The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate

Article abstract of DOI:10.1007/s00706-013-0982-y

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl 2-cyano-3-methoxyprop-2-enoate (ethyl ethoxymethylenecyanoacetate) is investigated. At -10°C reaction takes place on the exocyclic nitrogen atom, giving exclusively ethyl esters of 2-cyano-3-[(1-phenyl-4,5-dihydro-1H-imidazol- 2-yl)amino]prop-2-enoic acid. The formation of isomeric enamines which may be a theoretical product of the reaction on N3 ring nitrogen atom is not observed. The N6 enamines, heated in boiling acetic acid, yield cyclic 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles. Heating of the enamines to the temperature of 120-140 C without a solvent makes it possible to obtain a mixture of 1-aryl-5-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6- carbonitriles and ethyl 1-aryl-5-imino-2,3-dihydroimidazo[1,2-a]pyrimidine-6- carboxylates. The reaction of the respective hydrobromides of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with ethyl ethoxymethylenecyanoacetate in the presence of triethylamine gives selectively 1-aryl-5-oxo-1,2,3,5- dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles.

Full text of DOI:10.1007/s00706-013-0982-y

Monatsh Chem (2013) 144:1171–1182
DOI 10.1007/s00706-013-0982-y
ORIGINAL PAPER
The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-
2-amines with ethyl ethoxymethylenecyanoacetate
•
Agnieszka A. Kaczor Urszula Kijkowska-Murak
•
•
Kalevi Pihlaja Jari Sinkkonen Waldemar Wysocki
•
•
•
Zbigniew Karczmarzyk Dariusz Matosiuk
Received: 5 December 2012 / Accepted: 24 March 2013 / Published online: 14 May 2013
ꢀ The Author(s) 2013. This article is published with open access at Springerlink.com
Abstract The pseudo-Michael reaction of 1-aryl-4,5-
dihydro-1H-imidazol-2-amines with ethyl 2-cyano-3-meth-
oxyprop-2-enoate (ethyl ethoxymethylenecyanoacetate) is
investigated. At -10 ꢁC reaction takes place on the exocy-
clic nitrogen atom, giving exclusively ethyl esters of
2-cyano-3-[(1-phenyl-4,5-dihydro-1H-imidazol-2-yl)amino]-
prop-2-enoic acid. The formation of isomeric enamines
which may be a theoretical product of the reaction on N3 ring
nitrogen atom is not observed. The N6 enamines, heated in
boiling acetic acid, yield cyclic 1-aryl-5-oxo-2,3-dihydro-
imidazo[1,2-a]pyrimidine-6-carbonitriles. Heating of the
enamines to the temperature of 120–140 ꢁC without a sol-
vent makes it possible to obtain a mixture of 1-aryl-5-oxo-
2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles and
ethyl 1-aryl-5-imino-2,3-dihydroimidazo[1,2-a]pyrimidine-
6-carboxylates. The reaction of the respective hydrobro-
mides of 1-aryl-4,5-dihydro-1H-imidazol-2-amines with
ethyl ethoxymethylenecyanoacetate in the presence of
triethylamine gives selectively 1-aryl-5-oxo-1,2,3,5-dihy-
droimidazo[1,2-a]pyrimidine-6-carbonitriles.
Keywords Annelation ꢀ Michael addition ꢀ
X-ray structure determination
Introduction
Ethyl 2-cyano-3-methoxyprop-2-enoate (ethyl ethoxy-
methylenecyanoacetate, EMCA, 1) (Scheme 1) is a widely
used reagent for heterocyclic annelation [1]. In particular,
EMCA is applied as the Michael acceptor in Michael
addition [1]. Reaction of EMCA with 4,5-dihydro-
1H-imidazol-2-amines leads to 2,3-dihydroimidazo[1,2-
a]pyrimidines [1–4] and represents one of the synthetic
methods of this heterocyclic system by reaction of imida-
zol-2-amine derivatives with electrophilic compounds (the
main alternative involves the imidazole ring closure by
condensation of pyrimidin-2-amines with an appropriate
compound) [5]. The imidazo[1,2-a]pyrimidine system is
present in many biologically active compounds which have
been reported to exhibit anti-inflammatory and analgesic
[6–9], antibacterial [10–14], antiviral [15], antifungal [16,
17], insectidal, acaricidal, and nematocidal [18], central
nervous system (CNS) [19–23], hormonal [24], mutagenic
[25], anticancer [26, 27], and cardiovascular [28] activity.
We have previously reported the pseudo-Michael reac-
tion of 4,5-dihydro-1H-imidazol-2-amines with diethyl
(methoxymethylidene)propanedioate (diethyl ethoxymeth-
ylenemalonate, DEEM, 2) (Scheme 1) [29]. The isolation
of chain enamines was not possible for the adducts with
DEEM [29] which is in agreement with corresponding
literature data (for review see [1]). In the case of EMCA it
is relatively easy to isolate the adducts which are the direct
A. A. Kaczor (&) ꢀ U. Kijkowska-Murak ꢀ D. Matosiuk (&)
Department of Synthesis and Chemical Technology of
Pharmaceutical Substances with Computer Modeling Lab,
Faculty of Pharmacy with Division of Medical Analytics,
´
Medical University of Lublin, 4A Chodzki St, 20093 Lublin,
Poland
e-mail: agnieszka.kaczor@umlub.pl
D. Matosiuk
e-mail: darek.matosiuk@umlub.pl
K. Pihlaja ꢀ J. Sinkkonen
Department of Chemistry, University of Turku, Vatselankatu 2,
20014 Turku, Finland
W. Wysocki ꢀ Z. Karczmarzyk
Department of Chemistry, University of Podlasie, 3 Maja 54 St,
08110 Siedlce, Poland
123

1172
A. A. Kaczor et al.
contrast to our earlier results on the pseudo-Michael reac-
tion of 4,5-dihydro-1H-imidazol-2-amines with DEEM
[29]. In the case of DEEM, at -10 ꢁC reaction took place
on the N3 ring nitrogen atom, but the isolation of the
respective chain enamines was not possible due to the fast
cyclization process, even at low temperature. Instead, ethyl
1-aryl-7-oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-car-
boxylates were obtained exclusively. As was found
previously, the pseudo-Michael reaction of 4,5-dihydro-
1H-imidazol-2-amines with DEEM was temperature-
dependent; therefore, we tried first to perform the corre-
sponding reaction with EMCA at room temperature and
then at higher temperatures (up to the boiling point of
propan-2-ol). Theoretically, formation of the mixture of
isomeric N3 and N6 enamines is possible in the case of
both Michael reagents, but in the case of EMCA we
observed the formation of N3 enamines neither at -10 ꢁC
nor at higher temperatures. The N6 enamines 5a, 5c–5h
formed exclusively underwent cyclization to 1-aryl-5-oxo-
2,3-dihydroimidazo[1,2-a]pyrimidine-6-carbonitriles 6a,
6c–6h when the pseudo-Michael reaction was performed at
ambient or higher temperature (the derivative 6b could not
be obtained by this method as the preparation of enamine
5b was not successful). On the contrary, in the case of
DEEM, at room temperature the reaction yielded mixtures
with varying ratio of isomeric 1-aryl-5-oxo-2,3-dihydro-
imidazo[1,2-a]pyrimidine-6-carboxylates and 1-aryl-7-
oxo-2,3-dihydroimidazo[1,2-a]pyrimidine-6-carboxylates.
Alternatively, to obtain compounds 6a and 6c–6h, the
enamines 5a and 5c–5h should be heated in boiling acetic
acid (Scheme 2). In such conditions the cyclization takes
place via the ester group of 5a and 5c–5h, giving 6a and
6c–6h exclusively. Myiamoto [41], when performing the
similar cyclization reaction under acidic conditions (MeOH
Scheme 1
CN
COOEt
COOEt
EtO
COOEt
EtO
1
2
products of Michael reaction [1]. Such adducts may pos-
sess the EMCA part connected with nitrogen (enamines)
[30–32], carbon [33], and sulfur [34] atoms and may be
further cyclized via ester [1, 35, 36] or cyano [1, 37, 38]
group.
In this paper we present the pseudo-Michael reaction of
4,5-dihydro-1H-imidazol-2-amines with EMCA and struc-
tural studies of the respective products.
Results and discussion
The hydrobromides 3a–3f of 4,5-dihydro-1H-imidazol-2-
amines 4a–4f were obtained from the respective N-aryl-
1,2-diaminoethanes and cyanogen bromide, as previously
reported [29, 39, 40]. The hydrobromides 3a–3f were then
transformed into free bases 4a–4f by action of sodium
hydroxide and extraction with methylene chloride. The 4,5-
dihydro-1H-imidazol-2-amines 4a–4f were subjected to the
pseudo-Michael reaction with EMCA in propan-2-ol
solution at -10 ꢁC (Scheme 2). In these conditions the
only isolated products were chain enamines (5a, 5c–5h),
formed as a result of the reaction on the N6 exocyclic
nitrogen atom. The attempt to obtain derivative 5b with
2-chloro substituent failed, probably due to the steric hin-
drance. The reaction on the N6 nitrogen atom was in
Scheme 2
R
N
N
4'
AcOH
3'
5'
6'
N
6a-6h
R
R
reflux
EMCA
2'
CN
O
1'
i-PrOH
5
4'
4'
H
N
N
CN
3'
NH2
8a
3'
5'
6'
-10 oC
5'
6'
N
2
R
2'
6
R
7
melting
2'
N
3
N
COOEt
1'
1'
120-140 oC
N
4a-4h
5a-5h
N
8a
8a
N
N
2
2
+
7
7
N
3
3
N
5
5
6
6
R: a, H; b, 2-Cl; c, 3-Cl; d, 4-Cl; e, 2-CH3;
f, 4-CH3; g, 2-OCH3; h, 4-OCH3
COOEt
CN
HN
7a-7h
O
6a-6h
123

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines
1173
Scheme 3
R
R
R
EMCA
EtOH
N
H
N
N
CN
N
NH2
xHBr
N
N
N
N
COOEt
CN
O
not isolated
3a-3h
5a-5h
6a-6h
saturated with HCl), observed the cyclization via cyano
group only, leading to appropriate imines. Analogs of
6a–6h were obtained by Myiamoto [41] in basic conditions
(Et3N/MeOH).
COSY and HSQC spectra. The most difficult part is the
assignment of quaternary carbons at positions 5, 6, and 8a.
H-7 showed HMBC correlations to all of those. However,
C-8a can be identified by a long range correlation from
both H-2 and H-3. A correlation between H-3 and C-5 was
not observed, so the assignments of C-5 and C-6 were done
based on the very different chemical shift values. There-
fore, as an example, the structures of 5f and 7f were
modeled by DFT method B3LYP/6-31G(d,p) and the NMR
chemical shifts were calculated by the same method [42].
The good agreement (the results are not shown here) with
experimental values proved the correct assignments. The
multiplicities of proton signals H-2 and H-3 are notewor-
thy. Those methylene protons at positions 2 (H-2a and
H-2b) and 3 (H-3a and H-3b) have nearly the same
chemical shifts, respectively. However, the vicinal cou-
pling constants between H-2 and H-3 differ. Actually there
are four coupling constants: J2a,3a, J2a,3b, J2b,3a, and J2b,3b
and the signals can be analysed, for example by simulation
and iteration software PERCH [43].1 It was found that they
are all between 7 and 12 Hz. This makes the signals look
roughly like triplets, but the unequal coupling constants as
well as the second order effects make the signals rather
complicated. Therefore, these are stated as multiplets
(m) at the experimental section.
In the next stage we heated enamines 5a and 5c–5h to
120–140 ꢁC without a solvent. In such conditions the
mixtures of the cyclization products both via ester group
(6a and 6c–6h) and via cyano group, 1-aryl-5-imino-2,3-
dihydroimidazo[1,2-a]pyrimidine-6-carboxylates (7a and
7c–7h) were obtained (Scheme 2). The mixtures were
separated with preparative thin-layer chromatography.
After preparative TLC separation, compounds 7a and
7c–7h were extracted from silica gel with methanol. Dur-
ing extraction process some transesterification occurred
which resulted in mixtures of ethyl and methyl esters. The
percentage of methyl ester in the mixture depended on the
substituent in the phenyl group and varied from 10 to 45 %
by NMR. The obtained mixtures of ethyl and methyl esters
were practically impossible to separate, and thus, they were
analysed as received.
Finally, the reactions of respective 4,5-dihydro-1H-
imidazol-2-amine hydrobromides 3a–3h with EMCA in the
presence of base (Et3N) led to reaction on N6 nitrogen
atom (which is in agreement with our previous results
obtained for DEEM [29]) and cyclization via the ester
group, resulting in compounds 6a–6h (Scheme 3). This
method made it possible to obtain the derivative 6b with
2-chloro substituent.
The primary fragmentations of compounds 5a and
5c–5h as well as 7c–7h are mainly initiated from the ester
function (see ‘‘Experimental’’) or via the [M–H]? ions. As
mentioned in ‘‘Experimental’’, compounds 7 were transe-
sterified into mixtures of Me- and Et-esters when eluted
with methanol. Therefore, they show also variable amounts
of the M?ꢀ ions of the methyl esters. On the other hand,
with the exception of the [M–H]? ions, the other fragments
appear almost always at the same m/z-values, e.g.
[M–MeOH]?ꢀ and [M–EtOH]?ꢀ ions. The ion structures
were determined by accurate mass measurements and the
fragmentation routes with B/E spectra. When comparing
the fragmentation patterns of compounds 5 and 7 with each
The course of all reactions was confirmed by elementary
analysis and spectral data (1H and 13C NMR, MS). All the
compounds were characterized with the aid of NMR
1
spectroscopy. Assignments of H and 13C chemical shifts
1
and H–1H coupling constants were achieved by a combi-
nation of several 2D NMR techniques. Since there are not
that many protons in heterocyclic rings, the most important
experiment for assignments was HMBC spectrum. By
HMBC, one can see a long range correlation between H-2
and aromatic substituent at N-1. This proves the assign-
ment of H-2 and H-3 protons. The protons and the carbons
at the aromatic substituent are easily assigned by DQF-
1
PERCH Solutions Ltd. http://perchsolutions.com
123

1174
A. A. Kaczor et al.
other it appears that compounds 5 may partially rearrange
into compounds 7 under EI conditions (see ‘‘Experimen-
tal’’). However, some differences still exist. M?ꢀ is the base
peak only for 5g but in case of compounds 7 for 7e, 7g, and
7h. The base peak for 5a, 5e, 5f, and 5h is [M–C2H4CO2]?ꢀ
but only for 7d and 7f. The clearest difference is seen in the
abundance of [M–ROH]?ꢀ ion (R = Et for 5 and Me or Et
for 7) which is by far more abundant for compounds 5
being even the base peak for 5d and 5e. Compounds 5e and
5g show some ions which are indicative for the 2-Me and
2-OMe substitutions and are missing from the spectra of 5f
and 5g. For 5e these ions are [M–Me]? at m/z 283 (4 %)
and [M–Me–EtOH]? at m/z 237 (29) and for 5g [M–H–
Me]?ꢀ, [M–Et]?, and [M–OMe]? at m/z 298 (5), 285 (5),
and 283 (36 %), respectively. Similarly 2-Me derivative 7e
gives the ion [M–Me] at m/z 269 (8 %) and the Et- and Me-
esters the ions [M–Me–EtOH]? and [M–Me–MeOH]? at
m/z 237 (7 %) although the latter is weaker than that for 5e.
Compound 7g with 2-OMe substitution gives the ions
[M–Me]?ꢀ and [M–OMe]? at m/z 299 (14 %) and 285
(5 %), 283 (33 %) and 269 (47 %) for Et- and Me-esters,
respectively. It should be mentioned that m/z 269 corre-
sponds also [M–OEt]? for the Et-ester (7g).
Fig. 1 A view of the X-ray molecular structure of 6c with the atomic
labeling scheme
Compounds 6a–6h understandably behave differently.
M?ꢀ is always the base peak except the 2-Cl derivative 6b
where [M–Cl]? ion is the base peak due to the ortho effect.
Another ion which originates via the ortho effect is [M–Cl–
C2H2]? at m/z 211 (10 %). Similarly 2-Me derivative 6e
shows one ion which is indicative for the ortho methyl,
namely [M–Me]? at m/z 237 (24 %), which is absent from
the mass spectrum of 4-Me derivative 6f. The presence of
ortho-OMe substitution in 6g is reflected by the ions
[M–OMe]? at m/z 237 (92 %) and [M–CH2O]?ꢀ at m/z 238
(20 %) which are missing from the spectrum of 6h except
for a small amount of ion 237 (9 %). On the other hand, the
4-OMe derivative 6h shows the ions [M–Me]? at m/z 253
(32 %) and [M–Me–CO]? at m/z 225 (7 %) which are
missing from the spectrum of 6g.
six-member ring described by the S(6) graph-set symbol
[2, 45]; C26–H26 = 0.93, H26ꢀꢀꢀN6 = 2.25, C26ꢀꢀꢀN6 =
˚
2.894(4) A, and C26–H26ꢀꢀꢀN6 = 126ꢁ. In the crystal
structure, the molecules related by c glade plane and
b translation are linked to form C(7) chains along [011]
direction by C4-H4B…N11(i) intermolecular hydrogen
bonds (C4–H4B = 0.97, H4BꢀꢀꢀN11 = 2.56, C4ꢀꢀꢀN11 =
˚
3.281(5) A, C4–H4BꢀꢀꢀN11 = 132ꢁ and (i) = ‘-x,
-1 ? y, -‘ ? z) (Fig. 2). Moreover, the p-electron sys-
tems of the pairs of pyrimidine ring at (x, y, z) and phenyl
ring at (x, 1 ? y, z) and phenyl ring at (x, y, z) and pyrimidine
ring at (x, -1 ? y, z) overlap each other, with centroid-to-
´
˚
centroid separation of 3.5695(18) A. The pꢀꢀꢀp distances
between overlapping planes are alternately 3.4648(11) and
˚
3.4564(13) A and the angle between them is 3.21(14)ꢁ.
We also succeeded in the preparation of crystals suitable
for X-ray structure determination for 6c and 6d [44]. The
X-ray analyses of compounds 6c and 6d were performed in
order to confirm the synthetic pathway and the position of the
oxo group (5-oxo/7-oxo; Scheme 2). The crystal structure of
6c is shown in Fig. 1. It was found that the investigated
compounds contain an oxo group at position 5. The geo-
metric parameters (bond lengths, angles, torsion angles, and
planarity of the rings) are very similar to those observed in a
previously reported structure of 1-(4-chlorophenyl)-5-oxo-
1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-6-carbonitrile
(6d) [44]. The molecule as a whole adopts a nearly planar
conformation with the torsion angle C2–N1–C21–C26 of
1.2(4)ꢁ. This conformation is stabilized by an intramolec-
ular C26–H26ꢀꢀꢀN6 interaction leading to the formation of a
Theoretical calculations at DFT/B3LYP/6-311 ??
G(d,p) ab initio level [42] show that that 5-oxo isomeric
form of 6c and 6d (the initial geometries were built from
their crystallographic data) obtained after energy minimi-
zation and geometry optimization in the gaseous phase is
more energetically stable than 7-oxo form, with a differ-
ence in the energy between the 7-oxo and 5-oxo forms of
45.6 and 46.0 kJ mol-1 for 6c and 6d, respectively. In
solution (water (e = 78.35) and chloroform (e = 4.71),
CPCM model [46]) the energy difference between form
7-oxo and 5-oxo is 18.8 kJ mol-1 (aqueous solution) and
27.2 kJ mol-1 (chloroform solution) for 6c and
19.3 kJ mol-1 (aqueous solution) and 27.6 kJ mol-1
(chloroform solution) for 6d. Thus, the population of the
123

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines
1175
Fig. 2 A view of part of the
crystal structure of 6c. Dashed
lines indicate intermolecular
hydrogen bonds
7-oxo form in vacuum and polar (water) and non-polar
(chloroform) solutions estimated using a non-degenerate
Boltzmann distribution is below the threshold of the
detectability of conventional analytical methods.
spectra were acquired with hsqcetgpsisp.2 pulse program
(using shaped pulses) with 145 Hz one-bond coupling
constant. 1H-13C HMBC spectra were acquired with
hmbcgplpndqf pulse program with 10 Hz long-range cou-
pling constant. Computational methods were used to
confirm the assignment of some quaternary carbons. The
geometry optimizations and NMR chemical shift calcula-
tions were done by density functional B3LYP equipped
with basis set 6-31G(d,p). Calculations were done
by Gaussian 03 W software [42]. Numbering of atoms for
5a–5g in NMR assignments corresponds to the numbering
of the final products 6a–6g and 7a–7g and is shown in
Scheme 2.
Experimental
All reagents and solvents were purchased and used without
additional purification. In particular, EMCA was purchased
from Merck. Reactions were routinely monitored by thin-
layer chromatography (TLC) in silica gel (60 F254 Merck
plates, DS horizontal chamber, Chromdes, Lublin, Poland)
in toluene-ethyl acetate–methanol (1:3:0.5) eluent system
and the products were visualized with ultraviolet light of
254 nm wavelength.
The electron ionization (EI) mass spectra were recorded
on a VG Analytical (Manchester, UK) ZABSpec instru-
ment, equipped with Opus data system. Samples were
introduced using a direct insertion probe at ambient tem-
perature. Accurate mass measurements were performed at a
resolving power of 8,000–10,000 (10 % valley definition)
using peak matching technique and perfluorokerosene
(PFK) as a reference compound. The elementary analyses
were performed on a Perkin-Elmer analyzer. Melting
points were determined with a Boetius apparatus.
NMR spectra were acquired using Bruker Avance 500
spectrometer (equipped with BBO 5 mm Z-grad probe)
1
operating at 500.13 MHz for H and 125.77 MHz for 13C.
Spectra were recorded at 25 ꢁC using DMSO-d6 as solvent
with a non-spinning sample in 5 mm NMR tubes. Spectra
were processed by a PC with Windows XP operating sys-
tem and TopSpin software. Proton and carbon spectra were
referenced to tetramethylsilane (TMS: 0.00 ppm). In
addition to normal 1H and 13C NMR spectra, also a variety
of gradient selected 2D measurements were used to receive
an unequivocal assignment of all compounds. DQF-COSY
spectra were acquired with cosygpmfqf pulse program
(pulse programs refer to original ones installed by Bruker)
and NOESY spectra were acquired with noesygpph pulse
program with mixing time of 300 ms. 1H-13C HSQC
X-ray data of 6c were collected on a Kuma KM4 four-
circle diffractometer at room temperature; crystal sizes
˚
0.60 9 0.30 9 0.20 mm, CuKa (k = 1.54178 A) radia-
tion, x–2h scans. The XABS2 absorption correction was
applied [47]; Tmin = 0.2071, Tmax = 0.7898. The structure
was solved by direct methods using SHELXS97 [48] and
refined by full-matrix least-squares with SHELXL97 [48].
The H atoms were positioned geometrically and treated as
123

1176
A. A. Kaczor et al.
1H, J = 1.9 Hz, 8.2 Hz, H-60), 7.38 (t, 1H, J = 8.2 Hz,
H-50),7.18 (dd, 1H, J = 1.9 Hz, 8.2 Hz, H-40), 4.15 (m,
2H, H-2), 4.15 (q, 2H, J = 7.0 Hz, OCH2CH3), 3.68 (m,
2H, H-3), 1.23 (t, 3H, J = 7.0 Hz, OCH2CH3) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 165.16 (C=O), 164.23
(C-7), 160.87 (C-8a), 140.31 (C-10), 132.98 (C-30), 129.90
(C-50), 123.36 (C-40), 120.30 (C-20), 118.60 (C-60), 117.00
(C-5), 83.43 (C-6), 59.70 (OCH2CH3), 47.49 (C-2), 39.40
(C-3), 14.31 (OCH2CH3) ppm; MS (EI): M?ꢀ
C15H15ClN4O?2 ꢀ calc. for 35Cl 318.0884, found 318.0882;
m/z (%): M?ꢀ 37Cl: 320 (19), [M–H]? ? isotopic 319 (12),
[M–OEt]? 275 (6), [MꢀEtOH]?ꢀ ? isotopic 274 (7), [M–
H–EtOH]? 273 (23), [M–C2H4OOC]?ꢀ 248 (32), [M–H–
C2H4OOC]?ꢀ ? isotopic 247 (21), 35Cl: 318 (55), [M–H]?
317 (6), [M–OEt]? 273 (23), [M–EtOH]?ꢀ 272 (12), [M–
H–EtOH]? 271 (21), [M–C2H4OOC]?ꢀ 246 (100), [M–
EtOOC]? 245 (19), 152 (5), 142 (8), 140 (28), 138 (10),
111 (22), 105 (7), 77 (8), 75 (14).
riding on their parent C atoms with C–H distances of
˚
˚
0.93 A (aromatic) and 0.97 A (CH2). All H atoms were
refined with isotropic displacement parameters taken as 1.5
times those of the respective parent atoms. The flack
parameter of -0.02(2) confirmed that the correct absolute
structure was refined [49]. All calculations were performed
using WINGX version 1.64.05 package [50]. CCDC
912327 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Centre (CCDC), 12
Union Road, Cambridge CB2 1EZ, UK; fax: ?44(0) 1223
336 033; email: deposit@ccdc.cam.ac.uk).
General procedure to obtain compounds 5a–5h
1-Aryl-4,5-dihydro-1H-imidazol-2-amine (4a–4h, 0.01 mol)
wasdissolvedin40 cm3 ofpropan-2-ol andcooleddowntothe
temperature of -10 ꢁC. A solution of 1.69 g of EMCA (1,
0.01 mol) in 40 cm3 of propan-2-ol was added dropwise at
constant stirring. The reaction mixture was stirred at -10 ꢁC
for 2 h. The precipitation obtained was filtered off and washed
a few times with n-hexane, toluene, and a mixture of toluene-
ethyl acetate (10:1).
Ethyl 3-[[1-(4-chlorophenyl)-4,5-dihydro-1H-imidazol-2-
yl]amino]-2-cyanoprop-2-enoate (5d, C15H15ClN4O2)
According to general method with 1.95 g of 4d. The
method afforded 1.54 g (57 %) of 5d. M.p.: 134–136 ꢁC;
Rf = 0.48 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.92 (br s, 1H, H-8),
8.56 (s, 1H, H-7), 7.73 (d, 2H, J = 8.6 Hz, H-20, H-60),
7.40 (d, 2H, J = 8.6 Hz, H-30, H-50), 4.14 (m, 2H, H-2),
4.14 (q, 2H, J = 7.0 Hz, OCH2CH3), 3.68 (m, 2H, H-3),
1.22 (t, 3H, J = 7.0 Hz, OCH2CH3) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 165.26 (C=O), 164.42 (C-7),
160.94 (C-8a), 137.82 (C-10), 128.16 (C-30, C-50), 127.77
(C-40), 122.33 (C-20, C-60), 117.22 (C-50), 82.85 (C-6),
59.64 (OCH2CH3), 47.69 (C-2), 40.32 (C-3), 14.32
(OCH2CH3) ppm; MS (EI): M?ꢀ C15H15ClN4O2?ꢀ calc. for
35Cl 318.0884, found 318.0885; m/z (%): M?ꢀ 37Cl: 320
(8), [M–H–EtOH]?ꢀ 274 (34), [M–C2H4OOC]?ꢀ 248 (14),
[M–H–C2H4OOC]? ? isotopic 247 (9), [M–C2H4OOC]?ꢀ
246 (41), [M–H–C2H4OOC]? 245 (11), 35Cl: 318 (26),
35Cl: [M–OEt]? 273 (41), [M–EtOH]?ꢀ 272 (100), [M–H–
EtOH]? 271 (59), [M–C2H4OOC]?ꢀ 246 (41), [M–
EtOOC]? 245 (11), 152 (6), 140 (18), 138 (17), 125 (11),
111 (31), 105 (22), 77 (9), 75 (24).
Ethyl 2-cyano-3-[(1-phenyl-4,5-dihydro-1H-imidazol-2-
yl)amino]prop-2-enoate (5a, C15H16N4O2)
According to general method with 1.61 g of 4a. The
method afforded 1.42 g (60 %) of 5a. M.p.: 133–134 ꢁC;
Rf = 0.48 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.82 (br s, 1H, H-8),
8.56 (s, 1H, H-7), 7.69 (d, 2H, J = 7.7 Hz, H-20, H-60),
7.36 (t, 2H, J = 7.7 Hz, H-30, H-50), 7.14 (t, 1H,
J = 7.7 Hz, H-40), 4.14 (m, 2H, H-2), 4.14 (q, 2H,
J = 7.1 Hz, OCH2CH3), 3.69 (m, 2H, H-3), 1.22 (t, 3H,
J = 7.1 Hz, OCH2CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 165.37 (C=O), 164.55 (C-7), 161.23 (C-
8a), 138.82 (C-10), 128.38 (C-30, C-50), 123.96 (C-40),
120.86 (C-20, C-60), 117.30 (C-5), 82.30 (C-6), 59.56
(OCH2CH3), 47.83 (C-2), 40.31 (C-3), 14.33 (OCH2CH3)
ppm; MS (EI): M?ꢀ C15H16N4O?2 ꢀ calc. 284.1273, found
284.1272; m/z (%): M?ꢀ 284 (65), [M–H]? 283 (7), [M–
OEt]? 239 (22), [M–EtOH]?ꢀ 238 (26), [M–H–EtOH]?
237 (36), [M–C2H4OOC]?ꢀ 212 (100), [M–EtOOC]? 211
(6), 119 (6), 118 (8), 106 (30), 105 (12), 104 (13), 91 (12),
77 (42).
Ethyl 2-cyano-3-[[1-(2-methylphenyl)-4,5-dihydro-1H-imi-
dazol-2-yl]amino]prop-2-enoate (5e, C16H18N4O2)
According to general method with 1.75 g of 4e. The
method afforded 1.50 g (60 %) of 5e. M.p.: 117–118 ꢁC;
Rf = 0.49 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.62 (br s, 1H, H-8),
8.44 (s, 1H, H-7), 7.28 (m, 4H, H-30, H-40, H-50, H-60), 4.08
(q, 2H, J = 7.1 Hz, OCH2CH3), 3.98 (m, 2H, H-2), 3.74
(m, 2H, H-3), 2.21 (s, 3H, 20-CH3), 1.18 (t, 3H,
J = 7.1 Hz, OCH2CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 165.60 (C=O), 164.82 (C-7), 162.99 (C-
Ethyl 3-[[1-(3-chlorophenyl)-4,5-dihydro-1H-imidazol-2-
yl]amino]-2-cyanoprop-2-enoate (5c, C15H15ClN4O2)
According to general method with 1.95 g of 4c. The
method afforded 1.52 g (56 %) of 5c. M.p.: 128–129 ꢁC;
Rf = 0.50 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.96 (br s, 1H, H-8),
8.56 (s, 1H, H-7), 8.01 (t, 1H, J = 1.9 Hz, H-20), 7.60 (dd,
123

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines
1177
8a), 136.89, 135.61 (C-10, C-20), 130.75 (C-30), 127.73,
126.94, 126.53 (C-40, C-50, C-60), 117.22 (C-5), 80.77 (C-
6), 59.38 (OCH2CH3), 49.90 (C-2), 40.50 (C-3), 17.62 (20-
CH3), 14.32 (OCH2CH3) ppm; MS (EI): M?ꢀ C16H18N4O2
calc. 298.1430, found 298.1423; m/z (%): M?ꢀ 298 (79),
[M–H]? 297 (34), [M–OEt]? 253 (31), [M–EtOH]?ꢀ 252
(100), [M–H–EtOH]? 251 (99), [M–Me–EtOH]? 237 (29),
[M–C2H4OOC]?ꢀ 226 (47), [M–EtOOC]? 225 (22), 223
(8), 158 (82), 157 (18), 156 (10), 132 (11), 131 (15), 130
(16), 120 (13), 118 (31), 117 (22), 116 (13), 91 (55), 77
(21), 65 (40).
[M–OCH3]? 283 (36), [M–OEt]? 269 (26), [M–EtOH]?ꢀ
268 (32), [M–H–EtOH]? 267 (20), [M–C2H4OOC]?ꢀ 242
(79), [M–EtOOC]? 241 (24), 237 (48), 212 (17), 211 (26),
174 (29), 136 (20), 134 (14), 121 (16), 129 (30), 119 (10),
106 (16), 105 (18), 104 (10), 93 (11), 92 (21), 91 (18), 77
(32), 65 (28).
Ethyl 2-cyano-3-[[1-(4-methoxyphenyl)-4,5-dihydro-1H-
imidazol-2-yl]amino]prop-2-enoate (5h, C16H18N4O3)
According to general method with 1.91 g of 4h. The
method afforded 1.55 g (58 %) of 5h. M.p.: 173–174 ꢁC;
Rf = 0.51 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.66 (br s, 1H, H-8),
8.53 (s, 1H, H-7), 7.55 (d, 2H, J = 8.5 Hz, H-20, H-60),
6.93 (d, 2H, J = 8.5 Hz, H-30, H-50), 4.12 (m, 2H, H-2),
4.12 (q, 2H, J = 6.7 Hz, OCH2CH3), 3.75 (s, 3H, 40-
OCH3), 3.67 (t, 2H, J = 8.4 Hz, H-3), 1.21 (t, 3H,
J = 6.7 Hz, OCH2CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 165.56 (C=O), 164.71 (C-7), 161.45 (C-
8a), 156.10 (C-40), 131.72 (C-10), 123.03 (C-20, C-60),
117.38 (C-5), 113.62 (C-30, C-50), 81.66 (C-6), 59.49
(OCH2CH3), 55.18 (40-OCH3), 48.44 (C-2), 39.40 (C-3),
14.34 (OCH2CH3) ppm; MS (EI): M?ꢀ C16H18N4O3?ꢀ calc.
314.1379, found 314.1382; m/z (%): M?ꢀ 314 (87), [M–H]?
313 (22), [M–OEt]? 269 (23), [M–EtOH]?ꢀ 268 (32), [M–
H–EtOH]? 267 (29), [M–Me–HOEt]? 253 (15), [M–
C2H4OOC]?ꢀ 242 (100), [M–EtOOC]? 241 (27), 225 (7),
136 (45), 135 (11), 134 (218), 133 (12), 121 (17), 120
(26), 106 (7), 105 (13), 93 (6), 92 (19), 91 (6), 77 (23), 65
(16).
Ethyl 2-cyano-3-[[1-(4-methylphenyl)-4,5-dihydro-1H-imi-
dazol-2-yl]amino]prop-2-enoate (5f, C16H18N4O2)
According to general method with 1.75 g of 4f. The
method afforded 1.62 g (64 %) of 5f. M.p.: 127–128 ꢁC;
Rf = 0.50 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.77 (br s, 1H, H-8),
8.54 (s, 1H, H-7), 7.55 (d, 2H, J = 8.1 Hz, H-20, H-60),
7.17 (d, 2H, J = 8.1 Hz, H-30, H-50), 4.13 (m, 2H, H-2),
4.13 (q, 2H, J = 7.0 Hz, OCH2CH3), 3.67 (t, 2H,
J = 8.8 Hz, H-3), 2.29 (s, 3H, 40-CH3), 1.22 (t, 3H,
J = 7.0 Hz, OCH2CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 165.44 (C=O), 164.61 (C-7), 161.26 (C-
8a), 136.26 (C-10), 133.33 (C-40), 128.83 (C-30, C-50),
121.05 (C-20, C-60), 117.35 (C-5), 82.04 (C-6), 59.53
(OCH2CH3), 47.99 (C-2), 39.46 (C-3), 20.30 (40-CH3),
14.34 (OCH2CH3) ppm; MS (EI): M?ꢀ C16H18N4O2?ꢀ calc.
298.1430, found 298.1426; m/z (%): M?ꢀ 298 (69), [M–H]?
297 (11), [M–OEt]? 253 (23), [M–EtOH]?ꢀ 252 (42), [M–
H–EtOH]? 251 (41), [M–C2H4OOC]?ꢀ 226 (100), [M–
EtOOC]? 225 (25), 224 (7), 120 (35), 132 (6), 131 (6), 118
(13), 117 (7), 105 (14), 91 (42), 77 (10), 65 (20).
General procedure to obtain compounds 6a–6h
Method A
Ethyl 2-cyano-3-[[1-(2-methoxyphenyl)-4,5-dihydro-1H-
imidazol-2-yl]amino]prop-2-enoate (5g, C16H18N4O3)
According to general method with 1.91 g of 4g. The
method afforded 1.79 g (67 %) of 5g. M.p.: 135–136 ꢁC;
Rf = 0.49 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.60 (br s, 1H, H-8),
8.45 (s, 1H, H-7), 7.32 (dt, 1H, J = 1.2 Hz, 7.5 Hz, H-40),
7.28 (dd, 1H, J = 1.2 Hz, 7.8 Hz, H-60), 6.98 (t, 1H,
J = 7.4 Hz, H-50), 7.13 (d, 1H, J = 8.2 Hz, H-30), 4.09 (q,
2H, J = 7.0 Hz, OCH2CH3), 3.95 (dd, 2H, J = 8.5 Hz,
9.6 Hz, H-2), 3.81 (s, 3H, 20-OCH3), 3.71 (dd, 2H,
J = 8.5 Hz, 9.6 Hz, H-3), 1.18 (t, 3H, J = 7.0 Hz,
OCH2CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 165.71 (C=O), 164.88 (C-7), 163.73 (C-8a), 154.61
(C-20), 128.82 (C-40, C-60), 126.46 (C-10), 120.38 (C-50),
117.39 (C-5), 112.59 (C-30), 80.37 (C-6), 59.34
(OCH2CH3), 55.69 (20-OCH3), 49.14 (C-2), 40.43 (C-3),
14.34 (OCH2CH3) ppm; MS (EI): M?ꢀ C16H18N4O3?ꢀ calc.
314.1379, found 314.1385; m/z (%): M?ꢀ 314 (100), [M–
H]? 313 (18), [M–H–CH3]?ꢀ 298 (5), [M–Et]? 285 (5),
Enamine 5a–5h (0.01 mol) was dissolved in 10 cm3 of
glacial acetic acid and refluxed under mild boiling for 4 h.
The solvent was distilled off and the solid residue was
crystallized from DMF.
Method B
1-Aryl-4,5-dihydro-1H-imidazol-2-amine hydrobromides
(3a–3h, 0.01 mol) and 1.69 g of EMCA (1, 0.01 mol) were
dissolved in 20 cm3 of ethanol. The solution was stirred
under reflux for 4 h and then 1.02 g of triethylamine
(0.01 mol) was added dropwise over a period of 15 min
and the mixture was refluxed for additional 6 h. The pre-
cipitate was filtered off and washed with methanol.
5-Oxo-1-phenyl-2,3-dihydroimidazo[1,2-a]pyrimidine-6-
carbonitrile (6a, C13H10N4O)
According to general method A with 2.36 g of 5a. The
method afforded 1.36 g (57 %) of 6a. M.p.: 210–213 ꢁC;
Rf = 0.62 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.40 (s, 1H, H-7), 7.72
123

1178
A. A. Kaczor et al.
(d, 2H, J = 8.5 Hz, H-20, H-60), 7.45 (dd, 2H, J = 7.5 Hz,
8.5 Hz, H-30, H-50), 7.23 (t, 1H, J = 7.5 Hz, H-4), 4.26 (m,
2H, H-2), 4.15 (m, 2H, H-3) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 163.57 (C-7), 157.95 (C-5), 155.79 (C-
8a), 137.65 (C-10), 128.83 (C-30, C-50), 125.02 (C-40),
120.38 (C-20, C-60), 115.78 (6-CN), 90.55 (C-6), 46.00
(C-2), 40.31 (C-3) ppm; MS (EI): M?ꢀ C13H10N4O?ꢀ
calc. 238.0842, found 238.0855; m/z (%): M?ꢀ 238 (100),
[M–H]? 237 (71), [M–CN]? 212 (7), [M–HCN]?ꢀ 211 (4),
[M–H–CO]? 209 (5), 105 (10), 104 (5), 91 (7), 77 (17), 54
(9), 51 (8).
R = 0.033, wR = 0.099, S = 1.091 for 1304 reflections
with I [ 2r(I).
1-(4-Chlorophenyl)-5-oxo-2,3-dihydroimidazo[1,2-
a]pyrimidine-6-carbonitrile (6d, C13H9ClN4O)
According to general method A with 2.72 g of 5d. The
method afforded 2.05 g (75 %) of 6d. M.p.: 214–216 ꢁC;
Rf = 0.62 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.42 (s, 1H, H-7), 7.77
(d, 2H, J = 9.0 Hz, H-20, H-60), 7.51 (d, 2H, J = 9.0 Hz,
H-30, H-50), 4.24 (m, 2H, H-2), 4.14 (m, 2H, H-3) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 163.41 (C-7), 157.83
(C-5), 155.63 (C-8a), 136.65 (C-10), 128.72 (C-30, C-40),
121.70 (C-20, C-60), 115.64 (6-CN), 91.00 (C-6), 45.89 (C-
2), 40.30 (C-3) ppm; MS (EI): M?ꢀ C13H9ClN4O?ꢀ calc. for
35Cl 272.0465, found 272.0463; m/z (%): M?ꢀ 37Cl: 274
(33), 35Cl: 272 (100), [M–H]? 37Cl: 273 (29), 35Cl: 271
(48), [M–H–CO]? 243 (3), C7H5ClN? 138 (6), C7H6Cl?
125 (5), C6H4ClN? 111 (10), C5H3N3? 105 (10), C6H3? 75
1-(2-Chlorophenyl)-5-oxo-2,3-dihydroimidazo-
[1,2-a]pyrimidine-6-carbonitrile (6b, C13H9ClN4O)
According to general method B with 2.72 g of 5b. The
method afforded 1.64 g (60 %) of 6b. M.p.: 236-240 ꢁC;
Rf = 0.60 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.26 (s, 1H, H-7),7.65
(m, 2H, H-30, H-60), 7.49 (m, 2H, H-40, H-50), 4.28 (m, 2H,
H-2), 4.14 (m, 2H, H-3) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 164.03 (C-7), 157.99 (C-5), 157.54
(C-8a), 134.07 (C-10), 131.47 (C-20), 130.43 (C-50),
130.19 (C-60), 130.00 (C-30), 128.40 (C-40), 115.76
(6-CN), 90.18 (C-6), 47.63 (C-2), 41.45 (C-3) ppm; MS
(EI): M?ꢀ C13H9ClN4O?ꢀ calc. for 35Cl 272.0465, found
272.0477;m/z(%):M?ꢀ 37Cl:274(8), 35Cl: 272 (26), [M–Cl]?
237 (100), [M–Cl–C2H2]? 211 (10), 138 (3), 111 (6), 105 (4),
75 (5), 54 (7).
?
(7), C2H2N2 54 (10).
1-(2-Methylphenyl)-5-oxo-2,3-dihydroimidazo-
[1,2-a]pyrimidine-6-carbonitrile (6e, C14H12N4O)
According to general method A with 2.51 g of 5e. The
method afforded 1.94 g (77 %) of 6e. M.p.: 204–206 ꢁC;
Rf = 0.57 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.21 (s, 1H, H-7), 7.40
(dd, 1H, J = 1.8 Hz, 7.2 Hz, H-60), 7.30–7.35 (m, 3H,
H-30, H-40, H-50), 4.23 (m, 2H, H-3), 4.10 (m, 2H, H-2),
2.23 (s, 3H, CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 164.10 (C-7), 158.22 (C-5), 157.21 (C-8a), 135.88
(C-20), 135.48 (C-10), 130.89 (C-30), 128.59 (C-40), 127.20
(C-60), 126.88 (C-50), 116.04 (6-CN), 89.31 (C-6), 48.01
(C-2), 41.28 (C-3), 17.23 (20-CH3) ppm; MS (EI): M?ꢀ
C14H12N4O?ꢀ calc. 252.1001, found 252.1011; m/z (%):
M?ꢀ 252 (100), [M–H]? 251 (88), [M–CH3]? 237 (24),
1-(3-Chlorophenyl)-5-oxo-2,3-dihydroimidazo-
[1,2-a]pyrimidine-6-carbonitrile (6c, C13H9ClN4O)
According to general method A with 2.72 g of 5c. The
method afforded 1.47 g (54 %) of 6c. M.p.: 245–248 ꢁC;
Rf = 0.65 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.46 (s, 1H, H-7), 7.98
(t, 1H, J = 2.0 Hz, H-20), 7.64 (dd, 1H, J = 2.0 Hz,
8.1 Hz, H-60), 7.48 (t, 1H, J = 8.1 Hz, H-50), 7.29 (dd, 1H,
J = 2.0 Hz, 8.1 Hz, H-40), 4.26 (m, 2H, H-2), 4.15 (m, 2H,
H-3) ppm; 13C NMR (125 MHz, DMSO-d6): d = 163.42
(C-7), 157.79 (C-5), 155.68 (C-8a), 139.15 (C-10), 133.20
(C-30), 130.50 (C-50), 124.49 (C-40), 119.72 (C-20), 118.35
(C-60), 115.57 (6-CN), 91.27 (C-6), 45.84 (C-2), 40.32 (C-
3) ppm; MS (EI): M?ꢀ C13H9ClN4O?ꢀ calc. for 35Cl
272.0465, found 272.0467; m/z (%): M?ꢀ 37Cl: 274 (32),
35Cl: 272 (100), [M–H]? 37Cl: 273 (35), 35Cl: 271 (60),
[M–H–CO]? 243 (4), [M–HCl]?ꢀ 246 (12), 138 (5), 125
(5), 111 (11), 105 (10), 75 (8), 54 (11).
[M–C2H5]??[M–H–CO]? 223 (4), C10H10N2 158 (45),
?
C9H9N? 131 (5), 130 (5), C8H8N? 118 (6), 117 (6), 91
(13), C5H?5 ꢀ 65 (9), 54 (6).
1-(4-Methylphenyl)-5-oxo-2,3-dihydroimidazo-
[1,2-a]pyrimidine-6-carbonitrile (6f, C14H12N4O)
According to general method A with 2.51 g of 5f. The
method afforded 1.51 g (63 %) of 6f. M.p.: 250–254 ꢁC;
Rf = 0.62 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.38 (s, 1H, H-7), 7.59
(d, 2H, J = 8.5 Hz, H-20, H-60), 7.25 (d, 2H, J = 8.5 Hz,
H-30, H-50), 4.23 (m, 2H, H-2), 4.14 (m, 2H, H-3), 2.31 (s,
3H, CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 163.62 (C-7), 157.98 (C-5), 155.77 (C-8a), 135.14
(C-10), 134.42 (C-40), 129.24 (C-30, C-50), 120.48 (C-20,
C-60), 115.85 (6-CN), 90.22 (C-6), 46.13 (C-2), 40.29 (C-
3), 20.34 (40-CH3) ppm; MS (EI): M?ꢀ C14H12N4O?ꢀ calc.
252.1011, found 252.1019; m/z (%): M?ꢀ 252 (100),
Crystal data: C13H9ClN4O, M = 272.69, orthorhombic,
˚
space group Pca21, a = 22.8305(14) A, b = 5.4318(8) A,
˚
3
˚
˚
c = 9.5141(6) A, V = 1,179.9(2) A , Z = 4, dcalc = 1.535
Mg m-3 F(000) = 560, l(Cu Ka) = 2.851 mm-1
,
,
T = 293 K, 1825 measured reflections (h range
3.87–80.17ꢁ), 1,433 unique reflections (Rint = 0.051), final
123

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines
1179
[M–H]? 251 (53), [M–H–CO]? 223 (4), 118 (4), 105 (9),
91 (12), 65 (4), 54 (6).
separation of two products of melting (visualization in the
UV light at the wavelength of 254 nm). The band con-
taining the adsorbed imines (mixtures of ethyl and methyl
esters) was removed with the silica support and was three
times extracted with boiling ethanol for 30 min and then
the solvent was evaporated. Thus, compounds 7a and
7c–7h were obtained as mixtures of ethyl and methyl esters.
1-(2-Methoxyphenyl)-5-oxo-2,3-dihydroimidazo[1,2-
a]pyrimidine-6-carbonitrile (6g, C14H12N4O2)
According to general method A with 2.67 g of 5g. The
method afforded 1.61 g (61 %) of 6g. M.p.: 240–243 ꢁC;
Rf = 0.55 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.22 (s, 1H, H-7), 7.41
(d, 1H, J = 7.5 Hz, H-60), 7.40 (dt, 1H, J = 1.4 Hz,
7.5 Hz, H-40), 7.18 (d, 1H, J = 7.5 Hz, H-30), 7.03 (dt, 1H,
J = 1.4 Hz, 7.5 Hz, H-50), 4.22 (m, 2H, H-3), 4.08 (m, 2H,
H-2), 3.82 (s, 3H, OCH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 164.12 (C-7), 158.14 (C-5), 157.67
(C-8a), 154.72 (C-20), 129.74 (C-40), 128.62 (C-60),
124.78 (C-10), 120.53 (C-50), 116.01 (6-CN), 112.56
(C-30), 89.43 (C-6), 55.71 (20-OCH3), 47.30 (C-2), 41.16
(C-3) ppm; MS (EI): M?ꢀ C14H12N4O2?ꢀ calc. 268.0960,
found 268.0960; m/z (%): M?ꢀ 268 (100), [M–H]? 267 (22),
[M–H–CH3]? 252 (6), [M–H–H2O]? 249 (10), [M–H–CO]?
239 (13), C10H10N2O? 174 (10), C8H8NO? 134 (5),
Ethyl (methyl) 5-imino-1-phenyl-2,3-dihydro-
imidazo[1,2-a]pyrimidine-6-carboxylate
(7a, C15H16N4O2)
According to general method with 2.36 g of 5a. The
method afforded 0.33 g (23 %) of 7a (a 90:10 mixture of
the Et- and Me-esters based on the intensity of the CH2-
signals in the NMR spectrum. The abundance ratio of the
M?ꢀ ions 86:14). M.p.: 130–132 ꢁC; Rf = 0.00 (toluene/
ethyl acetate/methanol 1:3:0.5); 1H NMR (500 MHz,
DMSO-d6): d = 8.17 (s, 1H, H-7), 8.11 (br s, 1H, 5-NH),
7.74 (d, 2H, J = 7.4 Hz, H-20, H-60), 7.42 (t, 2H,
J = 7.4 Hz, H-30, H-50), 7.18 (t, 1H, J = 7.4 Hz, H-40),
4.23 (m, 2H, H-2), 4.20 (q, 2H, J = 7.1 Hz, OCH2CH3),
4.03 (m, 2H, H-3), 1.26 (t, 3H, J = 7.1 Hz, OCH2CH3)
ppm; 13C NMR (125 MHz, DMSO-d6): d = 165.23
(C=O), 157.40 (C-5), 155.27 (C-8a), 152.68 (C-7),
138.35 (C-10), 128.68 (C-30, C-50), 124.16 (C-40), 119.90
(C-20, C-60), 102.66 (C-6), 59.60 (OCH2CH3), 45.68 (C-2),
40.57 (C-3), 14.06 (OCH2CH3) ppm; MS (EI): calc. for
C15H16N4O2 284.1273, found 284.1269; m/z (%): Et-ester:
M?ꢀ 284 (89), [M–H]? 283 (8); Me-ester: M?ꢀ 270 (14),
[M–H]? 269 (3); [M–EtO]? and [M–MeO]? 239 (22), [M–
HOEt]? and [M–HOMe]? 238 (10), [M–H–HOEt]?ꢀ and
[M–H–HOMe]?ꢀ 237 (251), [M–C2H4OOC]?ꢀ and [M–
H2COOC]?ꢀ 212 (100), [M–H–C2H4OOC]? and [M–H–
H2COOC]? 211 (15), 161 (12), 160 (11), 149 (7), 118 (5),
106 (34), 105 (50), 104 (7), 91 (7), 77 (23).
?
C6H6N??C6H4O? (2:5) 92 (5), C6H5N?? C7H7 (1:3) 91
(5), 78 (6), 77 (9), 65 (7), 54 (8), 52 (5), 51 (6).
1-(4-Methoxyphenyl)-5-oxo-2,3-tetrahydro-
imidazo[1,2-a]pyrimidine-6-carbonitrile
(6h, C14H12N4O2)
According to general method A with 2.67 g of 5h. The
method afforded 1.45 g (54 %) of 6h. M.p.: 218–220 ꢁC;
Rf = 0.57 (toluene/ethyl acetate/methanol 1:3:0.5); 1H
NMR (500 MHz, DMSO-d6): d = 8.33 (s, 1H, H-7), 7.58
(d, 2H, J = 8.9 Hz, H-20, H-60), 7.00 (d, 2H, J = 8.9 Hz,
H-30, H-50), 4.20 (m, 2H, H-2), 4.13 (m, 2H, H-3), 3.76 (s,
3H, OCH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 163.72 (C-7), 158.04 (C-5), 156.83 (C-40), 155.91
(C-8a), 130.44 (C-10), 122.77 (C-20, C-60), 115.93 (6-CN),
114.04 (C-50), 114.04 (C-30), 89.85 (C-6), 55.26 (40-OCH3),
46.62 (C-2), 40.34 (C-3) ppm; MS (EI): M?ꢀ C14H12N4O2?ꢀ
calc. 268.0960, found 268.0969; m/z (%): M?ꢀ 268 (100),
[M–H]? 267 (14), [M–CH3]? 253 (32), [M–H–CH3]? 252
(6), [M–CH3O]? 237 (9), [M–CH3–CO]? 225 (7), 134 (9),
105 (4), 77 (5), 54 (6).
Ethyl (methyl) 1-(3-chlorophenyl)-5-imino-2,3-
dihydroimidazo[1,2-a]pyrimidine-6-carboxylate
(7c, C15H15ClN4O2)
According to general method with 2.72 g of 5c. The
method afforded 0.49 g (31 %) of 7c (a 56:44 mixture of
the Et- and Me-esters based on the intensity of the CH2-
signals in the NMR spectrum. The abundance ratio of the
M?ꢀ ions was 47:56). M.p.: 153–155 ꢁC; Rf = 0.00 (tol-
uene/ethyl acetate/methanol 1:3:0.5); NMR data for 7c: 1H
NMR (500 MHz, DMSO-d6): d = 8.23 (s, 1H, H-7), 8.18
(br s, 1H, 5-NH), 8.00 (m, 1H, H-20), 7.64 (m, 1H, H-60),
7.44 (t, 1H, J = 8.2 Hz, H-50), 7.23 (m, 1H, H-40), 4.22 (m,
2H, H-2), 4.22 (q, 2H, J = 7.1 Hz, OCH2CH3), 4.03 (m,
2H, H-3), 1.27 (t, 3H, J = 7.1 Hz, OCH2CH3) ppm; 13C
NMR (125 MHz, DMSO-d6): d = 165.11 (C=O), 157.27
(C-7), 155.15 (C-8a), 152.57 (C-5), 139.81 (C-10), 133.10
(C-30), 130.36 (C-50), 123.70 (C-40), 119.34 (C-20), 117.90
(C-60), 102.96 (C-6), 59.76 (OCH2CH3), 45.60 (C-2), 40.69
General procedure to obtain compounds 7a and 7c–7h
Compound 5a–5h (0.01 mol) was carefully heated in a
porcelain evaporating dish to complete melting and sub-
sequent solidification. After the chromatographic control of
the completeness of melting the mixture was dissolved in
4 cm3 of DMF and applied on two preparative 20 9 20
TLC plates (Merck). Each plate was developed twice with
toluene-ethyl acetate–methanol (1:3:0.5) eluent system and
then four times with a stronger eluent system containing
higher amount of the methanol (1:3:1) until the complete
123

1180
A. A. Kaczor et al.
(C-3), 14.04 (OCH2CH3) ppm; MS (EI): M?ꢀ
C15H15ClN4O?2 ꢀ calc. for 35Cl (Et-ester) 318.0884, found
318.0885; calc. for 35Cl (Me-ester) 304.0727, found
304.0730; m/z (%): Et-ester: M?ꢀ 37Cl 320 (12), 35Cl 318
(37); Me-ester: 37Cl 306 (14), 35Cl 304 (42), [M–H]? 303
(10); 37Cl: [M–OEt]? and [M–OMe]? 275 (8), 35Cl: [M–
OEt]? and [M–OMe]? 273 (32), [M–HOEt]?ꢀ and [M–
HOMe]?ꢀ 272 (14), [M–H–HOEt]? and [M–H–HOMe]?
271 (29), 37Cl: [M–C2H4OOC]?ꢀ and [M–H2COOC]?ꢀ 248
(31), [M–H–C2H4OOC]?ꢀ and [M–H–H2COOC]?ꢀ (?iso-
topic) 247 (21), 35Cl: [M–C2H4OOC]?ꢀ and [M–
H2COOC]?ꢀ 246 (100), [M–H–C2H4OOC]?ꢀ and [M–H–
H2COOC]?ꢀ 245 (18), 142 (10), 140 (34), 138 (12), 111
(27).
signals in the NMR spectrum and a 72:28 mixture 86:14
mixture based on the abundance of the M?ꢀ ions). M.p.:
155–160 ꢁC; Rf = 0.00 (toluene/ethyl acetate/methanol
1
1:3:0.5); NMR data for 7e: H NMR (500 MHz, DMSO-
d6): d = 8.09 (br s, 1H, 5-NH), 8.02 (s, 1H, H-7), 7.40 -
7.26 (m, 4H, H-30, H-40, H-50, H-60), 4.17 (q, 2H,
J = 7.1 Hz, OCH2CH3), 4.11 (m, 2H, H-2), 4.08 (m, 2H,
H-3), 2.22 (s, 3H, 20-CH3), 1.23 (t, 3H, J = 7.1 Hz,
OCH2CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 165.42 (C=O), 158.27 (C-7), 156.68 (C-8a), 152.95
(C-5), 136.15 (C-20), 135.96 (C-10), 130.82 (C-30), 128.23,
127.35, 126.80 (C-40, C-50, C-60), 101.51 (C-6), 59.38
(OCH2CH3), 47.95 (C-2), 41.59 (C-3), 17.36 (2-CH3),
14.12 (OCH2CH3) ppm; MS (EI): M?ꢀ C16H18N4O2?ꢀ calc.
(Et-ester) 298.1430, found 298.1429, calc. (Me-ester)
284.1174, found 284.1170; m/z (%): Et-ester: M?ꢀ 298
(100), [M–H]? 297 (44), Me-ester: M?ꢀ 284 (39), [M–H]?
283 (25), [M–Et]? and [M–Me]? 269 (8), [M–OEt]? and
[M–OMe]? 253 (25), [M–HOEt]?ꢀ and [M–HOMe]?ꢀ 252
(11), [M–H–HOEt]? and [M–H–HOMe]? 251 (35), [M–
C2H4OOC]?ꢀ and [M–H2COOC]?ꢀ 226 (70), [M–H–
C2H4OOC]? and [M–H–H2COOC]? 225 (27), 158 (61),
131 (10), 131 (12), 120 (18), 118 (32), 117 (18), 91 (48), 77
(15), 65 (28).
Ethyl (methyl) 1-(4-chlorophenyl)-5-imino-2,3-
dihydroimidazo[1,2-a]pyrimidine-6-carboxylate
(7d, C15H15ClN4O2)
According to general method with 2.72 g of 5d. The
method afforded 0.43 g (27 %) of 7d (a 75:25 mixture of
Et and Me esters based on the intensity of the CH2-signals
in the NMR spectrum. The abundance ratio of the M?ꢀ ions
was 76:24). M.p.: 170–171 ꢁC; Rf = 0.00 (toluene/ethyl
acetate/methanol 1:3:0.5); NMR data for 7d: 1H NMR
(500 MHz, DMSO-d6): d = 8.17 (s, 1H, H-7), 8.13 (br s,
1H, 5-NH), 7.79 (m, 2H, H-20, H-60), 7.48 (m, 2H, H-30,
H-50), 4.21 (m, 2H, H-2), 4.21 (q, 2H, J = 7.1 Hz,
OCH2CH3), 4.03 (m, 2H, H-3), 1.26 (t, 3H, J = 7.1 Hz,
OCH2CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 165.19 (C=O), 157.13 (C-7), 155.19 (C-8a), 152.58
(C-5), 137.38 (C-10), 128.56 (C-30, C-50), 127.91 (C-40),
121.28 (C-20, C-60), 103.03 (C-6), 59.67 (OCH2CH3), 45.63
(C-2), 40.58 (C-3), 14.06 (OCH2CH3) ppm; MS (EI): M?ꢀ
C15H15ClN4O?2 ꢀ calc. for 35Cl (Et-ester) 318.0884, found
318.0885, calc. for 35Cl (Me-ester) 304.0727, found
304.0732; m/z (%): Et-ester: M?ꢀ 37Cl 320 (17), 35Cl 318
(52), Me-ester: 37Cl 306 (5), 35Cl 304 (16), [M–H]? 303
(4), 37Cl: [M–OEt]? and [M–OMe]? 275 (7), 35Cl: [M–
OEt]? and [M–OMe]? 273 (28), [M–HOEt]?ꢀ and [M–
HOMe]?ꢀ 272 (12), [M–H–HOEt]? and [M–H–HOMe]?
271 (22), 37Cl: [M–C2H4OOC]?ꢀ and [M–H2COOC]?ꢀ 248
(32), [M–H–C2H4OOC]?ꢀ and [M–H–H2COOC]?ꢀ (?iso-
topic) 247 (21), 35Cl: [M–C2H4OOC]?ꢀ and [M–H2COOC]
?ꢀ 246 (100), [M–H–C2H4OOC]?ꢀ and [M–H–H2COOC]?ꢀ
245 (21), 142 (7), 140 (24), 138 (7), 111 (10).
Ethyl (methyl) 5-imino-1-(4-methylphenyl)-2,3-
dihydroimidazo[1,2-a]pyrimidine-6-carboxylate
(7f, C16H18N4O2)
According to general method with 2.51 g of 5f. The
method afforded 0.43 g (29 %) of 7f (a 68:32 mixture of
the Et- and Me-esters based on the intensity of the CH2-
signals in the NMR spectrum. The abundance ratio of the
M?ꢀ ions was 73:27). M.p.: 140–142 ꢁC; Rf = 0.00 (tol-
1
uene/ethyl acetate/methanol 1:3:0.5); NMR data for 7f: H
NMR (500 MHz, DMSO-d6): d = 8.15 (s, 1H, H-7), 8.09
(br s, 1H, 5-NH), 7.60 (m, 2H, H-20, H-60), 7.22 (m, 2H,
H-30, H-50), 4.19 (m, 2H, H-2), 4.19 (q, 2H, J = 7.1 Hz,
OCH2CH3), 2.30 (s, 3H, 40-CH3), 1.26 (t, 3H, J = 7.1 Hz,
OCH2CH3) ppm; 13C NMR (125 MHz, DMSO-d6):
d = 165.28 (C=O), 157.56 (C-7), 155.31 (C-8a), 152.72
(C-5), 135.82 (C-10), 133.51 (C-40), 129.11 (C-30, C-50),
120.11 (C-20, C-60), 102.39 (C-6), 59.54 (OCH2CH3), 45.84
(C-2), 40.57 (C-3), 20.31 (40-CH3), 14.08 (OCH2CH3)
ppm; MS (EI): M?ꢀ C16H18N4O?2 ꢀ calc. (Et-ester) 298.1430,
found 298.1426, calc. (Me-ester) 284.1284, found
284.1279; m/z (%): Et-ester: M?ꢀ 298 (61), [M–H]? 297
(10), Me-ester: M?ꢀ 284 (22), [M–H]? 283 (7), [M–OEt]?
and [M–OMe]? 253 (29), [M–HOEt]?ꢀ and [M–HOMe]?ꢀ
252 (14), [M–H–HOEt]? and [M–H–HOMe]? 251 (29),
[M–C2H4OOC]?ꢀ and [M–H2COOC]?ꢀ 226 (100), [M–H–
C2H4OOC]? and [M–H–H2COOC]? 225 (26), 120 (34),
118 (14), 91 (39), 77 (10), 65 (17).
Ethyl (methyl) 5-imino-1-(2-methylphenyl)-2,3-
dihydroimidazo[1,2-a]pyrimidine-6-carboxylate
(7e, C16H18N4O2)
According to general method with 2.51 g of 5e. The
method afforded 0.31 g (21 %) of 7e (a 70:30 mixture of
the Et- and Me-esters based on the intensity of the CH2-
123

The pseudo-Michael reaction of 1-aryl-4,5-dihydro-1H-imidazol-2-amines
1181
Ethyl (methyl) 5-imino-1-(2-methoxyphenyl)-2,3-
299 (6), [M–OEt]?ꢀ and [M–OMe]?ꢀ 269 (21), [M–HOEt]?
and [M–HOMe]? 268 (12), [M–H–HOEt]? and [M–H–
HOMe]? 267 (32), [M–C2H4OOC]?ꢀ and [M–H2COOC]?ꢀ
242 (87), [M–H–C2H4OOC]? and [M–H–H2COOC]? 241
(21), 136 (30), 134 (10), 121 (10), 77 (5).
dihydroimidazo[1,2-a]pyrimidine-6-carboxylate
(7g, C16H18N4O3)
According to general method with 2.67 g of 5g. The
method afforded 0.30 g (19 %) of 7g (a 68:32 mixture of
the Et- and Me-esters based on the intensity of the CH2-
signals in the NMR spectrum. The abundance ratio of the
M?ꢀ ions was 67:33). M.p.: 165–168 ꢁC; Rf = 0.00 (tol-
uene/ethyl acetate/methanol 1:3:0.5); NMR data for 7g: 1H
NMR (500 MHz, DMSO-d6): d = 8.08 (br s, 1H, 5-NH),
8.02 (s, 1H, H-7), 7.38 (m, 1H, H-60), 7.36 (m, 1H, H-40),
7.16 (d, 1H, J = 7.8 Hz, H-30), 7.01 (dt, 1H, J = 1.2 Hz,
7.6 Hz, H-50), 4.17 (q, 2H, J = 7.1 Hz, OCH2CH3), 4.06
(m, 2H, H-2), 4.06 (m, 2H, H-3), 3.82 (s, 3H, 20-OCH3),
1.20 (t, 3H, J = 7.1 Hz, OCH2CH3) ppm; 13C NMR
(125 MHz, DMSO-d6): d = 165.39 (C=O), 158.26 (C-7),
157.26 (C-8a), 154.90 (C-20), 152.86 (C-5), 129.35, 128.98
(C-40, C-60), 125.50 (C-10), 120.46 (C-50), 112.48 (C-30),
101.57 (C-6), 59.37 (OCH2CH3), 55.66 (20-OCH3), 47.26
(C-2), 41.50 (C-3), 14.11 (OCH2CH3) ppm; MS (EI): M?ꢀ
C16H18N4O?2 ꢀ calc. (Et-ester) 314.1379, found 314.1377,
calc. (Me-ester) 300.1223, found 300.1225; m/z (%): Et-
ester: M?ꢀ 314 (100), [M–H]? 313 (17), Me-ester: M?ꢀ 300
(50), [M–H]? 299 (11), [M–OMe]? 283 (29), [M–OEt]?ꢀ
and [M–OMe]?ꢀ 269 (47), [M–H–HOEt]? and [M–H–
HOMe]? 267 (17), [M–C2H4OOC]?ꢀ and [M–H2COOC]?ꢀ
242 (71), [M–H–C2H4OOC]? and [M–H–H2COOC]? 241
(11), 237 (17), 212 (14), 211 (17), 174 (34), 134 (10), 119
(11), 106 (6), 105 (5), 92 (6), 77 (8), 65 (6).
Acknowledgments The paper was developed using the equipment
purchased within the project ‘‘The equipment of innovative labora-
tories doing research on new medicines used in the therapy of
civilization and neoplastic diseases’’ within the Operational Program
Development of Eastern Poland 2007-2013, Priority Axis I modern
Economy, operations I.3 Innovation promotion.
Open Access This article is distributed under the terms of the
Creative Commons Attribution License which permits any use, dis-
tribution, and reproduction in any medium, provided the original
author(s) and the source are credited.
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Ethyl (methyl) 5-imino-1-(4-methoxyphenyl)-2,3-
dihydroimidazo[1,2-a]pyrimidine-6-carboxylate
(7h, C16H18N4O3)
According to general method with 2.67 g of 5h. The
method afforded 0.53 g (34 %) of 7h (a 85:15 mixture of
the Et- and Me-esters based on the intensity of the CH2-
signals in the NMR spectrum. The abundance ratio of the
M?ꢀ ions was 88:12). M.p.: 181–182 ꢁC; Rf = 0.00 (tol-
uene/ethyl acetate/methanol 1:3:0.5); NMR data for 7h: 1H
NMR (500 MHz, DMSO-d6): d = 8.13 (s, 1H, H-7), 8.08
(br s, 1H, 5-NH), 7.59 (dd, 2H, J = 2.4 Hz, 6.9 Hz, H-20,
H-60), 6.99 (dd, 2H, J = 2.3 Hz, 6.9 Hz, H-30, H-50), 4.18
(m, 2H, H-2), 4.18 (q, 2H, J = 7.1 Hz, OCH2CH3), 4.02
(m, 2H, H-3), 3.76 (s, 3H, 40-OCH3), 1.25 (t, 3H,
J = 7.1 Hz, OCH2CH3) ppm; 13C NMR (125 MHz,
DMSO-d6): d = 165.32 (C=O), 157.71 (C-7), 156.28 (C-
40), 155.42 (C-8a), 152.78 (C-5), 131.21 (C-10), 122.34 (C-
20, C-60), 113.91 (C-30, C-50), 102.07 (C-6), 59.49
(OCH2CH3), 55.21 (40-OCH3), 46.33 (C-2), 40.62 (C-3),
14.09 ppm (OCH2CH3); MS (EI): M?ꢀ C16H18N4O2?ꢀ calc.
(Et-ester) 314.1379, found 314.1374, calc. (Me-ester)
300.1223, found 300.1219; m/z (%): Et-ester: M?ꢀ 314
(100), [M–H]? 313 (22), Me-ester: M?ꢀ 300 (13), [M–H]?
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