Solvent-free and catalyst-free Biginelli reaction to synthesize ferrocenoyl dihydropyrimidine and kinetic method to express radical-scavenging ability

Article abstract of DOI:10.1021/jo300282y

Benzoyl and ferrocenoyl 3,4-dihydropyrimidin-2(1H)-ones (-thiones) (DHPMs) were synthesized in modest yields via catalyst-free and solvent-free Biginelli condensation of 1-phenylbutane-1,3-dione or 1-ferrocenylbutane-1,3-dione, hydroxyl benzaldehyde, and

Full text of DOI:10.1021/jo300282y

Article
pubs.acs.org/joc
Solvent-Free and Catalyst-Free Biginelli Reaction To Synthesize
Ferrocenoyl Dihydropyrimidine and Kinetic Method To Express
Radical-Scavenging Ability
Rui Wang and Zai-Qun Liu*
Department of Organic Chemistry, College of Chemistry, Jilin University, Changchun 130021, China
S
* Supporting Information
ABSTRACT: Benzoyl and ferrocenoyl 3,4-dihydropyrimidin-2(1H)-ones
(-thiones) (DHPMs) were synthesized in modest yields via catalyst-free
and solvent-free Biginelli condensation of 1-phenylbutane-1,3-dione or 1-
ferrocenylbutane-1,3-dione, hydroxyl benzaldehyde, and urea or thiourea.
This synthetic protocol revealed that catalysts may not be necessary for the
self-assembling Biginelli reaction. The radical-scavenging abilities of the
obtained 11 DHPMs were carried out by reacting with 2,2′-azinobis(3-
ethylbenzothiazoline-6-sulfonate) cationic radical (ABTS+•), galvinoxyl
radical, and 2,2′-diphenyl-1-picrylhydrazyl radical (DPPH), respectively.
The variation of the concentration of these radicals with the reaction time
(t) followed exponential function, [radical] = Ae−t/a + Be−t/b + C. Then, the
differential style of this equation led to the relationship between the
reaction rate (r) and the reaction time (t), −d[radical]/dt = (A/a)e−t/a
+
(B/b)e−t/b, which can be used to calculate the reaction rate at any time
point. On the basis of the concept of the reaction rate, r = k[radical][antioxidant], the rate constant (k) can be calculated with
the time point being t = 0. By the comparison of k of DHPMs, it can be concluded that phenolic ortho-dihydroxyl groups
markedly enhanced the abilities of DHPMs to quench ABTS+•, but the introduction of ferrocenoyl group made DHPMs efficient
ABTS+• scavengers even in the absence of phenolic hydroxyl group. This phenomenon was also found in DHPM-scavenging
galvinoxyl radical. In contrast, the ferrocenoyl group cannot enhance the abilities of DHPMs to scavenge DPPH, and phenolic
ortho-dihydroxyl groups still played the key role in this case.
proline24 were found to be catalysts for the Biginelli
INTRODUCTION
■
condensation. The catalysts for the Biginelli condensation
were well investigated in order to increase the yield and to
expand to much more substrates. The chiral BINOL-
phosphoric catalysts afforded chiral DHPMs with 88−97% ee
and 40−86% yield.25 In addition to the heating method, other
experimental techniques have been explored. In the presence of
polyphosphate ester or the polyaniline−bismoclite complex as
catalysts, the Biginelli condensation can be finished within a few
minutes under microwave irradiation26 and ultrasound
vibration27 or in ionic liquids.28 The microwave-assisted
synthesis improved the yield when acetylacetone or acetylace-
tate acted as the reagent and Yb(OTf)3 as the catalyst.29
The solvent-free reaction became a useful strategy for the
formation of heterocycles.30 Although some DHPMs can be
prepared in the absence of catalyst and solvent,31 the catalyst-
free and solvent-free Biginelli reaction was not usually reported.
The usage of solvent was beneficial for the reaction occurring in
the same phase with high enantioselectivities.32 The reaction
can also take place on the surface of resin linked with urea via a
N atom, leading to convenient isolation of DHPMs.33 The
The multicomponent condensation was an active field in the
research of organic reactions because it can readily construct
complicated heterocyclic scaffolds.1,2 Dihydropyrimidine
(DHPM) as a N-contained heterocycle attracted much
attention due to activities of anticancer, anti-inflammatory,
antibacterial, antifungal, anthelmintic, and antitopoisomer-
ase3−5 and functions of DHPM amidohydrolase, dihydropyr-
imidinase, and dehydrogenase.6−8 Hence, the old Biginelli
reaction for the synthesis of DHPMs became an attractive
topic, and the investigation on this reaction mainly focused on
the exploration of catalysts.9−12 The original catalyst for the
Biginelli reaction was Brønsted acid, thus, Lewis acids
reasonably became the candidates for the selection of catalysts.
A decade ago, the usage of BF3 resulted in a modest yield of
DHPMs by one-pot reaction of β-ketoester, aryl aldehyde, and
urea.13 Then, some transition metallic salts were found to
catalyze the Biginelli reaction. For example, the applications of
Fe(NO3)3·9H2O,14 TiCl4,15 and InCl3 lowered the temper-
16
ature for the occurrence of the Biginelli reaction. Some non-
acidic inorganic salts including CaF2,17 CeCl3·7H2O,18
iodotrimethylsilane/NaI,19 NH4Cl,20 and even NaCl21 were
proved to be active toward the Biginelli reaction. Recently,
basic compounds such as t-(CH3)3COK,22 Ph3P,23 and L-
Received: February 14, 2012
Published: April 10, 2012
© 2012 American Chemical Society
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Table 1. Synthesis and Structures of DHPMs Employed Herein
a
compound
R1
R2
R3
R4
X
yield (%)
1
2
3
4
5
6
7
8
9
10
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
O
S
77
61
60
55
34
31
50
43
41
37
25
H
H
H
H
H
H
H
H
H
O−
H
H
H
OH
OH
OH
OH
H
O
S
H
OH
OH
H
O
S
b
Fc
Fc
Fc
Fc
Fc
O
S
H
H
H
OH
OH
H
O
S
H
c
11
H
O
a
b
c
The isolation yields. The ferrocenyl group. The structure of 11 was
Scheme 1. Structures of ABTS Salt, Galvinoxyl Radical, and DPPH
substituents in benzaldehyde were electron-withdrawing groups
or methyl and methoxyl group, but a hydroxyl group was not
often found. This background motivated us to test whether the
Biginelli reaction can take place in the absence of solvents and
catalysts. Presented here was a study on the synthesis of
benzoyl and ferrocenoyl DHPMs (structures in Table 1) in the
absence of catalysts and solvents. The abilities of the obtained
11 DHPMs to scavenge 2,2′-azinobis(3-ethylbenzothiazoline-6-
sulfonate) cationic radical (ABTS+•), galvinoxyl radical, and
2,2′-diphenyl-1-picrylhydrazyl radical (DPPH) (structures in
Scheme 1) were investigated by calculating the rate constant
(k) of DHPMs trapping these radicals.
phenolic hydroxyl group that was able to deactivate Lewis acids,
but the catalyst-free method can avoid this shortcoming. The
yields of DHPMs obtained by this method were not as high as
that in the presence of a catalyst and a solvent because the
reagents not diluted by a solvent were readily oxidized during
heating. For example, the ortho-hydroxyl group in benzaldehyde
adds to the CC in DHPM via Michael addition, forming a
tricyclic compound, 11 (yield, 25%). It was reported that
compound 11 was formed by using InBr3 (yield, 62%) and
InCl3·4H2O (yield, 58%) as catalysts.34 However, the benefit of
the present method was to simplify the operation in the
synthesis, and the clean reaction mixture resulted in a simple
isolation procedure. The residual benzoylacetone and aldehyde
were extracted by organic solvents because DHPMs were
difficult to dissolve in usually used organic solvents. The excess
of urea or thiourea was washed by ice water. Finally, the
recrystallization from DMSO/H2O or DMF/C2H5OH afforded
pure DHPMs.
RESULTS AND DISCUSSION
■
Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones (-thio-
nes) (DHPMs). DHPMs mentioned in this work were known
compounds, but they were synthesized by directly heating the
solid states of benzoylacetone or ferrocenoylacetone (1.0
equiv), hydroxyl benzaldehyde (1.0 equiv), and urea or thiourea
(1.5 equiv). The absence of solvents increased the concen-
tration of the reagents and was beneficial for shortening the
reaction period. The hydroxyl benzaldehyde was not often used
when Lewis acids acted as catalysts. This may be due to a
Scavenging ABTS+• Kinetics. ABTS+• was usually used to
test the ability of an antioxidant to reduce radicals.35 A recent
report provided a method for calculating the number of single
electrons in ABTS+• trapped by an antioxidant, in which the
reaction between ABTS+• and the antioxidant was artificially
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divided into two period: ABTS+• was trapped by fresh
antioxidant and then by the oxidized products from the
antioxidant.36 However, it is difficult to divide these two
periods completely because the reaction of the oxidized
products from the antioxidant with ABTS+• may take place
before the whole antioxidant converts into the oxidized
products, viz., the first period does not finish, and the second
period may occur. The reaction rate between antioxidants and
ABTS+• is so fast that the absorbance of ABTS+• decreases
within a few seconds after the solution of antioxidant was mixed
with ABTS+•. It is difficult to measure the decay of the
absorbance of ABTS+• at the first period in the case of artificial
mixing of two solutions. Thus, some special apparatus were
designed to measure the decay of the concentration of radicals
during the first few seconds. For example, stopped-flow
injection equipment was used to test the reaction rate of
ABTS+• with an antioxidant.37 This equipment can measure the
absorbance of ABTS+• when fresh ABTS+• just contacts with
the fresh antioxidant, but the complicated apparatus and large
exhaustion of solutions limit its application. On the other hand,
the research interests focus on the improvement of
experimental skills when the visible spectrometer was employed
to follow the decay of the absorbance of ABTS+•. For example,
the pseudo-first-order kinetic method can be used to test the
ability of an antioxidant to quench radicals. In this method, the
concentration of the antioxidant is much higher than that of
ABTS+•, meaning the variation of the concentration of the
antioxidant can be neglected. However, this method makes the
measurement of the decay of the concentration of ABTS+•
more difficult because a low concentration of ABTS+• can be
depleted by the high concentration of the antioxidant within
much shorter period. On the contrary, when the concentration
of ABTS+• is assigned to be a high value, the absorbance of
ABTS+• does not decrease, one cannot measure the decay of
the concentration of radicals. In addition, the results from the
pseudo-first-order kinetic method do not embody the influence
of the reagent with high concentration on the reaction rate
because the high concentration is composed of the value of the
reaction rate. Hence, the measurement of the decay of the
concentration of ABTS+• should be carried out at appropriate
concentrations of the antioxidant and ABTS+•, and the aim of
this work is to find a suitable mathematical function to fit the
obtained data from the measurement of the decay of the
concentration of ABTS+•.
treat the reaction between the antioxidant and ABTS+•. In
addition to the improvement of the synthetic operation,
another aim of this work is to find a suitable function to fit
the decrease of the concentration of ABTS+• in the case of limit
measured data employed, and this function is suitable not only
for ABTS+• but also for other radicals regardless of the reaction
orders for the antioxidant and the radical. Although it is difficult
to measure the decay of the concentration of ABTS+• just after
being mixed with an antioxidant, Figure 1 shows that the
Figure 1. Decay of 42.96 μM ABTS+• in the presence of various
concentrations of DHPMs.
concentration of ABTS+• decreases as the reaction time
increases. One can observe the shape of the decay line and
find that this kind of line is suitable for the exponential decay
just in light of mathematics. In spite of the chemical kinetic
meaning, the multiexponential function is applied to fit the
decay line in Figure 1. The second order of exponential
function can perfectly express the decrease of the concentration
of ABTS+• as shown in eq 1, and the coefficients in the third
and much higher items of the exponential function are so low
that the second order of exponential function is sufficient for
mathematical fitting. Occasionally, one-order exponential
function is capable of fitting the decrease of the concentration
of the radical (see compound 5 and 6 in Table 3). Equation 1 is
just a mathematical equation to express the variation of
[ABTS+•] versus reaction time (t).
The most important index for a reaction is the rate constant
(k), which can be calculated by the relationship between the
concentration of reagents and the reaction rate (r), k = r/
([antioxidant]a[radical]b). The calculation of k is based on the
measurements of r and the reaction order for every reagent, a
and b. For example, in the oxidation of γ-terpinene by 2,2′-
azobis(isobutyronitrile) (AIBN), the reaction orders for γ-
terpinene and AIBN (a and b) were first confirmed by
measuring the formation rate of p-cymene in the case of fixing
the concentration of one reagent and varying another one.38
This method is a popular way to measure the reaction rate and
then to calculate the rate constant, but the amount of the
experimental operation of this method is very large. Previous
reports revealed that the reaction between an antioxidant and a
radical followed bimolecular kinetics, viz., first-order kinetics for
the antioxidant and for the radical.39 The kinetic equation for a
second-order reaction with different concentrations of two
[ABTS+•] = Ae−t/a + Be−t/b + C
(1)
reagents, ln([antioxidant]/[radical]) = kt([antioxidant]0
[radical]0) + ln([antioxidant]0/[radical]0), can be applied to
−
Figure 1 outlines that the concentration of ABTS+• decreased
with the reaction period (t) in the presence of DHPMs. The
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Table 2. Equation of [ABTS+•] ∼ t and Its Differential Style (−d[ABTS+•]/dt ∼ t), Reaction Rate at t = 0 (r0), and Rate
a
Constant (k)
compound
equation of [ABTS+• (μM)] ∼ t (s)
[ABTS+•] = 21.15e−t/164.48 + 13.06e−t/203.51 + 10.56
equation of −d[ABTS+•]/dt ∼ t
d[ABTS+•
r0 (μM·s−1
)
k (nM−1·s−1
)
6.40 × 10−3
2
0.078
]
]
]
]
]
]
]
]
]
]
−
−
−
−
−
−
−
−
−
−
= 0.018e−t/164.48 + 0.06e−t/203.51
= 1.32e−t/8.99 + 0.05e−t/287.60
= 0.79e−t/16.54 + 0.04e−t/293.26
= 4.43e−t/6.10 + 0.02e−t/548.81
= 5.56e−t/4.93 + 0.03e−t/515.67
= 1.53e−t/10.00 + 0.05e−t/381.56
= 1.13e−t/18.50 + 0.03e−t/554.44
= 1.77e−t/10.02 + 0.04e−t/447.03
= 1.82e−t/12.50 + 0.03e−t/434.25
= 1.85e−t/12.88 + 0.05e−t/251.51
dt
d[ABTS+•
[ABTS+•] = 11.91e−t/8.99 + 12.68e−t/287.60 + 16.62
[ABTS+•] = 13.11e−t/16.54 + 13.35e−t/293.26 + 14.85
[ABTS+•] = 27.04e−t/6.10 + 12.01e−t/548.81 + 4.69
[ABTS+•] = 27.42e−t/4.93 + 15.70e−t/515.67 + 0.00
[ABTS+•] = 15.33e−t/10.00 + 19.19e−t/381.56 + 7.93
[ABTS+•] = 24.67e−t/18.50 + 15.99e−t/554.44 + 2.46
[ABTS+•] = 17.71e−t/10.02 + 17.07e−t/447.03 + 8.05
[ABTS+•] = 22.80e−t/12.50 + 13.99e−t/434.25 + 5.53
[ABTS+•] = 23.89e−t/12.88 + 13.24e−t/251.51 + 5.20
3
4
1.37
0.83
4.45
5.59
1.58
1.36
1.81
1.85
1.90
0.21
dt
d[ABTS+•
0.13
dt
d[ABTS+•
5
4.14
dt
d[ABTS+•
6
5.20
dt
d[ABTS+•
7
0.24
dt
d[ABTS+•
8
0.21
dt
d[ABTS+•
9
0.28
dt
d[ABTS+•
10
11
0.29
dt
d[ABTS+•
0.30
dt
a
The concentration of 2 was 300 μM, and the concentrations of 5 and 6 were 25.0 μM. The concentrations of other compounds were 150 μM. The
concentration of ABTS+• was 42.96 μM.
data of [ABTS+•] and reaction period (t) were input into
statistical software, the coefficients, A, B, C, a, and b were given
and listed in Table 2.
Equation 2, the differential style of eq 1, indicated the
variation of the reaction rate (r = −d[ABTS+•]/dt) with the
reaction time (t). The obtained equations of −d[ABTS+•]/dt ∼
t are listed in Table 2.
The compound 1 was not able to quench ABTS+•, and
compound 2 just possessed a very low value of k, indicating
that the H in N−H of DHPMs cannot react with ABTS+• in the
absence of phenolic −OH. Contrarily, high values of k for 5
and 6 (4.14 and 5.20 nM−1·s−1, respectively) indicated that 5
and 6 were able to quench ABTS+• efficiently, owing to
phenolic ortho-dihydroxyl groups. The k value of 6 was higher
than that of 5, revealing that CS in the skeleton of DHPM
was beneficial for the phenolic −OH to react with ABTS+•.
This result also implicated that phenolic −OH existed in an
intramolecular synergistic effect with CS, although the
distance between these two functional groups was long.
Moreover, k values from compounds 7 to 11 ranged a narrow
scale from 0.21 to 0.30 nM−1·s−1, demonstrating that the
introduction of the ferrocene moiety to modify DHPM led to
an average effect on scavenging ABTS+•, but it was worthy to
note that k values of compounds 7 and 8 (0.24 and 0.21
nM−1·s−1, respectively) were much higher than that of
compounds 1 and 2 (not detected and 6.40 × 10−3 nM−1·s−1,
respectively), indicating that the ferrocene moiety markedly
enhanced the abilities of DHPMs to scavenge ABTS+•. This
phenomenon was also found by comparing k values of
compounds 9 and 10 with those of 3 and 4. The structures
of 3 and 4 were correspondingly similar to those of 9 and 10.
The phenyl group in 3 and 4 (k values were 0.21 and 0.13
nM−1·s−1, respectively) was replaced by ferrocenyl group to
form 9 and 10 (k values were 0.28 and 0.29 nM−1·s−1,
respectively), leading to high abilities of 9 and 10 to scavenge
ABTS+•. Thus, the ferrocenoyl group also existed in an
intramolecular synergistic effect with phenolic −OH on
reducing ABTS+•. On the other hand, it can be found that k
values of 9 and 10 were not remarkably higher than those of 7
and 8, indicating that phenolic −OH did not increase the
d(Ae−t/a + Be−t/b + C)
d[ABTS+•
]
=
=
dt
dt
d(Ae−t/a
)
d(Be−t/b
)
dC
dt
+
+
dt
dt
d[ABTS+•
]
A
a
B
b
viz. −
= r = e−t/a
+
e−t/b
(2)
dt
The reaction rate at t = 0 (r0) can be calculated by the equation
of −d[ABTS+•]/dt ∼ t when t was assigned to be 0, as shown in
eq 3, and the results were involved in Table 2, as well.
A
a
B
b
A
a
B
b
r0 = e−0/a
+
e−0/b
=
+
(3)
According to the concept of the reaction rate, r was the product
of the concentrations of ABTS+• and the antioxidant as shown
in eq 4.
r = k[ABTS+•][antioxidant]
(4)
Therefore, the rate constant, k (nM−1·s−1), can be calculated by
eq 5 when the value of every item was assigned at t = 0, and the
results were collected in Table 2, as well.
r0
k =
[ABTS+•]0[antioxidant]0
(5)
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abilities of ferrocenoyl DHPMs to scavenge ABTS+•. In
particular, the high value of k of compound 11 (0.30 nM−1·s−1)
revealed that N−H in ferrocenoyl DHPMs can also reduce
ABTS+• even without the aid of phenolic −OH. Therefore, it
can be concluded that the ferrocene moiety played the key role
in scavenging ABTS+• and even weakened the influence of
phenolic −OH on scavenging ABTS+•.
Scavenging Galvinoxyl Radical Kinetics. Galvinoxyl
radical was widely employed to evaluate the ability of an
antioxidant to contribute the hydrogen atom to the oxygen
radical.40 Figure 2 showed the decrease of the concentration of
the exponential function, and then, the derivation operation
was performed on the equations of [galvinoxyl] ∼ t to obtain
−d[galvinoxyl]/dt ∼ t. The following calculation was the same
as DHPM-scavenging ABTS+•, and the results are listed in
Table 3.
Among benzoyl DHPMs, only compounds 5 and 6 were
active to quench the galvinoxyl radical with relatively low values
of k, 0.43 and 0.64 nM−1·s−1, respectively, due to ortho-
dihydroxyl groups donating the H atom to the oxygen radical.
In contrast, all of the ferrocenoyl DHPMs can quench the
galvinoxyl radical and generate relative high k values ranging
from 1.34 to 2.14 nM−1·s−1. Hence, the introduction of the
ferrocene moiety enhanced the abilities of DHPMs to
contribute the H atom to the oxygen radical. In the absence
of phenolic −OH, compounds 7, 8, and 11 still generated 1.34,
1.50, and 1.60 nM−1·s−1 k values, respectively. The H atom in
N−H of DHPMs can be donated to the oxygen radical, owing
to the presence of the ferrocene moiety. Furthermore, only one
phenolic −OH increased k values of compounds 9 and 10 to
1.90 and 2.14 nM−1·s−1, respectively, demonstrating that the
ferrocene moiety can also enhance the abilities of DHPMs to
donate the H atom in phenolic −OH to the oxygen radical.
Scavenging DPPH Kinetics. DPPH was a nitrogen-
centered radical. Figure 3 shows the decrease of the
Figure 2. Decay of 7.49 μM galvinoxyl radical in the presence of
various concentrations of DHPMs.
Figure 3. Decay of 258.20 μM DPPH in the presence of various
concentrations of DHPMs.
galvinoxyl radical in the presence of compounds 5−11. Other
DHPMs cannot quench the galvinoxyl radical. The decay of the
concentration of galvinoxyl radical with reaction time also fitted
Table 3. Equation of [Galvinoxyl] ∼ t and Its Differential Style (−d[Galvinoxyl]/dt ∼ t), Reaction Rate at t = 0 (r0), and Rate
a
Constant (k)
compound
equation of [galvinoxyl (μM)] ∼ t
[galvinoxyl] = 6.76e−t/85.22 + 0.12
equation of −d[galvinoxyl]/dt ∼ t
r0 (μM·s−1
)
k (nM−1·s−1
)
5
0.08
0.43
d[galvinoxyl]
−
−
−
−
−
−
−
= 0.08e−t/85.22
dt
[galvinoxyl] = 6.66e−t/55.74 − 0.40
6
7
0.12
0.25
0.28
0.35
0.40
0.30
0.64
1.34
1.50
1.90
2.14
1.60
d[galvinoxyl]
= 0.12e−t/55.74
dt
[galvinoxyl] = 1.56e−t/6.19 + 0.57e−t/288.06 + 5.20
[galvinoxyl] = 1.86e−t/6.84 + 1.31e−t/194.10 + 4.16
[galvinoxyl] = 1.74e−t/5.01 + 1.11e−t/249.63 + 4.48
[galvinoxyl] = 2.57e−t/6.43 + 0.73e−t/255.63 + 4.04
[galvinoxyl] = 2.17e−t/7.26 + 0.57e−t/186.53 + 4.60
d[galvinoxyl]
= 0.25e−t/6.19 + 1.98 × 10−3e−t/288.06
= 0.27e−t/6.84 + 6.75 × 10−3e−t/194.10
= 0.35e−t/5.01 + 4.45 × 10−3e−t/249.63
= 0.40e−t/6.43 + 2.85 × 10−3e−t/255.63
= 0.30e−t/7.26 + 3.06 × 10−3e−t/186.53
dt
8
d[galvinoxyl]
dt
9
d[galvinoxyl]
dt
10
11
d[galvinoxyl]
dt
d[galvinoxyl]
dt
a
The concentration of DHPM was 25.0 μM, and the concentration of the galvinoxyl radical was 7.49 μM. The second items in the equation of
[galvinoxyl (μM)] ∼ t of compounds 5 and 6 were omitted because the coefficients were very small.
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Table 4. Equation of [DPPH] ∼ t and Its Differential Style (−d[DPPH]/dt ∼ t), Reaction Rate at t = 0 (r0), and Rate Constant
a
(k)
compound
equation of [DPPH (μM)] ∼ t
equation of −d[DPPH]/dt ∼ t
r0 (μM·s−1
)
k (nM−1·s−1
)
[DPPH] = 104.34e−t/387.83 + 130.59e−t/68.16 + 26.08
5
2.18
0.34
d[DPPH]
−
−
= 0.27e−t/387.83 + 1.91e−t/68.16
= 1.54e−t/94.45 + 0.25e−t/389.25
dt
[DPPH] = 147.29e−t/95.45 + 98.98e−t/389.25 + 19.83
6
1.79
0.28
d[DPPH]
dt
a
The concentration of DHPM was 25.0 μM, and the concentration of DPPH was 258.20 μM.
identified by 1H NMR. DHPMs were detected by gas chromatography
equipped with mass spectra (GC/MS).
concentration of DPPH in the presence of compounds 5 and 6.
The decay of the concentration of DPPH with the reaction
time also fitted the exponential function, and then, the
derivation operation was performed on the equations of
[DPPH] ∼ t to obtain −d[DPPH]/dt ∼ t as shown in eq 6.39
General Procedure for the Synthesis of DHPMs (Com-
pounds 1−11). 1-Phenylbutane-1,3-dione or 1-ferrocenylbutane-1,3-
dione (2 mmol), the corresponding aldehyde (2 mmol), and urea or
thiourea (3 mmol) were mixed at solid states and heated at 100 °C for
4 h under stirring. After the mixture was cooled to room temperature,
it was washed with ether or ethyl acetate. The residual solid was
washed with cold water (10 mL × 2) and dried to give crude DHPMs.
Compound 1−6 were recrystallized from DMSO/H2O, and
compounds 7−11 were recrystallized from DMF/C2H5OH.
5-Benzoyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-
d[DPPH]
−
= r = k[DPPH][antioxidant]
(6)
dt
The following calculation was the same as DHPM-scavenging
ABTS+•, and the results are listed in Table 4.
1
The data for DPPH showed a completely different picture
from that of either ABTS+• or the galvinoxyl radical. Except for
5 and 6, other DHPMs cannot trap DPPH, revealing that the H
atom in N−H of DHPMs and in single phenolic −OH cannot
be abstracted by the nitrogen radical, and the introduction of
the ferrocene moiety cannot ameliorate the abilities of DHPMs
to quench the nitrogen radical either. The phenolic ortho-
dihydroxyl groups in DHPMs acted as the scavengers toward
DPPH. The introduction of the ferrocenoyl group actually
enhances the reactivity of DHPMs toward radicals, but the
chemical mechanisms were different for a redox-active radical
(ABTS+·) and for a H acceptor (galvinoxyl radical and DPPH).
For example, ferrocene-appended chalcones without a phenolic
hydroxyl group attached were still able to reduce ABTS+• by
Fe(II)/Fe(III) redox, but the abilities to quench the galvinoxyl
radical and DPPH were lower than those chalcones with a
phenolic hydroxyl group attached. Thus, the phenolic hydroxyl
group played the main role in donating a H atom to the
galvinoxyl and DPPH radical.41
one (1): Yield 77%; mp 226−228 °C; H NMR (300 MHz, DMSO-
d6) δ 1.66 (s, 3H), 5.30 (s, 1H), 7.18−7.53 (m, 10H), 7.80 (s, 1H),
9.17 (s, 1H); MS m/z 291.07 [M+•].
(6-Methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-
1
yl)phenylmethanone (2): Yield 61%; mp 242−244 °C; H NMR
(300 MHz, DMSO-d6) δ 1.72 (s, 3H), 5.29 (s, 1H), 7.16−7.55 (m,
10H), 9.68 (s, 1H), 10.35 (s, 1H); MS m/z 307.98 [M+•].
5-Benzoyl-4-(4′-hydroxyphenyl)-6-methyl-3,4-dihydropyri-
1
midin-2(1H)-one (3): Yield 60%; mp 234−236 °C; H NMR (300
MHz, DMSO-d6) δ 1.66 (s, 3H), 5.19 (d, J = 2.4 Hz, 1H), 6.66 (d, J =
8.4 Hz, 2H), 6.98 (d, J = 8.4 Hz, 2H), 7.41−7.52 (m, 5H), 7.66 (s,
1H), 9.08 (s, 1H), 9.32 (s, 1H); MS m/z 307.99 [M+•].
(4-(4′-Hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahy-
dropyrimidin-5-yl)phenylmethanone (4): Yield 55%; mp 259−
260 °C; 1H NMR (300 MHz, DMSO-d6) δ 1.71 (s, 3H), 5.18 (s, 1H),
6.68 (d, J = 6.6 Hz, 2H), 6.96 (d, J = 8.7 Hz, 2H), 7.41−7.54 (m, 5H),
9.41 (s, 1H), 9.56 (s, 1H), 10.24 (s, 1H); MS m/z 323.98 [M+•].
5-Benzoyl-4-(3′,4′-dihydroxyphenyl)-6-methyl-3,4-dihydro-
1
pyrimidin-2(1H)-one (5): Yield 34%; mp >300 °C (decomp); H
NMR (300 MHz, DMSO- d6) δ 1.66 (s, 3H), 5.14 (s, 1H), 6.40 (d, J =
8.1 Hz, 1H), 6.61 (d, J = 9.6 Hz, 2H), 7.42−7.55 (m, 5H), 7.65 (d,
1H), 8.77 (s, 1H), 8.90 (s, 1H), 9.06 (s, 1H); MS m/z 323.07 [M+•].
(4-(3′,4′-Dihydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetra-
hydropyrimidin-5-yl)phenylmethanone (6): Yield 31%; mp >300
CONCLUSION
■
1
The catalyst seemed unnecessary for the Biginelli condensation,
which can take place under heating conditions in the absence of
any solvents. Therefore, the formation of DHPMs was a self-
assembling procedure occurring among aldehyde, β-diketone,
and urea or thiourea. The benzoyl and ferrocenoyl DHPMs
were able to quench ABTS+•, galvinoxyl radical, and DPPH.
Although phenolic hydroxyl was of importance for DHPMs to
quench ABTS+•, the presence of the ferrocene moiety
converted DHPMs into ABTS+• scavengers even without a
phenolic hydroxyl attached. This rule was reinforced in the
interaction between DHPMs and the galvinoxyl radical, but the
ferrocene moiety did not enhance the abilities of DHPMs to
scavenge DPPH, and phenolic ortho-dihydroxyl groups still
played the key role in this case.
°C (decomp); H NMR (300 MHz, DMSO-d6) δ 1.72 (s, 3H), 5.12
(s, 1H), 6.37−6.41 (dd, J = 1.8 Hz, J = 7.8 Hz, 1H), 6.59−6.65 (m,
2H), 7.42−7.58 (m, 5H), 8.88 (s, 1H), 8.98 (s, 1H), 9.54 (s, 1H),
10.23 (s, 1H); MS m/z 339.99 [M+•].
5-Ferrocenoyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-
1
2(1H)-one (7): Yield 50%; mp 270−274 °C (decomp); H NMR
(300 MHz, DMSO-d6) δ 1.85 (s, 3H), 3.82 (s, 5H), 4.42 (s, 1H), 4.53
(s, 2H), 4.77 (s, 1H), 5.43 (s, 1H), 7.27−7.43 (m, 5H), 7.66 (s, 1H);
MS m/z 400.05 [M+•].
5-Ferrocenoyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-
1
2(1H)-thione (8): Yield 43%; mp 262−265 °C (decomp); H NMR
(300 MHz, DMSO-d6) δ 1.89 (s, 3H), 3.83 (s, 5H), 4.46−4.79 (m,
4H), 5.44 (d, J = 3.3 Hz, 1H), 7.33−7.45 (m, 5H), 9.53 (s, 1H), 10.12
(s, 1H); MS m/z 415.96 [M+•].
5-Ferrocenoyl-6-methyl-4-(4′-hydroxyphenyl)-3,4-dihydro-
pyrimidin-2(1H)-one (9): Yield 41%; mp 240−246 °C (decomp);
1H NMR (300 MHz, DMSO-d6) δ 1.83 (s, 3H), 3.83 (s, 5H), 4.41−
EXPERIMENTAL SECTION
■
4.75 (m, 4H), 5.33 (s, 1H), 6.77 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.1
Hz, 2H), 7.54 (s, 1H); MS m/z 416.00 [M+•].
Materials and Instrumentation. Diammonium 2,2′-azinobis(3-
ethylbenzothiazoline-6-sulfonate) (ABTS), 2,2′-diphenyl-1- picrylhy-
drazyl radical (DPPH), and galvinoxyl radical were purchased from
ACROS ORGANICS, Geel, Belgium. Other agents were of analytical
grade and used directly. The structures of the obtained products were
5-Ferrocenoyl-6-methyl-4-(4′-hydroxyphenyl)-3,4-dihydro-
pyrimidin-2(1H)-thione (10): Yield 37%; mp 264−268 °C
1
(decomp); H NMR (300 MHz, DMSO-d6) δ 1.87 (s, 3H), 3.85 (s,
5H), 4.46 (s, 1H), 4.56 (s, 2H), 4.77 (s, 1H), 5.34 (s, 1H), 6.78 (d, J =
3957
dx.doi.org/10.1021/jo300282y | J. Org. Chem. 2012, 77, 3952−3958

The Journal of Organic Chemistry
Article
8.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 9.41 (s, 1H), 9.46 (s, 1H), 10.01
(s, 1H); MS m/z 431.90 [M+•].
(12) Biggs-Houck, J. E.; Younai, A.; Shaw, J. T. Curr. Opin. Chem.
Biol. 2010, 14, 371−382.
13-Ferrocenoyl-9-methyl-11-oxo-8-oxa-10,12-diazatricyclo-
(13) Hu, E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63,
3454−3457.
[7.3.1.02,7]trideca-2,4,6-triene (11): Yield 25%; mp 256−262 °C
1
(decomp); H NMR (300 MHz, DMSO-d6) δ 1.72 (s, 3H), 3.74 (s,
(14) Phukan, M.; Kalita, M. K.; Borah, R. Green Chem. Lett. Rev.
2010, 3, 329−334.
1H), 4.31 (s, 5H), 4.47−4.90 (m, 5H), 6.81−7.25 (m, 5H), 7.57 (s,
1H); MS m/z 415.99 [M+•].
(15) Nagawade, R. R.; Kotharkar, S. A.; Shinde, D. B. Mendeleev
Commun. 2005, 15, 150−151.
Scavenging DPPH, ABTS+•, and Galvinoxyl radicals. DPPH
and galvinoxyl radical were dissolved in 50 mL of ethanol to make the
absorbance around 1.00 at 517 nm (εDPPH = 4.09 × 103 M−1 cm−1)
and 428 nm (εgalvinoxyl = 1.4 × 105 M−1 cm−1), respectively. ABTS+•
was produced from 2.0 mL of aqueous solution containing 4.0 mM
ABTS and 1.41 mM K2S2O8 after kept for 16 h and diluted by 100 mL
of ethanol. The absorbance of ABTS+• solution was around 0.70 at 734
nm (εABTS+• = 1.6 × 104 M−1 cm−1). The DMSO solutions of DHPMs
(0.1 mL) were added to 1.9 mL of DPPH or galvinoxyl radical solution
with the final concentrations of DHPMs being 25.0 μM. The DMSO
solutions of DHPMs (0.1 mL) were added to 1.9 mL of ABTS+• with
the final concentrations of DHPMs being 300.0 μM for compounds 1
and 2, 150 μM for 3, 4, and 7−11, and 25 μM for 5 and 6. The
decreases of the absorbance of these radicals were recorded at 20 °C
with a certain time interval.
(16) Ranu, B. C.; Hajra, A.; Jana, U. J. Org. Chem. 2000, 65, 6270−
6272.
(17) Chitra, S.; Pandiarajan, K. Tetrahedron Lett. 2009, 50, 2222−
2224.
(18) Han, B.; Han, R.-F.; Ren, Y.-W.; Duan, X.-Y.; Xu, Y.-C.; Zhang,
W. Tetrahedron 2011, 67, 5615−5620.
(19) Sabitha, G.; Reddy, G. S. K. K.; Reddy, C. S.; Yadav, J. S. Synlett
2003, 6, 858−860.
(20) Shaabani, A.; Bazgir, A.; Teimouri, F. Tetrahedron Lett. 2003, 44,
857−859.
(21) Kolosov, M. A.; Orlov, V. D.; Beloborodov, D. A.; Dotsenko, V.
V. Mol. Diversity 2009, 13, 5−25.
(22) Shen, Z.-L.; Xu, X.-P.; Ji, S.-J. J. Org. Chem. 2010, 75, 1162−
1167.
Statistical Analysis. All of the data were the average value from at
least three independent measurements with the experimental error
within 10%. The relationships between the concentrations of radicals
and the reaction time were fitted by a second-order exponential
function in Origin 7.5 professional software.
(23) Debache, A.; Amimour, M.; Belfaitah, A.; Rhouati, S.; Carboni,
B. Tetrahedron Lett. 2008, 49, 6119−6121.
(24) Pandey, J.; Anand, N.; Tripathi, R. P. Tetrahedron 2009, 65,
9350−9356.
(25) Guillena, G.; Ramon
2007, 18, 693−700.
́
, D. J.; Yus, M. Tetrahedron: Asymmetry
ASSOCIATED CONTENT
(26) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem.
2004, 4957−4980.
■
S
* Supporting Information
(27) Cella, R.; Stefani, H. A. Tetrahedron 2009, 65, 2619−2641.
(28) Isambert, N.; del Mar Sanchez Duque, M.; Plaquevent, J.-C.;
1H NMR and MS spectra for compounds 1−11. This material
is available free of charge via the Internet at http://pubs.acs.org.
́
Genisson, Y.; Rodriguez, J.; Constantieux, T. Chem. Soc. Rev. 2011, 40,
1347−1357.
AUTHOR INFORMATION
(29) Piqani, B.; Zhang, W. Beilstein J. Org. Chem. 2011, 7, 1294−
■
1298.
Corresponding Author
*E-mail: zaiqun-liu@jlu.edu.cn.
(30) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.;
Machado, P. Chem. Rev. 2009, 109, 4140−4182.
(31) Ranu, B. C.; Hajra, A.; Dey, S. S. Org. Process Res. Dev. 2002, 6,
817−818.
(32) Lou, S.; Dai, P.; Schaus, S. E. J. Org. Chem. 2007, 72, 9998−
10008.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(33) Le Quement, S. T.; Petersen, R.; Meldal, M.; Nielsen, T. E.
Biopolymers 2010, 94, 242−256.
Financial support from Jilin Provincial Foundation for Natural
Science, China (201115017), is acknowledged gratefully.
(34) Fu, N.-Y.; Yuan, Y.-F.; Pang, M.-L.; Wang, J.-T.; Peppe, C. J.
Organomet. Chem. 2003, 672, 52−57.
(35) Scott, S. L.; Chen, W.-J.; Babac, A.; Espenson, J. H. J. Phys.
Chem. 1993, 97, 6710−6714.
REFERENCES
■
(1) Yu, J.; Shi, F.; Gong, L.-Z. Acc. Chem. Res. 2011, 44, 1156−1171.
(2) Dondoni, A.; Massi, A. Acc. Chem. Res. 2006, 39, 451−463.
(3) Sakata, K.-I.; Someya, M.; Matsumoto, Y.; Tauchi, H.; Kai, M.;
Toyota, M.; Takagi, M.; Hareyama, M.; Fukushima, M. Cancer Sci.
2011, 102, 1712−1716.
(36) Munoz-Munoz, J. L.; Garcia-Molina, F.; Varon, R.; Tudela, J.;
García-Can
58, 2062−2070.
(37) Ivekovic,
2005, 130, 708−714.
́
ovas, F.; Rodriguez-Lopez, J. N. J. Agric. Food Chem. 2010,
́
́ ́
D.; Milardovic, S.; Roboz, M.; Grabaric, B. S. Analyst
(4) Ramesh, B.; Bhalgat, C. M. Eur. J. Med. Chem. 2011, 46, 1882−
1891.
(38) Foti, M. C.; Sortino, S.; Ingold, K. U. Chem.Eur. J. 2005, 11,
1942−1948.
(5) Zhu, L.; Cheng, P.; Lei, N.; Yao, J.; Sheng, C.; Zhuang, C.; Guo,
W.; Liu, W.; Zhang, Y.; Dong, G.; Wang, S.; Miao, Z.; Zhang, W. Arch.
Pharm. Chem. Life Sci. 2011, 344, 726−734.
(39) Litwinienko, G.; Ingold, K. U. J. Org. Chem. 2005, 70, 8982−
8990.
(40) Havenith, R. W. A.; de Wijs, G. A.; Attema, J. J.; Niermann, N.;
Speller, S.; de Groot, R. A. J. Phys. Chem. A 2008, 112, 7734−7738.
(41) Nabi, G.; Liu, Z.-Q. Bioorg. Med. Chem. Lett. 2011, 21, 944−946.
(6) Schroeder, P. E.; Jensen, P. B.; Sehested, M.; Hofland, K. F.;
Langer, S. W.; Hasinoff, B. B. Cancer Chemother. Pharmacol. 2003, 52,
167−174.
(7) Schroeder, P. E.; Hasinoff, B. B. Drug Metab. Dispos. 2005, 33,
1367−1372.
(8) Kaira, K.; Serizawa, M.; Koh, Y.; Miura, S.; Kaira, R.; Abe, M.;
Nakagawa, K.; Ohde, Y.; Okumura, T.; Murakami, H.; Tsuya, A.;
Nakamura, Y.; Naito, T.; Takahashi, T.; Kondo, H.; Nakajima, T.;
Endo, M.; Yamamoto, N. Lung Cancer 2011, 74, 419−425.
(9) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879−888.
(10) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043−1052.
(11) Dondoni, A.; Massi, A. Mol. Diversity 2003, 6, 261−270.
3958
dx.doi.org/10.1021/jo300282y | J. Org. Chem. 2012, 77, 3952−3958