Regioselective chlorination at C-6 methyl position of 3,4-dihydropyrimidin- 2(1H)-ones using (dichloroiodo)benzene

Article abstract of DOI:10.1007/s00706-012-0908-0

The reaction of (dichloroiodo)benzene with 4-aryl-1,2,3,4-tetrahydro-6- methyl-2-oxopyrimidine-5-carboxylates and 5-acetyl-4-aryl-3,4-dihydro-6- methylpyrimidin-2(1H)-ones resulted in geminal dichlorination at the C-6 methyl position of 3,4-dihydropyrimid

Full text of DOI:10.1007/s00706-012-0908-0

Monatsh Chem (2013) 144:981–986
DOI 10.1007/s00706-012-0908-0
ORIGINAL PAPER
Regioselective chlorination at C-6 methyl position
of 3,4-dihydropyrimidin-2(1H)-ones using (dichloroiodo)benzene
•
•
•
Nilesh P. Tale Amol V. Shelke Bhagyashree Y. Bhong
Nandkishor N. Karade
Received: 29 August 2012 / Accepted: 16 December 2012 / Published online: 28 February 2013
Ó Springer-Verlag Wien 2013
Abstract The reaction of (dichloroiodo)benzene with
4-aryl-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-
carboxylates and 5-acetyl-4-aryl-3,4-dihydro-6-methylpyr-
imidin-2(1H)-ones resulted in geminal dichlorination at the
C-6 methyl position of 3,4-dihydropyrimidin-2(1H)-one.
compounds [5]. DHPMs functionalized at the C-6 methyl
group are convenient starting materials for the synthesis of
fused pyrimidines [6–10] (Scheme 1).
O
Ar
O
Ar
PhICl2
R
NH
R
NH
Keywords Chlorination Á Biginelli compounds Á
Hypervalent iodine Á Oxidation Á Halogenation
CH2Cl2, r. t.
Cl
N
H
O
N
H
O
Cl
R = OC2H5, CH3
Introduction
1a 1r
2a 2r
-
-
Scheme 1
4-Aryl-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-car-
boxylates (Biginelli DHPMs) have attracted considerable
interest in recent times because of their promising phar-
macological activity, e.g., they act as calcium channel
blockers, antihypertensive agents, and antagonists [1]. The
derivatization of DHPMs is therefore of immense signifi-
cance to produce ‘‘drug-like’’ molecules for biological
screening [2]. The functionalization at the C-6 methyl
group is one of the ways of elaborating the DHPM scaffold
[3]. For example, the halogenation at the C-6 methyl
position of DHPM can confer significant changes in the
chemical, physical, and biological properties of DHPM [4].
The reaction of the C-6 halomethyl group of DHPM with a
wide range of nucleophiles forms 6-substituted Biginelli
The stepwise substitution of the C-6 methyl group via
bromination to produce 6-(bromomethyl) or 6-(dibro-
momethyl) derivatives and their subsequent reaction with
various nucleophiles is commonly reported for the elabo-
ration of DHPMs at the C-6 position [11] (Fig. 1).
Bromination of the C-6 methyl group is a very critical
reaction and the procedure requires careful and dropwise
addition of molecular bromine to the DHPM at subambient
temperature to avoid overbromination to the corresponding
gem-dibromo derivative [10]. Apart from these halogena-
tion reports, metalation of the least acidic C-6 methyl of
DHPMs with LDA has been recently demonstrated for the
generation of a nucleophilic C-6 position and its trapping
with a range of electrophiles [12]. Another transformation
of the methyl group at the C-6 position of 3,4-dihydro-
pyrimidin-2(1H)-one involves its oxidation to an aldehyde
with SeO2 [13]. However, because of the low yield (10 %)
this reaction is of limited synthetic value.
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-012-0908-0) contains supplementary
material, which is available to authorized users.
N. P. Tale Á A. V. Shelke Á B. Y. Bhong Á N. N. Karade (&)
Department of Chemistry, Rashtrasant Tukadoji Maharaj Nagpur
University, Nagpur, Maharashtra 440 033, India
e-mail: nnkarade@gmail.com
The chlorination of DHPMs is a less investigated reaction.
The reported chlorination of DHPMs with elemental chlorine
in chloroform at 4 °C has been reported to give, after aqueous
123

982
N. P. Tale et al.
Fig. 1 Elaboration of DHPMs
via halogenation at the C-6
methyl position
R
O
R
O
NH
O
NH
EtO
N
H
O
N
H
O
Ref [5]
Ref [14]
O
Nu
R
R
R
O
halogenation
at C-6 methyl
O
Ref [6, 7]
NH
NH
EtO
EtO
NH
R N
N
N
H
O
O
N
H
O
H
X
Ref [10]
Ref [8]
Ref [9]
R
O
N
R
O
R
O
NH
EtO
N
HN
NH
Et
N
NH
O
N
R
N
O
N
H
O
H
N
N
O
H
NH
N
N
R
work-up, the hexahydropyrimidine with the net addition of
HOCl across the double bond [5]. The chlorination of DHPMs
with PCl5 and POCl3 also leads to the formation of a gem-
dichloromethyl derivative along with two other side products
[14]. In view of these difficulties with the clean chlorination
reactions of DHPMs, we have investigated their reaction with
(dichloroiodo)benzene which is a potent, fairly selective, and
easy to handle chlorinating agent and oxidizing agent [15].
The reaction of (dichloroiodo)benzene with 4-aryl-1,2,3,4-
tetrahydro-6-methyl-2-oxopyrimidine-5-carboxylates as well
as 5-acetyl-4-aryl-3,4-dihydro-6-methylpyrimidin-2(1H)-ones
was found to form the C-6 dichloromethyl derivatives of
DHPMs regioselectively.
midine-5-carboxylate (2a) in 48 % yield. The maximum
89 % yield of 2a was achieved in 2 h at room temperature
using a 1:2 stoichiometric ratio of 1a with PhICl2. The reason
for exclusive dichlorination at the C-6 methyl position is
uncertain but the possibility of allylic geminal dichlorination
via a free radical pathway cannot be ruled out. However, a
similar kind of geminal dibromination [10] as well as
hypothetical dinitration [16] at the C-6 methyl position of
DHPM is previously documented in the literature.
The generality of the method was examined by treating a
rangeofDHPMswithPhICl2 and theresults are summarized in
Table 2. Having succeeded with 1a–1h, the methodology was
extended to 5-acetyl-4-aryl-3,4-dihydro-6-methylpyrimidin-
2(1H)-ones for the possible chlorination reaction with PhICl2.
It is noteworthy that chlorination of 1i–1o took place again at
the C-6 methyl position to form 5-acetyl-4-aryl-6-(dichlo-
romethyl)-3,4-dihydropyrimidin-2(1H)-ones. The 5-acetyl
group of DHPMs remains unaltered under the chlorination
reaction conditions.
Results and discussion
We initially examined the chlorination of ethyl 1,2,3,4-tet-
rahydro-6-methyl-2-oxo-4-phenylpyrimidine-5-carboxylate
(1a, Ar = C6H5 and R = OC2H5) with PhICl2 under differ-
ent reaction conditions. The results are shown in Table 1. The
dichlorination product 2a was formed in relatively poor
yields of 23 and 36 % by using 1:1 or 1:1.5 stoichiometric
ratios of 1a and PhICl2, respectively. It is important to men-
tion that the monochlorination product was not isolated under
these reaction conditions.
In all the cases, good to excellent yields of the products
were obtained. The chlorinated products are new com-
pounds and their structures were confirmed by IR, NMR
1
(1H and 13C), and LC–MS spectroscopy. H NMR spectra
of 2a–2h and 2i–2o showed a characteristic sharp singlet
around d = 6.12–6.15 ppm and 5.79–5.82 ppm, respec-
tively, due to the –CHCl2 proton. Similarly, 13C NMR
spectra of 2a–2o showed a characteristic sharp singlet at
d = 66–67 ppm due to the –CHCl2 carbon. All the com-
pounds are thermally stable at room temperature and can be
stored for a long time without any thermal decomposition.
The reaction of 1a (1 mmol) with PhICl2 (1 mmol) in
dichloromethane at room temperature stirring for 5 h
resulted in formation of the dichlorination product ethyl
6-(dichloromethyl)-1,2,3,4-tetrahydro-2-oxo-4-phenylpyri-
123

Regioselective chlorination using (dichloroiodo)benzene
983
In conclusion, the reaction of (dichloroiodo)benzene
with 3,4-dihydro-6-methylpyrimidin-2(1H)-ones leads to
the formation of geminal dichlorination at the C-6 methyl
group to form 6-(dichloromethyl)-3,4-dihydropyrimidin-
2(1H)-ones in excellent yields. Taking the advantage of
doubly electrophilic reactivity of a geminal dichloromethyl
group, DHPMs can thus be elaborated at the 6-position by
reaction with suitable doubly nucleophilic molecules.
room temperature from CDCl3 solutions. Chemical shifts are
reported as ppm on the d scale and coupling constants (J) are
in Hz. Multiplicities are described as s (singlet), d (doublet), t
(triplet), q (quartet), m (multiplet). LC–MS spectra were
recorded using a Shimadzu LC 2010 (single quadrupole).
Thin-layer chromatography (TLC) was carried out on SiO2
(silica gel 60F254, Merck), and the spots were visualized with
UV light. Flash column chromatography was carried out on
SiO2 (silica gel 60, Qualigens, 230–400 mesh, particle size
0.040–0.063 mm). All other commercial reagents and sol-
vents were used without further purification. The starting
4-aryl-1,2,3,4-tetrahydro-6-methyl-2-oxopyrimidine-5-car-
boxylates and 5-acetyl-4-aryl-3,4-dihydro-6-methylpyrim-
idin-2(1H)-ones were prepared by literature methods
(stirring the respective aldehyde, urea, and ethyl acetoacetate
or acetylacetone in conc. HCl as catalyst in ethanol solvent
for 24 h at room temperature). (Dichloroiodo)benzene was
prepared by passing chlorine gas through an ice cold solution
of iodobenzene in chloroform.
Experimental
Solvents were purified by conventional methods prior to use.
1H (400 MHz) and 13C (100 MHz) NMR spectra were
recorded on Bruker Avance II 400 NMR spectrometer at
Table 1 Optimization of reaction conditions
Entry
Substrate
1a/mmol
PhICl2/
mmol
Solvent
Time/h
Yield of
2a/%
1
2
3
4
5
1
1
1
1
1
1
CH3COOH
CH3COOH
CH2Cl2
24
24
5
32
41
48
71
88
1.5
1
Representative experimental procedure
1.5
2
CH2Cl2
3
PhICl2 (4 mmol) was added to a solution of an appro-
CH2Cl2
2
priate 4-aryl-3,4-dihydro-6-methylpyrimidin-2(1H)-one
Table 2 Chlorination at the C-6 methyl position of 4-aryl-3,4-dihydro-6-methylpyrimidin-2(1H)-ones using PhICl2 in CH2Cl2 at 25 °C
O
Ar
O
Ar
PhICl2
R
NH
R
NH
CH2Cl2, r. t.
Cl
N
H
O
N
H
O
Cl
R = OC2H5, CH3
Substrate
Ar
R
Product
Yield/%a
1a
1b
1c
1d
1e
1f
C6H5
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3CH2O
CH3
2a
2b
2c
2d
2e
2f
88
81
82
78
80
71
77
69
84
80
72
71
70
76
69
3-CH3O-C6H4
4-CH3O-C6H4
3,4-(CH3O)2-C6H3
2-Cl-C6H4
4-Cl-C6H4
1g
1h
1i
4-Br-C6H4
2g
2h
2i
3-NO2-C6H4
C6H5
1j
4-CH3-C6H4
4-CH3O-C6H4
3,4-(CH3O)2-C6H3
2,5-(CH3O)2-C6H3
2-Cl-C6H4
CH3
2j
1k
1l
CH3
2k
2l
CH3
1m
1n
1o
a
CH3
2m
2n
2o
CH3
4-Br-C6H4
CH3
Isolated yields after column chromatography
123

984
N. P. Tale et al.
(2 mmol) in 10 cm3 CH2Cl2. The mixture was stirred at
25 °C for 1–2 h while checking the reaction progress by
TLC. After completion, the reaction mass was concentrated
under vacuum and the crude product was purified by col-
umn chromatography (petroleum ether/ethyl acetate 10:3)
to provide the analytically pure product. The identity of
products was determined by melting point, NMR, and MS
analysis.
Ethyl 6-(dichloromethyl)-4-(3,4-dimethoxyphenyl)-
1,2,3,4-tetrahydro-2-oxopyrimidine-5-carboxylate
(2d, C16H18Cl2N2O5)
Yellow solid; yield: 78 % (607 mg); TLC (EtOAc/PE 1:1):
Rf = 0.43; m.p.: 132–134 °C; 1H NMR (400 MHz,
CDCl3): d = 1.24 (t, 3H, J = 7.2 Hz, CH3), 3.84 (s, 3H,
OCH3), 3.87 (s, 3H, OCH3), 4.16 (q, 2H, J = 7.2 Hz,
OCH2), 4.80 (s, 1H, ArCH), 6.17 (s, 1H, CHCl2), 6.30 (br
s, 1H, NH), 6.78 (s, 1H, ArH), 6.80–6.85 (m, 2H, ArH),
7.13 (s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 13.74, 55.81, 62.82, 63.15, 65.17, 100.76, 110.65,
110.80, 120.96, 127.12, 132.79, 148.74, 149.76, 152.58,
Ethyl 6-(dichloromethyl)-1,2,3,4-tetrahydro-4-phenyl-
2-oxopyrimidine-5-carboxylate (2a, C14H14Cl2N2O3)
Yellow solid; yield: 88 % (579 mg); TLC (EtOAc/PE
1
ꢀ
164.58 ppm; IR (KBr): m = 3,229, 3,194, 3,045, 1,751,
1:1): Rf = 0.55; m.p.: 142–144 °C; H NMR (400 MHz,
1,638, 1,633, 1,265, 1,093, 757 cm-1; LC–MS: m/z = 389
(M? ? 1).
CDCl3): d = 1.23 (t, 3H, J = 7.2 Hz, CH3), 4.11 (q, 2H,
J = 7.1 Hz, OCH2), 4.79 (s, 1H, ArCH), 6.13 (s, 1H,
CHCl2), 7.14 (br s, 1H, NH), 7.24–7.27 (m, 2H, ArH),
7.31–7.36 (m, 3H, ArH), 7.37 (s, 1H, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 13.70, 63.22, 63.27,
65.20, 100.75, 128.17, 128.64, 129.63, 132.77, 134.93,
Ethyl 4-(2-chlorophenyl)-6-(dichloromethyl)-
1,2,3,4-tetrahydro-2-oxopyrimidine-5-carboxylate
(2e, C14H13Cl3N2O3)
Yellow solid; yield: 80 % (581 mg); TLC (EtOAc/PE 1:1):
Rf = 0.48; m.p.: 167–170 °C; 1H NMR (400 MHz,
CDCl3): d = 1.11 (t, 3H, J = 7.2 Hz, CH3), 4.13 (q, 2H,
J = 7.2 Hz, OCH2), 5.52 (s, 1H, ArCH), 6.24 (s, 1H,
CHCl2), 6.67 (br s, 1H, NH), 7.24–7.30 (m, 4H, ArH and
NH), 7.38 (d, 1H, J = 6.8 Hz, ArH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 13.51, 58.27, 63.48, 64.17,
101.05, 127.67, 127.71, 130.04, 130.39, 132.64, 133.97,
134.19, 151.84, 164.47 ppm; IR (KBr): ꢀm = 3,200, 3,167,
3,052, 1,727, 1,665, 1,643, 1,054, 756 cm-1; LC–MS:
m/z = 364 (M? ? 1).
ꢀ
152.49, 164.54 ppm; IR (KBr): m = 3,212, 3,194, 3,048,
1,752, 1,681, 1,642, 750 cm-1; LC–MS: m/z = 329
(M? ? 1).
Ethyl 6-(dichloromethyl)-1,2,3,4-tetrahydro-4-
(3-methoxyphenyl)-2-oxopyrimidine-5-carboxylate
(2b, C15H16Cl2N2O4)
Yellow solid; yield: 81 % (470 mg); TLC (EtOAc/PE 1:1):
Rf = 0.53; m.p.: 163–164 °C; 1H NMR (400 MHz,
CDCl3): d = 1.22 (t, 3H, J = 7.6 Hz, CH3), 3.78 (s, 3H,
OCH3), 4.17 (q, 2H, J = 7.2 Hz, OCH2), 4.82 (s, 1H,
ArCH), 6.15 (s, 1H, CHCl2), 6.25 (br s, 1H, NH), 6.81 (s,
1H, ArH), 6.85 (d, 1H, J = 8.0 Hz, ArH), 6.90 (d, 1H,
J = 8.4 Hz), 7.13 (s, 1H, NH), 7.26 (t, 1H, J = 8.4 Hz,
ArH) ppm; 13C NMR (100 MHz, DMSO-d6): d = 13.72,
55.26, 63.17, 63.31, 65.11, 100.71, 113.94, 114.97, 120.30,
129.70, 132.81, 136.31, 152.16, 159.60, 164.50 ppm; IR
Ethyl 4-(4-chlorophenyl)-6-(dichloromethyl)-
1,2,3,4-tetrahydro-2-oxopyrimidine-5-carboxylate
(2f, C14H13Cl3N2O3)
Yellow solid; yield: 71 % (516 mg); TLC (EtOAc/PE 1:1):
Rf = 0.37; m.p.: 148–150 °C; 1H NMR (400 MHz,
CDCl3): d = 1.22 (t, 3H, J = 7.2 Hz, CH3), 4.17 (q, 2H,
J = 7.2 Hz, OCH2), 4.82 (s, 1H, ArCH), 6.14 (s, 1H,
CHCl2), 6.58 (br s, 1H, NH), 7.19 (br s, 1H, NH), 7.23
(d, 2H, J = 8.4 Hz, ArH), 7.34 (d, 2H, J = 7.6 Hz, ArH)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 13.77, 62.58,
63.46, 64.97, 101.13, 128.89, 129.64, 132.47, 133.30,
135.67, 164.36 ppm; LC–MS: m/z = 364 (M? ? 1).
ꢀ
(KBr): m = 3,229, 3,202, 3,070, 1,750, 1,654, 1,222, 1,170,
778, 762, 694 cm-1; LC–MS: m/z = 359 (M? ? 1).
Ethyl 6-(dichloromethyl)-1,2,3,4-tetrahydro-4-
(4-methoxyphenyl)-2-oxopyrimidine-5-carboxylate
(2c, C15H16Cl2N2O4)
Ethyl 4-(4-bromophenyl)-6-(dichloromethyl)-
1,2,3,4-tetrahydro-2-oxopyrimidine-5-carboxylate
(2g, C14H13BrCl2N2O3)
Yellow solid; yield: 82 % (589 mg); TLC (EtOAc/PE 1:1):
Rf = 0.49; m.p.: 168–170 °C; 1H NMR (400 MHz,
CDCl3): d = 1.22 (t, 3H, J = 7.2 Hz, CH3), 3.78 (s, 3H,
OCH3), 4.13 (q, 2H, J = 7.2 Hz, OCH2), 4.77 (s, 1H,
ArCH), 6.12 (s, 1H, CHCl2), 6.85 (d, 2H, J = 8.4 Hz,
ArH), 6.89 (br s, 1H, NH), 7.19 (d, 2H, J = 8.4 Hz), 7.28
(s, 1H, NH) ppm; 13C NMR (100 MHz, DMSO-d6): d =
13.76, 55.26, 62.56, 63.23, 65.36, 100.72, 111.91, 126.73,
129.45, 132.05, 132.79, 152.78, 160.30, 164.63 ppm;
LC–MS: m/z = 359 (M? ? 1).
Yellow solid; yield: 77 % (628 mg); TLC (EtOAc/PE 1:1):
Rf = 0.41; m.p.: 170–172 °C; 1H NMR (400 MHz,
CDCl3): d = 1.22 (t, 3H, J = 7.2 Hz, CH3), 4.17 (q, 2H,
J = 7.2 Hz, CH2), 4.81 (s, 1H, ArCH), 6.14 (s, 1H,
CHCl2), 6.66 (s, 1H, NH), 7.17 (d, 3H, J = 8.0 Hz, ArH
and NH), 7.49 (d, 2H, J = 8.4 Hz, ArH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 13.77, 62.68, 63.47, 64.97,
123

Regioselective chlorination using (dichloroiodo)benzene
985
101.05, 123.99, 129.88, 131.87, 132.49, 133.77, 152.34,
ꢀ
5-Acetyl-6-(dichloromethyl)-4-(3,4-dimethoxyphenyl)-3,4-
dihydropyrimidin-2(1H)-one (2l, C15H16Cl2N2O4)
164.33 ppm; IR (KBr): m = 3,368, 3,360, 3,087, 1,072,
1,747, 1,662, 1,645, 849, 760, 732 cm-1; LC–MS:
Yellow solid; yield: 71 % (510 mg); TLC (EtOAc/PE 2:3):
Rf = 0.37; m.p.: 156–158 °C; 1H NMR (400 MHz, CDCl3):
d = 2.11 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 3.84 (s, 3H,
OCH3), 4.76 (s, 1H, ArCH), 5.84 (s, 1H, CHCl2), 6.83–6.87
(m, 3H, ArH), 7.83 (br s, 1H, NH), 7.91 (br s, 1H, NH) ppm;
13C NMR (100 MHz, DMSO-d6): d = 15.29, 20.70, 28.56,
55.36, 60.02, 62.34, 70.32, 97.95, 102.26, 110.31, 118.98,
121.01, 126.09, 129.54, 134.04, 148.25, 149.13, 151.69,
m/z = 409 (M? ? 1).
Ethyl 6-(dichloromethyl)-1,2,3,4-tetrahydro-4-
(3-nitrophenyl)-2-oxopyrimidine-5-carboxylate
(2h, C14H13Cl2N3O5)
Yellow solid; yield: 69 % (516 mg); TLC (EtOAc/PE 1:1):
Rf = 0.39; m.p.: 184–186 °C; 1H NMR (400 MHz,
CDCl3): d = 1.27 (t, 3H, J = 7.2 Hz, CH3), 4.21 (q, 2H,
J = 7.2 Hz, CH2), 5.01 (s, 1H, ArCH), 6.17 (s, 1H,
CHCl2), 6.40 (s, 1H, NH), 7.13 (s, 1H, NH), 7.60 (t, 1H,
J = 7.6 Hz, ArH), 7.69 (d, 1H, J = 8.0 Hz, ArH), 8.21 (s,
1H, ArH), 8.27 (d, 1H, J = 8.0 Hz, ArH) ppm; 13C NMR
(100 MHz, DMSO-d6): d = 13.20, 61.63, 63.03, 64.16,
100.15, 122.98, 123.62, 129.12, 131.83, 134.22, 137.43,
147.31, 151.17, 163.84 ppm;LC–MS:m/z = 415(M? ? 1).
ꢀ
152.38, 172.42, 198.67 ppm; IR (KBr): m = 3,253, 3,219,
3,042, 2,998, 1,714, 1,671, 1,632, 1,237, 1,166, 738 cm-1
;
LC–MS: m/z = 359 (M? ? 1).
5-Acetyl-6-(dichloromethyl)-4-(2,5-dimethoxyphenyl)-
3,4-dihydropyrimidin-2(1H)-one (2m, C15H16Cl2N2O4)
Yellow solid; yield: 70 % (502 mg); TLC (EtOAc/PE 2:3):
Rf = 0.35; m.p.: 168–170 °C; 1H NMR (400 MHz,
CDCl3): d = 2.37 (s, 3H, CH3), 3.71 (s, 3H, OCH3), 3.75
(s, 3H, OCH3), 5.31 (s, 1H, ArCH), 5.80 (s, 1H, CHCl2),
6.05 (br s, 1H, NH), 6.74 (s, 1H, ArH), 6.80 (s, 1H, ArH),
6.83–6.86 (m, 1H, ArH), 7.06 (br s, 1H, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 29.18, 54.98, 55.05,
71.16, 98.57, 110.87, 113.35, 113.88, 125.17, 133.19,
5-Acetyl-6-(dichloromethyl)-3,4-dihydro-4-
phenylpyrimidin-2(1H)-one (2i, C13H12Cl2N2O2)
Yellow solid; yield: 84 % (502 mg); TLC (EtOAc/PE 2:3):
Rf = 0.52; m.p.: 180–182 °C; 1H NMR (400 MHz,
CDCl3): d = 1.97 (s, 3H, CH3), 4.80 (s, 1H, ArCH), 5.84
(s, 1H, CHCl2), 5.92 (br s, 1H, NH), 7.19 (br s, 1H, NH),
7.35–7.43 (m, 5H, ArH) ppm; 13C NMR (100 MHz,
DMSO-d6): d = 28.40, 62.21, 64.29, 70.47, 73.67, 97.77,
104.70, 127.94, 128.05, 128.38, 128.70, 128.91, 132.81,
133.86, 134.35, 151.40, 154.27, 198.24, 199.01 ppm; IR
ꢀ
150.09, 151.33, 152.97, 198.31 ppm; IR (KBr): m = 3,202,
3,184, 3,045, 1,715, 1,640, 1,613, 1,223, 1,178 cm-1
;
LC–MS: m/z = 359 (M? ? 1).
5-Acetyl-4-(2-chlorophenyl)-6-(dichloromethyl)-3,4-
dihydropyrimidin-2(1H)-one (2n, C13H11Cl3N2O2)
ꢀ
(KBr): m = 3,223, 3,213, 3,060, 1,702, 1,676, 759,
679 cm-1; LC–MS: m/z = 299 (M? ? 1).
Yellow solid; yield: 76 % (507 mg); TLC (EtOAc/PE 2:3):
Rf = 0.56; m.p.: 180–182 °C; 1H NMR (400 MHz,
CDCl3): d = 2.32 (s, 3H, CH3), 5.49 (s, 1H, ArCH), 5.81
(s, 1H, CHCl2), 6.15 (br s, 1H, NH), 7.21 (br s, 1H, NH),
7.28–7.33 (m, 3H, ArH), 7.42 (d, 1H, J = 6.8 Hz, ArH)
ppm; 13C NMR (100 MHz, DMSO-d6): d = 29.33, 58.52,
70.02, 100.24, 127.80, 128.49, 130.28, 130.81, 132.49,
5-Acetyl-6-(dichloromethyl)-3,4-dihydro-4-(4-methyl-
phenyl)pyrimidin-2(1H)-one (2j, C14H14Cl2N2O2)
Yellow solid; yield: 80 % (501 mg); TLC (EtOAc/PE 2:3):
Rf = 0.48; m.p.: 192–194 °C; 1H NMR (400 MHz,
CDCl3): d = 2.11 (s, 3H, CH3), 2.31 (s, 3H, ArCH3),
4.80 (s, 1H, ArCH), 5.79 (s, 1H, CHCl2), 7.12–7.18 (m, 4H,
ArH), 7.95 (br s, 1H, NH), 8.13 (br s, 1H, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 20.72, 28.57, 61.89,
70.96, 97.92, 128.08, 128.68, 132.25, 134.15, 138.32,
151.50, 198.52 ppm; LC–MS: m/z = 313 (M? ? 1).
ꢀ
133.28, 134.58, 151.95, 198.97 ppm; IR (KBr): m = 3,240,
3,180, 3,035, 2,989, 1,715, 1,642, 1,044, 762, 734 cm-1
;
LC–MS: m/z = 334 (M? ? 1).
5-Acetyl-4-(4-bromophenyl)-6-(dichloromethyl)-3,4-
dihydropyrimidin-2(1H)-one (2o, C13H11BrCl2N2O2)
5-Acetyl-6-(dichloromethyl)-3,4-dihydro-4-(4-methoxy-
phenyl)pyrimidin-2(1H)-one (2k, C14H14Cl2N2O3)
Yellow solid; yield: 69 % (521 mg); TLC (EtOAc/PE 2:3):
Rf = 0.45; m.p.: 188–190 °C; 1H NMR (400 MHz,
CDCl3): d = 2.17 (s, 3H, CH3), 4.86 (s, 1H, ArCH), 5.79
(s, 1H, CHCl2), 7.23–7.30 (m, 2H, ArH), 7.42–7.49 (m, 2H,
ArH), 8.04 (br s, 1H, NH), 8.44 (br s, 1H, NH) ppm; 13C
NMR (100 MHz, DMSO-d6): d = 28.56, 61.37, 70.63,
98.40, 121.41, 127.31, 129.91, 131.19, 133.74, 137.87,
151.39, 198.40 ppm; LC–MS: m/z = 378 (M? ? 1).
Yellow solid; yield: 72 % (474 mg); TLC (EtOAc/PE 2:3):
Rf = 0.43; m.p.: 182–183 °C; 1H NMR (400 MHz,
CDCl3): d = 2.00 (s, 3H, CH3), 3.82 (s, 3H, OCH3), 4.76
(s, 1H, ArCH), 5.69 (br s, 1H, NH), 5.82 (s, 1H, CHCl2),
6.91 (d, 2H, J = 10.8 Hz, ArH), 7.12 (br s, 1H, NH), 7.27
(d, 2H, J = 10.2 Hz) ppm; 13C NMR (100 MHz, DMSO-d6):
d = 20.92, 29.14, 55.33, 62.82, 70.49, 100.01, 114.10, 124.75,
129.87, 133.87, 153.80, 160.61, 176.20, 199.53 ppm; IR
Acknowledgments The authors are thankful to the Department of
Science and Technology, New Delhi, India for the financial support
(No. SR/S1/OC-72/2009). The authors are also thankful to Mr. Avtar
ꢀ
(KBr): m = 3,200, 3,194, 3,038, 2,998, 2,962, 2,874, 1,727,
1,661, 1,643, 728 cm-1; LC–MS: m/z = 329 (M? ? 1).
123

986
N. P. Tale et al.
Singh, SAIF, Punjab University, Chandigarh, India for recording
NMR spectra.
7. Zigeuner G, Knopp C (1970) Monatsh Chem 101:1541
8. George T, Tahrlramani R, Metha DV (1975) Synthesis 405
9. Kappe CO (1990) Liebigs Ann Chem 505
10. Khanetskyy B, Dallinger D, Kappe CO (2004) J Comb Chem
6:884
11. Bullock E, Carter RA, Cochrane RM, Gregory B, Shields DC
(1977) Can J Chem 55:895
References
1. Kappe CO (2000) Eur J Med Chem 35:1043
2. Kappe CO (2000) Acc Chem Res 33:879
3. Kappe CO (1993) Tetrahedron 49:6937
4. Zanatta N, Fantinel L, Fernandes LS, Wouters AD, Bonacorso
HG, Martins MAP (2008) Synthesis 21:3492
5. Zigeuner G, Hamberger H, Blaschke H, Sterk H (1966) Monatsh
Chem 97:1406
12. Singh K, Singh S, Mahajan A (2005) J Org Chem 70:6114
13. Khanina EL, Duburs G (1982) Khim Geterotsikl Soedin 535
14. Khanina EL, Liepin’sh EE, Mutsenretse DK, Duburs G (1987)
Khim Geterotsikl Soedin 668
15. Chen JM, Zeng XM, Middleton K, Zhdankin VV (2011) Tetra-
hedron Lett 52:1952
16. Puchala A, Belaj F, Bergman J, Kappe CO (2001) J Heterocycl
Chem 38:1345
6. Namazi H, Mirzaei YR, Azamat H (2001) J Heterocycl Chem
38:1051
123