Synthesis and self-association of 4-pyrimidinones

Article abstract of DOI:10.1021/jo981285p

Crystallization of 4-pyrimidinone from CHCl₃ produced colorless needles that were shown by X-ray crystallography to consist of cyclic hydrogen- bonded dimers 2 of the 4(3H)-pyrimidinone tautomer 1. Vapor-pressure osmometry established that a simple derivative, 5-(2-phenylethyl)- 4(3H)pyrimidinone (5), self-associates in solution with a value of K(a) (220 ± 110 m^-1 at 26 °C in CH₂Cl₂) close to that measured for 2-pyridinone under similar conditions. These observations suggest that 4-pyrimidinones and 2-pyridinones have similar modes and degrees of association and should be equally suitable for use as sticky functional groups that can be incorporated in complex molecules to make them associate in particular ways. This hypothesis was tested by synthesizing three dipyrimidinones (12, 16, and 21) designed to form strongly hydrogen-bonded dimers and by making a tetrapyrimidinone (26) designed to self-associate and to thereby generate a three-dimensional hydrogen-bonded network. In all cases, however, the compounds proved to have very low solubilities in organic solvents, and crystals suitable for X-ray diffraction could not be obtained despite intensive effort. It is possible that the simultaneous presence of multiple tautomers, all capable of strong intermolecular association, disfavors the sustained growth of single crystalline phases.

Full text of DOI:10.1021/jo981285p

9746
J . Org. Chem. 1998, 63, 9746-9752
Syn th esis a n d Self-Associa tion of 4-P yr im id in on es
Louis Vaillancourt, Michel Simard,1 and J ames D. Wuest*
De´partement de Chimie, Universite´ de Montre´al, Montre´al, Que´bec H3C 3J 7 Canada
Received J uly 1, 1998
Crystallization of 4-pyrimidinone from CHCl3 produced colorless needles that were shown by X-ray
crystallography to consist of cyclic hydrogen-bonded dimers 2 of the 4(3H)-pyrimidinone tautomer
1. Vapor-pressure osmometry established that a simple derivative, 5-(2-phenylethyl)-4(3H)-
pyrimidinone (5), self-associates in solution with a value of Ka (220 ( 110 m-1 at 26 °C in CH2Cl2)
close to that measured for 2-pyridinone under similar conditions. These observations suggest that
4-pyrimidinones and 2-pyridinones have similar modes and degrees of association and should be
equally suitable for use as sticky functional groups that can be incorporated in complex molecules
to make them associate in particular ways. This hypothesis was tested by synthesizing three
dipyrimidinones (12, 16, and 21) designed to form strongly hydrogen-bonded dimers and by making
a tetrapyrimidinone (26) designed to self-associate and to thereby generate a three-dimensional
hydrogen-bonded network. In all cases, however, the compounds proved to have very low solubilities
in organic solvents, and crystals suitable for X-ray diffraction could not be obtained despite intensive
effort. It is possible that the simultaneous presence of multiple tautomers, all capable of strong
intermolecular association, disfavors the sustained growth of single crystalline phases.
In tr od u ction
use 4-pyrimidinone groups to direct intermolecular as-
sociation. In particular, we describe the association of
4(3H)-pyrimidinone (1) itself in the solid state, the
association of a simple derivative in solution, and the
synthesis of more complex derivatives that incorporate
multiple 4-pyrimidinone groups held in orientations
designed to favor specific patterns of self-association.
A powerful strategy for the designed construction of
new ordered materials is molecular tectonics,2 which
relies on the predisposition of sticky molecules called
tectons to associate in particular ways.3 An effective
method for making tectons is to modify geometrically
suitable molecules by attaching selected functional groups
that are known to participate reliably in specific inter-
molecular interactions. Various interactions can be used
to direct association, but hydrogen bonds have proven to
be particularly suitable because of their strength, direc-
tionality, and specificity. As a result, molecules designed
to associate by hydrogen bonding have been studied
extensively as components for supramolecular assembly,
and these molecules have incorporated a variety of groups
chosen for their ability to form hydrogen bonds. Con-
spicuously uncommon in previous studies of this type are
derivatives of 4(3H)-pyrimidinone (1) or its tautomers,4,5
despite the critical biological role of closely related
purines and pyrimidines in ensuring the self-association
of nucleic acids. In this paper, we describe our efforts to
Resu lts a n d Discu ssion
Self-Associa tion of 4(3H)-P yr im id in on e (1) in th e
Solid Sta te. In the solid state and in solution, deriva-
tives of 2(1H)-pyridinone (3) show a well-established
tendency to self-associate and to form cyclic hydrogen-
bonded dimers 4 (eq 2).6 This preference has been used
(1) Laboratoire de Diffraction des Rayons-X, De´partement de Chim-
ie, Universite´ de Montre´al.
(2) (a) Brunet, P.; Simard, M.; Wuest, J . D. J . Am. Chem. Soc. 1997,
119, 2737. (b) Su, D.; Wang, X.; Simard, M.; Wuest, J . D. Supramol.
Chem. 1995, 6, 171. (c) Wuest, J . D. In Mesomolecules: From Molecules
to Materials; Mendenhall, G. D., Greenberg, A., Liebman, J . F., Eds.;
Chapman & Hall: New York, 1995; p 107. (d) Wang, X.; Simard, M.;
Wuest, J . D. J . Am. Chem. Soc. 1994, 116, 12119. (e) Simard, M.; Su,
D.; Wuest, J . D. J . Am. Chem. Soc. 1991, 113, 4696.
(3) For recent reviews of related work, see: Aakero¨y, C. B. Acta
Crystallogr. 1997, B53, 569. Philp, D.; Stoddart, J . F. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 1154. Desiraju, G. R. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2311. Lawrence, D. S.; J iang, T.; Levett, M. Chem.
Rev. 1995, 95, 2229.
effectively to control the association of more complex
derivatives that incorporate multiple 2-pyridinone groups.2
An analogous association of 4-pyrimidinones to give cyclic
hydrogen-bonded dimers 2 (eq 1) is intrinsically more
problematic because more tautomeric forms are present;7
nevertheless, simple derivatives of dimer 2 have been
observed in the solid state.8 Surprisingly, however, no
(4) Boucher, EÄ .; Simard, M.; Wuest, J . D. J . Org. Chem. 1995, 60,
1408.
(6) For references, see: Gallant, M.; Phan Viet, M. T.; Wuest, J . D.
J . Am. Chem. Soc. 1991, 113, 721.
(7) Elguero, J .; Marzin, C.; Katritzky, A. R.; Linda, P. Adv. Hetero-
cycl. Chem., Suppl. 1 1976, 1.
(8) For example, see: Harker, C. S. W.; Tiekink, E. R. T.; White-
house, M. W. Inorg. Chim. Acta 1991, 181, 23. Kawai, T.; Yosuoka,
N.; Kasai, N.; Kakudo, M. Cryst. Struct. Commun. 1973, 2, 663.
(5) For recent related work, see: Beijer, F. H.; Sijbesma, R. P.;
Kooijman, H.; Spek, A. L.; Meijer, E. W. J . Am. Chem. Soc. 1998, 120,
6761. Branda, N.; Kurz, G.; Lehn, J .-M. J . Chem. Soc., Chem.
Commun. 1996, 2443. Liao, R.-F.; Lauher, J . W.; Fowler, F. W.
Tetrahedron 1996, 52, 3153. Schall, O. F.; Gokel, G. W. J . Chem. Soc.,
Chem. Commun. 1992, 748.
10.1021/jo981285p CCC: $15.00 © 1998 American Chemical Society
Published on Web 12/05/1998

Synthesis and Self-Association of 4-Pyrimidinones
J . Org. Chem., Vol. 63, No. 26, 1998 9747
F igu r e 1. ORTEP views of the structure of the cyclic hydrogen-bonded dimer 2 of 4(3H)-pyrimidinone (1). The upper figure
shows the atomic numbering, and the lower figure provides a stereoview of the unit cell along the a axis. Non-hydrogen atoms
are represented by ellipsoids corresponding to 50% probability, hydrogen atoms are shown as spheres of arbitrary size, and hydrogen
bonds are drawn using narrow lines.
Sch em e 1
crystal structure of 4(3H)-pyrimidinone (1) or a tautomer
has ever been reported. We have found that slow
evaporation of a saturated solution of 4-pyrimidinone in
CHCl3 produces colorless needles suitable for X-ray
crystallographic study. The results of this study, sum-
marized in Figure 1, confirm that the heterocycle is
present as cyclic hydrogen-bonded dimers 2 of the 4(3H)-
pyrimidinone tautomer 1. Bond lengths and angles in
this structure have normal values. In particular, the
average N-H‚‚‚O angle is 173(4)°, and the corresponding
average N-O distance is 2.791(8) Å.
Self-Associa tion of a Typ ica l 4-P yr im id in on e in
Solu tion . We then measured the self-association of a
typical 4-pyrimidinone in solution by vapor-pressure
that we suggest is due to dimerization for the following
osmometry. A derivative with adequate solubility in
two reasons: (1) dimerization is observed in the solid
suitable organic solvents, 5-(2-phenylethyl)-4(3H)-pyri-
state, and (2) the low concentrations used disfavor the
midinone (5),9 was prepared by the route summarized
formation of higher oligomers. The observed value of Ka,
220 ( 110 m-1, is closely similar to the value measured
in Scheme 1. Treatment of 4-chloro-5-iodopyrimidine
(6)10 with NaOCH3 provided a 91% yield of 5-iodo-4-
methoxypyrimidine (7), which was subjected to pal-
ladium-catalyzed coupling with phenylacetylene to give
derivative 8 in 67% yield. Hydrogenation then provided
a 51% yield of 4-methoxy-5-(2-phenylethyl)pyrimidine (9),
which was converted into the required 4-pyrimidinone 5
in 92% yield by treatment with aqueous HBr.
for 2-pyridinone in CDCl3 at 25 °C (150 m-1).11 Together,
our structural and colligative data indicate that 4-pyri-
midinones and 2-pyridinones have similar modes and
degrees of association and should be equally suitable as
sticky groups designed to induce complex molecules to
associate in particular ways.
Syn th esis of Com p lex Molecu les Con ta in in g Mu l-
tip le 4-P yr im id in on e Gr ou p s. To test this hypothesis,
we decided to synthesize a dipyrimidinone analogous to
dipyridinone 10,12 which is known to self-associate in the
solid state and in solution to form the strongly hydrogen-
bonded dimer 11 (eq 3). Analogous dipyrimidinone 129
was synthesized by the route summarized in Scheme 2.
Palladium-catalyzed coupling of 2-ethynyl-4-methoxypy-
Studies of the self-association of 4-pyrimidinone 5 were
carried out by vapor-pressure osmometry in CH2Cl2 at
26 °C using four dilute solutions with molal concentra-
tions ranging from 7.4 × 10-3 to 15 × 10-3 m. These
studies revealed a concentration-dependent association
(9) For simplicity, all such structures in this paper are represented
solely by the 4(3H)-pyrimidinone tautomer, even when other tautomers
are undoubtedly present.
(10) Sakamoto, T.; Kondo, Y.; Watanabe, R.; Yamanaka, H. Chem.
Pharm. Bull. 1986, 34, 2719.
(11) Hammes, G. G.; Lillford, P. J . J . Am. Chem. Soc. 1970, 92, 7578.
(12) Ducharme, Y.; Wuest, J . D. J . Org. Chem. 1988, 53, 5787.

9748 J . Org. Chem., Vol. 63, No. 26, 1998
Vaillancourt et al.
dine (22)15 with LDA (0.5 equiv), followed by the addition
of CH3COOH (0.5 equiv) and DDQ (2 equiv), gave a 20%
yield of bipyrimidine 23.16 Hydrogenolysis then con-
verted compound 23 into 4,4′-dimethoxy-2,5′-bipyrimi-
dine (24) in 53% yield, and target 21 was obtained in 65%
yield by standard deprotection. Unfortunately, the solu-
bility of bipyrimidinone 21 proved to be particularly low,
and we were unable to obtain crystals suitable for X-ray
diffraction or to study its self-association in solution.
In a final attempt to characterize the self-association
of a molecule incorporating multiple 4-pyrimidinone
groups, we decided to synthesize a tetrapyrimidinone
analogous to the known tetrapyridinone 25.2e Crystal-
Sch em e 2
lization of tecton 25 is directed by normal pairwise
hydrogen bonding of its four tetrahedrally oriented
2-pyridinone groups with those of four neighbors, thereby
producing a remarkable structure in which interpen-
etrating diamondoid networks define significant spaces
for the inclusion of guests. Analogous tetrapyrimidinone
269 was prepared according to Scheme 5. Treatment of
2-ethynyl-4-methoxypyrimidine (13)4 with BuLi (1 equiv)
and ZnCl2 (1 equiv), followed by palladium-catalyzed
coupling of the resulting chlorozinc acetylide with tet-
rakis(4-iodophenyl)methane (27),2e,17 gave tetrapyrimi-
dine 28 in 34% yield. Without extensive purification,
compound 28 was converted into tetrapyrimidinone 26
in 56% yield by normal deprotection. Once again,
however, the solubility of this compound was extremely
low, and we were not able to prepare crystals suitable
for X-ray diffraction.
rimidine (13)4 with 5-iodo-4-methoxypyrimidine (7) gave
an 86% yield of dipyrimidine 14, which was converted
into target 12 in 90% yield by treatment with KOH and
subsequent neutralization. Unfortunately, the very low
solubility of dipyrimidinone 12 in organic solvents, its
facile rearrangement to furopyrimidine 159 by a formal
5-endo-dig cyclization,4,13 and other factors prevented us
from obtaining crystals suitable for X-ray diffraction and
from studying its self-association in solution.
Con clu sion s
Our results establish that 4(3H)-pyrimidinone (1) self-
associates in the solid state to form the cyclic hydrogen-
bonded dimer 2 and simple derivatives also self-associate
in solution with values of Ka similar to those measured
for 2-pyridinones. These observations suggest that 4-py-
rimidinones and 2-pyridinones can both be used ef-
fectively in molecular tectonics as sticky groups that
predispose more complex molecules to which they are
attached to associate in particular ways. In addition, our
efficient syntheses of the potentially self-complementary
dipyrimidinones 12, 16, and 21, as well as our prepara-
tion of the self-complementary tetrapyrimidinone 26,
demonstrate that it is easy to make tectons with multiple
4-pyrimidinone groups held in orientations designed to
favor specific patterns of self-association. In fact, the
synthesis of complex pyrimidinones can be easier than
that of analogous pyridinones, because a variety of
appropriate pyrimidine precursors are readily and eco-
nomically available and special methods developed for
We then turned to the related dipyrimidinone 16,9
which was prepared according to Scheme 3. Palladium-
catalyzed coupling of 5-iodo-4-methoxypyrimidine (7)
with (trimethylsilyl)acetylene yielded pyrimidine 17,14
which was deprotected to give 5-ethynyl-4-methoxypyri-
midine (18) in 42% overall yield. Palladium-catalyzed
coupling of 2-ethynyl-4-methoxypyrimidine (13)4 with
1-bromo-4-iodobenzene gave a 91% yield of pyrimidine
19. Subsequent palladium-catalyzed coupling of com-
pound 19 with the chlorozinc acetylide derived from
5-ethynyl-4-methoxypyrimidine (18) then provided a 52%
yield of dipyrimidine 20, which was converted into target
16 in 71% yield by sequential treatment with KOH and
HCl. Again, however, the predisposition of dipyrimidi-
none 16 to undergo 5-endo-dig cyclization, its poor
solubility, and other factors prevented us from crystal-
lizing it and studying its self-association in solution.
To eliminate the possibility of cyclization, we decided
to link two 4-pyrimidinones without using an ethynyl
spacer at the 5-position. Compound 21,9 in which the
4-pyrimidinone rings are connected directly without a
spacer, was synthesized by the novel route summarized
in Scheme 4. The reaction of 4-chloro-6-methoxypyrimi-
(15) Isbecque, D.; Promel, R.; Quinaux, R. C.; Martin, R. H. Helv.
Chim. Acta 1959, 42, 1317.
(16) For related observations, see: Ple´, N.; Turck, A.; Bardin, F.;
Queguiner, G. J . Heterocycl. Chem. 1992, 29, 467. Radinov, R.; Chanev,
C.; Haimova, M. J . Org. Chem. 1991, 56, 4793. Harden, D. B.; Mokrosz,
M. J .; Strekowski, L. J . Org. Chem. 1988, 53, 4137.
(17) Su, D.; Menger, F. M. Tetrahedron Lett. 1997, 38, 1485. The
detailed procedure for the synthesis of tetrakis(4-iodophenyl)methane
that appears in this paper was actually taken from the Ph.D. thesis of
D. Su, Universite´ de Montre´al, 1995.
(13) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734.
(14) For related reactions, see: Sakamoto, T.; Shiraiwa, M.; Kondo,
Y.; Yamanaka, H. Synthesis 1983, 312.

Synthesis and Self-Association of 4-Pyrimidinones
J . Org. Chem., Vol. 63, No. 26, 1998 9749
Sch em e 3
Sch em e 4
4-pyrimidinones undoubtedly have complex origins. How-
ever, one likely cause is the simultaneous presence of
numerous tautomers, all capable of strong intermolecular
association, which may disfavor the sustained growth of
a single crystalline phase. Compounds with multiple
2-pyrimidinone groups that are symmetrically substi-
tuted will have smaller numbers of tautomers and may
therefore prove to be more useful in molecular tectonics.
Exp er im en ta l Section
Tetrahydrofuran (THF) was dried by distillation from the
sodium ketyl of benzophenone, triethylamine and diisopropyl-
amine were dried over KOH, and CH3OH was dried by treating
it with Mg and a catalytic amount of I2. PdCl2(PPh3)2 was
prepared in the normal way.18 All other reagents were
commercial products that were used without further purifica-
tion. Flash chromatography was performed in the usual
manner.19
Sch em e 5
X-r a y Cr ysta llogr a p h ic Stu d y of 4(3H)-P yr im id in on e
(1).20 Crystals of 4(3H)-pyrimidinone (1) belong to the mono-
clinic space group P21 with a ) 3.7166(3) Å, b ) 19.8584(13)
Å, c ) 11.6816(3) Å, â ) 94.272(4)°, V ) 859.77(9) Å3, Dcalcd
)
1.485 g cm-3, and Z ) 8. Data were collected at 295 K, and
the structure was refined to Rf ) 0.053, Rw ) 0.056 for 1408
reflections with I > 1.96σ(I).
5-Iod o-4-m eth oxyp yr im id in e (7). A stirred solution of
4-chloro-5-iodopyrimidine (0.839 g, 3.49 mmol)10 in CH3OH (15
mL) was treated with a solution of NaOCH3 (0.80 mL, 25 wt
% in CH3OH, 3.5 mmol), and the resulting mixture was stirred
at 25 °C for 24 h. Volatiles were then removed by evaporation
under reduced pressure, H2O (10 mL) was added to the
residue, and the mixture was extracted with CHCl3. The
extracts were combined and dried, volatiles were removed by
evaporation under reduced pressure, and the residue was
crystallized from hexane to give 5-iodo-4-methoxypyrimidine
(7) as analytically pure colorless needles (0.746 g, 3.16 mmol,
91%): mp 88.0-89.0 °C; 1H NMR (300 MHz, CDCl3) δ 4.05 (s,
3H), 8.66 (s, 1H), 8.75 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ
the synthesis of pyrimidines, such as those that yield
dipyrimidinone 21, cannot be used to make the corre-
sponding pyridines.
Unfortunately, our results also suggest that compounds
with multiple 4-pyrimidinone groups will be difficult to
use in molecular tectonics for two reasons: (1) they tend
to have very low solubilities in organic solvents, and (2)
they appear to be particularly hard to crystallize. Despite
determined effort, we were unable to grow single crystals
of complex 4-pyrimidinones 12, 16, 21, and 26 suitable
for structural studies using X-ray diffraction, even though
we have successfully used X-ray crystallography to solve
the structures of many closely analogous 2-pyridinones.
Our repeated failures to crystallize the corresponding
(18) Hartley, F. R. Organomet. Chem. Rev., Sect. A 1970, 6, 119.
(19) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923.
(20) The authors have deposited X-ray crystallographic data, a
description of the structure determination, and tables of atomic
coordinates and isotropic thermal parameters, bond lengths and angles,
anisotropic thermal parameters, and refined and calculated hydrogen
atom coordinates with the Cambridge Crystallographic Data Centre.
The data can be obtained, on request, from the Director, Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ,
U.K.

9750 J . Org. Chem., Vol. 63, No. 26, 1998
Vaillancourt et al.
55.0, 79.9, 157.2, 163.7, 167.0. Anal. Calcd for C5H5IN2O: C,
25.45; H, 2.14; N, 11.87. Found: C, 25.51; H, 2.11; N, 11.96.
4-Meth oxy-5-(p h en yleth yn yl)p yr im id in e (8). A stirred
solution of 5-iodo-4-methoxypyrimidine (7; 2.12 g, 8.98 mmol)
in N(C2H5)3 (4 mL) was treated with phenylacetylene (1.08 g,
10.6 mmol), PdCl2(PPh3)2 (0.145 g, 0.207 mmol), and CuI (0.064
g, 0.34 mmol), and the mixture was heated at reflux for 24 h.
The resulting mixture was then cooled, diluted with H2O, and
extracted with CH2Cl2. Volatiles were removed from the
combined extracts by evaporation under reduced pressure, and
the residue was purified by sublimation (65 °C/0.8 Torr) to give
4-methoxy-5-(phenylethynyl)pyrimidine (8; 1.27 g, 6.04 mmol,
67%) as a colorless solid. Resublimation provided a purified
sample: mp 72.5-75.5 °C; 1H NMR (300 MHz, CDCl3) δ 3.98
(s, 3H), 7.26 (m, 3H), 7.48 (m, 2H), 8.53 (s, 1H), 8.65 (s, 1H);
13C NMR (75 MHz, CDCl3) δ 54.0, 80.2, 97.0, 106.4, 122.0,
128.0, 128.5, 131.3, 156.2, 158.9, 167.9; MS (FAB, 3-nitrobenzyl
alcohol) m/e 211. Anal. Calcd for C13H10N2O: C, 74.27; H,
4.79; N, 13.33. Found: C, 74.71; H, 4.80; N, 12.83.
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 53.9, 54.4, 77.7, 95.1,
105.1, 107.9, 151.5, 156.9, 157.4, 160.3, 168.7, 169.1; MS (EI)
m/e 242; HRMS (EI) calcd for C12H10N4O2 + H m/e 243.0882,
found 243.0889.
2-[(3,4-Dih yd r o-4-oxo-5-p yr im id in yl)et h yn yl]-4(3H )-
p yr im id in on e (12). A stirred suspension of 4-methoxy-2-[(4-
methoxy-5-pyrimidinyl)ethynyl]pyrimidine (14; 49 mg, 0.20
mmol) in 1 M aqueous KOH (2 mL) was heated at reflux for
20 min, and the resulting homogeneous solution was then
cooled. Acidification with 3 M aqueous HCl caused the
precipitation of a colorless solid, which was separated by
centrifugation and washed with H2O, acetone, and CH2Cl2.
This yielded a pure sample of 2-[(3,4-dihydro-4-oxo-5-pyri-
midinyl)ethynyl]-4(3H)-pyrimidinone (12; 38 mg, 0.18 mmol,
90%): mp 240 °C dec; IR (KBr) 3500-2100, 2234, 1636 cm-1
;
1H NMR (300 MHz, DMSO-d6) δ 6.39 (d, 1H, 3J ) 6.7 Hz),
3
7.97 (d, 1H, J ) 6.7 Hz), 8.34 (s, 1H), 8.36 (s, 1H); MS (EI)
m/e 214; HRMS (EI) calcd for C10H6N4O2 m/e 214.0491, found
214.0482.
4-Meth oxy-5-(2-p h en yleth yl)p yr im id in e (9). A suspen-
sion prepared by treating 4-methoxy-5-(phenylethynyl)pyri-
midine (8; 95 mg, 0.45 mmol) in C2H5OH (4 mL) with 5% Pd/C
(190 mg) was shaken at 25 °C under H2 (1 atm) for 24 h. The
suspension was then filtered, and solvent was removed from
the filtrate by evaporation under reduced pressure. This
yielded a residue of 4-methoxy-5-(2-phenylethyl)pyrimidine (9;
49 mg, 0.23 mmol, 51%) as a colorless oil, which was used
without purification in the following step: 1H NMR (300 MHz,
CDCl3) δ 2.86 (m, 4H), 4.00 (s, 3H), 7.17 (m, 3H), 7.28 (m, 2H),
8.13 (s, 1H), 8.65 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 28.9,
34.5, 53.4, 121.1, 125.8, 128.1, 128.1, 140.6, 155.4, 156.1, 167.2;
MS (FAB, 3-nitrobenzyl alcohol) m/e 215; HRMS (FAB, 3-ni-
trobenzyl alcohol) calcd for C13H14N2O + H m/e 215.1184, found
215.1179.
5-(2-P h en yleth yl)-4(3H)-p yr im id in on e (5). A stirred
solution of 4-methoxy-5-(2-phenylethyl)pyrimidine (9; 155 mg,
0.723 mmol) in aqueous HBr (2.5 mL, 48 wt %) was heated at
reflux for 3 h. The mixture was cooled and made basic by
adding saturated aqueous Na2CO3. The basified mixture was
then extracted with CHCl3, the combined extracts were dried,
and volatiles were removed by evaporation under reduced
pressure. This provided a residue of 5-(2-phenylethyl)-4(3H)-
pyrimidinone (5; 133 mg, 0.664 mmol, 92%) as a colorless
4-Meth oxy-5-[(tr im eth ylsilyl)eth yn yl]p yr im id in e (17).
A stirred solution of 5-iodo-4-methoxypyrimidine (7; 1.02 g,
4.32 mmol) in N(C2H5)3 (5 mL) was treated with PdCl2(PPh3)2
(0.084 g, 0.12 mmol), CuI (0.052 g, 0.27 mmol), and (trimeth-
ylsilyl)acetylene (0.51 g, 5.2 mmol). The resulting mixture was
heated at 60 °C for 18 h, and volatiles were then removed by
evaporation under reduced pressure. The residue was dis-
solved in a mixture of CH2Cl2 (25 mL) and ethyl acetate (100
mL), the solution was passed through a short column of silica,
and volatiles were removed from the eluent by evaporation
under reduced pressure. Kugelrohr distillation (80 °C/0.03
Torr) of the residue gave 4-methoxy-5-[(trimethylsilyl)ethynyl]-
pyrimidine (17; 0.853 g, 4.13 mmol, 96%) as a pale yellow
liquid, which was used immediately in the following step: IR
1
(liquid film) 2158 cm-1; H NMR (300 MHz, CDCl3) δ 0.19 (s,
9H), 3.97 (s, 3H), 8.46 (s, 1H), 8.61 (s, 1H); 13C NMR (75 MHz,
CDCl3) δ -0.7, 53.9, 95.5, 103.1, 106.1, 156.3, 159.6, 168.1.
5-E t h yn yl-4-m et h oxyp yr im id in e (18). A solution of
4-methoxy-5-[(trimethylsilyl)ethynyl]pyrimidine (17; 1.07 g,
5.19 mmol) in THF (6 mL) was treated with CH3COOH (0.36
g, 6.0 mmol) and with a solution of tetrabutylammonium
fluoride (6.0 mL, 1.0 M in THF, 6.0 mmol), and the mixture
was stirred at 25 °C for 30 min. The resulting mixture was
then diluted with H2O and extracted with CH2Cl2. Volatiles
were removed from the combined extracts by evaporation
under reduced pressure, and the residue was purified by flash
chromatography (silica, hexane (85%)/ethyl acetate (15%)).
Further purification was achieved by sublimation (25 °C/0.2
Torr), which provided 5-ethynyl-4-methoxypyrimidine (18;
0.483 g, 2.30 mmol, 44%) as an analytically pure colorless
solid: mp 169-171 °C; IR (KBr) 3400-2300, 1671, 1652 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.80 (t, 2H), 2.93 (t, 2H), 7.19
(m, 3H), 7.27 (m, 2H), 7.76 (s, 1H), 8.12 (s, 1H), 11.6 (bs, 1H);
13C NMR (100.6 MHz, CDCl3) δ 29.4, 34.0, 126.1, 128.3, 128.4,
128.4, 140.8, 146.8, 152.3, 164.0; MS (FAB, 3-nitrobenzyl
alcohol) m/e 201; HRMS (FAB, 3-nitrobenzyl alcohol) calcd for
1
C
12H12N2O + H m/e 201.1028, found 201.1036.
Va p or -P r essu r e Osm om etr ic Stu d y of th e Self-As-
solid: mp 55.7-56.4 °C; IR (KBr) 3288, 3193 cm-1; H NMR
(300 MHz, CDCl3) δ 3.47 (s, 1H), 4.09 (s, 3H), 8.58 (s, 1H),
8.74 (s, 1H); 13C NMR (100.6 MHz, CDCl3) δ 54.1, 74.7, 85.4,
105.2, 156.7, 158.8, 168.5. Anal. Calcd for C7H6N2O: C, 62.68;
H, 4.51. Found: C, 62.34; H, 4.59.
socia tion of 5-(2-P h en yleth yl)-4(3H)-p yr im id in on e (5).
An Hitachi-Perkin-Elmer Model 115 molecular weight ap-
paratus was used to evaluate the self-association of 5-(2-
phenylethyl)-4(3H)-pyrimidinone (5). The instrument was
calibrated at 26 °C by using solutions of benzil in CH2Cl2, and
the association of pyrimidinone 5 in CH2Cl2 at 26 °C was then
measured using four standard solutions of concentrations 7.4
× 10-3 m, 9.8 × 10-3 m, 12 × 10-3 m, and 15 × 10-3 m.
4-Meth oxy-2-[(4-m eth oxy-5-p yr im id in yl)eth yn yl]p yr i-
m id in e (14). A stirred solution of 2-ethynyl-4-methoxypyri-
midine (13; 269 mg, 2.01 mmol)4 and 5-iodo-4-methoxypyri-
midine (7; 399 mg, 1.69 mmol) in N(C2H5)3 (2 mL) was treated
with PdCl2(PPh3)2 (40 mg, 0.057 mmol) and CuI (20 mg, 0.11
mmol), and the mixture was heated at reflux for 16 h. The
resulting mixture was then cooled, diluted with H2O, and
extracted with CHCl3. Volatiles were removed from the
combined extracts by evaporation under reduced pressure, and
the residue was purified by flash chromatography (silica, ethyl
acetate) to give 4-methoxy-2-[(4-methoxy-5-pyrimidinyl)eth-
ynyl]pyrimidine (14; 353 mg, 1.46 mmol, 86%) as a colorless
solid, which was further purified by crystallization from
acetone/hexane: mp 155.5-156.5 °C; IR (KBr) 2223 cm-1; 1H
NMR (300 MHz, CDCl3) δ 4.04 (s, 3H), 4.11 (s, 3H), 6.72 (d,
2-[(4-Br om oph en yl)eth yn yl]-4-m eth oxypyr im idin e (19).
A solution of 2-ethynyl-4-methoxypyrimidine (13; 0.967 g, 7.21
mmol)4 and 1-bromo-4-iodobenzene (2.04 g, 7.21 mmol) in
N(C2H5)3 (20 mL) was treated with PdCl2(PPh3)2 (0.148 mg,
0.211 mmol) and CuI (146 mg, 0.767 mmol), and the resulting
mixture was stirred at 25 °C for 24 h. Volatiles were then
removed by evaporation under reduced pressure, and the
residue was purified by flash chromatography (silica, hexane
(80%)/ethyl acetate (20%)) to give 2-[(4-bromophenyl)ethynyl]-
4-methoxypyrimidine (19; 1.90 g, 6.57 mmol, 91%) as a
colorless solid. A purified sample was prepared by recrystal-
lization from hexane/CHCl3: mp 125.5-126.5 °C; IR (KBr)
2222 cm-1; 1H NMR (300 MHz, CDCl3) δ 4.04 (s, 3H), 6.70 (d,
3
3
1H, J ) 5.9 Hz), 7.52 (m, 4H), 8.42 (d, 1H, J ) 5.9 Hz); 13C
NMR (75 MHz, CDCl3) δ 53.7, 85.2, 88.8, 107.3, 120.0, 123.7,
131.3, 133.5, 151.8, 156.7, 168.8; MS (EI) m/e 290, 288. Anal.
Calcd for C13H9BrN2O: C, 54.00; H, 3.14; N, 9.69. Found: C,
54.46; H, 3.07; N, 9.69.
4,4′-Dim et h oxy-2,5′-(1,4-p h en ylen ed i-2,1-et h yn ed iyl)-
bisp yr im id in e (20). A solution of 5-ethynyl-4-methoxypyri-
midine (18; 35.0 mg, 0.261 mmol) in THF (1 mL) was stirred
3
3
1H, J ) 5.8 Hz), 8.45 (d, 1H, J ) 5.8 Hz), 8.73 (s, 1H), 8.78

Synthesis and Self-Association of 4-Pyrimidinones
J . Org. Chem., Vol. 63, No. 26, 1998 9751
3
at -78 °C under dry N2 and treated dropwise with a solution
of butyllithium (104 µL, 2.5 M in hexane, 0.26 mmol). The
resulting mixture was kept at -78 °C for 30 min, the
temperature was subsequently allowed to rise to 0 °C, and then
a solution of ZnCl2 (42.3 mg, 0.310 mmol) in THF (1 mL) was
added slowly. After 30 min, 2-[(4-bromophenyl)ethynyl]-4-
methoxypyrimidine (19; 76.3 mg, 0.264 mmol) and PdCl2-
(PPh3)2 (11.2 mg, 0.0160 mmol) were added, and the mixture
was heated at reflux for 20 h. The resulting mixture was
cooled, treated with 5% aqueous NaHCO3, and extracted with
CH2Cl2. Volatiles were removed from the combined extracts
by evaporation under reduced pressure, and the residue was
purified by flash chromatography (silica, hexane (40%)/ethyl
acetate (60%)) to give 4,4′-dimethoxy-2,5′-(1,4-phenylenedi-2,1-
ethynediyl)bispyrimidine (20; 46.4 mg, 0.136 mmol, 52%) as
) 5.8 Hz), 8.57 (d, 1H, J ) 5.8 Hz), 8.85 (s, 1H), 9.10 (s, 1H);
13C NMR (100.6 MHz, CDCl3) δ 53.7, 54.3, 106.7, 119.7, 157.2,
158.5, 158.5, 161.3, 166.8, 169.3; MS (FAB, 3-nitrobenzyl
alcohol) m/e 219; HRMS (FAB, 3-nitrobenzyl alcohol) calcd for
10H10N4O2 + H m/e 219.0882, found 287.0874.
[2,5′-Bip yr im id in e]-4,4′(3H,3′H)-d ion e (21). A stirred
C
mixture of 4,4′-dimethoxy-2,5′-bipyrimidine (24; 18 mg, 0.082
mmol) in 1 M aqueous KOH (3 mL) was heated at reflux for 1
h, and the resulting homogeneous solution was then cooled.
Acidification with 2 M aqueous HCl caused the precipitation
of a solid, which was separated by centrifugation and washed
with H2O, CH3OH, and CH2Cl2. This yielded [2,5′-bipyrimi-
dine]-4,4′(3H,3′H)-dione (21; 10 mg, 0.053 mmol, 65%) as a
colorless solid: mp > 300 °C dec; IR (KBr) 3600-2300, 1655
cm-1; H NMR (400 MHz, CF3COOD) δ 7.09 (d, 1H, J ) 7.0
Hz), 8.51 (d, 1H, 3J ) 7.0 Hz), 9.24 (s, 1H), 9.57 (s, 1H).
Because of the very low solubility and volatility of this
compound, satisfactory 13C NMR and mass spectra could not
be obtained.
1
3
a pale yellow solid: mp 163.1-164.5 °C; IR (KBr) 2220 cm-1
;
1H NMR (300 MHz, CDCl3) δ 4.03 (s, 3H), 4.09 (s, 3H), 6.69
3
3
3
(d, 1H, J ) 5.9 Hz), 7.55 (d, 2H, J ) 8.6 Hz), 7.65 (d, 2H, J
3
) 8.6 Hz), 8.42 (d, 1H, J ) 5.9 Hz), 8.60 (s, 1H), 8.72 (s, 1H);
13C NMR (100.6 MHz, CDCl3) δ 54.0, 54.4, 82.8, 86.1, 89.8,
96.6, 106.4, 107.6, 121.8, 123.4, 131.5, 132.4, 152.1, 156.8,
157.1, 159.3, 168.2, 169.2; MS (EI) m/e 342. HRMS (EI) calcd
for C20H14N4O2 m/e 342.1117, found 342.1130.
2,2′,2′′,2′′′-[Meth a n etetr a yltetr a k is(4,1-p h en ylen e-2,1-
eth yn ed iyl)]tetr a k is[4-m eth oxyp yr im id in e] (28). A solu-
tion of 2-ethynyl-4-methoxypyrimidine (13; 1.22 g, 9.10 mmol)4
in THF (25 mL) was stirred at -78 °C under dry N2 and
treated dropwise with a solution of butyllithium (5.7 mL, 1.6
M in hexane, 9.1 mmol). The resulting mixture was kept at
-78 °C for 30 min, and then a solution of ZnCl2 (1.49 g, 10.9
mmol) in THF (20 mL) was added slowly. The temperature
was subsequently allowed to rise to 0 °C. After 30 min,
tetrakis(4-iodophenyl)methane (27; 1.25 g, 1.52 mmol)2e,17 and
PdCl2(PPh3)2 (0.195 g, 0.278 mmol) were added, and the
mixture was heated at reflux for 12 h. The resulting mixture
was cooled, and volatiles were removed by evaporation under
reduced pressure. The residue was treated with 5% aqueous
NaHCO3, and the mixture was extracted with CH2Cl2. Vola-
tiles were removed from the combined extracts by evaporation
under reduced pressure, and the residue was purified by
adsorbing it on a bed of Florisil, washing the bed with CH2Cl2,
and then desorbing the product with ethyl acetate. This
provided 2,2′,2′′,2′′′-[methanetetrayltetrakis(4,1-phenylene-2,1-
ethynediyl)]tetrakis[4-methoxypyrimidine] (28; 0.434 g, 0.511
mmol, 34%) as a colorless solid, which was used in the
following step without further purification: IR (KBr) 2221
cm-1; 1H NMR (300 MHz, CDCl3) δ 4.02 (s, 12H), 6.67 (d, 4H,
2,5′-(1,4-P h en ylen ed i-2,1-eth yn ed iyl)bis[4(3H)-p yr im i-
d in on e] (16). A stirred mixture of 4,4′-dimethoxy-2,5′-(1,4-
phenylenedi-2,1-ethynediyl)bispyrimidine (20; 35.3 mg, 0.103
mmol) in 1 M aqueous KOH (1.2 mL) and C2H5OH (1.5 mL)
was heated at reflux for 5 h, and the resulting homogeneous
solution was then cooled. Acidification with 3 M aqueous HCl
caused the precipitation of a solid, which was separated by
centrifugation and washed with H2O and acetone. This yielded
2,5′-(1,4-phenylenedi-2,1-ethynediyl)bis[4(3H)-pyrimidinone]
(16; 22.9 mg, 0.0729 mmol, 71%) as a pale yellow solid: mp
1
268 °C dec; IR (KBr) 3600-2300, 2214, 1684 cm-1; H NMR
3
(300 MHz, DMSO-d6) δ 6.40 (d, 1H, J ) 6.4 Hz), 7.61 (d, 2H,
3
3
3J ) 8.5 Hz), 7.69 (d, 2H, J ) 8.5 Hz), 7.97 (d, 1H, J ) 6.4
Hz), 8.28 (s, 1H), 8.29 (s, 1H), 13.2 (bs, 2H); MS (EI) m/e 314;
HRMS (EI) calcd for C18H10N4O2 m/e 314.0804, found 314.0800.
4,4′-Dich lor o-6,6′-d im eth oxy-2,5′-bip yr im id in e (23). A
solution of diisopropylamine (0.26 g, 2.6 mmol) in THF (1 mL)
was stirred at 0 °C under dry N2 and treated dropwise with a
solution of butyllithium (1.2 mL, 2.2 M in hexane, 2.6 mmol).
After 30 min, the resulting mixture was cooled to -78 °C and
treated dropwise with a solution of 4-chloro-6-methoxypyri-
midine (22; 0.746 g, 5.16 mmol)15 in THF (3 mL). After 1h at
-78 °C and 1h at -30 °C, the mixture was treated with CH3-
COOH (0.16 g, 2.7 mmol). The temperature was then allowed
to rise to 25 °C, and a solution of 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ; 1.29 g, 5.68 mmol) in THF (3 mL) was
added. After 5 min, the resulting mixture was poured into
1.5 M aqueous NaOH (20 mL), and the product was extracted
with CH2Cl2. Volatiles were removed from the combined
extracts by evaporation under reduced pressure, and the
residue was purified by flash chromatography (silica, hexane
(85%)/ethyl acetate (15%)) to give 4,4′-dichloro-6,6′-dimethoxy-
2,5′-bipyrimidine (23; 0.148 g, 0.515 mmol, 20%) as a colorless
solid. Further purification was achieved by crystallization
from hexane: mp 70.5-72.5 °C; 1H NMR (300 MHz, CDCl3) δ
3.99 (s, 3H), 4.00 (s, 3H), 6.80 (s, 1H), 8.63 (s, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 54.8, 55.0, 106.6, 118.7, 157.3, 158.4,
160.5, 160.7, 167.7, 170.8; MS (FAB, 3-nitrobenzyl alcohol) m/e
289, 287; HRMS (FAB, 3-nitrobenzyl alcohol) calcd for
3J ) 5.8 Hz), 7.21 (d, 8H, J ) 8.5 Hz), 7.59 (d, 8H, J ) 8.5
Hz), 8.41 (d, 4H, J ) 5.8 Hz).
3
3
3
2,2′,2′′,2′′′-[Meth a n etetr a yltetr a k is(4,1-p h en ylen e-2,1-
eth yn ed iyl)]tetr a k is[4(3H)-p yr im id in on e] (26). A stirred
mixture of 2,2′,2′′,2′′′[methanetetrayltetrakis(4,1-phenylene-
2,1-ethynediyl)]tetrakis[4-methoxypyrimidine] (28; 120 mg,
0.14 mmol) in 1 M aqueous KOH (3 mL) and dioxane (6 mL)
was heated at reflux for 18 h, and the resulting mixture was
then cooled and filtered. Acidification of the filtrate with 2 M
aqueous HCl caused the precipitation of a solid, which was
separated by centrifugation and washed with CH3OH, CH2Cl2,
and acetone. This yielded 2,2′,2′′,2′′′-[methanetetrayltetrakis-
(4,1-phenylene-2,1-ethynediyl)]tetrakis[4(3H)-pyrimidinone]
(26; 67 mg, 0.084 mmol, 60%) as a colorless solid: mp 264 °C
dec; IR (KBr) 3600-2500, 2221, 1670 cm-1; 1H NMR (300 MHz,
DMSO-d6) δ 6.39 (d, 4H, 3J ) 6.4 Hz), 7.30 (d, 8H, 3J ) 8.6
3
3
Hz), 7.65 (d, 8H, J ) 8.6 Hz), 7.95 (d, 4H, J ) 6.4 Hz), 13.2
(bs, 4H). Because of the very low solubility and volatility ofthis
compound, satisfactory 13C NMR and mass spectra could not
be obtained.
C
10H835Cl2N4O2 m/e 287.0102, found 287.0095.
4,4′-Dim eth oxy-2,5′-bip yr im id in e (24). A solution of 4,4′-
dichloro-6,6′-dimethoxy-2,5′-bipyrimidine (23; 160 mg, 0.557
mmol) in CH3OH (2 mL) was treated with 10% Pd/C (163 mg)
and MgO (326 mg), and the resulting suspension was stirred
at 25 °C under H2 (1 atm) for 72 h. The mixture was then
filtered, and volatiles were removed from the filtrate by
evaporation under reduced pressure. Purification of the
residue by flash chromatography (silica, ethyl acetate) provided
4,4′-dimethoxy-2,5′-bipyrimidine (24; 64.4 mg, 0.295 mmol,
53%) as a colorless solid. Further purification was achieved
by crystallization from hexane: mp 113.0-113.5 °C; 1H NMR
Ack n ow led gm en t. We are grateful to the Natural
Sciences and Engineering Research Council of Canada,
the Ministe`re de l’EÄ ducation du Que´bec, and Merck
Frosst for financial support. In addition, acknowledg-
ment is made to the donors of the Petroleum Research
Fund, administered by the American Chemical Society,
for support of this research. We also thank Prof. J acques
Prud’homme of the Universite´ de Montre´al for helpful
advice about vapor-pressure osmometry.
3
(300 MHz, CDCl3) δ 4.05 (s, 3H), 4.12 (s, 3H), 6.71 (d, 1H, J

9752 J . Org. Chem., Vol. 63, No. 26, 1998
Vaillancourt et al.
Su p p or tin g In for m a tion Ava ila ble: Tables of atomic
coordinates and isotropic thermal parameters, complete bond
lengths and angles, anisotropic thermal parameters, hydrogen
atom coordinates and thermal parameters, and distances to
weighted least-squares planes for the dimer 2 of 4(3H)-
pyrimidinone and NMR spectra for compounds 5, 17, 21, 26,
and 28 (23 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
J O981285P