Synthesis and antioxidative properties of some 3,4-dihydropyrimidin-2(1H) ones (-thiones)

Article abstract of DOI:10.1134/S107042720605017X

3,4-Dihydropyrimidinones (-thiones) were prepared by ternary condensation of various aromatic aldehydes with ethyl acetoacetate and urea (thiourea) in the presence of trichloroacetic acid in ethanol. Pleiades Publishing, Inc., 2006.

Full text of DOI:10.1134/S107042720605017X

ISSN 1070-4272. Russian Journal of Applied Chemistry, 2006, Vol. 79, No. 5, pp. 787 790. Pleiades Publishing, Inc., 2006.
Original Russian Text A.M. Magerramov, M.M. Kurbanova, R.T. Abdinbekova, I.A. Rzaeva, V.M. Farzaliev, M.A. Allakhverdiev, 2006, published
in Zhurnal Prikladnoi Khimii, 2006, Vol. 79, No. 5, pp. 796 800.
ORGANIC SYNTHESIS
AND INDUSTRIAL ORGANIC CHEMISTRY
Synthesis and Antioxidative Properties
of Some 3,4-Dihydropyrimidin-2(1H)ones (-thiones)
A. M. Magerramov, M. M. Kurbanova, R. T. Abdinbekova,
I. A. Rzaeva, V. M. Farzaliev, and M. A. Allakhverdiev
Baku State University, Baku, Azerbaijan
Received October 12, 2005; in final form, March 2006
Abstract 3,4-Dihydropyrimidinones (-thiones) were prepared by ternary condensation of various aromatic
aldehydes with ethyl acetoacetate and urea (thiourea) in the presence of trichloroacetic acid in ethanol.
DOI: 10.1134/S107042720605017X
Dihydropyrimidinones attract growing interest due
to their therapeutical and pharmacological activity [1].
Some functional derivatives of dihydropyrimidinones
exhibit a broad spectrum of biological activity, includ-
ing antiviral, antitumor, and antibacterial activity.
Furthermore, 4-aryldihydropyrimidinones are power-
ful blockators of calcium channels and antihypertonic,
-adrenergic, and neuropeptide antagonists [2].
and urea (thiourea) in the presence of CCl COOH as
catalyst. The reaction required refluxing in ethanol for
2 4 h.
3
O
O
X
RCHO + CH3
+
OC2H5 H2N
NH2
O
R
The simplest and direct route to dihydropyrimidi-
nones, suggested for the first time by Biginelli and
involving ternary condensation of an aldehyde, a
-keto ester, and urea, often gives the desired product
in a low yield, especially with aliphatic aldehydes [3].
Higher yields can be obtained by performing the reac-
tion in several steps, but in this case the process is not
so simple as the one-step Biginelli reaction. Therefore,
the Biginelli reaction continues to attract the attention
of researchers looking for facile and efficient proce-
dures for preparing dihydropyrimidinones.
C2H5OC
H3C
NH
,
X
NH
where X = O, R = CH (I), 2-HO-5-BrC H (IV),
3
6 3
1-naphthyl (V); X = S, R = 2-HOC H (III);
6
4
C2H5OOC
H3C
+
NH ClCH2COOH
S
NH
Somewhat improved procedures for preparing dihy-
dropyrimidinones were reported in [4 6]. However,
despite their potential significance, these methods
are characterized by long reaction time, low selectivi-
ty, and problems with isolation of the products from
the reaction mixture.
O
N
C2H5OOC
H3C
.
S
N
II
Thus, it is important to develop alternative one-pot
procedures for preparing 3,4-dihydropyrimidin-2(1H)-
ones.
The reaction progress was monitored by TLC on
Silufol UV-254 plates.
Here we report on a new procedure for preparing
3,4-dihydropyrimidin-2(1H)-ones (-thiones) in the
presence of trichloroacetic acid. We obtained 3,4-di-
hydropyrimidinones (-thiones) in high yield by the
reaction of various aldehydes with ethyl acetoacetate
The suggested procedure ensures higher product
yields (60 80%). The product can be readily isolated
from the reaction mixture by filtration and washing
with ethanol and water; recrystallization or chromato-
graphic purification is not required.
787

788
MAGERRAMOV et al.
Table 1. Physicochemical characteristics and spectral data for the compounds prepared
Com-
pound
no.
Found, %/Calculated, %
IR spec-
trum,
, cm
Yield,
%
mp,
C
Empirical
formula
1H NMR spectrum,
, ppm
Rf
1
C
H
N
S
I
65 0.72 194 196 54.50 7.02 14.22
54.54 7.07 14.14
C9H14N2O3
NH (3200) 1.09 d (3H, CH3), 1.28 t (3H,
C=O (1648) CH3), 2.15 s (3H, CH3), 3.86 d
(2H, CH2O), 4.06 s (1H, CH),
7.19 s (1H, NH), 8.97 s (1H,
NH)
II
60 0.36 192 193 60.80 5.15
69.75 5.06
8.92 10.10 C16H16N2SO3 C=O (1630) 1.17 t (3H, CH3), 2.35 s (3H,
8.86 10.12
CH3), 3.90 s (2H, CH2S), 4.30
d (2H, CH2O), 5.35 s (1H, CH),
7.50 7.70 s (5H, Ar)
III
80 0.54 215 216 57.65 5.51
57.53 5.47
9.62 10.87 C14H16N2O3S NH (3225) 1.30 t (3H, CH3), 2.35 s (3H,
9.58 10.95
C=O (1700) CH3), 4.36 d (2H, CH2O),
4.90 s (1H, CH), 7.10 7.60 m
(4H, Ar), 9.40 s (1H, NH),
9.75 s (1H, OH)
IV
V
75 0.27 190 191 49.59 4.50
49.55 4.42
8.27
8.25
C14H5N2O4Br NH (3175) 1.30 t (3H, CH3), 2.57 s (3H,
C=O (1635) CH3), 4.25 d (2H, CH2O),
5.70 s (1H, CH), 7.00 7.70 m
(4H, Ar), 8.00 s (1H, NH),
9.41 s (1H, NH), 10.4 s (1H,
OH)
7
0.21 210 212 66.31 5.47
8.63
C18H18N2O3 NH (3250) 1.21 t (3H, CH3), 2.60 s (3H,
C=O (1640) CH3), 4.42 d (2H, CH2O),
5.60 (1H, CH), 8.10 9.75 m
(7H, C10H7), 8.05 s (1H, NH),
9.91 s (1H, NH)
The mechanism of formation of dihydropyrimidin-
ones (-thiones) was studied for a long time; the major-
ity of researchers today agree with the following
transformation sequence suggested by Kappe [7]:
ureide 2. This is followed by cyclization with the
release of a water molecule.
The structures of the compounds were confirmed
1
13
by IR, H, and C NMR spectroscopy.
The physicochemical characteristics and spectral
properties of the compounds are given in Table 1.
X
X
+
N
R1 CHO + H2N
NH2
NH2
H
To evaluate the antioxidative power of I V in ele-
mentary steps of cumene oxidation, we studied the
reactions of I V with cumylperoxy radicals (CPRs)
and cumyl hydroperoxide (CHP).
R1
1
O
R1
O
OH
R3OC
R2
The capability of I V to terminate oxidation chains
by the reaction with CPRs was evaluated using as
example the cumene oxidation at 60 C, initiated with
azobis(isobutyronitrile) in a concentration of 2
NH
3
2
OR
R
CXNH2
O
2
O
2
R1
10 M. We found that compounds I V actively
R3OC
terminate oxidation chains by reacting with CPRs
(Fig. 1).
NH
H O
2
From the duration of the induction period
,
.
X
R2
NH
ind
we calculated the stoichiometric coefficient of inhibi-
tion f, equal to the number of oxidation chains ter-
minated on one inhibitor molecule and its transforma-
First, protonated imine 1 is formed; it subsequently
reacts with the enol form of the keto ester to give
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 79 No. 5 2006

SYNTHESIS AND ANTIOXIDATIVE PROPERTIES
789
tion products:
VO2
ml
,
f = indWi /[ln]0,
where W is the initiation rate and [In] is the initial
i
0
concentration of the inhibitor In.
From the kinetics of the oxygen uptake, we calcu-
lated the rate constants of the reactions of I V with
CPR, k [8, 9]. To this end, the kinetic curves of the
7
oxygen uptake [O ] were linearized in the coordi-
2
1
1
nates [O ]
, and k was calculated from the line
2
7
slope: tan = fk [In] /(k [RH]W ) [9, 10], hence, k =
7
0
2
i
7
(tan )k [RH]W /(f[In] ), where k is the chain initia-
2
1
0
2
1
1
tion rate [8, 9], equal to 1.51 l mol s , [RH] =
7.17 M.
, min
Fig. 1. Kinetic curves of initiated oxidation of cumene in
the presence of I V (curves 1 5, respectively). 60 C;
The high antioxidative activity and the kinetic
parameters of the reactions involving I V were also
confirmed in experiments on autooxidation of cumene
at 110 C (Fig. 2).
2
[AIBN] = 2 10 M. (V ) Oxygen volume and ( ) time;
O
2
5
the same for Fig. 2. [InH], M: (1 ) 0 and (1 5) 5 10 ; the
same for Fig. 2.
Table 2 shows that the parameter f for I V varies
VO2
ml
,
from 0.5 to 4.22, and the rate constants k of the reac-
7
4
tions of the inhibitors with CPR vary from 2.01 10
4
1
1
to 2.92 10 l mol s . The transformation products
of I V formed in the reactions with CPR also exhibit
certain inhibiting effect; the oxidation rate after the
induction period is somewhat lower than in the unin-
hibited oxidation (Fig. 1).
The reactions of I V with CHP were performed in
chlorobenzene in a nitrogen atmosphere at 110 C. All
these compounds decompose CHP. The kinetic curves
of CHP decomposition under the action of I V (the
curve obtained with I is shown as example in Fig. 3)
are S-shaped, which is characteristic of an autocatalyt-
ic process. The reaction has a certain induction period
in which the CHP consumption is insignificant; this is
followed by its catalytic decomposition, and then, as
the CHP is consumed, the reaction rate decreases.
, min
Fig. 2. Kinetic curves of cumene autooxidation in the pres-
ence of I V (curves 1 5, respectively) at 110 C.
chains in the reaction with CHP and catalytically
decomposing CHP.
Apparently, the inhibitor first reacts with CHP, and
the resulting transformation product catalytically de-
composes CHP. To determine the reaction stoichiom-
etry, CHP was taken in excess.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on
1
a Bruker-300 NMR spectrometer (300 MHz for H),
The catalytic factor is the number of CHP mole-
cules decomposed by one inhibitor molecule; it was
and the IR spectra, on a Specord 75-R spectrometer
(mulls in mineral oil). To check the purity of the
compounds prepared and monitor the reaction prog-
ress, we used TLC on Silufol UV-254 plates (eluent
isopropyl alcohol hexane, 1 : 1).
calculated as = ([ROOH]
[ROOH] )/[In] , where
0
0
[ROOH] and [ROOH] are, respectively, the initial
0
and final concentrations of CHP, and [In] is the ini-
0
tial inhibitor concentration.
3,4-Dihydropyrimidin-2(1H)-ones (-thiones).
A round-bottomed flask equipped with a reflux con-
denser and a power-driven stirrer was charged with
appropriate aldehyde (1.25 mol), ethyl acetoacetate
Our experiments showed that one molecule of I V
can decompose up to several ten thousands of CHP
molecules. Presumably, compounds I V exert a com-
bined inhibiting effect, terminating the oxidation
(1.90 mol), urea or thiourea (1.25 mol), CCl COOH
3
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 79 No. 5 2006

790
MAGERRAMOV et al.
Table 2. Kinetic parameters of the reactions of I V with cumylperoxy radicals (k7, f, 60 C, [AIBN] = 2 10 2 M) and of
the decomposition of cumyl hydroperoxide (k, , 110 C)
T = 60 C
T = 110 C
[In]0, M
Compound
4
1
1
f
k7 10 , l mol 1 s
k, l mol 1 s
, min
5
5
5
5
5
I
0.5
2.01
2.3
2.92
2.4
11
33
18.5
20.8
16.6
20000
27000
22000
25000
30000
5
5
5
5
5
10
10
10
10
10
100
120
180
200
220
II
III
IV
V
1.54
1.68
2.88
4.32
2.85
(25 mg), and 95% ethanol (10 ml). The mixture was
stirred for 2 4 h. The reaction progress was moni-
tored by TLC. After the reaction completion, the mix-
ture was cooled to room temperature, and the crystal-
line product was filtered off, washed with ethanol,
dried, and recrystallized from aqueous ethanol (1 : 3).
CONCLUSION
3,4-Dihydropyrimidinones (-thiones) exhibiting
high antioxidative power were prepared by ternary
condensation.
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Cumyl hydroperoxide was purified [10] and then
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4
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1
1
or we used AIBN (initiation rate 1 10 l mol
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2
the experiments). The concentrations of I V were
4
(1 5) 10 M.
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4
of I. 110 C; [In] = 1 10
and [CHP] = 0.275 M.
0
0
( ) Time.
RUSSIAN JOURNAL OF APPLIED CHEMISTRY Vol. 79 No. 5 2006