Reactions of ketene aminals with N-arylmaleimides and dimethyl acetylenedicarboxylate, a direct pathway to derivatives of pyrrolo[1,2-a] imidazole and imidazo[1,2-a]pyridine

Article abstract of DOI:10.1007/s10593-012-1123-y

The addition of N-arylmaleimides or dimethyl acetylenedicarboxylate to 2-imidazolideneacetophenones proceeds at the most nucleophilic carbon atom of the acetophenone derivatives and results in a rearrangement to give derivatives of 5-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazole or imidazo-[1,2-a] pyridine, respectively. In the case of 2-imidazolidenecyclopentanones and 2-imidazolidine-cyclohexanones, the reaction terminates upon the addition of imide or dimethyl acetylenedicarboxylate at the nitrogen atom of the imidazoline system.

Full text of DOI:10.1007/s10593-012-1123-y

Chemistry of Heterocyclic Compounds, Vol. 48, No. 8, November, 2012 (Russian Original Vol. 48, No. 8, August, 2012)
REACTIONS OF KETENE AMINALS WITH N-ARYLMALEIMIDES
AND DIMETHYL ACETYLENEDICARBOXYLATE, A DIRECT
PATHWAY TO DERIVATIVES OF PYRROLO[1,2-a]IMIDAZOLE
AND IMIDAZO[1,2-a]PYRIDINE
V. D. Orlov,1* Yu. V. Kharchenko2, I. M. Gella3, I. V. Omel'chenko3, and O. V. Shishkin3
The addition of N-arylmaleimides or dimethyl acetylenedicarboxylate to 2-imidazolideneacetophenones
proceeds at the most nucleophilic carbon atom of the acetophenone derivatives and results in a
rearrangement to give derivatives of 5-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazole or imidazo-
[1,2-a]pyridine, respectively. In the case of 2-imidazolidenecyclopentanones and 2-imidazolidine-
cyclohexanones, the reaction terminates upon the addition of imide or dimethyl acetylenedicarboxylate
at the nitrogen atom of the imidazoline system.
Keywords: N-arylmaleimides, dimethyl acetylenedicarboxylate, imidazo[1,2-a]pyridine, ketene
aminals, pyrrolo[1,2-a]imidazole, Michael adducts.
One of the rapidly developing areas in the chemistry of enamines [1, 2] is the study of acylketene
diaminals [3] containing a strongly polarized C=C bond with significantly enhanced electron density at the
α-carbon atom due to the conjugation of the electron-donor amino groups and electron-withdrawing acyl groups
[3, 4]. This feature of electronic structure leads to facile reactions of these compounds with electrophilic
reagents [5-7], which, in turn, permits their use in the synthesis of a new type of heterocycles [8, 9].
Maleic anhydride and maleimide have been used as electrophilic reagents in reactions with acylketene
diaminals [10]. However, reactions of these compounds with N-arylmaleimides have not been described in the
literature.
The aim of the present work was to study the reaction of such cyclic acylketene diaminals as 2,3,4,5-tetra-
hydro-1H-2-imidazolideneacetophenones 1a-d and 2,3,4,5-tetrahydro-1H-2-imidazolidenecycloalkanones 2a,b
and 3 with N-arylmaleimides 4a-e and the dimethyl ester of acetylenedicarboxylic acid (DMAD). This dimethyl
ester was selected for study since the extent of unsaturation and polarizability of the triple bond in this case
differ from the analogous properties of double bond in maleimide, and we might thus expect fundamentally
different reactions with the acylketene aminals examined.
_______
*To whom correspondence should be addressed, e-mail: orlov@univer.kharkov.ua.
1V. N. Karazin Kharkiv National University, 4. Svobody Sq., Kharkiv 61022, Ukraine.
2A. S. Makarenko Sumy State Pedagogical University, 98 Romenskaya St., Sumy 40030, Ukraine.
3Scientific-Technological Complex "Institute of Monocrystals", National Academy of Sciences of Ukraine, 60
Lenin Ave., Kharkiv 61001, Ukraine; igella@kharkov.ua.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1292-1300, August, 2012.
Original article submitted November 1, 2011.
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0009-3122/12/4808-1204©2012 Springer Science+Business Media New York

The starting compounds 1a-d were obtained by the reaction of the corresponding bis(methyl-
thio)methyleneacetophenones with ethylenediamine (EDA) [3, 11, 12]. Cycloalkanone derivatives 2a,b and 3
were synthesized analogously by the reaction of the corresponding bismethylthio derivatives described in our
previous work [13] with ethylenediamine. We should note that the 13C NMR spectra indicate that the
acetophenone derivatives 1a-d exist in solution in ketonic form (the δ values of the carbon atoms of the C(=O)–
CH=C(NH)2 fragment are 178-182, 72-73, and 164-165 ppm, respectively) [3, 4]. Aminals 2a,b and 3 also exist
in ketonic form, as indicated by the 13C NMR spectra, in which the signals of the enone fragment carbon atoms
lie in the same regions as in the spectra of aminals 1a-d.
New types of pyrrolo[1,2-a]imidazoles, namely, derivatives of N-aryl-2-(7-aroyl-5-oxo-2,3,5,6-tetra-
hydro-1H-pyrrolo[1,2-a]imidazol-6-yl)acetamides 5a-e were formed in the reaction of acetophenone derivatives
1a-d with N-arylmaleimides 4a-c in acetonitrile at reflux.
O
O
R
O
N
R1
H
N
O
SMe
SMe
O
HN
4a–c
EDA
R1
N
MeCN, 
N
R
R
N
H
H
1a–d
O
O
5a–e
1 a R = Ph, b R = 4-MeC6H4, c R = 4-BrC6H4, d R = 4-ClC6H4; 4 a R1 = Ph, b R1 = 3-FC6H4,
c R1 = 4-Br-2-EtC6H3; 5 a R = 4-MeC6H4, R1 = Ph; b R = 4-BrC6H4, R1 = Ph; c R = 4-ClC6H4, R1 = Ph;
d R = Ph, R1 = 4-Br-2-EtC6H3; e R = Ph, R1 = 3-FC6H4
In the case of aminals 2a,b and 3, obtained on the basis of cycloalkanone structures, the nucleophilic
α-carbon atom of the endiamine fragment is located within a carbocycle and cannot serve as a reaction site due
to steric considerations. Thus, the reaction with N-arylmaleimides 4a,b,d,e stops upon formation of the Michael
adducts 6a-f and 7a-c.
O
HN
H
O
O
N
SMe
SMe
N
R
O
4a,b,d,e
EDA
Py
(CH2)n
R
R
MeCN

N
NR1
H
(CH2)n
(CH2)n
2a,b, 3
O
6a–f, 7a–c
2a,b, 6a–f n = 1; 3, 7a–c n = 2; 2 a R = Ph, b R = 4-ClC6H4; 3 R = 4-MeOC6H4; 4 d R1 = 4-MeC6H4, е R1 = 2,5-Me2C6H3;
6 a R = R1 = Ph; b R = Ph, R1 = 2,5-Me2C6H3; c R = Ph, R1 = 3-FC6H4; d R = 4-ClC6H4, R1 = 4-MeC6H4;
e R = 4-ClC6H4, R1 = 2,5-Me2C6H3; f R = 4-ClC6H4, R1 = 3-FC6H4; 7 a R = 4-MeOC6H4, R1 = 4-MeC6H4;
b R = 4-MeOC6H4, R1 = 2,5-Me2C6H3; c R = 4-MeOC6H4, R1 = 3-FC6H4
The composition and structure of products 5-7 were supported by elemental analysis, 1H and 13C NMR
spectroscopy, and mass spectrometry data. In individual cases, the assignment of the NMR signals was made
using two-dimensional homo- and heteronuclear correlation spectra (1H COSY, 1H-13C HSQS, and HMBC).
The finding of cross peaks of proton H-6 with double bond carbon atoms in the HMBC spectrum of the
acetamide 5c (Fig. 1) at 84.9 and 157.7 ppm indicated that the reaction proceeds through the addition of
N-arylmaleimide 4a to the α-carbon atom of acetophenone 1d with subsequent rearrangement to give
tetrahydropyrrolo[1,2-a]imidazole. The rearrangement to an imidazo[1,2-a]pyridine is probably less favorable
1
due to steric considerations. The vicinal coupling constants of the acetamide fragment protons in the H NMR
spectrum at 1.6 and 7.2 Hz are in good accord with the proposed structure of 5c.
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At the same time, the signal of one NH group proton shifted downfield due to hydrogen bonding with a
1
1
carbonyl group is retained in the H and H COSY NMR spectra of the products from the reaction of aminals
2a,b and 3 with N-arylmaleimides 4, while additional signals of a CH–CH2 fragment arise in the resonance
region for aliphatic protons.
H
O
N
42.0
128.9
188.4
84.9
133.9
157.7
129.1
139.3
43.2
N
H
41.0
167.5
Cl
36.4
H
H
N
O
172.7
H
O
141.2
120.0
128.6
123.9
Fig. 1. Assignment of signals in the 13C NMR spectrum of acetamide 5c. The solid arrows show the most
important correlations in the HMBC spectrum, while the dashed arrow shows an important correlation in the
NOE spectrum.
Heating ketene aminals 1a-d with DMAD in acetonitrile or dioxane at reflux gave methyl 8-aroyl-
5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine-7-carboxylates 8a-d in good yields:
R
O
DMAD
O
O
HN
O
H
N
1a–d
3
MeO
N
OMe
4-MeOC6H4
MeCN
N

O
O
OMe
8a–d
9
8 a R = Ph, b R = 4-MeC6H4, c R = 4-BrC6H4, d R = 4-ClC6H4
The formation of ester 8a in an analogous reaction has already been reported by Huang and Liu [5].
Ketones 2a,b and 3 also react with DMAD in acetonitrile, but a mixture of mono- and diadducts is
formed in this case, which proved difficult to separate. When the reaction of ketone 3 was carried out in dioxane
without heating, we were able to isolate the diester 9 as a pure product in 25% yield. The 1H NMR spectrum of
diester 9 retains only the signal of the downfield NH proton in proximity to a carbonyl group; signals for one
vinyl proton at 5.72 ppm and two methoxycarbonyl groups also appear in this spectrum. Measurement of the
nuclear Overhauser effect for the vinyl proton shows that it is close to both methoxycarbonyl groups and, thus,
the reaction proceeds as a trans addition.
The structure of ester 8c was confirmed by X-ray diffraction structural analysis. The fused ring system
in this ester shown in Fig. 2 is virtually planar (the deviations of atoms from the mean-square plane do not
exceed 0.04 Å). The ester substituent is twisted relative to the six-membered heterocycle (the O(3)=C(8)–
C(5)=C(6) dihedral angle is -47.7(5)°), which leads to a breakdown in conjugation between them, as indicated
by the lengthening of the C(5)–C(8) bond to 1.497(5) Å in comparison to the standard value of 1.46 Å [14]. The
C(10)=O(2) carbonyl group has somewhat deviated from the plane of the fused ring system (the C(3)=C(4)–
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C(10)=O(2) dihedral angle is -15.6(5)°) and twisted relative to the bromophenyl substituent (the O(2)=C(10)–
C(11)–C(16) dihedral angle is 43.4(5)°). Such a conformation of these substituents is apparently a result of
repulsion between them as indicated by shortened intramolecular C(11)···C(8) (3.05 Å) and C(11)···O(4) (2.89 Å)
contacts, (the sum of the van der Waals radii are 3.42 and 3.00 Å, respectively). The formation the N(2)–
H(2N)···O(2) intramolecular hydrogen bond (H···O 2.13 Å, N-H···O 120°) leads to significant localization of
negative charge on the C(10)=O(2) carbonyl group, as indicated by lengthening of this bond to 1.255(4) Å in
comparison with the mean value of 1.22 Å [16]. Thus, the X-ray diffraction structural data clearly show that a
six-membered ring is formed in the course of the studied reaction to give imidazopyridones 8a-d, which is
possible only in the case of a trans addition of the α-enamine carbon at the DMAD triple bond in the first
reaction step.
Fig. 2. Molecular structure of the ester 8c.
Thus, the reaction of acyclic aminals with N-arylmaleimides and dimethyl acetylenedicarboxylate is
accompanied by rearrangements leading to the formation of derivatives of pyrrolo[1,2-a]imidazole and
imidazo[1,2-a]pyridine, while the analogous reactions of cyclic aminals containing a nucleophilic carbon site
within the carbocycle are limited to addition with the participation of the imidazoline N–H bond.
EXPERIMENTAL
1
13
The H and C NMR spectra were recorded on a Bruker Avance DRX-500 spectrometer (500 and 126
MHz, respectively) with TMS as internal standard. The electron impact mass spectra were recorded on a
Hewlett-Packard LC/MSD 1100 mass spectrometer at 70 eV. The elemental analysis was carried out on a
EuroVector EA-3000 CHNS-O analyzer. The melting points were measured on a Koefler hot stage apparatus.
2-Benzylidene-5-(imidazolidin-2-ylidene)cyclopentanone (2a). A mixture of 5-benzylidene-2-bismethyl-
thiomethylenecyclopentanone [12] (4.42 g, 16 mmol) and ethylenediamine (0.96 g, 16 mmol) was heated in
pyridine (25 ml) at reflux for 2 h. After cooling, the yellow crystalline precipitate was separated, washed on
filter with toluene, and dried in air. Yield 3.46 g (90%); mp 228-230°С. 1H NMR spectrum (DMSO-d6), δ, ppm:
10.29 (1H, s, NH); 7.43-7.17 (6H, m, Н Ph, NH); 7.10 (1H, s, =CH); 3.56-3.45 (4H, m, NCH2CH2N); 2.64-2.55
(2H, m, 3-CH2); 2.28-2.20 (2H, m, 4-CH2). Found, %: С 75.26; Н 6.50; N 11.80. C15H16N2O. Calculated, %:
С 74.97; Н 6.71; N 11.66.
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2-(4-Chlorobenzylidene)-5-(imidazolidin-2-ylidene)cyclopentanone (2b) was obtained analogously
to the cyclopentanone 2a. Yield 3.50 g (80%); mp 247-249°С. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.81
(1H, br. s, NH); 7.57-7.29 (5H, m, Н Ar, =CH); 6.76 (1H, t, J = 2.6, NH); 3.65-3.40 (4H, m, NCH2CH2N); 2.84-2.70
(2H, m, 3-CH2); 2.52-2.40 (2H, m, 4-CH2). 13C NMR spectrum (CDCl3), δ, ppm: 185.0 (CO); 162.0 (NHCNH);
144.4; 136.2; 132.0; 130.2; 128.3; 121.6; 89.7 (C-5); 45.9; 43.4; 26.4; 23.2. Found, %: С 65.56; Н 5.50; N 10.20;
Cl 12.92. C15H15ClN2O. Calculated, %: С 65.57; Н 5.50; N 10.20; Cl 12.90.
6-(Imidazolidin-2-ylidene)-2-(4-methoxybenzylidene)cyclohexanone (3) was obtained analogously to
the cyclopentanone 2a. Yield 3.40 g (75%); mp 173-175°С. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 10.26
(1H, br. s, NH); 7.30 (1Н, s, =CH); 7.27 (2H, d, J = 8.3, H Ar); 7.08 (1H, br. s, NH); 6.91 (2H, d, J = 8.3, H Ar);
3.72 (3H, s, CH3O); 3.70-3.45 (4H, m, NCH2CH2N); 2.64-2.53 (2H, m, 3-CH2); 2.24 (2H, t, J = 5.9, 5-CH2);
1.65-1.51 (2H, m, 4-CH2). 13C NMR spectrum (CDCl3), δ, ppm: 180.4 (CO); 165.1 (NHCNH); 158.6; 136.1;
131.1; 130.4; 129.1; 113.6; 87.1 (C-5); 55.3; 44.2; 43.0; 28.1; 24.6; 23.6. Found, %: С 71.90; Н 7.01; N 9.90.
C17H20N2O2. Calculated, %: C 71.81; H 7.09; N 9.85.
2-[7-(4-Methylbenzoyl)-5-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazol-6-yl]-N-phenylacet-
amide (5a). A mixture of acetophenone 1a (0.21 g, 1.12 mmol) and N-phenylmaleimide (4a) (0.28 g,
1.6 mmol) was heated in acetonitrile (25 ml) at reflux for 1.5 h. The colorless, fine crystalline precipitate was
1
filtered off, washed with acetonitrile, and dried in air. Yield 0.26 g (63%); mp 198-200°С. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 9.58 (1H, s, NH); 9.35 (1H, s, NH); 7.44 (2H, d, J = 8.1, H Ar); 7.27 (2H, t, J = 8.3,
H Ar); 7.21-7.09 (4H, m, H Ar); 7.02 (1H, t, J = 7.5, H Ar); 3.88-3.68 (5H, m, NCH2CH2N, CHCH2); 2.94 (1H, dd,
J = 16.5, J = 7.0) and 2.55 (1H, d, J = 16.5, CHCH2); 2.34 (3H, s, CH3). 13C NMR spectrum (CDCl3), δ, ppm:
189.8; 172.8; 167.5; 157.5; 139.7; 139.4; 138.8; 129.1; 129.0; 126.8; 123.8; 119.9; 84.9; 43.2; 41.9; 41.1; 36.6;
21.4. Found, %: С 70.44; Н 5.60; N 11.29. C22H21N3O3. Calculated, %: C 70.38; H 5.64; N 11.19.
2-[7-(4-Bromobenzoyl)-5-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazol-6-yl]-N-phenylacet-
1
amide (5b) was obtained analogously to the phenylacetamide 5a. Yield 0.38 g (77%); mp 148-150°С. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 9.58 (1H, s, NH); 9.39 (1H, s, NH); 7.54 (2H, d, J = 7.6, Н Ar); 7.42 (2H, d,
J = 7.0, Н Ar); 7.30-7.15 (4H, m, Н Ar); 7.02 (1H, br. t, J = 6.3, Н Ar); 3.88-3.61 (4H, m, NCH2CH2N); 3.58 (1H,
d, J = 6.0, CHCH2); 2.95 (1H, dd, J = 16.3, J = 6.5) and 2.54 (1H, d, J = 16.3, CHCH2). 13C NMR spectrum
(DMSO-d6), δ, ppm: 188.4; 172.7; 167.5; 157.7; 141.6; 139.3; 131.6; 129.1; 128.9; 123.9; 122.6; 120.0; 84.8; 43.2;
41.9; 40.9; 36.4. Found, %: С 57.33; Н 4.08; N 9.48. C21H18BrN3O3. Calculated, %: C 57.29; H 4.12; N 9.54.
2-[7-(4-Chlorobenzoyl)-5-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazol-6-yl]-N-phenylacet-
amide (5c) was obtained analogously to the phenylacetamide 5a. Yield 0.27 g (63%); mp 130-132°С. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 9.57 (1H, s, NH); 9.39 (1H, s, NH); 7.45-7.38 (4H, m, Н Ar); 7.28-7.22
(4H, m, Н Ar); 7.02 (1H, t, J = 7.4, Н Ar); 3.88-3.64 (4H, m, NCH2CH2N); 3.59 (1H, dd, J = 7.2, J = 1.6,
CHCH2); 2.95 (1H, dd, J = 16.6, J = 7.2) and 2.55 (1H, dd, J = 16.6, J = 1.6, CHCH2). 13C NMR spectrum
(CDCl3), δ, ppm: 188.4; 172.7; 167.5; 157.7; 141.2; 139.2; 133.9; 129.1; 128.7; 128.6; 123.9; 120.0; 84.8; 43.2;
42.0; 40.9; 36.4. Found, %: С 63.68; Н 4.66; N 10.55. C21H18ClN3O3. Calculated, %: C 63.72; H 4.58; N 10.62.
2-(7-Benzoyl-5-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazol-6-yl]-N-(4-bromo-2-ethylphenyl)-
acetamide (5d) was obtained analogously to the phenylacetamide 5a. Yield 0.32 g (60%); mp 189-191°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 9.21 (1H, br. s, NH); 9.12 (1H, s, NH); 7.43-7.38 (3H, m,
Н Ar); 7.38-7.30 (4H, m, Н Ar); 7.25 (1H, d, J = 8.2, Н Ar); 3.72 (1H, d, J = 7.2, CHCH2); 3.92-3.82 (1H, m)
and 3.75-3.61 (3H, m, NCH2CH2N); 2.95 (1H, dd, J = 16.5, J = 7.2) and 2.62 (1H, d, J = 16.4, CHCH2); 2.39
(2H, q, J = 7.5, CH2CH3); 1.02 (3H, t, J = 7.5, СН2CH3). 13C NMR spectrum (CDCl3), δ, ppm: 189.8; 173.0;
167.7; 157.4; 142.3; 140.6; 135.4; 131.5; 129.4; 129.3; 128.6; 127.7; 126.9; 118.2; 84.7; 43.2; 41.9; 40.6; 36.4;
23.9; 14.5. Found, %: С 58.98; Н 4.69; N 8.91. C23H22BrN3O3. Calculated, %: C 58.98; H 4.73; N 8.97.
2-(7-Benzoyl-5-oxo-2,3,5,6-tetrahydro-1H-pyrrolo[1,2-a]imidazol-6-yl]-N-(3-fluorophenyl)acet-
amide (5e) was obtained analogously to the phenylacetamide 5a. Yield 0.28 g (65%); mp 140-142°С. 1H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 9.78 (1H, s, NH); 9.43 (1H, s, NH); 7.44 (1H, d, J = 11.7, Н Ar);
7.39-7.25 (4H, m, Н Ar); 7.22 (2H, d, J = 6.0, Н Ar); 7.12 (1H, d, J = 7.4, Н Ar); 6.85 (1H, t, J = 6.5, Н Ar);
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3.89-3.64 (4H, m, NCH2CH2N); 3.59 (1H, d, J = 7.0, CHCH2); 2.98 (1H, dd, J = 16.6, J = 7.1) and 2.54 (1H, d,
J = 16.0, CHCH2). 13C NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 189.8; 173.2; 167.3; 157.5; 142.5; 141.1 (d,
J = 11.1); 130.8 (d, J = 9.5); 129.2; 128.6; 126.5; 115.5; 110.2 (d, J = 21.2); 106.6 (d, J = 26.2); 84.6; 62.5
(2С); 43.2; 42.0 (d, J = 25.5); 41.5; 36.4. Found, %: С 66.55; Н 4.81; N 11.18. C21H18FN3O3. Calculated, %:
C 66.48; H 4.78; N 11.08.
3-[2-(3-Benzylidene-2-oxocyclopentylidene)imdazolidin-1-yl]-1-phenylpyrrolidine-2,5-dione (6a)
1
was obtained analogously to the phenylacetamide 5a. Yield 0.36 g (77%); mp 244-246°С. H NMR spectrum
(CDCl3), δ, ppm (J, Hz): 7.75 (1H, s, NH); 7.60 (1H, s, =CH); 7.54 (2H, d, J = 6.0, Н Ar); 7.48-7.37 (4H, m,
Н Ar); 7.32-7.24 (3H, m, Н Ar); 7.10 (1H, t, J = 7.4, Н Ar); 3.92-3.82 (4H, m, NCH2CH2N); 3.41 (1H, t,
J = 7.5, 3-CH); 3.20-3.12 (1H, m, 4-CHА); 3.08-2.98 (3H, m, 4-CHВ, 4''-CH2); 2.52-2.45 (1H, m) and 2.31-2.22
(1H, m, 5''-CH2). 13C NMR spectrum (CDCl3), δ, ppm: 204.6; 167.5; 166.3; 158.8; 137.0; 136.9; 134.8 (2С);
131.2; 130.3; 129.0; 128.8; 124.9; 120.1; 53.8; 52.9; 43.4; 42.7; 31.9; 28.4; 26.1. Found, %: С 72.73; Н 5.66;
N 10.12. C25H23N3O3. Calculated, %: C 72.62; H 5.61; N 10.16.
3-[2-(3-Benzylidene-2-oxocyclopentylidene)imidazolidin-1-yl]-1-(2,5-dimethylphenyl)pyrrolidine-
2,5-dione (6b) was obtained analogously to the phenylacetamide 5a. Yield 0.44 g (90%); mp 282-284°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 9.64 (1H, s, NH); 7.69 (2H, d, J = 6.7, H Ar); 7.53-7.44 (3H, m,
Ar); 7.42 (1H, s, =CH); 7.11-7.07 (1H, m, H Ar); 7.05-6.99 (2H, m, H Ar); 3.80-3.60 (4H, m, NCH2CH2N);
3.19-3.12 (2H, m, 4''-CH2); 3.06 (1H, dd, J = 16.9, J = 6.0, 3-CH); 2.68-2.56 (3H, m, 4-CH2, 5''-CHА); 2.26-2.18
(4H, m, 5''-CHВ, ArCH3); 2.06 (3H, s, ArCH3). Mass spectrum, m/z (Irel, %): 442 (17), 441 [M]+ (52), 293 (100),
265 (25). Found, %: С 73.50; Н 6.22; N 9.55. C27H27N3O3. Calculated, %: C 73.45; H 6.16; N 9.52.
3-[2-(3-Benzylidene-2-oxocyclopentylidene)imidazolidin-1-yl]-1-(3-fluorophenyl)pyrrolidine-2,5-dione
1
(6c) was obtained analogously to the phenylacetamide 5a. Yield 0.43 g (90%); mp 228-230°С. H NMR
spectrum (DMSO-d6), δ, ppm (J, Hz): 10.41 (1H, s, NH); 7.71 (2H, d, J = 7.2, H Ar); 7.59-7.47 (4H, m, H Ar);
7.45 (1H, s, =CH); 7.37 (1H, dd, J = 15.1, J = 7.8, Н Ar); 7.28 (1H, d, J = 8.1, Н Ar); 6.93 (1H, t, J = 7.4,
Н Ar); 3.83-3.61 (4H, m, NCH2CH2N); 3.26-2.98 (4H, m) and 2.70-2.60 (2H, m, 3-СН, 4-СН2, 4''-CH2,
5''-CHA); 2.12 (1H, m, 5''-CHВ). Mass spectrum, m/z (Irel, %): 431 [M]+ (28), 293 (15), 266 (31), 265 (100), 239
(29), 149 (42), 115 (18). Found, %: С 69.65; Н 5.12; N 9.80. C25H22FN3O3. Calculated, %: C 69.59; H 5.14;
N 9.74.
3-{2-[3-(4-Chlorobenzylidene)-2-oxocyclopentylidene]imidazolidin-1-yl}-1-(4-methylphenyl)pyrroli-
dine-2,5-dione (6d) was obtained analogously to the phenylacetamide 5a. Yield 0.36 g (70%); mp 285-287°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 10.11 (1H, s, NH); 7.71 (2H, d, J = 8.5, H Ar); 7.55 (2H, d, J = 8.5,
H Ar); 7.44-7.38 (3H, m, H Ar); 7.09 (2H, d, J = 8.2, H Ar); 3.87-3.61 (4H, m, NCH2CH2N); 3.20-3.16 (1H, m,
3-CH); 3.13-3.07 (2H, m, 4''-CH2); 3.02 (1H, dd, J = 17.4, J = 5.8, 4-CHА); 2.63-2.55 (2H, m, 4-CHВ, 5''-CHA);
2.23 (3H, s, ArCH3); 2.15-2.08 (1H, m, 5-CHB). Found, %: С 67.66; Н 5.20; N 9.00. C26H24ClN3O3. Calculated,
%: C 67.60; H 5.24; N 9.10.
3-{2-[3-(4-Chlorobenzylidene)-2-oxocyclopentylidene]imidazolidin-1-yl}-1-(2,5-dimethylphenyl)-
pyrrolidine-2,5-dione (6e) was obtained analogously to the phenylacetamide 5a. Yield 0.34 g (63%); mp
275-277°С. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 9.64 (1H, s, NH); 7.74 (2H, d, J = 8.4, Н Ar); 7.58 (2H,
d, J = 8.5, Н Ar); 7.43 (1H, s, =CH); 7.16-6.99 (3H, m, Н Ar); 3.80-3.63 (4H, m, NCH2CH2N); 3.20-3.12 (2H,
m, 4''-CH2); 3.08 (1Н, dd, J = 17.3, J = 5.6, 3-CH); 2.71-2.55 (3H, m, 4-CH2, 5''-CHA); 2.30-2.20 (4H, m,
5''-CHB, ArCH3); 2.09 (3H, s, ArCH3). Mass spectrum, m/z (Irel, %): 477 (42), 475 [M]+ (100), 327 (95). Found,
%: С 68.09; Н 5.50; N 8.90. C27H26ClN3O3. Calculated, %: C 68.13; H 5.51; N 8.83.
3-{2-[3-(4-Chlorobenzylidene)-2-oxocyclopentylidene]imidazolidin-1-yl}-1-(3-fluorophenyl)pyrroli-
dine-2,5-dione (6f) was obtained analogously to the phenylacetamide 5a. Yield 0.45 g (87%); mp 231-233°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 10.40 (1H, s, NH); 7.73 (2H, d, J = 8.5, Н Ar); 7.63-7.50 (3H,
m, Н Ar); 7.43 (1H, s, =CH); 7.36 (1H, dd, J = 15.1, J = 8.1, Н Ar); 7.28 (1H, d, J = 8.5, Н Ar); 6.96-6.90 (1H,
m, Н Ar); 3.92-3.64 (4H, m, NCH2CH2N); 3.22-3.03 (4H, m, 3-CH, 4-CHA, 4''-CH2); 2.71-2.61 (1H, m,
1209

5''-CHA); 2.56 (1H, dd, J = 17.4, J = 5.7, 4-CHB); 2.20-2.08 (1H, m, 5''-CHB). Mass spectrum, m/z (Irel, %): 467
(28), 466(28), 465 [M]+ (100), 327 (11), 301 (13), 299 (20). Found, %: С 64.52; Н 4.61; N 9.08.
C25H21ClFN3O3. Calculated, %: C 64.45; H 4.54; N 9.02.
3-{2-[3-(4-Methoxybenzylidene)-2-oxocyclohexylidene]imidazolidin-1-yl}-1-(4-methylphenyl)-
pyrrolidine-2,5-dione (7a) was obtained analogously to the phenylacetamide 5a. Yield 0.43 g (82%); mp
197-199°С. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 10.22 (1H, s, NH); 7.51 (2H, d, J = 7.4, H Ar); 7.42
(2H, d, J = 7.7, H Ar); 7.36 (1H, s, =CH); 7.10 (2H, d, J = 7.6, H Ar); 7.03 (2H, d, J = 8.0, H Ar); 3.82 (3H, s,
CH3O); 3.80-3.62 (4H, m, NCH2CH2N); 3.56-3.48 (1H, m, 3-CH); 3.03-2.93 (1H, m) and 2.86-2.76 (1H, m,
4''-CH2); 2.73-2.55 (3H, m, 4-CH2, 6''-CHA); 2.24 (3H, s, ArCH3); 2.17-2.04 (1H, m, 6''-CHB); 2.00-1.78 (2H,
m, 5''-CH2). 13C NMR spectrum (DMSO-d6), δ, ppm: 199.3; 169.1; 165.9; 160.4; 159.9; 137.1; 136.39; 134.1;
133.3; 132.8; 129.6; 128.0; 119.9; 114.6; 55.8; 53.0; 51.4; 43.4; 43.2; 32.6; 29.7; 28.8; 20.9; 18.8. Found, %:
С 71.42; Н 6.23; N 9.02. C28H29N3O4. Calculated, %: C 71.32; H 6.20; N 8.91.
3-{2-[3-(4-Methoxybenzylidene)-2-oxocyclohexylidene]imidazolidin-1-yl}-1-(2,5-dimethylphenyl)-
pyrrolidine-2,5-dione (7b) was obtained analogously to the phenylacetamide 5a. Yield 0.46 g (85%); mp
196-198°С. NMR spectrum 1H (DMSO-d6), δ, ppm (J, Hz): 9.68 (1H, s, NH); 7.51 (2H, d, J = 8.6, H Ar); 7.39
(1H, s, =CH); 7.09-6.96 (5H, m, H Ar); 3.82 (3H, s, CH3O); 3.80-3.60 (5H, m, NCH2CH2N, 3-CH); 2.95-2.85
(2H, m, 4''-CH2); 2.73 (1H, dd, J = 13.1, J = 5.0) and 2.64 (1H, dd, J = 11.8, J = 5.0, 4-CH2); 2.50-2.45 (1Н, m)
and 2.04-1.97 (1Н, m, 6''-CH2); 2.24 (3H, s, ArCH3); 2.21-2.14 (1H, m) and 1.95-1.86 (1H, m, 5''-CH2); 2.05
(3H, s, ArCH3). Mass spectrum, m/z (Irel, %): 486 (4), 485 [M]+ (8), 337 (6), 309 (13), 149 (25), 121 (30), 62
(100). Found, %: С 71.69; Н 6.45; N 8.69. C29H31N3O4. Calculated, %: C 71.73; H 6.43; N 8.65.
3-{2-[3-(4-Methoxybenzylidene)-2-oxocyclohexylidene]imidazolidin-1-yl}-1-(3-fluorophenyl)pyrro-
lidine-2,5-dione (7c) was obtained analogously to the phenylacetamide 5a. Yield 0.39 g (73%); mp 207-209°С.
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 10.62 (1H, s, NH); 7.56-7.48 (3H, m, H Ar); 7.38 (1H, s, =CH);
7.35-7.31 (1H, m, H Ar); 7.28 (1H, d, J = 8.3, H Ar); 7.03 (2H, d, J = 8.7, H Ar); 6.93-6.87 (1H, m, H Ar);
3.92-3.62 (7H, m, CH3O, NCH2CH2N); 3.55 (1H, t, J = 5.0, 3-CH); 3.02-2.92 (1H, m) and 2.88-2.78 (1H, m,
4''-CH2); 2.72 (1H, dd, J = 18.2, J = 5.0) and 2.65 (1H, dd, J = 17.1, J = 5.0, 4-CH2); 2.49-2.41 (1H, m) and
2.18-2.08 (1H, m, 6''-CH2); 1.98-1.80 (2H, m, 5''-CH2). Mass spectrum, m/z (Irel, %): 476 (9), 475 [M]+ (20), 337
(50), 309 (100). Found, %: С 68.24; Н 5.57; N 8.90. C27H26FN3O4. Calculated, %: C 68.20; H 5.51; N 8.84.
8-Benzoyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic Acid Methyl Ester (8a). A
mixture of acetophenone 1a (0.36 g, 1.9 mmol) and DMAD (0.31 g, 2.2 mmol) in acetonitrile (30 ml) was heated
at reflux for 1 h. The precipitate was filtered off, washed with acetonitrile, and dried in air. Yield 0.52 g (92%); mp
187-189°С. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 8.68 (1H, s, NH); 7.56-7.35 (5H, m, H Ph); 5.74 (1H,
s, H-6); 4.08 (2H, t, J = 9.3, 3-CH2); 3.77 (2H, t, J = 9.2, 2-CH2); 3.01 (3H, s, COOCH3). 13C NMR spectrum
(DMSO-d6), δ, ppm: 191.5; 167.3; 159.9; 156.7; 145.8; 141.0; 131.6; 128.7; 127.9; 106.9; 93.8; 52.2; 43.8; 43.3.
Found, %: С 64.32; Н 4.81; N 9.44. C16H14N2O4. Calculated, %: C 64.42; H 4.73; N 9.39.
8-(4-Methylbenzoyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic Acid Methyl Ester
(8b) was obtained analogously to the ester 8a. Yield 0.46 g (78%); mp 183-185°С. 1H NMR spectrum (DMSO-d6),
δ, ppm (J, Hz): 8.58 (1H, s, NH); 7.33 (2H, d, J = 7.7, H Ar); 7.21 (2H, d, J = 7.7, H Ar); 5.73 (1H, s, Н-6); 4.07
(2H, t, J = 9.3, 3-CH2); 3.77 (2H, t, J = 9.2, 2-CH2); 3.04 (3H, s, СООCH3); 2.33 (3H, s, ArCH3). 13C NMR
spectrum (DMSO-d6), δ, ppm: 191.3; 167.3; 159.9; 156.5; 145.8; 141.7; 138.3; 129.2; 128.1; 106.7; 93.9; 52.3;
43.8; 43.2; 21.5. Found, %: С 65.45; Н 5.25; N 9.03. C17H16N2O4. Calculated, %: C 65.38; H 5.16; N 8.97.
8-(4-Bromobenzoyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic Acid Methyl
1
Ester (8c) was obtained analogously to the ester 8a. Yield 0.36 g (50%); mp 189-191°С. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 8.70 (1H, s, NH); 7.63 (2H, d, J = 8.4, H Ar); 7.36 (2H, d, J = 8.4, H Ar); 5.76 (1H,
13
s, H-6); 4.07 (2H, t, J = 9.3, 3-CH2); 3.78 (2H, t, J = 9.3, 2-CH2); 3.10 (3H, s, COOCH3). C NMR spectrum
(DMSO-d6), δ, ppm: 190.2; 167.2; 159.9; 156.7; 145.5; 140.1; 131.7; 130.0; 125.2; 107.2; 93.6; 52.4; 43.8;
43.3. Found, %: С 50.85; Н 3.44; N 7.51. C16H13BrN2O4. Calculated, %: C 50.95; H 3.47; N 7.43.
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8-(4-Chlorobenzoyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyridine-7-carboxylic Acid Methyl
1
Ester (8d) was obtained analogously to the ester 8a. Yield 0.52 g (83%); mp 192-194°С. H NMR spectrum
(DMSO-d6), δ, ppm (J, Hz): 8.67 (1H, s, NH); 7.50-7.42 (4H, m, H Ar); 5.76 (1H, s, H-6); 4.07 (2H, t, J = 8.9,
3-CH2); 3.78 (2H, t, J = 8.9, 2-CH2); 3.10 (3H, s, COOCH3). 13C NMR spectrum (CDCl3), δ, ppm: 190.1; 167.2;
159.9; 156.7; 145.5; 139.8; 136.3; 129.8; 128.8; 107.2; 93.7; 52.4; 43.8; 43.3. Found, %: С 57.70; Н 4.03;
N 8.38. C16H13ClN2O4. Calculated, %: C 57.75; H 3.94; N 8.42.
2-{[3-(4-methoxybenzylidene)-2-oxocyclohexylidene]imidazolidin-1-yl}fumaric Acid Dimethyl
Ester (9). A mixture of cyclohexanone 3 (0.32 g, 1.12 mmol) and DMAD (0.22 g, 1.5 mmol) in dioxane (10
ml) was stirred for 8 h and left overnight. The solvent was removed in vacuum. The residue was subjected to
chromatography on silica gel using 9:1 CH2Cl2–methanol as the eluent and recrystallized from ethyl acetate.
Yield 0.15 g (32%); mp 166-168°С. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 7.50 (1H, s, ArCH=); 7.46
(1H, s, NH); 7.34 (2H, d, J = 7.5, H Ar); 6.92 (2H, d, J = 7.5, H Ar); 5.72 (1H, s, =CHCOOMe); 4.05 (2H, t,
J = 8.4, 5'-CH2); 3.80 (3H, s, CH3O); 3.76 (3H, s, CH3O); 3.73 (3H, s, CH3O); 3.64 (2H, t, J = 8.2, 4'-CH2);
2.55-2.40 (4H, m, 4'',6"-CH2); 1.65-1.52 (2H, m, 5''-CH2). Mass spectrum, m/z (Irel, %): 426 [M]+ (5), 208 (27),
207 (100). Found, %: С 64.83; Н 6.06; N 6.51. C23H26N2O6. Calculated, %: C 64.78; H 6.15; N 6.57.
X-ray Diffraction Structural Analysis of Ester 8c. Crystals of ester 8c were grown by slow
evaporation from ethyl acetate solution. The unit cell parameters of monoclinic crystals of C16H13N2O4Br at
20°C were as follows: a 30.755(1), b 7.359(1), c 15.096(2) Å, β 114.78(2)°, V 3102.0(1) Å3, M 377.19, Z 8,
space group C2/c, dcalc 1.615 g/cm3, μ(MoKα) 2.672 mm-1, F(000) 1520. The unit cell parameters and intensities
of 18,138 reflections (3496 independent reflections, Rint 0.025) were measured on an Xcalibur-3 diffractometer
using MoKα radiation and a CCD detector, graphite monochromator, ω-scanning, 2θmax 55°. Absorption was
taken into account by multiscanning (Tmin = 0.2237, Tmax = 0.4145).
The structure was solved by the direct method using the SHELXTL software package [17]. The
positions of hydrogen atoms were found from the electron density difference map and refined using the "rider"
model with Uiso = nUeq (n = 1.5 for the methyl group and n = 1.2 for the other hydrogen atoms). The structure
was refined with the F2 full-matrix least-squares method anisotropically for the non-hydrogen atoms to wR2 =
0.188 for 3496 reflections (R1 = 0.060 for 2323 reflections with F > 4σ(F), S = 1.447). The complete data set of
the crystallographic study was deposited at the Cambridge Crystallographic Data Center (deposit CCDC
820408).
REFERENCES
1.
Z.-T. Huang and M.-X. Wang, in: Z. Rappoport (editor), The Chemistry of Enamines, Wiley, New York
(1994), p. 1303.
2.
3.
4.
P. W. Hickmott, Tetrahedron, 40, 2989 (1984).
Z.-T. Huang and Z.-R. Liu, Synth. Commun., 19, 943 (1989).
M.-X. Zhao, M.-X. Wang, and Z.-T. Huang, Tetrahedron, 58, 1309 (2002).
Z.-T. Huang and Z.-R. Liu, Heterocycles, 24, 2247 (1986).
5.
6.
7.
8.
9.
M.-X. Wang and Z.-T. Huang, J. Org. Chem., 60, 2807 (1995).
Z.-T. Huang and M.-X. Wang, J. Org. Chem., 57, 184 (1992).
Z.-T. Huang and M.-X. Wang, Heterocycles, 37, 1233 (1994).
Z.-T. Huang and Z.-R. Liu, Chem. Ber., 122, 95 (1989).
10.
11.
12.
13.
14.
A. K. Gupta, H. Ila, and H. Junjappa, Synthesis, 284 (1988).
J.-H. Zhang, M.-X. Wang, and Z.-T. Huang, J. Chem. Soc., Perkin Trans. 1, 2087 (1999).
Z.-T. Huang and M.-X. Wang, Synthesis, 1273 (1992).
A. V. Mirniy, I. M. Gella, and V. D. Orlov, Zh. Org. Farm. Khim., 1, issues 1-2, 55 (2003).
H. B. Burgi and J. D. Dunitz, Structure Correlation, vol. 2, VCH, Weinheim (1994), p. 741.
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15.
16.
Yu. V. Zefirov, Kristallografiya, 42, 936 (1997).
V. S. Berseneva, A. V. Tkachev, Y. Y. Morzherin, W. Dehaen, I. Luyten, S. Toppet, and V. A. Bakulev,
J. Chem. Soc., Perkin Trans. 1, 2133 (1998).
17.
G. M. Sheldrick, SHELXTL PLUS. PC Version. A System of Computer Programs for the Determination
of Crystal Structure from X-ray Diffraction Data, Rev. 5.1 (1998).
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