The psuedo-Michael reaction of 2-aminoimidazolines 2. Part 1. Synthesis and structure assignment of isomeric 5(1H)-oxo and 7(1H)-oxo-2,3-dihydroimidazo[1,2-alpyrimidine-6-carboxylates

Article abstract of DOI:10.1002/jhet.5570400112

The pseudo-Michael reaction of 1-aryl-2-aminoimidazolines-2 with diethyl ethoxymethylenemalonate (DEEM) was investigated. Extensive structural studies were performed to confirm the reaction course. For derivatives with N1 aromatic substituents, it was found that the reaction course was temperature dependent. When the reaction temperature was held at -10°C only the formation of 1-aryl-7(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates (4) was observed in contrast to earlier suggestions. Under the room temperature conditions, the same reaction yielded mixtures, with varying ratio, of isomeric 1-aryl-7(1H)-oxo- (4a-4f) and 1-aryl-5(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates (5a-5f). The molecular structure of selected isomers, 4b and 5c, was confirmed by X-ray crystallography. Frontal chromatography with delivery from the edge was applied for the separation of the isomeric esters. The isomer ratio of the reaction products depended on the character of the substituents on the phenyl ring. The 1-aryl-7(1H)-oxo-carboxylates (4a-4f) were preferably when the phenyl ring contained H, 4-CH₃, 4-OCH₃ and 3,4-Cl₂ substituents. Chloro substitution at either position 3 or 4 in the phenyl ring favored the formation of isomers 5a-5f. The isomer ratios were confirmed both by ¹H NMR and chromatography. The reaction of the respective hydrobromides of 1-aryl-2-aminoimidazoline-2 with DEEM, in the presence of triethylamine, gave selectively 5(1H)-oxo-esters (5a-5f).

Full text of DOI:10.1002/jhet.5570400112

Jan-Feb 2003
The Psuedo-Michael Reaction of 2-Aminoimidazolines 2. Part 1.
Synthesis and Structure Assignment of Isomeric 5(1H)-Oxo and
7(1H)-Oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates
Dariusz Matosiuk*
93
Dept. of Synthesis and Technology of Drugs, Faculty of Pharmacy, Medical University, 20081 Lublin, Poland
Kalevi Pihlaja and Vladimir V. Ovcharenko
Dept. of Chemistry, University of Turku, FIN-20014 Turku, Finland
/
/
Izabela Dybala and Anna E. Koziol
/
Dept. of Crystallography, Faculty of Chemistry, Maria Curie-Sklodowska University, 20031 Lublin, Poland
Maria Gdaniec
Dept. of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, 60780 Poznan´, Poland
/
Halina Szumilo
Dept. of Inorganic and Analytical Chemistry, Faculty of Pharmacy, Medical University, 20081 Lublin, Poland
Zbigniew Karczmarzyk
Dept. of Biophysics and Crystallography, Podlasie Academy, 08110 Siedlce, Poland
Received July 26, 2002
Dedicated to Professor T. Tkaczyn´ski with best wishes
The pseudo-Michael reaction of 1-aryl-2-aminoimidazolines-2 with diethyl ethoxymethylenemalonate
(DEEM) was investigated. Extensive structural studies were performed to confirm the reaction course. For
derivatives with N1 aromatic substituents, it was found that the reaction course was temperature dependent.
When the reaction temperature was held at –10 °C only the formation of 1-aryl-7(1H)-oxo-2,3-dihydroimi-
dazo[1,2-a]pyrimidine-6-carboxylates (4) was observed in contrast to earlier suggestions. Under the room
temperature conditions, the same reaction yielded mixtures, with varying ratio, of isomeric 1-aryl-7(1H)-
oxo- (4a-4f) and 1-aryl-5(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates (5a-5f). The mol-
ecular structure of selected isomers, 4b and 5c, was confirmed by X-ray crystallography. Frontal chro-
matography with delivery from the edge was applied for the separation of the isomeric esters. The isomer
ratio of the reaction products depended on the character of the substituents on the phenyl ring. The 1-aryl-
7(1H)-oxo-carboxylates (4a-4f) were preferably when the phenyl ring contained H, 4-CH , 4-OCH and
3
3
3,4-Cl substituents. Chloro substitution at either position 3 or 4 in the phenyl ring favored the formation of
2
1
isomers 5a-5f. The isomer ratios were confirmed both by H NMR and chromatography. The reaction of the
respective hydrobromides of 1-aryl-2-aminoimidazoline-2 with DEEM, in the presence of triethylamine,
gave selectively 5(1H)-oxo-esters (5a-5f).
J. Heterocyclic Chem., 40, 93 (2003).
Diethyl ethoxymethylenemalonate (DEEM) is a well-
At present the molecular geometry of three 5(1H)-oxo-
2,3-dihydroimidazo[1,2-a]pyrimidine derivatives are
known; two with N8-phenyl [5,6] and one with N1-methyl
[7] substitution. The 7(1H)-oxo-2,3-dihydroimidazo[1,2-
a]pyrimidine system has not been reported earlier.
Differences in the structures of 1-aryl-2,3-dihydroimi-
dazo[1,2-a]pyrimidine result from the location of the car-
bonyl group; in the 5-oxo compound, one of the guanidine
N-atoms is part of the lactam group whereas in the case of
the 7-oxo compound the carbonyl and the C5-C6 double
bond give the pyrimidine ring a pseudo-quinoid character.
Pharmacological activity of isomeric esters on the CNS
of laboratory animals (mice, rats) was reported [8] and
known reagent for heterocyclic annelation. Its reaction
with 2-aminoazaheterocycles has been widely used to
obtain fused pyrimidines bearing the β-oxo-acid moiety.
To date, the formation of 4-oxo-pyrimidine-3-carboxylates
has been reported [1]. Only Agata [2] and Koekoesi et al
[3,4] suggested that the NH-C=NH system (e.g. present in
cyclic amidines) can yield mixtures of isomeric products
(2- or 4-oxo esters) when reacted with Michael reagents
such as DEEM. Their results indicated that the isomer ratio
depended only on the ring size. The main product was
always a 4-oxo isomer, which suggested that reaction
starts at the exo N6 nitrogen atom.

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/
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94
D. Matosiuk, K. Pihlaja, V. V. Ovcharenko, I. Dybala, A. E. Koziol
M. Gdaniec,
Vol. 40
/
H. Szumilo, and Z. Karczmarzyk
evaluated in behavioral tests. The compounds exhibited
antinociceptive activity that seemed to be connected with
the opioid system, and also some serotonergic and CNS-
depressive activity. Both the activity and acute toxicity of
isomeric esters were structure-dependent. From this point
of view, the separation and identification of isomers is
important for further studies aimed at explaining their
mechanism of action.
The reaction of 2-aminoimidazolines-2 with DEEM was
studied to find a new method of annelation of the imidazo-
line ring. Previously, we found that 1-alkyl-5-aryl-2-
aminoimidazolines-2 and DEEM yielded a single product,
[8] whereas the 1-aryl-2-aminoimidazolines-2 yields mix-
tures of two isomeric oxo-dihydroimidazo[1,2-a]pyrimi-
dine esters. The proposed course of the latter reaction is
summarized in Scheme 1.
the presence of H5 and H7 hydrogens. These signals were
usually separated by ca. 0.05 ppm but nevertheless they
were easily recognizable even in the 100 MHz spectra.
Their integrals gave the ratio of isomeric esters in the prod-
uct mixture. Preparative thin-layer chromatography (PR-
TLC) on silica gel with benzene/ethyl acetate (1:3) as an
1
eluent confirmed the H NMR results (Table 1).
Refluxing 1-aryl-2-aminoimidazoline-2 hydrobromides
(2a-2f) with DEEM (3) in ethanol for 3 to 10 h (Method C)
led to the formation of one single isomer (Scheme 2) –
namely the 5(1H)-oxo esters (5a-5f) (Table 2). The exclu-
sive formation of isomers 5 in this reaction was probably
caused by a change in the nucleophilicity of the N3 endo
nitrogen due to its protonation. Thus only the exo N6 nitro-
gen was able to initiate the reaction despite its obviously
lower nucleophilicity.
Scheme 1
A careful analysis of the spectral and X-ray crystallo-
graphic data of selected crystals indicated that in the
majority of reactions the main products were 1-aryl-7(1H)-
oxo-esters (4a-4f). Condensation of 1-aryl-2-aminoimida-
zolines-2 (1a-1f) with DEEM (3) in ethanol at –10 °C
(Method A) gave the products identified as the 1-aryl-
7(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-car-
boxylates (4a-4f).
The molecular structures of 7(1H)-oxo and 5(1H)-oxo
esters were confirmed by X-ray structure analysis of single
crystals of 4b and 5c (Figure 1). The geometry of the
7(1H)-oxo and 5(1H)-oxo isomers and selected bond
lengths are presented in Table 3. The N1, N4 and N8 nitro-
gen atoms form a completely substituted guanidine moiety
at the ring junction. The C8-N bond lengths are typical for
this system, although a difference in the C8-N1 bond
lengths was observed.
The solid-state conformation of the five-membered dihy-
droimidazole ring is an envelope for 4b (maximal torsion
angle less than 20°) and a twist for 5c (torsion angles < 9°).
The geometries of the nearly planar pyrimidine moieties
Carrying out the condensation of 1-aryl-2-aminoimidazo-
lines-2 (1a-1f) at room temperature (Method B) led to the
1
formation of a mixture of isomers 4a-4f and 5a-5f. H NMR
spectra of the crude product (Table 1) showed two charac-
teristic singlets in the range of δ 8.0 - 8.5 ppm attributable to

Jan-Feb 2003
The Psuedo-Michael Reaction of 2-Aminoimidazolines 2
95
Table 3
Selected Bond Lengths [Å] for 4b and 5c
Table 1
Isomeric Compounds 4 and 5 Obtained by Method B
Symbol
R
m.p
[°C]
The
overall
Ratio
Ratio
calculated
4b
5c
calculated
1
yield from H NMR from TLC
[%]
N(1)-C(8)
N(8)-C(8)
N(1)-C(2)
N(8)-C(7)
C(2)-C(3)
C(7)-O(7)
N(4)-C(3)
C(5)-C(6)
N(4)-C(5)
C(6)-C(7)
N(4)-C(8)
N(1)-C(9)
1.357(3)
1.308(3)
1.468(3)
1.389(3)
1.519(3)
1.231(3)
1.463(3)
1.358(3)
1.345(3)
1.473(3)
1.370(2)
1.420(3)
N(1)-C(8) 1.340(2)
N(8)-C(8) 1.315(2)
N(1)-C(2) 1.467(2)
N(8)-C(7) 1.350(3)
C(2)-C(3) 1.514(3)
C(5)-O(5) 1.222(2)
N(4)-C(3) 1.462(2)
C(6)-C(7) 1.373(3)
N(4)-C(5) 1.386(3)
C(5)-C(6) 1.445(3)
N(4)-C(8) 1.364(2)
N(1)-C(9) 1.417(2)
C(6)-C(16) 1.471(3)
spectra
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
4f
C H
262-4
190-2
235-7
200-2
194-6
173-5
229-31
255-6
213-5
181-3
83
75 %
25 %
66 %
33 %
60 %
40 %
40 %
60 %
33 %
66 %
60 %
40 %
69 %
31 %
64 %
36 %
64 %
36 %
47 %
53 %
39 %
61 %
64 %
36 %
6
5
5
C H
6
4-CH C H
85
71
89
67
3
6
4
4
4-CH C H
3
6
4-CH OC H
3
6
4
4
4-CH OC H
3
6
4-ClC H
4-ClC H
3-ClC H
3-ClC H
6
4
4
4
4
6
6
6
C(6)-C(16) 1.476(3)
3,4-Cl C H >330(dec.) 76
2
6
3
3
5f
3,4-Cl C H
289-91
2
6
Scheme 2
Table 2
The Conditions for Formation of Isomeric Compounds 5
always shifted downfield compared to the respective C(7)H
signals. The C2 and C3 hydrogen atoms are represented in
the spectra by broad singlet or narrow multiplet signals at
ca. 4.2 ppm. Usually they take a dd form and are separated
by 0.2-0.4 ppm. The downfield shifting of the C2 is caused
by deshielding by the C=N double bond but not by the car-
bonyl group located at C5 or C7.
Symbol
R
Reaction time
Yield [%]
5a
5b
5c
5d
5e
5f
C H
3 h
4 h
32
27
34
39
44
48
6
5
4-CH C H
3
6 4
4-CH OC H
4 h
3
6 4
4-ClC H
8 h
6
4
13
The C NMR spectra of compounds 4 and 5 mainly dif-
3-ClC H
10 h
10 h
6
4
3,4-Cl C H
fer in the chemical shifts of the carbonyl (C=O) and car-
bimino (C=N) atoms. In both series the ester carbonyl car-
bons showed the highest chemical shift values (~165 and
~168 ppm, respectively). The amidic carbon atoms were
observed at 160-164 ppm. The greatest difference was
observed in the chemical shifts of the carbimino carbon
atoms. The carbimino carbon atoms resonances in the 7-oxo
esters were observed at ~158 ppm, whereas in the 5-oxo
esters they were observed at ~150 ppm. The clearly higher
value of this chemical shift in the 7-oxo isomers may be
caused by a strong anisotropic effect on the C=N double
bond exerted by other conjugated double bonds of the
pseudo-quinoid moiety. Surprisingly, no differences were
observed in the chemical shifts of the methylene carbon
atoms (~108 ppm). The C2 and C3 signals in 7-oxo esters
were separated by ~6 ppm whereas the same signals in
5-oxo esters were only separated by 1-1.5 ppm. The down-
field shift of the C3 carbon atom signals of 5 by ~4.5 ppm in
2
6 4
(torsion angles < 4°) of 4b and 5c are clearly different in the
four-bond fragments of N4-C5-C6-C7-N8. A characteristic
bond-distance pattern indicates a pseudoquinoid structure
for 4b. A comparison with other “quinoid” aminopyrimidi-
nones [9] is complicated by the protonation of their nitro-
gen atoms and by the presence of N-H N and N-H O
hydrogen bonds in the solid state, while in 4b only C-H O
contacts exist. Although the ester group is nonplanar with
the pyrimidine ring (angles between the planes are 20.7°
and 17.1° for 5c and 4b, respectively), syn- orientation of
the two C=O bonds is observed in both compounds.
…
…
…
1
The H NMR spectra of isomeric esters differ only by the
methylene –CH= hydrogen atom chemical shifts. Although
in the mixtures of isomeric esters these signals are sepa-
rated by 0.05-0.1 ppm only they can be used for calculating
the ratio of the isomeric esters. The C(5)H signals are

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96
D. Matosiuk, K. Pihlaja, V. V. Ovcharenko, I. Dybala, A. E. Koziol
M. Gdaniec,
Vol. 40
/
H. Szumilo, and Z. Karczmarzyk
regioselective fragmentations involving the ester function.
+•
The base peaks correspond to [M-COOC H ] and [M-
2
4
+
OC H ] ions in the spectra of compounds 4 and 5, respec-
2
5
+
tively. Moreover, the contribution of [M-OC H ] ions to
2
5
the total ion current in the spectra of compounds 5 is greater
by an order of magnitude than in compounds 4. The mass
spectra are described in more details elsewhere [10].
EXPERIMENTAL
Melting points were determined on a Boetius apparatus and are
1
13
uncorrected. NMR spectra ( H and C) were recorded on a
Varian Gemini 200 MHz spectrometer in [D ]DMSO with TMS
6
as an external standard at 295 K. EI-MS spectra were recorded at
70 eV (direct insertion probe, ion source temp. 160 °C) on a VG
ZabSpec spectrometer (Manchester, UK). UV spectra were
recorded on a Specord M40 (Carl-Zeiss Jena) spectrophotometer
in a 200-450 nm range. TLC was performed on commercial
Merck 60 F
SiO plates with eluent system: CHCl -CH OH
254
2 3 3
(9:1), visualization: UV light, I /CHCl solution. DEEM was
2
3
purchased from Merck and was used without further purification.
Ethyl 1-Aryl-7(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-
6-carboxylates (4a-4f) and Ethyl 1-Aryl-5(1H)-oxo-2,3-dihydro-
imidazo[1,2-a]pyrimidine-6-carboxylates (5a-5f).
Method A.
DEEM (3) 21.6 g (0.1 mol) was added slowly to the solution of
0.1 mol of the respective 1-aryl-2-aminoimidazoline-2 (1a-1f) in
150 mL of ethyl alcohol cooled to the –10 °C. The mixture was
stirred for 6 h at this temperature. The precipitated solid was sep-
arated by suction filtration, washed with cold 2-propanol and
crystallized from a DMF/2-propanol (1:2) mixture, to give car-
boxylates 4a-4f.
Method B.
DEEM (3) 21.6 g (0.1 mol) was added to the solution of 0.1
mol of the respective 1-aryl-2-aminoimidazoline-2 (1a-1f) in 150
mL of ethyl alcohol. The solution became orange-red and after
15-30 minutes a solid started to precipitate. A slight exothermic
effect (+6 to +10 °C) was observed. The mixture was stirred at
ambient temperature for 6 h. The crude product was collected by
filtration and separated by preparative TLC (see the
Chromatography section) to give carboxylates 4a-4f and 5a-5f.
5c
Figure 1. Perspective view of the 4b and 5c molecules with the atom
numbering.
comparison to 4 may be caused by the deshielding effect of
the C5=O double bond specifically on the C3 carbon atom.
The UV spectrometry of 4 and 5 revealed two absorp-
tion maxima in the carbonyl region of the spectra (200-250
nm) for each isomer. For compounds 4, peaks appearing at
~225 and ~250 nm had an absorption ratio 1.0 whereas for
5, they appeared at ~205 and ~250 nm with an absorption
ratio of 1.4. The location and equal intensities of the
absorption maxima of compounds 4 confirmed the pres-
ence of the pseudo-quinoid moiety. It also suggests that in
solution the C=O bonds and the quinoid system are pre-
dominantly in the syn conformation, which is consistent
with the crystal geometry.
Method C.
1-Aryl-2-aminoimidazoline-2 hydrobromide (2a-2f) (0.1 mol)
and 21.6 g (0.1 mol) of DEEM (3) were dissolved in 200 mL of
ethyl alcohol. The solution was stirred under reflux for 3 to 10 h
and then 10.2 g (0.1 mol) of triethylamine was added dropwise
over a period of 15 min, and the mixture was refluxed for addi-
tional 6 h. The precipitate was collected and recrystallized from
methanol, to give carboxylates 5a-5f.
The physical and spectral properties of the obtained com-
pounds are listed below.
Ethyl 1-Phenyl-7(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimi-
dine-6-carboxylate (4a).
The 70-eV EI spectra of compounds 4 and 5 show clear
differences between the 5-oxo and 7-oxo isomers due to
This compound has mp 202-4 °C; R = 0.68; EIMS (15eV), m/z:
f
+
285 (M , 42%), 213 (100%). UV (CH OH), λ
(A): 223
3
max

Jan-Feb 2003
The Psuedo-Michael Reaction of 2-Aminoimidazolines 2
97
1
C H Cl), 4.18 (s, 4H, C(2,3)H), 4.15 (q, J = 9 Hz, 2H, O-CH -
(0.4922), 252 (0.5019), 294 (0.2195), 347 (0.3291), 415 (0.344). H
6
4
2
13
CH ), 1.25 (t, J = 9 Hz, 3H, O-CH -CH ). C NMR, δ: 163.5
NMR, δ: 8.24 (s, 1H, C(5)H), 7.15-7.3 (m, 5H, C H ), 4.23 (s, 4H,
3
2
3
6
5
(CO-O), 160.3 (C7=O), 159.4 (C8’), 135.3 (C -Cl), 134.3 (C -
C(2,3)H), 4.2 (q, J = 9 Hz, 2H, O-CH -CH ), 1.15 (t, J = 9 Hz, 3H,
ar
ar
2
3
13
N), 129.1 (C (2)), 128.4 (C (4)), 124.7 (C (6)), 118.4
O-CH -CH ). C NMR, δ: 164.4 (CO-O), 163.1 (C7=O), 158.1
ar
ar
ar
2
3
(C (5)), 107.9 (=CH), 61.0 (O-CH -CH ), 45.7 (C2), 40.1 (C3),
(C8’), 134.2 (C -N), 129.8 (C (2,6)), 126.3 (C (4)), 123.7
ar
2
3
ar
ar
ar
14.5 (O-CH -CH ).
(C (3,5)), 107.6 (=CH), 60.5 (O-CH -CH ), 45.3 (C2), 44.1 (C3),
2
3
ar
2
3
14.2 (O-CH -CH ).
Anal. Calcd for C H ClN O : C 56.34; H 4.41; N 13.14; Cl
2
3
15 14 3 3
11.09. Found: C 56.76; H 4.50; N 13.08; Cl 11.21.
Anal. Calcd for C
H N O : C 63.15; H 5.30; N 14.73.
15 15 3 3
Found: C 63.03; H 5.22; N 14.80.
Ethyl 1-(3,4-Dichlorophenyl)-7(1H)-oxo-2,3-dihydroimi-
dazo[1,2-a]pyrimidine-6-carboxylate (4f).
Ethyl 1-(4-Methylphenyl)-7(1H)-oxo-2,3-dihydroimidazo-
[1,2-a]pyrimidine-6-carboxylate (4b).
This compound has mp >330 °C (dec.); R = 0.67; EIMS
f
+
(15eV), m/z: 354 (M , 48%), 282 (100%). UV (CH OH), λ
This compound has mp 228-230 °C; R = 0.71; EIMS (15eV),
3
max
f
+
(A): 219 (0.4995), 247 (0.5037), 283 (0.2234), 340 (0.3201), 413
m/z: 299 (M , 40%), 227 (100%). UV (CH OH), λ
(A): 226
3
max
1
(0.3353). H NMR, δ: 8.54 (s, 1H, C(5)H), 7.15-7.95 (m, 3H,
(0.4973), 252 (0.5009), 298 (0.2207), 341 (0.3278), 412
1
C H Cl ), 4.24 (s, 4H, C(2,3)H), 4.2 (q, J = 9 Hz, 2H, O-CH -
(0.3434). H NMR, δ: 8.38 (s, 1H, C(5)H), 7.24,7.65 (2 x d, 4H,
C H CH ), 4.27 (s, 4H, C(2,3)H), 4.23 (q, J = 9 Hz, 2H, O-CH -
6
3
2
2
13
CH ), 1.24 (t, J = 9 Hz, 3H, O-CH -CH ). C NMR, δ: 165.1
3
2
3
6
4
3
2
(CO-O), 161.5 (C7=O), 159.7 (C8’), 133.3 (C -N), 136.7
ar
CH ), 2.3 (s, 3H, C H CH ), 1.2 (t, J = 9 Hz, 3H, O-CH -CH ).
3
6
4
3
2
3
(C (4)-Cl), 135.2 (C (3)-Cl), 129.1 (C (2)), 128.8 (C (5))
13
ar
ar
ar
ar
C NMR, δ: 164.8 (CO-O), 162.9 (C7=O), 158.1 (C8’), 135.6
(C -N), 135.2 (C -CH ), 129.9 (C (2,6)), 120.6 (C (3,5)),
128.3 (C (6)), 107.4 (=CH), 60.3 (O-CH -CH ), 47.9 (C2), 43.1
ar
2
3
ar
ar
3
ar
ar
(C3), 14.1 (O-CH -CH ).
2
3
108.0 (=CH), 60.5 (O-CH -CH ), 46.4 (C2), 40.2 (C3), 21.0
2
3
Anal. Calcd for C
H Cl N O : C 50.86; H 3.70; N 11.86; Cl
15 13 2 3 3
(C -CH ), 14.4 (O-CH -CH ).
ar
3
2
3
20.02. Found: C 51.02; H 3.73; N 11.83; Cl 19.94.
Anal. Calcd for C
H N O : C 64.20; H 5.72; N 14.04.
16 17 3 3
Found: C 64.20; H 5.64; N 14.07.
Ethyl 1-Phenyl-5(1H)-oxo-2,3-dihydroimidazo[1,2-a]pyrimi-
dine-6-carboxylate (5a).
Ethyl 1-(4-Methoxyphenyl)-7(1H)-oxo-2,3-dihydroimidazo-
[1,2-a]pyrimidine-6-carboxylate (4c).
This compound has mp 182-4 °C; R = 0.24; EIMS (15eV),
f
+
m/z: 285 (M , 100%). UV (CH OH), λ
(A): 208 (0.5087),
3
max
This compound has mp 194 – 196 °C; R = 0.72; EIMS (15eV),
f
1
253 (0.3564), 328 (0.3715), 388 (0.1793), 421 (0.5501).
H
+
m/z: 315 (M , 31%), 243 (100%). UV (CH OH), λ
(A): 229
3
max
NMR, δ: 8.28 (s, 1H, C(7)H), 7.15-7.3 (m, 5H, C H ), 4.2 (s, 4H,
6
5
(0.5013), 250 (0.4977), 294 (0.2123), 349 (0.3228), 427
C(2,3)H), 4.18 (q, J = 9 Hz, 2H, O-CH -CH ), 1.19 (t, J = 9 Hz,
2
3
1
(0.3098). H NMR, δ: 8.4 (s, 1H, C(5)H), 7.25, 7.55 (2 × d, 4H,
13
3H, O-CH -CH ). C NMR, δ: 167.9 (CO-O), 164.3 (C5=O),
2
3
C H OCH ), 4.3 (s, 4H, C(2,3)H), 4.25 (q, J = 9 Hz, 2H, O-CH -
6
4
3
2
150.1 (C8’), 136.8 (C -N), 129.8 (C (3,5)), 125.4 (C (4)),
ar
ar
ar
CH ), 2.78 (s, 3H, C H OCH ), 1.2 (t, J = 9 Hz, 3H, O-CH -
3
6
4
3
2
120.8 (C (2,6)), 107.7 (=CH), 60.1 (O-CH -CH ), 45.7 (C2),
ar
2
3
13
CH ). C NMR, δ: 163.9 (CO-O), 161.7 (C7=O), 158.9 (C8’),
3
44.6 (C3), 14.4 (O-CH -CH ).
2
3
137.6 (C -OCH ), 134.7 (C -N), 130.1 (C (2,6)), 124.5
ar
3
ar
ar
Anal. Calcd for C
H N O : C 63.15; H 5.30; N 14.73.
15 15 3 3
(C (3,5)), 108.3 (=CH), 60.5 (O-CH -CH ), 58.3 (C -OCH ),
ar
2
3
ar
3
Found: C 63.21; H 5.27; N 14.7.
47.5 (C2), 42.7 (C3), 14.6 (O-CH -CH ).
2
3
Ethyl 1-(4-Methylphenyl)-5(1H)-oxo-2,3-dihydroimidazo[1,2-a]-
pyrimidine-6-carboxylate (5b).
Anal. Calcd for C
Found: C 61.18; H 5.34; N 13.21.
H N O : C 60.94; H 5.43; N 13.33.
16 17 3 4
This compound has mp 196-198 °C; R = 0.25; EIMS (15eV),
f
Ethyl 1-(4-Chlorophenyl)-7(1H)-oxo-2,3-dihydroimidazo[1,2-a]-
pyrimidine-6-carboxylate (4d).
+
m/z: 299 (M , 100%), 254 (94%). UV (CH OH), λ
(A): 206
3
max
(0.5197), 251 (0.3654), 320 (0.3634), 383 (0.1715), 426
This compound has mp 257-258 °C; R = 0.74; EIMS (15eV),
1
f
(0.5433). H NMR, δ: 8.42 (s, 1H, C(7)H), 7.18, 7.6 (2 × d, 4H,
+
m/z: 319 (M , 48%), 247 (100%). UV (CH OH), λ
(A): 220
3
max
C H CH ), 4.26 (s, 4H, C(2,3)H), 4.18 (q, J = 9 Hz, 2H, O-CH -
6
4
3
2
(0.5111), 259 (0.5093), 279 (0.215), 339 (0.3231), 407 (0.3148).
CH ), 2.3 (s, 3H, C H CH ), 1.23 (t, J = 9 Hz, 3H, O-CH -CH ).
3
6
4
3
2
3
1
H NMR, δ: 8.38 (s, 1H, C(5)H), 6.9, 7.45 (2 × d, 4H, C H Cl ),
13
6
4
C NMR, δ: 167.5 (CO-O), 163.9 (C5=O), 150.6 (C8’), 135.6
(C -N), 134.4 (C -CH ), 129.5 (C (3,5)), 119.3 (C (2,6)),
4.28 (s, 4H, C(2,3)H), 4.18 (q, J = 9 Hz, 2H, O-CH -CH ), 1.27
2
3
ar
ar
3
ar
ar
13
(t, J = 9 Hz, 3H, O-CH -CH ). C NMR, δ: 163.7 (CO-O),
108.0 (=CH), 60.8 (O-CH -CH ), 45.8 (C2), 44.3 (C3), 20.8
2
3
2
3
162.1 (C7=O), 158.4 (C8’), 138.2 (C -Cl), 134.1 (C -N), 131.8
(C -CH ), 14.3 (O-CH -CH ).
ar
ar
ar
3
2
3
(C (2,6)), 126.2 (C (3,5)), 108.4 (=CH), 60.6 (O-CH -CH ),
Anal. Calcd for C
H N O : C 64.20; H 5.72; N 14.04.
ar
ar
2
3
16 17 3 3
47.1 (C2), 41.1 (C3), 14.4 (O-CH -CH ).
Found: C 63.84; H 5.63; N 14.10.
2
3
Anal. Calcd for C
H ClN O : C 56.34; H 4.41; N 13.14; Cl
15 14 3 3
Ethyl 1-(4-Methoxyphenyl)-5(1H)-oxo-2,3-dihydroimidazo[1,2-a]-
pyrimidine-6-carboxylate (5c).
11.09. Found: C 56.55; H 4. 47; N 13.07; Cl 11.14.
Ethyl 1-(3-chlorophenyl)-7(1H)-oxo-2,3-dihydroimidazo[1,2-a]-
pyrimidine-6-carboxylate (4e).
This compound has mp 173-175 °C; R = 0.26; EIMS (15eV),
f
+
m/z: 315 (M , 100%). UV (CH OH), λ
248 (0.3313), 327 (0.3512), 397 (0.2001), 419 (0.5353).
(A): 201 (0.5037),
3
max
1
This compound has mp 210-212 °C; R = 0.7; EIMS (15eV),
H
f
+
m/z: 319 (M , 48%), 247 (100%). UV (CH OH), λ
(A): 229
NMR, δ: 8.45 (s, 1H, C(7)H), 7.2, 7.5 (2 × d, 4H, C H OCH ),
3
max
6 4 3
(0.5031), 247 (0.5023), 273 (0.2281), 337 (0.3312), 418
(0.3334). H NMR, δ: 8.44 (s, 1H, C(5)H), 7.22-8.05 (m, 4H,
4.27 (s, 4H, C(2,3)H), 4.19 (q, J = 9 Hz, 2H, O-CH -CH ), 2.8 (s,
2 3
1
13
3H, C H OCH ), 1.22 (t, J = 9 Hz, 3H, O-CH -CH ). C NMR,
6 4 3 2 3

/
/
,
98
D. Matosiuk, K. Pihlaja, V. V. Ovcharenko, I. Dybala, A. E. Koziol
M. Gdaniec,
Vol. 40
/
H. Szumilo, and Z. Karczmarzyk
δ: 166.9 (CO-O), 164.7 (C5=O), 151.3 (C8’), 138.9 (C -OCH ),
Germany) with 0.5-mm layer thickness in sandwich-type cham-
bers (ChromDes, Lublin, Poland) [16,17]. The mixture of isomers
(60 mg) was dissolved in DMF (4 ml) and subsequently introduced
from the edge of the layer. The chromatograms were developed
with binary mixture of ethyl acetate:toluene (7:3 v/v) and dried.
Chromatograms were detected under UV light at λ = 254 nm. The
stripes of absorbent containing separated isomers were scraped off
the plate, and the fractions were isolated by extraction with hot
methanol. The solvent was evaporated and the residue was crystal-
lized from an appropriate solvent (methanol or DMF/2-propanol
mixture). Compound purity was confirmed by analytical TLC.
ar
3
136.8 (C -N), 127.7 (C (3,5)), 121.3 (C (2,6)), 108.4 (=CH),
ar
ar
ar
60.1 (O-CH -CH ), 59.3 (C -OCH ), 46.9 (C2), 44.8 (C3), 14.4
2
3
ar
3
(O-CH -CH ).
2
3
Anal. Calcd for C
H N O : C 60.94; H 5.43; N 13.33.
16 17 3 4
Found: C 60.98; H 5.49; N 13.41.
Ethyl 1-(4-Chlorophenyl)-5(1H)-oxo-2,3-dihydroimidazo-
[1,2-a]pyrimidine-6-carboxylate (5d).
This compound has mp 201-203 °C; R = 0.25; EIMS (15eV),
f
+
m/z: 319 (M , 100%). UV (CH OH), λ
(A): 218 (0.5235),
3
max
1
264 (0.3793), 329 (0.3513), 374 (0.2015), 404 (0.5339).
H
Crystal data for 4b.
NMR, δ: 8.42 (s, 1H, C(7)H), 6.85, 7.4 (2 × d, 4H, C H Cl ), 4.25
6
4
Compound 4b has C
H N O , FW = 299.33, triclinic, P, a =
16 17 3 3
(s, 4H, C(2,3)H), 4.16 (q, J = 9 Hz, 2H, O-CH -CH ), 1.3 (t, J =
2
3
13
6.880(1) Å, b = 7.417(1) Å, c = 15.056(3) Å, α = 101.08(3)°, β =
9 Hz, 3H, O-CH -CH ). C NMR, δ: 166.4 (CO-O), 163.2
2
3
3
95.77(3)°, γ = 104.60(3)°, V = 720.6(2) Å , Z = 2, d
= 1.380
(C5=O), 151.2 (C8’), 138.8 (C -Cl), 136.9 (C -N), 130.5
calcd
ar
ar
-3
-1
g cm , µ(CuKα) = 0.799 mm . Crystals were obtained from a
DMF solution. A colorless crystal (0.55 x 0.07 x 0.07 mm) was
used for measurements at 293 K on a KM-4 diffractometer using
(C (3,5)), 124.6 (C (2,6)), 108.1 (=CH), 61.7 (O-CH -CH ),
ar
ar
2
3
44.9 (C2), 44.1 (C3), 14.1 (O-CH -CH
2
3
Anal. Calcd for C
H ClN O : C 56.34; H 4.41; N 13.14; Cl
15 14 3 3
graphite-monochromated CuK radiation (λ = 1.54178 Å) and ω-
11.09. Found: C 56.49; H 4.53; N 13.27; Cl 11.17.
α
2θ scan method. Up to θ
= 65.1°, 2360 reflections were col-
max
Ethyl 1-(3-Chlorophenyl)-5(1H)-oxo-2,3-dihydroimidazo-
[1,2-a]pyrimidine-6-carboxylate (5e).
lected. The structure was solved by direct methods using the pro-
gram SHELXS-86 [18]. Full-matrix least-squares refinement on
2
F was carried out using the SHELXL-97 program system [19].
This compound has mp 203-205 °C; R = 0.23; EIMS (15eV),
f
+
Non-H atoms were refined with anisotropic displacement para-
meters. H-atoms were located from the geometry and were given
m/z: 319 (M , 100%). UV (CH OH), λ
(A): 221 (0.5201),
3
max
1
268 (0.3683), 333 (0.3603), 372 (0.2107), 413 (0.5393).
H
isotropic factors of 1.2 U of the bonded C-atom; the ‘riding’
NMR, δ: 8.49 (s, 1H, C(7)H), 7.2-7.9 (m, 4H, C H Cl), 4.22 (s,
eq
6
4
model was used in the refinement. 200 parameters were refined,
the final discrepancy factors were R1 = 0.0556, wR2 = 0.1616,
and S = 1.038, for 2040 reflections with I > 2σ(I).
4H, C(2,3)H), 4.17 (q, J = 9 Hz, 2H, O-CH -CH ), 1.28 (t, J = 9
2
3
13
Hz, 3H, O-CH -CH ). C NMR, δ: 168.8 (CO-O), 164.9
2
3
(C5=O), 151.7 (C8’), 139.8 (C -Cl), 136.6 (C -N), 130.1
ar
ar
(C (2,4)), 123.1(C (6)), 121.1 (C (5)), 107.3 (=CH), 59.7
ar
ar
ar
Crystal Data for 5c.
(O-CH -CH ), 45.2 (C2), 44.2 (C3), 14.3 (O-CH -CH ).
2
3
2
3
Compound 5c has C
H N O , FW = 315.33, monoclinic,
16 17 3 4
Anal. Calcd for C
H ClN O : C 56.34; H 4.41; N 13.14; Cl
15 14 3 3
P2 /c, a = 6.962(1) Å, b = 29.693(6) Å, c = 7.514(2) Å, β =
1
11.09. Found: C 56.56; H 4.45; N 13.19; Cl 11.23.
3
-1
107.89(3)°, V = 1478.2(5) Å , Z = 4, µ(Cu Kα) = 0.862 mm .
Crystals were obtained from a methanol solution. A colorless crys-
tal (0.6 x 0.19 x 0.22 mm) was used for measurements at 293 K on a
Ethyl 1-(3,4-Dichlorophenyl)-5(1H)-oxo-2,3-dihydroimidazo-
[1,2-a]pyrimidine-6-carboxylate (5f).
KM-4 diffractometer using graphite monochromated Cu K radia-
α
This compound has mp 289-291 °C; R = 0.21; EIMS (15eV),
f
tion (λ=1.54178 Å) and ω-2θ scan. Up to θ
= 80.0°, 3229 reflec-
+
max
m/z: 354 (M , 100%). UV (CH OH), λ
(0.3723), 337 (0.3692), 379 (0.1995), 417 (0.5374). H NMR, δ:
(A): 213 (0.5195), 270
3
max
tions were collected. The structure was solved by direct methods
using the program SHELXS-97 [18]. Full-matrix least-squares
1
8.61 (s, 1H, C(5)H), 7.2-7.95 (m, 3H, C H Cl ), 4.25 (s, 4H,
6
3
2
2
refinement on F was carried out using the SHELXL-97 program
C(2,3)H), 4.21 (q, J = 9 Hz, 2H, O-CH -CH ), 1.25 (t, J = 9 Hz,
2
3
system [19]. Non-H atoms were refined with anisotropic parame-
ters. H-atoms were located from the geometry and were given
13
3H, O-CH -CH ). C NMR, δ: 168.9 (CO-O), 164.1 (C5=O),
2
3
150.9 (C8’), 137.7 (C (3)-Cl), 137.2 (C (4)-Cl), 133.7 (C -N),
ar
ar
ar
isotropic factors of 1.2U of the bonded C-atoms, ‘riding’ model
eq
130.1 (C (2)), 129.7 (C (5)), 127.3 (C (6)), 107.9 (=CH), 60.1
ar
ar
ar
was used in the refinement. 209 parameters were refined, final dis-
crepancy factors were R1 = 0.0558, wR2 = 0.1360, S = 1.096, and an
extinction coefficient κ = 0.089(5), for 3091 reflections I > 2σ(I).
Crystallographic data (excluding structure factors) for the
structures reported in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary pub-
lications numbers CCDC-171746 and 171747. Copies of the data
can be obtained free of charge on application to CCDC, 12 Union
Road, Cambridge CB2 1EZ, UK [Fax: int. code + 44(1223)336-
033; E-mail: deposit@ccdc.cam.ac.uk].
(O-CH -CH ), 45.1 (C2), 44.7 (C3), 14.2 (O-CH -CH ).
2
3
2
3
Anal. Calcd for C
H Cl N O : C 50.86; H 3.70; N 11.86; Cl
15 13 2 3 3
20.02. Found: C 50.94; H 3.67; N 11.74; Cl 20.13.
Chromatography.
Thin layer chromatography (TLC) is frequently used for the
isolation of compounds required for physicochemical (e.g. struc-
ture assignment), biological or other investigations. The use of
“frontal + elution TLC” for separation of the mixture of isomeric
compounds has been described in the literature [11-15]. The
delivery of the sample to be separated from the edge of the layer,
in the frontal chromatography mode, markedly improved the
preparative separation owing to partial separation of the mixture
during the sample application.
REFERENCES AND NOTES
[1] The literature concerning pseudo-Michael reactions of
2-aminoazaheterocycles with DEEM contains about 150 items. The
full list of references is available upon request.
Microscale preparative and analytical TLC was performed on
200 x 200 mm precoated silica gel plates (Si60F , Merck,
254

Jan-Feb 2003
The Psuedo-Michael Reaction of 2-Aminoimidazolines 2
99
[2] J. Agata, S. Naguchi and K. Tanaka, JP 73 34 897 (1973),
Commun. Mass Spectrom., 15, 2502 (2001).
Chem. Abstr., 79, 42537d (1974).
[11] E. Soczewin´ski and W. Maciejewicz, J. Chromatogr.,
176, 247 (1979).
[12] E. Soczewin´ski, J. Kuczmierczyk and B. Psionka, J. Liq.
Chromatogr., 3, 1829 (1980).
[3] J. Koekoesi, G. Szasz, J. Hermecz, Z. Meszaros, C. M.
Pongar and G. Toth, Magy. Kem. Foly., 88, 222 (1982), Chem. Abstr.
97, 109954t (1983).
[4] J. Koekoesi, J. Hermecz, G. Szasz, Z. Meszaros, G. Toth,
and C. M. Pongar, J. Heterocyclic Chem., 19, 909 (1982).
[5] Cambridge Structural Database: F. H. Allen and O.
Kennard, Chemical Design Automation News, 8, 31 (1993).
[6] H. P. Weber and T. J. Petcher, Helv. Chim. Acta, 59, 1389
(1976).
[13] T. Wawrzynowicz, E. Soczewin´ski and K. Czapin´ska,
Chromatographia, 20, 223 (1985).
[14] H. Szumilo and T. Dzido, J. Liq. Chromatogr., 115, 337
(1992).
/
[15] M. Waksmundzka-Hajnos, M. Gadzikowska and W.
/
Golkiewicz, J. Planar Chromatogr,, 13, 205 (2000).
[7] J. V. Greenhill, I. Chaaban, and P. J. Steel, J. Heterocyclic
Chem., 29, 1375 (1992).
[16] T. Dzido, J. Planar Chromatogr., 3, 199 (1990).
[17] T. Dzido and E. Soczewin´ski, J. Chromatogr., 516, 461
(1990).
//
[8] D. Matosiuk, T. Tkaczyn´ski, E. Jagiello-Wójtowicz, M.
Wielosz, G. Szurska, A. Chodkowska, W. Janusz and Z. Kleinrok,
Pol. J. Pharmacol. Pharm., 44, 307 (1992).
[18] G. M. Sheldrick, SHELXS-86: Acta Crystallogr. A, 46, 467
(1990).
[9] The CSD refcodes are: FETSEC, ICYTIN, VIPXEX,
ZERLUD, ZERMAK, ZUKXOS, ZUKXUY.
[19] G. M. Sheldrick, SHELXL-97: Program for the refinement
of a crystal structure from diffraction data, Univ. Göttingen,
Germany, 1997.
[10] V. V. Ovcharenko, K. Pihlaja and D. Matosiuk, Rapid