Light-induced dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones

Article abstract of DOI:10.1007/s00706-009-0156-0

UV light irradiation of Biginelli 3,4-dihydropyrimidin-2(1H)-ones in chloroform in an argon atmosphere leads to dehydrogenation of these compounds to their corresponding pyrimidin-2(1H)-ones in excellent yields. Irradiation in the same solvent under an ox

Full text of DOI:10.1007/s00706-009-0156-0

Monatsh Chem (2009) 140:1217–1220
DOI 10.1007/s00706-009-0156-0
ORIGINAL PAPER
Light-induced dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones
Hamid Reza Memarian Æ Asadollah Farhadi
Received: 6 July 2008 / Accepted: 21 January 2009 / Published online: 29 April 2009
Ó Springer-Verlag 2009
Abstract UV light irradiation of Biginelli 3,4-dihydro-
pyrimidin-2(1H)-ones in chloroform in an argon atmosphere
leads to dehydrogenation of these compounds to their cor-
responding pyrimidin-2(1H)-ones in excellent yields.
Irradiation in the same solvent under an oxygen atmosphere
generates, in addition, various hitherto unidentified products.
A light-induced electron transfer from the substrate to the
solvent is proposed as the initial event, supported by the
detection of dichloromethane and hydrogen chloride in
the photolysate.
stability of these compounds towards oxidizing agents and
also to investigate their photochemical behavior, since they
may readily lose their activity due to partial oxidation
during preparation and storage, which is a point of concern
for drug designers.
Ethyl 1,2,3,4-tetrahydro-2-oxopyrimidine-5-carboxy-
lates can be dehydrogenated by various mild and powerful
oxidizing agents, such as MnO2 [7], PCC [7], chloranil [7],
KMnO4/Clay [7], DDQ [7], NaNO2/AcOH [7], Pd/C [6],
RuCl3/O2 in AcOH [8], Br2 [9], sulfur [10], FeCl3 [11],
HNO3 [12], CuCl2/K2CO3/tert-butylhydroperoxide [13],
CAN/AcOH [14], and Co(NO3)2 ꢀ 6H2O/K2S2O8 [15].
However, many of these methods suffer from disadvan-
tages, such as the use of strong oxidants, extended reaction
times, the need of excess oxidant, and especially low
yields. To the best of our knowledge, there is no report on
the photo-oxidation of dihydropyrimidinones.
Keywords Dihydropyrimidinones ꢀ Electron-transfer ꢀ
Heterocycles ꢀ Pyrimidinones ꢀ Photochemistry
Introduction
Dihydropyrimidinone derivatives are of considerable
interest in industry as well as in pharmaceutical research
because of their biological activities as antihypertensive [1]
and anti-cancer agents [2], as calcium channel blockers [3],
as antibacterial agents, and also as anti-staphylococcal
antibiotics [4]. In particular, batzelladine alkaloids have
been found to be potent HIV gp-120 CD4 inhibitors [5],
and MKC-442 is also one of the most important classes of
drugs to inhibit the HIV virus [6].
Oxidation and photo-oxidation of a range of symmetri-
cal and unsymmetrical 1,4-dihydropyridines, as widely
used calcium channel blockers, to the pyridine derivatives
has been reported and is still under investigation by many
research groups. Among them, especially photo-oxidation
of these compounds as a cost-effective procedure is of
interest, since it avoids the use of harmful or expensive
oxidizing agents [16–21]. The interesting aspect is that the
light sensitivity of 1,4-dihydropyridines should motivate
medicinal chemists to protect these compounds from light
during their preparations. Recently, we have reported on
sono-thermal oxidation of various ethyl 1,2,3,4-tetrahydro-
2-oxopyrimidine-5-carboxylates by K2S2O8 to their corre-
sponding pyrimidin-2(1H)-one derivatives to explain the
effect of the 4 substituent on the rate of the reaction [22].
In continuation of our work and also the studies on the
light sensitivity of 1,4-dihydropyridines, we were inter-
ested in investigating the photochemical behavior of the
The development of various thermal or photochemical
oxidation methods for conversion of different organic
compounds, especially with pharmaceutical properties, to
their oxidized form is an important way to study the
H. R. Memarian (&) ꢀ A. Farhadi
Department of Chemistry, Faculty of Science,
University of Isfahan, 81746-73441 Isfahan, Iran
e-mail: memarian@sci.ui.ac.ir
123

1218
H. R. Memarian, A. Farhadi
title compounds to elucidate the effect of the substituent in
position 4 of the dihydropyrimidinone ring and also the
presence of oxygen and argon atmospheres on the rate of
possible photo-oxidation.
Table 1 Photo-oxidation of 1a–1j in CHCl3 under argon atmosphere
1
R
2
Irrad. time/ha
Yield/%b
-
a
b
c
d
e
f
C6H5
a
b
c
d
e
f
26
93
95
94
92
96
92
92
96
95
92
-
4-CH3C6H4
7.5
-
-
-
4-CH3OC6H4
3-CH3OC6H4
2-CH3OC6H4
9.15
12.5
11.5
20
Results and discussion
-
3-ClC6H4
Since the rate of photo-oxidation of organic compounds
is dependent on the spin multiplicity of the excited state
of the light absorbing compounds, singlet or triplet
states, which can be affected by the presence of oxygen
atmosphere during UV irradiation, we first carried out
irradiation of 4-phenyl substituted compound 1a as a model
substrate in CHCl3 as solvent under oxygen and argon
atmospheres. Irradiation of 1a under oxygen atmosphere
resulted in the formation of the oxidation product 2a
besides various hitherto unidentified by-products, while
irradiation under argon atmosphere led to the formation of
the sole product 2a. In continuation, a 0.003 M solution of
each of the 3,4-dihydropyrimidinones 1a–1j in chloroform
was irradiated under argon atmosphere until total disap-
pearance of 1a–1j as monitored by TLC (Scheme 1). The
solvent was evaporated, and the pure products were
obtained by recrystallization from n-hexane/ethyl acetate.
The results are summarized in Table 1.
-
g
h
i
2-ClC6H4
g
h
i
13.5
16
-
2-BrC6H4
-
4-NO2C6H4
28.45
20.5
-
j
PhCH2CH2
j
a
The times are given after total disappearance of 1a–1j (100%
conversion according to TLC observation)
b
Isolated yields after recrystallization
and formation of product type 200, namely the pyrimidine
ring, a bathochromic shift of the UV spectra should be
expected (k [ 300 nm, log e * 1–2) [23], which was not
observed in this study. It should also be noted that the X-
ray structure of 2 g has confirmed that the CO NH(1) group
existed in amide form in solid state [14], which supports
the formation of product type 2. The UV data are presented
in Table 2.
A comparison of the IR spectra of the products 2a–2j
with those of 1a–1j showed a decrease in the intensity of
the NH vibration and a little shift to lower frequency, a
small shift of the CO group (5-CO2C2H5) to higher fre-
quency, and the shift of 2-CO and C5=C6 double bond to
lower frequency. These data are presented in Table 3.
The data shown in Table 1 indicate that the nature of the
4-substituent plays an important role in the rate of photo-
oxidation of the 3,4-dihydropyrimidinone ring. As is
expected the electron-donating groups such as methyl (1b)
or methoxy groups (1c, 1d, and 1e) decrease the time of
photo-oxidation. It is interesting to compare the time of
reactions of 1c, 1d, and 1e, which is dependent on the
balance of the inductive and the resonance effects of the
methoxy group located on the 4-, 3-, and 2-positions,
respectively. Another interesting point is the effect of
oxygen atmosphere on the number of products derived on
the irradiation of 1a as a model substrate under this atmo-
sphere, which leads to the formation of 2a and some
1
IR, UV, H NMR, 13C NMR, and MS data gave useful
information on the structural assignment of the photo-
products 2a–2j. Owing to tautomerization of N(1) to N(3)
and N(1) or N(3) to 2-CO in solution, three different
structures for the photoproducts types 2, 20, and 200 should
be considered (Scheme 2). Yamamoto et al. have reported
the formation of various enol forms type 200 by oxidation of
various 1,2,3,4-tetrahydro-2-oxopyrimidine-5-carboxylates
using CuCl2/K2CO3/tert-butylhydroperoxide [13]. A com-
parison of the UV data of the photoproducts 2a–2j with
those of the starting materials 1a–1j showed a bathochro-
mic shift in the spectra and an increased molar extinction
coefficient (k [ 300 nm, log e * 3–4) owing to the for-
mation of the 4-amino-1-aza-1,3-diene system [due to
elimination of 3- (or 1-) and 4-hydrogens], which is also
cross-conjugated or conjugated with the 4-aryl substituent
upon photo-oxidation. In case of aromatization of the ring
O
R
O
H
R
H
O
h
> 280 nm
ν
H5C2O
H3C
N
H5C2O
H3C
N
R
R
R
+ CH2Cl2 + HCl
O
O
O
CHCl3 / Ar
O
H
N
N
H
EtO
H3C
N
EtO
N
EtO
H3C
N
H
1a-1j
2a-2j
H3C
N
OH
N
O
N
O
R = a: C6H5, b: 4-CH3C6H4, c: 4-CH3OC6H4, d: 3-CH3OC6H4, e: 2-CH3OC6H4
f: 3-ClC6H4, g: 2-ClC6H4, h: 2-BrC6H4, i: 3-NO2C6H4, j: PhCH2CH2
H
2
2'
2"
Scheme 1
Scheme 2
123

Light-induced dehydrogenation of 3,4-dihydropyrimidin-2(1H)-ones
Table 2 Comparison of the UV
1219
1
k
max/nm (log e)
2
k
max/nm (log e)
absorption [kmax/nm] of the
starting materials 1a–1j with
those of the photoproducts
2a–2j in acetonitrile solution
a
b
c
d
e
f
278.4 (4.01), 228.6 (3.91)
278.4 (4.12), 226.4 (4.07)
274 (3.47), 230 (3.75)
276.5 (3.52), 227 (3.36)
276 (3.58), 225 (3.47)
278.5 (3.23), 229 (3.07)
272.0 (3.92), 232.8 (3.85)
275.5 (3.87), 232 (3.81)
264 (3.31), 225 (3.17)
277 (3.24), 223 (2.77)
a
b
c
d
e
f
314.8 (3.70), 289.6 (3.67), 244 (4.15)
328 (3.90), 276.0 (sh, 4.32), 249.6 (sh, 4.40)
302.2 (3.88), 238.8 (3.84)
293 (3.83), 241 (3.81)
305.4, (3.88), 239.4 (3.98)
304.5 (3.58), 239.5 (3.99)
g
h
i
g
h
i
305.4 (3.79), 240 (3.94)
303.5 (3.73), 237.5 (3.85)
336.0 (sh, 3.99), 300 (sh, 4.30), 252.0 (4.53)
296.5 (3.32), 241.5 (3.63)
j
j
Table 3 Comparison of the IR spectra (vꢀ/cm-1) of 1a–1j with those
of 2a–2j
*
O
R
H
O
R
H
H
O
h
ν
H
O
H5C2O
H3C
N
H5C2O
H3C
N
1
CO2C2H5 2-CO C=C
2
CO2C2H5 2-CO C=C
N
N
a
b
c
d
e
f
1,720
1,705
1,725
1,700
1,720
1,710
1,705
1,705
1,725
1,720
1,700 1,645
1,700 1,635
1,700 1,650
1,645 1,595
1,695 1,630
1,690 1,650
1,690 1,635
1,690 1,635
1,700 1,640
1,700 1,650
a
b
c
d
e
f
1,730
1,720
1,715
1,720
1,720
1,710
1,705
1,710
1,710
1,710
1,650 1,600
1,700 1,645
1,665 1,559
1,650 1,590
1,650 1,595
1,690 1,640
1,655 1,590
1,660 1,595
1,650 1,590
1,650 1,595
H
H
PM-H2
PM-H2
*
O
R
H
.
+
.
CHCl3
H
O
CHCl3
ET
H5C2O
N
PMH2
+
g
h
i
g
h
i
H3C
N
H
PM-H2
-HCl
O
j
j
R
.
.
H5C2O
H3C
N
PMH
CHCl2
+
CH2Cl2
+
N
H
O
hitherto unidentified products. As a control experiment, we
have carried out the irradiation of the photoproduct 2a
under oxygen and argon atmospheres. The results of the
reactions of 2a after 8 h irradiation showed that only one
product is formed under oxygen atmosphere in *10%
yield, which has also been obtained by irradiation of 1a
under this atmosphere according to TLC observation,
whereas the irradiation of 2a under argon atmosphere did
not result in the occurrence of these products. This is an
indication that the other products observed by irradiation of
1a under oxygen atmosphere may be formed by the reaction
of oxygen with the other active sites of the molecule 2a on
further irradiation under oxygen atmosphere.
PM
Scheme 3
radical pair, namely hydropyrimidinoyl (PM-Hꢀ) and di-
chloromethyl (ꢀCHCl2) radicals. Hydrogen abstraction by
CHCl2 radical completes the reaction by formation of the
pyrimidinone compound PM and dichloromethane. Other
studies have also proposed this mechanism for the photo-
oxidation of symmetrical 1,4-dihydropyridines in CCl4 [24]
and CBrCl3 solutions [25, 26] and unsymmetrical 1,4-di-
hydropyridines in CHCl3 solution [21].
Owing to the formation of dichloromethane during the
reaction, which has been confirmed by GC analysis of the
reaction mixture and by testing for acidity of the solution
after irradiation (due to formation of HCl), we propose an
electron-transfer mechanism for this conversion in which
chloroform is involved in the reaction (Scheme 3).
According to the proposed mechanism, excited 3,4-dihy-
dropyrimidinone (PM-H*2) donates an electron to chloroform
with formation of PM-H2ꢀ? and CHClꢀ3- radicals. Elimination
of HCl from both intermediates leads to the formation of a
Conclusion
In conclusion, this work describes electron-transfer-induced
photo-oxidation of various 3,4-dihydropyrimidinones to their
corresponding pyrimidinones in chloroform solution. The
presence of an oxygen or argon atmosphere plays an impor-
tant role in the rate of reaction and also the formed products.
The nature of the 4-substituent influences the rate of reaction.
123

1220
H. R. Memarian, A. Farhadi
Ethyl 1,2-dihydro-6-methyl-2-oxo-4-(4-nitrophenyl)
pyrimidine-5-carboxylate (2i, C14H13N3O5)
Yellow solid. Mp: 154–156 °C
Experimental
Melting points were determined on a Stuart Scientific
SMP2 apparatus. IR spectra were recorded from KBr discs
on a Shimadzu apparatus IR 435. 1H and 13C NMR spectra
were recorded with a Bruker instrument at 300 and
75.48 MHz. Mass spectra were obtained on a Platform II
spectrometer from Micromass; EI mode at 70 eV. UV
spectra (in CH3CN) were taken with a Shimadzu UV-160
spectrometer.
Ethyl 1,2-dihydro-6-methyl-2-oxo-4-(2-phenylethyl)
pyrimidine-5-carboxylate (2j, C16H18N2O3)
Yellow solid. Mp: 142–143 °C.
Acknowledgments We are thankful to the Center of Excellence
(Chemistry) and Office of Graduate Studies of the University of
Isfahan for their financial support.
A solution of 3,4-dihydropyrimidinones (0.03 mmol) in
10 cm3 of distilled chloroform (c = 0.003 M) was irradi-
ated with a 400-W high-pressure mercury lamp in a Pyrex
tube while bubbling argon through the solution at ambient
temperature. The reaction was followed by thin layer
chromatography (TLC) until total disappearance of dihy-
dropyrimidinones. The solvent was evaporated at room
temperature under reduced pressure, and the products were
recrystallized from n-hexane/ethyl acetate. The photo-
products 2a–2j were identified by comparing melting
points, IR, 1H NMR, MS, and UV spectra with those
reported earlier [22].
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123