An unusual oxidation-dealkylation of 3,4-dihydropyrimidin-2(1H)-ones mediated by Co(NO3)2·6H2O/K2S2O8 in aqueous acetonitrile

Article abstract of DOI:10.1016/j.tet.2006.11.010

4-Aryl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (DHPM) scaffolds of Biginelli type were oxidized using Co(II)/S₂O₈^2- and the?reaction afforded 6-unsubstituted pyrimidin-2(1H)-ones through an unprecedented dealkylation process. 4-Alkyl DHPMs under similar conditions afforded yet another unusual product, ethyl tetrahydropyrimidin-2,4(1H,3H)-dione-5-carboxylate.

Full text of DOI:10.1016/j.tet.2006.11.010

Tetrahedron 63 (2007) 666–672
An unusual oxidation–dealkylation of 3,4-dihydropyrimidin-
2(1H)-ones mediated by Co(NO3)2$6H2O/K2S2O8
in aqueous acetonitrile
*
Pachaiyappan Shanmugam and Paramasivan T. Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
Received 20 April 2006; revised 17 October 2006; accepted 2 November 2006
Available online 27 November 2006
Abstract—4-Aryl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (DHPM) scaffolds of Biginelli type were oxidized using Co(II)/S2O28ꢀ and
the reaction afforded 6-unsubstituted pyrimidin-2(1H)-ones through an unprecedented dealkylation process. 4-Alkyl DHPMs under similar
conditions afforded yet another unusual product, ethyl tetrahydropyrimidin-2,4(1H,3H)-dione-5-carboxylate.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
development of advanced electronic and photonic materials.
Kang et al.10b have employed readily accessible multi-
functionalized pyrimidine templates for diversity-oriented
synthesis. Consequently it is of interest to synthesize struc-
turally diverse pyrimidines by the oxidation of DHPMs.
The synthesisof 3,4-dihydropyrimidin-2(1H)-ones (DHPMs)
also called Biginelli compounds, has gained importance
because they exhibit illustrious biological and medicinal
applications.1 Unlike facile oxidation of 1,4-dihydropyri-
dines (DHPs) in vitro and in vivo,2 structurally similar
DHPMs, second generation lead compounds, are resistant
to oxidants.3 Furthermore, literature reported protocols are
focused on the oxidation of DHPMs of selective type4 and
require the use of excess corrosive or harmful reagents in
highly acidic conditions to yield the corresponding pyri-
midines.5 For instance, Eynde’s procedure6a,b to oxidize
DHPMs, involved the multistep synthesis of 1,4-dihydropyr-
imidines that were oxidized and hydrolyzed to furnish only
moderate yields of the desired pyrimidines. CuCl2/TBHP/
2. Results and discussion
Oxidants such as PCC, KMnO4/clay, DDQ, chloranil, CAN,
and NaNO2 are inefficient for the conversion of DHPMs to
pyrimidines.6a We therefore, considered the Co2+/S2O28ꢀ
couple,11a–c one of the most powerful oxidants,12 for the de-
hydrogenation process. In a trial run, DHPM 1a in aqueous
acetonitrile was stirred with 2 mmol of Co(NO3)2$6H2O and
1 mmol of K2S2O8 mixture at 80 ꢁC. Interestingly, the reac-
tion yielded an unusual product through oxidation–dealkyla-
K2CO3 and Jones reagents6d have also been employed
recently for the oxidation of DHPMs.
6c
1
tion (Scheme 1); the H NMR spectrum showed that the
6-methyl group has been replaced by a D2O-unexchangeable
H-atom resonating around 8.5 ppm. The disappearance of
methyl group was further confirmed by mass spectrometry
and elemental analysis. The NH proton (D2O-exchangeable)
of the product appeared in deshielded region (d 10–12 ppm)
and, for a few substrates, it was not observed at all.
MKC-442, a HEPT(1-[(2-hydroxyethoxy)methyl]-6-(phe-
nylthio)thymine) analogue finds application in clinical trials
and similar compounds are also expected to inhibit the HIV
virus.7 5-Methyl-2,4-diaminopyrimidines were found to in-
hibit exquisitely HIV and moloney murine sarcoma virus-
induced cytopathicity in cell culture.8 In addition, several
nucleosides containing 5-substituted pyrimidine moiety
have been shown to inhibit the growth of murine mammary
carcinoma virus.9 Itami et al.10a have reported that pyrimi-
dine-cores with extended p-systems have interesting fluo-
rescent properties and similar compounds are useful in the
O
H
O
Ph
Ph
.
Co(NO3)2 6H2O/ K2S2O8
EtO
N
EtO
Me
NH
aq. CH3CN, 80 °C
N
H
O
N
H
O
Keywords: Dehydrogenation; Cobalt; C–C cleavage reaction; Heterocycles.
* Corresponding author. Tel.: +91 44 2491 1386; fax: +91 44 2491 1589;
e-mail: ptperumal@gmail.com
1a
2a
Scheme 1.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.11.010

P. Shanmugam, P. T. Perumal / Tetrahedron 63 (2007) 666–672
667
Oxidation of organic compounds with Co2+/S2O82ꢀ is often
mediated by in situ generation of powerful oxidants such
O2’
O2
C16
ꢂ
as Co3+ (emf 1.92 V) and SOꢀ4 (emf 2.6 V). For the com-
C17
C7
plete conversion of 1a to 2a, 4 equiv of Co2+ and 2 equiv
C2
O3
of persulfate are needed as per stoichiometry.13
C8
N2
C1
C3
C4
C6
The reaction was optimized by using 5:2.5 equiv of Co2+/
S2O28ꢀ and heating at 80 ꢁC. Stirring the mixture at room
temperature for 48 h gave no appreciable amount of product,
but oxidation mediated by K2S2O8 without Co(NO3)2$6H2O
proceeded very slowly to furnish 5% of 2a. Other metal ion-
persulfate couples were also screened however, they were
either unsuccessful (AgNO3/K2S2O8 and FeSO4/Na2S2O3/
K2S2O8) or afforded very low yields (Co(OAc)2$4H2O/
K2S2O8 and FeSO4/K2S2O8 at reflux) of 2a. Table 1 shows
the results obtained for the oxidation of 1a–l to 2a–l medi-
ated by Co2+/K2S2O8.
C9
C13
C14
C10
C5
N1
O1
C12
C11
Figure 1. XRD of ethyl 4-(1-naphthyl)-pyrimidin-2(1H)-one-5-carboxyl-
ate, 2f.
O
Ar
EtO
NH
O
N
H
O
DHPMs bearing naphthyl and biphenyl pendent groups
(Table 1, Compounds 1f and 1g) invariably afforded compa-
rable yields of 2f and 2g with respect to DHPMs bearing
phenyl groups (Table 1, 2a and 2l). DHPMs with aryl groups
containing electron-withdrawing and electron-releasing
functionalities showed no resistance to oxidation and af-
forded the corresponding products in good yields (Com-
pounds 1b–e, 1h, 1i, and 1k). The N-methyl DHPMs also
afforded moderate to good yields, with the N-methyl group
remaining intact throughout the oxidation. Of the oxidized
compounds studied, 1d afforded the highest yield of product,
2d. The structure of the product (2f) was confirmed by X-ray
crystallography (Fig. 1).14
Ar = C6H5, 2-Cl-C6H4,
4-Cl-C6H4, 1-Naphthyl
Figure 2. Structure of 6-aryl-1,2,3,4-tetrahydropyrimidine-2,4(1H,3H)-
diones.
3. Mechanistic investigation on oxidative-dealkylation
of DHPMs
The oxidation–dealkylation reaction of DHPM to give 6-un-
substituted pyrimidin-2(1H)-ones by Co2+/S2O82ꢀ is an un-
common organic transformation and therefore, necessitates
some mechanistic investigation.
For 1a, 1b, 1c, and 1f, the reaction also furnished small
amounts (<5%) of 6-aryl-1,2,3,4-tetrahydropyrimidin-
2,4(1H,3H)-diones as well (Fig. 2).
(i) Co2+/O2, used to oxidize toluene to benzene,15a did not
demethylate 1a. Formation of 2a under anaerobic con-
ditions confirmed that the atmospheric oxygen has no
role during the oxidation.
(ii) We have also subjected 4-tolyl-6-methyl-DHPM, 4
to oxidation under typical Co2+/S2O82ꢀconditions
(Scheme 2). The reaction yielded 5a as the sole product
without the formation of 4-(4-pyrimidyl)benzoic acid
derivative, 5b.15a,b
The C-4 carbons and substituted aromatic quaternary car-
bons of the products generally appeared with less intensity
but were clearly detectable for N-methyl products, 2i–l.
Table 1. Unprecedented oxidation of 1a–l to 2a–l mediated by Co2+/S2O82ꢀ
O
Ar
O
Ar
.
Co(NO3)2 6H2O/ K2S2O8
R1
R1
N
NH
Me
COOH
Me
aq. CH3CN, 80 °C
H
O
Me
O
N
R
N
R
.
Co(NO3)2 6H2O
1a-l
2a-l
O
O
H
O
H
K2S2O8, CH3CN
Reflux, 2 h
Yielda,b
EtO
Me
NH
EtO
N
EtO
N
Compound
R
R1
Ar
Time (h)
76b
77b
71c
84
N
H
O
N
H
O
N
H
O
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
H
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OMe
OEt
OEt
Me
C6H5
3
7
6
8
8
8
6
6
4
4
4
8
2-Cl–C6H4
4-Cl–C6H4
2-NO2–C6H4
3-NO2–C6H4
1-Naphthyl
Biphenyl
4-MeO–C6H4
4-MeO–C6H4
C6H5
5b
5a
4
(Not formed)
78
Scheme 2.
69c
74
83
81
74
81
H
To trace the source of hydrogen at C(6) of the pyrimidin-
2(1H)-ones, the oxidation of 1d was conducted in D2O in-
stead of water. The height of the unexchangeable hydrogen
of the product 3a(CH(6)) was reduced by 70% in 1H NMR
spectra due to the formation of C–D bond (Table 2, Entry 1).
Mass spectrometry also substantiated the observations that
deuterium had been introduced at C(6) of the pyrimidin-
2(1H)-one scaffold.
1j
1k
1l
Me
Me
Me
4-Cl–C6H4
C6H5
77
a
The reaction was conducted using 1 mmol of DHPM with 2.5 mmol of
K2S2O8 and 5 mmol of Co(NO3)2 in aqueous acetonitrile at 80 ꢁC.
Isolated yield.
A small amount of 4-aryl-tetrahydropyrimidine-2,4(1H,3H)-diones (5%)
was also formed.
b
c

668
Table 2. Oxidation of structurally diverse DHPMs by Co2+/S2O82ꢀ
Entry Reactant Product
P. Shanmugam, P. T. Perumal / Tetrahedron 63 (2007) 666–672
4-alkyl DHPMs 6 and 7 led to the formation of ethyl 2,4-di-
oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate8(Scheme3).
The structure of 8 was confirmed by NMR spectroscopy,
mass spectrometry, and elemental analysis.
Yielda
O
NO2
NH
O
NO2
O
1
78b
EtO
N
EtO
H3C
O
O
O
R3
O
N
H
D
N
H
2-
Co2+/S2O8
EtO
NH
EtO
NH
3a
CH3CN, Reflux
O
N
H
O
N
H
O
O
Ar
Ar
6,7
8 (73%)
EtO
R3
EtO
R3
N
NH
R3 = C2H5 (6)
R3 = (CH3)2CH (7)
2
65c
N
H
O
N
H
O
Scheme 3.
Ar¼4-MeO–C6H4; R3¼C6H5
3b
3c
3
4
Ar¼4-MeO–C6H4; R3¼CF3
52c
45c
The unprecedented dealkylation reaction was also unsuc-
cessful for 6-phenyl substituted and cyclic DHPMs, which
underwent simple dehydrogenation (Table 2, Products 3b,
3d, and 3e). The reaction also afforded the desired product
when one of the methyl hydrogens was substituted by a
bromine atom (Table 2, Entry 6). Pyrazolyl DHPM provided
reasonably good yield of the corresponding 6-unsubstituted
pyrimidin-2(1H)-one (Table 2, Product 3f). The dealkylation
reaction was not observed during the oxidation of 6-tri-
fluoromethyl DHPM (Table 2, Product 3c).
O
Ph
O
Ph
NH
N
O
N
H
N
H
O
O
3d
Ph
Ph
O
O
77c
NH
N
5
6
N
H
O
N
H
3e
An interesting observation was made while subjecting 9 to
typical Co2+/S2O28ꢀ oxidation. The reaction mixture upon
careful separation through flash column yielded 10, 11, 12,
and 8 (Scheme 4). The typical oxidized product, 10 and its
subsequent intra-molecular Friedel–Craft acylated product,
11, accounted for 35% and 15% yield, respectively.
O
O
65
EtO
EtO
Br
NH
N
N
O
H
N
O
H
H
2a
N
N
N
N
EtOOC
O
H
O
N
O
+
N
7
71
OMe
OMe
N
EtO
EtO
H3C
NH
N
H
O
H
N
H
O
H
O
N
2-
Co2+/S2O8
O
N
10 (35%)
11(15%)
CH3
3f
CH3
O
EtOOC
Me
aq. CH3CN
O
NH
a
Isolated yield.
The reaction conducted in D2O–CH3CN.
+
EtO
b
c
NH
N
H
O
Co2+/S2O28ꢀ of 2.5:1.3 equiv was used.
O
N
H
O
9
O
12(19%)
8 (20%)
Scheme 4.
The incomplete introduction of deuterium at C(6) of the pyr-
imidin-2(1H)-one might be due to the competitive reaction
of H2O molecules (30 mmol in 5 mmol of Co(NO3)2$6H2O)
under the reaction conditions. Therefore, the source of hy-
drogen at position-6 need not be from 6-methyl group of
DHPM. In order to obtain a completely deuteriated product,
the reaction was conducted at 80 ꢁC with K2S2O8 alone in
D2O–CH3CN. However, the reaction was too slow to isolate
appreciable amounts of the product for characterization even
after 48 h.
Additionally, the reaction afforded substantial amount of 8
(20%), yet another unusual product of the reaction. Com-
pound 8 was the major oxidation product of 4-alkyl DHPMs,
6 and 7. The formation of 8 from 9 could be rationalized as
follows: the bulky anthryl group in 9 could be partially lost to
form the 4-unsubstituted pyrimidin-2(1H)-one in situ that
could be converted to 8, in a reaction similar to the oxida-
tions of 6 and 7 to 8 (cf. Scheme 3). The resultant anthryl
radical was subsequently oxidized to 9,10-anthraquinone
12. The oxidation of 9 corroborates that the 4-aryl group is
mandatory for the unusual transformation of 6-methyl 4-
aryl DHPMs (1a–l) into 6-unsubstituted 4-aryl pyrimidin-
2(1H)-ones (2a–l).
The above findings provide additional support to the indis-
pensable role of Co2+ and the in situ generated oxidant,
Co3+ (1.92 V). The aryl group at the C(4) of the pyrimidin-
2(1H)-one was essential for the oxidative-dealkylation as

P. Shanmugam, P. T. Perumal / Tetrahedron 63 (2007) 666–672
669
Kappe et al.5b isolated nitrolic acid (13) during the oxidation
of DHPMs with concd HNO3. The hydrolysis of 13 under
acidic conditions was expected to produce 14 (Scheme 5).
To trace whether our reaction was proceeding through 13,
the oxidation of 1a using Co(NO3)2/K2S2O8/AcOH was con-
ducted. Notably the reaction afforded 2a as the major prod-
uct. In addition, both Co(OAc)2/K2S2O8 and FeSO4/K2S2O8
mediated oxidations also furnished 2a as the major product
indicating that a pathway via 13 was unlikely.
with CHCl3 (2ꢃ20 mL). The organic extracts were pooled
up, washed with brine solution, dried over anhydrous
Na2SO4, and concentrated in vacuum to afford 0.23 g of
crude product. The column purification of residue using
1:1 petroleum ether/ethyl acetate afforded 0.19 g of 2a
as yellow viscous compound, which crystallized to form
yellow crystalline solid on cooling.
The same procedure was followed for redox couples,
namely, Ag+/S2O82ꢀ, Fe2+/S2O82ꢀ, and Fe3+/S2O23ꢀ/S2O82ꢀ
to oxidize 1a. Fe2+/S2O82ꢀ mediated reaction under reflux
conditions afforded 23% yield and rest of the redox couples
were ineffective for the conversion.
C6H5
O
O
C6H5
NH
O
Co2+/S2O82-/AcOH
1
1
R
R
N
N
1a
O2N
O
N
R
O
The above procedure was also followed for the syntheses
of 2b–l, 3f, 5, 8, 10, 11, and 12. Characterization of the
compounds by IR, 1H NMR, and 13C NMR spectroscopies,
mass spectrometry, elemental analysis, and crystallographic
analysis confirms the formation of the products.
NOH R
14a
13a
Scheme 5.
In conclusion we have oxidized 4-aryl/4-alkyl, 6-methyl-
DHPMs using Co(NO3)2/K2S2O8 to unique rearranged
products. The current procedure enabled the synthesis of
structurally diverse pyrimidin-2(1H)-ones in moderate to
good yields. The mechanistic investigation revealed that
the conversion of a methyl group into a hydrogen atom on
a pyrimidine scaffold was unprecedented. Ongoing studies
in our laboratory are focused on further mechanistic details
of the oxidation–dealkylation process.
4.2.2. Ethyl 4-phenyl-pyrimidin-2(1H)-one-5-carboxyl-
ate (2a). Yellow solid. Mp: 130–132 ꢁC. IR (KBr): 1020,
1187, 1423, 1508, 1663, 1710, 3204 cmꢀ1 1H NMR
.
(300 MHz): d 0.94 (t, J¼6.8 Hz, 3H), 3.96 (q, J¼6.8 Hz,
2H), 7.39 (m, 5H), 8.50 (s, 1H, D2O-unexchangeable),
11.50 (s, 1H). 13C NMR (75 MHz): d 12.8, 60.3, 107.9,
127.9, 127.9, 129.1, 130.5, 146.1, 155.7, 163.9, 174.1. MS
(EI, m/z): 244 (M+). Anal. Calcd for C13H12N2O3: C,
63.93; H, 4.95; N, 11.47. Found: C, 63.91; H, 4.89; N, 11.54.
4. Experimental section
4.1. General
4.2.3. Ethyl 4-(2-chlorophenyl)-pyrimidin-2(1H)-one-5-
carboxylate (2b). Yellow solid. Mp: 155–157 ꢁC. IR
(KBr): 1013, 1165, 1422, 1506, 1738, 3151 cmꢀ1 1H
.
NMR (300 MHz): d 1.08 (t, J¼6.8 Hz, 3H), 4.09 (q,
J¼6.8 Hz, 2H), 7.23 (m, 4H), 8.84 (s, 1H, D2O-unexchange-
able), 11.51 (s, 1H). 13C NMR (75 MHz): d 13.8, 61.2,
108.6, 113.4, 128.1, 129.7, 130.7, 145.6, 152.3, 157.5,
162.1, 163.9, 173.2. MS (EI, m/z): 278 (M+). Anal. Calcd
for C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05. Found: C,
56.04; H, 3.99; N, 10.07.
Melting points were determined in open capillary tubes and
are uncorrected. IR measurements were carried out using
KBr pellets in FTIR spectrometer. The 1H NMR and
13C NMR were recorded in 500, 400, 300 MHz high resolu-
tion NMR spectrometers with TMS as an internal standard.
All NMR spectra of pyrimidin-2(1H)-ones were recorded in
CDCl3. Mass spectra were obtained in EI ionization mode at
70 eV. TLC was performed on precoated Polygram sheets.
Column chromatography was carried out using 100–
200 mesh silica gel or flash-column with 200–400 mesh
silica gel and flushing out N2 on the head of the column. Ace-
tonitrile was distilled from P2O5 prior to use. DHPMs were
prepared using reported literature procedures.1d,3,16
4.2.4. Ethyl 4-(4-chlorophenyl)-pyrimidin-2(1H)-one-5-
carboxylate (2c). Yellow solid. Mp: 154–155 ꢁC. IR
(KBr): 1424, 1627, 1636, 1699, 1721, 3320 cmꢀ1 1H
.
NMR (300 MHz): d 1.11 (t, J¼7.3 Hz, 3H), 4.08 (q,
J¼7.3 Hz, 2H), 7.42 (dd, J¼8.3 and 9.3 Hz, 4H), 8.46 (s,
1H, D2O-unexchangeable), 11.50 (s, 1H). 13C NMR
(75 MHz): d 13.6, 60.5, 107.2, 127.6, 129.8, 131.8, 135.4,
145.6, 155.4, 163.3, 173.7. MS (EI, m/z): 278 (M+). Anal.
Calcd for C13H11ClN2O3: C, 56.03; H, 3.98; N, 10.05.
Found: C, 56.04; H, 3.90; N, 10.06.
4.2. Experimental procedure for the cobalt nitrate
and potassium persulfate mediated oxidation of
3,4-dihydropyrimidin-2(1H)-ones
4.2.1. Typical procedure for the oxidative-dealkylation of
1a. A 50-mL round bottom flask containing magnetic bar
was charged with 1 mmol (0.260 g) of 1a and 10 mL aceto-
nitrile. To this solution was added a mixture of cobalt(II)
nitrate hexahydrate (5 mmol, 1.46 g) and potassium persul-
fate (2.5 mmol, 0.68 g) in 3 mL of water and the solution
was stirred at 80 ꢁC on an oil bath. The stirring was contin-
ued at 80 ꢁC for 3 h (Table 1) and TLC showed the complete
disappearance of 1a. The reaction mixture was diluted with
CHCl3 (2ꢃ20 mL) and the supernatant was decanted. The
residue was poured into 20 g of crushed ice and extracted
4.2.5. Ethyl 4-(2-nitrophenyl)-pyrimidin-2-(1H)-one-5-
carboxylate (2d). Pale yellow crystalline solid. Mp: 140–
1
141 ꢁC. IR (KBr): 1420, 1616, 1630, 1695, 3430 cmꢀ1. H
NMR (500 MHz): d 0.89 (t, J¼7.7 Hz, 3H), 3.87 (q,
J¼7.7 Hz, 2H), 7.42 (t, J¼6.9 Hz, 2H), 7.67 (t, J¼7.7 Hz,
1H), 8.17 (t, J¼8.4 Hz, 1H), 8.61 (s, 1H, D2O-unexchange-
able). 13C NMR (125 MHz): d 14.0, 61.3, 107.1, 124.3,
129.9, 130.3, 130.8, 134.9, 146.6, 150.9, 155.6, 162.9,
174.3. MS (EI, m/z): 289 (M+). Anal. Calcd for
C13H11N3O5: C, 53.98; H, 3.83; N, 14.53. Found: C,
53.96; H, 3.82; N, 14.52.

670
P. Shanmugam, P. T. Perumal / Tetrahedron 63 (2007) 666–672
4.2.6. Ethyl 4-(3-nitrophenyl)-pyrimidin-2(1H)-one-5-
carboxylate (2e). Yellow solid. Mp: 151–153 ꢁC. IR
2990 cmꢀ1
.
1H NMR (500 MHz): d 1.03 (t, J¼7.7 Hz,
3H), 3.36 (s, 3H), 4.07 (q, J¼7.7 Hz, 2H), 7.35 (t,
J¼6.9 Hz, 2H), 7.41 (t, J¼7.7 Hz, 1H), 7.49 (t, J¼6.9 Hz,
2H), 8.41 (s, 1H). 13C NMR (125 MHz): d 13.8, 39.3,
61.5, 108.82, 127.9, 128.6, 130.6, 137.7, 153.5, 155.2,
164.1, 174.3. MS (EI, m/z): 258 (M+). Anal. Calcd for
C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C,
64.09; H, 5.43; N, 10.88.
(KBr): 1421, 1615, 1638, 1694, 3429 cmꢀ1 1H NMR
.
(500 MHz): d 0.96 (t, J¼7.5 Hz, 3H), 3.94 (q, J¼7.5 Hz,
2H), 7.25 (t, J¼8.0 Hz, 1H), 7.72 (d, J¼6.9 Hz, 1H), 8.17
(m, 2H), 8.49 (s, 1H), 11.54 (s, 1H). 13C NMR (125 MHz):
d 12.2, 59.3, 105.1, 121.8, 122.8, 127.4, 129.3, 133.1,
145.7, 149.8, 154.5, 161.4, 174.2. MS (EI, m/z): 289 (M+).
Anal. Calcd for C13H11N3O5: C, 53.98; H, 3.83; N, 14.53.
Found: C, 53.96; H, 3.84; N, 14.51.
4.2.12. Ethyl 1-methyl-4-(4-chlorophenyl)-pyrimidin-
2(1H)-one-5-carboxylate (2k). Colorless crystalline solid.
Mp: 160–162 ꢁC. IR (KBr): 1425, 1625, 1638, 1699, 1720,
4.2.7. Ethyl 4-(1-naphthyl)-pyrimidin-2(1H)-one-5-car-
boxylate (2f). Yellow solid. Mp: 155–157 ꢁC. IR (KBr):
1199, 1320, 1372, 1421, 1613, 1654, 1711, 2872, 3084,
3251 cmꢀ1. 1H NMR (500 MHz): d 0.50 (t, J¼7.7 Hz, 3H),
3.73 (q, J¼7.7 Hz, 2H), 7.37 (m, 1H), 7.42 (q, J¼3.1 and
3.9 Hz, 2H), 7.48 (d, J¼8.4 Hz, 2H), 7.71 (d, J¼7.7 Hz,
1H), 7.87 (d, J¼8.4 Hz, 1H), 8.89 (s, 1H, D2O-unexchange-
able), 11.52 (s, 1H). 13C NMR (125 MHz): d 13.2, 61.1,
110.5, 124.0, 125.0, 126.0, 126.4, 127.2, 128.7, 130.2,
130.4, 130.5, 133.0, 145.9, 157.8, 163.2, 172.6. MS (EI,
m/z): 294 (M+). Anal. Calcd for C17H14N2O3: C, 69.38; H,
4.79; N, 9.52. Found: C, 69.32; H, 4.82; N, 9.43.
3319 cmꢀ1
.
1H NMR (500 MHz): d 1.12 (t, J¼7.5 Hz,
3H), 3.67 (s, 3H), 4.14 (q, J¼7.5 Hz, 2H), 7.36 (doublet of
triplet, J¼8.6 and 2.3 Hz, 2H), 7.47 (doublet of triplet,
J¼8.6 and 2.3 Hz, 2H), 8.44 (s, 1H, D2O-unexchangeable).
13C NMR (125 MHz): d 14.0, 39.4, 61.7, 108.4, 128.1,
130.2, 136.0, 136.9, 153.6, 155.1, 163.7, 173.2. MS (EI,
m/z): 292 (M+). Anal. Calcd for C14H13ClN2O3: C, 57.44;
H, 4.48; N, 9.57. Found: C, 57.25; H, 4.43; N, 9.71.
4.2.13. 5-Acetyl-1-methyl-4-phenyl-pyrimidin-2(1H)-one
(2l). Yellow solid. Mp: 139–141 ꢁC. IR (KBr): 1108, 1290,
1370, 1441, 1675, 1726, 2953 cmꢀ1. H NMR (500 MHz):
1
4.2.8. Ethyl 4-biphenyl-pyrimidin-2(1H)-one-5-carboxyl-
ate (2g). Yellow solid. Mp: 180–182 ꢁC. IR (KBr): 1419,
d 3.67 (s, 6H), 7.39 (t, J¼6.9 Hz, 2H), 7.45 (d, J¼5.3 Hz,
1H), 7.52 (t, J¼6.9 Hz, 2H), 8.41 (s, 1H, D2O-unexchange-
able). 13C NMR (125 MHz): d 39.3, 52.3, 108.4, 129.9,
128.6, 130.8, 137.4, 153.4, 155.1, 164.4, 174.2. MS (EI,
m/z): 228 (M+). Anal. Calcd for C13H12N2O2: C, 68.41; H,
5.30; N, 12.27. Found: C, 68.43; H, 5.33; N, 12.25.
1614, 1653, 1704, 3429 cmꢀ1 1H NMR (500 MHz):
.
d 0.97 (t, J¼6.9 Hz, 3H), 3.90 (q, J¼6.9 Hz, 2H), 7.34 (t,
J¼7.7 Hz, 1H), 7.43 (t, J¼7.7 Hz, 2H), 7.50 (d, J¼8.4 Hz,
2H), 7.66 (d, J¼7.7 Hz, 2H), 7.69 (d, J¼8.4 Hz, 2H), 8.56
(s, 1H, D2O-unexchangeable), 11.52 (s, 1H). 13C NMR
(125 MHz): d 14.1, 61.4, 108.1, 126.5, 127.3, 128.6,
129.6, 129.7, 139.6, 142.4, 145.7, 156.1, 158.91, 164.4,
173.6. MS (EI, m/z): 320 (M+). Anal. Calcd for
C19H16N2O3: C, 71.24; H, 5.03; N, 8.74. Found: C, 71.25;
H, 5.01; N, 8.73.
4.3. Preparation of ethyl 6-deuterio-4-(2-nitrophenyl)-
pyrimidin-2-(1H)-one-5-carboxylate (3a)
A 50-mL round bottom flask containing magnetic bar was
charged with 1 mmol (0.308 g) of 1d and 10 mL acetonitrile.
To this solution was added a mixture of cobalt(II) nitrate
hexahydrate (5 mmol, 1.46 g) and potassium persulfate
(2.5 mmol, 0.68 g) in 3 mL of D2O and the solution was
stirred at 80 ꢁC on an oil bath. The stirring was continued
at 80 ꢁC for 8 h (Table 2) and TLC showed the complete dis-
appearance of 1d. The reaction mixture was diluted with
20 mL of CHCl3 and the supernatant was decanted. The resi-
due was poured into 20 g of crushed ice and extracted with
CHCl3 (2ꢃ20 mL). The organic extracts were pooled up,
washed with brine solution, dried over anhydrous Na2SO4,
and concentrated in vacuum to afford 0.290 g of crude prod-
uct. The column purification of residue using 1:1 petroleum
ether/ethyl acetate afforded 0.23 g of 3a as pale yellow crys-
talline solid.
4.2.9. Ethyl 4-(4-methoxyphenyl)-pyrimidin-2(1H)-one-
5-carboxylate (2h). Yellow solid. Mp: 147–148 ꢁC. IR
(KBr): 1260, 1416, 1511, 1602, 1681, 1724, 2897, 2986,
3072, 3433 cmꢀ1
.
1H NMR (500 MHz): d 1.07 (t,
J¼7.4 Hz, 3H), 3.80 (s, 3H), 4.10 (q, J¼7.4 Hz, 2H), 6.84
(d, J¼8.8 Hz, 2H), 7.44 (d, J¼8.8 Hz, 2H), 8.71 (s, 1H),
11.49 (s, 1H). 13C NMR (125 MHz): d 13.8, 58.2, 61.2,
108.6, 113.4, 130.7, 132.4, 143.2, 157.5, 162.1, 164.0,
172.8. MS (EI, m/z): 274 (M+). Anal. Calcd for
C14H14N2O4: C, 61.31; H, 5.14; N, 10.21. Found: C,
61.34; H, 5.15; N, 10.19.
4.2.10. Ethyl 4-(4-methoxyphenyl)-pyrimidin-2(1H)-one-
5-carboxylate (2i). Yellow solid. Mp: 175–177 ꢁC. IR
(KBr): 1284, 1566, 1604, 1675, 1722, 2935, 3024, 3059,
4.3.1. Ethyl 6-deuterio-4-(2-nitrophenyl)-pyrimidin-2-
(1H)-one-5-carboxylate (3a). Pale yellow solid. Mp: 148–
150 ꢁC. IR (KBr): 1142, 1224, 1345, 1446, 1517, 1599,
1701, 1720, 2280, 2808, 2984, 3273 cmꢀ1. MS (EI, m/z):
290 (M+). The intensity of CH(6) proton was reduced by
70%. Other spectral characterizations were similar to 2d.
1
3415 cmꢀ1. H NMR (500 MHz): d 3.72 (s, 3H), 3.84 (s,
3H), 6.94 (d, J¼8 Hz, 2H), 7.52 (d, J¼8 Hz, 2H), 8.80 (s,
1H), 11.54 (s, 1H). 13C NMR (125 MHz): d 52.3, 55.5,
108.8, 113.8, 120.2, 130.9, 146.3, 158.1, 162.5, 164.6,
174.1. MS (EI, m/z): 260 (M+). Anal. Calcd for
C13H12N2O4: C, 60.00; H, 4.65; N, 10.76. Found: C,
60.02; H, 4.67; N, 10.78.
4.4. Experimental procedure for preparation of 3b–e
4.2.11. Ethyl 1-methyl-4-phenyl-pyrimidin-2(1H)-one-5-
carboxylate (2j). Yellow solid. Mp: 131–132 ꢁC. IR
(KBr): 1103, 1197, 1286, 1494, 1439, 1616, 1679, 1722,
4.4.1. Typical procedure for the preparation of ethyl 4-
(4-methoxyphenyl)-6-phenyl-pyrimidin-2(1H)-one-5-
carboxylate (3b). A 50-mL round bottom flask containing

P. Shanmugam, P. T. Perumal / Tetrahedron 63 (2007) 666–672
671
magnetic bar was charged with 1 mmol (0.352 g) of ethyl 4-
(4-methoxyphenyl)-6-phenyl-3,4-dihydropyrimidin-2(1H)-
one-5-carboxylate and 10 mL acetonitrile. To this solution
was added a mixture of cobalt(II) nitrate hexahydrate
(2.5 mmol, 0.73 g) and potassium persulfate (1.3 mmol,
0.351 g) in 3 mL of H2O and the solution was stirred at
80 ꢁC on an oil bath. The stirring was continued at 80 ꢁC
for 4 h (Table 2) and TLC showed the complete disappear-
ance of the starting material. The reaction mixture was
diluted with 20 mL of CHCl3 and the supernatant was
decanted. The residue was poured into 20 g of crushed ice
and extracted with CHCl3 (2ꢃ20 mL). The organic extracts
were pooled up, washed with brine solution, dried over
anhydrous Na2SO4, and concentrated in vacuum to afford
0.263 g of crude product. The column purification of residue
using 1:1 petroleum ether/ethyl acetate afforded 0.227 g
of 3b. The same procedure was followed for the synthesis
of 3d–e.
1H), 7.82 (d, J¼7.5 Hz, 1H), 7.89 (d, J¼7.5 Hz, 2H), 8.11
(d, J¼6.8 Hz, 1H). 13C NMR (125 MHz): d 106.2, 120.8,
121.5, 126.7, 128.3, 128.9, 130.1, 132.1, 133.7, 135.2,
143.5, 151.2, 157.4, 173.9, 187.5. MS (EI, m/z): 274 (M+).
Anal. Calcd for C17H10N2O2: C, 74.44; H, 3.67; N, 10.21.
Found: C, 74.46; H, 3.69; N, 10.20.
4.4.6. Ethyl 1-methyl-4-[3-(4-methoxyphenyl)-1-phenyl-
1H-pyrazolyl]-pyrimidin-2(1H)-one-5-carboxylate (3f).
Yellow solid. Mp: 183–184 ꢁC. IR (KBr): 1413, 1623,
1
1693, 1721, 2855, 3034, 3231 cmꢀ1. H NMR (500 MHz):
d 0.96 (t, J¼6.9 Hz, 3H), 3.66 (m, 5H), 3.80 (s, 3H), 6.86
(d, J¼8.5 Hz, 2H), 7.30 (t, J¼7.5 Hz, 1H), 7.43 (m, 4H),
7.81 (d, J¼8.1 Hz, 2H), 8.22 (s, 1H, pyrazole-H), 8.55 (s,
1H, D2O-unexchangeble). 13C NMR (125 MHz): d 13.7,
29.8, 55.6, 57.0, 105.1, 114.1, 119.2, 125.6, 129.0, 129.6,
129.9, 130.1, 131.2, 138.2, 139.6, 152.5, 156.0, 167.2,
168.2, 177.7. MS (EI, m/z): 430 (M+). Anal. Calcd for
C24H22N4O4: C, 66.97; H, 5.15; N, 13.02. Found: C,
66.98; H, 5.14; N, 13.03.
4.4.2. Ethyl 4-(4-methoxyphenyl)-6-phenyl-pyrimidin-
2(1H)-one-5-carboxylate (3b). Yellow solid. Mp: 153–
154 ꢁC. IR (KBr): 1163, 1238, 1328, 1446, 1517, 1599,
4.4.7. Ethyl 4-(4-tolyl)-pyrimidin-2(1H)-one-5-carboxyl-
ate (5a). Pale yellow crystalline solid. Mp: 160–162 ꢁC.
1668, 1709, 2280, 2808, 2984, 3213 cmꢀ1 1H NMR
.
1
(500 MHz): d 0.85 (t, J¼6.9 Hz, 3H), 3.82 (s, 3H), 3.90 (q,
J¼6.9 Hz, 2H), 6.94 (d, J¼9.2 Hz, 1H), 7.00 (d, J¼8.5 Hz,
1H), 7.40 (sextet, J¼7 and 7.7 Hz, 2H), 7.49 (d, J¼3.8 Hz,
1H), 7.58 (t, J¼8.5 Hz, 2H), 8.01 (q, J¼8.5 and 9.2 Hz,
2H), 13.32 (s, 1H, D2O-exchangeable). 13C NMR
(125 MHz): d 13.5, 55.4, 61.9, 106.5, 114.2, 128.6, 129.2,
129.6, 130.2, 138.5, 139.7, 150.2, 158.2, 162.2, 162.9,
174.1. MS (EI, m/z): 350 (M+). Anal. Calcd for
C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.57;
H, 5.17; N, 8.02.
IR (KBr): 1183, 1425, 1512, 1666, 1712, 3213 cmꢀ1. H
NMR (500 MHz): d 1.09 (t, J¼6.9 Hz, 3H), 2.35 (s, 3H),
4.11 (q, J¼6.9 Hz, 2H), 7.19 (d, J¼8 Hz, 2H), 7.38 (d,
J¼8 Hz, 2H), 8.78 (s, 1H, D2O-unexchangeable). 13C
NMR (125 MHz): d 13.9, 21.7, 61.5, 109.0, 128.7, 128.8,
128.9, 131.6, 141.8, 157.8, 164.0, 169.4. MS (EI, m/z):
258 (M+). Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46;
N, 10.85. Found: C, 65.01; H, 5.38; N, 10.87.
4.4.8. Ethyl tetrahydropyrimidin-2,4(1H,3H)-dione-5-
carboxylate (8). Colorless crystalline solid. Mp: 225–
228 ꢁC. IR (KBr): 1478, 1619, 1668, 1744, 2855, 3034,
4.4.3. Ethyl 4-(4-methoxyphenyl)-6-trifluoromethyl-pyr-
imidin-2(1H)-one-5-carboxylate (3c). Red viscous liquid
crystallized to intense yellow solid. Mp: 136–138 ꢁC. IR
(KBr): 1017, 1127, 1162, 1210, 1299, 1509, 1605, 1699,
3335 cmꢀ1
.
1H NMR (400 MHz): d 1.15 (t, J¼6.9 Hz,
3H), 4.09 (q, J¼6.9 Hz, 2H), 8.08 (s, 1H, D2O-exchange-
able), 11.27 (s, 1H, D2O-exchangeable), 11.57 (s, 1H,
D2O-exchangeable). 13C NMR (100 MHz): d 14.7, 60.5,
103.6, 149.92, 151.1, 160.6, 163.6. MS (EI, m/z): 184
(M+). Anal. Calcd for C7H8N2O4: C, 45.66; H, 4.38; N,
15.21. Found: C, 45.67; H, 4.39; N, 15.19.
1739, 3188 cmꢀ1
.
1H NMR (500 MHz): d 1.15 (t,
J¼6.9 Hz, 3H), 3.85 (s, 3H), 4.17 (q, J¼6.9 Hz, 2H), 7.05
(d, J¼8.4 Hz, 2H), 7.54 (d, J¼8.4 Hz, 2H), 11.50 (s, 1H).
13C NMR (125 MHz): d 13.7, 55.6, 62.8, 109.5, 114.9,
122.0 (q, J¼275 Hz), 130.2, 138.6, 155.6 (q, J¼34 Hz),
161.2, 163.2, 164.1, 174.2. MS (EI, m/z): 342 (M+). Anal.
Calcd for C15H13F3N2O4: C, 52.64; H, 3.83; N, 8.18. Found:
C, 52.65; H, 3.83; N, 8.19.
4.4.9. Ethyl 4-(9-anthryl)-pyrimidin-2(1H)-one-5-car-
boxylate (10). Yellow solid. Mp: 180–182 ꢁC. IR (KBr):
1
1142, 1230, 1459, 1648, 1698 cmꢀ1. H NMR (400 MHz):
d 0.35 (t, J¼6.9 Hz, 3H), 3.58 (doublet of quartet,
J¼6.9 Hz, 2H), 7.48 (t, J¼6.9 Hz, 2H), 7.56 (d, J¼6.9 Hz,
2H), 7.61 (t, J¼7.7 Hz, 2H), 7.78 (q, J¼3.8 and 2.3 Hz,
1H), 7.88 (d, J¼9.2 Hz, 2H), 9.10 (s, 1H), 11.50 (s, 1H).
13C NMR (100 MHz): d 12.9, 61.4, 106.1, 121.8, 123.1,
124.9, 125.7, 127.3, 127.7, 127.9, 128.0, 128.9, 132.1,
133.7, 134.3, 144.7, 145.9, 150.9, 156.5, 163.1, 174.5. MS
(EI, m/z): 344 (M+). Anal. Calcd for C21H16N2O3: C,
73.24; H, 4.68; N, 8.13. Found: C, 73.24; H, 4.69; N, 8.12.
4.4.4. 7,7-Dimethyl-4-phenyl-7,8-dihydroquinazoline-
2,5(1H,6H)-dione (3d). Pale yellow solid. Mp: 196–
198 ꢁC. IR (KBr): 1092, 1323, 1640, 1722, 2956,
1
3208 cmꢀ1. H NMR (500 MHz): d 1.35 (s, 6H), 2.58 (s,
2H), 2.88 (s, 2H), 7.01 (q, J¼1.7 , 5.2, and 7.5 Hz, 2H),
7.40 (q, J¼1.7 and 5.2 Hz, 3H), 11.83 (s, 1H). 13C NMR
(125 MHz): d 25.4, 28.3, 32.1, 48.1, 54.1, 108.5, 126.6,
127.8, 128.0, 138.8, 152.3, 167.7, 172.2, 194.8. MS (EI,
m/z): 268 (M+). Anal. Calcd for C16H16N2O2: C, 71.62; H,
6.01; N, 10.44. Found: C, 71.61; H, 6.02; N, 10.46.
4.4.10. 3H-1,3-Diaza-naphtho[3,2,1-de]anthracene-2,5-
dione (11). Yellow solid. Mp: 230–232 ꢁC. IR (KBr):
1
4.4.5. 4-Phenyl-1H-indeno[1,2-d]pyrimidin-2,5-dione
(3e). Colorless crystalline solid. Mp: 210–212 ꢁC. IR
(KBr): 1276, 1378, 1459, 1576, 1617, 1617, 1659, 1723,
1145, 1233, 1460, 1645, 1696 cmꢀ1. H NMR (400 MHz):
d 7.95 (m, 1H), 8.23 (m, 1H), 8.39 (d, J¼9.2 Hz, 1H), 8.43
(d, J¼9.2 Hz, 2H), 8.58 (d, J¼9.2 Hz, 1H), 8.66 (d,
J¼9.2 Hz, 2H), 8.79 (s, 1H, D2O-unexchangeable), 11.52
(s, 1H). MS (EI, m/z): 298 (M+). Anal. Calcd for
2854, 2923, 3484 cmꢀ1 1H NMR (500 MHz): d 7.6 (t,
.
J¼6.9 Hz, 2H), 7.65 (q, J¼6.9 Hz, 2H), 7.71 (t, J¼7.5 Hz,

672
P. Shanmugam, P. T. Perumal / Tetrahedron 63 (2007) 666–672
Y. V.; Vanden, L. T. ARKIVOC 2003, 22; (c) Yamamoto, K.;
Chen, Y. G.; Buono, F. G. Org. Lett. 2005, 7, 4673; (d)
Dondoni, A.; Massi, A.; Minghini, E.; Sabbatini, S.;
Bertolasi, V. J. Org. Chem. 2003, 68, 6172.
C19H10N2O2: C, 76.50; H, 3.38; N, 9.39. Found: C, 76.53; H,
3.40; N, 9.38.
Acknowledgements
7. Rizzo, R. C.; Tirado-Rives, J.; Jorgensen, W. L. J. Med. Chem.
2001, 44, 145.
One of the authors (P.S.) would like to thank the Council of
Scientific and Industrial Research, New Delhi for financial
support. We are grateful to Mr. D. Muralidharan and Dr. R.
Sridhar, CLRI for meticulously correcting the manuscript.
8. Hockova, D.; Holy, A.; Masojidkova, M.; Andrei, G.; Snoeck,
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X.-J.; Chen, T.-K.; Bozigian, H.; Grigoriadis, D. E. J. Med.
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