Free-radical oxidation of 1,2,3,4-tetrahydro-2-oxopyrimidines

Article abstract of DOI:10.1007/s00706-011-0573-8

Free-radical oxidation of 4-substituted 5-acetyl-and 5-carboethoxy-1,2,3,4- tetrahydro-2-oxopyrimidines using benzoyl peroxide under thermal conditions has been investigated to elucidate the effects of the nature of the substituents in the 4- and 5-positi

Full text of DOI:10.1007/s00706-011-0573-8

Monatsh Chem (2012) 143:277–281
DOI 10.1007/s00706-011-0573-8
ORIGINAL PAPER
Free-radical oxidation of 1,2,3,4-tetrahydro-2-oxopyrimidines
•
Hamid Reza Memarian Nazanin Jafarpour
•
Asadallah Farhadi
Received: 23 December 2010 / Accepted: 12 July 2011 / Published online: 24 August 2011
Ó Springer-Verlag 2011
Abstract Free-radical oxidation of 4-substituted 5-acetyl-
and 5-carboethoxy-1,2,3,4-tetrahydro-2-oxopyrimidines using
benzoyl peroxide under thermal conditions has been inves-
tigated to elucidate the effects of the nature of the
substituents in the 4- and 5-positions on the rate of reac-
tion. Whereas the presence of the acetyl group instead of
the carboethoxy group in position 5 decreases the rate of
oxidation, the nature of the additional substituent (electron-
releasing or electron-withdrawing group) and also its
location on the phenyl ring attached to C-4 of the tetra-
hydropyrimidinone ring effectively influence the rate of
reaction. The latter observation supports the proposal that
the removal of the 4-hydrogen on the heterocyclic ring
occurs in the rate-determining step.
these compounds and their substituted derivatives have
well-known biological and medicinal applications, such as
antifungal, antiviral, anticancer, antibacterial, anti-inflam-
matory, antitubercular, and antihypertensive effects [1–6].
The development of efficient methods for the oxidation
of various organic compounds is of interest [7]. The course
of the dehydrogenation of THPMs as a route to the syn-
thesis of 1,2-dihydropyrimidinones (DHPMs) depends on
the effects of the nature of the substituents located on the
4- and 5-positions of the heterocyclic ring. Various meth-
ods have been utilized for the synthesis of DHPMs by
oxidation of the corresponding THPMs, but many methods
faced major drawbacks due to harsh reaction conditions,
longer reaction time, low yield, and formation of undesir-
able side products [8–10]. Recently, we reported the
efficient oxidation of these compounds by potassium per-
oxydisulfate in aqueous acetonitrile under thermal [11],
sono-thermal [12, 13], and microwave [14] activation.
According to the proposed mechanism removal of the
4-hydrogen is the rate-determining step. The hydroxyl rad-
ical formed by the reaction of potassium sulfate radical and
water acts as the active hydrogen-abstracting species. This
argument is supported by the influence of the steric and
electronic effects of the substituents attached to C-4 and C-5
of the heterocyclic ring on the rate of the hydrogen removal.
Benzoyl peroxide (BPO) is used as a catalyst, initiator,
oxidizing, and curing agent [15, 16]. The half-life of BPO
is one of the lowest for the cross-linking peroxides (10 h at
73 °C and 1 h at 92 °C) [17]. BPO decomposes thermally
to produce high energy benzoyloxy radicals (*500 kJ/mol
[18]) and is a widely used initiator for radical reactions.
Major examples are intermolecular additions and cycliza-
tion reactions [19]. Also the oxidation of different types of
1,4-dihydropyridines to pyridine derivatives with BPO as
free-radical oxidizing agent is reported [20, 21].
Keywords Benzoyl peroxide ꢀ
Tetrahydropyrimidinones ꢀ Free radical ꢀ
Oxidation ꢀ Substituent effects
Introduction
The synthesis of 1,2,3,4-tetrahydro-2-oxopyrimidines
(THPMs), also known as 3,4-dihydropyrimidin-2(1H)-ones
or Biginelli compounds, has gained importance because
H. R. Memarian (&) ꢀ N. Jafarpour
Catalysis Division, Department of Chemistry,
Faculty of Science, University of Isfahan,
81746-73441 Isfahan, Iran
e-mail: memarian@sci.ui.ac.ir
Present Address:
A. Farhadi
Faculty of Petroleum Engineering, Petroleum University
of Technology of Ahwaz, 44471-61981 Ahwaz, Iran
123

278
H. R. Memarian et al.
In continuation to these works, we were interested to
Table 2 Oxidation of 1a by BPO in dry acetonitrile under different
atmospheres
investigate the oxidation of the title compound by another
radical species to elucidate the steric and electronic effects
of substituents on the rate of reaction and also to confirm
the earlier proposed mechanism, namely oxidation by way
of radicals. Herein, we wish to report the results concerning
thermal oxidation of THPMs by BPO on free-radical oxi-
dation and analyze the following aspects:
Atmosphere
Time/ha
Yield/%
Air saturated
Oxygen
6
6
3
95
70
95
Argon
1a/BPO = 1:3.5
a
Maximum progression of the reaction
1. To determine the effect of the substituent in the 4- and
5- positions of the THPM ring on the rate of oxidation
2. To determine the occurrence of any possible side
reactions due to the presence of allylic hydrogen in the
methyl group in position 6.
2a was formed and possible further oxidation or dealky-
lation of 6-CH3 was not observed, as are reported by using
other oxidants [9, 10].
Since oxygen inhibits the radical reactions, the oxidation
of 1a was performed in air-saturated acetonitrile and also
by bubbling oxygen or argon during the reaction under
reflux conditions. The data presented in Table 2 indicate
that the presence of oxygen decreases the rate and yield of
reaction.
Results and discussion
Optimization of reaction conditions
Under optimized reaction conditions, various 5-carbo-
ethoxy-1,2,3,4-tetrahydro-2-oxopyrimidines 1a–1n and
5-acetyl-1,2,3,4-tetrahydro-2-oxopyrimidines 3a–3n were
subjected to the oxidation reaction by BPO in acetonitrile
under an argon atmosphere at 100 °C (Scheme 1). The
results are summarized in Tables 3 and 4.
To optimize the reaction conditions and evaluate the fac-
tors that influence the rate of reaction, the following points
were taken into account:
1. The nature and effects of solvent and its boiling point
on the solubility of the starting material and especially
on the lifetime of BPO
The results presented in Tables 3 and 4 indicate that
5-carboethoxy-THPMs 1a–1n were oxidized faster than the
corresponding 5-acetyl-THPMs 3a–3n. The same trends
were also observed in the oxidation reactions of these
compounds by potassium peroxydisulfate under thermal
conditions [11], sono-thermal reaction [12, 13], or under
microwave irradiation [14]. These observations led us to
propose the following mechanism for the oxidation of
THPMs by BPO (Scheme 2).
2. The presence of an oxygen or argon atmosphere
3. The molar ratios of the reactants.
We first investigated the oxidation of ethyl 1,2,3,4-tet-
rahydro-6-methyl-2-oxo-4-phenylpyrimidine-5-carboxylate
(1a) as a model compound in the presence of various
amounts of BPO by refluxing in ethanol/acetonitrile under
an argon atmosphere. The results presented in Table 1
indicate that acetonitrile is a suitable solvent for this pur-
pose. These results also indicate that in this oxidative
reaction a 3.5:1 ratio of BPO/1a is necessary for the
effective removal of two hydrogens from 1a in a shorter
reaction time. It is noteworthy that with an increase of the
BPO/1a ratio, the time of oxidation was shortened, but only
According to the proposed mechanism, thermolysis of
the weakest O–O bond in BPO in the first step leads to the
formation of a benzoyloxy radical (BOꢀ). In the next step,
BOꢀ abstracts a hydrogen atom from the more covalent
C–H bond rather than from the less covalent N–H bond
leading to formation of a trihydropyrimidinyl radical
R2
R2
H
O
Table 1 Oxidation of 1a by BPO in refluxing acetonitrile and ethanol
under an argon atmosphere
O
BPO
R1
H3C
R1
H3C
NH
N
1a/BPO
Solvent
Time/ha
Yield/%
Δ
N
O
N
H
O
1:1
1:2
1:3
1:3.5
1:4
1:3.5
a
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Acetonitrile
Ethanol
8
50
70
95
95
95
95
H
8
2a-2n
4a-4n
1a-1n
3a-3n
6
3
1 and 2 R1 = H5C2O
3 and 4 R1 = H3C
R2 = various substituents
R2 = various substituents
3
10
Maximum progression of the reaction
Scheme 1
123

Free-radical oxidation of 1,2,3,4-tetrahydro-2-oxopyrimidines
279
radical, should decrease the activation energy of its for-
mation (Scheme 3).
Table 3 Oxidation of 5-carboethoxy-1,2,3,4-tetrahydro-2-oxopyr-
imidines 1a–1n to 2a–2n by BPO under thermal conditions
A comparison of BPO oxidation of these two classes of
compounds under thermal conditions can be explained by the
ab initio calculation at the B3LYP/6-311??G** level of
theory for the optimized structures of THPMs considered in
this study [22]. According to these results, the heterocyclic
ring appears as quasi-planar structure (boat conformation),
in which the aryl groups occupy a pseudo-axial position. In
this structure, the C-4 and N-1 atoms are not in the same
plane as the other remaining four atoms (C-2, N-3, C-5, and
C-6). The interesting points in this study were to find the
factors which influence the following items:
1,2
R2
Time/ha
Yield/%
a
b
c
d
e
f
C6H5–
3
85
80
70
83
78
71
85
80
60
80
82
87
89
86
2-CH3OC6H4–
3-CH3OC6H4–
4-CH3OC6H4–
2-ClC6H4–
2.5
6
2
3.5
8
3-ClC6H4–
g
h
i
4-ClC6H4–
2.5
4
4-BrC6H4–
4-NO2C6H4–
4-CH3C6H4–
3,4-(CH3O)2C6H3–
PhCH2CH2–
4-(CH3)2NC6H4–
2-Thienyl
6
j
2.5
3
1. The degree of deviations of the C-4 and N-1 centers
from planarity
k
l
2.5
1
2. The dihedral angles of the 5-CO groups of the ester or
the acetyl moiety with respect to the C5=C6 bond
3. The dihedral angles formed by C02 ꢁ C10 and C4–N3
4. The electron density of the heterocyclic ring atoms.
m
n
a
8
Maximum progression of the reaction
The results showed that items 1–4 were influenced by
the orientation of the aryl group attached to C-4 of the
heterocyclic ring, especially the position of the additional
substituent on the phenyl ring, and also by the stereoelec-
tronic effect of the carboethoxy and the acetyl groups
located on C-5.
Table 4 Oxidation of 5-acetyl-1,2,3,4-tetrahydro-2-oxopyrimidines
3a–3n to 4a–4n by BPO under thermal conditions
3,4
R2
Time/ha
Yield/%
a
b
c
d
e
f
C6H5–
6
7
8
4
7
9
5
7
6
8
6
5
3
10
86
82
70
86
80
78
88
85
60
70
50
83
86
80
2-CH3OC6H4–
3-CH3OC6H4–
4-CH3OC6H4–
2-ClC6H4–
The results shown in Tables 3 and 4 indicate that the
rate of oxidation of 5-acetyl-THPMs is less than that of
5-carboethoxy-THPMs. The substituents on the phenyl ring
located in the 4-position of the THPM ring also affect the
rate of oxidation. Electron-donating substituents at the
ortho- or para-positions of the phenyl ring increase the rate
of the reaction by stabilizing the trihydropyrimidinyl rad-
ical intermediate and by facilitating the homolytic cleavage
of the C-4–H bond. Whereas the presence of the methoxy
group in the correct position (2- or 4-, 1b, 1d and 3b, 3d)
decreases the reaction time, the presence of the same
substituent but in the 3-position (1c, 3c) increases the
reaction time. This indicated that as expected the electron-
donating group (located in the correct position) increases
the rate of reaction because these groups stabilize the for-
mation of the trihydropyrimidinyl radical intermediate.
This suggestion is also supported by the influence of the
electron-withdrawing group 4-nitro (1i and 3 k) vs. the
electron-releasing group 4-(H3C)2N (1m and 3m) on
decreasing the rate of oxidation.
3-ClC6H4–
g
h
i
4-ClC6H4–
4-BrC6H4–
2-NO2C6H4–
3-NO2C6H4–
4-NO2C6H4–
4-CH3C6H4–
4-(CH3)2NC6H4–
2-Thienyl
j
k
l
m
n
a
Maximum progression of the reaction
(TrHPMꢀ) and benzoic acid. The abstraction of a second
hydrogen atom in the final step by another BOꢀ completes
the reaction with formation of dihydropyrimidinone prod-
uct (DHPM).
The observed effects of substituents on the rate of
reaction, especially the substituents in the 4-position of the
heterocyclic ring, indicate that the removal of the first
hydrogen atom, namely 4-H, occurs in the rate-determining
step (step 2). This suggestion is supported by the fact that
the stability of a trihydropyrimidinyl radical intermediate
(TrHPMꢀ), which is formally a benzylic and an allylic
Experimental
THPMs were prepared by adoption of the known procedure
[23]. Melting points were determined on a Stuart Scientific
SMP2 apparatus. IR spectra were recorded using KBr discs
123

280
H. R. Memarian et al.
Scheme 2
.
1) (C6H5COO)2
2 C6H5COO
.
R2
BO
O
2
O
H
N
R
2)
H
.
H
O
R1
N
R1
.
+ C6H5COOH
C6H5COO
+
H3C
N
O
H3C
N
H
H
.
THPM
TrHPM
R2
R2
O
O
3)
H
.
R1
H3C
N
R1
H3C
N
.
C6H5COOH
+
+
C6H5COO
N
H
O
N
H
O
.
TrHPM
DHPM
R1 : OC2H5, CH3
Scheme 3
X
X
.
δ
OOCC6H5
H
O
O
H
H
H
.
N
δ
.
R1
H3C
R1
H3C
N
H5C6COO
+
-C6H5COOH
.
N
H
O
N
H
O
BO
X
O
H
O
.
R1
H3C
N
R1 : OC2H5, CH3
N
H
on a Shimadzu IR spectrometer IR-435. The 1H and 13C NMR
spectra (DMSO-d6) were recorded on Bruker DRX-300
Avance and Bruker Avance III 400 spectrometers at 300 and
100.62 MHz. Mass spectra were obtained on a Micromass
Platform II spectrometer in EI mode at 70 eV. UV spectra
were recorded with a Shimadzu UV-160 spectrometer. Ele-
mental analyses were done with a Leco 932 CHNS-analyzer,
and results agreed favorably with calculated values.
an argon atmosphere. The results are given in Tables 3 and
4. The reaction was monitored by TLC (n-hexane/ethyl
acetate, 2:1) until maximum progression of the reaction.
Solvent was evaporated and the product was isolated by
column chromatography (n-hexane/ethyl acetate, 2:1). The
known products were characterized by comparison of their
physical and spectral data with those of authentic samples
[11, 14], and the data of the new products are given below.
Ethyl 4-(4-bromophenyl)-1,2-dihydro-6-methyl-2-
oxopyrimidin-5-carboxylate (2h, C14H13BrN2O3)
General procedure for oxidation of 1,2,3,4-tetrahydro-
2-oxopyrimidines
ꢀ
M.p.: 186–188 °C; IR (KBr): m = 3,350 (NH), 1,705
(CO2C2H5), 1,665 (2-CO) cm-1 1H NMR (300 MHz,
;
BPO (3.5 mmol) was added to a solution of THPM
(1 mmol) in 10 cm3 dry acetonitrile, and then the reaction
mixture was refluxed at 100 °C (bath temperature) under
DMSO-d6): d = 0.87 (t, J = 7.09 Hz, 3H, CH2CH3), 2.39
(s, 3H, 6-CH3), 3.97 (q, J = 7.10 Hz, 2H, CH2CH3), 7.38
123

Free-radical oxidation of 1,2,3,4-tetrahydro-2-oxopyrimidines
281
(d, J = 8.33 Hz, 2H, 30-H, 50-H), 7.67 (d, J = 8.30 Hz,
2H, 20-H, 60-H) ppm; 13C NMR (100.62 MHz, DMSO-d6):
d = 13.26 (CH3CH2O), 17.94 (6-CH3), 60.91 (CH3CH2O),
108.50, 123.63, 129.56, 131.22, 137.64, 155.07, 160.82,
165.54, 171.33 (CH3CH2OC=O) ppm; MS (70 eV): m/z
(%) = 338 (M?81Br, 2), 337 (M?81Br–H, 3), 336
(M?79Br, 2), 309 (M?81Br–C2H5, 11), 307 (M?79Br–
C2H5, 8), 293 (M?81Br–C2H5O, 2), 291 (M?79Br–C2H5O,
3), 229 (M?–Br–C2H4, 4), 181 (M?–C6H4Br, 3), 155
(C6H479Br?, 3), 76 (C6H4?, 14), 57 (100); UV–Vis
(CH3CN, c = 6.23 9 10-5 mol dm-3): kmax (e) = 326
(sh, 5,457), 250.2 (14,559) nm (mol-1 dm3 cm-1).
DMSO-d6): d = 2.24 (s, 3H, 6-CH3), 2.27 (t, 3H, CH3CO),
7.20 (dd, J3 4 = 3.91 Hz, J4 5 = 4.89 Hz, 1H, 40-H), 7.27
0
0
0 0
(m, 1H, 30-H), 7.92 (dd, J5 3 = 0.8 Hz, J5 4 = 4.41 Hz,
1H, 50-H), 12.15 (br s, 1H, NH) ppm; 13C NMR
(100.62 MHz, DMSO-d6): d = 17.31 (6-CH3), 32.25
(CH3CO), 116.32, 128.77, 130.78, 132.82, 140.76,
155.32, 157.64, 162.07, 201.97 (CH3C=O) ppm; MS
(70 eV): m/z (%) = 234 (M?, 41), 219 (M?–CH3, 48),
191 (M?–CH3CO, 2), 136 (M?–C4H3S–CH3, 9), 110
(100), 108 (M?–C4H3S–CH3CO, 4); UV–Vis (CH3CN,
c = 1 9 10-4 mol dm-3): kmax (e) = 313.6 (12,770), 258
(10,720) nm (mol-1 dm3 cm-1).
0
0
0 0
Ethyl 1,2-dihydro-6-methyl-2-oxo-4-(2-thienyl)pyrimidin-
5-carboxylate (2n, C12H12N2O3S)
Acknowledgements We are thankful to the Center of Excellence
(Chemistry), Research Council and Office of Graduate Studies of the
University of Isfahan for their financial support.
ꢀ
M.p.: 220 °C (dec.); IR (KBr): m = 3,400 (NH), 1,705
(CO2C2H5), 1,660 (2-CO) cm-1 1H NMR (300 MHz,
;
DMSO-d6): d = 1.18 (t, J = 7.05 Hz, 3H, CH2CH3), 2.30
(s, 3H, 6-CH3), 4.26 (q, J = 7.08 Hz, 2H, CH2CH3), 7.18
(t, J = 3.94 Hz, 1H, 40-H), 7.35 (d, J = 3.56 Hz, 1H,
30-H), 7.87 (d, J = 4.93 Hz, 1H, 50-H), 12.28 (s, 1H, NH)
ppm; 13C NMR (100.62 MHz, DMSO-d6): d = 13.57
(CH3CH2O), 17.50 (6-CH3), 61.69 (CH3CH2O), 108.10,
128.60, 130.0, 132.57, 140.66, 155.13, 158.86, 162.28,
166.39 (CH3CH2OC=O) ppm; MS (70 eV): m/z (%) = 264
(M?, 83), 235 (M?–C2H5, 14), 219 (M?–C2H5O, 49), 191
(M?–CO2C2H5, 17), 136 (M?–C4H3S–C2H5O, 23), 110
(M?–C4H3S–CO2C2H5, 100), 94 (M?–C4H3S–CO2C2H5–
CH3, 12), 83 (C4H3S?, 21); UV–Vis (CH3CN,
c = 1 9 10-4 mol dm-3): kmax (e) = 318.4 (15,720),
271.2 (sh, 5,850), 246 (9,250) nm (mol-1 dm3 cm-1).
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5-Acetyl-3,4-dihydro-6-methyl-4-(20-thienyl)
pyrimidin-2(1H)-one (3n, C11H12N2O2S)
ꢀ
M.p.: 226–228 °C; IR (KBr): m = 3,300 (NH), 1,720
(CH3CO), 1,680 (2-CO) cm-1 1H NMR (300 MHz,
;
DMSO-d6): d = 2.19 (s, 3H, 6-CH3), 2.27 (s, 3H, CH3CO),
5.52–5.53 (d, J = 2.99 Hz, 1H, 4-H), 6.95 (m, 2H, 30-H
and 40-H), 7.35–7.37 (dd, J4 5 = 4.7 Hz, J3 5 = 1.5 Hz,
1H, 50-H), 7.99 (s, 1H, 1-NH), 9.34 (s, 1H, 3-NH) ppm; 13C
NMR (100.62 MHz, DMSO-d6): d = 18.83 (6-CH3), 30.14
(CH3CO), 49.23 (C4), 110.46, 123.90, 124.85, 126.70,
148.20, 148.59, 152.24 (2-CO), 193.80 (CH3C=O) ppm;
MS (70 eV): m/z (%) = 236 (M?, 100), 221 (M?–CH3,
47), 193 (M?–COCH3, 31), 153 (M?–C4H3S, 21), 138
(M?–C4H3S–CH3, 10), 110 (M?–C4H3S–COCH3, 36), 83
(C4H3S?, 26); UV–Vis (CH3CN, c = 1 9 10-4 mol
dm-3): kmax (e) = 290.5 (11,490), 238.0 (9,410) nm
(mol-1 dm3 cm-1).
0
0
0 0
5-Acetyl-6-methyl-4-(20-thienyl)pyrimidin-2(1H)-one
(4n, C11H10N2O2S)
ꢀ
M.p.: 240 °C (dec.); IR (KBr): m = 3,000 (NH), 1,695
23. Shaabani A, Bazgir A, Teimouri F (2003) Tetrahedron Lett
44:857
(CH3CO), 1,640 (2-CO) cm-1 1H NMR (300 MHz,
;
123