Light-induced dehydrogenation of 2-oxo-1,2,3,4-tetrahydropyrimidine-5- carboxamides

Article abstract of DOI:10.1007/s13738-012-0097-0

The light sensitivity of various 2-oxo-1,2,3,4- tetrahydropyrimidine-5- carboxamides (THPMs) was investigated by exposing them to UV light in order to elucidate the effects of the nature of the substituents located on the 4- and 5-positions of the heteroc

Full text of DOI:10.1007/s13738-012-0097-0

J IRAN CHEM SOC (2012) 9:805–813
DOI 10.1007/s13738-012-0097-0
ORIGINAL PAPER
Light-induced dehydrogenation of 2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxamides
•
H. R. Memarian M. Soleymani H. Sabzyan
•
Received: 6 January 2012 / Accepted: 17 April 2012 / Published online: 4 May 2012
ꢀ Iranian Chemical Society 2012
Abstract The light sensitivity of various 2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxamides (THPMs) was inves-
tigated by exposing them to UV light in order to elucidate
the effects of the nature of the substituents located on the
4- and 5-positions of the heterocyclic ring and also the
effect of an oxygen or argon atmosphere on the rate of
reaction. The rate of reaction is faster under argon than
under oxygen and is influenced by the nature of the
substituent on the 4- and 5-positions of the THPM ring.
Furthermore, it is found that the dehydrogenation of
THPM-amides is faster than that of the corresponding
5-ethoxycarbonyl- and 5-acetyl-THPMs. In contrast to the
solution photochemistry, no changes have been observed
by irradiation in the solid state. A mechanism concerning
an electron transfer from excited THPM to acetonitrile has
been proposed for this reaction.
products of this reaction were 2-oxo-1,2,3,4-tetrahydro-
pyrimidines (THPMs), known also as 3,4-dihydropyri-
midinones or Biginelli compounds which, based on their
biological activities such as calcium channel blockers [2],
as antihypertensive [3, 4], antitubercular [5], antitumor
[6], antiviral [7] and anticancer [8] agents are important
compounds. Efficient methods of their synthesis, their
chemical and photochemical behavior, and their phar-
macological properties are still under investigation.
Dehydrogenation of the title compounds to the corre-
sponding 2-oxo-1,2-dihydropyrimidines (DHPMs) or
pyrimidin-2(1H)-ones may be useful for the preparation
of the parent unsaturated heterocycles. Several oxidants
have been applied in connection with thermal, microwave
and ultrasound activation for this conversion [9–13].
Recently, we have investigated the effect of the nature of
the substituent on 4-position of various 5-ethoxycarbonyl-
and 5-acetyl-2-oxo-1,2,3,4-tetrahydropyrimidines in the
dehydrogenation of these compounds by potassium per-
oxydisulfate (K2S2O8) under thermal [10, 13], microwave
[11], and ultrasound [12, 13] activation. The results of
these studies indicated that the ethoxycarbonyl derivatives
are oxidized faster than the corresponding acetyl
compounds. In continuation to these works, we have
synthesized various 2-oxo-1,2,3,4-tetrahydropyrimidine-5-
carboxamides [14] and investigated also their sensitivity
towards dehydrogenation by tetrabutylammonium per-
oxydisulfate [(n-Bu4N)2S2O8] in order to elucidate the
effects of the substituent on the 4-position and especially
the effects of the substituent in the 5-carboxamide group
on the rate of reaction in comparison to the ethoxycar-
bonyl and the acetyl derivatives [15]. The new results
support our suggestion of a rate enhancement by the
presence of the less electron withdrawing amide group
compared with the acetyl and ethoxycarbonyl groups.
Keywords Biginelli compounds ꢀ 2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxamides ꢀ Photooxidation ꢀ
Photodehydrogenation ꢀ Electron transfer
Introduction
In 1893, a multi-component reaction was discovered by
Pietro Biginelli [1] which involves condensation of an
aldehyde, a ketoester and urea in acidic medium. The
Electronic supplementary material The online version of this
article (doi:10.1007/s13738-012-0097-0) contains supplementary
material, which is available to authorized users.
H. R. Memarian (&) ꢀ M. Soleymani ꢀ H. Sabzyan
Department of Chemistry, Faculty of Science, University
of Isfahan, Isfahan 81746-73441, Iran
e-mail: memarian@sci.ui.ac.ir
123

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J IRAN CHEM SOC (2012) 9:805–813
When evaluating the suitability of the title compounds
pressure Hg lamp from NARVA in Pyrex tubes and a
Duran cell, which were placed in a distance of 20 cm from
the light source. The UV reaction spectra were taken (in
CH3CN) with a Shimadzu UV-160 spectrometer.
as pharmaceuticals, the knowledge of any light sensitivity
may be important, because they can easily lose their bio-
logical activities due to some molecular changes by
exposing them to UV light. One class of these compounds
is 1,4-dihydropyridines (DHPs) and their pharmaceutical
properties such as their activity as calcium channel
blockers are well known [16]. Our experience concerning
the photochemistry of these compounds either in solution
phase [17] or in the solid state [18], especially to elucidate
the effect of the nature of the substituents located on 3-, 4-
and 5-positions of dihydropyridine ring on the rate of
photoreactions [17, 18], led us to extend our investigation
to another class of heterocyclic compounds with pharma-
ceutical properties, namely Biginelli compounds. Recently,
we have reported on the electron transfer-induced photo-
dehydrogenation of various 4-aryl-substituted tetrahydro-
pyrimidinones bearing carboethoxy or acetyl groups on
5-position of the heterocyclic ring [19, 20]. The results
indicated that the presence of the ethoxycarbonyl or the
acetyl groups on 5-position has a larger effect on the rate of
reaction than the nature of 4-substituent. These results also
indicated that due to the bathochromic shift of the acetyl
group in 5-acetyl-THPMs, the rate of photodehydrogena-
tion has been increased compared with those of the
5-ethoxycarbonyl derivatives. This can be attributed to
the higher light absorbance of the acetyl derivatives com-
pared to the ethoxycarbonyl derivatives. The obtained
photochemical findings and also the recent publications
concerning the pharmaceutical properties of 2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxamides [5, 8] led us to
investigate the photoreaction of these compounds in solu-
tion under oxygen and argon atmosphere and also in the
solid state.
The procedure for photodehydrogenation of 2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxamides
Two separate Pyrex tubes (280 nm) containing 0.01 mmol
of each of THPMs 1a–p in 10 mL of dry acetonitrile
(c = 1 mM) were irradiated while bubbling argon or
oxygen through the solution during irradiation. The reac-
tion was followed by thin layer chromatography (TLC)
until maximum conversion of 2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxamides. For the preparative work
to obtain a large amount of products, a solution containing
0.1 mmol of THPMs in 100 mL of dry acetonitrile in a
Duran cell is irradiated until maximum conversion of
THPMs. The solvent was evaporated and the products were
obtained by recrystallization from n-hexane/ethyl acetate.
The photoproducts 2a–p were identified by comparison of
1
their melting points, UV, IR, H NMR, and mass spectra
with those reported earlier [15].
Irradiation of a solid sample
A sample of 1f (113 mg) was ground in a mortar and
strewn on a glass surface (15 cm 9 15 cm) placed on a
water cooled plate and exposed to the Pyrex-filtered light
of a 400 W high-pressure mercury light source mounted
inside a reflector at a distance of 40 cm from the glass
surface.
The aims of the present work were:
Results and discussion
•
•
To elucidate the effect of the nature of 4-substituent on
the rate of reaction.
A solution of 1a–p in CH3CN was irradiated under oxygen
and argon atmosphere until maximum conversion of
1a–p (Scheme 1). The results are summarized in Table 1.
The characterization of the products 2a–p was achieved
To elucidate the effect of various 5-carboxamide
groups as less electron withdrawing groups compared
with 5-ethoxycarbonyl or 5-acetyl groups on the rate of
reaction.
by comparison of their IR, H NMR, 13C NMR, MS and
1
•
•
To investigate the effect of oxygen or argon atmosphere
on the rate of reaction.
UV data with those of the starting materials 1a–p as
follows:
To compare the photochemical behavior of these
compounds in solution phase and in the solid state.
•
•
IR spectra showed a decrease in the intensity of the NH
vibration with small shift to lower frequency in 2a–p
when compared with those in 1a–p.
1H NMR spectra of 2a–p compared with those of 1a–
p showed following changes:
Experimental
–
–
the lack of 3-NH and 4-H resonances,
the shifts of 1-NH and ArNH resonances to lower
field, and
2-Oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides (1a–p)
were synthesized according to the reported procedure [14].
All irradiations were carried out using a 400 W high-
123

J IRAN CHEM SOC (2012) 9:805–813
807
O
R1
O
H
R1
R2
R2
hυ
N
H
N
N
H
NH
>280 nm
CH 3CN
H3C
N
H
O
H3C
N
H
O
2a-p
1a-p
Scheme 1 Photodehydrogenation of 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides
Table 1 Photodehydrogenation of 2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxamides (1a–p) under oxygen and argon atmosphere
1
R1
R2
2
Time/h (yield/%)a
Ar
O2
a
b
c
d
e
f
C6H5–
C6H5–
a
b
c
d
e
f
6 (89)
7.5 (91)
4 (91)
8 (86)b
9 (88)b
5 (89)b
6.5 (86)b
7 (86)b
C6H5–
C6H5CH2–
o-ClC6H4–
p-ClC6H4–
p-BrC6H4–
o-ClC6H4–
o-ClC6H4–
o-ClC6H4–
o-ClC6H4–
o-ClC6H4–
o-ClC6H4–
o-ClC6H4–
o-ClC6H4–
o-ClC6H4–
o-ClC6H4–
o-ClC6H4–
C6H5–
C6H5–
4.5 (89)
5 (88)
C6H5–
o-ClC6H4–
m-ClC6H4–
p-ClC6H4–
o-BrC6H4–
p-BrC6H4–
m-NO2C6H4–
p-NO2C6H4–
m-MeOC6H4–
p-MeOC6H4–
p-MeC6H4–
MeCHC6H5–
1.75 (92)
3.5 (89)
2.5 (90)
2 (93)
2.5 (92)
6 (87)b
g
h
i
g
h
i
5.5 (87)b
3.25 (91)
6.5 (84)b
12 (85)c
4 (90)
6.5 (82)b,c
5 (87)b
7 (84)b
j
j
4.5 (89)
10 (86)c
2.5 (90)
3 (87)c
k
l
k
l
m
n
o
p
a
m
n
o
p
2.5 (90)
4.5 (88)
2.5 (75)
3.5 (65)b
Isolated yields
b
The formation of trace amounts of unidentified products is observed
c
The reactions were not complete in these cases and the times are given after maximum conversion of these THPMs
–
the shift of the 6-CH3 resonance to lower field due
to the attachment of this group to the extended C=O
conjugated aza-diene system.
in the reaction, since the reaction was not totally
quenched by carrying out the experiment under oxygen
purging during the irradiation. We have followed the
photooxidation of compound 1c as a representative
example in argon saturated solution and also in oxygen
saturated solution (each c = 5.32 9 10-5 M). Two
isosbestic points were observed in each reaction spec-
trum. A comparison of the slope in the extinction versus
time diagrams (ET diagrams) [19] at 335 nm equal to
119.5 9 10-4 (under argon) and 115.0 9 10-4 (under
oxygen) showed that the reaction is faster under argon
than under oxygen atmosphere, which supports the
above-mentioned argument and also the required irra-
diation time of 4 and 5 h under argon and oxygen,
respectively, by the experimental work (Fig. 1). The
results of this experiment are also supported by plotting
•
A comparison of the UV data of 2a–p with those of 1a–
p indicates that the formation of the aza-diene system
in 2a–p, which is cross conjugated with 4-aryl
substituent and also conjugated with 1-NH lone pair
and 2-CO, causes a bathochromic shift in the UV
spectra.
The results presented in Table 1 indicate that the rate of
reaction is dependent on the following factors:
1. In all cases, the irradiation times are shorter by carrying
out the experiments under argon atmosphere. It seems
that both excited states (singlet and triplet) are involved
123

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J IRAN CHEM SOC (2012) 9:805–813
of the ET diagrams for reaction of compound 1l (with p-
nitrophenyl) and 1n (with p-methoxyphenyl) on C-4 in
argon saturated solution. Total disappearance of 1l and
1n is observed after 2.5 h, which is in agreementwith the
values obtained for the slopes of the ET dia-
grams 149.0 9 10-4 and 150.0 9 10-4, respectively.
after 3 and 1 h irradiations, respectively, whereas these
dehydrogenations under oxygen atmosphere were com-
pleted after 4.5 and 2 h of irradiation, while the formation
of the oxidation products 2c and 2f besides hitherto
unidentified by-products was also observed under both
atmospheres. Therefore, for better comparison of
the results in our new study with those obtained by irra-
diation of 5-ethoxycarbonyl and 5-acetyl derivatives in
chloroform [20, 21], we have carried out simultaneous
irradiation of some 5-ethoxycarbonyl and 5-acetyl deriva-
tives (Scheme 2) and some carboxamide derivatives with
the same concentration in acetonitrile solution under argon
atmosphere, to elucidate the nature of solvent on the rate of
reaction. The results are presented in Table 2.
2. The nature of both R1 at C4 and R2 in the C5-
carboxamide function influences the rate of reaction.
3. Whereas a clean and faster reaction has been observed
when irradiating under argon atmosphere, irradiation
under oxygen atmosphere resulted in the formation of
trace amounts of some hitherto unidentified by-prod-
ucts and in a retarded reaction.
4. Variation of the 4-aryl groups while keeping the
5-carboxamide group constant (in 1c, f–p) influences
the rate of reaction to a larger extent than varying the
substitution in the N=aryl moiety of the 5-carboxamide
while maintaining the 4-aryl group constant (as in 1a–e).
This clearly showed that the balance of the electronic
(inductive and resonance) effects and the location of
the additional substituent on the phenyl ring influences
the rate of reaction.
The results show that the three amide derivatives 1c, f,
are dehydrogenated significantly faster than the
n
corresponding ethoxycarbonyl and acetyl derivatives. A
comparison of the UV data of 2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxamides (Table 3) with those of
5-ethoxycarbonyl and 5-acetyl derivatives (given as sup-
plementary materials and also reported earlier [20, 21])
indicates that almost all these compounds absorb the UV
light in the same region with the same intensities. Since the
same concentrations of these compounds were exposed to
the UV light, either the extent of the possible deactivation
processes of the molecules in the singlet or triplet excited
states must be the reason for the observed different irra-
diation time required for maximum conversion, or the role
of the nature of 5-substituent on the heterocyclic ring
influences the time of reaction. Since the electron with-
drawing character of the carbonyl group in the amide
Since we have observed a clean photodehydrogenation
reaction of 5-ethoxycarbonyl- and 5-acetyl-2-oxo-1,2,3,4-
tetrahydropyrimidines in chloroform solution under argon
atmosphere [20, 21], we have also carried out the photo-
reactions of 5-carboxamide derivatives (1c and 1f) as test
substrates in chloroform under oxygen or argon atmo-
sphere. TLC monitoring of the reaction mixtures showed
that the reactions were completed under argon atmosphere
(a)
0.25
0.2
0.15
0.1
y =0.01195x + 0.03780
R2 = 0.97523
2
1.5
1
0.05
0
0.5
0
0
2
4
6
8
10
12
14
200
250
300
350
400
λ(nm)
Time (min)
(b)
0.25
0.2
2
1.5
1
y = 0.01150x + 0.03380
R2 = 0.97948
0.15
0.1
0.5
0
0.05
0
0
2
4
6
8
10
12
14
200
250
300
350
400
λ(nm)
Time (min)
Fig. 1 The reaction spectra of (a) argon and (b) oxygen saturated solution of 1c and the corresponding ET diagrams at 335 nm in acetonitrile
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J IRAN CHEM SOC (2012) 9:805–813
809
O
R1
O
H
R1
R2
N
R2
NH
hυ
>280 nm
CH3CN
H3C
N
H
O
H3C
N
H
O
3: R 2 = OC2H5
5: R 2 = CH3
4: R 2 = OC2H5
6: R 2 = CH3
Scheme 2 Photodehydrogenation of 5-acetyl- and 5-ethoxycarbonyl-2-oxo-1,2,3,4-tetrahydropyrimidines to 5-acetyl- and 5-ethoxycarbonyl-2-
oxo-1,2-dihydropyrimidines
Table 2
THPM
R1
Product
Time (h)
Conversion (%)
Photodehydrogenation of 5-N-
(2-chlorophenyl)-carboxamido-,
5-acetyl- and 5-ethoxycarbonyl-
2-oxo-1,2,3,4-
tetrahydropyrimidines in
acetonitrile under argon
atmosphere
1c
3a
5a
1f
Ph
2c
4a
6a
2f
4
100
0
Ph
4
Ph
4
*5
100
*5
*20
100
*20
*40
2-ClC6H4
2-ClC6H4
2-ClC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
1.75
1.75
1.75
2.5
2.5
2.5
3b
5b
1n
3c
5c
4b
6b
2n
4c
6c
Table 3 UV-absorption [kmax
nm] of 5-carboxamide
/
1
kmax (log e)
2
kmax (log e)
derivatives (1a–p) and the
corresponding photoproducts
(2a–p) in ethanol solution
a
b
c
d
e
f
282.5 (4.01), 205.5 (4.31)
272.5 (3.69), 206.5 (4.32)
288 (4.26), 210 (4.56)
279 (4.32), 206 (4.40)
286 (4.16), 206 (4.37)
289 (3.84), 206 (4.33)
285 (3.80), 206.5 (4.22)
275 (4.11), 205 (4.24)
279 (4.27), 209 (4.53)
290 (4.08), 210 (4.49)
266 (4.21), 209.5 (4.47)
272 (4.22), 206 (4.38)
282 (3.86), 204.5 (4.31)
283 (4.35), 212 (4.32).
288.5 (4.15), 208.5 (4.49)
283.5 (4.04), 207.5 (4.44)
a
b
c
d
e
f
320 (3.61), 251 (4.13), 205 (4.31)
319 (3.71), 205.5 (4.32)
319 (4.05), 245 (4.48), 210.5 (4.59)
318 (3.87), 254.5 (4.40), 206 (4.45)
317 (3.76), 257.5 (4.36), 205.5 (4.39)
306 (4.05), 240 (4.41), 213 (4.62)
317 (3.52), 244 (4.02), 206.5 (4.31)
318 (3.37), 248.5 (3.84), 205.5 (4.09)
304 (3.67), 246 (4.01), 207.5 (4.37)
316 (4.06), 248 (4.51), 211 (4.61)
318 (3.68), 232.5 (4.34), 208.5 (4.42)
336 (3.88), 259.5 (4.32), 209 (4.51)
316 (3.43), 254 (3.78), 204 (4.08)
319.8 (4.13), 264.8 (4.10), 212.4 (4.16)
306 (3.90), 248 (4.23), 207.5 (4.48)
302 (3.50), 242 (3.91), 206.5 (4.26)
g
h
i
g
h
i
j
j
k
l
k
l
m
n
o
p
m
n
o
p
moiety compared to the ester or the acetyl moieties is
expected to be lower, it should be expected that photode-
hydrogenation of the carboxamide derivatives be faster
than that of corresponding ethoxycarbonyl and acetyl
derivatives. It should be noted that due to very low solu-
bility of the oxidation products in acetonitrile, these were
precipitated during the irradiation and did not compete
effectively with the THPMs by light absorption.
123

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J IRAN CHEM SOC (2012) 9:805–813
We have proposed earlier a rationale for the electron
electron-acceptor species, also proposed in our reaction, is
supported by the following reactions:
transfer-induced photooxidation of 5-ethoxycarbonyl and
5-acetyl derivatives in chloroform, in which chloroform
was involved as an electron-acceptor species from excited
THPMs [20, 21]. A comparison of the irradiation times
required for compounds 1c, f in acetonitrile (Table 1) with
those obtained in chloroform clearly showed that the
reaction is faster in chloroform. These results support also
our suggestion to propose the same reaction mechanism by
carrying the irradiation in acetonitrile. The slower reaction
in acetonitrile relative to chloroform can be explained by
comparison of the reduction potentials of both solvents.
The reduction potentials of acetonitrile and chloroform are
reported -3.1 and -1.77 V (vs. FC?/FC, Ferrocene),
respectively [22, 23]. Therefore, according to the proposed
mechanism, the electron transfer from excited THPMs to
CHCl3 should occur faster than that to CH3CN.
•
Photooxidation of some nickel(II) macrocyclic com-
plexes caused by the electron transfer from excited
molecule to acetonitrile [26, 27].
•
Cyanation and cyanomethylation of kopsamine by the
electrolysis of kopsamine in acetonitrile solution [28].
This is occurred in part by decomposition of the
acetonitrile solvent after accepting an electron and
following cyanation and cyanomethylation of
kopsamine.
The proposed mechanism of photodehydrogenation of
THPM-carboxamides in acetonitrile is illustrated in
Scheme 3.
According to the proposed rationale for the electron
transfer from excited THPM either in the singlet or triplet
states to acetonitrile resulted in the occurrence of the ionic
species, namely, tetrahydropyimidine radical cation
(THPM?ꢀ) and acetonitrile radical anion (CH3CN-ꢀ). De-
protonation at C4 resulted in the formation of 2-oxo-1,2,3-
trihydropyrimidinyl radical (TrHPMꢀ), which is simulta-
neously an allylic and a benzylic radical. Further electron
detachment and the proton removal from TrHPMꢀ resulted
in the formation of the oxidation products, namely, the
corresponding 2-oxo-1,2-dihydropyrimidines (DHPMs).
The effect of the nature of the substituent especially in
4-position on the time of irradiation prompted us to carry
the computational study to explain the obtained results by
photodehydrogenation of these compounds and to compare
them with those of 5-ethoxycarbonyl and 5-acetyl deriva-
tives and finally to confirm the proposed mechanism.
Density functional theory at B3LYP/6-31??G** level
has been applied to study structural, electronic and bonding
characteristics of various 4-substituted 2-oxo-1,2,3,4-tet-
rahydropyrimidines containing acetyl, ethoxycarbonyl [29]
or carboxamide groups [30] on 5-position. The results
indicate that:
The molar absorption coefficient for compound 1c at
300 nm in acetonitrile (e = 13,534) and in chloroform
(e = 11,466) and also for compound 1f at 300 nm in ace-
tonitrile (e = 8,853) and in chloroform (e = 12,105) is
obtained. Due to different values and irrespective of the
reduction potential of solvent, we should expect a faster
reaction for 1c in acetonitrile than that in chloroform, but
slower reaction for 1f in acetonitrile than that in chloro-
form, because the excited 1c and 1f are formed better in
acetonitrile and chloroform, respectively. The experimental
results indicate that all photoreactions are faster in chlo-
roform than in acetonitrile. This means, that independent of
the efficiency of light absorption of THPM, the important
factor is the reduction potential of solvent, as electron-
acceptor molecule in our reaction. The UV spectra of 1c
and 1f as the representative examples are shown in Fig. 2.
Furthermore, activation entropy for the electron transfer
to CHCl3 is expected to be lower than CH3CN due to the
threefold symmetry of the bridging atom (3 chlorine atoms)
in the former as compared to onefold symmetry of the
bridging atom (N on the CN group) in the latter for
accepting an electron from excited THPMs. In other words,
stereoselectivity of the electron transfer reaction [24, 25] to
CHCl3 is lower than that to CH3CN. This supports more
efficient electron transfer to chloroform as compared to that
to acetonitrile. The involvement of acetonitrile as an
1. The six-membered heterocyclic ring in all series of
compounds adopts a boat conformation, flatted at N1
towards an envelope conformation, with a pseudoaxial
orientation of the C4-substituent (Fig. 3).
Fig. 2 UV spectra of
30000
1f
30000
20000
10000
0
1c
compounds 1c and 1f in
acetonitrile and chloroform
Acetonitrile
Chloroform
20000
Acetonitrile
Chloroform
10000
0
200
250
300
350
400
200
250
300
350
400
λ(nm)
λ(nm)
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J IRAN CHEM SOC (2012) 9:805–813
811
*
Scheme 3 The proposed
rationale for
O
O
H
R1
H
R1
R2
photodehydrogenation of 2-oxo-
1,2,3,4-tetrahydropyrimidine-5-
carboxamides
R2
N
H
NH
N
H
NH
hυ
1)
H3C
N
H
O
H3C
N
H
O
THPM*
THPM
*
O
H
R1
O
.
H
R1
+
R2
R2
N
H
NH
N
H
NH
CH 3CN
ET
.
−
2)
+ CH 3CN
H3C
N
H
O
H3C
N
H
O
.
+
THPM
THPM*
O
O
R1
H
R1
.
+
R2
R2
.
H +
N
H
NH
N
H
NH
−
3)
H3C
N
H
O
H3C
N
H
O
.
.
+
THPM
TrHPM
R1
O
O
R1
R2
R2
.
N
H
N
N
H
NH
e
−
4)
H +
−
H3C
N
H
O
H3C
N
H
O
.
TrHPM
DHPM
14
2. The aryl and THPM rings are not co-planar and
deviation of the dihedral angle between both rings
from co-planarity are dependent on the additional
substituent on the aryl group on 4-position and also on
the presence of the ethoxycarbonyl, acetyl or amide
groups on 5-position.
3. The dihedral angle between CO group (C7=O8) with
respect to C5=C6 is dependent on its attachment to the
ethoxy, methyl or the aryl/alkylamino substituents.
Whereas the angles in 3a and 5a are -173.9o and
-175.0o, respectively, the angle in 1c is 148.7o. This
indicates the reduced electron withdrawing character
(via conjugation) of the amide group in comparison to
that of ethoxycarbonyl and the acetyl groups.
13
12
15
16
X
11
H
H
4
N
1
9
H
3
N
2
O
5
6
CH3
10
7
O
8
R
R= OC 2H5, CH3, NHR'
4. The calculated dihedral angles for the CO group in the
corresponding oxidation products 4a, 6a and 2c (which
are, respectively, -128.0, -122.9 and 51.4 ) explain
Fig. 3 Boat conformation of the heterocyclic ring of THPMs 1 with
pseudoaxial orientation of the C4-substituent
123

812
J IRAN CHEM SOC (2012) 9:805–813
Fig. 4 The optimized structures
of 1c, 3a and 5a and the
corresponding dehydrogenation
products 2c, 4a and 6a at the
B3LYP/6-31 ??G** level of
theory
O8-C7-C5-C6 = 148.7o, C2'-C1'-C4-N3 = –70.4o
O8-C7-C5-C6 = 51.4o, C2'-C1'-C4-N3 = 39.1o
O8-C7-C5-C6 = –173.9 o, C2'-C1'-C4-N3 = – 41.6 o
O8-C7-C5-C6 = –128.0 o, C2'-C1'-C4-N3 = 39.3 o
O8-C7-C5-C6 = –175.0 o, C2'-C1'-C4-N3 = –36.1o O8-C7-C5-C6 = –122.9o, C2'-C1'-C4-N3 = 39.6o
clearly that the heterocyclic ring in the amide
compounds tends to have more conjugative character,
which explains a lower activation energy for its
formation (Fig. 4). This results in faster oxidation of
amides. The same trends have also been observed for
the thermal and ultrasound-assisted oxidation of
5-carboxamide derivatives [15] compared with those
for 5-ethoxycarbonyl- [10, 12] and 5-acetyl-THPMs
[11, 13]. It should be noted that electron transfer-
induced oxidation of THPM-esters by cerric ammo-
nium nitrate (CAN) in acetic acid and acetone has also
been reported [31].
photoreaction of these compounds bearing carboxy [32],
some heterocyclic [33], secondary alkyl and benzyl groups
[33] in this position, but in the present study the loss of
secondary and benzylic group such as PhCHCH3 (1p) was
not observed.
Conclusions
We investigated the photodehydrogenation of some 2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxamides to the corre-
sponding 2-oxo-1,2-dihydrpyrimidine-5-carboxamide in
acetonitrile under argon and oxygen atmospheres and also
in the solid state. The rate of reaction is faster under argon
than under oxygen and is influenced by the nature of the
substituent on 4- and 5-positions of the THPM ring. Fur-
thermore, it is found that dehydrogenation rates of THPM-
amides are faster than for the corresponding THPM-esters
and THPM-ketones. In contrast to the solution photo-
chemistry, no changes have been observed by irradiation of
1f in the solid state. Therefore, due to the pharmaceutical
Another point is the lake of light sensitivity of THPMs
in the solid state. Whereas irradiation of 1f as test substrate
in acetonitrile under argon or oxygen resulted in the
complete conversion of 1f after 1.75 and 2.5 h, respec-
tively, irradiation of 1f in the solid state had not effected
any reactions after 9 h.
The loss of the substituent in 4-position of Hantzsch 1,4-
dihydropyridines has earlier been reported by the
123

J IRAN CHEM SOC (2012) 9:805–813
813
13. H.R. Memarian, A. Farhadi, H. Sabzyan, Ultrason. Sonochem.
17, 579 (2010)
14. M. Soleymani, H.R. Memarian, Z. Naturforsch. 65b, 485 (2010)
15. H.R. Memarian, M. Soleymani, Ultrason. Sonochem. 18, 745
(2011)
16. S. Goldmann, J. Stoltefuss, Angew. Chem. Int. Ed. Engl. 30, 1559
activity of these compounds, protection of the reaction
mixture from light during their preparation is necessary;
however, protection during packing as a tablet or capsule is
not important, which is important for drug design and
manufacturing.
(1991)
17. H.R. Memarian, M. Abdoli-Senejani, D. Dopp, J. Chin. Chem.
Soc. 54, 131 (2007) (and references cited therein)
18. H.R. Memarian, A. Mirjafari, Bioorg. Med. Chem. Lett. 15, 3423
(2005)
¨
Acknowledgments 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.
19. The absolute term’’extinction’’ is a German word and has now
been replaced with’’absorbance’’, but the phrase’’Extinction
time’’ is still using
20. H.R. Memarian, A. Farhadi, Monatsh. Chem. 140, 1217 (2009)
21. H.R. Memarian, A. Farhadi, H. Sabzyan, M. Soleymani, J. Pho-
tochem. Photobiol. A Chem. 209, 95 (2010)
22. K. Izutsu, Electrochemistry in Nonaqueous Solutions, vol. 8
(Wiley, 2002), p. 224
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123