Regioselective synthesis of 1-allyl- and 1-arylmethyl uracil and thymine derivatives

Article abstract of DOI:10.1016/j.tet.2005.02.047

2,4-Bis(trimethylsiloxy) pyrimidines 1 with allyl halides and arylmethyl halides in 1,2-dichloroethane in the presence of I₂ regioselectively provide 1-allyl-/1-arylmethyl-uracil and thymine derivatives. The secondary aryl alkyl and diaryl meth

Full text of DOI:10.1016/j.tet.2005.02.047

Tetrahedron 61 (2005) 4009–4014
Regioselective synthesis of 1-allyl- and 1-arylmethyl uracil and
thymine derivatives
Vaishali Malik, Palwinder Singh and Subodh Kumar
*
Department of Chemistry, GuruNnanak Dev University, Amritsar, 143005, India
Received 22 October 2004; revised 4 February 2005; accepted 18 February 2005
Available online 16 March 2005
Abstract—2,4-Bis(trimethylsiloxy) pyrimidines 1 with allyl halides and arylmethyl halides in 1,2-dichloroethane in the presence of I
2
regioselectively provide 1-allyl-/1-arylmethyl-uracil and thymine derivatives. The secondary aryl alkyl and diaryl methyl halides with 1
provide chiral 1-arylalkyl/1-(diarylmethyl) uracil/thymine derivatives. The procedure has been extended to the synthesis of fluorescent
uracil/thymine derivatives.
q 2005 Elsevier Ltd. All rights reserved.
1
. Introduction
available methodologies through base mediated allylation
9
–11
of free nucleic bases
or Lewis acid catalysed allylation
2
b
The nucleoside analogues have been cornerstones for
1
chemotherapy of cancer and viral diseases. However, the
of 2,4-bis(trimethylsiloxy)pyrimidines suffer with non-
regioselectivity of reactions at N-1 and N-3 and poor yields.
clinical toxicities arising due to the various reasons, limited
uptake, high susceptibility to catabolism and rapid
emergence of resistance towards virus or cancer cells has
2
led to diversification to non-nucleoside inhibitors (NNIs).
The NNIs do not interact at the catalytic site of the enzyme
2. Results and discussion
In the present manuscript, a simple and general approach for
the synthesis of pyrimidine-2,4-diones bearing allyl,
arylmethyl, alkyl aryl methyl, diarylmethyl substituents at
N-1 is presented (Scheme 1).
but interact in a hydrophobic pocket through p–p or p–HC
interactions. These feeble interactions through their
multiple interacting features become significant structural
3
4
force to inhibit the functioning of enzyme. The role of p–p
interactions is emphasized in the development of new multi
5
drug resistance modulators as well as in the interactions of
olefinic and arene moieties of aromatic amino acids
phenylalanine, tyrosine, tryptophane, which constitute
(
w8% of the known protein sequence) with the most
6
,7
C
C
prevalent biological cations Na and K . Distinctly, in
NNIs the phosphorylation is not an obligatory step for their
ability to block the DNA replication and cell growth.
Scheme 1.
This role of arene moieties and p-bonds in effective
participation in biological systems has drawn the attention
to the development of synthetic procedures for arene/allyl
substituted nucleic bases—uracil and thymine, etc. Such
1
2
Refluxing of a solution of 1a with allyl bromide
(1.2 equiv) in 1,2-dichloroethane in the presence of I
5 mol%, catalyst), after usual reaction workup regio-
2
(
1
1
selectively provides 3a (93%), mp 109 8C (lit. mp
1
by the presence of H-5 and H-6 doublets at d 5.74 and 7.16
1
synthons for the development of new drug molecules.
-allyl-and 1-arylmethyl nucleobases can prove vital
C
10 8C)., M (m/z) 152. The structure of 3a was confirmed
8
However, their synthesis has found scarce attention and
and one 2H doublet at d 4.38 due to NCH along with the
2
1
olefinic protons and exchangeable NH (d 9.68) in its H
Keywords: Regioselective; Allylation; Arylmethyl; Uracil and thymine.
*
NMR spectrum. Similarly, 1b with allyl bromide in 1,2-
DCE and I gave 4a (68%), mp 77 8C, M m/z 166. On
Corresponding author. Tel.: C91 183 2258802; fax: C91 183 2258820;
e-mail: subodh_gndu@yahoo.co.in
C
2
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.047

4010
V. Malik et al. / Tetrahedron 61 (2005) 4009–4014
using benzene as solvent, the yields of 3a (54%) and 4a
52%) were lowered and in solvents like CH CN and CHCl3
Table 2. Synthesis of 1-arylmethyluracil and 1-arylmethylthymine
derivatives
(
3
the allylation product was not formed. In these reactions, the
formation of 1,3-diallyluracil/thymine was not observed
S. no
R in 1
and 6
X in 5/6
Time
(h)
Yield
(%)
1
2
even in traces (tlc). Similarly, 1a/1b with cinnamyl
bromide, ethyl 4-bromocrotonate and 1-bromo-2-butene
provide respective compounds 3b–d and 4b–d in 64–85%
yields. (Table 1, entries 2–8).
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
2-Cl
3-Cl
4-Cl
4-F
2,4-diCl
2-NO2
2,4,6-triMe
2-Cl
2,4-diCl
24
48
72
48
48
36
36
36
36
36
6a (87)
6b (74)
6c (81)
6d (81)
6e (70)
6f (69)
6g (68)
6h (62)
6i (87)
6j (85)
a
a
Table 1. Synthesis of 1-allyluracil and 1-allylthymine derivatives
0
S. no
R in 1
R in 2/3/4
Reaction
time (h)
Product
(yield %)
CH
CH
3
1
0
3
1
2
3
4
5
6
7
8
H
H
H
H
CH
CH
CH
CH
H
CH
24
24
36
36
24
36
36
36
3a (93)
3b (85)
3c (75)
3d (70)
4a (68)
4b (67)
4c (68)
4d (64)
a
In these cases 1,3-bis(2-chlorophenylmethyl)uracil (7a) and 1,3-bis(2,4-
dichlorophenylmethyl)uracil (7b) derivatives were isolated in !3%
yields.
3
C
6
H
5
CO
H
2
C
2
H
H
5
5
3
3
3
3
CH
3
C
6
H
5
CO
2
C
2
The earlier reported Pd (0) catalyzed allylation of uracil and
1
0
derivatives performed in DMSO or organic aqueous
medium (H O–CH CN) or (H O–THF) in the presence of
base DBU, and water soluble sulphonated triphenyl-
2
3
2
1
1
phosphine P(C H -m-SO Na) , gave mixture of 1-allyl-
6
Scheme 2.
4
3
3
and 1,3-diallyluracil derivatives and in general, large excess
4–8 equiv) of the allylating reagent has to be used.
(
present approach can provide synthons for developing uracil
1
4
based isosteres of cetirizine. 1 on reaction with secondary
chiral and achiral halides provided respective 1-substituted
uracil derivatives 9 in 65–80% yields (Table 3, Scheme 3).
Therefore, the present procedure which requires only
equivalent amounts of expensive allylating reagent and
provides regioselectively 1-allyl products irrespective of the
nature of allyl halide, provides a general and economical
procedure for the synthesis of 1-allyl uracil/thymine
derivatives.
Table 3. Synthesis of 1-diarylalkyl/1-alkyaryl uracil/thymine derivatives
0
S. no.
R
R
Reaction
time
Yield (%)
(
h)
The presence of benzyl group on the nucleobase due to its
higher participation in cation-p and p–p interactions can
provide more opportunities for their interactions in
biological systems. Further, it is possible to tune these
interactions by the presence of electron-withdrawing or
electron-donating groups on the aryl rings and the bulk of
the substituents. So, the above methodology was extended
for the synthesis of 1-(arylmethyl) uracil derivatives.
1
2
3
4
5
H
H
H
CH
CH
CH
C H
6 5
4-ClC
3
36
36
48
36
36
9a (69)
9b (70)
9c (65)
9d (78)
9e (80)
1
3
6 5
H
3
CH
3
3
6 5
C H
2
,4-Bis(trimethylsiloxy) pyrimidine (1a) on refluxing with
phenylmethyl chloride in 1,2-dichloroethane gave 1-phenyl-
C
methyluracil 6a (87%) mp 160 8C, M m/z 203 (Table 2,
entry 1) (Scheme 2). Similarly, 1a and 1b with substituted
aryl-methyl halides provided respective 1-arylmethyluracil/
thymine derivatives 6b–6j in 68–87% yields. In all these
cases, the assignment of H-5 and H-6 signals was made on
the basis of decoupling of H-5 which appeared at d 5.54–
Scheme 3.
1
5
The presence of a fluorescent moiety on the pyrimidine
base could provide a handle to study the interactions of
nucleobases through fluorescence measurements. 1a/1b on
reaction with 9-anthracenylmethyl chloride 10 provided 11a
6
7
.10. It is observed that in cases of 6a–6g H-6 is present at d
.14–7.20 and in 6h, the C-6H signal is shifted considerably
upfield (d 6.66) which may be attributed to the increased
shielding by phenyl ring to H-6 due to the presence of three
electron-donating methyl groups at the phenyl moiety.
C
(84%), mp 240 8C, M (m/z) 302 and 11b (80%), mp
2
C
60 8C, M m/z 316 (Scheme 4). An upfield shift of C-6H
The reactions of 1 with secondary alkyl halides would
provide an opportunity to synthesize the chiral uracil
molecules. The role of 4-chlorophenyl methyl group in
cetirizine defines the importance of such moieties and the
((d 6.86) from their normal position, i.e. d 7.14 clearly
showed the shielding of H-6 by anthracene moiety.
Compounds 11 in their UV–vis spectra showed lmax at
387, 367, 349, 333 nm and their fluorescence spectra gave

V. Malik et al. / Tetrahedron 61 (2005) 4009–4014
4011
1693 (C]O), 3566 (NH); HRMS: found 152.0588,
C H N O requires 152.0586.
7
8 2 2
4.2.2. 1-But-2-enyl-1H-pyrimidine-2,4-dione (3b). 85%;
White solid, mp 88 8C (ethanol); H NMR (CDCl ): d 1.76
1
3
(
3H, d, JZ6.4 Hz, CH ), 4.27 (2H, d, JZ6.2 Hz, NCH ),
3
2
5
5
.46–5.57 (1H, m, ]CH), 5.71 (1H, d, JZ8 Hz, H-5), 5.73–
.83 (1H, m, ]CH), 7.18 (1H, d, JZ8 Hz, H-6), 9.58 (1H,
1
3
bs, NH, exchanges with D O); C NMR (normal/DEPT)
2
(
(
1
(
1
CDCl ): d 17.65 (Cve, CH ), 49.39 (Kve, CH ), 102.16
3 3 2
Scheme 4.
Cve, CH-5), 124.20 (Cve, ]CH), 131.74 (Cve, ]CH),
43.78 (Cve, CH-6), 151.02 (ab, C), 164.28 (ab, C); n
KBr) cm : 1683 (C]O), 3486 (NH); HRMS found:
max
K1
lmax at 412, 390, 363 nm, the characteristic spectral features
of anthracene moiety. On excitation at lmax 365 nm, the
66.0745, C H N O requires 166.0742.
8 10 2 2
solutions of compounds 11 in acetonitrile gave f Z0.23C
f
4
7
.2.3. 1-(3-Phenyl-allyl)-1H-pyrimidine-2,4-dione (3c).
5%; Light yellow crystals, mp 170 8C (ethanol);
0
.01.
1
H
NMR (CDCl ): d 4.52 (2H, d, JZ6.2 Hz, NCH ), 5.75
3
2
(
1
1H, d, JZ8.0 Hz, H-5), 6.23 (1H, dt, J Z6.2 Hz, J Z
6 Hz, ]CH), 6.65 (1H, d, JZ16 Hz, ]CH), 7.24 (1H, d,
1 2
3. Conclusions
JZ8.0 Hz, H-6), 7.26–7.38 (5H, m, ArH), 8.77 (1H, b, NH,
2
,4-Bis(trimethylsiloxy)pyrimidines 1 on refluxing with
13
exchanges with D O); C NMR (normal/DEPT-135)
2
allyl halides and primary and secondary arylalkyl halides
provide a simple and general methodology for 1-allyl- and
1-arylmethyl- and 1-diarylmethyl- uracil/thymine
derivatives.
(
CDCl ): d 47.52 (Kve, CH ), 100.12 (Cve, CH-5),
3 2
1
]
(
21.88 (Cve, CH), 124.82 (Cve, ArCH), 126.34 (Cve,
CH), 126.94 (Cve, ArCH), 131.65 (Cve, ]CH), 134.25
ab, C),143.05 (Cve, CH-6), 149.40 (ab, C), 162.40 (ab, C);
K1
nmax (KBr) (cm ): 1685 (C]O), 3480 (NH); HRMS
found: 228.0898, C H N O requires 228.0899.
1
3 12 2 2
4
. Experimental
4
.2.4. 1-(3-Ethoxycarbonyl-allyl)-1H-pyrimidine-2,4-
1
4
.1. General
dione (3d). 70%; White solid, mp 110 8C (ethanol); H
NMR (CDCl ,): d 1.28 (3H, t, JZ7.2 Hz, CH ), 4.23 (2H, q,
3
3
The melting points were determined in capillaries and are
JZ7.2 Hz, OCH ), 4.49 (2H, d, JZ6.0 Hz, NCH ), 5.76
2
2
1
13
uncorrected. H and C NMR spectra were recorded on
Bruker AC 200 MHz and JEOL JNM 300 MHz machines.
High resolution mass spectra were recorded on micromass
(1H, d, JZ8.0 Hz, H-5), 5.87 (1H, d, JZ16 Hz, ]CH),
6.89 (1H, dt, J Z6.0 Hz, J Z16 Hz, ]CH), 7.11 (d, JZ
1
2
1
3
8.0 Hz, H-6), 9.43 (1H, bs, NH, exchanges with D O);
C
2
(
using GC–MS).
NMR (normal/DEPT-135) (CDCl ): d 14.09 (Cve, CH ),
3 3
4
1
8.24 (Kve, CH ), 60.83 (Kve, CH ), 103.01 (Cve, CH-5),
2 2
24.02 (Cve, ]CH), 140.14 (Cve, ]CH), 143.70 (Cve,
4
1
.2. General procedure for the preparation of
-substituted uracil/thymine derivatives
CH-6) 150.64 (ab, C), 163.80 (ab, C), 165.16 (ab, C).
HRMS found: 224.0798, C H N O requires 224.0797.
1
0 12 2 4
A
solution of 2,4-bis-(trimethylsiloxy)pyrimidine
0.01 mol), allyl/arylmethyl/arylalkyl halide (0.012 mol)
(
and I (20 mg) in 1,2-DCE (20 ml) was refluxed. After
4.2.5. 1-Allyl-5-methyl-1H-pyrimidine-2,4-dione (4a).
68%; White solid, mp 77 8C (ethanol); H NMR (CDCl ):
1
2
3
completion of the reaction (tlc), the cooled reaction mixture
was treated with ethanol (10 ml). The solid separated was
filtered and recrystallized from ethanol or acetonitrile to get
pure 1-substituted uracil/thymine derivative. In case of
reactions with 2-chloro- and 2,4-dichloroarylmethyl
chloride, the respective 1,3-bis (arylmethyl)uracils were
isolated from filtrate by column chromatography using ethyl
acetate and hexane mixtures as eluents.
d 1.90 (3H, s, CH ). 4.32 (2H, d, JZ6.8 Hz, NCH ), 5.21–
3
2
5.33 (2H, m, ]CH ), 5.79–5.88 (1H, m, ]CH), 6.95 (1H, s,
2
1
3
H-6), 8.35 (1H, s, NH, exchanges with D O.); C NMR
2
(normal/DEPT-135) (CDCl ): d 12.25 (Cve, CH ), 49.70
3
3
(Kve, CH ), 110.92 (ab, C-5), 119.08 (Kve, ]CH ),
2
2
131.70 (Cve, ]CH), 141.21 (Cve, CH-6), 150.99 (ab, C),
164.47 (ab, C); HRMS found: 166.0743, C H N O
10 2 2
8
requires 166.0742.
4.2.1. 1-Allyl-1H-pyrimidine-2,4-dione (3a). 93%; White
solid, mp 109 8C (ethanol) (lit. mp 110 8C); H NMR
4.2.6. 1-But-2-enyl-5-methyl-1H-pyrimidine-2,4-dione
(4b). 67%; White solid, mp 110 8C (ethanol); H NMR
1
1
1
1
(
CDCl ,): d 4.38 (d, 2H, JZ7.0 Hz, NCH ), 5.22–5.34 (m,
(CDCl ,): d 1.74(3H, d, JZ6.4 Hz, CH ), 1.93 (3H, s, CH ),
3
2
3
3
3
2
H, ]CH ), 5.74 (1H, d, JZ7.8 Hz, H-5), 5.81–5.95 (1H,
4.32 (2H, dd, J Z7.0 Hz, J Z24 Hz NCH ), 5.31–5.47
2
1 2 2
m, ]CH), 7.16 (1H, d, JZ7.8 Hz, H-6), 9.68 (1H, bs, NH,
(1H, m, ]CH), 5.65–5.83 (1H, m, ]CH), 6.98 (1H, s, H-6),
8.68 (1H, bs, NH, exchanges with D O); C NMR (normal/
1
exchanges with D O); C NMR (normal/DEPT-135)
3
13
2
2
(
CDCl ): d 47.24 (Kve, CH ), 99.37 (Cve, CH-5),
3
DEPT-135) (CDCl ): d 12.24 (Cve, CH ), 17.64 (Cve,
3
2
3
1
CH-6), 148.83 (ab, C), 161.87 (ab, C); nmax (KBr) cm
15.71 (Kve, ]CH ), 130.76 (Cve, CH), 143.18 (Cve,
:
CH ), 49.15 (Kve, CH ), 110.55 (ab, C-5), 124.55 (Cve,
3 2
]CH), 131.23 (Cve, ]CH), 139.76 (Cve, CH-6), 151.49
2
K1

4012
V. Malik et al. / Tetrahedron 61 (2005) 4009–4014
3
5
(
requires 180.0899.
ab, C), 164.65 (ab, C); HRMS found: 180.0898 C H N O
2
236.0351, C H ClN O requires 236.0353. found
11 9 2 2
9
12
2
3
7
238.0323 C H ClN O requires 238.0323.
11 9 2 2
4
.2.7. 1-(3-Phenyl-allyl)-5-methyl-1H-pyrimidine-2,4-
dione (4c). 68%; Light yellow crystals, mp 208 8C
4
(
.2.12. 1-(4-Chlorobenzyl)-1H-pyrimidine-2,4-dione
6d). 81%; White solid, mp 180 8C (ethanol); H NMR
1
1
(
ethanol); H NMR (CDCl ): d 1.86 (3H, s, CH ), 4.49 (d,
3 3
(CDCl CTFA): d 4.94 (2H, s, NCH ), 5.97 (1H, d, JZ
3
2
1
3
JZ6.4 Hz, 2H, NCH ), 6.24 (1H, dt, J Z6.4 Hz, J Z
2
1
2
7.8 Hz, H-5), 7.25–7.37 (5H, m, 4!ArH, H-6); C
normal/DEPT-135) (CDCl CTFA): d 51.83 (Kve,
1
s, H-6), 7.21–7.34 (5H, m, ArH), 8.68 (1H, bs, NH,
5.8 Hz, ]CH), 6.62 (1H, d, JZ15.8 Hz, ]CH), 7.04 (1H,
(
NCH ), 102.76 (Cve, CH-5), 129.59 (Cve, ArCH),
3
2
1
exchanges with D O); C NMR (normal/DEPT-135)
3
2
129.63(Cve, ArCH), 131.98 (ab, ArC), 135.40 (ab, ArC),
146.27 (Cve, CH-6), 151.99 (ab, C), 166.47 (ab, C); HRMS
found: 236.0352, C H ClN O requires 236.0353. found
(
(
1
]
1
CDCl ): d 11.83 (Cve, CH ), 48.74 (Kve, CH ), 109.94
3 3 2
3
9
5
ab, C-5), 122.75 (Cve, ArCH), 126.03 (Cve, ArCH),
27.61 (Cve, ]CH), 128.13 (Cve, ArCH), 133.29 (Cve,
CH), 135.45 (ab, C), 139.63 (Cve, CH-6), 150.82 (ab, C),
64.42 (ab, C); HRMS found: 241.1051 C H N O
1
1
2 2
3
7
2
38.0325 C H ClN O requires 238.0323.
11 9 2 2
1
4
14
2
2
4
7
.2.13. 1-(4-Fluorobenzyl)-1H-pyrimidine-2,4-dione (6e).
0%; White solid, mp 230 8C (ethanol); H NMR (CDCl C
requires 241.1055.
1
3
TFA): d 4.97 (2H, s, NCH ), 6.04 (1H, d, JZ7.8 Hz, H-5),
2
4.2.8. 1-(3-Ethoxycarbonyl-allyl)-5-methyl-1H-pyri-
midine-2,4-dione (4d). 64%; White solid, mp 105 8C
7
.10 (2H, t, JZ8.4 Hz, (CH) CF), 7.28–7.38 (2H, m, 2!
2
13
ArH), 7.43 (1H, d, JZ7.8 Hz, H-6); C (normal/DEPT-
35) (CDCl CTFA): d 51.71 (Kve, NCH ), 102.71 (Cve,
1
(
ethanol); H NMR (CDCl ): d 1.30 (3H, t, JZ7.2 Hz,
3
1
3
2
CH ), 1.92 (3H, s, CH ), 4.20 (2H, q, JZ7.2 Hz, OCH ),
2
3
3
2
CH-5), 116.34 (Cve, d, JZ21.6 Hz, CH-CF), 129.40 (ab,
4
.48 (2H, dd, J Z5.2 Hz, J Z1.8 Hz, NCH ), 5.91 (1H, dt,
4
3
1
2
2
d, JZ3 Hz, C-F), 130.29 (Cve, d, JZ8.7 Hz, CH-CF),
45.98 (Cve, CH-6), 151.90 (ab, C), 161.452, 164.75 (ab, d,
J Z1.8 Hz, J Z16 Hz, ]CH), 6.88 (1H, dt, J Z5.2 Hz,
1
2
1
1
J Z16 Hz, ]CH), 6.96 (1H, s, H-6), 8.50 (1H, bs, NH,
2
JZ247 Hz, C-F), 166.33 (ab, C); HRMS found: 220.0645,
1
3
exchanges with D O); C NMR (normal/DEPT-135)
2
C H FN O requires 220.0648.
1
1
9
2 2
(
(
(
(
CDCl ): d 12.18 (Cve, CH ), 14.05 (Cve, CH ), 50.44
3 3 3
Kve, CH ), 60.67 (Kve, CH ), 110.99 (ab, C-5), 123.69
2
2
4
(
.2.14. 1-(2,4-Dichlorobenzyl)-1H-pyrimidine-2,4-dione
6f). 69%; White solid, mp 140 8C (ethanol); H NMR
Cve, CH), 139.58 (Cve, CH), 140.58 (Cve, CH), 150.82
ab, C), 164.57 (ab, C), 165.45 (ab, C); HRMS found:
1
(
CDCl CTFA): d 5.09 (2H, s, NCH ), 6.00 (1H, d, JZ
3
2
2
38.0957 C H N O requires 238.0954.
11 14 2 4
7
7
.8 Hz, H-5), 7.25–7.46 (3H, m, ArH), 7.51 (1H, d, JZ
13
.8 Hz, H-6); C(normal/DEPT-135) (CDCl CTFA): d
3
4.2.9. 1-Benzyl-1H-pyrimidine-2,4-dione (6a). 87%;
White solid, mp 160 8C (ethanol), H NMR (CDCl ): d
1
49.72 (Kve, NCH ), 102.32 (Cve, CH-5), 128.03 (Cve,
2
3
ArCH), 129.70 (ab, ArC), 130.08 (Cve, ArCH), 132.29
(Cve, ArCH), 134.54 (ab, ArC), 136.18 (ab, ArC), 146.23
(Cve, CH-6), 151.61(ab, C), 166.12 (ab, C); HRMS
4
.94 (2H, NCH ), 5.72 (1H, d, JZ7.9 Hz, H-5), 7.17 (1H, d,
2
JZ7.9 Hz, H-6), 7.31–7.42 (5H, m, ArH), 9.01 (1H, bs, NH,
1
exchanges with D O); C NMR (normal/DEPT-135)
3
2
C
found: 292.9853 (M CNa) C H Cl N O Na requires
35
8
1
1
2 2 2
(
CDCl CTFA): d 52.30 (Kve, CH ), 102.67 (Cve, CH-
3 2
2
92.9855.
5
), 128.16 (Cve, ArCH), 129.17 (Cve, ArCH), 129.37
(
1
Cve, ArCH), 133.48 (ab, ArC), 146.04 (Cve, CH-6),
51.94 (ab, C), 166.19 (ab, C); HRMS found: 202.0741,
C H N O requires 202.0742.
4
6
.2.15. 1-(2-Nitrobenzyl)-1H-pyrimidine-2,4-dione (6g).
8%; Light yellow solid, mp 120 8C (ethanol); H NMR
1
1
1 10 2 2
(
CDCl CTFA) d: 5.12 (2H, s, NCH ), 6.04 (1H, d, JZ
3
2
7
.8 Hz, H-5), 7.41 (1H, d, JZ8.0 Hz, ArH-3), 7.55 (1H, d,
4
.2.10. 1-(2-Chlorobenzyl)-1H-pyrimidine-2,4-dione
1
JZ7.8 Hz, H-6), 7.59 (1H, t, JZ8.0 Hz, ArH-4), 772 (1H, t,
JZ8.0 Hz, ArH-5), 8.15 (1H, t, JZ8.0 Hz, ArH-3); C
NMR (normal/DEPT-135) (CDCl CTFA) d: 50.09 (Kve,
(
(
6b). 74%; White solid, mp 210 8C (ethanol); H NMR
CDCl CTFA): d 5.11 (2H, s, NCH ), 6.04 (1H, d, JZ
1
3
3
2
7
7
4
.8 Hz, H-5), 7.25–7.47 (4H, m, ArH), 7.54 (1H, d, JZ
3
1
3
.8 Hz, H-6); C (normal/DEPT-135) (CDCl CTFA): d
CH ), 102.82 (Cve, C-5), 125.88 (Cve, ArCH), 130.17
2
3
(
Cve, ArCH), 130.36 (Cve, ArCH), 134.56 (Cve, ArCH),
9.98 (Kve, CH ), 102.28 (Cve, CH-5), 127.70 (Cve,
2
1
1
35.08 (ab, ArC), 146.86 (Cve, CH-6), 147.87 (ab, C),
51.62 (ab, C), 166.26 (ab, C); HRMS found: 247.0654
ArCH), 130.23 (Cve, ArCH), 130.74 (Cve, ArCH), 131.09
ab, ArC), 131.34 (Cve, ArCH), 133.86 (ab, ArC),
46.23(Cve, CH-6), 151.66 (ab, C), 166.17 (ab, C);
(
1
C H N O requires 247.0593.
11 9 3 4
3
9
5
HRMS found: 236.0358 C H ClN O requires 236.0353.
2 2
1
1
3
9
7
found 238.0327 C H ClN O requires 238.0323.
1
1
2 2
4.2.16. 1-(2,4,6-Trimethylbenzyl)-1H-pyrimidine-2,4-
dione (6h). 62%; White solid, mp 230 8C (ethanol); H
1
4
.2.11. 1-(3-Chlorobenzyl)-1H-pyrimidine-2,4-dione
NMR (CDCl ): d 2.24 (6H, s, 2!CH ), 2.30 (3H, s, CH ),
3
3
3
1
(
(
6c). 81%; White solid, mp 140 8C (ethanol); H NMR
CDCl CTFA): d 4.87 (2H, s, NCH ), 5.69 (1H, d, JZ
4.90 (2H, s, NCH ), 5.54 (1H, d, JZ8.0 Hz, H-5), 6.66 (1H,
2
d, JZ8.0 Hz, H-6), 6.93 (2H, s, ArH), 9.12 (1H, b, NH,
3
2
1
exchanges with D O); C NMR (normal/DEPT-135)
3
7
m, ArH); C (normal/DEPT-135) (CDCl CTFA): d 51.84
.8 Hz, H-5), 7.18 (1H, d, JZ7.8 Hz, H-6), 7.25–7.35 (4H,
2
1
3
(CDCl ): d 19.73 (Cve, CH ), 21.02 (Cve, CH ), 44.81
3
3
3
3
(
Kve, CH ), 102.96 (Cve, CH-5), 126.24 (Cve, ArCH),
2
(Kve, CH ), 101.94 (Cve, CH-5), 126.27 (ab, ArC), 129.82
2
128.23 (Cve, ArCH), 129.51 (Cve, ArCH), 130.77 (Cve,
ArCH), 131.5 (ab, ArC), 135.41 (ab, ArC), 146.09 (Cve,
CH-6), 152.00 (ab, C), 166.40 (ab, C); HRMS found:
(Cve, ArCH), 138.27 (ab, ArC), 139.24 (ab, ArC), 141.36
(Cve, CH-6), 151.68 (ab, C), 162.08 (ab, C); HRMS found:
244.1213, C H N O requires 244.1212.
1
4 16 2 2

V. Malik et al. / Tetrahedron 61 (2005) 4009–4014
4013
4.2.17. 1-(2-Chlorobenzyl)-5-methyl-1H-pyrimidine-2,4-
dione (6i). 87%; White soild, mp 132 8C (ethanol); H NMR
138.57 (ab, ArC), 141.05 (Cve, CH-6), 151.28 (ab, C),
163.72 (ab, C); HRMS found: 216.0901 C H N O
2 12 2 2
1
1
(
7
CDCl CTFA): d 1.97 (3H, s, CH ), 5.12 (2H, s, NCH ),
3
requires 216.0899.
3
2
1
3
.28–7.51 (5H, m, 4!ArHCH-6); C (normal/DEPT-135)
(
1
CDCl CTFA): d 11.94 (Cve, CH ), 50.01 (Kve, CH ),
3
12.32 (ab, C-5), 127.82 (Cve, ArCH), 130.38 (Cve,
4.2.22. 1-Benzhydryl-1H-pyrimidine-2,4-dione (9b).
70%; White solid, mp 180 8C (ethanol); H NMR
3
2
1
ArCH), 130.90 (Cve, ArCH), 131.10 (ab, ArC), 133.90 (ab,
ArC), 142.66 (Cve, CH-6), 152.46 (ab, C), 166.66 (ab, C);
HRMS found: 250.0513 C H ClN O requires 250.0509.
(CDCl ): d 5.67 (1H, d, JZ7.8 Hz, H-5), 7.07 (1H, d, JZ
3
7.0 Hz, H-6), 7.13–7.36 (11H, m, ArHCCH), 9.53 (1H, bs,
ArH, exchanges with D O); C NMR (normal/DEPT-135)
3
11
5
13
1
2
2
2
2
3
7
found: 252.0488 C H ClN O requires 252.0479.
1
(CDCl ) d: 62.19 (Cve, CH), 102.06 (Cve, C-5), 128.38
3
2
11
2
2
(
137.49 (ab, C), 142.39 (Cve, CH-6), 151.21 (ab, C), 163.71
Cve, ArCH), 128.44 (Cve, ArCH), 129.00 (Cve, ArCH),
4
2
.2.18. 1-(2,4-Dichlorobenzyl)-5-methyl-1H-pyrimidine-
,4-dione (6j). 85%; White solid, mp 140 8C (ethanol); H
1
(ab, C; HRMS found: 278.1055, C H N O requires
7 14 2 2
1
NMR (CDCl CTFA): d 1.99 (3H, s, CH ), 5.09 (2H, s,
3
278.1055.
3
1
NCH ), 7.32–7.51 (5 H, m, 4!ArHCH-6); C NMR
3
2
(
4
1
normal/DEPT-135) (CDCl CTFA): d 11.98 (Cve, CH ),
3
9.48 (Kve, CH ), 108.73 (ab, C-5), 127.95 (Cve, ArCH),
2
29.85 (ab, ArC), 129.98 (Cve, ArCH), 131.81 (Cve,
4.2.23. 1-(4-Chlorophenyl phenyl methyl)-1H-pyri-
midine-2,4-dione (9c). 65%; Thick yellow oil; H NMR
3
1
(CDCl ): d 5.68 (1H, d, JZ8.4 Hz, H-5), 7.06 (1H, d, JZ
3
ArCH), 134.53 (ab, ArC), 136.24 (ab, ArC), 142.29 (Cve,
CH-6), 152.33 (ab, C), 166.41 (ab, C); HRMS found:
8.4 Hz, CH-6), 7.11–7.42 (10H, m, 9!ArHCCH),
9.47(1H, bs, NH, exchanges with D O); C NMR
(normal/DEPT-135) (CDCl ): d 61.32 (Cve, CH), 102.31
3
1
3
2
3
5
2
2
84.0119, C H Cl N O requires 284.0119. found
1
2
10
2
2
2
3
5
37
86.0094, C H Cl ClN O requires 286.0089.
1
2
10
2 2
(Cve, CH-5), 126.49 (Cve, ArCH), 128.38 (Cve, ArCH),
128.74 (Cve, ArCH), 129.21 (Cve, ArCH), 129.60 (Cve,
ArCH), 134.45 (ab, ArC), 136.06 (ab, ArC), 141.95 (Cve,
CH-6) 151.13 9 (ab, C), 163.46 (ab, C).
4.2.19. 1,3-Bis(2-chlorobenzyl)-1H,3H-pyrimidine-2,4-
dione (7a). White solid, mp 74 8C; FAB Mass m/z 361,
C
1
3
63, 365 (100: 62: 10) (M ); H NMR (CDCl ): d 4.97 (2H,
3
s, CH ), 5.22 (2H, s, CH ), 5.74 (1H, d, JZ7.8 Hz, 5-H),
4.2.24. 1-(1-Phenyl-ethyl)-5-methyl-1H-pyrimidine-2,4-
dione (9d). 78%; White solid, mp 110 8C (ethanol); H
2
2
1
6
.91–7.01(1H, m, ArH), 7.11–7.17 (2H, m, ArH), 7.24–7.43
4H, m, 5 ArH, C-6H), C (normal/DEPT-135) (CDCl ): d
1
3
(
NMR (CDCl ): d 1.69 (3H, d, JZ7.0 Hz, CH ), 1.84 (3H, s,
3
3
3
4
1
2.23 (Kve, CH ), 49.95 (Kve, CH ), 101.81 (Cve, CH),
2
26.59 (Cve, ArCH), 126.73 (Cve, ArCH), 127.42 (Cve,
CH ), 6.02 (1H, q, JZ7.0 Hz, CH), 6.82 (1H, s, H-6), 7.27–
2
3
7.39 (5H, m, ArH), 9.58 (1H, bs, NH, exchanges with D O);
C NMR (normal/DEPT-135) (CDCl ): d 11.94 (Cve,
3
2
1
3
ArCH), 128.23 (Cve, ArCH), 129.55 (Cve, ArCH), 129.97
Cve, ArCH), 130.57 (Cve, ArCH), 132.94 (Cve, ArCH),
32.58 (ab, C), 132.94 (ab, C),133.58 (ab, C), 133.93 (ab,
(
1
CH ), 17.99 (Cve, CH ), 55.66 (Cve, CH), 112.67 (ab,
3 3
C-5), 127.38 (Cve, ArCH), 129.42 (Cve, ArCH), 129.60
(Cve, ArCH), 137. 37 (ab, ArC), 140.35 (Cve, CH-6),
152.58 (ab, C]O)), 166.80 (ab, C]O); HRMS found:
230.1057 C H N O requires 230.1055.
C), 142.31 (Cve, CH), 151.49 (ab, C), 162.63 (ab,
C).(found: C, 59.63; H, 3.62; N, 7.42%; C H Cl N O
2 2 2
requires C, 59.66; H, 3.86; N, 7.73%).
1
8
14
1
3 14 2 2
4
2
.2.20. 1,3-Bis(2,4-dichlorobenzyl)-1H,3H-pyrimidine-
,4-dione (7b). 72%; White solid, mp 72 8C; FAB mass
4.2.25. 1-Benzhydryl-5-methyl-1H-pyrimidine-2,4-dione
(9e). 80%; White solid, mp 180 8C (ethanol); H NMR
1
C
1
m/z 429, 431, 433, 435 (78:100: 50:12) (M ); H NMR
CDCl ): d 5.01 (2H, s, CH ), 5.21 (2H, s, CH ), 5.85 (1H, d,
(CDCl ): d 1.93 (3H, s, CH ), 6.88 (1H,s, CH), 7.07 (1H, s,
3
3
(
H-6), 7.14–7.41 (10H, m, ArH), 9.52 (1H, b, NH, exchanges
3
2
2
1
3
JZ7.8 Hz, C5H), 6.91(1H, d, JZ8.0 Hz, ArH), 7.15 (1H, d,
JZ8.0 Hz, ArH), 7.24–7.51 (5H, m, 4!ArH, C-6H). The
decoupling of C-5H doublet at d 5.85 converts d 7.37
with D O); C NMR (normal/DEPT-135) (CDCl ): d 12.18
2 3
(Cve, CH ), 64.19 (Cve, CH), 111.96 (ab, C-5), 128.51
3
(Cve, ArCH), 129.26 (Cve, ArCH), 129.50 (Cve, ArCH),
136.28 (ab, ArC), 143.02 (Cve, CH-6), 152.61 (ab, C]O),
166.53 (ab, C]O); HRMS found: 292.1214, C H N O
18 16 2 2
1
3
doublet into singlet;
C NMR (normal/DEPT-135)
CDCl ): d 41.88 (Kve, CH ), 49.71 (Kve, CH ), 101.97
(
(
3
2
2
Cve, CH), 127.07 (Cve, ArCH), 127.80 (Cve, ArCH),
27.99 (Cve, ArCH), 129.41 (Cve, ArCH), 129.82 (Cve,
ArCH), 131.11 (ab, C), 131.71 (Cve, ArCH), 132.31 (ab,
requires 292.1212.
1
4.2.26. 1-Anthracen-9-ylmethyl-1H-pyrimidine-2,4-
dione (11a). 84%; Yellow solid, mp 240 8C (ethanol);
C), 133.46 (ab, C), 133.73 (ab, C), 134.28 (ab, C), 135.39
(
ab, C), 142.40 (Cve, CH), 151.41 (ab, C), 162.49 (ab, C).
Found: C, 49.84; H, 2.42; N, 6.21%. C H Cl N O
UV–vis (CH CN): l
3
387(3 6300), 367(3 7100), 349(3
max
1
4800), 333(3 2400); H NMR (CDCl CTFA) d: 5.71 (1H, d,
(
requires C, 50.12; H, 2.78; N, 6.50%).
1
8
12
4
2
2
3
JZ7.8 Hz, H-5), 5.97 (2H, s, NCH ), 6.86 (1H, d, JZ
2
8.0 Hz, H-6), 7.56-7.68 (4H, m, ArH), 8.06 (2H, d, JZ
4
6
1
5
7
.2.21. 1-(1-Phenyl-ethyl)-1H-pyrimidine-2,4-dione (9a).
8.4 Hz, ArH), 8.10 (2H, d, JZ8.4 Hz, ArH), 8.64 (1H, s,
1
9%; White solid, mp 85 8C (ethanol); H NMR (CDCl ): d
13
ArH); C (normal/DEPT-135) (CDCl CTFA): d 43.34
3
3
.70 (3H, d, JZ7.2 Hz, CH ), 5.66 (1H, d, JZ8.0 Hz, H-5),
(Kve, NCH ), 102.01 (Cve, CH-5), 120.95 (ab, ArC),
2
3
.99 (1H, q, JZ7.2 Hz, CH), 7.03 (1H, d, JZ8.0 Hz, H-6),
.24-7.37 (5H, m, ArH), 9.26 (1H, bs, NH, exchanges with
122.07 (Cve, ArCH), 125.90 (Cve, ArCH), 128.70 (Cve,
ArCH), 130.04 (Cve, ArCH), 131.18 (Cve, ArCH), 131.56
(ab, ArC), 131.68 (ab, ArC), 145.21(Cve, CH-6), 153.47
(ab, C]O), 167.47 (ab, C]O); HRMS found: 302.1056,
C H N O requires 302.1055.
1
3
D O); C (normal/DEPT-135) (CDCl ): d 18.33 (Cve,
2
CH ), 53.20 (Cve, CH), 102.66 (Cve, CH-5), 127.18
3
3
(
Cve, ArCH), 128.32 (Cve, ArCH), 128.99 (Cve, ArCH),
1
9 14 2 2

4014
V. Malik et al. / Tetrahedron 61 (2005) 4009–4014
4
.2.27. 1-Anthracen-9-ylmethyl-5-methyl-1H-pyrimi-
dine-2,4-dione (11b). 80%; Yellow solid, mp 260 8C
ethanol); UV–vis (CH CN): l 387(3 7500), 367(3
Natl. Acad. Sci. U.S.A. 1994, 91, 3911–3915. (b) Spence,
R. A.; Kati, W. M.; Anderson, K. S.; Johnson, K. A. Science
1995, 267, 988–993. (c) Ding, J.; Das, K.; Moerless, H.;
Koymans, L.; Andries, K.; Janseen, P. A. J.; Hughes, S. H.;
Arnold, E. Nat. Struct. Biol. 1995, 2, 407–415. (d) Ren, J.;
Esnouf, R.; Garman, E.; Somers, D.; Ross, C.; Kirby, I.;
Keeling, J.; Darby, G.; Jones, Y.; Stammers, D. Nat. Struct.
Biol. 1995, 2, 293–302.
(
3
max
1
7
TFA): d 1.58 (3H, s, CH ), 5.92 (2H, s, NCH ), 6.65 (1H, s,
H-6), 7.53–7.69 (4H, m, ArH), 8.06 (4H, t, JZ8.4 Hz, ArH),
8
TFA): d 11.95 (Cve, CH ), 43.22 (Kve, CH ), 111.96 (ab,
800), 349(3 4800), 333(3 1600); H NMR (CDCl C
3
3
2
1
3
.64 (1H, s, ArH); C NMR (normal/DEPT-135) (CDCl C
3
3
2
CH-5), 121.85 (ab,ArC), 122.20 (Cve, ArCH), 125.61
Cve, ArCH), 128.32 (Cve, ArCH), 129.74 (Cve, ArCH),
4. Nisho, M.; Hirota, M.; Umerzawa, Y. The CH–p Interactions;
Wile-VCH: New York, 1988.
(
1
30.67 (Cve, ArCH), 131.44 (ab, ArC), 131.46 (ab, ArC),
40.01 (Cve, CH-6), 152.40 (ab, C]O), 166.21 (ab,
5. (a) Lawrence, D. S.; Copper, J. E.; Smith, C. D. J. Med. Chem.
2001, 44, 594–601. (b) Sarhar, S.; Zhang, C.; Moran, E.;
Krane, S.; Rodrate, J. C.; Benbatoul, K. D.; Dixon, R.; Mjalli,
A. M. M. Bioorg. Med. Chem. Lett. 2000, 10, 2599–2601. (c)
Liu, L.; Stelmach, J. E.; Natarajan, S. R.; Chen, M.; Singh,
S. B.; Schwaartz, C. D.; Fitzgerald, C. E.; O’Keefe, S. J.;
Zaller, D. M.; Schmatz, D. M.; Doherty, J. B. Bioorg. Med.
Chem. Lett. 2003, 12, 3979–3982.
1
C]O); HRMS found: 316.1207, C H N O requires
3
2
0 16 2 2
16.1212.
Acknowledgements
We thank CSIR, New Delhi for financial assistance
and DST, New Delhi for the FIST programme. Mass
spectrometery laboratory, University of Alberta is acknowl-
edged for providing the high resolution mass spectral
facility.
6. (a) Gokel, G. W. Chem. Commun. 2003, 2847–2852. (b) De
Wall, S. L.; Meadows, E. S.; Barbour, L. J.; Gokel, G. W.
J. Am. Chem. Soc. 1999, 121, 5613–5614. (c) Meadows, E. S.;
De Wall, S. L.; Barbour, L. J.; Gokel, G. W. J. Am. Chem. Soc.
2001, 123, 3092–3107.
7
. Kumpf, R. A.; Dougherty, D. A. Science 1993, 261,
708–1710.
1
8
. Only reports on the synthesis of 1,3-bis(1-uracilylmethyl)
benzene derivatives as calixarene synthons are available (a)
Kumar, S.; Hundal, G.; Paul, D.; Singh, M. S.; Singh, H.
J. Org. Chem. 1999, 64, 7717–7726. (b) Kumar, S.; Paul, D.;
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1
Plexitas, r.; Vilarroyea, M. Tetrahedron Lett. 1994, 35,
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12. (a) Wittenberg, E. Chem. Ber. 1968, 101, 2132–2142. (b)
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. (a) Smerdon, S. J.; Jager, J.; Wang, J.; Kohlstaedt, L. A.;
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