Unique chlorine effect in regioselective one-pot synthesis of 1-alkyl-/allyl-3-(o-chlorobenzyl) uracils: anti-HIV activity of selected uracil derivatives

Article abstract of DOI:10.1016/j.tet.2006.04.018

2,4-Bis(trimethylsilyloxy)pyrimidines 1/2 on reaction with o-chlorobenzyl chlorides in 1,2-dichloroethane in the presence of I₂ undergo single step 1,3-dibenzylation to provide 1,3-bis(o-chlorobenzyl)pyrimidine-2,4-diones. The reactions of 1 wi

Full text of DOI:10.1016/j.tet.2006.04.018

Tetrahedron 62 (2006) 5944–5951
Unique chlorine effect in regioselective one-pot synthesis of
1-alkyl-/allyl-3-(o-chlorobenzyl) uracils: anti-HIV activity
of selected uracil derivatives
*
Vaishalli Malik, Palwinder Singh and Subodh Kumar
*
Department of Chemistry, Guru Nanak Dev University, Amritsar 143005, India
Received 27 January 2006; revised 24 March 2006; accepted 6 April 2006
Available online 3 May 2006
Abstract—2,4-Bis(trimethylsilyloxy)pyrimidines 1/2 on reaction with o-chlorobenzyl chlorides in 1,2-dichloroethane in the presence of I2
undergo single step 1,3-dibenzylation to provide 1,3-bis(o-chlorobenzyl)pyrimidine-2,4-diones. The reactions of 1 with allyl/alkyl bromide
followed by subsequent addition of o-chlorobenzyl chloride provide a simple one-pot synthesis of 1,3-unsymmetrical pyrimidine-2,4-diones.
Amongst these, 1,3-bis(o-chlorobenzyl)uracil (6a) shows anti-HIV-1 activity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
During the synthesis of N-1, N-3 unsymmetrically
substituted pyrimidine-2,4-diones, we have observed that
the alkylation of 2,4-bis(trimethylsilyloxy)pyrimidine (1)
stops at N-1 substitution stage.7 The present work shows
that alkylation of 1 with o-chlorobenzyl chlorides on
prolonged heating provide N-1 and N-3 dialkylated products.
This unique ability of N-3 o-chlorobenzylation has been
exploited for the synthesis of 1-allyl-/alkyl-/benzyl-3-
(o-chlorobenzyl) pyrimidine-2,4-diones. The mechanism
for such unique ability of o-chlorobenzyl chlorides to pro-
mote the benzylation at N-3 of 1-substituted pyrimidine-2,4-
diones has been discussed. The selected 1,3-substituted pyri-
midine-2,4-diones have been evaluated for their in vitro
anti-HIVactivities.
Due to the clinical toxicities involved in the use of nucleoside
inhibitors of reverse transcriptase (NRTIs)1 and high fre-
quency of viral mutations, the use of non-nucleoside inhibi-
tors of reverse transcriptase (NNRTIs)2 (enzyme responsible
for encoding viral RNA to host DNA) has been overcoming
the use of nucleoside inhibitors. The presence of hydro-
phobic residues lining the non-nucleoside binding pocket
(NNBP) of HIV-1 RT has necessitated the development of
NNIs with allyl/benzyl/alkyl groups at suitable sites of
nucleobases which could facilitate the p–p or p–CH inter-
actions with the amino acid residues of the enzyme.3,4 The
presence of these moieties generally enhances the potency
profile of lead drug molecules e.g., the presence of allyl/
amidophenyl/thiophenyl/aminophenyl moieties at the end
of N-1 chain of HEPT along with a thiophenyl/benzyl group
at C-6 of pyrimidine has led to higher anti-HIV-1 activity
than that observed with HEPT.5,6 It was envisaged that the
presence of hydrophobic moieties at N-1 and N-3 of pyri-
midinedione might enhance the anti-HIV activities of the
resulting compounds. 1,3-Disubstituted pyrimidinediones
are little explored for their anti-HIV activities, which might
be due to the difficulty in synthesis of such compounds.
This led us to design and synthesise new molecules with an
allyl/alkyl/benzyl substituent at N-1 and a benzyl group at
N-3 of the pyrimidinedione.
2. Results and discussion
2,4-Bis(trimethylsilyloxy)pyrimidine (1) on refluxing with
2-chlorobenzyl chloride (3a) (3 equiv) in 1,2-dichloroethane
(1,2-DCE) in the presence of I2 (0.1 equiv) for 96 h, after the
usual work-up and column chromatography gave two com-
pounds 4a (<1%) and 6a (74%). Compound 6a, mp 72 ꢀC,
M+ m/z 361, 363, 365 (100:60:10), shows the signals of H-
5 and H-6 protons as doublets at d 5.74 and 7.24 and N-1
and N-3 CH2 as singlets at d 4.97 and 5.22 along with aro-
matic protons in its 1H NMR spectrum and the presence of
10 positive (due to CH), two negative (due to CH2) and six
quaternary carbons in 13C normal and DEPT-135 spectra,
which corroborate the structure 6a (Scheme 1).
Keywords: Uracil; Thymine; N1-Alkylation; o-Chlorobenzyl chloride; 1,3-
Unsymmetrical dialkylation.
* Corresponding authors. Tel.: +91 183 2258802-09x3206; fax: +91 183
2258820/2258819; e-mail addresses: palwinder_singh_2000@yahoo.com;
subodh_gndu@yahoo.co.in
Similarly, the refluxing of solutions of 1 with 2,4-dichloro-
benzyl chloride 3b and 2,6-dichlorobenzyl chloride 3c in
1,2-DCE in the presence of I2 for 96 h gave 1,3-disubstituted
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.04.018

V. Malik et al. / Tetrahedron 62 (2006) 5944–5951
5945
O
N
Cl
O
of the reaction mixture of 1 and 2-chlorobenzyl chloride
3a, recorded by quenching the reaction after 48 h, shows
two sets of signals each due to H-5 (at d 5.74 and 5.89),
N1-CH2 (two singlets d 4.97 and 5.06) and two singlets due
to N3-CH2 (at d 5.22 and 5.47) in the 96:4 ratio (entry 1,
R
R
Cl
HN
N
Cl
+
O
Si
O
N
Y
O
Y
R
N
3
Y
Y
Si
Cl
Cl
6a R = H, Y = H
6b R = H, Y = 4-Cl
6c R = H, Y = 6-Cl
7a R = CH3, Y = H
7b R = CH3, Y = 4-Cl
7c R = CH3, Y = 6-Cl
O
N
(<1%)
1,2-DCE
1
I2,
(69-90%)
Table 2). The major component on the basis of H NMR
4a R = H, Y = H
1 R = H
2 R = Me
3a, Y = H
3b, Y = 4-Cl
3c, Y = 6-Cl
4b R = H, Y = 4-Cl
4c R = H, Y = 6-Cl
5a R = CH3, Y = H
5b R = CH3, Y = 2-Cl
5c R = CH3, Y = 4-Cl
spectrum has been assigned the structure 6a. The minor
component could be due to 11a/12a formed due to O-alkyl-
ation at C2]O or C4]O (Scheme 2). Similarly, the reaction
of 1 with 2,4-dichlorobenzyl chloride 3b on work-up after
1
Cl
48 h, in its H NMR spectrum shows two sets of signals
O
each due to H-5 (d 5.85 and 5.95), N1-CH2 (d 5.01 and
5.12) and N3-CH2 (d 5.21 and 5.48) protons in 75:25 ratio
(entry 2, Table 2). The H NMR spectrum of the reaction
R
9a R = H, Y = 3-Cl
Y
HN
9b R = H, Y = 4-Cl
8
1
9c R = H, Y = 2-NO2
1, 2
O
N
I2,
9d R = H, Y = 2,4,6-triMe
10a R = CH3, Y = 3-Cl
10b R = CH3, Y = 4-Cl
10c R = CH3, Y = 2-NO2
10d R = CH3, Y = 2,4,6-triMe
1,2-DCE
of 1 with 2,6-dichlorobenzyl chloride 3c recorded after
48 h of reaction shows three singlets each due to N1-CH2
at d 5.20, 5.28 and 5.35, N3-CH2 at d 5.40, 5.46 and 5.68
in the ratio 27:24:49 indicating it to be a mixture of three
components.
Y
8a, Y = 3-Cl
8b, Y = 4-Cl
8c, Y = 2-NO2
9, 10
(68-87%)
8d, Y = 2,4,6-triMe
Scheme 1.
uracil derivatives 6b and 6c, respectively. In these reactions,
only traces (<1%) of 4b and 4c were isolated (Table 1).
Furthermore, the reactions of 2,4-bis(trimethylsilyloxy)-
5-methylpyrimidine (2) with 3a–c gave the respective 1,3-
bis(o-chlorobenzyl)thymines 7a–7c along with small
amounts of 5a–5c (Scheme 1, Table 1).
Table 2. Product distribution ratio for the reaction of 1/2 with substituted
benzyl chlorides quenched after 48 h (Scheme 2)
Entry
R in
1/2
Benzyl
halide
Product ratio
(6: 11+12)
Product 6
(yield %a)
1
2
3
H
H
H
3a
3b
3c
96:4
75:25
27:73
6a (70)
6b (70)
6c (72)
However, the reactions of 1 and 2 with 3-chloro-/4-chloro-/
2-nitro-/2,4,6-trimethyl-benzyl chlorides (8a–8d) (3 equiv)
did not provide respective 1,3-disubstituted uracil/thymine
derivatives even on prolonged refluxing (7 days) and the
reactions stopped at the 1-substituted stage yielding N1-sub-
stituted uracils 9(a–d) and 10(a–d) (Scheme 1, Table 1).
a
Yield after work-up with 4 M HCl.
Cl
Si
O
R
Cl
N
+
Si
Y
O
N
Amongst various substituted benzyl halides 3(a–c) and 8(a–
d), which were made to react with 1 and 2, only 3(a–c) gave
dibenzylated products 6 and 7, while in all other cases the re-
action stops at the N1-substitution stage. These results clearly
point to the unique role of o-chlorine in benzyl halides 3(a–c)
in yielding 1,3-dibenzyl pyrimidine-2,4-diones 6 and 7. The
reasons for this differential reactivity remain unexplained.
3a-3c
1/2, R = H, CH3
Cl
I2, 1,2-DCE
O
Y
Cl
O
N
O
N
N
N
+
+
Cl
O
N
O
Y
O
N
Y
Y
Y
Cl
Cl
The monitoring of reactions of 1 with 3a/3b/3c by 1H NMR
spectroscopy unravels the plausible mechanism in transfer-
ring o-chlorobenzyl group at N-3. The H NMR spectrum
Cl
6
11
a, Y = H; b, Y = 4-Cl; c, Y = 6-Cl
12
1
Scheme 2.
Table 1. Reactions of 1/2 with substituted 2-chlorobenzyl chlorides
However, TLC of these mixtures shows the presence of only
one component and even on repeated chromatography these
could not be separated.
Entry R in Benzyl Rx time N1-alkylated,
1/2
N1,N3-alkylated,
yield %
halide
(h)
yield %
1
H
H
H
3a
3b
3c
96
96
96
96
96
96
96
96
96
96
96
96
96
96
4a (<1)
4b (<1)
4c (<1)
5a (<1)
5b (<1)
5c (<1)
9a (74)
6a (74)
6b (82)
6c (89)
7a (72)
7b (76)
7c (67)
—
—
—
—
—
2
3
The crude reaction mixtures obtained after 48 h of refluxing
of 1 with 3(a–c) on further heating with 4 M HCl at 80 ꢀC for
1 h gave pure products 6a–6c (Table 2) along with small
quantities of respective 1-(o-chlorobenzyl)uracil derivatives
4(a–c) (<1%). Alternatively, these reaction mixtures on
further heating in 1,2-DCE for >24 h underwent rearrange-
ment to 1,3-disubstituted uracil derivatives 6a–6c.
4
5
CH3 3a
CH3 3b
6
7
8
9
10
11
12
13
14
CH3
H
H
H
H
CH3 8a
CH3 8b
CH3 8c
CH3 8d
3c
8a
8b
8c
8d
9b (78)
9c (74)
9d (68)
10a (79)
10b (82)
10c (82)
10d (87)
—
—
—
These observations indicate that probably after N-1 alkyl-
ation, the ortho-chlorobenzyl promotes N-3, C2]O and
C4]O alkylation to provide mixture of N3-alkyl derivative

5946
V. Malik et al. / Tetrahedron 62 (2006) 5944–5951
6 and O-alkyl derivatives 11 and 12 (Scheme 2), which on
heating in HCl or 1,2-DCE undergo rearrangement to
provide 6.
Si
Cl
O
N
O
N
(i) R'-CH2Br, 1,2-DCE, reflux
N
N
Y
Cl
Cl
Y
O
Si
O
The participation of intermediates 11 and 12 has been further
confirmed by silylation of 4(a–c) and subsequent alkylation
with o-chlorobenzyl chlorides 3(a–c). Compound 4a on
heating with N,O-bis(trimethylsilyl)acetamide (BSA) gave
(2 eq) reflux
(ii)
R'
15-17
1
3a-3c
1
a clear solution, which confirms its complete silylation. H
16; a, R'=-CH=CH2, Y=4-Cl
b, R'=-CH3, Y=4-Cl
NMR (CDCl3) spectrum of this silylated mixture shows
the presence of two NCH2 signals at d 4.93 and 5.07 and
two H-5 doublets at d 5.61 and 5.79 in 22:78 ratio and
confirms it to be a mixture of C2]O and C4]O silylated
derivatives 13 and 14 (Scheme 3). The mixture of 13 and
14 on refluxing with 2-chlorobenzyl chloride in the presence
of I2 on work-up after 48 h provided a mixture of 6a and
11/12. Similarly, 4b and 4c on silylation showed the pres-
15, a, R'=-CH=CH2, Y=H
b, R'=-CH=CHC6H5, Y=H
c, R'=-CH3, Y=H
c, R'=-(CH2)2CH3, Y=4-Cl
d, R'=-CO2C2H5, Y=4-Cl
d, R'=-(CH2)2CH3, Y=H
e, R'=-(CH2)6CH3, Y=H
f, R'=-CO2C2H5, Y=H
17; a, R'=-CH=CH2, Y=6-Cl
b, R'=-(CH2)2CH3, Y=6-Cl
c, R'=-CO2C2H5, Y=6-Cl
Scheme 4.
1
ence of 13b, 14b and 13c, 14c in their H NMR spectra.
The silylated pyrimidines 13 and 14 on subsequent refluxing
with o-chlorobenzyl chlorides for 48 h provided mixtures
of 6, 11 and 12 in nearly similar ratios as observed in direct
alkylation of 1 as given in Table 2.
Table 3. Percentage yield and melting points of 1-allyl/arylmethyl/alkyl-3-
(o-chlorobenzyl) uracil derivatives (15–17)
Entry
Y
R0
Yield (%)
Mp (ꢀC)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
4-Cl
4-Cl
4-Cl
4-Cl
6-Cl
6-Cl
6-Cl
CH]CH2
CH]CHC6H5
CH3
(CH2)2CH3
(CH2)6CH3
CO2C2H5
CH]CH2
CH3
(CH2)2CH3
CO2C2H5
CH]CH2
(CH2)2CH3
CO2C2H5
15a (73)
15b (72)
15c (63)
15d (78)
15e (67)
15f (64)
16a (62)
16b (70)
16c (63)
16d (64)
17a (65)
17b (62)
17c (62)
liq
110
liq
liq
liq
liq
94
98
94
120
110
140
120
Cl
Si
O
N
O
N
O
N
Cl
HN
N
Y
N
BSA
Y
+
O
O
Si
6
11 12
+
+
O
1,2-DCE
I2
Y
Y
Cl
Cl
9
Cl
10
11
12
13
4
13
14
a, Y = H; b, Y = 4-Cl; c, Y = 6-Cl
Scheme 3.
Therefore, 1 initially undergoes regioselective alkylation at
N-1 and then 2-chloro-/2,4-dichloro-/2,6-dichloro-benzyl
chloride causes alkylation at N-3, C2]O and C4]O to pro-
vide a mixture of 6, 11 and 12, which on heating undergoes
rearrangement to the respective 1,3-disubstituted uracil
derivatives 6a–6c. This provides a simple approach for the
1,3-disubstituted uracil and thymine derivatives under neu-
tral or mild acidic conditions. Significantly, in the case of re-
actions of 2 with 2-chlorobenzyl chlorides 3a–3c, even after
work-up at different intervals of time, the formation of re-
spective O-alkylated products 11 and 12 was not observed.
provided the respective compounds 16a and 17a (entries 7
and 11, Table 3).
To check the competition between the allyl bromide and
o-chlorobenzyl chloride for N-3 alkylation, 1 was refluxed
with 1.2 equiv of allyl bromide for 24 h and then 2 equiv
each of allyl bromide and o-chlorobenzyl chloride was
added and the reaction mixture was refluxed for 48 h. The
reaction mixture on work-up provided only 15a (73%).
1,3-Diallyluracil was not isolated from the reaction mixture.
The reaction of 1 with cinnamyl bromide (1.5 equiv) and
subsequent alkylation with 2-chlorobenzyl chloride gave
uracil derivative 15b (72%). Similarly, the reactions of 1
with various alkyl/alkyl ester halides followed by addition
of 2 equiv of 3a/3b/3c provided respective compounds
15–17 (Scheme 4, Table 3).
This ability of o-chlorobenzyl chlorides to promote N3-
benzylation of O-silylated uracil derivatives has been
advantageously used for the one-pot synthesis of 1-alkyl/
allyl/3-(o-chlorobenzyl) uracil derivatives (Scheme 4). The
reactions of 1 with various alkyl/allyl/benzyl halides and
subsequent in situ reactions with o-chlorobenzyl chlorides
provide 1,3-unsymmettrically substituted uracil derivatives.
2.1. In vitro anti-HIV activities
The in vitro anti-HIV activities of the six selected com-
pounds in terms of 50% effective concentration against
HIV cytopathic effects and 50% inhibitory concentration
for cell growth have been evaluated against human immuno-
deficiency virus (HIV). The biological results as inhibition
of HIV-1 replication in T4 lymphocytes (CEM-SS cell
line) are given in Table 4.
The refluxing of 1 with allyl bromide (1.5 equiv) in 1,2-DCE
containing I2 (0.1 equiv) provided O-silylated derivatives of
1-allyluracil (TLC comparison with authentic sample).
Then, 3a (2 equiv) was added to the reaction mixture and
refluxing was continued (Scheme 4). The reaction mixture
on work-up and column chromatography gave a pale yellow
liquid 15a (73%), [M+ m/z 277, 279 (3:1)] (entry 1, Table 3,).
Similarly, the reaction of 1 with allyl bromide (1.5 equiv)
followed by subsequent reaction with 3b and 3c (2 equiv)
Among the compounds tested (6a–6c, 15a, 16a, 17a) for
anti-HIV-1 activity, 6a possessing 2-chlorobenzyl groups

V. Malik et al. / Tetrahedron 62 (2006) 5944–5951
5947
Table 4. Inhibition of HIV-1 replication in T4 lymphocytes (CEM-SS cell
line) by compounds 6a–6c and 15a, 16a, 17a
cooled reaction mixture was treated with ethanol (10 ml).
The solvent was distilled off under vacuum and the residue
was column chromatographed over silica-gel using ethyl
acetate and hexane mixtures as eluents to isolate the pure
compounds.
a
IC50 (mM)
b
EC50 (mM)
Compd
TIc
6a
6b
6c
15a
16a
17a
HEPT
AZT
36.4
35.5
35.4
121
111
42.7
740
20
9.19
3.65
>200
>200
>200
>200
>200
7
<0.17
<0.17
<0.6
<0.5
<0.2
106
4.2.1. 1-(2-Chlorobenzyl)-1H-pyrimidine-2,4-dione (4a).
<1%; White solid, mp 209 ꢀC (lit.7 mp 210 ꢀC).
4.2.2. 1,3-Bis(2-chlorobenzyl)-1H-pyrimidine-2,4-dione
(6a). 74%; White solid, mp 72 ꢀC (CH3CN); FAB mass m/z
0.016
1250
a
1
361, 363, 365 (100:62:10) (M+); H NMR (CDCl3): d 4.97
Concentration of compound required to achieve 50% inhibition of cell
growth.
Compound dose required to achieve 50% protection of T4 lymphocyte
cells from HIV-1 induced cytopathogenecity.
Therapeutic Index (TI¼IC50/EC50).
b
c
(2H, s, CH2), 5.22 (2H, s, CH2), 5.74 (1H, d, J¼7.8 Hz,
C5-H), 6.91–7.01 (1H, m, ArH), 7.11–7.17 (2H, m, ArH),
7.24–7.43 (6H, m, 5ArH, C-6H); 13C (normal/DEPT-135)
(CDCl3): d 42.23 (ꢁve, CH2), 49.95 (ꢁve, CH2), 101.81
(+ve, 5-CH), 126.59 (+ve, ArCH), 126.73 (+ve, ArCH),
127.42 (+ve, ArCH), 128.23 (+ve, ArCH), 129.55 (+ve,
ArCH), 129.97 (+ve, ArCH), 130.57 (+ve, ArCH), 132.94
(+ve, ArCH), 132.58 (ab, C), 132.94 (ab, C), 133.58 (ab,
C), 133.93 (ab, C), 142.31 (+ve, CH-6), 151.49 (ab, C),
162.63 (ab, C); nmax (KBr)/cmꢁ1: 3100, 1708, 1670, 1658,
742, 798; (Found: C, 59.6; H, 4.0; N, 7.9. C18H14Cl2N2O2
requires C, 59.85; H, 3.91; N, 7.76%).
at N-1 and N-3 of uracil shows highest anti-HIV-1 activity
with EC50¼9.19 mM, which is comparable to HEPT
(7.0 mM) but lacks the selectivity. The replacement of
o-chlorobenzyl group at N-1 with allyl moiety (15a, 16a,
17a) results in total loss of anti-HIV activity. The presence
of another chlorine atom at 4 or 6 positions of the benzyl
group in 6b and 6c increases the effective concentration
required to achieve 50% protection of HIV infected cells
while the IC50 values of these compounds are parallel with
6a. It seems as if the presence of a phenyl moiety at N-1 is
the essential requirement for these compounds to exhibit
anti-HIV-1 activities.
4.2.3. 1-(2,4-Dichlorobenzyl)-1H-pyrimidine-2,4-dione
(4b). <1%; White solid, mp 140 ꢀC (lit.7 mp 140 ꢀC).
4.2.4. 1,3-Bis(2,4-dichlorobenzyl)-1H-pyrimidine-2,4-
dione (6b). 82%; White solid, mp 72 ꢀC (CH3CN); FAB
mass m/z 429, 431, 433, 435 (78:100:50:12) (M+); 1H
NMR (CDCl3): d 5.01 (2H, s, CH2), 5.21 (2H, s, CH2), 5.85
(1H, d, J¼7.8 Hz, C-5H), 6.91 (1H, d, J¼8.0 Hz, ArH),
7.15 (1H, d, J¼8.0 Hz, ArH), 7.24–7.51 (5H, m, 4ꢂArH,
C-6H). ThedecouplingofC-5Hsignalatd5.85givesasinglet
at d 7.37; 13C (normal/DEPT-135) (CDCl3): d 41.88 (ꢁve,
CH2), 49.71 (ꢁve, CH2), 101.97 (+ve, 5-CH), 127.07 (+ve,
ArCH), 127.80 (+ve, ArCH), 127.99 (+ve, ArCH), 129.41
(+ve, ArCH), 129.82 (+ve, ArCH), 131.11 (ab, C), 131.71
(+ve, ArCH), 132.31 (ab, C), 133.46 (ab, C), 133.73 (ab,
C), 134.28 (ab, C), 135.39 (ab, C), 142.40 (+ve, 6-CH),
151.41 (ab, C), 162.49 (ab, C); nmax (KBr)/cmꢁ1: 3200,
1708, 1654, 727, 813; (Found: C, 50.3; H, 2.6; N, 6.2.
C18H12Cl4N2O2 requires C, 50.26; H, 2.81; N, 6.51%).
3. Conclusions
2,4-Bis(trimethylsilyloxy)pyrimidines1onreactionwithallyl/
arylmethyl/alkyl/alkoxycarbonylmethyl halides followed
by reactions with 2-chloro/2,4-dichloro-/2,6-dichloro benzyl
chlorides provides simple one-pot methodology for the
synthesis of 1-allyl-/alkyl-/benzyl-3-(o-chlorobenzyl) uracil
derivatives.
4. Experimental
4.1. General
Melting points were determined in capillaries and are uncor-
rected. 1H and 13C NMR spectra were run on JEOL JNM-AL
spectrometer at 300 MHz and 75 MHz, respectively, using
CDCl3 as solvent and TMS as an internal standard. In 13C
NMR spectral data, +ve signals correspond to CH3 and CH
and ꢁve signals correspond to CH2 carbons in DEPT-135
spectrum. J values are given in Hertz. Mass spectra were
recorded at CDRI, Lucknow. IR spectra were recorded by
using CHCl3 or KBr (solid) as medium. CHN analysis was
performed on thermoelectron CHN analyser EA1112.
4.2.5. 1-(2,6-Dichlorobenzyl)-1H-pyrimidine-2,4-dione
(4c). <1%; White solid, mp 256 ꢀC (CH3CN); FAB mass
1
m/z 270, 272, 274 (100:60:10) (M+); H NMR (CDCl3+
TFA): d 5.34 (2H, s, CH2), 6.00 (1H, d, J¼8.0 Hz, C5-H),
7.19 (1H, d, J¼8.0 Hz, C6-H), 7.39–7.49 (3H, m, ArH); 13C
(normal/DEPT-135) (CDCl3+TFA): d 46.83 (ꢁve, CH2),
102.38 (+ve, 5-CH), 128.56 (ab, C), 129.24 (+ve, ArCH),
131.83 (+ve, ArCH), 137.14 (ab, C), 144.80 (+ve, 6-CH),
151.78 (ab, C), 166.45 (ab, C); nmax (KBr)/cmꢁ1: 3029,
1691,1658, 781, 767; (Found: C, 48.42; H, 2.89; N, 10.15.
C11H8Cl2N2O2 requires C, 48.7; H, 2.95; N, 10.33%).
4.2. General procedure for the reactions of 1/2 with
benzyl chlorides 3(a–c) and 8(a–d)
4.2.6. 1,3-Bis(2,6-dichlorobenzyl)-1H-pyrimidine-2,4-
dione (6c). 89%; White solid, mp 120 ꢀC (CH3CN); FAB
mass m/z 429, 431, 433, 435 (78:100:50:12) (M+); 1H
NMR (CDCl3): d 5.20 (2H, s, CH2), 5.42 (2H, s, CH2),
5.63 (1H, d, J¼8.0 Hz, C5-H), 6.78 (1H, d, J¼8.0 Hz,
C6-H), 7.12 (1H, t, J¼8.0 Hz, ArH), 7.16–7.41 (5H, m,
Procedure A: A solution of 2,4-bis-(trimethylsilyloxy)pyri-
midine (1/2) (0.01 mol), the appropriate benzyl chloride
(0.03 mol) and I2 (0.001 mol) in 1,2-DCE (20 ml) was re-
fluxed for 96 h. After completion of the reaction (TLC), the

5948
V. Malik et al. / Tetrahedron 62 (2006) 5944–5951
ArH). The decoupling of the C-5H signal at d 5.63 converts
the doublet at d 6.78 to a singlet; 13C (normal/DEPT-135)
(CDCl3): d 41.16 (ꢁve, CH2), 46.18 (ꢁve, CH2), 101.79
(+ve, 5-CH), 128.48 (+ve, ArCH), 128.76 (+ve, ArCH),
128.91 (+ve, ArCH), 130.10 (ab, C), 130.20 (ab, C), 130.96
(+ve, ArCH), 131.88 (ab, C), 139.73 (+ve, 6-CH), 135.82
(ab, C), 137.05 (ab, C), 151.05 (ab, C), 162.49 (ab, C); nmax
(KBr)/cmꢁ1: 3100, 1716, 1668, 759, 777; (Found C, 49.9;
H, 2.4; N, 6.8%. C18H12Cl4N2O2 requires C, 50.26; H,
2.81; N, 6.51%).
50.23; H, 3.53; N, 9.69. C12H10Cl2N2O2 requires C, 50.52;
H, 3.50; N, 9.82%).
4.2.12. 1,3-Bis(2,6-dichlorobenzyl)-5-methyl-1H-pyri-
midine-2,4-dione (7c). 67%; White solid, mp 128 ꢀC
(CH3CN); FAB mass m/z 443, 445, 447, 449 (76:100:
1
48:12) (M+); H NMR (CDCl3): d 1.81 (3H, s, CH3), 5.22
(2H, s, CH2), 5.45 (2H, s, CH2), 6.65 (1H, s, C6-H), 7.07–
7.15 (1H, m, ArH), 7.29–7.42 (5H, m, ArH); 13C (normal/
DEPT-135) (CDCl3): d 13.26 (+ve, CH3), 41.47 (ꢁve,
CH2), 110.08 (ab, C-5), 128.47 (+ve, ArCH), 128.74 (+ve,
ArCH), 128.92 (+ve, ArCH), 130.43 (ab, C), 130.82
(+ve, ArCH), 132.04 (ab, C), 135.81 (ab, C), 135.88 (+ve,
C6-H), 136.98 (ab, C), 151.91 (ab, C), 163.33 (ab, C); nmax
(KBr)/cmꢁ1: 1710, 1662, 1649, 775, 763; (Found C, 51.12;
H, 3.13; N, 6.11%. C19H14Cl4N2O2 requires C, 51.3; H,
3.15; N, 6.30%).
4.2.7. 1-(2-Chlorobenzyl)-5-methyl-1H-pyrimidine-2,4-
dione (5a). <1%; White solid, mp 130 ꢀC (lit.7 mp 132 ꢀC).
4.2.8. 1,3-Bis[(2-chlorobenzyl]-5-methyl-1H-pyrimidine-
2,4-dione (7a). 72%; White solid, mp 136 ꢀC (CH3CN);
1
FAB mass m/z 375, 377, 379 (100:62:10) (M+); H NMR
(CDCl3): d 1.93 (3H, s, CH3), 5.05 (2H, s, CH2), 5.29 (2H,
s, CH2), 6.94–6.99 (1H, m, ArH), 7.13–7.27 (3H, m, ArH),
7.29–7.44 (5H, m, ArH, C6-H); 13C (normal/DEPT)
(CDCl3): d 13.12 (+ve, CH3), 42.46 (ꢁve, CH2), 49.54
(ꢁve, CH2), 110.24 (ab, C-5), 126.73 (+ve, ArCH), 126.79
(+ve, ArCH), 127.40 (+ve, ArCH), 128.19 (+ve, ArCH),
129.54 (+ve, ArCH), 129.75 (+ve, ArCH), 129.91 (+ve,
ArCH), 130.13 (+ve, ArCH), 133.01 (ab, C), 133.41 (ab,
C), 133.85 (ab, C), 138.37 (+ve, C-6H), 151.58 (ab, C),
163.43 (ab, C); nmax (KBr)/cmꢁ1: 3066, 2360, 2339, 1703,
1643, 748; (Found C, 60.88; H, 4.31; N, 7.26%.
C19H16Cl2N2O2 requires C, 60.88; H, 4.26; N, 7.46%).
4.2.13. 1-(3-Chlorobenzyl)-1H-pyrimidine-2,4-dione
(9a). 74%; White solid, mp 140 ꢀC (lit.7 mp 140 ꢀC).
4.2.14. 1-(4-Chlorobenzyl)-1H-pyrimidine-2,4-dione
(9b). 78%; white solid, mp 178 ꢀC (lit.7 mp 180 ꢀC).
4.2.15. 1-(2-Nitrobenzyl)-1H-pyrimidine-2,4-dione (9c).
74%; white solid, mp 119 ꢀC (lit.7 mp 120 ꢀC).
4.2.16. 1-(2,4,6-Trimethylbenzyl)-1H-pyrimidine-2,4-
dione (9d). 68%; White solid, mp 230 ꢀC (CH3CN) (lit.7
mp 230 ꢀC).
4.2.9. 1-(2,4-Dichlorobenzyl)-5-methyl-1H-pyrimidine-
2,4-dione (5b). <1%; White solid, mp 138 ꢀC (lit.7 mp
140 ꢀC).
4.2.17. 1-(3-Chlorobenzyl)-5-methyl-1H-pyrimidine-2,4-
dione (10a). 79%; White solid, mp 140 ꢀC (CH3CN);
1H NMR (CDCl3+TFA): d 1.93 (3H, s, CH3), 4.92 (2H, s,
CH2), 7.15–7.38 (6H, m, ArH+C6-H); 13C (normal/DEPT-
135) (CDCl3+TFA): d 11.80 (+ve, CH3), 51.64 (ꢁve, CH2),
112.90 (ab, C-5), 126.20 (+ve, ArCH), 128.13 (+ve,
ArCH), 129.41 (+ve, ArCH), 130.75 (+ve, ArCH), 135.38
(ab, C), 135.78 (ab, C), 142.25 (+ve, C-6), 152.38 (ab, C),
4.2.10. 1,3-Bis(2,4-dichlorobenzyl)-5-methyl-1H-pyri-
midine-2,4-dione (7b). 76%; White solid, mp 152 ꢀC
(CH3CN); FAB mass m/z 443, 445, 447, 449 (78:100:
1
50:12) (M+); H NMR (CDCl3): d 1.95 (3H, s, CH3), 5.01
(2H, s, CH2), 5.23 (2H, s, CH2), 6.92 (1H, d, J¼8.0 Hz,
ArH), 7.12–7.17 (2H, m, ArH), 7.27–7.28 (2H, m, ArH),
7.38–7.45 (2H, m, ArH, C6-H); 13C (normal/DEPT)
(CDCl3): d 13.11 (+ve, CH3), 42.07 (ꢁve, CH2), 49.25
(ꢁve, CH2), 110.45 (ab, C-5), 127.05 (+ve, ArCH), 127.76
(+ve, ArCH), 128.14 (+ve, ArCH), 129.37 (+ve, ArCH),
129,75 (+ve, ArCH), 131.24 (+ve, ArCH), 131.54 (ab, C),
132.57 (ab, C), 133.38 (ab, C), 133.76 (ab, C), 134.10
(ab, C), 135.12 (ab, C), 138.35 (+ve, C-6H), 151.46
(ab, C), 163.27 (ab, C); nmax (KBr)/cmꢁ1: 2360, 2339,
1704, 1666, 1643, 775; (Found C, 51.12; H, 3.12;
N, 6.11%. C19H14Cl4N2O2 requires C, 51.3; H, 3.15; N,
6.30%).
166.58 (ab, C); nmax (KBr)/cmꢁ1: 3022, 2999, 1685, 1656,
35
11
775; HRMS found: 250.0513, C12H ClN2O2 requires
37
250.0509; found: 252.0488, C12H ClN2O2 requires
252.0479; (Found: C, 57.1; H, 4.29; N, 11.20.
C12H11ClN2O2 requires C, 57.4; H, 4.39; N, 11.2%).
11
4.2.18. 1-(4-Chlorobenzyl)-5-methyl-1H-pyrimidine-2,4-
dione (10b). 82%; White solid, mp 160 ꢀC (CH3CN); FAB
1
mass m/z 251, 253 (3:1) (M+); H NMR (CDCl3+TFA):
d 1.95 (3H, s, CH3), 4.95 (2H, s, CH2), 7.23–7.25 (3H, m,
ArH+C6-H), 7.37–7.40 (2H, m, ArH); 13C (normal/DEPT-
135) (CDCl3+TFA): d 11.89 (+ve, CH3), 51.56 (ꢁve, CH2),
112.80 (ab, C5-H), 129.51 (+ve, ArCH), 129.65 (+ve,
ArCH), 132.26 (ab, C), 135.37 (ab, C), 142.00 (+ve, C6-
H), 152.32 (ab, C), 166.43 (ab, C); nmax (KBr)/cmꢁ1: 3170,
2358, 1702, 1656, 746, 692; (Found: C, 56.68; H, 4.23; N,
11.4. C12H11ClN2O2 requires C, 57.4; H, 4.39; N, 11.2%).
4.2.11. 1-(2,6-Dichlorobenzyl)-5-methyl-1H-pyrimidine-
2,4-dione (5c). <1%; White solid, mp 240 ꢀC (CH3CN);
1H NMR (CDCl3+TFA): d 1.93 (3H, s, CH3), 5.30 (2H, s,
CH2), 6.93 (1H, s, C6-H), 7.31–7.47 (3H, m, ArH); 13C (nor-
mal/DEPT-135) (CDCl3+TFA): d 12.02 (+ve, CH3), 46.24
(ꢁve, CH2), 129.07 (+ve, ArCH), 112.19 (ab, C-5), 128.88
(ab, C), 129.21 (+ve, ArCH), 131.65 (+ve, ArCH), 137.04
(ab, C), 140.32 (+ve, 6-CH), 151.95 (ab, C), 166.20 (ab, C).
4.2.19. 1-(2-Nitrobenzyl)-5-methyl-1H-pyrimidine-2,4-
dione (10c). 82%; White solid, mp 242 ꢀC (CH3CN); FAB
mass m/z 262 (M++1); 1H NMR (CDCl3+TFA): d 1.99
(3H, s, CH3), 5.40 (2H, s, CH2), 7.35 (1H, d, J¼9.0 Hz,
ArH), 7.40 (1H, s, C6-H), 7.60 (1H, t, J¼9.0 Hz, ArH),
7.72 (1H, t, J¼9.0 Hz, ArH), 8.18 (1H, d, J¼9.0 Hz, ArH);
nmax (KBr)/cmꢁ1: 3002, 2829, 1703, 1658, 784, 756; HRMS
35
10
found 284.0119, C12H Cl2N2O2 requires 284.0119; found
286.0091, C12H Cl37ClN2O2 requires 286.0089; (Found: C,
35
10

V. Malik et al. / Tetrahedron 62 (2006) 5944–5951
5949
13C (normal/DEPT-135) (CDCl3+TFA): d 11.75 (+ve, CH3),
49.83 (ꢁve, CH2), 112.58 (ab, C-5), 125.89 (+ve, ArCH),
129.56 (+ve, ArCH), 129.62 (+ve, ArCH), 129.93 (ab, C),
134.74 (+ve, ArCH), 142.85 (+ve, 6-CH), 147.72 (ab, C),
152.42 (ab, C), 166.58 (ab, C); nmax (KBr)/cmꢁ1: 3039,
1691, 1517, 1353, 727; (Found: C, 54.97; H, 4.18; N,
15.83. C12H11N3O4 requires C, 55.2; H, 4.21; N, 16.09%).
(ab, C), 135.45 (ab, C), 143.98 (+ve, 6-CH), 150.85 (ab,
C), 162.48 (ab, C); nmax (CHCl3)/cmꢁ1: 3104, 1712, 1643,
752, 810; (Found C, 60.9; H, 4.76; N, 9.97%.
C14H13ClN2O2 requires C, 60.7; H, 4.70; N, 10.12%).
4.4.2. 1-Cinnamyl-3-(2-chlorobenzyl)-1H-pyrimidine-
2,4-dione (15b). 72%; Light yellow solid, mp 110 ꢀC
1
(CH3CN); FAB mass m/z 353, 355 (3:1) (M+); H NMR
4.2.20. 1-(2,4,6-Trimethyl)-5-methyl-1H-pyrimidine-2,4-
dione (10d). 87%; White solid, mp 210 ꢀC (CH3CN); FAB
(CDCl3): d 4.53 (2H, d, J¼6.0 Hz, CH2), 5.17 (2H, s, CH2),
5.84 (1H, d, J¼7.8 Hz, C5-H), 6.22 (1H, dt, J1¼16.0 Hz,
J2¼6.0 Hz, ]CH), 6.87 (1H, d, J¼16.0 Hz, ]CH),
7.15–7.51 (10H, m, ArH+C6-H); 13C (normal, DEPT-135)
(CDCl3): d 42.14 (ꢁve, CH2), 50.78 (ꢁve, CH2), 101.75
(+ve, 5-CH), 122.14 (+ve, ArCH), 126.54 (+ve, ArCH),
126.74 (+ve, ArCH), 126.77 (+ve, ArCH), 128.22 (+ve,
ArCH), 128.37 (+ve, ArCH), 128.62 (+ve, ArCH), 129.51
(+ve, CH), 132.94 (ab, C), 133.68 (ab, C), 135.04 (+ve,
CH), 135.47 (ab, C), 141.93 (+ve, 6-CH), 151.22 (ab, C),
162.78 (ab, C); nmax (KBr)/cmꢁ1: 3050, 1706, 1643, 752;
(Found C, 67.9; H, 5.0; N, 8.2%. C20H17ClN2O2 requires
C, 68.09; H, 4.86; N, 7.94%).
1
mass m/z 259 (M++1); H NMR (CDCl3): d 1.77 (3H, s,
CH3), 2.25 (6H, s, 2ꢂCH3), 2.33 (3H, s, CH3), 4.93 (2H, s,
CH2), 6.48 (1H, s, C6-H), 6.94 (2H, s, ArH), 8.91 (1H, br
s, NH); 13C (normal/DEPT-135) (CDCl3): d 12.51 (+ve,
CH3), 19.76 (+ve, CH3), 20.99 (+ve, CH3), 44.38 (ꢁve,
CH2), 110.52 (ab, C5), 126.82 (ab, ArCH), 129.75
(+ve, ArCH), 137.16 (+ve, 6-CH), 138.16 (ab, C), 138.92
(ab, C), 151.24 (ab, C), 163.90 (ab, C); nmax (KBr)/cmꢁ1
:
3033, 2385, 1701, 1676, 864; (Found: C, 69.56; H, 6.84; N,
10.83. C15H18N2O2 requires C, 69.7; H, 6.97; N, 10.85%).
4.3. N3-(o-Chlorobenzylation) of 4a–4c
4.4.3. 1-Ethyl-3-[(2-chlorobenzyl)-1H-pyrimidine-2,4-
dione (15c). 63%; Transparent liquid, FAB mass m/z 265,
267 (3:1) (M+); 1H NMR (CDCl3): d 1.27 (3H, t, J¼7.8 Hz,
CH3), 3.82 (2H, q, J¼7.8 Hz, CH2), 5.25 (2H, s, CH2),
5.82 (1H, d, J¼7.8 Hz, C-5H), 6.94–6.98 (1H, m, ArH),
7.12–7.46 (4H, m, ArH+C6-H); 13C (normal/DEPT-135)
(CDCl3): d 14.24 (+ve, CH3), 41.86 (ꢁve, CH2), 44.89
(ꢁve, CH2), 101.51 (+ve, 5-CH), 126.59 (+ve, ArH),
126.74 (+ve, ArH), 128.17 (+ve, ArH), 129.47 (+ve, ArH),
131.63 (ab, C), 133.48 (ab, C), 142.31 (+ve, 6-CH), 150.99
(ab, C), 162.88 (ab, C); nmax (CHCl3)/cmꢁ1: 3050, 2900,
2950, 1710, 1618, 810; (Found: C, 58.92; H, 5.02; N, 9.86.
C13H13ClN2O2 requires C, 58.97; H, 4.95; N, 10.59%).
Procedure B: 4a (2.36 g, 1 mmol) was heated with N,O-bis-
(trimethylsilyl)acetamide (BSA) at 110 ꢀC in an oil bath
and a clear solution was obtained in 3–4 h. 3a (2 equiv) and
1,2-DCE (10 ml) were added to the above solution and re-
fluxing was continued for 48 h. The reaction mixture was
treated with ethanol (10 ml). The solvent was distilled off
under vacuum and the residue was column chromatographed
over silica-gel column using hexane–ethyl acetate mixture
as eluent to isolate mixture of 6a, 11a and 12a. Similarly,
4b and 4c on silylation with BSA followed by reactions
with 3b and 3c gave respective mixtures of 6b+11b+12b
and 6c+11c+12c.
4.4. General procedure for the synthesis of 1-allyl/alkyl/
ethoxycarbonylmethyl 3-(2-Cl/2,4-diCl/2,6-diCl-benzyl-
2,4-1H,3H-pyrimidine-2,4-dione derivatives
4.4.4. 1-Butyl-3-(2-chlorobenzyl)-1H-pyrimidine-2,4-
dione (15d). 78%; Transparent liquid, FAB mass m/z
1
293, 295 (3:1) (M+); H NMR (CDCl3): d 0.98 (3H, t,
J¼7.2 Hz, CH3), 1.32 (2H, hextet, J¼7.2 Hz, CH2), 1.68
(2H, quintet, J¼7.2 Hz, CH2), 3.74 (2H, t, J¼7.2 Hz,
CH2), 5.28 (2H, s, CH2), 5.84 (1H, d, J¼8.0 Hz, C5-H),
6.97–7.01 (1H, m, ArH), 7.13–7.48 (4H, m, ArH+C6-H);
The decoupling of the C5-H signal at d 5.84 gives a singlet
at d 7.19 embedded into a multiplet; 13C (normal/DEPT-
135) (CDCl3): d 13.56 (+ve, CH3), 19.61 (ꢁve, CH2),
30.97 (ꢁve, CH2), 42.04 (ꢁve, CH2), 49.63 (ꢁve, CH2),
101.32 (+ve, 5-CH), 126.61 (+ve, ArH), 126.72 (+ve,
ArH), 128.16 (+ve, ArH), 129.51 (+ve, ArH), 132.97 (ab,
C), 133.76 (ab, C), 142.62 (+ve, 6-CH), 151.23 (ab, C),
162.96 (ab, C); nmax (CHCl3)/cmꢁ1: 3050, 2958, 1708,
1662, 810 cmꢁ1; (Found C, 61.5; H, 5.68; N, 9.38%.
C15H17ClN2O2 requires C, 61.5; H, 5.81; N, 9.57%).
Procedure C: A solution of 2,4-bis-(trimethylsilyloxy)pyri-
midine (1) (0.01 mol), alkyl/allyl halide (0.15 mol) and I2
(127 mg, 0.001 mol) in 1,2-DCE (20 ml) was refluxed for
24–48 h. Then appropriately substituted o-chlorobenzyl
chloride (0.02 mol) was added and the refluxing was con-
tinued. After completion of the reaction (TLC), it was cooled
and treated with ethanol (10 ml). The solvent was distilled
off under vacuum and the residue was column chromato-
graphed over silica-gel column using hexane–ethyl acetate
as eluents to isolate the pure compounds.
4.4.1. 1-Allyl-3-(2-chlorobenzyl)-1H-pyrimidine-2,4-
dione (15a). 73%; Pale yellow liquid, FAB mass m/z
1
277, 279 (3:1) (M+); H NMR (CDCl3): d 4.30 (2H, d,
J¼6.2 Hz, CH2), 5.24 (2H, s, CH2), 5.29–5.35 (2H,
m, ]CH2), 5.88 (1H, d, J¼8.0 Hz, C5-H), 5.91–5.95 (1H,
m, ]CH), 6.96–7.11 (1H, m, ArH), 7.15–7.35 (4H, m,
ArH+C6-H). The decoupling of 5-H doublet at d 5.88 gives
a sharp singlet at d 7.24 embedded into a multiplet; 13C
(normal/DEPT-135) (CDCl3): d 41.76 (ꢁve, CH2), 50.95
(ꢁve, CH2), 101.45 (+ve, 5-CH), 117.53 (ꢁve, CH2),
126.46 (+ve, ArCH), 126.62 (+ve, ArCH), 127.89 (+ve,
ArCH), 129.42 (+ve, ArCH), 131.52 (+ve, CH), 133.27
4.4.5. 1-Octyl-3-(2-chlorobenzyl)-1H-pyrimidine-2,4-di-
one (15e). 67%; Transparent liquid, FAB mass m/z 349,
351 (3:1) (M+); 1H NMR (CDCl3): d 0.87 (3H, t,
J¼7.2 Hz, CH3), 1.27–1.29 (8H, m, 4ꢂCH2), 1.64–1.68
(4H, m, 2ꢂCH2), 3.74 (2H, t, J¼7.2 Hz, CH2), 5.25 (2H,
s, CH2), 5.80 (1H, d, J¼8.0 Hz, C5-H), 6.93–6.98 (1H, m,
ArH), 7.24 (1H, d, J¼8.0 Hz, C6-H), 7.26–7.38 (3H, m,
ArH); 13C (normal/DEPT-135) (CDCl3): d 13.99 (+ve,
CH3), 22.52 (ꢁve, CH2), 26.43 (ꢁve, CH2), 29.03 (ꢁve,

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V. Malik et al. / Tetrahedron 62 (2006) 5944–5951
CH2), 31.65 (ꢁve, CH2), 49.89 (ꢁve, CH2), 101.31 (+ve, 5-
CH), 126.62 (+ve, ArH), 126.91 (+ve, ArH), 128.15 (+ve,
ArH), 129.35 (+ve, ArH), 132.99 (ab, C), 133.80 (ab, C),
142.6 (+ve, 6-CH), 150.99 (ab, C), 162.87 (ab, C); nmax
(CHCl3)/cmꢁ1: 3043, 2923, 1689, 1641, 813; (Found: C,
65.48; H, 7.23; N, 7.87. C19H25ClN2O4 requires C, 65.41;
H, 7.22; N, 8.03).
J¼8.0 Hz, C6-H), 7.13–7.48 (3H, m, ArH); 13C (normal/
DEPT-135) (CDCl3): d 13.59 (+ve, CH3), 19.63 (ꢁve,
CH2), 30.90 (ꢁve, CH2), 41.64 (ꢁve, CH2), 49.67 (ꢁve,
CH2), 101.32 (+ve, 5-CH), 127.02 (+ve, ArH), 127.96
(+ve, ArH), 131.38 (+ve, ArH), 131.75 (absent, C), 133.38
(absent, C), 133.78 (absent, C), 142.8 (+ve, 6-CH), 151.18
(absent, C), 163.04 (absent, C); nmax (KBr)/cmꢁ1: 3056,
2960, 1703, 1672, 811; HRMS found: 327.0662,
C15H Cl2N2O2 requires 327.0659.
35
17
4.4.6. 1-(Ethoxycarbonylmethyl)-3-(2-chlorobenzyl)-1H-
pyrimidine-2,4-dione (15f). 64%; Transparent liquid,
1
FAB mass m/z 323, 325 (3:1) (M+); H NMR (CDCl3):
4.4.10. 1-(Ethoxycarbonylmethyl)-3-(2,4-dichloro-
benzyl)-1H-pyrimidine-2,4-dione (16d). 64%; White solid,
mp 120 ꢀC (CH3CN); FAB mass m/z 357, 359, 361
(100:70:10) (M+); 1H NMR (CDCl3): d 1.28 (3H, t,
J¼7.2 Hz, CH3), 4.23 (2H, q, J¼7.2 Hz, OCH2), 4.64
(2H, s, NCH2), 5.20 (2H, s, CH2), 5.83 (1H, d, J¼8.0 Hz,
C-5H), 6.93 (1H, d, J¼8.0 Hz, C-6H), 7.07–7.38 (3H, m,
ArH); 13C (normal/DEPT-135) (CDCl3): d 14.04 (+ve,
CH3), 41.62 (ꢁve, CH2), 49.76 (ꢁve, CH2), 62.05 (ꢁve,
CH2), 102.03 (+ve, 5-CH), 127.03 (+ve, ArCH), 127.90
(+ve, ArCH), 129.28 (+ve, ArCH), 132.40 (ab, C), 133.57
(ab, C), 133.86 (ab, C), 142.32 (+ve, 6-CH), 151.26 (ab,
C), 162.28 (ab, C), 167.10 (ab, C); nmax (KBr)/cmꢁ1: 3074,
2995, 2958, 1743, 1720, 1683, 1236, 779; (Found: C, 50.3;
H, 3.9; N, 7.8. C15H14Cl2N2O4 requires C, 50.44; H, 3.95;
N, 7.84%).
d 1.29 (3H, t, J¼7.2 Hz, CH3), 4.22 (2H, q, J¼7.2 Hz,
CH2), 4.46 (2H, s, CH2), 5.24 (2H, s, CH2), 5.85 (1H, d,
J¼7.8 Hz, C5-H), 6.95–7.51 (5H, m, ArH+C6-H); 13C (nor-
mal/DEPT-135) (CDCl3): d 13.98 (+ve, CH3), 42.11 (ꢁve,
CH2), 49.87 (ꢁve, CH2), 62.09 (ꢁve, CH2), 102.13 (+ve,
CH-5), 126.65 (+ve, ArH), 127.50 (+ve, ArH), 129.44
(+ve, ArH), 129.64 (+ve, ArH), 132.92 (ab, C), 133.43 (ab,
C), 142.52 (+ve, CH-6), 151.34 (ab, C), 162.62 (ab, C),
167.29 (ab, C); nmax (CHCl3)/cmꢁ1: 3064, 2987, 1747,
1704, 1658, 1207, 811; (Found: C, 55.79; H, 4.77; N, 8.60.
C15H15ClN2O4 requires C, 55.80; H, 4.65; N, 8.60).
4.4.7. 1-Allyl-3-(2,4-dichlorobenzyl)-1H-pyrimidine-2,4-
dione (16a). 62%; Solid, mp 94 ꢀC (CH3CN); FAB mass
m/z 311, 313, 315 (100:62:1) (M+); 1H NMR (CDCl3):
d 4.36 (2H, d, J¼8 Hz, CH2), 5.21 (2H, s, CH2), 5.25–5.35
(2H, m, ]CH2), 5.72 (1H, d, J¼8.0 Hz, C5-H), 5.79–5.90
(1H, m, ]CH), 6.96 (1H, d, J¼8.0 Hz, Ar-60H), 7.12 (1H,
dd, J1¼8.0 Hz, J2¼1.2 Hz, Ar-50H) 7.21 (1H, d, J¼8.0 Hz,
C6-H), 7.78 (1H, d, J¼1.2 Hz, Ar-30H); 13C (normal/
DEPT-135) (CDCl3): d 41.75 (ꢁve, CH2), 51.09 (ꢁve,
CH2), 101.63 (+ve, 5-CH), 119.58 (ꢁve, ]CH2), 127.06
(+ve, ArCH), 128.02 (+ve, ArCH), 129.32 (+ve, ArCH),
131.27 (+ve, CH), 131.43 (ab, C), 132.40 (ab, C), 133.37
(ab, C), 142.27 (+ve, 6-CH), 151.06 (ab, C), 162.97 (ab,
C); nmax (KBr)/cmꢁ1: 3089, 1708, 1658, 808; (Found: C,
53.9; H, 3.9; N, 9.3. C14H12Cl2N2O2 requires C, 54.04; H,
3.89; N, 9.00%).
4.4.11. 1-Allyl-3-(2,6-dichlorobenzyl)-1H-pyrimidine-
2,4-dione (17a). 65%; White solid, mp 110 ꢀC (CH3CN);
1
FAB mass m/z 311, 313, 315 (100: 62:1) (M+); H NMR
(CDCl3): d 4.30 (2H, d, J¼6.0 Hz, CH2), 5.13–5.23 (2H,
m, ]CH2), 5.41 (2H, s, CH2), 5.72–5.87 (1H, m, ]CH),
5.88 (1H, d, J¼8.0 Hz, C5-H), 7.12 (1H, d, J¼8.0 Hz, C6-
H), 7.17 (1H, t, J¼8.0 Hz, Ar-40H), 7.37 (2H, d, J¼8.0 Hz,
Ar-30/50H); 13C (normal/DEPT-135) (CDCl3): d 40.93
(ꢁve, CH2), 50.77 (ꢁve, CH2), 101.73 (+ve, 5-CH),
118.99 (ꢁve, CH2), 128.53 (+ve, ArCH), 128.79 (+ve,
ArCH), 131.61 (+ve, ]CH), 131.87 (ab, C), 135.73 (ab,
C), 141.74 (+ve, CH), 150.99 (ab, C), 162.73 (ab, C); nmax
(KBr)/cmꢁ1: 3050, 1708, 1656, 736; (Found: C, 53.9; H,
3.7; N, 9.1. C14H12Cl2N2O2 requires C, 54.04; H, 3.89; N,
9.00%).
4.4.8. 1-Ethyl-3-(2,4-dichlorobenzyl)-1H-pyrimidine-2,4-
dione (16b). 70%; White solid, mp 98 ꢀC (CH3CN); FAB
1
mass m/z 299, 301 (100: 62:1) (M+); H NMR (CDCl3):
d 1.27 (3H, t, J¼7.2 Hz, CH3), 3.81 (2H, q, J¼7.2 Hz,
CH2), 5.19 (2H, s, CH2), 5.83 (1H, s, J¼7.8 Hz, C5-H),
6.92 (1H, d, J¼8.4 Hz, Ar60-H); 7.14 (1H, dd, J1¼8.4 Hz,
J2¼1.8 Hz, Ar-50H), 7.23 (1H, d, J¼7.8 Hz, C6-H),
7.37 (1H, d, J¼1.8 Hz, Ar-30H); 13C (normal/DEPT-135)
(CDCl3): d 14.25 (+ve, CH3), 41.68 (ꢁve, CH2), 45.03
(ꢁve, CH2), 101.42 (+ve, 5-CH), 127.05 (+ve, ArCH),
128.09 (+ve, ArCH), 129.31 (+ve, ArCH), 132.45 (ab, C),
133.39 (ab, C), 133.76 (ab, C), 142.51 (+ve, 6-CH),
150.94 (ab, C), 163.28 (ab, C); nmax (KBr)/cmꢁ1: 3087,
3060, 2897, 1708, 1656, 808 cmꢁ1; (Found: C, 51.9; H,
3.8; N, 9.5. C13H12Cl2N2O2 requires C, 52.19; H, 4.04; N,
9.36%).
4.4.12. 1-Butyl-3-(2,6-dichlorobenzyl)-1H-pyrimidine-
2,4-dione (17b). 62%; Solid, mp 140 ꢀC (CH3CN); FAB
mass m/z 327, 329, 331 (100: 72:1) (M+); 1H NMR
(CDCl3): d 0.98 (3H, t, J¼7.2 Hz, CH3), 1.25–1.37 (2H, m,
CH2), 1.40–1.72 (2H, m, CH2), 3.73 (2H, t, J¼7.2 Hz,
CH2), 5.18 (2H, s, CH2), 5.80 (1H, d, J¼9.0 Hz, C5-H),
6.92 (1H, d, J¼9.0 Hz, C6-H), 7.09–7.45 (3H, m, ArH);
13C (normal/DEPT-135) (CDCl3): d 13.56 (+ve, CH3),
19.54 (ꢁve, CH2), 30.93 (ꢁve, CH2), 40.87 (ꢁve, CH2),
49.46 (ꢁve, CH2), 101.23 (+ve, 5-CH), 128.50 (+ve,
ArCH), 128.68 (+ve, ArCH), 131.94 (ab, C), 135.65 (ab,
C), 142.35 (+ve, 6-CH), 151.03 (ab, C), 162.87 (ab, C);
nmax (KBr)/cmꢁ1: 3070, 2952, 1712, 1656, 800; (Found: C,
55.36; H, 4.60; N, 8.19. C15H16Cl2N2O2 requires C, 55.04;
H, 4.89; N, 8.56%).
4.4.9. 1-Butyl-3-(2,4-dichlorobenzyl)-1H-pyrimidine-2,4-
dione (16c). 63%; White solid, mp 60 ꢀC (CH3CN); FAB
mass m/z 327, 329, 331 (100:62:1) (M+); 1H NMR
(CDCl3): d 0.98 (3H, t, CH3), 1.25–1.42 (2H, m, CH2),
1.62–1.72 (2H, m, CH2), 3.76 (2H, t, CH2), 5.17 (2H, s,
CH2), 5.83 (1H, d, J¼8.0 Hz, C5-H), 6.94 (1H, d,
4.4.13. 1-Ethoxycarbonylmethyl-3-(2,6-dichlorobenzyl)-
1H-pyrimidine-2,4-dione (17c). 62%; White solid, mp
120 ꢀC (CH3CN); FAB mass m/z 357, 359, 361 (100: 62:1)
1
(M+); H NMR (CDCl3): d 1.29 (3H, t, J¼7.2 Hz, CH3),

V. Malik et al. / Tetrahedron 62 (2006) 5944–5951
5951
Nanni, R. G.; Boyer, P. L.; Hughes, S. H.; Pauwels, R.;
Andries, K.; Janssen, P. A.; Arnold, E. J. Mol. Biol. 1994, 243,
369–387.
4.14 (2H, q, J¼7.2 Hz, OCH2), 4.39 (2H, s, CH2), 5.38 (2H,
s, CH2), 5.78 (1H, d, J¼7.8 Hz, C5-H), 7.06 (1H, d,
J¼7.8 Hz, C6-H), 7.08–7.27 (3H, m, ArH); 13C (normal/
DEPT-135) (CDCl3): d 14.00 (+ve, CH3), 40.88 (ꢁve,
CH2), 49.55 (ꢁve, CH2), 61.86 (ꢁve, CH2), 101.98 (+ve,
5-CH), 128.37 (+ve, ArCH), 128.60 (+ve, ArCH), 131.89
(ab, C), 136.00 (ab, C), 141.90 (+ve, 6-CH), 151.05 (ab,
2. (a) Ragno, R.; Mai, A.; Sbardella, G.; Artico, M.; Massa, S.;
Musiu, C.; Mura, M.; Marturana, F.; Cadeddu, A.; Colla, P. L.
J. Med. Chem. 2004, 47, 928–934; (b) Pederson, O. S.;
Pederson, E. B. Antiviral Chem. Chemother. 1999, 10, 285–
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C), 162.31 (ab, C), 167.13 (ab, C); nmax (KBr)/cmꢁ1
:
3083, 2985, 2958, 1743, 1720, 1683, 1236, 779 (Found: C,
49.8; H, 3.8; N, 7.8. C15H14Cl2N2O4 requires C, 50.04; H,
3.95; H, 7.84%).
3. (a) Smerdon, S. J.; Jager, J.; Wang, J.; Kohlstaedt, L. A.; Chirino,
A. J.; Frieduan, J. M.; Rice, P. A.; Steitz, T. A. Proc. Natl. Acad.
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Ding, J.; Das, K.; Moereels, H.; Koyuans, L.; Andries, K.;
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Acknowledgements
We thank CSIR, New Delhi for financial assistance and DST,
New Delhi for the FIST programme. NIH, Bethesda USA is
gratefully acknowleged for evaluating anti-HIV activites.
References and notes
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