Conformational chirality and chiral crystallization of N-sulfonylpyrimidine derivatives

Article abstract of DOI:10.1016/j.tet.2006.10.048

New N-sulfonylpyrimidine derivatives 1-(p-toluenesulfonyl)uracil (1), 1-(p-toluenesulfonyl)thymine (2), 5-bromo-1-(p-toluenesulfonyl)uracil (3), 1-(methanesulfonyl)uracil (4), 1-(1-naphthylsulfonyl)uracil (5), and 1-(1-naphthylsulfonyl)thymine (6) were pr

Full text of DOI:10.1016/j.tet.2006.10.048

Tetrahedron 63 (2007) 86–92
Conformational chirality and chiral crystallization
of N-sulfonylpyrimidine derivatives
a
Aleksandar Visnjevac, Mladen Zinic, Marija Luic, Dinko Ziher, Tanja Kajfez Novak
a
a
b
c
ˇ
ˇ
´
and Biserka Zinic
´
ꢀ
ꢀ
a,
ˇ
*
´
a
ˇ
´
Ru;er Boskovic Institute, PO Box 180, HR-10002 Zagreb, Croatia
b
´
Pliva Research Institute Ltd, Prilaz baruna Filipovica 29, 10000 Zagreb, Croatia
cFaculty of Science, University of Zagreb, Horvatovac 102A, 10000 Zagreb, Croatia
Received 18 July 2006; revised 29 September 2006; accepted 19 October 2006
Available online 9 November 2006
Abstract—New N-sulfonylpyrimidine derivatives 1-(p-toluenesulfonyl)uracil (1), 1-(p-toluenesulfonyl)thymine (2), 5-bromo-1-(p-toluene-
sulfonyl)uracil (3), 1-(methanesulfonyl)uracil (4), 1-(1-naphthylsulfonyl)uracil (5), and 1-(1-naphthylsulfonyl)thymine (6) were prepared by
the condensation reaction of silylated pyrimidine derivatives with selected sulfonyl chlorides in acetonitrile. Some members of the series
showed unexpected crystal properties as a consequence of their conformational chirality in the solid state. Compounds 1 and 5 exhibited chiral
crystallization, which was, in the case of 1, accompanied by the formation of racemically twinned crystals regardless of the solvent used, while
5 gave a conglomerate of enantiomorphous crystals. For 2, 3, and 6, substituents at the C-5 position of the pyrimidine ring prevented chiral
crystallization by influencing the crystal packing. Analysis of the crystal structures of 1, 4, and 5, reveals the influence of the arylsulfonyl
group on the occurrence or absence of chiral crystallization.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
chiral crystallization from achiral compounds is very low
(only 8%).5
Spontaneous resolution of racemates by crystallization giv-
ing conglomerates of enantiomorphous crystals is an old
and well known phenomenon, now belonging to the classics
of stereochemistry.1–3 However, there are averylimitednum-
ber of apparently achiral organic molecules lacking any ele-
ment of chirality (center, axes, or plane), which can adopt
chiral conformation that could be ‘frozen’ in the solid state.
In such a case, conglomerates of chiral crystals could be
obtained and the phenomenon represents an example of
spontaneous generation of chirality.4,5 In addition, the achiral
molecules could be chirally organized in the solid state by
various non-covalent intermolecular interactions. The lat-
ter case exemplifies a supramolecular chirality that could
also give conglomerates of enantiomorphous crystals.6,7
Spontaneous generation of chiral crystals has important
implications for the themes such as the occurrence of homo-
chirality in nature,8 enantioselective synthesis starting from
achiral compounds,9–12 crystal engineering,13,14 and the pre-
paration of chiral advanced materials possessing a long range
order.15,16 However, the probability of the appearance of
Recently, we have prepared a series of novel pyrimidine de-
rivatives I (Fig. 1) possessing a sulfonamide and a nucleic
base pharmacophore, which exhibit strong antitumor activity
and ability to induce apoptosis in treated tumor cells.17–20
Crystal structures of the N-sulfonylpyrimidine derivatives
1–6 (Fig. 1) revealed that such molecules can adopt chiral
conformations possessing M and P helicities (Fig. 2) that
O
O
O
R
R
HN
O
HN
O
HN
O
z
O
N
S
O
N
S
H
O
O
N
S
N
O
O
O
O
CH3
N
S
'
R
O
Z = O or NH
CH3
R = H
R = CH3
5
4
I
R = H
1
2
6
Keywords: N-1-Sulfonylpyrimidine derivatives; Conformational (molecu-
lar) chirality; Spontaneous resolution; Racemic twinning.
* Corresponding author. Tel.: +385 1 456 10 66; fax: +385 1 468 01 95;
e-mail: bzinic@irb.hr
R = CH3
R = Br
3
Figure 1. N-Sulfonylpyrimidines I and structures of derivatives 1–6.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.10.048

A. Viꢀsnjevac et al. / Tetrahedron 63 (2007) 86–92
87
O
OSiMe3
R
O
O
CH3
CH3
R
R
R'-SO2-Cl
NH
BSA
N
HN
O
HN
CH3CN
N
S
O
Me3SiO
N
O
N
S
O
N
H
O
O
R'
O
O
O
S
S
R'-SO2-Cl / Py
Scheme 1. Synthesis of N-sulfonylpyrimidine derivatives.
1 - 6
O
O
O
O
P-1
CH3
M-1
1
Figure 2. Chiral conformations of N-sulfonylpyrimidine 1 with M- and
P-helicity.
involved bromination of 1-(p-toluenesulfonyl)uracil (1) us-
ing bromine in CH2Cl2/DMF at room temperature gave 3
in comparable yield of 54%. The second route used conden-
sation of 5-bromouracil with tosyl chloride in pyridine giv-
ing 3 after several recrystallizations from methanol in an
even lower yield (45%). Condensation of silylated uracil
with methanesulfonyl chloride or 1-naphthalenesulfonyl
chloride gave the corresponding 1-(methanesulfonyl)uracil
(4) in 75% yield and 1-(1-naphthylsulfonyl)uracil (5) in
81% yield. Reactionof silylatedthyminewith1-naphthalene-
sulfonyl chloride gave 1-(1-naphthylsulfonyl)thymine (6) in
78% yield.
could be frozen in the crystalline state. Here, we present the
crystallographic evidence that some members of the series
crystallize as conglomerates of enantiomorphous crystals,
racemically twinned crystals, or simply as racemic single
crystals, depending on the presence or absence of the C-5 py-
rimidine substituents and the size of R0 of the R0SO2– groups.
To the best of our knowledge, the phenomenon of chiral crys-
tallization has not been described so far for the compounds of
N-1-arylsulfonylpyrimidine type and the results presented
here may endow new examples for the phenomenon based
on a general arylsulfonyl-nucleic base type of structure.
2.2. Molecular and crystal structures
2. Results and discussion
2.1. Synthesis
Table 1 summarizes the basic crystallographic data for com-
pounds 1–6. 1-(p-Toluenesulfonyl)uracil (1) was found to
exhibit the formation of racemically twinned crystals con-
taining various portions of enantiomerically related blocks
(space group P212121), regardless of the solvent used for
crystallization. Evaporation of THF gave crystals of two dis-
tinct morphologies, prisms, and rods. Full sphere X-ray data
collection was performed on several crystals of both mor-
phologies, and Flack parameters were determined. Typical
prisms contain roughly 50% of each homomeric crystal do-
main, whereas a minor domain contribution ranges roughly
from 10 to 40% in rod-shaped crystals. Slow evaporation
from DMSO solution gave crystals of a single morphology
and the Flack parameter corresponding to the minor domain
contribution of less than 25%. The crystals were not of su-
preme quality and the Flack parameters are somewhat poorly
refined, thus, only the data for the structure with roughly
50% of each crystal block are presented in the Table 1.
As regards biological activity, the N-sulfonylpyrimidine de-
rivatives are interesting compounds since they represent
a combination of biologically active sulfonylcyclourea and
nucleic acid base components.21–28 Despite extensive bio-
logical activities of the components, only very few reports
on the synthesis of derivatives combining both active com-
ponents in the molecule can be found in the literature. Mar-
tirosyan et al.29 isolated 1-(p-toluenesulfonyl)uracil as an
unwanted product in the transformation of the C-4 keto
group of uracil, and Kaldrikyn et al.30 examined the synthe-
sis of 1-p-alkoxybenzenesulfonyl-5-bromouracil derivatives
possessing antibacterial activity. According to Tada,31 ben-
zoyl and arenylsulfonyl-5-fluorouracil derivatives are more
active and less toxic than 1-(2-tetrahydrofuryl)uracil in the
leukemia L/1210 system. Synthesis and in vitro anticancer
activity of 1-sulfonylcytosine derivatives were described in
the patent.19
Unlike 1, crystallization of 1-(p-toluenesulfonyl)thymine
(2), differing from 1 only in a methyl group at the C-5 posi-
tion of the pyrimidine ring, gives rise to racemic single crys-
tals with the space group Pbca. Comparison of cell
parameters of 1 and 2 reveals that the cell of 2 is twice as
large as that of 1, by doubling of one crystallographic axis
(Table 1). A closer insight into the crystal packing of both
compounds offers the explanation. In 1 (Fig. 3), N3 of mol-
ecule A is directed toward O4 of molecule B, generated by
the symmetry operation of the 21 screw axis parallel to c.
N3 of molecule B is oriented toward the O4 of the next mol-
ecule C, again generated by the same screw axis operation,
etc. In such a way, endless N3H/O4 hydrogen bonded
homochiral molecular ribbons are formed. A possible sub-
stituent at position C-5 of the pyrimidine ring of molecule
B would obviously disturb such molecular organization, be-
ing too close to the O4 of the neighboring molecule and
Two methods previously described for this series of com-
pounds were used for the preparation of 1–6: (a) condensa-
tion of silylated pyrimidine bases with selected sulfonyl
chlorides in acetonitrile, and (b) reaction of pyrimidine bases
with sulfonyl chlorides in pyridine.17–19 Silylation of uracil
(R¼H), thymine (R¼CH3), and 5-bromouracil (R¼Br) was
accomplished with bis(trimethylsilyl)acetamide (BSA) in
acetonitrile at 80 ꢀC (Scheme 1).
Silylated derivatives were condensed with p-toluenesulfonyl
chloride, giving 1-(p-toluenesulfonyl)uracil (1) (95%), 1-(p-
toluenesulfonyl)thymine (2) (86%), and 5-bromo-1-(p-tol-
uenesulfonyl)uracil (3) (57%). To improve the overall yield,
compound 3 was also prepared by two other routes. The first

88
A. Viꢀsnjevac et al. / Tetrahedron 63 (2007) 86–92
Table 1. Crystallographic data of N-sulfonylpyrimidine derivatives 1–6
Compound
1
2
3
4
5
6
Mol. formula
Mr
C11H10N2O4S
266.06
C12H12N2O4S
280.31
C11H9BrN2O4S
345.17
C5H6N2O4S
190.18
C14H10N2O4S
302.3
C15H12N2O4S
316.33
Crystal system
Space group
Orthorhombic
P212121
6.8883(3)
12.3467(5)
13.5068(4)
90.00
1148.72(8)
4
1.540
Orthorhombic
Pbca
12.8617(5)
13.8495(5)
14.1720(6)
90.00
2524.43(17)
8
1.475
Monoclinic
P21/a
Monoclinic
P21/c
Orthorhombic
P212121
6.971(2)
10.568(3)
18.076(4)
90.00
1331.7(6)
4
1.508
Monoclinic
P21/c
˚
a/A
4.9562(2)
23.540(10)
11.2432(8)
101.847(5)
1283.8(6)
4
6.8490(2)
8.9117(4)
12.9350(4)
102.381(2)
771.14(5)
4
11.8733(5)
5.5842(3)
21.4698(13)
100.976(4)
1397.14(13)
4
˚
b/A
˚
c/A
b/ꢀ
˚
V/A
3
Z
Dx/g cmꢁ3
1.786
1.638
1.503
Solvent used
Crystal color
Crystal dim. (mm)
m (Cu Ka)/mmꢁ1
Absorption corr.
Total data
Unique data
Observed data
Rint
Methanol
Colorless
0.12ꢂ0.14ꢂ0.15
2.621
None
29,252
2609
2193
0.0789
0.0615
76.49
Methanol
Colorless
0.13ꢂ0.14ꢂ0.15
2.414
J-Scans
2644
2644
2007
0.0000
0.0253
76.38
Methanol
Colorless
0.10ꢂ0.12ꢂ0.18
6.022
J-Scans
2999
2686
1620
0.0515
0.0922
76.25
Methanol
Colorless
0.18ꢂ0.20ꢂ0.24
3.623
J-Scans
1692
1619
1506
0.0927
0.0189
76.33
Methanol
Colorless
0.10ꢂ0.12ꢂ0.16
2.342
None
3098
2651
2473
0.0221
0.0278
76.51
Methanol
Colorless
0.10ꢂ0.15ꢂ0.18
2.258
J-Scans
2999
2914
2092
0.0325
0.0399
76.30
Rs
qmax
ꢀ
/
hkl limits
ꢁ8/8; ꢁ16/16;
ꢁ17/17
0.075, 0.071a
0.137, 0.132a
1.191, 1.084a
0.44(3), 0.45(3)b
164
ꢁ17/0; ꢁ16/0;
0/6; 0/29;
ꢁ14/13
0.0610
0.1557
1.081
—
173
0.66, ꢁ0.68
ꢁ8/8; 0/11;
ꢁ8/8; ꢁ13/13;
ꢁ22/22
0.0295
0.0770
1.073
0.004(18)
191
0.21, ꢁ0.22
ꢁ14/14; 0/7;
ꢁ27/0
0.0487
0.1427
1.008
—
203
0.39, ꢁ0.30
0/17
0.0426
0/16
0.0483
R1 [Fo>4s(Fo)]
wR2 (F2), all data
Goodness of fit
Flack parameter
Variables
0.1268
1.027
—
175
0.1326
1.118
—
122
ꢁ3
˚
Dr max, Drmin/eA
0.30, ꢁ0.25
0.26, ꢁ0.19
0.55, ꢁ0.59
a
The values obtained with the TWIN/BASF refinement.
BASF parameter.
b
hence producing strong repulsive interactions. One of the
possible solutions to avoid repulsion and reestablish the sus-
tainable structure would be the rotation of the pyrimidine
ring of molecule B by 180ꢀ. This motion changes the chiral-
ity of molecule B, and brings its N3H into the position to
donate a hydrogen bond to the O4 of molecule A, hence
forming the hydrogen bonded heterochiral molecular dimer
AB. This is precisely the molecular arrangement observed in
the structure of 2. Compound 2 crystallizes in a centro-
symmetric space group, with the crystal structure being
dominated by molecular dimers instead of the zigzag homo-
chiral ribbons like in 1.
packing of 5-bromo-1-(p-toluenesulfonyl)uracil (3) (Fig. 4),
expectedly, greatly resembles that of 2. In this compound,
position C-5 of the pyrimidine ring is occupied by a bromine
atom, which, like the methyl group in 2, prevents the forma-
tion of homochiral zigzag ribbons and causes the formation
of packed heterochiral dimers. Hence, no spontaneous
resolution was observed for 3 either.
In order to investigatewhether the size and type of the substit-
uent at the sulfonyl group could possibly trigger crystalliza-
tion of the conglomerate, the synthesis and structural studies
of 1-(methanesulfonyl)uracil (4) and 1-(1-naphthylsul-
fonyl)uracil (5) were performed. Unlike the case of 1, which
revealed the formation of racemically twinned crystals, its
analogue with a small methyl substituent (CH3–SO2–),
Similar phenomena occurring in some structurally different
sulfonyl compounds were recently reported.32,33 Crystal
Figure 3. Crystal packing of 1-(p-toluenesulfonyl)uracil (1).
Figure 4. Crystal packing of 5-bromo-1-(p-toluenesulfonyl)uracil (3).

A. Viꢀsnjevac et al. / Tetrahedron 63 (2007) 86–92
89
compound 4 crystallizes in a centrosymmetric space group
P21/c. Crystal packing relies on the centrosymmetric dimers.
We assumed that the introduction of an Ar–SO2– substituent,
sufficiently large to raise the racemization barrier above the
value enabling a fast spontaneous enantiomeric interconver-
sion, would result in enantiomerically pure single crystals.34
Indeed, the randomly selected single crystal (denoted 51) of
the naphthyl analogue 5 exhibited spontaneous chiral crystal-
lization (space group P212121). As demonstrated by the Flack
parameter refinement, no racemic twinning like that in 1 was
observed. The crystal and molecular structure of 51 revealed
the exclusive presence of homochiral molecules possessing
the M helicity (Fig. 2).
(Fig. 2). Analysis of crystal structures of derivatives possess-
ing pyrimidine C-5 substituents (2, 3, and 6) shows that these
derivatives organize in the solid state into heterochiral meso-
dimers, giving centrosymmetric crystals of the racemic
compound. In contrast, the absence of pyrimidine C-5 sub-
stituents in 1 and 5 results in the formation of racemically
twinned crystals regardless of the solvent used and the for-
mation of the conglomerate of the enantiomerically pure
crystals, respectively. Two randomly chosen single crystals
of 5 gave mirror like solid-state CD spectra confirming the
presence of the conglomerate of enantiomerically pure sin-
gle crystals. The solid-state supramolecular organization of
1 and 5 is similar, showing in each case the formation of in-
finite ribbons of intermolecularly hydrogen bonded homo-
chiral molecules. Analysis of such organization reveals
that it would be energetically much less favorable for the de-
rivatives with C-5 pyrimidine substituents 2, 3, and 6 due to
steric repulsion between the carbonyl O4 atom and the sub-
stituent in the C-5 position, as seen for the A/C and B/D
molecules in Figure 3. The size and the structure of the sulfo-
nylsubstituents (R0, see Fig. 1) also have a profound influence
on the occurrence of chiral crystallization. In the series
methanesulfonyl 4, p-toluenesulfonyl 1, and 1-naphthylsul-
fonyl 5, the racemic compound, the racemically twinned
crystals containing various portions of enantiomerically re-
lated blocks and the conglomerate of the enantiomorphous
crystals were obtained, respectively. The results presented
here along with the observed substituent effects may endow
the preparation of various new molecules of the general
arylsulfonyl-nucleic base type capable of undergoing chiral
crystallization and provide new examples of spontaneous
generationof chirality bycrystallization of achiral molecules.
The presence of the conglomerate of 5 is additionally proven
by the CD of solid pellets prepared by grinding the single
crystal 51 and randomly selected another single crystal 52
with KBr.35 Strong negative (51) and strong positive (52)
CD peaks at l¼250 nm and two less intensive ones at 278
and 330 nm were observed, which correspond to lmax in
the absorption spectrum of 5 in acetonitrile (Fig. 5). In con-
trast, dissolution of each 51 or 52 crystal sample in aceto-
nitrile showed no CD peaks, pointing to fast equilibrium
between the two enantiomeric conformers in solution.
The crystal packing of 5 is analogous to that of compound
1, with the molecules connected through hydrogen bonds
N3–H/O4i, into endless homochiral ribbons. Derivative
6, differing from 5 only in a methyl group at position C-5
of the pyrimidine ring, crystallized in P21/c, with the centro-
symmetric H-bonded dimers as the main structural motif. Its
structure proved again the important role of the C-5 substi-
tuent for the absence or occurrence of spontaneous resolu-
tion in this class of compounds.
4. Experimental
3. Conclusions
4.1. General remarks
N-1-Sulfonyluracil derivatives 1–6 were prepared by the
condensation of silylated pyrimidine bases with different
sulfonyl chlorides in acetonitrile. We present the crystallo-
graphic evidence that this type of sulfonylpyrimidines ex-
hibit conformational chirality in the solid state by the
formation of chiral conformations of opposite helicity
Solvents were distilled from appropriate drying agents
shortly before use. TLC was carried out on DC-plastikfolien
Kieselgel 60 F254 and preparative thick layer (2 mm) chro-
matography was done on Merck 60 F254. Flash column
chromatography was performed on silica gel Merck
0.040–0.063 mm. Melting points were determined on a
Kofler hot-stage apparatus and were uncorrected. UV spec-
tra [lmax/nm, log 3/dm3 molꢁ1 cmꢁ1] were taken on a Philips
PU8700 UV–Vis spectrophotometer. IR spectra were ob-
tained as KBr pellets on a Perkin–Elmer 297 spectropho-
tometer. 1H and 13C NMR spectra were recorded in
DMSO-d6 on a Bruker AV 300 and 600 MHz spectrometers
using TMS or DMSO-d6 as the internal standard.
3
2
8
7
6
5
4
3
2
1
1
0
4.2. Synthesis
-1
-2
-3
4.2.1. Reactions of silylated pyrimidine bases with differ-
ent sulfonyl chlorides. General procedure. A mixture of
pyrimidine base (1 mmol) and N,O-bis(trimethylsilyl)aceta-
mide (BSA) (2 mmol) was heated under reflux in dry aceto-
nitrile (3.3 mL) for 1 h. The solution was cooled to 0 ꢀC and
sulfonyl chloride (2 mmol) was added. The reaction mixture
was heated for 20 h at 80 ꢀC, cooled, and treated with a small
amount of methanol. The resulting solid was filtered off and
recrystallized.
0
450
210
240
270
3
00
330
360
390
420
/ nm
Figure 5. Solid-state CD spectra of 1-(1-naphthylsulfonyl)uracil (5)/KBr
pellet: 51 (solid line, c¼4.966ꢂ10ꢁ3 mol dmꢁ3, l¼0.5 mm) and 52 (dashed
line, c¼3.384ꢂ10ꢁ3 mol dmꢁ3, l¼0.5 mm). Solid-state absorption spectra
of 51 (dotted line, c¼4.966ꢂ10ꢁ3 mol dmꢁ3, l¼0.5 mm).

90
A. Viꢀsnjevac et al. / Tetrahedron 63 (2007) 86–92
4.2.2. 1-(p-Toluenesulfonyl)uracil (1). Starting materials:
uracil (1 g, 8.9 mmol) and p-toluenesulfonyl chloride (3.39 g,
17.8 mmol). Recrystallization from hot methanol gave 1-
[(4-methylphenyl)sulfonyl]pyrimidine-2,4(1H,3H)-dione (1),
2.25 g (95%) as white crystals: mp¼259 ꢀC (lit.29 mp¼238–
239 ꢀC); Rf ¼0.65 (CH2Cl2/MeOH, 9:1); UV (MeOH):
lmax/nm: 235 and 249 (log 3/dm3 molꢁ1 cmꢁ1: 3.78 and
3.81); lit.29 lmax¼256 nm (log 3/dm3 molꢁ1 cmꢁ1: 3.95).
molꢁ1 cmꢁ1: 3.05 and 3.02); IR (KBr) nmax/cmꢁ1: 3150
(w), 3050 (w), 2920 (w), 2840 (w), 1750 (s), 1675 (s),
1610 (m), 1590 (m), 1420 (m), 1250 (s), 1175 (s), 1080
(m), 1060 (m), 995 (m); 1H NMR (DMSO-d6) d/ppm:
12.12 (s, 1H, NH), 8.43 (s, 1H, H-6), 8.00 (d, 2H,
J¼8.1 Hz, Ts-b), 7.51 (d, 2H, J¼8.1 Hz, Ts-c), 2.44 (s,
3H, CH3); 13C NMR (DMSO-d6) d/ppm: 159.06 (s, C-4),
146.77 (s, C-2), 146.65 (s, Ts-d), 136.88 (d, C-6), 132.86
(s, Ts-a), 129.94 (d, Ts-c), 129.35 (d, Ts-b), 98.91 (s, C-5),
21.32 (q, CH3). Anal. Calcd for C11H9N2O4SBr
(Mr¼345.17): C 38.28, H 2.63, N 8.12; found: C 38.34, H
2.47, N 8.10%.
Additional data for 1-(p-toluenesulfonyl)uracil 1: IR (KBr)
nmax/cmꢁ1: 3120 (w), 3030 (w), 2830 (w), 1730 (s), 1700
(s), 1615 (w), 1595 (w), 1405 (m), 1355 (m), 1250 (s),
1
1190 (s), 1170 (s), 1030 (m), 680 (m), 655 (m); H NMR
(DMSO-d6) d/ppm: 11.74 (s, 1H, NH), 8.15 (d, 1H,
J6,5¼8.4 Hz, H-6), 7.93 (d, 2H, J¼8.3 Hz, Ts-b), 7.50 (d,
2H, J¼8.3 Hz, Ts-c), 5.86 (d, 1H, J5,6¼8.4 Hz, H-5), 2.42
(s, 3H, CH3); 13C NMR (DMSO-d6) d/ppm: 163.07 (s,
C-4), 147.54 (s, C-2), 146.64 (s, Ts-d), 138.26 (d, C-6),
133.42 (s, Ts-a), 130.16 (d, Ts-c), 129.19 (d, Ts-b), 104.05
(d, C-5), 21.27 (q, CH3). Anal. Calcd for C11H10N2O4S
(Mr¼266.22): C 49.63, H 3.79, N 10.53; found: C 49.62,
H 3.65, N 10.51%.
4.2.4.2. Bromination of 1-(p-toluenesulfonyl)uracil (1).
1-(p-Toluenesulfonyl)uracil 1 (200 mg, 0.75 mmol) was dis-
solved in dry DMF (13 mL), and a solution of bromine in
dichloromethane (2.2 mL, 1.65 mmol; 1 mL Br2/25 mL
CH2Cl2) was added dropwise. The red solution was stirred
at room temperature for 4 h, and the solvent was evaporated
under pressure. Ethanol was added into the remaining oil,
and the obtained solid was filtered off and recrystallized
from hot water, yielding product 3, as white crystals,
140 mg (54%), identical to those obtained by the method
in Section 4.2.4.1.
The phenyl proton (Ts) assignments were confirmed by car-
bon–proton connectivity in the 1H/13C heteronuclear corre-
lation spectra (HETCOR). Additionally, in the NOESY
spectrum of 1, the assignment of Ts-c protons was proved
by their interaction with methyl protons.
4.2.4.3. Reaction of 5-bromouracil with p-toluenesul-
fonyl chloride in pyridine. A solution of 5-bromouracil
(2) (2 g, 10.5 mmol) in dry pyridine (40 mL) was cooled
to 0 ꢀC and p-toluenesulfonyl chloride (4 g, 21 mmol) was
added. After stirring at room temperature overnight, the re-
sulting dark suspension was evaporated under pressure.
Methanol was added and the obtained brown solid was fil-
tered off. After a few recrystallizations from the hot metha-
nol/water mixture (1:1), product 3 was obtained in 45%
yield.
4.2.3. 1-(p-Toluenesulfonyl)thymine (2). Starting mate-
rials: thymine (1 g, 7.93 mmol) and p-toluenesulfonyl chlo-
ride (3.02 g, 15.86 mmol). The reaction mixture was
evaporated under reduced pressure and the residue was
treated with methylene chloride and filtered. The filtrate
was washed with water and the organic layer was dried over
anhydrous sodium sulfate. The filtrate was evaporated under
reduced pressure, and the crude product was recrystallized
from methylene chloride/hexane mixture yielding 5-methyl-
1-[(4-methylphenyl)sulfonyl]pyrimidine-2,4(1H,3H)-dione
(2) as white crystals: 1.91 g (86%); mp¼118–120 ꢀC; Rf¼0.8
(CH2Cl2/MeOH, 9:1); UV (MeOH) lmax/nm: 233 and 252
4.2.5. 1-(Methanesulfonyl)uracil (4). Starting materials:
uracil (0.5 g, 4.45 mmol) and methanesulfonyl chloride
(0.69 mL, 8.9 mmol). Recrystallization from hot methanol
gave the analytically pure product 1-(methylsulfonyl)-
pyrimidine-2,4(1H,3H)-dione (4) as white crystals: 7.6 g
(75%); mp¼228–231 ꢀC; Rf ¼0.81 (CH2Cl2/MeOH, 3:1);
(log 3/dm3 molꢁ1 cmꢁ1: 3.85 and 3.92); IR (KBr) nmax/cmꢁ1
:
3174 (w), 3053 (w), 2824 (w), 1728 (s), 1675 (s), 1590 (m),
1416 (m), 1331 (s), 1251 (s), 1167 (s), 1082 (s), 1034 (s),
987 (s), 886 (m), 812 (m), 743 (m), 674 (m); H NMR
UV (MeOH) lmax/nm: 211 and 245 (log 3/dm3 molꢁ1 cmꢁ1
:
3.86 and 3.93); IR (KBr) nmax/cmꢁ1: 3200 (m), 3080 (m),
2950 (w), 2850 (w), 1725 (s), 1695 (s), 1640 (m), 1440 (s),
1360 (s), 1275 (s), 1180 (s), 1170 (s), 970 (s), 820 (m), 780
1
(DMSO-d6) d/ppm: 11.74 (s, 1H, NH), 8.04 (d, 1H,
J¼1.3 Hz, H-6), 7.91 (d, 2H, J¼8.1 Hz, Ts-b), 7.49 (d, 2H,
J¼8.1 Hz, Ts-c), 2.43 (s, 3H, CH3-Ts) 1.86 (d, 3H, J¼1.3 Hz,
C-5–CH3); 13C NMR (DMSO-d6) d/ppm: 163.48 (s, C-4),
147.28 (s, C-2), 146.10 (s, Ts-d), 133.44 (s, Ts-a), 132.97
(d, C-6), 129.81 (d, Ts-c), 128.75 (d, Ts-b), 111.54 (s, C-5),
21.15 (q, CH3-Ts), 12.12 (q, C-5–CH3). Anal. Calcd for
C12H12N2O4S (Mr¼280.30): C 51.42, H 4.32, N 9.99; found:
C 51.39, H 4.36, N 10.02%.
1
(m), 760 (m); H NMR (DMSO-d6) d/ppm: 11.87 (s, 1H,
NH), 7.87 (d, 1H, J¼8.3 Hz, H-6), 5.80 (d, 1H, J¼8.3 Hz,
H-5), 3.70 (s, 3H, CH3); 13C NMR (DMSO-d6) d/ppm:
163.28 (s, C-4), 148.76 (s, C-2), 138.23 (d, C-6), 103.41
(d, C-5), 41.62 (q, CH3). Anal. Calcd for C5H6N2O4S
(Mr¼190.18): C 31.58, H 3.18, N 14.73; found: C 31.81,
H 3.06, N 14.89%.
4.2.6. 1-(1-Naphthylsulfonyl)uracil (5). Starting materials:
uracil (0.5 g, 4.46 mmol) and 1-naphthalenesulfonyl chlo-
ride (2.08 g, 8.92 mmol). The reaction mixture was evapo-
rated under reduced pressure and the residue was treated
with methylene chloride and filtered. The filtrate was
washed with water and the organic layer was dried over an-
hydrous sodium sulfate. The filtrate was evaporated under
reduced pressure, and the crude product was recrystallized
from methylene chloride/methanol mixture yielding
4.2.4. 5-Bromo-1-(p-toluenesulfonyl)uracil (3).
4.2.4.1. General procedure. Starting materials: 5-bro-
mouracil (1 g, 5.24 mmol) and p-toluenesulfonyl chloride
(2 g, 10.48 mmol). Recrystallization from a hot mixture
methanol/water (1:1) gave 5-bromo-1-[(4-methylphenyl)-
sulfonyl]pyrimidine-2,4(1H,3H)-dione (3) as white crystals:
1.03 g (57%); mp¼248–250 ꢀC; Rf ¼0.63 (CH2Cl2/MeOH,
20:1); UV (MeOH) lmax/nm: 233 and 270 (log 3/dm3

A. Viꢀsnjevac et al. / Tetrahedron 63 (2007) 86–92
Table 2. CD and absorption bands in crystal samples of 5
91
1-(1-naphthylsulfonyl)pyrimidine-2,4(1H,3H)-dione (5) as
white crystals: 1.09 g (81%); mp¼185–186 ꢀC; Rf ¼0.71
(CH2Cl2/MeOH, 9:1); UV (MeOH): lmax/nm: 209, 233,
300, and 321 (log 3/dm3 molꢁ1 cmꢁ1: 4.75, 4.62, 4.00, and
3.79); IR (KBr) nmax/cmꢁ1: 3430 (w), 3031 (w), 2840 (w),
1733 (s), 1697 (s), 1558 (w), 1542 (w), 1460 (m), 1243 (s),
51
52
51
CD
CD
A
l
3
l
3
l
3
(nm) (mmolꢁ1 cm2) (nm) (mmolꢁ1 cm2) (nm) (mmolꢁ1 cm2)
1
1176 (m), 1089 (m) 1032 (w), 750 (m), 580 (s); H NMR
249
277
299
ꢁ2.7
250
276.5 0.64
298 1.31
318.5 1.06
329 1.2
2.55
ꢁ0.43
ꢁ1.22
(DMSO-d6) d/ppm: 11.73 (s, 1H, NH), 8.54 (pt, 2H, Ph,
H-6), 8.47 (d, 1H, Ph), 8.21 (br d, 2H, Ph), 7.80 (m, 2H,
Ph), 7.72 (t, 1H, Ph), 5.94 (d, 1H, J5,6¼8.4 Hz, H-5); 13C
NMR (DMSO-d6) d/ppm: 162.54 (s, C-4), 147.06 (s, C-2),
138.01 (d, C-6), 136.92 (d, Ph), 133.97 (d, Ph), 133.59 (s,
Ph), 130.61 (s, Ph), 129.81 (d, Ph), 129.55 (d, Ph), 127.36
(d, Ph), 126.87 (s, Ph), 124.60 (d, Ph), 122.25 (d, Ph),
104.10 (d, C-5). Anal. Calcd for C14H10N2O4S (Mr¼
302.31): C 55.62, H 3.33, N 9.27; found: C 55.59, H 3.38,
N 9.30%.
319.5 ꢁ0.99
301.5 2134.6
329
ꢁ1.23
610050; 4, CCDC 610051; 5, CCDC 610052; 6, CCDC
610053). Copies of the data can be obtained, free of charge,
on application to CCDC, 12 Union Road, Cambridge CB12
1EZ, UK [fax: +44 1223 336033 or e-mail: deposit@ccdc.
cam.ac.uk].
4.4. CD spectroscopy
4.2.7. 1-(1-Naphthylsulfonyl)thymine (6). Starting mate-
rials: thymine (0.5 g, 3.96 mmol) and 1-naphthalenesulfonyl
chloride (1.85 g, 7.92 mmol). The reaction mixture was
evaporated under reduced pressure and the residue was
treated with methylene chloride and filtered. The filtrate
was washed with water and the organic layer was dried
over anhydrous sodium sulfate. The filtrate was evaporated
under reduced pressure, and the crude product was recrys-
tallized from hot methanol yielding 5-methyl-1-(1-naphthyl-
sulfonyl)pyrimidine-2,4(1H,3H)-dione (6) as white crystals:
0.98 g (78%); mp¼155–157 ꢀC; Rf ¼0.87 (CH2Cl2/MeOH,
9:1); UV (MeOH): lmax/nm: 232, 254, 300, and 321 (log 3/
dm3 molꢁ1 cmꢁ1: 4.62, 4.14, 4.08, and 3.84); IR (KBr)
nmax/cmꢁ1: 3448 (m), 3040 (w), 2850 (w), 1735 (s), 1672
(s), 1427 (m), 1370 (m), 1257 (s), 1174 (s), 1181 (m),
1038 (m), 765 (m), 686 (m), 579 (s); 1H NMR (DMSO-d6)
d/ppm: 11.70 (s, 1H, NH), 8.51–8.40 (m, 3H, Ph and H-6),
8.25–8.17 (m, 2H, Ph), 7.77–7.68 (m, 3H, Ph), 1.94 (s, 3H,
CH3); 13C NMR (DMSO-d6) d/ppm: 163.38 (s, C-4),
147.14 (s, C-2), 136.65 (d, Ph), 133.65 (d, Ph), 133.52 (s,
Ph), 132.69 (d, C-6), 130.95 (s, Ph), 129.67 (d, Ph), 129.43
(d, Ph), 127.26 (d, Ph), 126.87 (s, Ph), 124.52 (d, Ph),
122.38 (d, Ph), 112.01 (s, C-5), 12.13 (q, CH3). Anal. Calcd
for C15H12N2O4S (Mr¼316.33): C 56.95, H 3.82, N 8.86;
found: C 56.91, H 3.80, N 8.81%.
Thesolid-state circular dichroism spectra of the singlecrystal
51 whose crystal structure was determined and the randomly
selected another single crystal 52 from the same batch were
recorded as KBr discs on a JASCO J-810 spectropolarimeter.
For each sample, the KBr disc was rotated atw30ꢀ intervals
and at least fivespectra were averaged to cancel the inevitable
slight inhomogeneities in the disc. The value of D3, given in
CD spectra was calculated by using the concentration as mo-
larity of the sample in KBr after correction for density of KBr
disc, and using measured thickness of the KBr disc (by
micrometer) as a path length (Table 2). Use of absorption
for calibration is not recommended, because the absolute
value is unreliable due to light scattering.40
Acknowledgements
We thank the Ministry of Science, Education, and Sport of
the Republic of Croatia for financial support of this study.
Supplementary data
Supplementary data, including ortep plots for compounds
1–6 and crystal packing for compounds 2, 4, 5, and 6 can
be found in the online version. Supplementary data associ-
ated with this article can be found in the online version, at
doi:10.1016/j.tet.2006.10.048.
4.3. X-ray structural analysis
Data collection was done on an Enraf Nonius CAD4 diffrac-
tometer using the graphite monochromated Cu Ka radiation.
The structures were solved with SIR9735 and refined with
SHELXL97.36 The models were refined using the full matrix
least squares refinement. The atomic scattering factors were
those included in SHELXL97. Hydrogen atoms were refined
as the riding entities, except for those included in hydrogen
bonds, which were located in the Fourier maps and freely
refined. In the final steps of refinement, the proposed weight-
ing schemes were applied. Molecular geometry calculations
were performed with PLATON,37 and molecular graphics
were prepared using ORTEP-338 and CCDC-Mercury.39
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