Cytosine modules in quadruple hydrogen bonded arrays

Article abstract of DOI:10.1039/c0nj00197j

Cytosine modules have been investigated for applications in supramolecular quadruple hydrogen bonded arrays. Notably, the importance of the C-5-H in the formation of unfolded and folded arrays by substitution to C-5-F was established. In addition, the incorporation of different alkyl chain lengths at N-1 and N-9 indicated that longer alkyl chains give rise to more of the unfolded rotamer, with the chain length and degree of unsaturation at N-1 having the major effect. Methyl cytosine modules were also able to readily form hetero-associated Upy-UCyt dimers as efficiently as the hexyl cytosine modules and a polyadipate telechelic polymer was used to prepare cytosine polymers.

Full text of DOI:10.1039/c0nj00197j

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Cytosine modules in quadruple hydrogen bonded arrays
a
a
a
b
Elisabetta Greco, Abil E. Aliev, Valerie G. H. Lafitte, Kason Bala,
b
b
b
a
David Duncan, Laura Pilon, Peter Golding and Helen C. Hailes*
Received (in Montpellier, France) 15th March 2010, Accepted 5th June 2010
DOI: 10.1039/c0nj00197j
Cytosine modules have been investigated for applications in supramolecular quadruple hydrogen
bonded arrays. Notably, the importance of the C-5–H in the formation of unfolded and folded
arrays by substitution to C-5–F was established. In addition, the incorporation of different alkyl
chain lengths at N-1 and N-9 indicated that longer alkyl chains give rise to more of the unfolded
rotamer, with the chain length and degree of unsaturation at N-1 having the major effect.
Methyl cytosine modules were also able to readily form hetero-associated Upy–UCyt dimers as
efficiently as the hexyl cytosine modules and a polyadipate telechelic polymer was used to
prepare cytosine polymers.
In addition, studies investigating heterodimeric arrays
Introduction
between 1 and 3 suggested that the UCyt DDAA unit
competed well with the Upy module. One advantage of
modules such as the ureidocytosines is that they can readily
be functionalised at N-1, enabling the introduction of alter-
native moieties or properties into the arrays. In our current
work we have investigated the effect of substituting the
hydrogen at C-5 with fluorine, to determine the effect on the
ratio of unfolded to folded conformers. Also alternative side
groups at N-1 were introduced with a view to understanding
the behaviour of the modules and identifying suitable modules
for applications in polymer synthesis.
The design of supramolecular arrays based on non-covalent
interactions, particularly hydrogen bonds, holds significant
potential for the synthesis of new materials. For the range of
properties required from supramolecular materials, there is a
need for strong hydrogen bonded modules, which can be used
in polymer or co-polymer synthesis via the self- or hetero-
1
–4
association of complementary units.
Self-complementary
quadruple hydrogen bonding linear arrays comprised of two
donors (DD) and two acceptors (AA), to give DDAA modules,
3
–5
have proven to be particularly effective. These include the
4
ureidopyrimidinones (UPy) 1, ureidonaphthyridine (UN) 2
3b
5
and the recently described ureidocytosine (UCyt) modules 3
reported by our group (Fig. 1). The DDAA modules reported
have several features which can influence the resulting
performance in arrays. For example, the UPy modules can
exist in three different tautomeric forms depending on the
environment and substituents attached, which can increase the
Results and discussion
In the ureido substituted cytosine, conformationally both
0
folded (3 ) and unfolded (3) forms may exist (Fig. 2), with
the desired unfolded form stabilized by quadruple hydrogen
4
bonding on dimerization. In previous work a single crystal
1
XRD of 3a (R = R = C
complexity of the species present. Despite this Upy DDAA
6
H
13) revealed that the side chain
arrays have been used in a range of polymeric materials, cyclic
carbonyl (C-8QO) and the C-5–H of the ring were nearly
planar with measured geometry in agreement with that for a
dimers have been reported, and redox materials incorporating
4
ferrocene have been described. Dimerization constants (Kdim
)
ꢀ1
5
0
7
when R is alkyl for the DDAA unit of approximately 10 M
weak hydrogen bond.
4c
Initial studies therefore investigated the role of C5-H in the
2
formation of unfolded and folded arrays by substitution at R .
3
in CDCl were observed. Modules including 2 and 3 that do
not undergo such tautomeric changes may be preferable for use
in controlled material design. However, the replacement of NH
moieties with CH groups results in removal of the intramolecular
N–HꢁꢁꢁO hydrogen bond and some conformational flexibility in
1
Two analogues were prepared possessing a methyl group at R
2
and H or F at R (Fig. 2 and Scheme 1).
There have been several reports in the literature for the
6
conversion of cytosine (4a) into 1-methylcytosine (5a).
,7
3
b,5
the ureido fragment between folded and unfolded forms.
For
was
However, the most convenient method was found to be the
use of a one-pot procedure and basic phase transfer conditions
with aqueous tetrabutylammonium hydroxide which had been
example, the Kdim for UN dimer 2ꢁ2 (R is C
4 9 3
H ) in CDCl
2
ꢀ1
1
1
.1 ꢂ 10 M but UCyt 3a (R = R = C
stable unfolded dimer 3aꢁ3a with a Kdim > 2.5 ꢂ 10 M in
CDCl with some folded dimer present (5%). The unfolded
dimer 3aꢁ3a also had a Kdim > 2 ꢂ 10 M in C
6
H13) formed the
5
–1
3
7
ꢀ1
3b,5
D .
6 6
a
Department of Chemistry, University College London,
0 Gordon Street, London, WC1H 0AJ, UK.
2
Scheme 1 Synthesis of 5a, 5b, 3b and 3c. Reagents and conditions:
E-mail: h.c.hailes@ucl.ac.uk; Fax: +44 (0)20 7679 7463;
Tel: +44 (0)20 7679 4654
AWE plc., Aldermaston, Reading, Berkshire, RG7 4PR, UK
(
4 2 2 6
i) 40% Bu NOH, CH Cl , MeI; 5a 78%, 5b 59%; (ii) C H13NCO,
b
pyr, 90 1C; 3b 87%, 3c 74%.
2
634 New J. Chem., 2010, 34, 2634–2642 This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010

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8
reported to generate 5a in 45% yield. Use of this procedure
DDAA array 3bꢁ3b with the unfolded rotamer and that a small
0
0
gave 5a in 78% after purification by recrystallisation
amount of the folded rotamer 3b ꢁ3b was also present in a
(
Scheme 1). 5-Fluorocytosine (4b) was methylated at N-1
using the same procedure to give 5-fluoro-1-methylcytosine
5b) in 59% yield. Compounds 5a and 5b were then readily
converted to the ureidocytosines 3b and 3c.
higher ratio (11 : 1) than that reported for 3a (19 : 1)
5
(Table 2). In DMSO-d , a strong hydrogen bond acceptor,
6
(
compound 3b formed the folded rotamer as has been described
for 3a, and identical chemical shifts were observed (Table 1).
1
1
The H NMR spectrum of 3b in CDCl
two hydrogen bonded protons 7-H and 9-H at 10.9 and
.0 ppm, respectively, confirming the involvement of 7-H
3
at 298 K showed the
H NMR spectroscopy data of the fluorinated analogue 3c
3
in solution indicated that in CDCl only one rotamer was
9
observed. At 298 K 7-H was not readily detected due to line
broadening and possible superimposition with the chloroform
signal. However at lower temperatures 7-H was clearly
and 9-H in a hydrogen bonding (Table 1). The chemical shifts
were comparable to that of the previously described dihexyl
1
analogue 3a (Fig. 1; R = R = C
0
6
H13) for 7-H and 9-H at
observed at 7–8 ppm, indicative of the folded rotamer 3c
1
0.9 and 9.0 ppm when in the unfolded conformation and
5
(Table 1), rather than at 11 ppm when in the DDAA array.
Chemical shifts for 9-H were similar at both 298 K and 256 K,
suggesting presence of the same folded rotamer. At low
temperatures no further rotamers were detected, and in
addition the temperature dependence of 7-H from 7.7 ppm
to 8.2 ppm at 223 K, suggested population of a double
3
aꢁ3a DDAA dimeric array. A 30 mM solution of 3b in
1
CDCl was also studied by H NMR at different temperatures
3
because line broadening, due to an exchange process, was
observed at 298 K for signals corresponding to 7-H and 9-H
and 5-H. At 256 K the signals became much sharper together
with the appearance of a second set of small signals at 9.7, 7.4
and 6.1 ppm, assignable to 9-H and 7-H (superimposed), 6-H
0
0
5
hydrogen bonded dimer (3c ꢁ3c ) on lowering the temperature.
Formation of the folded rotamer is consistent with destabilization
of the unfolded rotamer by the removal of the H-bonding
interaction between 5-H and O-8 of the cytosine unit. Upon
formation of the folded rotamer an intramolecular H-bond
between N-3 and 9-H (Fig. 2) will be formed.
0
and 5-H, respectively, of the folded rotamer 3b , in accordance
5
with a previous detailed study on 3a. The change in chemical
shift of 5-H from 7.5 ppm in unfolded 3b to 6.1 ppm in folded
0
3
b can be attributed to a loss of 5-Hꢁ ꢁ ꢁO proximity and
hydrogen bonding or magnetic anisotropy of the carbonyl
0
Previously the single crystal XRD of 3a revealed a short
intermolecular distance between C-6–H and OQC-8 which
seemed to order the dimeric system into infinite 1-D chains,
suggesting that stacking-type interactions may be important in
group. Peak integration gave a ratio of 11 : 1 for 3b : 3b
with the unfolded rotamer 3b the major species in CDCl3.
Overall these experiments indicated that 3b in CDCl formed a
3
5
the interlayer separation of the dimers. Also, the alkyl chains
1
Table 1 Chemical shift for 3a–3c for key H NMR signals
of the unit were not parallel to each other: while the hexyl
chain attached to the urea bond was in the plane of the dimer,
the hexyl group at N-1 deviated from the plane by
approximately 701. In addition to the p-stacking interactions
and inter- and intramolecular hydrogen bonding the alkyl side
chains at N-1 and N-9 may also influence dimer organisation,
particularly at N-1 due to its deviation from the plane. A range
of analogues were therefore prepared to investigate side chain
variation in the formation of the unfolded array which is
important when considering the construction of polymers
conjugated at N-1 or N-9. Different alkyl chains were selected
for attachment at N-1, where van der Waals interactions may
influence array formation, and in addition alkene and alkyne
groups for potential subsequent coupling via click or metathesis
strategies. Two different alkyl chains were attached at N-9
5
3
a d/ppm
3b d/ppm
3c d/ppm
Proton
CDCl
3
at 298 K
7.6
7.4
10.9
9.0
5
6
7
9
-H
-H
-H
-H
7.6
7.4
10.9
9.0
—
7.5
Not detected
9.1
CDCl
3
at 256 K
5
6
7
9
-H
-H
-H
-H
7.5 (6.1 folded)
7.5 (6.1 folded)
7.5 (7.4 folded)
11.0 (9.7 folded) 7.7 (8.2 at 223 K)
—
7.5 (7.4 folded)
11.1 (9.6 folded)
9.0 (9.7 folded)
7.5 (7.6 at 223 K)
9.0 (9.7 folded)
9.2 (9.3 at 223 K)
DMSO-d
6
5
6
7
9
-H
-H
-H
-H
6.2
7.9
9.7
9.0
6.2
7.9
9.7
9.0
—
8.3
9.8
9.4
0
0
Fig. 1 DDAA module dimers 1ꢁ1, 2ꢁ2, and 3ꢁ3.
Fig. 2 Unfolded and folded form of dimers 3ꢁ3 and 3 ꢁ3 .
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010 New J. Chem., 2010, 34, 2634–2642 2635

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Table 2 Compounds 3a–3m and unfolded : folded ratio in CDCl
3
highlighted a decrease in the unfolded : folded ratio with a
methyl group at N-1. For 3d, also with a Me group at N-1, but
propyl chain at N-9, a further small decrease in the ratio was
observed. By comparison, for 3i, with C H at N-1 and a
1
Compound R at N-1
a
R at N-9 Ratio unfolded : folded
5
3
3
3
3
3
3
3
3
3
3
3
3
3
a
b
c
d
e
f
g
h
i
C
6
H
13
C
C
C
C
C
C
C
C
C
C
C
C
C
6
6
6
3
3
6
3
6
3
3
6
3
6
H
H
H
H
H
H
H
H
H
H
H
H
H
13
13
13
7
19 : 1
11 : 1
R is F only folded
9 : 1
3 : 1
13 : 1
7 : 1
8 : 1
19 : 1
15 : 1
17 : 1
17 : 1
20 : 1
6
13
CH
CH
CH
CH
CH
CH
CH
C
C
C
C
C
3
3
3
2
2
2
2
2
propyl group at N-9, the ratio was 19 : 1, suggesting that the
alkyl group at N-1 has the major influence on the conformer
ratio, with the group at N-9 having a secondary (if any) effect.
CHQCH
CHQCH
CꢃCH
2
7
1
2
13
7
The other saturated longer chain analogues at R , 3j–3m,
possessed higher ratios of unfolded to folded conformers than
3b, with the propyl groups at N-9 giving slightly lower ratios
compared to hexyl moieties. This is consistent with enhanced
van der Waals interactions for longer alkyl chains at N-1,
stabilising intermolecular interactions and arrangement of the
array into the unfolded conformer. With the alkyl group at
N-9 in the plane of the dimer this is likely to have less influence
on the dimeric array, as observed.
CꢃCH
13
7
6
H
8
H
8
H
13
17
17
j
7
k
l
m
13
7
12
H
25
12
H
25
13
a
Ratio measured at 256 K (3a–3b) and 248 K (3d–3m).
since they were in the plane of the dimer in 3a and therefore
Interestingly, for the allyl analogues at N-1, 3e and 3f and
particularly for 3e, a low ratio of 3 : 1 was observed, possibly due
to unfavourable destabilising side chain interactions, although 3f
with a hexyl chain at N-9 significantly increased this ratio. The
propargyl side chain at N-1 gave rise to similar ratios for 3g and
3h (approximately 8 : 1), but again the value was lower than for
saturated alkyl chains, possibly due to unfavourable p–p inter-
actions and destabilisation of the linear AADD array. Overall,
shorter alkyl and unsaturated chains at N-1 had the most marked
effect, leading to lower unfolded : folded ratios, and the length of
the side chain at N-9 had a secondary effect on the conformer
ratio. This observation may be important when designing
polymers linked via N-1 or N-9, or bifunctional polymers. To
investigate this further, experiments with the methyl-cytosine unit
were performed and polymers prepared.
expected to have less influence on the array formed.
1
The effect of R and R on the ratio of unfolded to folded
1
conformers was assessed in detail: when R was C
6
H13 and
3 6
CH (and R was C H13) the ratios were 19 : 1 and 11 : 1
respectively. Cytosine analogues were prepared possessing
1
allyl, propargyl, hexyl, octyl and dodecyl groups at R and
propyl and hexyl urea side chains at R. Compounds 3d–3m
were prepared as outlined in Scheme 2. The one-pot procedure
and basic phase transfer conditions used to generate 5a was
also successfully used with allyl bromide and propargyl
6
9
bromide to N-1 alkylate cytosine (4a) directly to 5c and 5d,
in 45% and 81% yield respectively. This method was
attempted with the longer chain alkyl bromides, but problems
have been reported with competing O-2 as well as N-1 alkylation
9
which was observed. This is normally alleviated to some
The methyl-cytosine based modules were of interest
because they gave moderate ratios (approximately 10 : 1) of
unfolded : folded conformers, and were an ideal substrate to
therefore probe whether the conformer ratio had a significant
effect on the resulting conjugated polymers. They were also
more synthetically accessible in high yield compared to the
N-1 hexyl analogues. Initially, their use in heterodimeric
arrays was explored further with the Upy analogues 1a and
1b possessing pendant propyl and hexyl alkyl groups, which
degree by using N-4-acetylcytosine. Accordingly, N-4-acetyl-
cytosine was reacted under basic conditions with the corres-
5
ponding alkyl bromide to give 6–8. Compounds 6–8 were
then readily hydrolysed in ammoniacal methanol (7 N) to give
5
e–5g. Urea formation was achieved using hexyl isocyanate
,9
5
and propyl isocyanate in pyridine and compounds 3d–3m were
formed in 16% to 92% yield (Scheme 2, Table 2), the yield
being dependent on the scale of reaction and ease of
purification.
4
f,10
were synthesised as previously described.
This would
1
Following the low temperature H NMR method used for
establish their capacity to disrupt Upy dimerisation and assess
whether the presence of the Me group at N-1 in 3, and lower
ratio of unfolded : folder conformation present in solution,
would influence the array for applications in heterosupra-
molecular polymers. Interestingly, combinations of 1a and
3
a and 3b, experiments were performed in order to assess the
ratio of the major (unfolded) and minor (folded) rotamers and
the data are summarised in Table 2. Analysis of 3a and 3b
3
2
5
d, and 1b and 3b (Fig. 3) as a 1 : 1 mixture in CDCl3 at
56 K revealed the ratio of 1ꢁ1 : 1ꢁ3 : 3ꢁ3 as approximately
: 6 : 5 which was identical to that previously reported for 1b
5
and 3a. This indicated that the methyl-cytosine based
modules still competed well with Upy, despite the lower
3
unfolded : folded ratio observed in CDCl and that it would
be suitable for applications in supramolecular polymers.
To provide a preliminary assessment of the methyl cytosine
module compared to hexyl cytosine, and a Upy supramolecular
material for comparison purposes, polymers were prepared.
Scheme 2 Synthesis of 3a–3m. Reagents and conditions: (i) 40%
1
1
Bu
respectively; (ii) Ac
iv) NH in MeOH, 5f 79%, 5g 98%; (v) RNCO, 90 1C, 3d 92%, 3e 16%,
4 2 2
NOH, CH Cl , R Br (R = allyl, propargyl), 45% and 81%,
4g,11
1
Accordingly, 5a, 5e and 9
were reacted with 1,6-dihexyl-
2
O, pyr or purchased; (iii) R Br, 7 29%, 8 71%;
(
3
isocyanate and the monoisocyanates formed were reacted with
telechelic hydroxy terminated poly(2-methyl-1,3-propylene
3f 37%, 3g 55%, 3h 70%, 3i 63%, 3j 65%, 3k 51%, 3l 68%, 3m 68%.
2
636 New J. Chem., 2010, 34, 2634–2642 This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010

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In general, the chain length at N-9 only had a minor effect on
the rotamer ratio, although this was dependent on the group at
N-1 since for 3e and 3f the difference was more marked.
N-Methyl cytosine modules were also able to disrupt Upy
dimers and form hetero-associated Upy–UCyt dimers as
efficiently as the N-hexyl cytosine modules, indicating its
suitability for use in supramolecular polymer synthesis.
Finally, a polyadipate telechelic polymer was used to prepare
cytosine polymers which had similar properties to the
analogous Upy-based polymer. These results will be used in
future work when preparing bifunctional polymers and UCyt
materials with polymers linked via N-1.
Fig. 3 Upy 1a, 1b and UCyt 3b, 3d used in hetero-association
experiments and mixed heterodimer 1ꢁ3.
ꢀ1
adipate) (molecular weight 2000 g mol ) as a soft block,
1
2
which has previously been used with difunctional Upys. This
gave polymers 10–12 (Scheme 3) and differential scanning
calorimetry (DSC) of the polymers indicated similar glass
transition temperatures of ꢀ45 1C for 10, ꢀ49 1C for 11 and
Experimental
General methods
ꢀ
44 1C for 12.
Unless otherwise noted, solvents and reagents were reagent
grade from commercial suppliers and used without further
purification. Anhydrous solvents were obtained using anhydrous
These were comparable to a difunctional Upy polyadipate
described with a T
g
of ꢀ46 1C, and can also be compared to
of
57 1C. In addition, diffusion coefficient measurements of
0 mM solutions in CDCl were performed to compare the
degree of self-association of 11 and 12. The measured values
that of the propylene adipate prepolymer which has a T
g
1
3
1
2
alumina columns. All moisture-sensitive reactions were
performed under a nitrogen atmosphere using oven-dried
glassware. Reactions were monitored by TLC on Kieselgel
60 F254 plates with detection by UV, or permanganate, and
phosphomolybdic acid stains. Flash column chromatography
was carried out using silica gel (particle size 40–63 mm).
ꢀ
2
3
ꢀ
11
2
ꢀ1
ꢀ11
2
ꢀ1
were 5.7 ꢂ 10
m s for 11 and 2.2 ꢂ 10
m s for 12
ꢀ1
s for the telechelic polymer
ꢀ
10
2
m
(
compared to 2 ꢂ 10
5
alone). The diffusion rates were consistent with the presence
1
13
Melting points are uncorrected. H NMR and C NMR
of oligomers in solution in CDCl , and the faster diffusion rate
3
spectra were recorded in CDCl at the field indicated. J values
3
for 11 suggested there existed slightly weaker hydrogen-bonding
and polymerisation levels compared to 12. Overall, the results
from the heterodimeric arrays and polymer synthesis
confirmed that methyl cytosine-based modules can readily be
used in supramolecular synthesis, despite the lower ratio of
unfolded to folded conformers observed in solution NMR
studies.
are given in Hz.
N-4-Acetylcytosine was prepared as previously described or
1
purchased (Sigma-Aldrich). Compounds 3a, 5e, and 6 were
4
5
prepared as previously described. The Upys 1a and 1b were
4f,10
synthesised using established procedures.
2-(6-Isocyanato-
hexylaminocarbonylamino)-6-methyl-4[1H]pyrimidone was
1
prepared as previously described. Full details of methods
1
for diffusion NMR experiments (all at 298 K) were previously
15
described.
Conclusions
In summary, the role of C-5–H in the cytosine module in the
formation of unfolded and folded arrays by substitution at
2
R with F established that a weak hydrogen-bonding interaction
Synthesis
1-Methyl-4-aminopyrimidin-2-(1H)-one (1-methylcytosine)
is important to maintain the unfolded array. Substitution with
a range of groups at N-1 indicated that longer alkyl chains give
rise to more of the unfolded rotamer in solution NMR studies,
but the presence of an allyl group lowers this significantly.
2 2
5a. To cytosine (1.66 g, 15.0 mmol) in CH Cl (45 ml) was
added tetrabutylammonium hydroxide (40% in water;
9.71 ml, 15.0 mmol). Methyl iodide (8.58 g, 60.0 mmol) was
then added and the reaction stirred at rt for 18 h. Water was
2 6 2 2 2 6
Scheme 3 Synthesis of 10–12. Reagents and conditions: (i) for 5a, OCN(CH ) NCO, CH Cl , 72 h at 40 1C; for 5e and 9, OCN(CH ) NCO
CH
2 2
Cl , 18 h at 40 1C; quantitative, 90%, 77%, respectively; (ii) hydroxy terminated polyadipate, dibutyltindilaurate, heat at reflux; 30%, 65%,
40% respectively.
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010 New J. Chem., 2010, 34, 2634–2642 2637

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added (150 ml), the mixture was extracted with CH
2
Cl
2
(2H, q, J 6.8 Hz, NCH
(6H, m, 3 ꢂ CH ), 0.89 (3H, t, J 6.8 Hz, CH
(100 MHz; CDCl ) d 171.3 (NHCOCH ), 153.3 (d, J 11.8 Hz,
2 2 2
), 1.58 (2H, m, NCH CH ), 1.31
1
3
(
100 ml) and the aqueous layer was concentrated by rotary
2
3
); C NMR
evaporation. The solid residue was recrystallized from ethanol
3
2
CF
to afford 5a as a white solid (1.46 g, 78%). Mp 294–298 1C
C-4), 152.3 (C-2), 134.8 (d, JCF 242 Hz, C-5), 132.0
6
1
decomp. (EtOH) (lit. 296 1C, decomp.); H NMR (400 MHz;
DMSO-d ) d 7.54 (1H, d, J 7.1 Hz, 6-H), 6.98 (2H, br s, NH ),
(d, JCF 29.7 Hz, C-6), 40.4 (NCH ), 38.4 (CH ), 31.5 (CH ),
3
2
2
1
29.6 (CH ), 26.6 (CH ), 22.6 (CH ), 14.0 (CH ); F NMR
9
6
2
2
2
2
3
1
9
5
.59 (1H, d, J 7.1 Hz, 5-H), 3.18 (3H, s, NCH
+
26 (MH , 100%).
3
); m/z (ES+)
(282 MHz; CDCl
3
) d ꢀ169.5; F CPD NMR (282 MHz;
3
1
CDCl
3
+
)
d ꢀ169.5 (d,
JHF 6.7 Hz); m/z (CI+) 271
(
4 2
MH , 35%). 144 (100); HRMS calculated for C12H20FN O
+
MH ) 271.15702, measured 271.15725.
5
-Fluoro-1-methyl-4-aminopyrimidin-2-(1H)-one (5-fluoro-1-
methylcytosine) 5b. To 5-fluorocytosine (1.00 g, 7.70 mmol), in
5 ml of CH Cl , was added 40% tetrabutylammonium
(
3
2
2
1
-Allyl-4-aminopyrimidin-2-(1H)-one 5c. The reaction was
carried out as described above for 5a using cytosine (402 mg,
.62 mmol), CH Cl (15 ml), tetrabutylammonium hydroxide
hydroxide (40% in water; 5.00 ml, 7.72 mmol). The mixture
was stirred at rt until the 5-fluorocytosine had dissolved.
To the resulting solution, methyl iodide (4.43 g, 31.0 mmol)
was added and the reaction was stirred at rt for 18 h. Water
3
2
2
(
40% in water; 2.34 ml, 3.62 mmol) and allyl bromide (1.20 ml,
4.0 mmol). The product was recrystallized from ethanol to
afford 5c as a white solid (240 mg, 44%). Mp 241–244 1C
1
(
100 ml) was added and the mixture extracted with CH
2 2
Cl
(
100 ml). The aqueous layer was concentrated in vacuo and the
17
ꢀ1
(
EtOH) (lit. 242–245 1C);
nmax/cm
(nujol) 3245, 2934,
704, 1662; H NMR (400 MHz; DMSO-d ) d 7.54 (1H, d,
), 5.92 (1H, m, CQCHCH ),
.70 (1H, d, J 7.1 Hz, 5-H), 5.16 (1H, dd, J 10.3 and 1.5 Hz,
HHCQCH), 5.10 (1H, J 17.1 and 1.5 Hz, HHCQCH), 4.29
solid residue recrystallized from ethanol to afford 5b as a white
1
1
6
1
6
solid (0.65 g, 59%). Mp 275–280 1C (ethanol) (lit. 297–299 1C);
n
J 7.1 Hz, 6-H), 7.08 (2H, br, NH
2
2
ꢀ1
1
max/cm (solid) 3304, 3137, 3071, 1674, 1613; H NMR
5
(
400 MHz; DMSO-d
6
) d 7.92 (1H, d, JHF 6.0 Hz, 6-H), 7.48
1
3
(
1H, br s, NH), 7.31 (1H, br s, NH), 3.16 (3H, s, NCH
3
);
C
13
(
2H, m, NCH
2
); C NMR (150 MHz; CDCl
3
) d 163.0 (C-4),
);
6
NMR (75 MHz; DMSO-d ) d 157.3 (d, JCF 12.7 Hz, C-4),
155.1 (C-2), 144.1 (C-6), 130.4, 120.3, 96.7 (C-5), 50.8 (NCH
+
m/z (ES+) 152 (MH , 100%).
2
1
54.5 (C-2), 135.5 (d, JCF 240 Hz, C-5) 131.2 (d, JCF 30.7 Hz,
1
9
N); F NMR (282 MHz; DMSO-d
C-6), 36.5 (CH
1
3
6
) d ꢀ170.5;
9
3
F CPD NMR (282 MHz; CDCl
+
3
) d ꢀ170.4 (d, JHF 6.0 Hz);
1
-(Prop-2-ynyl)-4-aminopyrimidin-2-(1H)-one 5d. The reaction
was carried out as described above for 5a using cytosine
4.44 g, 40.0 mmol), CH Cl (90 ml), tetrabutylammonium
m/z (ES+) 144 (MH , 60%); HRMS calculated for
+
C H FN O (MH ) 144.05731, measured 144.05754.
5
7
3
(
2
2
hydroxide (40% in water; 25.9 ml, 40.0 mmol) and propargyl
bromide (12.7 ml, 160 mmol) and the reaction was stirred for
1
-(1-Methyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-hexyl urea
b. To a solution of 5a (200 mg, 1.60 mmol) in dry pyridine
10 ml) was added hexyl isocyanate (0.35 ml, 2.40 mmol). The
3
9
6 h. The product was recrystallized from ethanol to afford 5d as
(
9
a white solid (4.85 g, 81%). H NMR (400 MHz; DMSO-d
1
6
)
resulting yellow solution was stirred at 90 1C for 16 h. The
solution was cooled to rt, hexane was added and a white
precipitate obtained which was collected by filtration, then
washed with hexane to afford 3b as a colourless solid (350 mg,
d 7.63 (1H, d, J 7.2 Hz, 6-H), 7.20 (2H, br, NH ), 5.72
2
(1H, d, J 7.2 Hz, 5-H), 4.46 (2H, m, CH N), 3.38
2
+
(1H, t, J 2.4 Hz HCRC); m/z (ES+) 150 (MH , 100%).
ꢀ
1
1
8
3
7%). Mp 206–208 1C (pyridine/hexane); nmax/cm (solid)
214, 3044, 2958, 2926, 1696, 1642, 1621, 1599; H NMR
N-(1-Octyl-2-oxo-1,2-dihydropyrimidin-4-yl)-acetamide 7. To a
solution of N-4-acetylcytosine (1.00 g, 6.53 mmol), in dry
(
400 MHz; CDCl
3
) major rotamer d 10.85 (1H, br s,
), 8.98 (1H, br s, NHCONHCH ), 7.52
N),
.25 (2H, q, J 6.3 Hz, NHCH ), 1.58 (2H, m, CH ), 1.32
DMF (40 ml), was added anhydrous potassium carbonate
NHCONHCH
2
2
(
1.35 g, 9.80 mmol) and after 30 min 1-bromooctane
(
1H, br s, 5-H), 7.45 (1H, d, J 7.3 Hz, 6-H), 3.47 (3H, s, CH
3
(1.89 g, 9.80 mmol). The solution was heated at 80 1C for 24 h.
3
2
2
1
3
Any residual solid was then removed by filtration and the
filtrate evaporated under reduced pressure. The crude product
(
6H, m, 3 ꢂ CH ), 0.87 (3H, t, J 6.8 Hz, CH ); C NMR
2
3
(
125 MHz; CDCl ) d 165.1 (C-4), 157.7 (C-2), 154.3 (NHCONH),
3
3
was redissolved in CHCl (100 ml) and washed with (1 N) HCl
1
2
47.2 (C-6), 97.4 (C-5), 40.1 (CH N), 38.0 (NCH ), 31.5, 29.4,
2
3
+
3
6.6, 22.6, 14.0 (CH ); m/z (ES+) 275 (MNa , 100%);
+
(100 ml), water (100 ml) and saturated sodium chloride
solution (100 ml), then dried (MgSO ). The solvents were
4
HRMS calculated for C12
measured 275.14789.
20 4 2
H N NaO (MNa ) 275.14839,
evaporated in vacuo and the product purified using flash silica
chromatography (CHCl /EtOAc 5 : 1 then CHCl /MeOH 9 : 1)
3
3
1
-(5-Fluoro-1-methyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-hexyl-
urea 3c. The reaction was carried out under anhydrous
conditions. To a solution of 5b (8.34 g, 66.6 mmol) in CH Cl
250 ml) was added hexylisocyanate (64.7 ml, 400 mmol).
to give 7 as a white solid (500 mg, 29%). Mp 122–124 1C
ꢀ1
(CHCl
3
); nmax/cm
H NMR (600 MHz; CDCl
(1H, d, J 7.2 Hz, 5-H), 7.41 (1H, d, J 7.2 Hz, 6-H), 3.85
(2H, t, J 7.2 Hz, CH N), 2.30 (3H, s, COCH ), 1.73 (2H, m, CH ),
1.20 (10H, m, 5 ꢂ CH ), 0.86 (3H, t, J 6.8 Hz, CH ); C NMR
(150 MHz; CDCl ) d 171.5 (COCH ), 163.0 (C-4), 155.7 (C-2),
(solid) 3229, 2922, 2851, 1693, 1670;
1
2
2
3
) d 10.51 (1H, s, NH), 7.60
(
The reaction was stirred at 40 1C for 72 h. Hexane was added
and a white precipitate obtained. The product was collected by
filtration to afford 3c (15.1 g, 77%) as a white solid. Mp
2
3
2
1
3
2
3
3
3
ꢀ1
1
1
7
60–164 1C (hexane); nmax/cm
671, 1635; H NMR (400 MHz; CDCl ) d 9.14 (1H, br s),
(solid) 3170, 2953, 1709,
148.7 (C-6), 96.8 (C-5), 51.1 (CH N), 31.7, 29.1, 28.9, 26.5
2
1
(signals superimposed), 24.8 (CH CO), 22.6, 14.2 (CH );
3
3
3
+
+
.46 (1H, d, JHF 6.7 Hz, 6-H), 3.47 (3H, s, NCH ), 3.33
3
m/z (ES+) 266 (MH , 100%), 225 (M ꢀ C OH , 15%);
2
2
638 New J. Chem., 2010, 34, 2634–2642 This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010

View Article Online
+
(MH ) 266.18685,
HRMS calculated for
measured 266.18686.
C
14
H
24
3
N O
2
1-(1-Methyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-propyl urea
3d. To a solution of 5a (200 mg, 1.60 mmol) in dry pyridine
(
10 ml) was added propyl isocyanate (0.23 ml, 2.40 mmol). The
N-(1-Dodecyl-2-oxo-1,2-dihydropyrimidin-4-yl)-acetamide 8.
To a solution of N-4-acetylcytosine (1.00 g, 6.53 mmol) in dry
DMF (40 ml) was added anhydrous potassium carbonate (1.35 g,
reaction was stirred at 90 1C for 16 h, cooled to rt and hexane
added. A white precipitate was formed which was collected by
filtration and washed with hexane to afford 3d as a colourless
9
.80 mmol) followed after 30 min by 1-bromododecane
2.35 ml, 9.80 mmol). The solution was heated at 80 1C for
4 h. The residual solid was then removed by filtration and the
filtrate evaporated under reduced pressure. The solid was
redissolved in CHCl and washed with HCl (1 N; 100 ml),
water (100 ml) and saturated sodium chloride solution
100 ml), and the organic phase was dried (MgSO ). The
solvents were evaporated in vacuo and the crude solid purified
using flash silica chromatography (CHCl /EtOAc 5 : 1 then
CHCl /MeOH 9 : 1) to give 8 as a white solid (1.50 g, 71%).
Mp 84–86 1C (CHCl
ꢀ1
solid (310 mg, 92%). Mp 226–230 1C (pyridine/hexane); nmax/cm
(
1
solid) 3220, 3053, 2959, 1699, 1650, 1619, 1564; H NMR
(
2
(
500 MHz; CDCl
), 8.97 (1H, br s, NHCONHCH
br s, 5-H), 7.45 (1H, d, J 7.4 Hz, 6-H), 3.46 (3H, s, CH
.19 (2H, q, J 6.0 Hz, NHCH ), 1.57 (2H, m, CH ), 0.96
); C NMR (150 MHz; DMSO-d
d 162.9 (C-4), 157.0 (C-2), 154.2 (NHCONH), 149.7 (C-6),
3.6 (C-5), 39.3 (CH N), 37.1 (NCH ), 23.0, 11.7 (CH ); m/z
3
) major rotamer d 10.83 (1H, br s,
), 7.57 (1H,
N),
NHCONHCH
2
2
3
3
3
2
2
(
4
13
(
3H, t, J 7.4 Hz, CH
3
6
)
3
9
3
2
3
+
3
(
ES+) 211 (MH , 100%); HRMS calculated for C H N O
9 15 4 2
+
ꢀ
1
3
); nmax/cm (solid) 3208, 2917, 2850,
712, 1662; H NMR (600 MHz; CDCl ) d 10.85 (1H, s, NH),
(
MH ) 210.11168, measured 210.11160.
1
1
3
7
.57 (1H, d, J 7.2 Hz, 5-H), 7.36 (1H, d, J 7.2 Hz, 6-H), 3.80
1
-(1-Allyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-propyl urea 3e.
(
2H, t, J 7.2 Hz, CH N), 2.20 (3H, s, COCH ), 1.67 (2H, m,
2
3
To a solution of 5c (80 mg, 0.53 mmol) in dry pyridine (5 ml)
was added propyl isocyanate (0.07 ml, 0.76 mmol). The
reaction was stirred at 90 1C for 16 h, cooled to rt, hexane
was added and the white precipitate formed collected by
filtration then washed with hexane to afford 3e as a colourless
solid (20 mg, 16%). Mp 186–190 1C (pyridine/hexane);
CH
2
), 1.20 (18H, m, 9 ꢂ CH
2
3
), 0.80 (3H, t, J 7.0 Hz, CH );
1
3
C NMR (150 MHz; CDCl
3
) d 171.7 (COCH
3
), 163.1 (C-4),
N), 31.9, 29.5,
9.2, 29.0, 28.8, 27.4, 26.8 (signals superimposed), 25.5
1
2
55.8 (C-2), 148.7 (C-6), 96.9 (C-5), 50.9 (CH
2
+
(
CH
3
CO), 22.7, 14.0 (CH ); m/z (ES+) 322 (MH , 100%),
3
+
OH , 10); HRMS calculated for C18
2
81 (M ꢀ C
2
32 3 2
H N O
ꢀ
1
+
MH ) 322.24945, measured 322.25039.
n
max/cm
(solid) 3212, 3070, 2962, 1702, 1641, 1618;
H NMR (400 MHz; CDCl3 at 248 K) d 11.13 (1H, br s,
NHCONHCH ), 9.02 (1H, br s, NHCONHCH ), 7.59
1H, d, J 8.0 Hz, 5-H), 7.51 (1H, d, J 8.0 Hz, 6-H), 5.93
1H, m, CH QCH), 5.32 (1H, d, J 12.0 Hz, CHHQCH), 5.22
1H, d, J 16.0 Hz, CHHQCH), 4.50 (2H, d, J 4.0 Hz, NCH ),
(
1
1
-Octyl-4-aminopyrimidin-2-(1H)-one 5f. Compound
7
2
2
(
(
480 mg, 1.81 mmol) was dissolved in ammonia in MeOH
7 N; 50 ml). The solution was stirred at rt in a sealed tube for
(
(
(
2
2
4 h. The solvent was evaporated in vacuo to afford a solid.
2
Purification using flash silica chromatography (CHCl /MeOH
3
3.34 (2H, m, NHCONHCH ), 1.56 (2H, m, CH ), 0.90 (3H, m,
2
2
1
8
1
); C NMR (150 MHz; CDCl
3
9
: 1 to 7 : 1) afforded 5f (320 mg, 79%). Mp 202–204 1C
CH
3
3
) d 164.8 (C-4), 158.6 (C-2),
ꢀ
1
(
CHCl ); nmax/cm
(solid) 3346, 3106, 2925, 2854, 1654;
H NMR (600 MHz; CDCl ) d 7.30 (1H, d, J 7.0 Hz, 6-H),
.05 (1H, d, J 7.0 Hz, 5-H), 5.74 (2H, br s, NH ), 3.74 (2H, t,
J 7.1 Hz, CH N), 1.73 (2H, m, CH ),
), 1.28 (10H, m, 5 ꢂ CH
.87 (3H, t, J 6.4 Hz, CH ); C NMR (150 MHz; CDCl
d 164.6 (C-4), 156.0 (C-2), 145.8 (C-6), 94.9 (C-5), 50.2
3
2
154.3 (NHCONH), 146.3 (C-6), 131.8 (CH QCH), 119.5
1
3
(
CH QCH), 97.7 (C-5), 59.2 (NCH ), 42.0 (NCH ), 22.9,
2 2 2
1.6 (CH ); m/z (ES+) 237 (MH , 100%); HRMS calculated
3
+
+
6
2
1
2
2
2
for C H N O (MH ) 237.12733, measured 237.13515.
1
1
17
4
2
1
3
0
3
3
)
1
-(1-Allyl-2-oxo-1,2-dihydro-pyrimidin-4-yl)-3-hexyl urea 3f.
2 3
(CH N), 31.7, 29.3, 29.2, 29.0, 26.5, 22.7, 14.1 (CH ); m/z
+
(ES+) 224 (MH , 100%); HRMS calculated for C12H N O
22 3
+
(MH ) 224.17629, measured 224.17675.
To a solution of 5c (150 mg, 0.99 mmol) in dry pyridine (10 ml)
was added hexyl isocyanate (0.21 ml, 1.50 mmol). The reaction
was stirred at 90 1C for 16 h. The solution was cooled to rt,
hexane was added and a white precipitate obtained which was
collected by filtration then washed with hexane to afford 3f as a
white solid (100 mg, 37%). Mp 198–200 1C (pyridine/hexane);
1
-Dodecyl-4-aminopyrimidin-2-(1H)-one 5g. Compound 8
(
(
450 mg, 1.42 mmol) was dissolved in ammonia in MeOH
7 N; 50 ml). The solution was stirred at rt in a sealed tube for
ꢀ
1
1
2
4 h. The solvent was evaporated in vacuo to afford a solid.
nmax/cm (solid) 3212, 3054, 2928, 1699, 1654, 1614; H NMR
(400 MHz; CDCl ) d 10.91 (1H, br s, NHCONHCH ),
Purification using flash silica chromatography (CHCl /MeOH
3
3
2
9
: 1 to 7 : 1) afforded 5g as a colourless solid (390 mg, 98%).
ꢀ
8.99 (1H, br s, NHCONHCH ), 7.61 (1H, br s, 5-H), 7.44
2
1
Mp 118–123 1C (CHCl
2
3
); nmax/cm (solid) 3340, 3112, 2915,
) d 8.32 (1H, br s,
(1H, d, J 4.0 Hz, 6-H), 5.93 (1H, m, CH
J 8.0 Hz, CHHQCH), 5.26 (1H, d, J 16.0 Hz, CHHQCH),
4.47 (2H, m, NCH ), 3.26 (2H, m, NHCH ), 1.57 (2H, m,
CH ), 0.89 (3H, t, J 4.0 Hz, CH );
), 1.31 (6H, m, 3 ꢂ CH
C NMR (150 MHz; CDCl ) d 165.0 (C-4), 157.1 (C-2),
154.2 (NHCONH), 146.1 (C-6), 131.6 (CH QCH), 119.3
(CH QCH), 97.7 (C-5), 51.9 (NCH ), 40.1 (NCH ),
31.5, 29.4, 26.6, 22.6, 14.1 (CH3); m/z (FAB+) 301
2
QCH), 5.32 (1H, d,
1
847, 1657; H NMR (600 MHz; CDCl
3
NH), 7.30 (1H, d, J 7.3 Hz, 6-H), 6.15 (1H, d, J 7.3 Hz, 5-H),
.81 (1H, br s, NH), 3.73 (2H, t, J 7.4 Hz, CH N), 1.67 (2H, m,
CH ), 0.87 (3H, t, J 7.0 Hz, CH );
), 1.27 (18H, m, 9 ꢂ CH
C NMR (150 MHz; CDCl ) d 164.3 (C-4), 157.2 (C-2), 145.8
C-6), 95.2 (C-5), 50.2 (CH N), 31.8, 29.6, 29.3, 29.1 (signals
2
2
5
2
2
2
3
1
3
2
2
3
3
1
3
3
2
(
2
2
2
2
superimposed), 26.4, 22.6 (signals superimposed), 14.1 (CH );
3
+
m/z (ES+) 280 (MH , 100%); HRMS calculated for
+
+
(MNa , 50%), 279 (MH , 100%), 242 (90); HRMS calculated
+
+
C H N O (MH ) 280.23889, measured 280.23861.
for C H N O (MH ) 279.18209, measured 279.18212.
1
6
30
3
15 24
4 2
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010 New J. Chem., 2010, 34, 2634–2642 2639

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1
-(2-Oxo-1-prop-2-ynyl-1,2-dihydropyrimidin-4-yl)-3-propyl
1-(1-Octyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-propyl urea 3j.
To a solution of 5f (100 mg, 0.450 mmol) in dry pyridine (7 ml)
was added propyl isocyanate (0.06 ml, 0.67 mmol). The
reaction was stirred at 90 1C for 16 h, cooled to rt, hexane
was added and a white precipitate obtained which was
collected by filtration and washed thoroughly with hexane to
afford compound 3j as a colourless solid (90 mg, 65%). Mp
urea 3g. To a solution of 5d (150 mg, 1.00 mmol) in dry
pyridine (9 ml) was added propyl isocyanate (0.14 ml, 1.50 mmol).
The reaction was stirred at 90 1C for 16 h, then cooled down to
rt, hexane was added and a white precipitate obtained which
was collected by filtration and washed with hexane to afford 3g as
a white solid (130 mg, 55%). Mp 204–208 1C (pyridine/hexane);
ꢀ1
ꢀ1
n
1
max/cm (solid) 3292, 3211, 3050, 2966, 2295, 1699, 1651,
196–198 1C (pyridine/hexane); nmax/cm (solid) 3348, 3105,
1
1
621, 1556; H NMR (400 MHz; CDCl
), 8.89 (1H, br s, NHCONHCH
1H, d, J 7.5 Hz, 6-H), 7.69 (1H, br s, 5-H), 4.67 (2H, m,
3
) d 10.86 (1H, br s,
2925, 2854, 1698, 1654; H NMR (400 MHz; CDCl
3
) major
), 9.01 (1H, br s,
), 7.55 (1H, br, 5-H), 7.45 (1H, br d, J 8.0 Hz
6-H), 3.83 (2H, t, 4.0 Hz, CH N), 3.22 (2H, m,
NHCONHCH ), 1.72 (2H, m, CH ), 1.59 (2H, m, CH ),
1.32 (10H, m, 5 ꢂ CH ), 1.00 (3H, t, J 7.2 Hz, CH ), 0.95
NHCONHCH
2
2
), 7.82
rotamer d 10.96 (1H, s, NHCONHCH
NHCONHCH
2
(
2
NCH
2
), 3.23 (2H, m, NHCH
), 1.61 (2H, m, CH ), 0.91 (3H, t, J 7.2 Hz, CH
C NMR (150 MHz; CDCl ) d 165.3 (C-4), 156.8 (C-2), 154.2
2
), 2.56 (1H, t, J 4.0 Hz,
J
2
HCCCH
2
2
3
);
2
2
2
1
3
3
2
3
1
3
(
NHCONH), 144.9 (C-6), 98.1 (C-5), 76.6, 76.0, 42.0 (NCH ),
2
(3H, t, J 7.0 Hz, CH ); C NMR (150 MHz; CDCl ) d 164.8
3
3
+
8.8, 22.9, 11.7 (CH ); m/z (EI) 234 (M , 10%), 205 (40), 176
3
(C-4), 157.2 (C-2), 154.4 (NHCONH), 146.7 (C-6), 97.3 (C-5),
3
+
100); HRMS calculated for C H N O (M ) 234.11113,
11 14 4 2
(
50.8 (CH N), 41.9 (NCH ), 31.7, 29.1 (signals superimposed),
2
2
measured 234.11049.
29.0, 26.5, 22.7, 22.6, 14.1 (CH
3
), 11.5 (CH
3
); m/z (ES+) 331
NaO
2
+
MNa , 100%); HRMS (ES+) calculated for C16
(
(
28
H N
4
+
MNa ) 331.2110, measured 331.2105.
1
-(2-Oxo-1-prop-2-ynyl-1,2-dihydropyrimidin-4-yl)-3-hexyl
urea 3h. To a solution of 5d (1.00 g, 6.71 mmol) in dry pyridine
45 ml) was added hexyl isocyanate (1.46 ml, 10.0 mmol). The
1
-(1-Octyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-hexyl urea 3k.
(
To a solution of compound 5f (100 mg, 0.450 mmol) in dry
reaction was stirred at 90 1C for 16 h, then cooled to rt, hexane
was added and a white precipitate obtained which was
collected by filtration and washed with hexane to afford 3h as
a white solid (1.30 g, 70%). Mp 198–200 1C (pyridine/hexane);
pyridine (7 ml) was added hexyl isocyanate (0.10 ml,
0
.67 mmol). The reaction was stirred at 90 1C for 16 h, cooled
to rt, hexane was added and a white precipitate obtained
which was collected by filtration and washed thoroughly with
hexane to afford compound 3k as a white solid (80 mg, 51%).
ꢀ1
nmax/cm (solid) 3307, 3211, 3061, 2928, 2295, 1698, 1654,
1
1
615, 1565; H NMR (600 MHz; CDCl
NHCONHCH ), 8.86 (1H, br s, NHCONHCH
J 7.5 Hz, 6-H), 7.68 (1H, br s, 5-H), 4.67 (2H, m, NCH
2H, m, NHCH ), 2.56 (1H, t, J 2.5 Hz, CHCCH
), 0.88 (3H, t, J 5.5 Hz, CH
) d 165.2 (C-4), 156.7 (C-2), 154.1
),
8.7 (NCH ), 31.6, 29.4, 26.7, 22.6, 14.1 (CH ); m/z (FAB+)
3
) d 10.86 (1H, br s,
), 7.82 (1H, d,
), 3.26
), 1.52
);
ꢀ
1
Mp 199–200 1C (pyridine/hexane); nmax/cm (solid) 3212,
2
2
1
3
172, 3051, 2964, 2854, 1698, 1650; H NMR (400 MHz;
CDCl ) d 10.94 (1H, br s, NHCONHCH ), 9.01 (1H, br s,
NHCONHCH ), 7.54 (1H, br), 7.45 (1H, br), 3.84 (2H, t,
J 6.0 Hz, CH N), 3.25 (2H, m, NHCONHCH ), 1.74 (2H, m, CH ),
.57 (2H, quint, J 7.0 Hz, CH ), 0.90
), 1.30 (16H, m, 8 ꢂ CH
2
3
2
(
2
2
2
(
2H, m, CH
2
), 1.36 (6H, m, 3 ꢂ CH
2
3
1
3
2
2
2
C NMR (150 MHz; CDCl
3
1
2
2
(
NHCONH), 144.8 (C-6), 98.0 (C-5), 76.4, 75.9, 40.2 (NCH
2
1
3
(
6H, t, J 4.0 Hz, 2 ꢂ CH ); C NMR (150 MHz; CDCl ) d
3
3
3
2
2
+
3
1
64.9 (C-4), 157.2 (C-2), 154.4 (NHCONH), 146.7 (C-6), 97.3
+
99 (MNa , 70%), 277 (MH , 100); HRMS calculated for
+
(
C-5), 50.8 (CH N), 40.2 (NCH ), 31.6 (signals superimposed),
2 2
C H N O (MH ) 277.16644, measured 277.16681.
1
4
21
4
2
2
9.6, 29.4, 29.1 (signals superimposed), 26.7, 26.5, 22.6, 14.1
+
(
3
CH ); m/z (ES+) 373 (MNa , 100%); HRMS (ES+)
+
1-(1-Hexyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-propyl-urea 3i.
calculated for C19
373.2588.
34 4 2
H N NaO (MNa ) 373.2579, measured
To a solution of 5e (100 mg, 0.51 mmol) in dry pyridine (10 ml)
was added propyl isocyanate (0.07 ml, 0.77 mmol). The
reaction was stirred at 90 1C for 16 h, cooled to rt, hexane was
added and a white precipitate obtained which was collected by
filtration and washed thoroughly with hexane to afford
compound 3i as a colourless solid (90 mg, 63%). Mp
1-(1-Dodecyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-propyl urea 3l.
To a solution of compound 5g (150 mg, 0.540 mmol) in dry
pyridine (10 ml) was added propyl isocyanate (0.07 ml,
0.80 mmol). The reaction was stirred at 90 1C for 16 h. The
solution was then cooled down to room temperature, hexane
was added and a white precipitate obtained which was
collected by filtration and washed thoroughly with hexane to
afford compound 3l as a white solid (130 mg, 68%). Mp
ꢀ
1
2
3
18–220 1C (pyridine/hexane); nmax/cm (solid) 3308, 3211,
1
056, 2925, 2853, 1698, 1651; H NMR (600 MHz; CDCl )
3
major rotamer d 10.95 (1H, s, NHCONHCH ), 9.00 (1H, br s,
2
NHCONHCH
2
), 7.55 (1H, br d, 5-H), 7.45 (1H, d, J 7.3 Hz,
-H), 3.82 (2H, t, 7.3 Hz, CH N), 3.22 (2H, m,
), 1.72 (2H, m, CH ), 1.58 (2H, m, CH ),
), 0.94 (3H, t, J 7.4 Hz, CH ), 0.89
) d 165.0
C-4), 157.4 (C-2), 154.5 (NHCONH), 146.8 (C-6), 97.4 (C-5),
0.9 (CH N), 41.9 (NCH ), 31.5, 29.0, 26.2, 22.8, 22.6, 14.1
CH ), 11.7 (CH ); m/z (FAB+) 319 (MK , 100%), 281
ꢀ
1
6
J
2
198–200 1C (pyridine/hexane); nmax/cm (solid) 3213, 3173,
3053, 2962, 2918, 2851, 1699, 1650; H NMR (600 MHz;
1
NHCONHCH
2
2
2
1
.31 (6H, m, 3 ꢂ CH
2
1
3
CDCl
NHCONHCH
6-H), 3.82 (2H, t,
NHCONHCH ), 1.73 (2H, m, CH
(18H, m, 9 ꢂ CH ), 0.96 (3H, t, J 7.3 Hz, CH ), 0.89 (3H, t,
3
) d 10.95 (1H, s, NHCONHCH
), 7.56 (1H, br s, 5-H), 7.43 (1H, d, J 5.5 Hz,
7.2 Hz, CH N), 3.23 (2H, m,
), 1.60 (2H, m, CH ), 1.28
2
), 9.01 (1H, br s,
3
(
(
3H, t, J 6.5 Hz, CH
3
); C NMR (150 MHz; CDCl
3
2
J
2
5
2
2
2
2
2
+
(
(
3
+
3
2
3
13
MH , 100%), 196 (50); HRMS (CI) calculated for
+
J 7.0 Hz, CH ); C NMR (150 MHz; CDCl ) d 164.9 (C-4),
3
3
C H N O (MH ) 281.19775, measured 281.19673.
157.3 (C-2), 154.4 (NHCONH), 146.7 (C-6), 97.3 (C-5), 50.8
1
4
25
4
2
2
640 New J. Chem., 2010, 34, 2634–2642 This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010

View Article Online
1
3
(
CH
2
N), 41.8 (NCH
2
), 31.9, 29.5 (signals superimposed), 29.0,
), 11.6 (CH ); m/z
CI+) 365 (MH , 100%); HRMS (CI+) calculated for
3 3
0.88 (3H, t, J 5.2 Hz, CH ); C NMR (100 MHz; CDCl )
2
6.5, 22.7 (signals superimposed), 14.1 (CH
3
3
d 164.6 (C-4), 155.1 (C-2), 154.3 (NHCONH), 146.6 (C-6), 121.8
(NCO), 97.3 (C-5), 50.7 (CH N), 42.8 (CH NCO), 39.8, 31.1,
+
(
2
2
+
C H N O (MH ) 365.29165, measured 365.29255.
37
28.8, 28.0, 27.9, 27.4, 23.0, 22.4, 22.0, 13.9 (CH ); m/z (ES+) 386
3
20
4
2
+
MNa , 30%), 364 (MH , 100); HRMS (ES+) calculated for
+
(
1-(1-Dodecyl-2-oxo-1,2-dihydropyrimidin-4-yl)-3-hexyl urea 3m.
+
C H N O Na (MH ) 364.23570, measured 364.23490.
18
30
5 3
To a solution of compound 5g (150 mg, 0.540 mmol) in dry
pyridine (10 ml) was added propyl isocyanate (0.07 ml,
Synthesis of polymers 10–12. The procedure for 10 is given
0
.80 mmol). The reaction was stirred at 90 1C for 16 h, cooled
below. To a solution of hydroxy terminated poly(2-methyl-
to rt, hexane was added and a white precipitate obtained
which was collected by filtration and washed thoroughly with
hexane to afford compound 3l as a white solid (150 mg, 68%).
ꢀ1
1
0
,3-propylene adipate) (MW 2000
g
mol
)
(0.682 g,
.34 mmol), in chloroform (15 ml), was added 1-(6-isocyanato-
hexyl)-3-(1-methyl-2-oxo-1,2-dihydro-pyrimidin-4-yl)-urea
0.300 mg, 1.02 mmol) and one drop of dibutyltindilaurate.
The reaction mixture was heated at reflux for 20 h, chloroform
10 ml) was then added and the mixture was filtered to remove
ꢀ1
Mp 188–190 1C (pyridine/hexane); nmax/cm (solid) 3308,
(
1
3
211, 3059, 2925, 2849, 1699, 1651; H NMR (400 MHz;
CDCl ) d 10.94 (1H, br s, NHCONHCH ), 9.00 (1H, br s,
NHCONHCH ), 7.56 (1H, br, 5-H), 7.45 (1H, br d, J 5.5 Hz 6-H),
.82 (2H, t, J 7.1 Hz, CH N), 3.25 (2H, m, NHCONHCH ),
.72 (2H, m, CH ), 1.57 (2H, quint, J 7.3 Hz, CH ), 1.32
3
2
(
2
the excess of monoisocyanate. The filtrate was concentrated
down to 10 ml, and silica gel (200 mg) was added with a
further drop of dibutyltindilaurate and the solution was
heated at 60 1C for 2 h. The silica gel was then removed by
filtration and the chloroform was evaporated in vacuo to give
the polymers which were purified using flash silica chromato-
3
1
2
2
2
2
1
3
(
(
(
(
24H, m, 12 ꢂ CH ), 0.89 (6H, t, J 7.0 Hz, CH ); C NMR
2
3
150 MHz; CDCl ) d 164.9 (C-4), 157.3 (C-2), 154.4
3
NHCONH), 146.7 (C-6), 97.3 (C-5), 50.8 (CH
NCH ), 32.0, 31.9, 29.5 (signals superimposed), 29.2, 29.0,
6.7, 26.6, 26.5, 22.7, 22.6, 14.2 (CH ), 14.1 (CH ); m/z (CI+)
07 (MH , 75%), 280 (100); HRMS (CI+) calculated for
2
N), 40.1
2
3
graphy (CHCl /MeOH, 20 : 1 to 10 : 1) where required.
2
4
3
3
Polymer 10 was generated in 30% yield, as an opaque
1
+
flexible plastic. H NMR (400 MHz; CDCl ) d 10.81 (2H, br
3
+
23 43 4 2
C H N O (MH ) 407.33860, measured 407.33885.
s, 7-H), 9.01 (2H, br s, 9-H), 7.52 (2H, br s, 5-H), 7.45 (2H, d,
J 7.1 Hz, 6-H), 4.82 (2H, br s, NHCOO), 3.96 (40H, m,
1
-(6-Isocyanatohexyl)-3-(1-methyl-2-oxo-1,2-dihydro-pyrimidin-
CH
NHCONHCH
36H, m, CH
CH , OCH
C NMR (100 MHz; CDCl
57.8 (NHCOO), 156.4 (C-2), 154.2 (NHCONH), 147.3 (C-6),
2
OOC, CH
2
OCONH), 3.47 (6H, s, CH
), 3.12 (4H, br q, J 6.3 Hz, CH
COO), 2.11 (10H, m, CHCH ), 1.64 (52H, m,
CH , CH ), 0.95 (30H, d, J 6.9 Hz, CH );
) d 173.1 (CH COO), 160.4 (C-4),
3
N), 3.26 (4H, br q,
4
-yl)-urea. The reaction was carried out under anhydrous
conditions. To a solution of 5a (8.34 g, 66.6 mmol) in CH Cl
250 ml) was added hexylisocyanate (64.7 ml, 400 mmol). The
2
2
NHCOO), 2.32
2
2
(
2
3
(
NHCH
2
2
2
2
2
3
reaction was stirred at 40 1C for 72 h, hexane was added and
the white precipitate was collected by filtration, giving the
monourea which was directly used in the next step (19.6 g,
1
3
3
2
1
ꢀ1
65.6, 40.8, 39.7, 38.0, 33.6, 32.6, 29.7, 29.3, 26.3, 24.2, 13.7.
quantitative). Mp 224–226 1C (hexane); nmax/cm
(solid)
312, 3047, 2930, 2858, 2260, 1698, 1657, 1620; H NMR
400 MHz; CDCl ) d 10.84 (1H, br s, NHCONHCH ), 9.06
1H, br s, NHCONHCH ), 7.58 (1H, br, 5-H), 7.44 (1H, d,
7.3 Hz 6-H), 3.48 (3H, s, NCH ), 3.28 (4H, m,
NHCONHCH , CH ), 1.29
NCO), 1.59 (4H, m, 2 ꢂ CH
) d 164.9
C-4), 157.6 (C-2), 154.2 (NHCONH), 147.3 (C-6), 121.7
NCO), 97.2 (C-5), 42.7 (CH NCO), 40.8 (NCH ), 39.8,
7.8, 31.0, 29.1, 26.1; m/z (ES+) 316 (MNa , 100%); HRMS
1
Polymer 11 was generated using the same method as for 10
1
in 65% yield, as an opaque brittle solid. H NMR (400 MHz;
3
(
(
3
2
CDCl ) d 10.89 (2H, br s, 7-H), 8.98 (2H, br s, 9-H), 7.50
3
2
(
2H, br s, 5-H), 7.42 (2H, d, J 7.2 Hz, 6-H), 4.80 (2H, br s,
J
3
NHCOO), 3.95 (38H, m, CH OOC, CH OCONH), 3.81
2
2
2
2
2
1
3
(4H, t, J 7.2 Hz, CH N), 3.20 (4H, br q, NHCONHCH ),
2
2
(
(
(
4H, m, 2 ꢂ CH
2 3
); C NMR (100 MHz; CDCl
3
.10 (4H, br q, CH
10H, m, CHCH
OCH CH , CH ), 0.95 (30H, t, J 6.9 Hz, CH ), 0.84
2
NHCOO), 2.32 (36H, m, CH
2
COO), 2.07
(
3 2 2
), 1.64–1.27 (68H, m, NHCH CH ,
2
3
+
2
2
2
3
3
1
3
+
(6H, m, 2 ꢂ CH CH ); C NMR (100 MHz; CDCl ) d 173.1
2
3
3
(
ES+) calculated for C H N O Na (MNa ) 316.13855,
13 19 5 3
(
CH
2
COO), 164.7 (C-4), 157.1 (NHCOO), 156.4 (C-2), 154.3
OCONH),
measured 316.13769.
(
NHCONH), 146.7 (C-6), 97.2 (C-5), 65.8 (CH
2
1-(6-Isocyanatohexyl)-3-(1-hexyl-2-oxo-1,2-dihydro-pyrimidin-
65.6 (CH OOC), 50.6 (CH N), 40.7, 39.7, 33.6, 31.2, 29.5
2 2
4
-yl)-urea. The reaction was carried out under anhydrous
(signals superimposed), 26.4, 24.2, 22.5, 13.8, 13.7.
conditions. To a solution of 5e (1.50 g, 7.70 mmol) in dry
Polymer 12 was generated using the same method as for 10
1
in 40% yield, as an opaque flexible plastic. H NMR
CH Cl2 (60 ml) was added hexylisocyanate (7.45 ml,
2
4
6.1 mmol). The reaction was stirred at rt for 15 h, hexane
(400 MHz; CDCl
10.08 (2H, s, 9-H), 5.78 (2H, s, 5-H), 4.90 (2H, s, NHCOO),
3.94 (40H, m, 20 ꢂ OCH ), 3.21 (4H, m, NHCONHCH ), 3.12
(4H, m, CH NHCOO), 2.28 (40H, m, CH OCO, CH COO,
CH ), 2.12 (10H, oct, J 6.3 Hz,
OCONH), 2.21 (6H, s, 2 ꢂ CH
CHCH ), 0.95 (33H, d, J 6.9 Hz,
), 1.64 (44H, m, 22 ꢂ CH
CH CH); C NMR (100 MHz; CDCl ) d 173.1 (C-4), 156.5
3
) d 13.07 (2H, s, 1-H), 11.80 (2H, s, 7-H),
was added and the white precipitate was collected by filtration,
giving the monourea which was directly used in the next step
ꢀ
2
2
1
(
2.50 g, 90%). Mp 191–193 1C (hexane); nmax/cm (solid)
2
2
2
1
3
211–3293, 2964, 2286, 1700, 1653; H NMR (400 MHz;
CDCl ) d 10.90 (1H, br s, NHCONHCH ), 9.06 (1H, br s,
NHCONHCH ), 7.54 (1H, br, 5-H), 7.43 (1H, d, J 7.2 Hz
-H), 3.81 (2H, t, 7.2 Hz, NCH2), 3.27 (4H, m,
NHCONHCH , CH NCO), 1.71 (2H, m, CH ), 1.65 (4H, m,
2
3
3
2
3
2
1
3
2
3
3
6
J
(NHCOO), 156.4 (NHCONH), 154.6 (C-2), 148.2 (C-6), 106.5
(C-5), 65.7 (OCH ), 40.6, 39.5, 33.7, 31.8, 29.6, 29.4, 26.6, 26.2,
2
2
2
2
2
ꢂ CH ), 1.40 (4H, m, 2 ꢂ CH ), 1.29 (6H, m, 3 ꢂ CH ),
24.2, 13.8.
2
2
2
This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010 New J. Chem., 2010, 34, 2634–2642 2641

View Article Online
Acknowledgements
R. P. Sijbesma, R. M. Versteegen, J. A. J. van der Rijt and
E. W. Meijer, Adv. Mater., 2000, 12, 874; (e) S. H. M. Sontjens,
R. P. Sijbesma, M. H. P. van Genderen and E. W. Meijer,
Macromolecules, 2001, 34, 3815; (f) V. G. H. Lafitte, A. E. Aliev,
H. C. Hailes, K. Bala and P. Golding, J. Org. Chem., 2005, 70,
2701; (g) V. G. H. Lafitte, A. E. Aliev, P. N. Horton,
M. B. Hursthouse and H. C. Hailes, Chem. Commun., 2006,
We thank AWE plc. for studentships (V.G.H.L. and E.G.).
Notes and references
1
For examples of general reviews on hydrogen bonded supra-
molecular polymers and assemblies see: (a) L. Brunsveld, B. J. B.
Folmer, E. W. Meijer and R. P. Sijbesma, Chem. Rev., 2001, 101,
2
173; (h) A.-M. Alexander, M. Bria, G. Brunklaus, S. Caldwell,
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V. G. H. Lafitte, A. E. Aliev, P. N. Horton, M. B. Hursthouse,
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201, 143; (d) A. J. Wilson, Soft Matter, 2007, 3, 409; (e) J. L.
1
28, 6544.
D. H. Helfer, R. S. Hosmane and N. J. Leonard, J. Org. Chem.,
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P. J. Atkins and C. D. Hall, J. Chem. Soc., Perkin Trans. 2, 1983,
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E. W. Meijer, Chem. Rev., 2009, 109, 5687.
6
7
8
9
1
1
2
3
For examples of triple hydrogen bonded modules, see:
(a) T. J. Murray and S. C. Zimmerman, J. Am. Chem. Soc., 1992,
6
W. E. Lindsell, C. Murray, P. N. Preston and T. A. J. Woodman,
Tetrahedron, 2000, 56, 1233.
0 J. R. Quinn, S. C. Zimmerman, J. E. Del Bene and I. Shavitt,
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1 B. J. B. Folmer, R. P. Sijbesma, R. M. Versteegen, J. A. J.
van der Rijt and E. W. Meijer, Adv. Mater., 2000, 12, 874.
2 S. H. M. Sontjens, R. A. E. Renken, G. M. L. van Gemert, T. A. P.
¨
114, 4010; (b) E. E. Fenlon, T. J. Murray, M. H. Baloga and
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For examples of quadruple hydrogen bonded modules, see:
1
1
1
(
a) C. Schmuck and W. Wienand, Angew. Chem., Int. Ed., 2001,
0, 4363; (b) P. S. Corbin, S. C. Zimmerman, P. A. Theissen,
N. A. Hawryluk and T. J. Murray, J. Am. Chem. Soc., 2001, 123,
4
1
2
2
0475; (c) U. Lu
¨
ning, C. Ku
¨
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16 G. J. Durr, J. Med. Chem., 1965, 8, 253.
17 M. Hayashi, K. Yamauchi and M. Kinoshita, Bull. Chem. Soc.
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For examples of Upy quadruple hydrogen bonded systems, see:
4
(a) R. P. Sijbesma, F. H. Beijer, L. Brunsveld, B. J. B. Folmer, J. H.
K. K. Hirschberg, R. F. M. Lange, J. K. L. Lowe and
E. W. Meijer, Science, 1997, 278, 1601; (b) F. H. Beijer,
R. P. Sijbesma, H. Kooijman, A. L. Spek and E. W. Meijer,
J. Am. Chem. Soc., 1998, 120, 6761; (c) S. H. M. Sontjens,
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18 M. Salas, B. Gordillo and F. J. Gonzalez, ARKIVOC, 2005, (vi),
172.
2
642 New J. Chem., 2010, 34, 2634–2642 This journal is c The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2010