The question of the cyclization of 3-{(2-carboxyethyl)-3-[bis(2- carboxyethyl)amino]anilino}propanoic acid [2]

Full text of DOI:10.1007/s10593-007-0018-9

Chemistry of Heterocyclic Compounds, Vol. 43, No. 1, 2007
THE QUESTION OF THE CYCLIZATION OF 3-{(2-CARBOXYETHYL)-
3-[BIS(2-CARBOXYETHYL)AMINO]ANILINO}PROPANOIC ACID
1
1
2
V. Novikovaite , Z. I. Beresnevicius , and G. Mikulskiene
Keywords: carboxyethylaminoanilinopropanoic and quinolinylpropanoic acids, N-(pyridoquinolinyl)-β-
alanine, pyridophenanthrolinetrione, cyclization.
The benzo[i,j]quinolizine (julolidine) system occurs in the composition of a series of alkaloids [1].
Quinolizine derivatives are used as medicinal compounds [2], several of which have antimicrobial activity [3].
Cyclization of N-aryl-N-carboxyethyl-β-alanines to 1-(2-carboxy-ethyl)tetrahydroquinolinone has been reported
in a series of studies while the cyclization leading to the formation of quinolizine derivatives is a greater
problem. One of the first syntheses of diketo julolidine derivatives was brought about by cyclization of N,N-
bis(2-cyanoethyl)aniline in the presence of aluminium chloride [4]. The action of PPA on N-carboxyethyl-N-
O
O
1
4
HO
HO
OH
O
13
1
5
(
MeCO) O
2
H
N
2
N
N
N
∆
10
7
8
3
1
11
12
OH
4
6
5
9
O
O
1
O
O
4
MeCOOH
∆
MeCOOH
∆
HO
O
O
1
5
14
OH
O
1
4
9
13
1
5
13
2
H
2
7
8
N
N
N
N
1
0
10
11
3
1
3
1
6
12
7
8
1
1
12
6
OH
OH
4
9
4
5
5
O
O
O
O
2
3
_
________________________________________________________________________________________
1
Kaunas
Technological
University,
Kaunas
LT-50254,
Lithuania;
e-mail:
2
zigmuntas.beresnevicius@ktu.lt.
Biochemistry Institute, Vilnius LT-08662, Lithuania; e-mail:
gemam@bchi.lt. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 1, pp. 130-132, January, 2007.
Original article submitted October 30, 2006.
0
009-3122/07/4301-0113©2007 Springer Science+Business Media, Inc.
113

methylenedioxy- and N-ethylenedioxyphenyl-β-alanines gave the corresponding benzo[i,j]quinolizinediones [5].
Heating 3-{(2-carboxyethyl)-3-[bis(2-carboxy-ethyl)amino]anilino}propanoic acid (1) (prepared by treatment of
m-phenylenediamine with acrylic acid) in acetic acid gives the products of partial cyclization 3-{7-[bis(2-
carboxyethyl)amino]-4-oxo-3,4-dihydro-1(2H)-quinolinyl}propanoic acid (2) and 3-[9-(3-hydroxy-3-
oxopropyl)-4,6-dioxo-3,4,6,7,8,9-hexahydropyrido[3,2-g]quinoline-1(2H)-propanoic acid. A more detailed study
of this process shows that, after heating the tetraacid 1 in glacial acetic acid, along with compound 2 were able to
separate from the reaction mixture the tricyclic N-(1,7-dioxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-
8
-yl)-β-alanine (3). Refluxing compound 1 in acetic anhydride causes dealkylation of the carboxyethyl group
and cyclization to form the 2,3,11,12-tetrahydro-1H,5H-pyrido[3,2,1-gh]phenanthroline-1,7,9(6H,10H)-trione
4).
(
1
13
H NMR and C NMR spectra were recorded on a Varian Unity Inova instrument (300 and 75 MHz
respectively) with TMS as internal standard. Mass spectra were taken on a Waters ZQ 2000 instrument.
-{(2-Carboxyethyl)-3-[bis(2-carboxyethyl)amino]anilino}propanoic acid (1) was prepared in 70%
yield by method [6]. Mp 157.0-157.7°C (mp 159-160°C [6]).
-{7-[Bis(2-carboxyethyl)amino]-4-oxo-3,4-dihydro-1(2H)-quinolinyl}propanoic acid (2) and
N-(1,7-Dioxo-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolin-8-yl)-β-alanine (3). The tetracarboxylic acid
(5 g, 13 mmol) was refluxed in acetic acid (30 ml) for 8 h. The liquid fractions were distilled off and the
3
3
1
remaining mass was dissolved in alcohol and left at 4°C. The crystals of 3 formed were filtered off, washed with
1
ethanol and crystallized from acetic acid. Yield of 3 0.95 g (26%). Mp 192-193°C. H NMR spectrum
(
DMSO-d ), δ, ppm (J, Hz): 2.51-2.57 (4H, m, H-11,14); 2.65 (2H, t, J = 6.7, H-8); 3.39-3.45 (4H, m, H-10,13);
6
3
.50 (2H, dt, J = 6.1, 5.8, H-7); 6.22 (1H, d, J = 9.2, H-6); 7.71 (1H, d, J = 9.2, H-5); 10.21 (1H, t, J = 5.8, NH).
1
3
C NMR spectrum (DMSO-d ), δ, ppm: 33.55 (C(8)); 36.02 (C(11)); 37.12 (C(14)); 37.84 (C(7)); 49.08 (C(10)); 50.01
6
(
(
C(13)); 100.95 (C ); 101.53 (C ); 108.01 (C ); 134.71 (C ); 155.61 (C ); 156.91 (C ); 172.66 (C ); 188.96
(6)
(2)
(4)
(5)
(3)
+
(1)
(9)
C ); 194.36 (C ). Mass spectrum (20 eV), m/z (I , %): 289 [M+H] (100). Found, %: C 62.33; H 5.49;
(
12
(15
rel
N 9.41. C H N O . Calculated, %: C 62.56; H 5.62; N 9.73.
1
5
15
2
4
After removal of the acid 3 and distillation of the liquid fractions, the remaining product was dissolved
in methanol and passed through a silica gel column (eluent methanol). Yield of 2 1.95 g (41%). Mp 197-198°C
1
(
mp 194-195°C [6]). H NMR spectrum (DMSO-d ), δ, ppm (J, Hz): 2.42 (2H, t, J = 6.8, H-11); 2.48-2.54 (6H,
6
m, H-8,14); 3.43 (2H, t, J = 6.8, H-10); 3.61-3.65 (6H, m, H-7,13); 5.82 (1H, d, J = 1.8, H-2); 6.14 (1H, dd,
1
3
J = 9.0, J = 1.8, H-6); 7.53 (1H, d, J = 9.0, H-5); 12.33 (3H, br. s, COOH). C NMR spectrum (DMSO-d ), δ,
6
ppm: 31.10 (C(14)); 32.21 (C ); 37.32 (C ); 46.29 (C ); 46.54 (C(13)); 48.89 (C(10)); 92.76 (C ); 102.54 (C );
(8)
(11)
(7)
(2)
(6)
1
10.56 (C ); 129.56 (C ); 152.15 (C or C ); 152.20 (C or C ); 173.06 (C ); 173.28 (C(15)); 190.03 (C(12)).
(4) (5) (1) (3) (1) (3) (9)
+
Mass spectrum (20 eV), m/z (I , %): 379 [M+H] (100). Found, %: C 57.01; H 6.11; N 6.99. C H N O .
rel
18 22
2
7
Calculated, %: C 57.19; H 5.87; N 7.41.
2
,3,11,12-Tetrahydro-1H,5H-pyrido[3,2,1-gh][1,7]phenanthroline-1,7,9(6H,10H)-trione (4). The
tetracarboxylic acid 2 (8.77 g, 22 mmol) was dissolved in acetic anhydride (50 ml) and refluxed for 3 h. The
liquid fraction was distilled off and the remaining mass was purified by rapid passage through a chromatography
-
1
column (eluent methanol). Yield 1.19 g (20%). Mp 287-288°C. IR spectrum (KBr), ν, cm : 3218 (NH),
1
2
852-2962 (aliph. C–H); 1577, 1626, 1661 (C=O). H NMR spectrum (CDCl ), δ, ppm: 2.63-2.67 (2H, m, H-8);
3
2
.72-2.82 (4H, m, H-11,14); 3.55-3.60 (4H, m, H-10,13); 3.66-3.72 (2H, m, H-7); 8.60 (1H, s, H-5); 10.34 (1H,
1
br. s NH). H NMR spectrum (DMSO-d ), δ, ppm: 2.49-2.71 (6H, m, H-8,11,14); 3.55-3.67 (6H, m, CH N,
H-7,10,13); 8.20 (1H, s, H-5); 10.21 (1H, br. s, NH). C NMR Spectrum (DMSO-d ), δ, ppm: 35.63 (C(11));
6
2
1
3
6
3
5.89 (C(14)); 36.41 (C ); 48.7 (C ); 49.21 (C(13)); 49.21 (C(10)); 100.68 (C ); 108.68 (C ); 109.42 (C );
(8) (7) (2) (4) (6)
1
33.39 (C ); 156.24 (C ); 158.12 (C ); 189.72 (C ); 190.46 (C ); 193.77 (C(15)). Mass spectrum, (20 eV),
(
5)
(1)
+
(3)
(12)
(9)
m/z (I , %): 271 [M+H] (100). Found, %: C 66.22; H 5.09; N 9.99. C H N O . Calculated, %: C 66.66;
rel
15 14
2
3
H 5.22; N 10.36.
1
14

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.
4
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