 2 (0.4 g, 30%); mp 47-48°C. Found, %: C 59.62; H 7.20; N 9.83.
C14H20N2O4. Calculated, %: C 60.01; H 7.14; N 10.00.
1
The fraction with Rf 0.47 gave 0.4 g (20%) of the tetraethyl ester 3 as a viscous oil. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 1.04 (6H, t, J = 7, 2CH3); 1.06 (6H, t, J = 7, 2CH3); 2.73 (4H, d, J = 4.2, 2CHCH2);
3.7-4.2 (10H, m, 2CH, 4CH2); 6.3 (4H, s, ArH). Found, %: C 58.51; H 7.32; N 6.39. C22H32N2O8. Calculated, %:
C 58.40; H 7.07; N 6.19.
N-(4-Aminophenyl)aspartic Acid (4). A. A mixture of p-phenylenediamine (10.8 g, 100 mmol), maleic
acid (5.8 g, 50 mmol), and water (200 ml) was refluxed for 20 h, NaOH (45%, 50 ml) was added, and the heating
was continued for a further 6 h. The cooled reaction mixture was neutralized with acetic acid to pH 6. The
crystals formed were filtered off and washed with water, alcohol, and ether. Yield of 17.66 g (79%); mp 230-
231.5°C.
794

B. A mixture of ester 2 (28.0 g, 100 mmol), water (100 ml), ethanol (20 ml), and NaOH (25 g,
625 mmol) was refluxed for 2 h. After cooling, the reaction mixture was treated with acetic acid to pH 6 and the
precipitated compound was filtered, washed with water, alcohol, and ether to give a yield of 20.16 g (90%).
C. N-(4-Nitrophenyl)aspartic acid (25.4 g, 100 mmol) was dissolved in 10% ammonia (180 ml) and
Na2S2O4 was added to the disappearance of the yellow color in the solution. The reaction mixture was then
filtered and the filtrate was diluted with water (200 ml) and neutralized with acetic acid to pH 6. The crystals
formed were filtered off and washed with water, alcohol and ether to give a yield of 9.5 g (42%).
D. A solution of the amine 1 (5.4 g, 50 mmol) and maleic acid (5.8 g, 50 mmol) in water (100 ml) was
refluxed for 6 h. After cooling, the crystals formed were filtered off and washed with water, alcohol, and ether.
Yield 10.0 g (89%). 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.55 (2H, d, J = 5, CH2); 3.9 (1H, t, J = 5,
CH); 6.4 (4H, dd, J = 7.3; J = 2, ArH); 6.6-7.2 (2H, br. s, NH2). Found, %: C 53.18; H 5.62; N 12.44.
C10H12N2O4. Calculated, %: C 53.57; H 5.36; N 12.28. A mixed sample of the substance 4 prepared by the
methods A-D did not show a depression of melting point.
N-[4-(1,2-Dicarboxyethyl)amino]phenylaspartic Acid (5). Compound 1 (5.04 g, 50 mmol) and maleic
acid (11.6 g, 100 mmol) in water (100 ml) was refluxed for 6 h. The mixture was cooled and the precipitate was
1
filtered off and washed with water and acetone. Yield 5.52 g (53%); mp 203-204°C (ethanol). H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 2.54 (4H, d, J = 5, 2CH2); 3.9 (2H, t, J = 5, 2CH); 6.47 (4H, s, ArH);
6.6-7.38 (4H, br. s, 4OH). Found, %: C 49.81; H 4.98; N 8.38. C14H16N2O8. Calculated, %: C 49.41; H 4.70;
N 8.23.
N-[4-(2-Carboxyethyl)amino]phenylaspartic Acid (6). A mixture of the aspartic acid 4 (2.24 g,
10 mmol), acrylic acid (0.75 ml, 11 mmol), and 60% acetic acid (50 ml) was refluxed for 4 h. The liquid
fractions were distilled in vacuo and the remaining viscous mass was treated with acetone, whereupon it
crystallized. The crystals were filtered off, crystallized from a mixture of acetic acid and acetone (1:5), and
washed with alcohol. Yield 2 g (67%); mp 97-98.5°C. 1H NMR spectrum (CF3COOH), δ, ppm (J, Hz); 2.55 (2H,
t, J = 6, COCH2); 2.87-3.25 (2H, m, CH2); 3.42-3.85 (2H, m, NCH2); 4.45-4.75 (1H, m, CH); 6.0-7.75 (4H,
ArH). Found, %; C 52.48; H 5.08; N 9.45. C13H16N2O6. Calculated, %: C 52.70; H 5.40; N 9.46.
1,4-Bis[2,4-(1H,3H)-dioxohexahydropyrimidin-1-yl]benzene (7). A mixture of the tricarboxylic acid 6
(14.8 g, 50 mmol) and urea (12 g, 200 mmol) in acetic acid (100 ml) was refluxed for 8 h, HCl (30 ml) was
added, and refluxing was continued for a further 2 h. The reaction mixture was cooled and the crystals were
filtered off and washed with refluxing acetic acid and acetone. Yield 6.75 g (45%); mp 320°C. According to the
study [5] the mp is 320°C. 1H NMR spectrum (CF3COOH), δ, ppm (J, Hz): 2.7 (4H, t, J = 5, COCH2); 3.67 (4H,
t, J = 5, NCH2); 7.07 (4H, s, ArH). Found, %: C 55.36; H 4.82; N 18.58. C14H14N4O4. Calculated, %: C 55.63;
H 4.63; N 18.54.
1-[4-(Hexahydro-4-oxo-2-thioxopyrimidin-1-yl)phenyl]-4-oxo-2-thioxo-5-imidazolidineacetic Acid
(8). A mixture of the acid 6 (19.8 g, 50 mmol), acetic acid (70 ml), and potassium thiocyanate (20 g, 200 mmol)
was refluxed for 10 h, conc. HCl (15 ml) was added, and the refluxing was continued for a further 2 h. The
reaction mixture was cooled, diluted with water (200 ml), and the crystals formed were filtered off. Yield 12.5 g
1
(66%); mp 210-211°C (ethanol). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.55 (2H, d, J = 4, CHCH2);
2.8 (2H, t, J = 5, COCH2); 3.93 (2H, t, J = 5, NCH2); 5.02 (1H, t, J = 4, CH); 7.47 (4H, s, ArH); 11.23 (1H, s,
NH); 12.1-12.5 (1H, br. s, NH). Found, %: C 47.92; H 4.07; N 14.71. C15H14N4O4S2. Calculated, %: C 47.62;
H 3.70; N 14.81.
1-[-4-(5-Carboxymethyl)-4-oxo-2-thioxoimidazolidin-1-yl]phenyl-4-oxo-2-thioxo-5-imidazolidine-
acetic Acid (9). A mixture of the acid 5 (6.8 g, 20 mmol), potassium thiocyanate (3.84 g, 60 mmol) and 70%
acetic acid (70 ml) was refluxed for 8 h, hydrochloric acid (20 ml) was added, and heating was continued for a
further 2 h. The reaction mixture was cooled, neutralized with sodium carbonate, and the crystals formed were
1
filtered off and washed with water and acetone. Yield 5.1 g (60%); mp 221-222.5°C (ethanol–water). H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 3.21 (4H, d, J = 5, 2CH2); 4.92 (2H, t, J = 5, 2CH); 6.91 (4H, s, ArH);
9.81 (2H, s, 2NH). Found, %: C 45.72; H 3.41; N 13.49. C16H14N4O6S2. Calculated, %: C 47.62; H 3.70;
N 14.81.
795

1,4-Bis[2,4-(1H,3H)-dioxohexahydropyrimidin-1-yl]benzene (7) and 1,4-Bis(5-carboxymethyl-2,4-
dioxoimidazolidin-1-yl)benzene (10). A mixture of the acid 5, (3.4 g, 10 mmol), urea (5 g, 88 mmol), and acetic
acid (50 ml) was refluxed for 16 h. HCl (15 ml) was added to the reaction mixture and refluxing was continued
for a further 30 min. The mixture was cooled and poured into water (200 ml). The precipitated crystalline
compound 7 was filtered off. Yield 1.55 g (45%); mp 320°C. A mixed sample of compound 7 with that prepared
from the tricarboxylic acid 6 did not give a depression of melting point. The filtrate obtained after the removal of
compound 7 was evaporated in vacuo and the residue was refluxed in acetone, filtered, and the acetone
1
evaporated to give the acid 10 (0.92 g, 27%); mp 254-255.5°C (water). H NMR spectrum (DMSO-d6), δ, ppm
(J, Hz): 2.67 (4H, d, J = 5, 2CH2); 4.21 (2H, d, J = 5, 2CH); 6.9 (4H, s, ArH); 11.3 (2H, s, NH). Found, %: C
50.04; H 3.71; N 14.53. C16H14N4O8. Calculated, %: C 49.23; H 3.59; N 14.36.
1-[4-(5-Carboxymethyl-2,4-dioxoimidazolidin-1-yl)phenyl]dihydropyrimidin-2,4-(1H,3H)-dione (11).
A mixture of the tricarboxylic acid 6 (5.92 g, 20 mmol), sodium isocyanate (5.2 g, 80 mmol), and acetic acid
(40 ml) was refluxed for 4 h. The reaction mixture was cooled and poured into acetone (200 ml). The
precipitated NaCl was separated and the filtrate was evaporated to dryness in vacuo. The oily mass was treated
with water (20 ml) and allowed to stand for 20 h at 6°C. The crystals formed were filtered off. Yield 4.4 g
1
(64%); mp 291-292.5°C (ethanol–water). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 2.51 (2H, d, J = 5,
CHCH2); 2.82 (2H, t, J = 7, COCH2); 3.94 (2H, t, J = 7, NCH2); 5.13 (1H, t, J = 5, CH); 7.43 (1H, s, NH); 7.48
(4H, s, ArH); 11.5 (1H, br. s, NH). Found, %: C 55.62; H 4.42. C15H14N4O6. Calculated, %: C 52.02; H 4.05.
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796