3-Ethyl-6-methyl-isocytosines: Synthesis and solid state structural analysis

Article abstract of DOI:10.1016/S0040-4020(00)00288-X

The syntheses and solid state structures of 3-ethyl-6- methyl-5-alkyl-isocytosines (alkyl=H, Me, Et, n-Pr, n-Bu) are presented. These heterocycles consistently self-assemble into N-H N hydrogen-bonded dimers, which further associate by N-H···O=C interactions, or N-H···O-H···O=C hydrogen bonds involving water of crystallization, generating extended supramolecular networks. Crystal packing analysis indicates that although hydrogen bonding is the primary intermolecular interaction in these molecular crystals, the dispersion forces may play a decisive role in determining their final three-dimensional arrangements. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00288-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5067±5075
3-Ethyl-6-methyl-isocytosines:
Synthesis and Solid State Structural Analysis
b,²
Radu Custelceana, and Liliana Craciun
*
aDepartment of Chemistry, Michigan State University, East Lansing, MI 48824-1322, USA
bDepartment of Organic Chemistry, `Babes-Bolyai' University, 11 Arany Janos Str., 3400 Cluj-Napoca, Romania
Received 8 February 2000; accepted 5 April 2000
AbstractÐThe syntheses and solid state structures of 3-ethyl-6-methyl-5-alkyl-isocytosines (alkylˆH, Me, Et, n-Pr, n-Bu) are presented.
These heterocycles consistently self-assemble into N±H´´´N hydrogen-bonded dimers, which further associate by N±H´´´OvC interactions,
or N±H´´´O±H´´´OvC hydrogen bonds involving water of crystallization, generating extended supramolecular networks. Crystal packing
analysis indicates that although hydrogen bonding is the primary intermolecular interaction in these molecular crystals, the dispersion forces
may play a decisive role in determining their ®nal three-dimensional arrangements. q 2000 Elsevier Science Ltd. All rights reserved.
The last decade witnessed a spectacular growth of supra-
molecular synthesis1±5 and crystal engineering,6±21 as a
result of extensive efforts to exert structural control beyond
molecular level, with the ultimate task to build new materi-
als with desired structures and properties.22±24 This objec-
tive proved to be extremely challenging, as the weak forces
that govern the organization of molecules in supramolecular
structures are dif®cult to predict and control. In addition,
other factors such as molecular symmetry and shape,14,25
close packing requirement,26 solvent of crystallization, or
kinetics of nucleation,25 render this problem even more dif®-
cult. Until the ab initio calculation of the three dimensional
arrangement of molecules in crystals becomes feasible,27±29
the systematic approach based on the empirical observation
of crystal packing changes in response to gradual modi®ca-
tions in molecular structure,30±35 remains the only practical
solution to this problem. When suf®cient understanding of
intra- and intermolecular interactions, as well as of other
pertinent factors is acquired, the successful building of
desired supramolecular structures can be eventually accom-
plished.
ing motifs are usually possible.40 The isocytosine (2-amino-
4-pyrimidinone) system has been recently explored, as a
versatile, easily accessible building block for supramolecu-
lar synthesis.40±42 However, the occurrence of two tauto-
mers in solid state has severely limited its applicability to
date. For example, isocytosine exhibits both the N1 and the
N3 tautomeric forms coexisting in the crystal.43 The same
situation is present in 5-(p-chlorophenyl)-6-ethyl-isocyto-
sine.44 The 6-methyl-isocytosine can be found as two poly-
morphs, one similar to the one found in the parent ring,41
and the other containing only the N1 tautomer.45 This tauto-
mer, on the other hand, is exclusively present in the 6-ethyl
and the 6-phenyl derivatives in the solid state.41 In order to
effectively use the isocytosine functionality for crystal
engineering, this rather unpredictable tautomerization
should be therefore controlled.
Because of their strong ability to self-assemble in extended
hydrogen-bonded arrays, heterocycles have been exten-
sively used in supramolecular synthesis.2,19,36±39 However,
due to the high density of hydrogen bonding donors and
acceptors present, the prediction of their crystal packing is
very often extremely dif®cult, as numerous hydrogen bond-
In this paper we describe the synthesis and self-assembly
of the 3-ethyl-6-methyl-isocytosines (2-amino-3-ethyl-6-
methyl-4(3H)-pyrimidinones) 1±5 in the solid state.
While ethylation at N(3) eliminated the possibility of the
above mentioned tautomerization, we hoped that it would
also simplify the intermolecular associations by elimina-
tion of one H-bonding donor site, making the crystal pack-
ing more predictable and therefore easier to control.
Keywords: dispersion interactions; hydrogen bonding; isocytosine; self-
assembly.
* Corresponding author. Tel.: 11-517-355-9715, ext. 143; fax: 11-517-
353-1793; e-mail: custelce@argus.cem.msu.edu
Present address: Ciba Specialty Chemicals, West Memphis, AR 72301,
²
USA.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00288-X

5068
R. Custelcean, L. Craciun / Tetrahedron 56 (2000) 5067±5075
Scheme 1.
Results and Discussion
Syntheses
2-Amino-3-ethyl-6-methyl-4(3H)-pyrimidinone (1) was
®rst isolated by Reznik and Shvetsov as a byproduct of
the reaction of 2-amino-6-methyl-4(3H)-pyrimidinone (6)
with paraformaldehyde and triethylphosphite.46 However,
no physical characterization is given for the new compound
in this paper. Taran and Raimanova47 reported the use of
compound 1 as an additive that improves the brightness of
nickel electrodeposits, but they do not disclose the synthetic
route followed to make 1 and once again, no physical
characterization is reported. We synthesized 2 in moderate
yield by ethylation of 6 with ethyl iodide in a biphasic
water±benzene mixture, following a literature method for
phase-transfer-catalyzed N-alkylation of amides (Scheme
1).48 The precursor, compound 6, was made by conden-
sation of ethyl acetoacetate (9) with guanidine sulfate
(8), following prior reported methodologies.49±51 The
previously
unknown
2-amino-3-ethyl-5,6-dimethyl-
4(3H)-pyrimidinone (2) was prepared similarly, by
ethylation of 2-amino-5,6-dimethyl-4(3H)-pyrimidinone
(7), which in turn was synthesized from ethyl 2-methyl-
acetoacetate (10) and 8.
To our knowledge, 2-amino-3,5-diethyl-6-methyl-4(3H)-
pyrimidinone (3) and 2-amino-3-ethyl-6-methyl-5-n-propyl-
4(3H)-pyrimidinone (4) have not been previously
reported in the literature. We prepared compounds 3
and 4 by a method analogous with the reported synthe-
sis of 2-amino-5-n-butyl-3-ethyl-6-methyl-4(3H)-pyrimidi-
none (5).52 Thus, 3 and 4 were obtained as byproducts
in the condensation of N-ethylguanidine sulfate (11)
with ethyl 2-ethylacetoacetate (12) and ethyl 2-n-
propylacetoacetate (13), respectively (Scheme 1). This
route failed when applied for compounds 1 and 2,
where condensation of N-ethylguanidine with 9 or 10
gave exclusively 2-ethylamino-6-methyl-4(3H)-pyrimidi-
none (15) and 2-ethylamino-5,6-dimethyl-4(3H)-pyrimidi-
none (16).53
Figure 1. Crystal structure of 4: (a) self-assembly in dimers. (b) tetrahedral
orientation of dimers, linked by N±H´´´OvC hydrogen bonds.

R. Custelcean, L. Craciun / Tetrahedron 56 (2000) 5067±5075
5069
group in the 6th position shows no effect on the NH2 1H
NMR signal. These results strongly con®rm the prevalence
of the amino-oxo forms in solution for 1±5.
Ê
Table 1. Hydrogen bonding parameters (A, 8) for 1±5
D±H´´´A
D´´´A
H´´´A
/D±H´´´A
1
N(2)±H´´´N(4)
N(5)±H´´´N(1)
N(2)±H´´´O(1)
N(5)±H´´´O
3.007
2.953
2.895
2.937
2´0.5 H2O
3.019
2.964
3.105
2.892
2.767
2.796
2.141
2.074
2.095
2.114
175.1
171.5
159.7
141.8
Solid state structural analysis
This study was inspired from the crystal structure of
2-amino-3-ethyl-6-methyl-5-n-propyl-4(3H)-pyrimidinone
(4), part of an extensive project investigating the structure-
property relationships in isocytosine derivatives.49±53 The
compound crystallized from CH3OH/CHCl3 in the space
group P42/n, belonging to the tetragonal crystal system.
As depicted in Fig. 1, 4 forms centrosymmetric dimers in
the solid state, held together by NH´´´N hydrogen bonds
(Table 1), with observed H´´´N contact distances of
N(2)±H´´´N(1A)
N(2A)±H´´´N(1)
N(2)±H´´´O(A)
N(2A)±H´´´O(B)
O(B)±H´´´O
2.117
2.083
2.459
2.037
1.922
1.960
172.1
173.1
135.5
163.7
167.8
170.9
O(B)±H´´´O(A)
(3)0.77(4)0.23´0.5 H2O
N(2)±H´´´N(1A)
N(2A)±H´´´N(1)
N(2)±H´´´O(B)
N(2A)±H´´´O(B)
O(B)±H´´´O
2.984
3.001
3.161
3.038
2.739
2.802
2.191
175.9
173.5
165.0
162.0
163.7
173.2
2.122
2.291
2.176
1.980
1.985
Ê
2.103 A. The dimers are approximately planar, with the
CvO groups, however, signi®cantly deviated from the
least-squares plane de®ned by N1, N2, N(1A), N(2A)
O(B)±H´´´O(A)
4
N(2)±H´´´N(1A)
N(2)±H´´´O
2.987
2.925
2.103
2.027
176.6
169.9
5a
N±H´´´N(1)
N±H´´´O
3.005
2.884
2.160
2.071
161.8
160.7
a Ref. 54.
The tautomerism of compounds 1±5 in solution was
addressed by NOE experiments. A positive NOE enhance-
ment (2±3%) of the NH2 signal is observed on irradiation of
the exocyclic NCH2 peak, whereas irradiation of the methyl
Figure 3. Crystal structure of 5: (a) hydrogen bonding network; (b) crystal
packing viewed along the c axis.
Figure 2. Crystal packing of 4, viewed along the c axis.

5070
R. Custelcean, L. Craciun / Tetrahedron 56 (2000) 5067±5075
Ê
(0.159(3) and 0.101(3) A for O and C1, respectively). These
deviations can be explained by the additional hydrogen
bonding present, involving the CvO groups and the
remaining NH protons, forming a three-dimensional
network, with the dimers disposed in a tetrahedral orienta-
tion (Fig. 1b), re¯ecting thus the overall tetragonal sym-
metry of the crystal. The N±H´´´OvC contact distances
c axis, occupied by the hydrophobic propyl chains. There-
fore, it appeared to us very appealing the prospect of
removing these groups from the isocytosine rings, which
would result in a porous structure, provided the crystal pack-
ing remains the same. The previously determined crystal
structure of 5 was encouraging, as it adopts the same pack-
ing as 4 (Fig. 3), with a slightly bigger unit cell, as expected
due to the extra methylene group.54 This fact suggested that
the three-dimensional hydrogen bonding network found in 4
might be robust enough to tolerate even more profound
structural modi®cations in the 5-alkyl chain. We therefore
synthesized the 2-amino-3-ethyl-6-methyl-4(3H)-pyrimidi-
none (1) and determined its crystal structure. Like 4, 1
associates into hydrogen-bonded dimers in solid state
(Fig. 4). However, no center of symmetry relates the two
isocytosine rings, as both ethyl groups are oriented on the
same side of the dimer's plane. The two NH´´´N hydrogen
bonds (Table 1) are also slightly different, with H´´´N
Ê
are 2.027 A long and approximately linear, with the
N±H´´´O angles of 169.98. The dihedral angle between
the least-squares planes (de®ned by the four N atoms
involved in hydrogen bonding) of two adjacent dimers is
70.98. A closer examination of the crystal packing of 4
(Fig. 2) reveals the presence of in®nite channels along the
Ê
contact distances of 2.074 and 2.141 A, respectively. The
planarity of the dimers is more severely distorted than in 4,
with the largest deviations from the least-squares plane
de®ned by N1, N2, N4 and N5 as big as 0.659(3) and
Ê
0.448(2) A for O(1) and C(9), respectively. Further
N±H´´´OvC hydrogen bonds (Table 1) link the dimers
(Fig. 4b), with H´´´O contact distances of 2.095 and
Ê
2.114 A. The dihedral angle of 71.18 between adjacent
dimers is very similar to the corresponding value in 4.
However, despite the similar appearance, the crystal pack-
ings of 1 and 4 are signi®cantly different. Fig. 5 shows the
relationship between the two H-bonding motifs, A and B,
interrelated by 1808 out-of-plane rotation of half of the
dimers, and gliding. This interconversion might occur
during the molecular recognition process accompanying
nucleation. In the absence of the 5-alkyl groups, the more
compact motif B is eventually preferred, leading thus to a
more ef®cient packing in 1, which unfortunately precludes
the formation of the desired porous solid. Instead, two-
dimensional hydrogen-bonded corrugated sheets are
formed, self-assembled into bilayers, with all N-Et groups
pointing inward, which presumably optimizes their van der
Waals interactions (Fig. 6). The contribution of these weak
forces to the overall lattice energy is probably small
compared to the corresponding energy of the much stronger
hydrogen bonds. Nevertheless, under the present circum-
stances, with the two H-bonding motifs seemingly equally
favored, the dispersion interactions become decisive in
determining the ®nal three-dimensional crystal packing.55
Attempts to enforce the H-bonding motif A by using
different hydrocarbons such as hexane, heptane, methyl-
cyclohexane or benzene, as potential templates that might
compensate the absence of the 5-n-propyl or 5-n-butyl
groups, were unsuccessful to date.
Having de®ned the two limits of the series, we naturally
became interested to ®nd out the transition point between
the two crystal packings, or to possibly identify other
H-bonding motifs. We therefore synthesized the 5-Me (2)
and 5-Et (3) derivatives, and pursued their solid state
structural investigations. The 2-amino-3-ethyl-5,6-
dimethyl-4(3H)-pyrimidinone (2) crystallized from THF
with 0.5 mol of H2O, as revealed by X-ray analysis.
Attempts to crystallize it free of water, by using different
solvents, were unsuccessful to date. Nevertheless, 2 exhibits
Figure 4. Crystal structure of 1: (a) self-assembly in dimers; (b) hydrogen
bonding network.

R. Custelcean, L. Craciun / Tetrahedron 56 (2000) 5067±5075
5071
Figure 5. Schematic representation of the relationship between the hydrogen bonding motifs in 4±5 (A) and 1 (B).
the same association in dimers that was observed in the
previous structures (Fig. 7). However, the isocytosine
rings are signi®cantly twisted relative to each other, with
a dihedral angle between the planes de®ned by the nitrogen
atoms in each ring, of 31.28. The water of crystallization
interconnects the dimers by participating to two
O±H´´´OvC interactions as a H-bonding donor, and as an
acceptor in a N±H´´´OH hydrogen bond (Fig. 7b). The
remaining N(2)±H, however, prefers to interact with the
CvO(A) carbonyl group, in a weaker hydrogen bond
(Table 1). The result is a complex three-dimensional
H-bonding network.
analysis of this compound, also revealed the presence of 4
in the crystal, as a result of accidental contamination. The
extra C atoms in the two unique isocytosine rings were
re®ned with the partial occupancy of 0.254 and 0.211,
estimating thus the proportion of the 5-n-Pr derivative
1
around 23%. H NMR analysis con®rmed the presence of
about 20±25% of 4 in the sample used for the X-ray investi-
gation. The rest of the atoms corresponding to the two
structures are not distinguishable, the only effect of the
disorder being a slight increase in the displacement para-
meters, especially for the C atoms in the alkyl chains. Once
again, the isocytosine rings associate into N±H´´´N hydro-
gen bonded dimers (Fig. 8), that, however, are severely
deviated from planarity, exhibiting a dihedral angle between
Similarly, 3 crystallized with 0.5 mol of H2O. The X-ray
Figure 6. Crystal packing of 1: (a) hydrogen-bonded corrugated sheet; (b) self-assembly in bilayers.

5072
R. Custelcean, L. Craciun / Tetrahedron 56 (2000) 5067±5075
Figure 7. Crystal structure of 2´0.5 H2O: (a) self-assembly in dimers; (b) hydrogen bonding network involving water of crystallization (alkyl groups not shown
for clarity).
the planes de®ned by the N atoms, of 46.88. The water
molecules play both the role of donors and acceptors in
O±H´´´OvC and N±H´´´OH interactions (Table 1), respec-
tively, linking the dimers in a three-dimensional H-bonding
network (Fig. 8b).
resulted in a porous molecular crystal. However, while
adopting a very similar H-bonding motif, 1 found an alter-
native arrangement into 2-D sheets, self-assembled into
bilayers, leading to a more effective crystal packing,
which presumably optimized the dispersion interactions of
the N-Et chains. Thus, although hydrogen bonding is the
dominant intermolecular interaction in these crystals, it
appears that the cooperative effect of the dispersion forces
makes a signi®cant contribution to the overall lattice energy,
decisively in¯uencing the three-dimensional crystal
packing.
Conclusions
3-Et-6-Me-isocytosines 1±5 consistently self-assemble into
N±H´´´N hydrogen bonded dimers in the solid state. More-
over, the dimers can further associate by N±H´´´OvC
hydrogen bonds into extended supramolecular arrays.
However, the presence of water of crystallization can
disrupt this H-bonding motif, as illustrated by the crystal
structures of 2´0.5 H2O and (3)0.76(4)0.23´0.5 H2O. In
these hydrates, the water molecules link the dimers by
O±H´´´OvC and N±H´´´OH hydrogen bonds, into three-
dimensional hydrogen-bonded networks. The signi®cantly
different packing arrangements of 4±5 and 1 emphasize
once again the dif®culties associated with the ab initio
prediction of the three-dimensional organization of
molecules in crystals. While 4 and 5 form 3-D hydrogen
bonding networks, a similar packing in 1 would have
Experimental
Ê
Solvents were distilled and/or stored over 4 A molecular
sieves prior to use. All other reagents were used as obtained
from commercial sources or puri®ed according to standard
procedures. Experimental yields were not optimized. Melt-
ing points were determined in sealed capillaries on a
Thomas Hoover Unimelt apparatus, and are uncorrected.
Proton (1H) and carbon (13C) NMR spectra were measured
at ambient temperature on a Varian 500 MHz spectrometer,
and were referenced to solvent signals. Infrared spectra

R. Custelcean, L. Craciun / Tetrahedron 56 (2000) 5067±5075
5073
11 mmol) 12 or 13, was added dropwise to the ®ltrate
under stirring, and the reaction mixture was re¯uxed for
12 h. After cooling, water was added and the reaction
mixture was made strongly basic with 25% aqueous
NaOH. Filtration, followed by recrystallization of the
white solid from CH3NO2 gave 3 or 4 in yields of 27 and
22%, respectively.
2-Amino-3-ethyl-6-methyl-4(3H)-pyrimidinone (1) was
obtained as white crystals with mp 223±2248C; H NMR
1
(CDCl3) d 5.80 (s, 1H), 5.18 (s, broad, 1H, exchangeable),
4.00 (q, Jˆ7.3 Hz, 2H), 2.12 (s, 3H), 1.33 (t, Jˆ7.3 Hz, 3H);
13C NMR (CDCl3) d 163.32 (C(4)), 162.32 (C(2)), 154.06
(C(6)), 103.01 (C(5)), 36.70 (NCH2CH3), 23.60
(NCH2CH3), 12.67 (CH3); IR (KBr) nmax 3351, 3156,
3086, 2985, 1692, 1657 (s), 1521 (s), 1491, 1452, 1427,
1452, 1188, 1146, 1016, 810, 786 cm21; MS (EI) m/z for
C7H11N3O 153 (M1, 15), 138 (61), 125 (481), 109 (100), 97
(100), 84 (35), 82 (31), 69 (36), 67 (36), 54 (37). Single
crystals suitable for X-ray analysis were grown by slow
evaporation from chloroform±acetone.
2-Amino-3-ethyl-5,6-dimethyl-4(3H)-pyrimidinone (2) was
obtained as white crystals with mp 176±1788C; H NMR
1
(CDCl3) d 4.73 (s, broad, 1H, exchangeable), 4.01 (q,
Jˆ7.3 Hz, 2H), 2.15 (s, 3H), 1.98 (s, 3H), 1.33 (t,
Jˆ7.3 Hz, 3H); 13C NMR (CDCl3) d 161.84 (C(4)),
159.00 (C(2)), 152.53 (C(6)), 105.04 (C(5)), 35.85
(NCH2CH3), 21.45 (NCH2CH3), 12.49 (C(6)CH3), 11.10
(C(5)CH3); IR (KBr) nmax 3390, 3348, 3153, 3117, 2982,
2940, 1681, 1639 (s), 1536 (s), 1502, 1456, 1209, 1131, 979,
791 cm21; MS (EI) m/z for C8H13N3O 167 (M1, 28), 139
(100), 138 (53), 124 (21), 111 (59), 110 (51), 96 (28), 69
(31), 55 (27), 53 (28). Single crystals suitable for X-ray
analysis were grown by slow evaporation from THF.
Figure 8. Crystal structure of (3)0.76(4)0.23´0.5 H2O: (a) self-assembly in
dimers; (b) hydrogen bonding network involving water of crystallization
(alkyl groups not shown for clarity).
were recorded on a Nicolet 730 FT-IR spectrophotometer.
GC/MS analyses were carried out on a Hewlett-Packard
5890/5971 gas chromatograph-mass selective detector.
2-Amino-3,5-diethyl-6-methyl-4(3H)-pyrimidinone (3) was
obtained as white needle crystals with mp 172±1738C; H
1
2-Amino-3-ethyl-6-methyl-4(3H)-pyrimidinone (1) and
2-amino-3-ethyl-5,6-dimethyl-4(3H)-pyrimidinone (2).
A solution of ethyl iodide (650 mg, 4.2 mmol) in benzene
was added dropwise with ef®cient stirring to the re¯uxing
mixture of 2-amino-6-methyl-4(3H)-pyrimidinone 6 or 7
(2.7 mmol), ®nely powdered potassium hydroxide
(550 mg), potassium carbonate (750 mg), tetra-n-butyl-
ammonium hydrogen sulfate (91 mg), and benzene
(10 mL). Stirring was continued for 4 h at re¯ux. The result-
ant mixture was cooled to room temperature, treated with
water, and extracted with chloroform. The organic phase
was separated, washed with water, dried over anhydrous
magnesium sulfate, and evaporated to give a white solid.
Recrystallization from ethanol gave 2-amino-3-ethyl-6-
methyl-4(3H)-pyrimidinone (1) in 15% yield, and
2-amino-3-ethyl-5,6-dimethyl-4(3H)-pyrimidinone (2) in
28% yield.
NMR (CDCl3) d 11.35 (s, broad, 1H, exchangeable), 4.00
(q, Jˆ7.3 Hz, 2H, NCH2CH3), 2.45 (q, Jˆ7.3 Hz, 2H,
CH2CH3), 2.15 (s, 3H), 1.32 (t, Jˆ7.3 Hz, 3H, NCH2CH3),
1.06 (t, Jˆ7.3 Hz, 3H, CH2CH3); 13C NMR (CDCl3) d
161.97 (C(4)), 157.87 (C(2)), 151.66 (C(6)), 115.63
(C(5)), 36.95 (NCH2CH3), 20.74 (NCH2CH3), 19.34
(CH2CH3), 13.13 (CH2CH3), 12.53 (CH3); IR (KBr) nmax
3421, 3340, 3144, 3099, 2976, 2929, 1669, 1625 (s), 1524
(s), 1444, 1410, 1318, 1198, 792 cm21; MS (EI) m/z for
C9H15N3O 181 (M1, 33), 166 (100), 150 (25), 138 (70),
110 (10), 96 (32), 69 (10). Single crystals suitable for X-
ray analysis were grown by slow evaporation from chloro-
form±acetone.
2-Amino-3-ethyl-6-methyl-5-n-propyl-4(3H)-pyrimidinone
(4) was obtained as white needle crystals with mp 193±
1948C; H NMR (CDCl3) d 5.43 (s, broad, 1H, exchange-
1
able), 3.99 (q, Jˆ7.3 Hz, 2H, NCH2CH3), 2.39 (t, Jˆ7.3 Hz,
2H, CH2CH2CH3), 2.13 (s, 3H), 1.44 (sextet, Jˆ7.3 Hz, 2H,
CH2CH2CH3), 1.31 (t, Jˆ7.3 Hz, 3H, NCH2CH3), 0.91 (t,
Jˆ7.3 Hz, 3H, CH2CH2CH3); 13C NMR (CDCl3) d 162.26
(C(4)), 158.58 (C(2)), 151.88 (C(6)), 113.96 (C(5)), 36.87
(NCH2CH3), 28.12 (CH2CH2CH3), 22.03 (CH2CH2CH3),
21.05 (NCH2CH3), 14.11 (CH2CH2CH3), 12.49 (CH3); IR
(KBr) nmax 3370, 3343, 3145, 3109, 2959, 2932, 1683, 1631
2-Amino-3,5-diethyl-6-methyl-4(3H)-pyrimidinone (3),
and 2-amino-3-ethyl-6-methyl-5-n-propyl-4(3H)-pyrimi-
dinone (4). To a stirred solution of sodium n-butoxide
(11 mmol) in anhydrous n-butanol (100 mL) was added
1.5 g of N-ethylguanidine sulfate 11 (5.5 mmol) and the
mixture was re¯uxed for 30 min, cooled in an ice bath and
®ltered. Ethyl 2-alkylacetoacetate (freshly distilled;

5074
R. Custelcean, L. Craciun / Tetrahedron 56 (2000) 5067±5075
Table 2. Crystallographic data for 1±4
1
2´(H2O)0.5
(3)0.77(4)0.23´(H2O)0.5
4
Formula
C7H11N3O
153.19
C8H14N3O1.5
176.22
C9.23H16.46N3O1.5
193.47
C10H17N3O
195.27
Formula weight
Dimensions, mm
Crystal system
Space group, Z
0.41£0.36£0.10
Monoclinic
P21/n, 8
12.1028(5)
10.3188(4)
12.7922(5)
90
97.7500(10)
90
1582.98(11)
173
1.286
0.60£0.57£0.18
Monoclinic
P21/n, 8
11.7406(6)
8.7183(4)
19.0055(9)
90
105.9080(10)
90
1870.86(16)
173
1.251
0.60£0.49£0.08
Monoclinic
P21/n, 8
14.3955(2)
9.2865(1)
17.57120(10)
90
114.0320(10)
90
2145.37(3)
173
1.198
0.44£0.34£0.26
Tetragonal
P42/n, 8
16.4048(4)
16.4048(4)
8.5052(3)
90
Ê
a, A
Ê
b, A
Ê
c, A
a, deg
b, deg
g, deg
90
90
Ê 3
V, A
Temperature, K
dcalcd, g/cm23
2288.90(11)
173
1.133
Re¯ections collected
Unique re¯ections
2umax, deg
9667
3704
28.30
287
10894
4313
28.27
339
12759
4918
28.19
381
7148
2376
27.49
196
No. of parameters
a
b
R1 , wR2 (I.2s)
R1, wR2 (all data)
Goodness of ®t
0.0390, 0.1026
0.0508, 0.1090
1.029
0.0417, 0.1181
0.0540, 0.1263
1.038
0.0640, 0.1565
0.0887, 0.1732
1.020
0.0386, 0.0965
0.0569, 0.1043
1.047
P
P
a R1 ˆ ꢀuF0u 2 uFcu†= uF0u:
P
P
b wR2 ˆ { ‰WꢀF02 2 Fc2† Š= ‰wꢀF02† Š}1=2
2
2
(s), 1524 (s), 1443, 1409, 1198, 1126, 792 cm21; MS (EI)
m/z for C10H17N3O 195 (M1, 11), 167 (11), 166 (100), 138
(28), 96 (19). Single crystals suitable for X-ray analysis
were grown by slow evaporation from chloroform±
methanol.
4. Stang, P. J.; Olenyuk, B. Acc. Chem. Res. 1997, 30, 502±518.
5. Fyfe, M. C. T.; Stoddart, F. Coord. Chem. Rev. 1999, 18, 139±
155.
6. Desiraju, G. R. Angew. Chem. Int. Ed. 1995, 34, 2311±2327.
7. Desiraju, G. R. Chem. Commun. 1997, 1475±1482.
8. MacDonald, J. C.; Whitesides, G. M. Chem. Rev. 1994, 94,
2383±2420.
X-Ray crystal structure determination of 1±4. X-Ray
crystallographic measurements (Table 2) were carried out
on a Siemens SMART CCD diffractometer with graphite-
9. Ermer, O.; Eling, A. J. Chem. Soc., Perkin Trans. 2 1994, 925±
944.
Ê
monochromated Mo Ka radiation (lˆ0.71073 A), operated
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137, 357±401.
at 50 kV and 40 mA. The structures were solved by direct
methods and re®ned on F2 using the shelxtl software pack-
age.56 Absorption corrections were applied using sadabs,
part of the shelxtl software package. All non-hydrogen
atoms were re®ned anisotropically. Hydrogen atoms were
located from difference Fourier maps and re®ned isotropi-
cally, except for the methyl hydrogens from the propyl
groups of 4, in (3)0.76(4)0.23´0.5 H2O, which were calculated
and placed in idealized positions.
11. Aakeroy, C. B. Acta. Cryst. 1997, B53, 569±586.
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41.
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Acknowledgements
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R. C. gratefully acknowledges his advisor, Professor James
E. Jackson (MSU), for promoting intellectual independence
and a stimulating and creative ambience in his research
group, without which this project would have never been
possible.
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