Strong dimerization of ureidopyrimidones via quadruple hydrogen bonding

Article abstract of DOI:10.1021/ja974112a

6-Methyl-2-butylureidopyrimidone dimerizes via four hydrogen bonds in the solid state as well as in CHCl₃ solution via a donor-donor-acceptor-acceptor (DDAA) array of hydrogen bonding sites in the 4[1H]-pyrimidinone tautomer. An intramolecular hydrogen bond from the pyrimidine NH group to the urea oxygen atom preorganizes the molecules for dimerization. The dimerization constant of the dimer in CHCl₃ exceeds 10⁶ M^-1. In CHCl₃ containing DMSO, the dimer is in equilibrium with the monomeric G[1H]-pyrimidinone tautomer. In 6-phenyl-2-butylureidopyrimidone, the 4[1H]-pyrimidinone tautomer coexists with the pyrimidin-4-ol form, which dimerizes with similar high dimerization constants via four hydrogen bonds in a DADA array. The latter tautomer predominates in derivatives with electronegative 6-substituents, like 6-nitrophenyl- and 6-trifluoromethyl-2-butylureidopyrimidone Due to its simple preparation and high dimerization constant, the ureidopyrimidone functionality is a useful building block for supramolecular chemistry.

Full text of DOI:10.1021/ja974112a

J. Am. Chem. Soc. 1998, 120, 6761-6769
6761
Strong Dimerization of Ureidopyrimidones via Quadruple Hydrogen
Bonding
Felix H. Beijer,1 Rint P. Sijbesma,*,1 Huub Kooijman,2 Anthony L. Spek,2 and
E. W. Meijer*,1,3
Contribution from the Laboratory of Organic Chemistry, EindhoVen UniVersity of Technology,
P.O. Box 513, 5600 MB EindhoVen, The Netherlands, and the BijVoet Center for Biomolecular Research,
Crystal and Structural Chemistry Padualaan 8, 3584 CH, Utrecht, The Netherlands
ReceiVed December 3, 1997. ReVised Manuscript ReceiVed April 23, 1998
Abstract: 6-Methyl-2-butylureidopyrimidone dimerizes via four hydrogen bonds in the solid state as well as
in CHCl3 solution via a donor-donor-acceptor-acceptor (DDAA) array of hydrogen bonding sites in the
4[1H]-pyrimidinone tautomer. An intramolecular hydrogen bond from the pyrimidine NH group to the urea
oxygen atom preorganizes the molecules for dimerization. The dimerization constant of the dimer in CHCl3
exceeds 106 M-1
. In CHCl3 containing DMSO, the dimer is in equilibrium with the monomeric
6[1H]-pyrimidinone tautomer. In 6-phenyl-2-butylureidopyrimidone, the 4[1H]-pyrimidinone tautomer coexists
with the pyrimidin-4-ol form, which dimerizes with similar high dimerization constants via four hydrogen
bonds in a DADA array. The latter tautomer predominates in derivatives with electronegative 6-substituents,
like 6-nitrophenyl- and 6-trifluoromethyl-2-butylureidopyrimidone. Due to its simple preparation and high
dimerization constant, the ureidopyrimidone functionality is a useful building block for supramolecular chemistry.
Introduction
In many synthetic self-assembling structures, the components
are held together by arrays of double or triple hydrogen bonds.4
Due to their strength, directionality, and specificity, arrays of
multiple hydrogen bonds are useful building blocks for the
reliable assembly of complex structures. This combination of
advantageous properties is expected to be particularly pro-
nounced in large arrays of hydrogen bonds. That such arrays
indeed form very stable complexes has been shown for receptors
for urea,5 guanines,6 and barbiturates,7 for self-assembled
receptors,8 and for cyclic peptides that self-assemble to form
nanotubes.9 However, the use of these arrays is limited by the
synthetic efforts required for their preparation. Recently, we
reported on the dimerization of acylated triazines10 and pyri-
midines via DADA (donor-acceptor-donor-acceptor) arrays,
and on the stabilization of these dimers by intramolecular
hydrogen bonds.11 On the basis of differences in secondary
interactions,12 dimers of DDAA arrays are predicted to be more
stable than DADA dimers (Figure 1). In search of stable
Figure 1. Interactions in DADA and DDAA dimers. While both dimers
have four primary attractive hydrogen bonds, the DADA dimer has
six repulsive secondary interactions, whereas the DDAA dimer has two
repulsive and four attractive secondary interactions.
hydrogen-bonded dimers, we have therefore turned our attention
to ureidopyrimidinones 1.13
In analogy to parent isocytosines,14 the 6[1H]-pyrimidinone
tautomer (Figure 2) is expected to be the most stable tautomeric
form of an isolated 2-ureido-4-pyrimidinone molecule. How-
ever, ureidopyrimidinones may actually exist as dimers of 4[1H]-
pyrimidinone and pyrimidinol tautomeric forms, since consid-
erable stabilization is expected by dimerization of the linear
array of four hydrogen bonds. Notably, both dimerization via
(1) Eindhoven University of Technology.
(2) Bijvoet Center for Biomolecular Research.
(3) To whom correspondence should be addressed.
(4) For a review with many examples of hydrogen-bonded self-
assembling complexes, see: Lawrence, D. S.; Jiang, T.; Levitt, M. Chem.
ReV. 1995, 95, 2229.
(5) (a) Bell, T. W.; Liu, J. J. Am. Chem. Soc. 1988, 110, 3673. (b) Bell,
T. W.; Hou, Z. Angew. Chem. 1997, 109, 1601; Angew. Chem., Int. Ed.
Engl. 1997, 36, 1536.
(6) Bell, T. W.; Hou, Z.; Zimmerman, S. C.; Thiesen, P. A. Angew. Chem.
1995, 107, 2321; Angew. Chem., Int. Ed. Eng. 1995, 34, 2163.
(7) Geib, S. J.; Hirst, S. C.; Vicent, C.; Hamilton, A. D. J. Chem. Soc.,
Chem. Commun. 1991, 1283.
(8) Wyler, R.; de Mendoza, J.; Rebek, J., Jr. Angew. Chem. 1993, 105,
1820; Angew. Chem., Int. Ed. Engl. 1993, 32, 1699.
(9) Ghadiri, M. R.; Granja, J. R.; Milligan, R. A.; McRee, D. E.;
Khazanovich, N. Nature 1993, 366, 324.
(11) Beijer, F. H.; Kooijman, H.; Spek, A. L.; Sijbesma, R. P.; Meijer,
E. W. Angew. Chem. 1998, 110, 79; Angew. Chem., Int. Ed. Engl. 1998,
37, 75.
(12) (a) Jorgensen, W. L.; Pranata, J. J. Am. Chem. Soc. 1990, 112, 2008.
(b) Pranata, J.; Wierschke, S. G.; Jorgensen, W. L. J. Am. Chem. Soc. 1991,
113, 2810.
(13) The synthesis of several ureidopyrimidones has been reported: (a)
Fan, J.; Cheng, C. C. J. Heterocycl. Chem. 1993, 30, 1273. (b) Urbanski,
T.; Serafin, B.; Zylowski, J. J. Med. Chem. 1967, 10, 521. (c) Kreutzberger,
A.; Schimmelpfennig, H. Arch. Pharm. 1981, 314, 34. (d) Vasilev, G. Dokl.
Bolg. Akad. Nauk 1990, 43, 57.
(10) Beijer, F. H.; Sijbesma, R. P.; Vekemans, J. A. J. M.; Meijer, E.
W.; Kooijman, H.; Spek, A. L. J. Org. Chem. 1996, 61, 6371.
S0002-7863(97)04112-7 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/27/1998

6762 J. Am. Chem. Soc., Vol. 120, No. 27, 1998
Beijer et al.
Figure 2. Equilibria between tautomeric forms and between monomer and dimer of compounds 1.
Scheme 1
a DDAA array as well as via a DADA array is possible. In
both cases, the linear array of the four hydrogen bonds is
preorganized by an intramolecular hydrogen bond, a concept
shown previously to enhance the stability of dimers consider-
ably.11
is investigated in a range of derivatives, which dimerize via
four hydrogen bonds in either DDAA or DADA dimers.
Results
Ureidopyrimidinone Dimers. 2-Butylureido-4-pyrimidinone
1a is readily prepared by reaction of commercially available
6-methylisocytosine 3a with with butyl isocyanate (Scheme 1).
Compound 1a indeed forms quadruply hydrogen-bonded DDAA-
dimers, both in the solid state as well in chloroform solution,
as is evident from FTIR, X-ray diffraction, and NMR spectros-
copy. The crystal structure of 1a (Figure 3) shows that the
molecules are in the 4[1H]-pyrimidinone form. The urea
functionality is in a trans-trans conformation, and an intramo-
lecular hydrogen bond is present from the pyrimidine N-H to
the urea carbonyl group. This results in a preorganized DDAA
array of hydrogen bonding sites, which forms a centrosym-
Here we report on the formation of exceptionally stable
DDAA dimers of a simple ureidopyrimidinone derivative, which
is synthesized in one step from commercially available starting
materials. The full scope of dimerization of ureido pyrimidones
(14) For studies of tautomerization of isocytosine, see: (a) Stephanian,
S. G.; Radchenko, E. D.; Sheina, G. G.; Blagoi, Y. P. J. Mol. Struct. 1990,
216, 77. (b) Sheina, G. G.; Stephanian, S. G.; Radchenko, E. D.; Blagoi,
Y. P. J. Mol. Struct. 1987, 158, 275. (c) Toledo, L. M.; Musa, K.; Lauher,
J. W.; Fowler, F. W. Chem. Mater. 1995, 7, 1639. (d) Elguero, J.; Marzin,
C.; Katritzky, A. R.; Linda, P. The Tautomerism of Heterocycles, AdVances
in Heterocyclic Chemistry; Academic Press: New York, 1976. (e) Bu¨hl-
mann, P.; Badertscher, M.; Simon, W. Tetrahedron 1993, 49, 595. (f)
Bu¨hlmann, P.; Simon, W. Tetrahedron 1993, 49, 7627.

Dimerization of Ureidopyrimidones
J. Am. Chem. Soc., Vol. 120, No. 27, 1998 6763
independent dimers, without internal crystallographic symmetry.
The molecules in the platelike crystals of 1h were found to exist
as pyrimidin-4-ol dimers (Figure 5b). X-ray diffraction on
several crystals revealed that at least three crystal modifications
had formed, with a similar dimer geometry. In all modifications,
the dimers are packed in layers. The main difference between
the modifications is the relative position of the layers with
respect to each other. The pyrimidinol units are dimerized via
a DADA array, which is further stabilized by an intramolecular
NsH‚‚‚N hydrogen bond. The OH‚‚‚O hydrogen bonds are
short (2.58 Å), while the NH‚‚‚N distance of 2.98 Å is similar
to the NH‚‚‚N distance in the 4[1H]-pyrimidinone dimer (Table
1). FTIR spectra of the two forms of 1h (see Experimental
Section) confirm the presence of strong hydrogen bonds in the
crystals of both modifications. In particular the band of the
hydrogen-bonded OH group of the pyrimidin-4-ol tautomer is
found at low wavenumbers (2500 cm-1 ).
Figure 3. PLUTON representation of the dimer geometry of 1a in
the crystal.
1
metrical dimer. The DDAA array deviates slightly from
linearity, the outer NsH‚‚‚O hydrogen bonds being 0.209 Å
shorter than the inner NsH‚‚‚N hydrogen bonds (Table 1).
Strong similarity of the FTIR spectra of 1a in the crystal and
in CDCl3 solution indicates that the DDAA dimers persist in
solution. Bands at 3212 and 3147 cm-1 are assigned to
hydrogen-bonded NH groups, while bands of free NH groups
are not observed. In the1H NMR spectrum of 1a in CDCl3
(Figure 4) the NH proton signals are found at 13.15, 11.86,
and 10.15 ppm, indicative of extensive hydrogen bonding.
Strong intramolecular nuclear Overhauser effects, which were
used to assign the NH proton signals, confirm the 4[1H]-
pyrimidinone dimer geometry in solution. Upon dilution of a
CDCl3 solution of 1a to 10-4 M, the NH proton resonances do
not shift, nor do any new peaks due to monomeric species
appear, putting a lower limit on the dimerization constant of
4.5 × 105 M-1 (for determination of dimerization constants,
vide infra).
Tautomeric Equilibrium between 4[1H]-Pyrimidinone and
Pyrimidin-4-ol Dimers. The scope of the dimerization of the
ureidopyrimidinone functionality was investigated in a range
of derivatives 1b-k, bearing different substituents at the
6-position and at the terminal urea nitrogen atom. These
compounds were prepared as depicted in Scheme 1. Condensa-
tion of â-keto esters 2b-e with guanidine (added as guanidinium
carbonate) afforded 6-substituted isocytosines 3b-e. Subse-
quently, the isocytosine was reacted with the appropriate
isocyanate to give the compounds 1b-k. To improve the
solubility of 6-phenyl-substituted compounds, compounds 10a-
dswhich have three dodecyloxy chains on the phenyl groups
were prepared via the route depicted in Scheme 2. Ester 4 was
hydrolyzed to acid 5 and then converted to acid chloride 6 by
refluxing in thionyl chloride.15 Acid chloride 6 was converted
to â-keto ester 8 via intermediate 7.16 â-Keto ester 8 in turn
was reacted with guanidinium carbonate to afford isocytosine
9 and subsequent reaction with the appropriate isocyanate
afforded target molecules 10a-d.
The H NMR spectrum in CDCl3 of compound 1h shows
two sets of signals. One set of N-H signals at δ ) 13.95,
12.06, 10.23 ppm, is assigned to the 4[1H]-pyrimidinone
tautomer, a second set of signals at 13.6, 11.3, and 10.0 ppm,
with an abundance of 13%, is assigned to the pyrimidin-4-ol
tautomer. The aromatic proton signal of this tautomer resonates
0.5 ppm downfield of the alkylidene signal of the 4[1H]-
pyrimidinone tautomer. The presence of the pyrimidin-4-ol
tautomer is confirmed by the FTIR spectrum in CHCl3. In
toluene-d8, the two tautomers of 1h are present in approximately
equal amounts.
In the 1H NMR spectra of compounds 1, the aromatic proton
signal of the pyrimidin-4-ol tautomer is found 0.3-0.5 ppm
downfield from the alkylidene proton signal of the 4[1H]-
pyrimidinone tautomer. By using this assignment, the relative
amounts of 4[1H]-pyrimidinone and pyrimidinol tautomers of
different compounds were determined by integration of peak
areas. As is evident from these data (Table 2), the pyrimidinol
form is favored14d in ureidopyrimidinone derivatives with
electron-withdrawing substituents at the 6-position. The highest
amount of pyrimidinol tautomer is found in 6-nitrophenyl
derivative 1j (60% enol in CDCl3) and 6-trifluoromethyl
derivative 1k (>99% enol in CDCl3). The electronic substituent
effect may be rationalized by the reduced stability of the enone
structure in the pyrimidinone when an electron-withdrawing
6-substituent is present, while the hydrogen bond acceptor
capability of its carbonyl group is reduced. Comparison of the
tautomeric equilibria in compounds 10a-d shows that electron-
withdrawing substituents on the ureido group favor the 4[1H]-
pyrimidinone tautomer. The different acidities of the NH group
adjacent to the substituents are also reflected in the relative
exchange rates of N-H signals with D2O. The N-H protons
adjacent to the butyl substituent in 10a or the p-di(ethylamino)-
phenyl substituent in 10d exchange slower than corresponding
protons adjacent to a phenyl or p-nitrophenyl substituents in
compounds 10b and 10c.
Depending on conditions, phenyl-substituted compound 1h
crystallizes from CHCl3 either as needles, or as plates. Single-
crystal X-ray analysis of the needles revealed DDAA dimers
of the 4[1H]-pyrimidinone tautomer (Figure 5a), similar to the
dimer of 1a (Table 1). Four independent molecules form two
The ratio of 4[1H]-pyrimidinone and pyrimidin-4-ol tautomers
of compound 10a in THF-d8 is concentration-dependent (Figure
6), and the position of the N-H and O-H signals of the
pyrimidin-4-ol tautomer shifts upfield upon dilution, while the
positions of the 4[1H]-pyrimidinone signals do not shift. These
observations suggest that the 4[1H]-pyrimidinone tautomer is
dimeric troughout the concentration range studied, whereas the
pyrimidin-4-ol dimer dissociates at low concentrations. Hence,
the pyrimidin-4-ol tautomer is the most stable form of mono-
meric 10a in THF-d8.
(15) Palmans, A. R. A.; Vekemans, J. A. J. M.; Fischer, H.; Hikmet, R.
A.; Meijer, E. W. Chem. Eur. J. 1997, 3, 300.
(16) (a) Perkin, W. H.; Weizmann, C. J. Chem. Soc. 1906, 89 II, 1655.
(b) Bradley, W.; Robinson, R. J. Chem. Soc. 1928, 1548. (c) Hunsdiecker,
H. Berichte 1942, 75, 1190. (d) Gu¨nthard, H. H.; Heinemann, S. D.; Prelog,
V. HelV. Chim. Acta 1953, 36, 1147.

6764 J. Am. Chem. Soc., Vol. 120, No. 27, 1998
Beijer et al.
Table 1. Bond Distances (Å) and X-H-X Angles (deg) in the Crystal Structures of 1a and of the 4[1H]-Pyrimidinone and Pyrimidin-4-ol
Tautomers of 1h
NsH‚‚‚N
distance
XsH‚‚‚O
distancea
compound
angle
angle
hydrogen bond length difference
1a
2.966(3)
2.95(1)
2.98(1)
175(3)
172(6)
173(4)
2.757(3)
2.78(5)
2.58(1)
163(3)
166(3)
169(3)
0.209
∼0.17
∼0.40
4[1H]-pyrimidinone 1hb
pyrimidin-4-ol 1hc
a X ) N in 1a and 4[1H]-pyrimidinone tautomer of 1h; X ) O in pyrimidin-4-ol tautomer of 1h. b Average values of the four independent
molecules in the crystal. c Average of six values from two crystallographically nonequivalent molecules in each of the three pyrimidin-4-ol polymorphs.
Figure 4. 1H NMR spectrum of 1a in CDCl3. Nuclear Overhauser effects between protons are indicated with arrows.
Scheme 2
Dimerization Constants. Strong dimerization of compounds
1 in CDCl3 prevented us from using the concentration depen-
dence of the 1H NMR spectrum for determination of the
dimerization constant. As was discussed above, dilution of 1a
in chloroform did not result in perceivable dissociation. Dilution
of trifluoromethyl derivative 1k, which exists exclusively as
dimers of the pyrimidin-4-ol tautomer in chloroform, to 10-4
M does also not result in perceivable dissociation. Dilution of
a CDCl3 solution of compound 1iswhich is present as a 1:1
mixture of 4[1H]-pyrimidinone and pyrimidin-4-ol dimerssto
10-4 M-1 does not affect the ratio of 4[1H]-pyrimidinone to
pyrimidin-4-ol signals. A conservative estimate of less than

Dimerization of Ureidopyrimidones
J. Am. Chem. Soc., Vol. 120, No. 27, 1998 6765
Figure 6. Plot of the fraction of 4[1H]-pyrimidinone tautomer vs
concentration in solutions of 10a in THF-d8. The solid line serves to
guide the eye.
Dimerization of compounds 1 was studied in mixtures of
CDCl3 with DMSO-d6, a strong hydrogen bond acceptor solvent.
We found that in these solvent mixtures the dimers of the 4[1H]-
pyrimidinone tautomer of 1a (NH signals at 13.95, 12.06, and
10.23 ppm), are in equilibrium with a second tautomer, which
is the only tautomer present in pure DMSO-d6. This tautomer
has one hydrogen-bonded NH proton at 11.4 ppm and two non-
hydrogen-bonded NH protons at 9.4 and 7.2 ppm. The signals
are assigned to a presumably monomeric 6[1H]-pyrimidinone
tautomeric form (Figure 2). The assignment is confirmed by
the observation that 6-phenyl-2-tert-butylureido derivative 1i,
which exists as a 1:1 mixture of 4[1H]-pyrimidinone and
pyrimidin-4-ol dimers in pure CDCl3, coexists with the third
tautomer in CDCl3/DMSO-d6 mixtures. The NH peak positions
agree best with the conformation of the 6[1H]-pyrimidinone
tautomer as drawn in Figure 2, with an intramolecular hydrogen-
bonded pyrimidone NH group and two non-hydrogen-bonded
ureido NH groups.
Figure 5. (a) Dimer geometry of the molecules of 1h in the 4[1H]-
pyrimidinone tautomer in the needle-shaped crystal and (b) dimer
geometry of the molecules of 1h in the pyrimidin-4-ol tautomer in the
plate-shaped crystals.
Table 2. Relative Amounts 4[1H]-Pyrimidinone and
a
Pyrimidin-4-ol Tautomers in CDCl3 and Toluene-d8
1
The H NMR spectrum of trifluoromethyl derivative 1ks
entirely in the pyrimidin-4-ol dimeric form in pure chloroforms
also shows a second set of signals in CDCl3/DMSO-d6 mixtures,
which were assigned to the 6[1H]-pyrimidinone tautomer. The
ratio between the dimeric forms and the 6[1H]-pyrimidinone
tautomer varies upon dilution in a CDCl3/DMSO-d6 mixture of
constant composition.
% 4[1H]-pyrimidinone
compound
R1
R2
in CDCl3 in toluene-d8
Complex dimerization constants, Kdim*, were assigned to the
equilibria of 1a and 1k; the constants are based on the
dimerization constant (Kdim) and the tautomeric equilibrium
constant (Ktaut). In a given solvent mixture, the ratio Kdim* of
dimeric tautomer (the 4[1H]-pyrimidinone tautomer of 1a and
the pyrimidin-4-ol tautomer of 1k, respectively) to the square
of the concentration of 6[1H]-pyrimidinone tautomer has a
constant value within experimental error. This implies a dimer-
monomer relationship, with the 6[1H]-pyrimidinone tautomer
as the most stable form of monomeric 1 in CDCl3/DMSO-d6
mixtures (see Discussion).
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
10a
10b
10c
10d
CH3
CH3
n-C4H9
t-C4H9
n-C4H9
t-C4H9
>99
97
>99
96.5
insoluble
C13H27
C13H27
C13H27
C13H27
C13H27
C6H5
87
76
C6H5
>99
>99
>99
87
98
insoluble
97
42
44
p-NO2C6H5
p-NEt2C6H5
n-C4H9
t-C4H9
n-C18H37
n-C4H9
C6H5
50
p-NO2C6H5
40
insoluble
CF3
<1
87
C6H2(OC12H25)3 n-C4H9
C6H2(OC12H25)3 C6H5
C6H2(OC12H25)3 p-NO2C6H5
C6H2(OC12H25)3 p-NEt2C6H5
57
93
>99
85
77
>99
51
The values of Kdim* of compounds 1a and 1k were determined
in several CDCl3/DMSO-d6 mixtures with the objective of
extrapolating the values to a value in pure CDCl3.
a Ratios were identical at low ((1 mM) and high (>50 mM)
concentration. For compounds 1f and 1j, only spectra at low concentra-
tion were taken in CDCl3.
A plot of log Kdim* vs solvent composition is strongly curved
(Figure 7), rendering extrapolation to a K value in pure
chloroform impossible without a quantitative model for fitting
the relation between dimerization constant and solvent composi-
tion. The solvent dependence of Kdim* is particularly strong at
low concentrations of DMSO-d6.
10% dissociation at 10-4 M-1 results in a lower limit of 4.5 ×
105 M-1 for the dimerization constant of both pyrimidin-4-ol
and 4[1H]-pyrimidinone tautomers of 1a, 1k, and 1i.

6766 J. Am. Chem. Soc., Vol. 120, No. 27, 1998
Beijer et al.
Only a lower limit can be given for the dimerization constant
of the DDAA system of 1a in chloroform, because the complex
Kdim* values in a mixed-solvent system could not be extrapolated
to pure chloroform. The results show that the dimerization
constant is at least of the same order of magnitude as predicted
by Schneider (3.6 × 106 M-1). The actual value may be higher,
because Kdim* (which is smaller than Kdim) is already 1.2 × 106
in CDCl3 containing 0.3% v/v DMSO-d6, while it is strongly
dependent on the presence of small amounts of DMSO.
Conclusions
We have shown that a novel building block for self-assembly,
ureidopyrimidinone, is readily synthesized, and forms excep-
tionally stable dimers via quadruple hydrogen bonds, with
dimerization constants exceeding 106 M-1 in CDCl3. The
tautomeric form of the compound changes from keto to enol
when electron-withdrawing substituents are introduced at the
6-position, thus affording two discrete self-complementary
hydrogen-bonding units with DDAA and DADA arrays, re-
spectively. The dimerization constant of the enol form of 1a
is very much higher than predicted in the literature for dimers
of DADA arrays. Derivatives with n-alkyl substituents at both
the ureido group and at the 6-position are excusively present
as 4[1H]-pyrimidinone tautomers.
Figure 7. Plot of log Kdim* vs solvent composition of compounds 1a
(2) and 1k (]) in CDCl3/DMSO-d6 mixtures; solid lines serve to guide
the eye.
Nevertheless, from inspection of Figure 7, the conclusion can
be drawn that the complex dimerization constant Kdim* of
6-methylisocytosine derivative 1a in pure chloroform signifi-
cantly exceeds 106 M-1, and that Kdim* of 6-trifluoromethyl-
isocytosine derivative 1kspresent as a DADA dimer of a
pyrimidin-4-ol tautomersis lower than that of 1a by roughly 4
orders of magnitude in CDCl3/DMSO-d6 mixtures.
The ready availability of compounds with high dimerization
strength and predictable tautomerism opens the way to su-
pramolecular architectures such as supramolecular polymers
with a high degree of polymerization, which is the subject of a
recent paper by us.18
Discussion
In solution, three different tautomeric forms of 2-ureido-4-
pyrimidinone derivatives are observed, which are proposed to
be related by the equilibria shown in Figure 2. The equilibrium
constants are dependent on substituent, solvent, and concentra-
tion. Two of the tautomers strongly dimerize via quadruple
hydrogen bonds. For application as a supramolecular building
block, a high dimerization constant is advantageous, and for a
predictable recognition process a single tautomer should be
present in solution. In chloroform, 6-alkyl derivatives of
ureidopyrimidinone like 1a and trifluoromethyl derivative 1k
meet these requirements.
As can be seen from Figure 2, the Kdim* values that were
used as an expression for the complex dimerization constant of
1a and 1k in CDCl3/DMSO-d6 mixtures, are equivalent to the
product of the Kdim of a single tautomer and the square of the
tautomeric equilibrium constant Ktaut. As in CDCl3/DMSO-d6
mixtures the latter constant is smaller than one (nearly all
monomer is in the 6[1H]-pyrimidinone form), the actual Kdim
Experimental Section
General Methods. Chemicals, including â-keto esters 2c, 2d, 2e,
and methylisocytosine 3a were purchased from Acros Chimica, Fluka,
or Aldrich and used as received unless otherwise stated. All reactions
were carried out under an atmosphere of dry nitrogen unless otherwise
stated. Solvents were of technical grade unless otherwise stated.
Anhydrous THF and diethyl ether were obtained by distillation from
sodium/potassium/benzophenone; analytical grade pyridine, ethanol and
2-propanol were dried over 4 Å molecular sieves. NMR spectra were
recorded on a Varian Gemini 300 or a Bruker AC400 spectrometer.
Chemical shifts are given in parts per million (ppm) relative to TMS.
1
For the H NMR titrations, deuteriochloroform was used as received.
IR spectra were recorded on a Perkin-Elmer 1600 FTIR spectrometer.
Dry chloroform for the infrared experiments in solution was obtained
by purification of analytical grade chloroform by several extractions
with water, followed by drying over calcium chloride for 2 h and
distillation under an atmosphere of dry nitrogen. Spectra at concentra-
tions higher than 5 mM were taken in a 0.1 mm NaCl cell, for lower
concentrations a 1 mm cell was used. Melting points were determined
on a Jenaval THMS 600 melting point microscope and are uncorrected.
Liquid crystalline materials are characterized by their isotropization
temperatures Ti.
values of the pure tautomers are higher than Kdim*
.
On the basis of an empirical evaluation, Schneider17 has
predicted association constants for the DADA and DDAA
dimers of 3.1 × 102 and 3.6 × 106 M-1 in chloroform. The
values of Kdim* observed for the DADA and DDAA arrays of
2-ureido-4-pyrimidinone derivatives led us to infer that the Kdim
values are higher than predicted by Schneider. The value found
for Kdim* of the pyrimidin-4-ol tautomer (>4.5 × 105 M-1) with
a DADA array exceeds the predicted Kdim value (310 M-1 for
DADA arrays) by at least 32 kJ mol-1. The high stability of
pyrimidin-4-ol dimers may be attributed to a combination of
two effects. First, the DADA array is preorganized by an
intramolecular hydrogen bond. In a recent paper,11 we have
shown that this strongly increases dimerization constants of
multiple hydrogen-bonded dimers. Second, the dimers of the
pyrimidin-4-ol tautomer contain a strong OsH‚‚‚OdC hydrogen
bond, whereas the free energy relationships of Schneider are
entirely based on NsH‚‚‚N and NsH‚‚‚OdC hydrogen bonds.
Determination of Kdim*. In each solvent mixture, integrated peak
areas of appropriate 1H NMR signals at 2-10 different concentrations
of 1a or 1k were measured. Kdim* was assigned the average value of
the intensity ratio (Idimeric tautomer)/(Imonomeric tautomer)2. For compound 1a,
the sharp CH3 signals were used, allowing integration down to 10-5
M
with an estimated relative error of 20%. For compound 1k, the broader
N-H signals were used. The relative error is estimated to be 40%.
X-ray Crystal Structure Analyses. Pertinent data for the structure
determinations are collected in tabular form in the Supporting Informa-
tion.
All data were collected on an Enraf-Nonius CAD4T diffractometer
on rotating anode (ω scan, T ) 150 K, Mo KR radiation, graphite
(18) Sijbesma, R. P.; Beijer, F. H.; Brunsveld, L.; Folmer, B. J. B.;
Hirschberg, J. H. K. K.; Lange, R. F. M.; Lowe, J. K. L.; Meijer, E. W.
Science 1997, 278, 1601.
(17) Sartorius, J.; Schneider, H.-J. Chem. Eur. J. 1996, 2, 1446.

Dimerization of Ureidopyrimidones
J. Am. Chem. Soc., Vol. 120, No. 27, 1998 6767
ν: 3365, 3146, 2920, 2850, 2713, 1662, 1634, 1553, 1468, 1400 cm-1
Anal. Calcd for C17H31N3O: C, 69.58; H, 10.65; N, 14.32. Found:
C, 69.74; H, 10.80; N, 14.00.
monochromator, λ ) 0.710 73 Å). Accurate unit-cell parameters and
an orientation matrix were determined by least-squares fitting of the
setting angles of 25 well-centered reflections (SET4).19 The unit-cell
parameters were checked for the presence of higher lattice symmetry.20
Data were corrected for Lp effects and for the observed linear decay
of the reference reflections. Structures were solved with SHELXS9621
and refined on F2 using SHELXL96.22 No observance criterion was
applied during refinement on F2. The hydrogen atoms of 1h (pyrimi-
dinone tautomer) were included in the refinement on calculated
positions; the hydrogen atoms of all other structures were located on a
difference Fourier map and their coordinates were included as
parameters in the refinement. The non-hydrogen atoms of all structures
were refined with anisotropic thermal parameters. The hydrogen atoms
were refined with a fixed isotropic displacement parameter related to
the value of the equivalent isotropic displacement parameter of their
carrier atoms. Neutral atom scattering factors and anomalous dispersion
corrections were taken from the International Tables for Crystal-
lography.23 Geometrical calculations and illustrations were performed
with PLATON;24 all calculations were performed on a DEC station
5000 cluster.
N-[(butylamino)carbonyl]-6-methylisocytosine (1a). A suspension
of 6-methylisocytosine 3a, (6.20 g, 0.050 mol) and butyl isocyanate
(10 mL, 0.090 mol) in dry pyridine (200 mL) was heated under reflux
for 2 h, giving a clear solution. Cooling induced the formation of
crystals. Acetone was added (200 mL), and the resulting microcrys-
talline powder was filtered. Recrystallization from ethanol/chloroform
9:1 v/v gave analytically pure 1a (3.30 g, 0.0197 mol, 99%), mp 225
°C with sublimation. X-ray-quality crystals were obtained by slow
evaporation of a dichloromethane solution to air. 1H NMR (CDCl3)
δ: 13.15 (s, 1H), 11.85 (s, 1H), 10.16 (s, 1H), 5.81(s, 1H), 3.24 (dd,
2H), 2.23 (s, 3H), 1.58 (m, 2H), 1.37 (m, 2H), 0.94 (tr, 3H). 13C NMR
(CDCl3) δ: 173.0, 156.5, 154.7, 148.1, 106.6, 39.7, 31.5, 20.1, 18.9,
13.7. IR (KBr) ν: (dimeric 4[1H]-pyrimidinone) 3215, 3147, 3036,
2954, 2916, 2870, 1704, 1665, 1583, 1528, 1252 cm-1. Anal. Calcd
for C10H16N4O2: C, 53.56; H, 7.19; N, 24.98. Found: C, 53.57; H,
7.36; N, 25.18.
.
N-[(Butylamino)carbonyl]-6-tridecylisocytosine (1c). A solution
of 6-tridecylisocytosine, 3b (10.22 g, 0.036 mol), and butyl isocyanate
(6.8 mL, 0.060 mol) in dry pyridine (200 mL) was heated under reflux
for 2h. After cooling, the solution was evaporated to dryness.
Treatment of the residue in hot acetone with active carbon and
crystallization afforded analytically pure 1c as tiny needles (11.6 g,
82%), mp 118 °C. 1H NMR (CDCl3) δ: 13.18 (s, 1H), 11.88 (s, 1H0,
10.17 (s, 1H), 5.82 (s, 1H), 3.24 (q, 2H), 2.45 (t, 2H), 1.62 (m, 4H),
1.31 (m, 22 H), 0.90 (m, 6H). 13C NMR (CDCl3) δ: 174, 157, 155,
152, 106, 41, 33, 32, 30 (multiple peaks), 24, 21, 15, 14. IR (KBr) ν:
(pyrimidin-4-ol tautomer) 3203, 3130, 3012, 2955, 2920, 2849, 2498,
1666, 1610, 1557, 1453, 1318 cm-1. Anal. Calcd for C22H41N4O2:
C, 67.31; H, 10.27; N, 14.35. Found: C, 67.31; H, 10.41; N, 14.35.
N-[(tert-Butylamino)carbonyl]-6-tridecylisocytosine (1d). A solu-
tion of 6-tridecylisocytosine, 3b (0.56 g, 2 mmol) and tert-butyl
isocyanate (0.3 mL, 2.6 mmol) in dry pyridine (10 mL) was heated
under reflux for 2 h. After cooling, the suspension was diluted with
acetone, and the precipitated powder was filtered. Crystallization from
acetone gave pure 1c as needles (0.55 g, 70%), mp 117.3-117.9 °C.
1H NMR (CDCl3) δ: 13.22 (s, 1H), 11.72 (s, 1H0, 9.57 (s, 1H), 5.81
(s, 1H), 2.45 (t, 2H), 1.63 (m, 2H), 1.42 and 1.31 (m, 29H), 0.88 (t,
3H); furthermore 3.5% of pyrimidin-4-ol tautomer: 13.5 (s, 1H), 11.0
(s, 1H), 10.0 (s, 1H), 6.1 (s, 1H), 2,6 (m, 2H), other peaks overlap
with peaks of main tautomer. 13C NMR (CDCl3) δ: 173.0, 155.9,
155.0, 152.1, 105.7, 51.2, 32.6, 31.7, 29.6, 29.6, 29.4 (multiple peaks),
29.3, 29.2, 29.0, 28.8, 26.9, 22.7, 14.1. IR (KBr) ν: (pyrimidin-4-ol
tautomer) 3224, 3133, 2922, 2850, 2490, 1664, 1612, 1560, 1458, 1330
cm-1. Anal. Calcd for C22H41N4O2: C, 67.31; H, 10.27; N, 14.35.
Found: C, 67.57; H, 10.36; N, 14.30.
N-[(Phenylamino)carbonyl]-6-tridecylisocytosine (1e). A solution
of 6-tridecylisocytosine, 3b, (2.93 g, 0.010 mol) and phenyl isocyanate
(2.1 mL, 0.018 mol) in dry pyridine (50 mL) was heated under reflux
for 2 h. After cooling, the suspension was diluted with acetone and
the resulting powder was filtered. Crystallization from acetone/
chloroform 2:1 v/v afforded analytically pure 1e (1.25 g, 30%), mp
155-156 °C. 1H NMR (CDCl3) δ: 13.0 (s, 1H), 12.21 and 12.19 (2*m,
1H), 7.70 (d, 2H), 7.34 (t, 2H), 7.09 (t, 1H), 5.83 (s, 1H), 2.30 (t, 2H),
1.53 (m, 2H), 1.26 (m, br, 20 H), 0.88 (t, 3H). 13C NMR (CDCl3) δ:
173.0, 154.6, 152.8, 142.0, 138.2, 128.9, 123.9, 120.6, 106.0, 32.5,
32.0, 29.6, 29.6, (multiple peaks), 29.4, 29.4, 29.2, 28.8, 26.6, 22.7,
14.1. IR (KBr) ν: (4[1H]-pyrimidinone tautomer) 3133, 3022, 2910,
2850, 1701, 1660, 1580, 1500 cm-1. Anal. Calcd for C24H36N4O2:
C, 69.87; H, 8.79; N, 13.58. Found: C, 69.97; H, 8.99; N, 13.49.
N-[(tert-Butylamino)carbonyl]-6-methylisocytosine (1b). A sus-
pension of 6-methylisocytosine 3a, (1.24 g, 0.010 mol) and tert-butyl
isocyanate (1.7 mL, 0.015 mol) in dry pyridine (25 mL) was heated
under reflux for 4 h, giving a clear solution. Cooling induced the
formation of crystals. Acetone was added (50 mL), and the resulting
powder was filtered. Recrystallization from acetone/chloroform 1:1
v/v gave analytically pure 1b (0.46 g, 21%), mp 203-204 °C (dec).
1H NMR (CDCl3) δ: 13.14 (s, 1H), 11.73 (s, 1H), 9.53 (s, 1H), 5.81
(s, 1H), 2.22 (s, 3H), 1.43 (s, 9H). 13C NMR (CDCl3) δ: 172.8, 155.8,
154.9, 147.9, 106.7, 51.3, 28.8, 18.9. IR (KBr) ν: (dimeric 4[1H]-
pyrimidinone) 3212, 2970, 1698, 1674, 1636, 1586, 1521, 1265 cm-1
.
N-[[(p-Nitrophenyl)amino]carbonyl]-6-tridecylisocytosine (1f). A
solution of 6-tridecylisocytosine, 3b, (0.44 g, 1.5 mmol) and p-
nitrophenyl isocyanate (0.27 g, 1.6 mmol) in dry pyridine (20 mL)
was heated under reflux overnight. The resulting suspension was
evaporated to dryness, and the yellow powder was extracted with hot
toluene. Crystallization from acetic acid afforded analytically pure 1f,
mp 234.5-237.5 °C. 1H NMR (CDCl3, 55 °C, saturated at low
concentration) δ: 12.83 (s, 1H), 12.7 (s, br, 1H), 12.36 (s, br, 1H),
8.20 (d, 2H), 7.94 (d, 2H), 5.99 (s, 1H), 2.56 (t, 2H), 1.71 (s, 2H),
1.27 (s, br, 20 H), 0.88 (t, 3H). IR (KBr) ν: (4[1H]-pyrimidinone
tautomer) 3067, 2920, 2850, 2750, 1712, 1656, 1625, 1574, 1511, 1500,
1334, 1240 cm-1. Anal. Calcd for C24H35N5O4: C, 63.00; H, 7.71;
N, 15.31. Found: C, 62.65; H, 7.63; N, 15.49.
N-[[[p-(diethylamino)phenyl]amino]carbonyl]-6-tridecylisocy-
tosine (1g). A solution of 6-tridecyl-isocytosine, 3b (2.93 g, 10 mmol),
and p-(diethylamino)phenyl isocyanate25 (3.0 g, 15 mmol) in dry
pyridine (20 mL) was heated under reflux for 4 h. Water was added
to the cooled solution, resulting in precipitation of a brown gum, which
was crystallized from acetone/water/ethanol 20:10:1 v/v/v with treatment
with active carbon. Recrystallization from acetone/ethanol 1:1 v/v gave
analytically pure 1g (1.04 g, 22%), mp 76-90 °C. 1H NMR (CDCl3)
δ: 13.09 (s, 1H), 12.12 (s, 1H), 11.97 (s, 1H), 7.49 (d, 2H), 6.67 (d,
Anal. Calcd for C10H16N4O2: C, 53.56; H, 7.19; N, 24.98. Found:
C, 53.76; H, 7.29; N, 25.04.
6-Tridecylisocytosine (3b). Crude â-keto ester 2b11 (136.1 g,
containing 0.29 mol of keto ester) in ethanol (220 mL) was heated
under reflux with guanidinium carbonate (30.6 g, 0.17 mol) overnight.
The resulting clear, yellow solution was partially evaporated, and then
cooled, inducing precipitation of a white powder. Addition of hexane
(500 mL) and then water (500 mL) resulted in the precipitation of more
white powder, which was filtered off, and washed thoroughly with water
and acetone. Crystallization from ethanol gave pure 3b as tiny plates
(39.7 g, 36%), mp 181 °C. 1H NMR (DMSO-d6) δ: 10.57 (s, 1H),
6-7 (br, 2H), 5.36 (s, 1H), 2.24 (t, 2H), 1.55 (t, 2H), 1.26 (m, 20 H),
0.86 (t, 3H). 13C NMR (DMSO-d6) δ: 171.8, 162.7, 155.0, 99.2, 36.1,
30.4, 28.1 (multiple peaks), 26.6 (multiple peaks), 21.1, 12.6. IR (KBr)
(19) de Boer, J. L.; Duisenberg, A. J. M. Acta Crystallogr. 1984, A40,
C-410.
(20) Spek, A. L. J. Appl. Crystallogr. 1988, 21, 578.
(21) Sheldrick, G. M. SHELXS96 Program for crystal structure deter-
mination; University of Go¨ttingen: Germany, 1996.
(22) Sheldrick, G. M. SHELXL96 Program for crystal structure refine-
ment; University of Go¨ttingen: Germany, 1996.
(23) Wilson, A. J. C., Ed. International Tables for Crystallography,
Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992; Volume
C.
(25) Benn, M. H.; Creighton, A. M.; Owen, L. N.; White, G. R. J. Chem.
Soc. 1961, 2365.
(24) Spek, A. L. Acta Crystallogr. 1990, A46, C-34.

6768 J. Am. Chem. Soc., Vol. 120, No. 27, 1998
Beijer et al.
2H), 5.75 (s, 1H), 3.32 (m, 4H), 2.19 (m, 2H), 1.48 (m, 2H), 1.24 (m,
br, 20 H), 1.14 (tr, 3H), 0.88 (t, 3H). 13C NMR (CDCl3): 173.0, 154.6,
152.5, 144.8, 126.8, 122.5, 112.7, 105.6, 44.6, 32.3, 31.7, 29.6-29.2
(multiple peaks), 28.7, 26.5, 22.6, 14.1, 12.5. IR (KBr) ν: (4[1H]-
pyrimidinone tautomer) 3128, 3030, 2923, 2851, 1698, 1663, 1616,
1587, 1512, 1326, 1243 cm-1. Anal. Calcd for C28H45N5O2: C, 69.53;
H, 9.38; N, 14.48. Found: C, 69.99; H, 9.56; N, 14.33.
was prepared by trituration with hot acetic acid, mp 271-283 °C (dec).
1H NMR (CDCl3, 60 °C) 4[1H]-pyrimidinone tautomer (40%): 14.35,
12.10, 10.10, 8.4, 8.05, 6.44, pyrimidin-4-ol tautomer (60%): 13.93,
11.32, 9.74, 8.4, 6.80. Not assigned: 3.5, 3.3, and 3.1 (m, CH2-N),
1.7-1.0 (CH2), 0.9 (CH3). 13C NMR (DMSO-d6, 110 °C): 161.2,
158.7, 154.0, 151.8, 148.2, 142.2, 127.3, 122.8, 103.5, 30.6, 29.4, 28.7
(multiple peaks), 25.7, 21.2, 12.9. IR (KBr) ν: (pyrimidin-4-ol
tautomer) 3228, 3136, 3091, 3024, 2953, 2919, 2849, 2516, 1665, 1618,
1567, 1533, 1456, 1348, 1331 cm-1. Anal. Calcd for C29H45N5O4:
C, 66.00; H, 8.59; N, 13.27. Found: C, 65.94; H, 8.79; N, 12.81.
6-(Trifluoromethyl)isocytosine26 (3e). A mixture of ethyl trifluo-
roacetoacetate, 2e, (9.2 g, 0.05 mol) and guanidinium carbonate (4.68
g, 0.026 mol) in absolute ethanol (50 mL) was heated under reflux
overnight. After cooling, water (100 mL) was added. The solvent
was partially removed by evaporation, resulting in precipitation of pure
3e (5.63 g, 63%). Sublimation at 220-240 °C yields large crystals,
which melt at 289 °C (Lit.26 mp 282 °C). 1H NMR (DMSO-d6): 9-12
(br, 1H), 6.99 (br, 2H), 5.90 (s, 1H). 13C NMR (DMSO-d6): 162.9,
157.2, 153.0 (q), 120.8 (q), 98.5. IR (KBr) ν: 3456, 3330, 3166, 2938,
2767, 1678, 1644, 1496, 1446 cm-1. Anal. Calcd for C5H4N3OF3:
C, 33.53; H, 2.25; N, 23.46. Found: C, 32.05; H, 2.73; N, 24.04.
N-[(Butylamino)carbonyl]-6-(trifluoromethyl)isocytosine (1k). A
suspension of 6-(trifluoromethyl)isocytosine, 3e (1.79 g, 10 mmol), and
butyl isocyanate (1.0 mL, 18 mmol) in dry pyridine (25 mL) was heated
under reflux for 4 h. After cooling, the solution was evaporated to
dryness, and the resulting powder was crystallized from acetone with
treatment with active carbon. Cooling to 0 °C resulted in the formation
of white crystals (0.74 g, 27%), mp 178.3-185.5. 1H NMR (CDCl3)
δ: 14.30 (s, 1H), 11.14 (s, 1H), 9.30 (s, 1H), 6.64 (s, 1H), 3.38 (m,
2H), 1.58 (m, 2H), 1.43 (m, 2H), 0.97 (t, 3H) ppm. 13C NMR (CDCl3,
60 °C) δ: 172.6, 157.8, 156.4, 155.5 (q), quartet at (124.4, 121.6, 118.9,
116.2), 100.1, 40.0, 31.3, 19.9, 13.5 ppm. IR (KBr) ν: (pyrimidin-4-
ol tautomer) 3263, 3150, 3115, 3052, 2969, 2937, 2864, (2594, 2529,
2466, 2398), 1673, 1622, 1563, 1477, 1453, 1340, 1268, 1196, 1143
cm-1. Anal. Calcd for C10H13N4O2F3: C, 43.17; H, 4.71; N, 20.14.
Found: C, 43.54; H, 4.89; N, 20.23.
6-Phenylisocytosine (3c). A mixture of ethyl benzoylacetate 2c
(19.2 g, 0.10 mol) and guanidinium carbonate (9.09 g, 0.05 mol) in
absolute ethanol (100 mL) was heated overnight. After cooling, the
precipitated white powder was filtered off, and washed thoroughly with
ethanol, water, and acetone. Drying gave pure 3c (12.02 g, 64%), mp
312 °C. 1H NMR (DMSO-d6, 115 °C): 10.84 (br, 1H), 7.9 (m, 2H),
7.43 (m, 3H), 6.62 (br, 2H), 6.11 (s, 1H). 13C NMR (DMSO-d6) δ:
162.8, 162.2, 155.2, 137.1, 128.9, 127.4, 125.9, 97.4. IR (KBr) ν: 3350,
3087, 2956, 1658, 1502, 1476, 1380 cm-1
.
Anal. Calcd for
C10H9N3O: C, 64.16; H, 4.85; N, 22.45. Found: C, 64.05; H, 4.85;
N, 22.52.
N-[(Butylamino)carbonyl]-6-phenylisocytosine (1h). A suspension
of 6-phenylisocytosine 3c (1.93 g, 10 mmol) and butyl isocyanate (1.7
mL, 15 mmol) in dry pyridine (40 mL) was heated under reflux for 4
h. After cooling, acetone was added, and the precipitated white powder
was filtered off. Crystallization from ethanol/chloroform 1:1 v/v gave
analytically pure 1h (2.34 g, 82%), mp 245 °C (pyrimidin-4-ol
tautomer). 1H NMR (CDCl3) δ: 13.92 (s, 1H), 12.04 (s, 1H), 10.21,
s, 1H), 7.67 (m, 2H), 7.54 (m, 3H), 6.35 (s, 1H), 3.30 (m, 2H), 1.65
(q, 2H), 1.42 (q, 2H), 0.88 (t, 3H); 14% of pyrimidin-4-ol tautomer at
13.6 (2, 1H), 11.3 (s, 1H), 10.0 (s, 1H), 6.7 (m, 2H), 3.5-3.4 (m, 2H),
other peaks obscured by signals of main tautomer. 13C NMR (CDCl3)
δ: 173.2, 157.0, 155.4, 148.8, 131.4, 129.6, 125.8, 104.4, 40.0, 31.6,
20.2, 13.9; pyrimidin-4-ol tautomer at 157.0, 137.0, 130.7, 128.9, 126.9,
39.9, 31.8, other peaks obscured by signals of main tautomer. IR (KBr)
ν: (pyrimidin-4-ol tautomer) 3208, 3134, 3025, 2955, 2930, 2870, 2502,
1657, 1612, 1556, 1441, 1328 cm-1. (4[1H]-pyrimidinone tautomer)
3202, 3133, 3010, 2958, 2871, 1692, 1656, 1588, 1528, 1255 cm-1
Anal. Calcd for C15H18N4O2: C, 62.92; H, 6.34; N, 19.57. Found:
C, 63.10; H, 6.41; N, 19.34.
Methyl 3,4,5-Tris(dodecyloxy)benzoylacetate (8). To a solution
of ethyl acetoacetate (10.93 g, 0.084 mol) in dry ether (68 mL) was
added a solution of sodium ethoxide (0.0808 mol) in absolute ethanol
(40 mL), while the temperature was maintained below 5 °C by cooling
with an ice-salt bath. At the same temperature, crude acid chloride
615 (0.040 mol) in dry ether (100 mL) was added dropwise, and the
resulting thick suspension was stirred overnight at room temperature.
The suspension was poured into dilute sulfuric acid, and dichlo-
romethane was added. The layers were separated, and the aqueous
layer was extracted with dichloromethane. Further workup of the
combined organic phases included washing with a dilute sodium
hydrogen carbonate solution (twice), dilute hydrochloric acid (twice),
and water (three times), drying over sodium sulfate, filtration, and
evaporation to dryness. The resulting white solid (crude 7) was
dissolved in dry toluene (20 mL), and a solution of sodium methoxide
(0.06 mol) in methanol (70 mL) was added slowly. The suspension
was heated to reflux to achieve complete dissolution and then stirred
overnight at room temperature. The solution was poured into ice-cold
dilute sulfuric acid, and the aqueous phase was extracted with ether/
hexane. The combined organic phases were consecutively extracted
with dilute hydrochloric acid (twice), sodium hydrogen carbonate
solution (twice), and finally with water (three times). The organic phase
was dried over sodium sulfate, filtered, and evaporated to dryness. Two
repetitive recrystallizations from 2-propanol afforded 8 (20.58 g, 70%),
of sufficient for purity (>98%) for further synthesis. An analytically
pure sample was obtained by column chromatography with hexane/
ethyl acetate 5:1 v/v, followed by crystallization from 2-propanol. Ti
) 46 °C. 1H NMR (CDCl3): 7.17 (s, 2H), 4.03 (m, 6H), 3.75 (s, 3H),
1.8-1.7 (m, 6H), 1.47 (m, 6H), 1.28 (m, 48H), 0.88 (t, 9H). 13C NMR
(CDCl3) δ: 191.0, 167.9, 152.9, 143.4, 130.7, 107.2, 73.5, 69.2, 69.1,
52.3, 45.6, 31.8, 30.3, 29.6-29.2 (multiple peaks), 26.0, 29.95, 22.6,
14.0 ppm. IR (KBr) ν: 2919, 2849, 1744, 1725, 1677, 1583, 1468,
1429, 1341, 1121 cm-1. Anal. Calcd for C46H80O6: C, 75.78; H, 11.06.
Found: C, 75.63; H, 10.91.
N-[(tert-Butylamino)carbonyl]-6-phenylisocytosine (1i). A sus-
pension of 6-phenylisocytosine 2c (0.98 g, 5 mmol) and tert-butyl
isocyanate (0.86 mL, 7.5 mmol) in dry pyridine (20 mL) was heated
under reflux for 2 h. After cooling, acetone was added, and the white
crystals were filtered off (1.14 g, 80%), mp 259 °C (dec). 1H NMR
(CDCl3) δ: (equimolar ratio of pyrimidin-4-ol and 4[1H]-pyrimidinone
tautomer) 14.03 (br, 0.5H), 13.79 (s, 0.5H), 11.90 (s, 0.5 H) and 11.12
(s, 0.5 H), 10.02 (s, 0.5 H) and 9.60 (br, 0.5H), 7.90 (1H), 7.67 (1H),
7.54 and 7.49 (3H), 6.70 (br, 0.5H), 6.36 (s, 0.5H), 1.47 (s, 9H). 13C
NMR (CDCl3) δ: 158, 148.6, 136.8, 131.4, 130.7, 129.6, 128.7, 126.9,
125.7, 104.4, 98, 51.4, 51.1, 29.1, 29.8. IR (KBr) ν: (pyrimidin-4-ol
tautomer) 3214, 3138, 3030, 2974, 2502, 1658, 1609, 1560 cm-1. Anal.
Calcd for C15H18N4O2: C, 62.92; H, 6.34; N, 19.57. Found: C, 63.40;
H, 6.46; N, 19.67.
6-(p-Nitrophenyl)isocytosine (3d). A mixture of ethyl p-nitroben-
zoylacetate, 2d (11.86 g, 0.05 mol), and guanidinium carbonate (4.86
g, 0.027 mol) in absolute ethanol (50 mL) was heated overnight. After
cooling, the dark yellow powder was filtered off and washed thoroughly
with acetone, water, and ethanol. The dark yellow-brown powder was
triturated at reflux temperature with water/ethanol 1:1 v/v (1 L) resulting
in partial solution, then cooled, to afford yellow microneedles. This
procedure was repeated twice and then the nice yellow microneedles
in suspension were decanted and filtered from a brown residue. Drying
the needles gave pure 2d (3.49 g, 30%), mp >300 °C (dec). 1H NMR
(DMSO-d6) δ: 11.05 (s, 1H), 8.28 (d, 2H), 8.21 (d, 2H), 6.78 (br,
2H), 6.30 (s, 1H). 13C NMR (DMSO-d6) δ: 163.3, 161.0, 156.0, 148.1,
143.5, 127.9, 123.5, 99.6. IR (KBr) ν: 3440, 3286, 3167, 3116, 2966,
1662, 1611, 1544, 1345 cm-1. Anal. Calcd for C10H8N4O3: C, 51.60;
H, 3.71; N, 24.07. Found: C, 51.33; H, 3.91; N, 24.44.
N-[(Octadecylamino)carbonyl]-6-(p-nitrophenyl)isocytosine (1j).
A suspension of 6-(p-nitrophenyl)isocytosine, 3d (0.92 g, 4 mmol),
and octadecyl isocyanate (2.36 g, 8 mmol) in dry pyridine (15 mL)
was heated under reflux for 4 h. After cooling, acetone was added,
and the powder was filtered off (2.16 g, 105%). An analytical sample
(26) Giner-Sorolla, A.; Bendich, A. J. Am. Chem. Soc. 1958, 80, 5744.

Dimerization of Ureidopyrimidones
J. Am. Chem. Soc., Vol. 120, No. 27, 1998 6769
6-[3,4,5-Tris(dodecyloxy)phenyl]isocytosine (9). A solution of
methyl 3,4,5-tris(dodecyloxy)benzoylacetate, 8 (5.86 g, 0.008 mol), and
guanidinium carbonate (0.87 g, 0.0048 mol) in absolute ethanol (30
mL) was heated under reflux overnight. The solution was evaporated
to dryness and the residue was dissolved in dichloromethane (300 mL).
The solution was extracted with water several times, and dried over
sodium sulfate. Ethanol was added (200 mL), and the solution was
heated under reflux, treated with active carbon, and filtered. Slow
addition of water to the colorless filtrate, and slow reduction of the
volume by evaporation resulted in the precipitation of pure 9 (3.2 g,
54%), Ti ) 130 °C. 1H NMR (CDCl3): 12.35 (br, 1H), 7.11 (s, 2H),
6.16 (s, 1H), 5.88 (br, 2H), 4.01 (s, 6H), 1.8-1.7 (m, 6H). 1.48 (m,
6H), 1.26 (m, br, 48H), 0.88 (t, 9H). 13C NMR (CDCl3) δ: 159.8,
154.0, 153.8, 151.4, 142.7, 123.6, 105.8, 100.4, 73.7, 70.0, 31.9, 30.5,
29.7-29.5 (multiple peaks), 29.3, 26.2, 26.1, 22.6, 13.9 ppm. IR (KBr)
13C NMR (CDCl3) δ: (4[1H]-pyrimidinone tautomer) 173.2, 154.9,
154.7, 153.8, 149.1, 141.1, 138.2, 128.7, 125.5, 123.7, 120.4, 104.0,
103.8, 73.6, 69.3, 31.9, 30.3, 29.8-29.3 (multiple peaks), 26.1, 22.7,
14.1. IR (KBr) ν: 3205, 3128, 3060, 2919, 2050, 1691, 1646, 1590,
1567, 1499, 1329, 1258, 1120 cm-1. Anal. Calcd for C53H86N4O5‚
H2O: C, 72.6; H, 10.1; N, 6.4. Found: C, 72.85; H, 10.09; N, 6.18.
N-[[(p-Nitrophenyl)amino]carbonyl]-6-[3,4,5-tris(dodecyloxy)phe-
nyl]isocytosine (10c). A solution of 6-[3,4,5-tris(dodecyloxy)phenyl]-
isocytosine (9) (0.37 g, 0.50 mmol) and p-nitrophenyl isocyanate (0.16
g, 1.0 mmol) in dry pyridine (5 mL) was heated under reflux for 3 h.
After cooling, acetone was added, and the resultant white powder was
filtered. The powder was dissolved in hot chloroform/acetone 1:1 v/v,
treated hot with active charcoal, and filtered hot. Cooling resulted in
the precipitation of pure 10c as a white powder, which was filtered
(0.23 g, 51%), Ti ) 261 °C (dec). 1H NMR (CDCl3) δ: (4[1H]-
pyrimidinone tautomer) 13.51 (s, 1H), 12.85 (s, 1H), 12.46 (s, 1H),
8.09 (d, 2H), 7.88 (d, 2H), 6.74 (d, 2H), 6.29 (s, 1H), 4.00 (m, 6H),
1.83 (m, 4H), 1.78 (m, 2H), 1.49 (m, 6H), 1.27 (m, br, 48H), 0.88 (t,
9H). 13C NMR (CDCl3 50 °C) δ: 172.9, 154.9, 154.5, 154.1, 149.1,
144.5, 143.4, 142.4, 124.5, 124.3, 119.4, 104.3, 103.4, 73.8, 69.8, 32.0,
30.5, 29.8-29.4 (multiple peaks), 26.2, 26.2, 22.7, 14.0. IR (KBr) ν:
3052, 2955, 2920, 2849, 1701, 1649, 1629, 1582, 1567, 1512, 1498,
1332, 1264, 1226 cm-1. Anal. Calcd for C53H85N5O7: C, 70.40; H,
9.47; N, 7.74. Found: C, 70.51; H, 9.50; N, 7.72.
ν: 3155, 2922, 2851, 1654, 1467, 1119 cm-1
. Anal. Calcd for
C46H80N3O4: C, 74.75; H, 10.91; N, 5.68. Found: C, 74.67; H, 10.91;
N, 5.73.
N-[(Butylamino)carbonyl]-6-[3,4,5-tris(dodecyloxy)phenyl]isocy-
tosine (10a). A solution of 6-[3,4,5-tris(dodecyloxy)phenyl]isocytosine
(9) (1.70 g, 0.0023 mol) and butyl isocyanate (0.73 mL, 0.0065 mol)
in dry pyridine (20 mL) was heated under reflux for 3 h. The solution
was evaporated to dryness, and the residue was codistilled with toluene.
The resultant dark yellow gum was dissolved in hot hexane, and the
resultant solution was treated with sodium dihydrogen phosphate with
a few drops water, dried over sodium sulfate, treated with active carbon,
and then filtered through Celite. Evaporation gave a yellowish gum,
which was dissolved in hot dichloromethane/acetone 1:1 v/v. Cooling
and slow evaporation in air resulted in the precipitation of white
microneedles (1.09 g, 56%), Ti ) 131 °C. 1H NMR (CDCl3) δ: (4[1H]-
pyrimidinone tautomer) 13.9, (s, 1H), 12.04 (s, 1H), 10.19 (s, 1H),
6.82 (s, 2H), 6.25 (s, 1H), 4.02 (m, 6H), 3.29 (m, 2H), 1.84 (m, 6H),
1.75 (m, 2H), 1.63 (m, 2H), 1.42 (m, 6H), 1.27 (m, br, 48H), 0.94 (m,
3H), 0.88 (m, 9H); [pyrimidin-4-ol tautomer (13%)] 13.62 (s, 1H), 11.38
(s, 1H), 10.00 (s, 1H), 7.05 (s, 2H), 6.62 (s, 1H), 3.42 (m, br, 2H),
other peaks overlap with peaks of main tautomer. 13C NMR (CDCl3)
δ: (4[1H]-pyrimidinone tautomer) 173.3, 156.7, 155.0, 153.8, 149.1,
140.9, 125.9, 104.1, 103.6, 73.6, 69.3, 39.8, 31.9, 31.5, 30.3, 29.7-
29.2 (multiple peaks), 26.0, 22.7, 20.2, 14.1, 13.8. IR (KBr) ν: 3226,
N-[[[p-(Diethylamino)phenyl]amino]carbonyl]-6-[3,4,5-tris(dode-
cyloxy)phenyl]isocytosine (10d). A solution of 6-[3,4,5-tris(dodecyl-
oxy)phenyl]isocytosine (9) (0.37 g, 0.50 mmol) and p-(diethylamino)-
phenyl isocyanate (0.19 g, 1.0 mmol) in dry pyridine (5 mL) was heated
under reflux for 3 h. The solution was cooled to room temperature,
acetone was added, and the white powder was filtered off. Dissolution
of the powder in hot dichloromethane/acetone mixture and slow
evaporation of the solution resulted in the precipitation of 10d as a
creamy-white powder (0.28 g, 60%), Ti ) 134.5-135 °C. 1H NMR
(CDCl3) δ: (4[1H]-pyrimidinone tautomer) 13.83 (s, 1H), 12.34 (s,
1H), 11.91 (s, 1H), 7.51 (d, 2H), 6.84 (s, 2H), 6.68 (d, 2H), 6.33 (s,
1H), 4.0 (m, 6H), 3.33 (dd, 4H), 1.84 (m, 4H), 1.73 (m, 2H), 1.47 (m,
6H), 1.26 (m, 48 H), 1.15 (t, 4H), 0.88 (t, 9H); [pyrimidin-4-ol tautomer
(15%)] 13.45 (s, 1H), 12.04 (s, 1H), 11.49 (s, 1H), 7.38 (d, 2H), 7.13
(s, 2H), 6.65 (s, 1H), other peaks overlap with peaks of main tautomer.
13C NMR (CDCl3) δ: (4[1H]-pyrimidinone tautomer) 173.3, 155.0,
154.6, 153.8, 153.5, 149.1, 144.9, 141.0, 126.8, 125.9, 122.4, 112.7,
112.3, 105.4, 104.1, 103.8, 73.6, 69.3, 44.6, 44.5, 31.9, 30.4, 30.3, 29.7-
29.2 (multiple peaks), 26.1, 26.0, 22.7, 14.1, 12.5. IR (KBr) ν: 3215,
3128, 2923, 2852, 2500, 1691, 1643, 1606, 1514, 1332, 1257, 1229,
1118 cm-1. Anal. Calcd for C57H95N5O5: C, 73.58; H, 10.29; N, 7.53.
Found: C, 73.91; H, 10.39; N, 7.54.
3132, 3020, 2952, 2920, 2850, 1694, 1639, 1608, 1336, 1121 cm-1
.
Anal. Calcd for C51H90N4O5: C, 72.99; H, 10.81; N, 6.68. Found:
C, 73.19; H, 11.12; N, 6.94.
N-[(Phenylamino)carbonyl]-6-[3,4,5-tris(dodecyloxy)phenyl]iso-
cytosine (10b). A solution of 6-[3,4,5-tris(dodecyloxy)phenyl]isocy-
tosine, 9 (0.37 g, 0.50 mmol), and phenyl isocyanate (0.22 mL, 2.0
mmol) in dry pyridine (5 mL) was heated under reflux for 3 h. The
solution was cooled to room temperature, acetone was added, and the
white powder was filtered off. Crystallization from ethanol gave
analytically pure 10b as a white powder (0.03 g, 7%), Ti ) 235-240
°C. 1H NMR (CDCl3) δ: (4[1H]-pyrimidinone tautomer) 13.77 (s,
1H), 12.39 (s, 1H), 12.24 (s, 1H), 7.72 (d, 2H), 7.28 (d, 2H), 7.06 (t,
1H), 6.60 (s, 2H), 6.32 (s, 1H), 4.0 (m, 6H), 1.84 (m, 4H), 1.73 (m,
2H), 1.47 (m, 6H), 1.26 (m, 48H), 1.15 (t, 4H), 0.88 (t, 9H); [pyrimidin-
4-ol tautomer (7%)] 13.25 (s, 1H), 12.40 (s, 1H), 11.49 (s, 1H), 7.55
(br, 2H), 6.66 (s, 1H), other peaks overlap with peaks of main tautomer.
Supporting Information Available: Further details of the
structure determinations, including atomic coordinates, bond
lengths and angles and thermal parameters (1 page, print/PDF).
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JA974112A