Synthesis of imines based on orotic aldehyde and amino acids

Full text of DOI:10.1134/S1070363213050216

ISSN 1070-3632, Russian Journal of General Chemistry, 2013, Vol. 83, No. 5, pp. 1000–1001. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © A.I. Rakhimov, R.B. Shul’man, R.G. Fedunov, 2013, published in Zhurnal Obshchei Khimii, 2013, Vol. 83, No. 5, pp. 866–867.
LETTERS
TO THE EDITOR
Synthesis of Imines Based on Orotic Aldehyde and Amino Acids
A. I. Rakhimova, R. B. Shul’manb, and R. G. Fedunovb
a Volgograd State Technical University, pr. Lenina 28, Volgograd, 400131 Russia
e-mail: rakhimov@sprint-v.com.ru
b Institute of Chemical Problems of Environment, Russian Academy of Natural Sciences, Volgograd, Russia
Received October 4, 2011
DOI: 10.1134/S1070363213050216
It was shown previously that orotic aldehyde re-
acted with α-amino acids to form imines having a wide
spectrum of biological activity [1, 2]. Therefore a
necessity appeared to to study the synthetic oppor-
tunities of the orotic aldehyde reactions with acids,
their esters and oligomers which also can exhibit a
high biological activity.
of imines is 32–81%. The highest yield (81%) was
obtained in the case of p-aminobenzoic acid, while the
lowest (32%), with aminoacetic acid. This is due to the
availability of amino group in p-aminobenzoic acid
and hindrances in the reaction with α-amino acids. The
deamination in the case of oligomers of ε-amino-
caproic acid leads to an increase in the reaction yield.
The structure of imines was confirmed by IR spec-
troscopy, and the composition was determined by
elemental analysis. All obtained imines are yellow
crystalline substances with high melting points.
In this work we investigated the synthesis of imine
derivatives by reacting of orotic aldehyde with glycine,
esters of ε-aminocaproic and p-aminobenzoic acids.
One of the possible mechanisms of this reaction is
considered.
The IR spectra of the compounds obtained contain
the absorption bands of amide group at 3288 (N–H),
1716 (C=O), 1636 (amide I) and 1540 cm–1 (amide II),
and ester group C=O at 1724 cm–1.
O
COOR2
HN
+
R1
O
The mechanism of the reaction of orotic aldehyde
with aminocarboxylic acids was considered by the
example of glycine. Analysis of the possible reaction
pathways was performed using quantum chemical
method AM1 [3].
O
N
C
H
NH2
H
COOR2
O
R1
N
The first stage occurs through the formation of
four-membered transition state as a result of the
approach of the amino group of carboxylic acid to the
aldehyde group of orotic aldehyde (there is an
interaction between the atoms N1–С1 and О1–Н1). The
second stage is dehydration of an intermediate alcohol
to form imine.
HN
O
N
C
H
I_IV
H
I, R1 = [(CH2)5С(O)NH]2(CH2)5, R2 = Bu-n; II, R1 = C6H4-p,
R2 = Et; III, R1 = C6H4-p, R2 = H; IV, R1 = CH2, R2 = H.
At the first stage of the reaction there should be
overcome the sufficiently high activation barrier
(61.3 kcal mol–1) to form the four-membered transition
state. The saddle point is reached when the reaction
coordinates RN1–С1 and RO1–H1 are 0.18 and 0.14 nm,
respectively. In this connection the reaction should be
carried out at a high temperature. Note also that the
The reaction was carried out in an organic solvent
(acetic acid) in the case of esters of amino acids and
oligomers or in water (in the case of amino acids). The
reaction temperature ranges from 40 to 70°C. Depend-
ing on the structure of the starting compounds the yield
1000

1001
SYNTHESIS OF IMINES BASED ON OROTIC ALDEHYDE AND AMINO ACIDS
H2
H1
O1
C1
H1
H2
C3
O1
H
H
N1
H
H
N1
O3
H
H
H
O
N1
C1
C1
H
C3
C3
H
H
1
2
H
H3
O
C
C
C
N3
H
O
O3
N3
O
H3
H3
O3
H
N3
O
H
H
O
O
O1
N
N
N
H
H1
O
O
H2
H
H
reaction is accompanied by a small positive thermal
effect (5 kcal mol–1).
(E)-Ethyl 4-[(2,6-dioxo-1,2,3,6-tetrahydropyrimi-
din-4-yl)methyleneamino]benzoate (II) was prepared
similarly. Yield 59%, mp 245°C. Found, %: C 57.8; H
5.0; N 14.9. С14H13N3O4.Calculated, %: C 58.5; H 4.5;
N 14.6.
The second stage, unlike the first one, is
characterized by a lower activation barrier. The saddle
point is reached when the reaction coordinate RH2–O1
(0.13 nm) is located at 53.8 kcal mol–1. This stage is ac-
companied by a slight negative heat effect (4 kcal mol–1).
However, the water release in the second stage leads to
irreversible process.
(E)-4-[(2,6-Dioxo-1,2,3,6-tetrahydropyrimidin-4-
yl)methyleneamino]benzoic acid (III) was prepared
similarly. Yield 81%, mp 275°C. Found, %: C 55.9; H
4.0; N 16.0. С12H9N3O4. Calculated, %: C 55.6; H 3.5;
N 16.2.
The quantum chemical calculation was performed
for the gaseous systems excluding the solvents
participation (water, acetic acid), which can reduce the
activation barrier and facilitate the reaction progress.
The total energy gain during the formation of imine
from the reactants is small (1 kcal mol–1).
(E)-4-[(2,6-Dioxo-1,2,3,6-tetrahydropyrimidin-4-
yl)methyleneamino]acetic acid (IV) was prepared
similarly (solvent – water, 80°C). Yield 32%, mp 265°C.
Found, %: C 41.7; H 3.7; N 22.5. С7H7N3O4. Cal-
culated, %: C 42.6; H 3.6; N 21.3.
Thus, the stage determining the formation of
iminoesters is the first stage, when the hydroxyl-
containing compound is formed. Dehydration of the
latter requires less energy and leads to irreversible
reaction.
The IR spectra were obtained on a Specord M-82
instrument from mulls in mineral oil.
REFERENCES
1. Rakhimov, A.I. and Shul’man, R.B., Novye dostizheniya
v khimii karbonil’nykh i geterotsyklicheskikh soedinenii
(New Advances in the Chemistry of Carbonyl and
Heterocyclic Compounds), Saratov: Saratov. Univ.,
2000, p. 186.
2. Rakhimov, A.I., Shul’man, R.B., Sinel’nikov, P.Yu.,
and Storozhakova, N.A., Novye dostizheniya v khimii
karbonil’nykh i geterotsyklicheskikh soedinenii (New
Advances in the Chemistry of Carbonyl and Hetero-
cyclic Compounds), Saratov: Saratov. Univ., 2000, p. 188.
3. Schmidt, M.W., Baldridge, K.K., Boatz, J.A., Elbert, S.T.,
Gordon, M.S., Jensen, J.H., Koseki, S., Matsunaga, N.,
Nguyen, K.A., Su, S.J., Windus, T.L., Dupuis, M., and
Montgomery, J.A., J. Comput. Chem., 1993, vol. 14,
p. 1347.
(E)-Butyl 6-(6-{6-[(2,6-dioxo-1,2,3,6-tetrahydro-
pyrimidin-4-yl)methyleneamino]hexanamido} hexan-
amido)hexanoate (I). A mixture of 2.57 g (0.0048 mol)
of n-butyl ester of ε-aminocaproic acid trimer, 25 ml of
glacial acetic acid, and 0.56 g (0.004 mol) of orotic
aldehyde was refluxed with stirring for 2 h and then
cooled to room temperature. The precipitate was
filtered off, washed successively with ethanol and
diethyl ether to remove the initial reagents, and dried.
The reaction products were purified by sublimation in
vacuo. Yield 1.1 g (56%), mp 178–180°C. Found, %:
C 59.1; H 9.0; N 13.9. С27H45N5O6. Calculated, %: C
60.6; H 8.4; N 13.1.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 83 No. 5 2013