Transformations of enaminones. A simple one-pot synthesis of imidazolone derivatives

Article abstract of DOI:10.1016/j.tet.2011.11.013

Ethyl (5-benzoyl-2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1-yl) carbamates 7 were prepared by the Michael addition of diethyl azodicarboxylate (3) to (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2) followed by substitution of the dimethylamino group

Full text of DOI:10.1016/j.tet.2011.11.013

Tetrahedron 68 (2012) 516e522
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Transformations of enaminones. A simple one-pot synthesis of imidazolone
derivatives
*
ꢀ
ꢀ
ꢀ
Jure Bezensek, Uros Groselj, Katarina Stare, Jurij Svete, Branko Stanovnik
ꢀ
ꢀ
Faculty of Chemistry, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 25 July 2011
Received in revised form 20 October 2011
Accepted 7 November 2011
Available online 13 November 2011
Ethyl (5-benzoyl-2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1-yl)carbamates 7 were prepared by
the Michael addition of diethyl azodicarboxylate (3) to (E)-3-(dimethylamino)-1-phenylprop-2-en-1-
one (2) followed by substitution of the dimethylamino group with primary amines 5aen to afford
a mixture of (E) and (Z) diethyl 1-(1-(substituted)amino)-3-oxo-3-phenylprop-1-en-2-yl)hydrazine-1,2-
dicarboxylates (6aen), followed by cyclization to give final products 7aen. The intermediate 6i was
isolated and characterized and transformed into 7i. All imidazolones 7aen were synthesized in one pot
reaction sequences with individual reactions being very clean.
Keywords:
Enaminones
Michael additions
One-pot synthesis
Imidazolones
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Nitrogen containing heterocycles1 are of special interest in or-
ganic synthetic chemistry, since they occur in a wide variety of
natural products. The imidazolone motif appears in many natural
products,2 which possess interesting biological activities.3 They are
inhibitors of V-RAF murine sarcoma viral oncogene homologue B1.4
They are antagonists of many receptors including the neurokinin-1
receptor5 and the dopamine receptor.6 They were applied as in-
termediates in the synthesis of many natural products, such as bi-
otin,7 slagenins,8 axinohydantoins,9 oroidin-derived alkaloids,10
aplysinopsins,11 Lancetta-derived alkaloid carcaridine A,12 and
others. Due to their importance, many methods have been de-
veloped for the construction of the imidazole ring.13,14 Recently,
there has been great progress in copper-catalysed N-arylation.15,16
4-Aroyl-1,3-dihydro-2H-imidazol-2-ones, have been prepared by
acylation of the appropriate 2H-imidazol-2-ones and evaluated as
a new class of cardiotonic agents.17 The most important compound
in this series is 4-methyl-5-[4-(methylthio)benzoyl]-1H-imidazol-
2(3H)-one (PerfanÒ or EnoximoneÒ) (Fig. 1), a selective phospho-
diesterase inhibitor, which has significant inotropic and vaso-
dilating properties that have proved useful in the postoperative
management of infants and children having cardiac surgery.18,19
The effects of phosphodiesterase (III/IV)-inhibitors and cytokines
on mechanical properties of neutrophilic granulocytes in neonates
and adults have been studied.20
Fig. 1. 4-Methyl-5-[4-(methylthio)benzoyl]-1H-imidazol-2(3H)-one (PerfanÒ or
EnoximoneÒ).
In this communication we report a simple one-pot synthesis of
imidazolone derivatives using enaminone methodology recently
extensively studied in our laboratory. The wide applicability of 3-
(dimethylamino)propenoates and related enaminones as versatile
reagents in heterocyclic synthesis,21 including natural products and
their analogues11,22 and regiospecific microwave-assisted [2þ2]
cycloadditions with electron-poor acetylenes and their trans-
formations into highly substituted heterocyclic systems has been
demonstrated.23
In this communication we report a simple one-pot synthesis of
ethyl (5-benzoyl-2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1-
yl)carbamates, which were prepared by the Michael addition of
diethyl azodicarboxylate to (E)-3-(dimethylamino)-1-phenylprop-
2-en-1-one followed by substitution of the dimethylamino group
with primary amines and cyclization into imidazolone derivatives.
2. Results and discussion
First, (E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2)
prepared from acetophenone (1) and N,N-dimethylformamide
* Corresponding author. Tel.: þ386 1 2419238; fax: þ386 2419220; e-mail ad-
dress: Branko.Stanovnik@fkkt.uni-lj.si (B. Stanovnik).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.11.013

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J. Bezensek et al. / Tetrahedron 68 (2012) 516e522
517
dimethylacetal (DMFDMA) according to known procedure24 was
3. Structure determination
treated with diethyl azodicarboxylate (DEAD) (3) in toluene for 24 h
at room temperature to give a 1:1 mixture of (E)- and (Z)-1-(1-
(dimethylamino)-3-oxo-3-phenylprop-1-en-2-yl)hydrazine-1,2-di
carboxylate (4) in 95% yield. Substitution of the dimethylamino
group with 3-nitroaniline (5i) in acetic acid under reflux for 3 h
afforded a 7:3 mixture of diethyl (E)- and diethyl (Z)-[1-(3-(nitro-
phenyl)amino]-3-oxo-3-phenylprop-1-en-2-yl)hydrazine-1,2-di-
carboxylate 6i in 93% yield. Cyclization of 6i was achieved
by heating in an ethanol solution of NaOH for 2.5 h to give ethyl
(5-benzoyl-3-(3-nitrophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-
yl)carbamate 7i in 93% yield. The formation of 1,2,4-triazin-3-ones
(8aen) was not observed (Scheme 1).
The cyclization can take place either at the NH group at position
30 and the ester group at position 1 of conformer 6 to give imidazole
derivative 7, or alternatively at the NH group at position 30 and the
ester group at position 2 of conformer 60 to give 1,2,4-triazine de-
rivative 8 (Scheme 4).
The 1H NMR spectra of the products show, besides the signals
characteristic for the aromatic group, the ethyl ester group at
d
¼1.21e1.30 ppm for the Me group and
CH2 group. Also a CH singlet in the range
a broad singlet originating from the primary amine in the range
¼7.03e10.11 ppm are visible in the spectra. On the basis of spectral
d
¼4.11e4.24 ppm for the
d
¼6.83e7.97 ppm and
d
Scheme 1. Reagents and conditions: (i) dimethylformamide dimethylacetale, (ii) diethyl azodicarboxylate (3), acetonitrile, rt, (iii) primary amine 5, acetic acid, reflux, (iv) NaOH,
EtOH, reflux.
Table 1
Substituted (2-oxo-2,3-hihydro-1H-imidazol-1-yl)carbamates
This reaction sequence can be carried out as a one-pot pro-
cedure. To a solution of 2 in ethanol, a solution of DEAD (3) in
toluene was added and the reaction mixture was stirred at room
temperature for 4 h. Primary amines 5aen and an aqueous solution
of hydrochloric acid (or amine hydrochloride) were added and the
reaction mixture was stirred again at room temperature for
12e240 h. The solution was made alkaline by addition of sodium
hydroxide and the reaction mixture was stirred for a further
24e144 h. Then the volatile components were evaporated in vacuo.
The crude products 7aen were purified by column chromatography
and recrystallized from appropriate solvents. In the case of com-
pound 7c the methyl ester group was hydrolysed under these
conditions and only the corresponding acid was isolated.
(Scheme 2, Table 1).
Compound 7
RNH2 (5)
Yield (%)
74
Mp (ꢀC)
a
210.5e212.5
b
c
35
94
Oil
Oil
d
e
f
82
74
75
78
206.9e208.5
153.4e154.6
217.1e219.2
164.5e166.1
The same reaction sequence was used for the transformation of
bis enaminone 9 into bis imidazolone derivative 10 (Scheme 3).
g
h
92
164.7e165.3
Scheme 2. Reagents and conditions: (i) diethyl azodicarboxylate (3), EtOH, rt,
(ii) primary amine 5, EtOH, rt, (iii) NaOH, EtOH, rt.
(continued on next page)

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J. Bezensek et al. / Tetrahedron 68 (2012) 516e522
518
Table 1 (continued )
Compound 7
amino)-3-oxo-3-phenylprop-1-en-2-yl)hydrazine-1,2-dicarboxyla
tes (6aen) in good to excellent yields.
RNH2 (5)
Yield (%)
85
Mp (ꢀC)
5. Experimental
5.1. General
i
j
181.2e182.1
Melting points were determined on an Optimelt MPA100. 1H
NMR spectra were obtained on a Bruker Avance DPX 300 at
300 MHz for 1H, and 75.5 MHz for 13C and a Bruker Avance III
500 MHz at 500 MHz for 1H and 126 MHz for 13C, using DMSO-d6
and CDCl3 as solvents and TMS as the internal standard. Mass
spectra were recorded on an AutoSpecQ and QTof-premier spec-
trometers, IR spectra on a PerkineElmer Spectrum BX FTIR spec-
trophotometer. Microanalyses were performed on a PerkineElmer
CHN Analyser 2400. Column chromatography was performed
on silica gel (Fluka, Silica gel 60, 0.04e0.06 mm). (E)-3-(Dimethy-
lamino)-1-phenylprop-2-en-1-one (2) and (2E,20E)-1,10-(1,3-
phenylene)bis(3-(dimethylamino)prop-2-en-1-one) (9) were pre-
pared according to procedures described in the literature.24
68
185.3e187.6
k
l
92
68
167.6e169.7
162.4e167.6
m
n
49
69
118.9e119.7
194.7e197.0
5.2. Diethyl 1-(1-(dimethylamino)-3-oxo-3-phenylprop-1-en-
2-yl)hydrazine-1,2-dicarboxylate (4)
To a solution of (E)-3-(dimethylamino)-1-phenylprop-2-en-1-
one (2) (175 mg, 1 mmol) in MeCN (2 mL) was added a solution of
Scheme 3. Reagents and conditions: (i) diethyl azodicarboxylate (3), EtOH, rt, (ii) aniline hydrochloride (5e), EtOH, rt, (iii) NaOH, EtOH, rt.
Scheme 4.
characteristics one can not differentiate between imidazolone de-
rivatives 7 and 1,2,4-triazine derivatives 8, therefore the X-ray
structural analysis of good monocrystals of 7i shows that in this
reaction imidazolone derivatives 7 were formed (Fig. 2).
DEAD (3) in toluene (512
m
L, w¼39%, 1.1 mmol). The reaction
mixture was stirred for 24 h at room temperature. Volatile
components were evaporated in vacuo and product was purified
by column chromatography (ethyl acetate/petroleum ether¼1:2)
to afford 1:1 as inseparable mixture of E/Z isomers. Yield: 331 mg
4. Conclusion
(95%) of white oil. 1H NMR (CDCl3, 300 MHz):
d 1.25e1.30 (12H,
m, 4ꢁ CH3); 3.04 (6H, br s, 2ꢁ NCH3); 3.46 (6H, br s, 2ꢁ NCH3);
4.15e4.27 (8H, m, 4ꢁ CH2); 6.93 (1H, s, CH); 6.97 (1H, s, CH);
7.35e7.43 (6H, m, 2ꢁ Ph); 7.45e7.50 (4H, m, 2ꢁ Ph); 7.61 (1H, br
A simple synthesis of ethyl (5-benzoyl-2-oxo-3-substituted-2,3-
dihydro-1H-imidazol-1-yl)carbamate (7aen) was developed from
(E)-3-(dimethylamino)-1-phenylprop-2-en-1-one (2) in a three
step one-pot synthesis via (E) and (Z) diethyl (1-(1-(substituted)
s, NH); 7.73 (1H, br s, NH). 13C NMR (CDCl3, 75.5 MHz):
d 14.6,
38.1, 48.1, 61.6, 63.2, 114.7, 128.3, 128.5, 130.2, 140.1, 151.9, 152.4,

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J. Bezensek et al. / Tetrahedron 68 (2012) 516e522
519
Fig. 2. Ethyl (5-benzoyl-3-(3-nitrophenyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)carbamate (7i).
156.2, 158.3, 191.8. EI-HRMS: m/z¼350.1699 (MHþ); C17H24N3O5
requires: m/z¼350.1716 (MHþ); nmax (NaCl) 2950, 1721, 1693,
1605, 1495, 1433, 1398, 1244, 1217, 1087, 1042, 979, 785,
nmax (KBr) 3308, 3114, 3008, 1763, 1745, 1723, 1637, 1575, 1534,
1435, 1398, 1348, 1241, 1211, 1139, 1097, 1055, 960, 870, 809, 741,
717 cmꢂ1
.
763 cmꢂ1
.
5.5. General procedure for the synthesis of ethyl (5-benzoyl-
2-oxo-3-substituted-2,3-dihydro-1H-imidazol-1-yl)
carbamates (7aen)
5.3. Diethyl 1-(1-((3-nitrophenyl)amino)-3-oxo-3-
phenylprop-1-en-2-yl)hydrazine-1,2-dicarboxylate (6i)
To
a
solution of diethyl 1-(1-(dimethylamino)-3-oxo-3-
To a solution of (E)-3-(dimethylamino)-1-phenylprop-2-en-1-
one (2) (175 mg, 1 mmol) in EtOH (2 mL) was added a solution of
phenylprop-1-en-2-yl)hydrazine-1,2-dicarboxylate (4) (280 mg,
0.75 mmol) in AcOH (2 mL) was added m-nitroaniline (5i) (104 mg,
0.75 mmol). The reaction mixture was refluxed for 3 h. Volatile
components were evaporated in vacuo and the product was purified
by column chromatography (ethyl acetate/petroleum ether¼1:2) to
afford a 7:3 inseparable mixture of E/Z isomers. Yield: 411 mg (93%)
of white solid. Mp 127.3e155.5 ꢀC 1H NMR (CDCl3, 300 MHz):
DEAD (3) in toluene (512
mL, w¼39%, 1.1 mmol). The reaction
mixture was stirred for 4 h at room temperature. Then, amine
(5aen) (1 mmol) with 4 drops of concd HClaq or amine hydro-
chloride (1 mmol) was added and the reaction mixture was stirred
for t1. NaOH (100 mg, 2.5 mmol) was then added and the reaction
mixture was stirred for t2. Volatile components were evaporated in
vacuo and products were purified by column chromatography and
crystallised from appropriate solvents.
d
1.18e1.30 (6H, m, 2ꢁ CH3); 4.17e4.30 (4H, m, 2ꢁ CH2); 7.29 (1H, br
s, CH); 7.43e7.59 (4H, m, Ph); 7.63e7.69 (3H, m, PhþNH); 7.75e7.78
(1H, m, Ph); 7.81e7.88 (2H, m, Ph); 9.87 (0.3H, d, J¼11.9 Hz, NH);
10.02 (0.7H, d, J¼12.7 Hz, NH). 13C NMR (CDCl3, 75.5 MHz):
d 14.5,
5.5.1. Ethyl (5-benzoyl-2-oxo-3-propyl-2,3-dihydro-1H-imidazol-1-
63.1, 63.6, 110.2, 117.8, 120.1, 122.1, 128.5, 128.7, 130.7, 131.6, 138.6,
141.3, 142.4, 156.6, 159.6, 190.9. (C21H22N4O7 requires: C, 57.01; H,
5.01; N, 12.66. found C, 57.26; H, 4.74; N, 12.72); EI-HRMS: m/
z¼443.1550 (MHþ); C21H23N4O7 requires: m/z¼443.1567 (MHþ);
nmax (NaCl) 1734, 1707, 1655, 1602, 1572, 1536, 1483, 1373, 1354,
yl)carbamate (7a). Prepared from propylamine (5a) (82.4
mL,
1.0 mmol), t1¼240 h, t2¼72 h, chromatography (chloroform/
methanol¼30:1). Crystallised from ethyl acetate/petroleum ether;
yield: 236 mg (74%) of white solid. Mp 210.5e212.5 ꢀC 1H NMR
(CDCl3, 300 MHz):
d
0.96 (3H, t, J¼7.2 Hz, CH3); 1.28 (3H, t, J¼6.9 Hz,
1320, 1264, 1179, 1092, 1055, 938, 871, 797, 736 cmꢂ1
.
CH3); 1.75 (2H, sep, J¼7.2 Hz, CH2); 3.69 (2H, t, J¼7.2 Hz, CH2); 4.22
(2H, q, J¼6.9 Hz, CH2); 6.83 (1H, s, CH); 7.32 (1H, br s, NH);
7.45e7.51 (2H, m, Ph); 7.57e7.62 (1H, m, Ph); 7.76e7.79 (2H, m, Ph).
5.4. Ethyl (5-benzoyl-3-(3-nitrophenyl)-2-oxo-2,3-dihydro-
1H-imidazol-1-yl)carbamate (7i)
13C NMR (CDCl3, 75.5 MHz):
d 11.1, 14.5, 22.7, 46.4, 62.8, 121.5, 123.6,
128.38, 128.9, 132.8, 137.5, 152.2, 155.6, 183.1. (C16H19N3O4 requires:
C, 60.56; H, 6.03; N, 13.24. found C, 60.33; H, 6.08; N, 13.24); EI-
HRMS: m/z¼318.1455 (MHþ); C16H20N3O4 requires: m/z¼318.1454
(MHþ); nmax (KBr) 3097, 3000, 2963, 1751, 1695, 1636, 1584, 1511,
1447, 1368, 1332, 1251, 1174, 1133, 1099, 1054, 992, 895, 837, 784,
To a solution of diethyl 1-(1-((3-nitrophenyl)amino)-3-oxo-3-
phenylprop-1-en-2-yl)hydrazine-1,2-dicarboxylate (6i) (310 mg,
0.70 mmol) in EtOH (10 mL) was added NaOH (28 mg, 0.70 mmol).
The reaction mixture was refluxed for 2.5 h. Volatile components
were evaporated in vacuo and product was purified by column
chromatography (ethyl acetate/petroleum ether¼1:1). Yield:
273 mg (95%) of white solid. Mp 181.2e182.1 ꢀC 1H NMR (CDCl3,
750, 721 cmꢂ1
.
5.5.2. Ethyl (5-benzoyl-2-oxo-3-(prop-2-yn-1-yl)-2,3-dihydro-1H-
imidazol-1-yl)carbamate (7b). Prepared from propargylamine hy-
drochloride (5b) (92.0 mg, 1.0 mmol), t1¼168 h, t2¼144 h, chro-
matography (ethyl acetate/petroleum ether¼1:2). yield: 111 mg
300 MHz):
d
1.24 (3H, t, J¼7.2 Hz, CH3); 4.18 (2H, t, J¼7.2 Hz, CH2);
7.34 (1H, s, CH); 7.45e7.50 (2H, m, Ph); 7.56e7.64 (2H, m, Ph);
7.84e7.87 (2H, m, Ph); 8.03e8.10 (2H, m, Ph); 8.26 (1H, br s, NH);
8.42 (1H, t, J¼2.1 Hz, Ph). 13C NMR (CDCl3, 75.5 MHz):
d
14.2, 62.7,
(35%) of colourless oil. 1H NMR (CDCl3, 300 MHz):
d 1.28 (3H, t,
116.7, 119.8, 121.6, 122.7, 127.7, 128.7, 128.9, 130.4, 133.1, 136.6,
136.7, 148.5, 150.6, 155.5, 183.0. (C19H16N4O6 requires: C, 57.58; H,
4.07; N, 14.14. found C, 57.62; H, 4.03; N, 14.08); EI-HRMS: m/
z¼397.1142 (MHþ); C19H17N3O4 requires: m/z¼397.1148 (MHþ);
J¼7.2 Hz, CH3); 4.22 (2H, q, J¼7.2 Hz, CH2); 5.59 (2H, d, J¼6.6 Hz,
CH2); 6.88 (1H, s, CH); 7.08 (1H, t, J¼6.6 Hz, CH); 7.33(1H, br s, NH);
7.47e7.52 (2H, m, Ph); 7.59e7.64 (1H, m, Ph); 7.78e7.82 (2H, m, Ph).
13C NMR (CDCl3, 75.5 MHz):
d 14.3, 62.9, 89.9, 94.5, 118.9, 122.4,

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J. Bezensek et al. / Tetrahedron 68 (2012) 516e522
520
128.8, 128.9, 133.0, 137.0, 150.1, 155.4, 183.1, 201.2. EI-HRMS: m/
z¼314.1149 (MHþ); C16H16N3O4 requires: m/z¼314.1154 (MHþ);
nmax (KBr), 2974, 1719, 1636, 1577, 1508, 1448, 1366, 1326, 1245,
z¼366.1454 (MHþ); nmax (KBr) 3015, 1752, 1726, 1625, 1894, 1573,
1525, 1497, 1448, 1431, 1401, 1323, 1240, 1211, 1132, 1056, 1000, 956,
889, 859, 795, 721 cmꢂ1
.
1239, 1176, 1580, 856, 713 cmꢂ1
.
5.5.7. Ethyl (5-benzoyl-2-oxo-3-(p-tolyl)-2,3-dihydro-1H-imidazol-
1-yl)carbamate (7g). Prepared from p-toluidine hydrochloride (5g)
(143.0 mg, 1.0 mmol), t1¼24 h, t2¼24 h, chromatography (ethyl
acetate/petroleum ether¼1:2). Crystallised from ethyl acetate/pe-
troleum ether; yield: 271 mg (78%) of white solid. Mp
5.5.3. (S)-2-(4-Benzoyl-3-((ethoxycarbonyl)amino)-2-oxo-2,3-
dihydro-1H-imidazol-1-yl)propanoic acid (7c). Prepared from -al-
anine methyl ester hydrochloride (5c) (139.0 mg, 1.0 mmol),
L
t1¼168 h, t2¼144 h, extraction ethyl acetate/1 M HCl. Yield: 326 mg
21
(94%) of colourless oil; ½
a
ꢃ
5.2 (c 0.58, MeOH). 1H NMR (CDCl3,
164.5e166.1 ꢀC 1H NMR (CDCl3, 300 MHz):
d
1.25 (3H, t, J¼7.2 Hz,
589
300 MHz):
d
1.27 (3H, t, J¼7.2 Hz, CH3); 1.64 (3H, d, J¼7.5 Hz, CH3);
CH3); 2.35 (3H, s, CH3); 4.20 (2H, t, J¼7.2 Hz, CH2); 7.10 (1H, s, CH);
7.19e7.22 (2H, m, Ph); 7.41e7.49 (4H, m, Ph); 7.55e7.61 (1H, m, Ph);
7.81e7.84 (2H, m, Ph); 7.88 (1H, br s, NH). 13C NMR (CDCl3,
4.21 (2H, q, J¼7.2 Hz, CH2); 5.06 (1H, q, J¼7.5 Hz, CH); 5.51 (1H, br s,
COOH); 7.03 (1H, br s, NH); 7.45e7.50 (2H, m, Ph); 7.56e7.62 (2H, m,
PhþCH); 7.77e7.81 (2H, m, Ph). 13C NMR (CDCl3, 75.5 MHz):
d
14.4,
75.5 MHz): d 14.5, 21.2, 62.9, 122.1, 122.2, 122.7, 128.0, 129.0, 130.2,
16.9, 51.7, 63.0, 121.7, 128.8, 129.0, 132.9, 137.1, 152.2, 156.0, 172.2,
183.3. (C16H17N3O6ꢁ0.5H2O requires: C, 53.93; H, 5.09; N, 11.79.
found C, 53.92; H, 5.11; N,11.44); EI-HRMS: m/z¼346.1045 (MꢂHþ);
C16H16N3O6 requires: m/z¼346.1039 (MHþ); nmax (KBr) 2996, 1723,
1635, 1576, 1520, 1493, 1447, 1405, 1374, 1327, 1238, 1176, 1095,
133.0, 133.3, 137.3, 137.8, 151.1, 155.7, 183.3. (C20H19N3O4 requires: C,
65.74; H, 5.24; N, 11.50. found C, 65.72; H, 4.98; N, 11.52); EI-HRMS:
m/z¼366.1459 (MHþ); C20H20N3O4 requires: m/z¼366.1454 (MHþ);
nmax (KBr) 3021, 1746, 1709, 1637, 1575, 1519, 1478, 1433, 1399, 1328,
1253, 1218, 1052, 938, 895, 815, 779, 754 cmꢂ1
.
1060, 1021, 959, 894, 852, 831, 753, 715 cmꢂ1
.
5.5.8. Ethyl (5-benzoyl-3-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-
imidazol-1-yl)carbamate (7h). Prepared from p-metoxyaniline (5h)
(123.2 mg, 1.0 mmol), 4 drops of concd HCl, t1¼12 h, t2¼24 h, chro-
matography (ethyl acetate/petroleum ether¼1:2). Crystallised from
ethyl acetate/petroleum ether; yield: 350 mg (92%) of white solid.
5.5.4. Ethyl (5-benzoyl-3-benzyl-2-oxo-2,3-dihydro-1H-imidazol-1-
yl)carbamate (7d). Prepared from benzylamine hydrochloride
(5d) (143.6 mg, 1.0 mmol), t1¼48 h, t2¼24 h, chromatography (ethyl
acetate/petroleum ether¼1:2). Crystallised from ethyl acetate/pe-
troleum ether; yield: 298 mg (82%) of white solid. Mp
Mp 164.7e165.3 ꢀC 1H NMR (CDCl3, 300 MHz):
d
1.24 (3H, t, J¼7.2 Hz,
206.9e208.5 ꢀC 1H NMR (DMSO-d6, 300 MHz):
d
1.22 (3H, t,
CH3); 3.79 (3H, s, OCH3); 4.19 (2H, t, J¼7.2 Hz, CH2); 6.90e6.94 (2H,
m, Ph); 7.07 (1H, s, CH); 7.40e7.48 (4H, m, Ph); 7.54e7.60 (1H, m, Ph);
7.80e7.83 (2H, m, Ph); 8.00 (1H, br s, NH). 13C NMR (CDCl3,
J¼7.2 Hz, CH3); 4.11 (2H, t, J¼7.2 Hz, CH2); 4.89 (2H, s, CH2);
7.27e7.39 (5H, m, Ph); 7.51e7.55 (2H, m, Ph); 7.61e7.72 (4H, m,
PhþCH); 10.11 (1H, br s, NH). 13C NMR (DMSO-d6, 75.5 MHz):
d
14.4,
75.5 MHz): d 14.7, 55.6, 62.7, 114.6, 121.8, 122.3, 124.4, 128.6, 128.7,
47.1, 61.2, 120.2, 125.1, 127.5, 127.7, 128.4, 128.5, 128.6, 132.3, 136.6,
137.4, 151.5, 155.5, 181.6. (C20H19N3O4 requires: C, 65.74; H, 5.24; N,
11.50. found C, 65.84; H, 5.13; N, 11.47); EI-HRMS: m/z¼366.1561
(MHþ); C20H20N3O4 requires: m/z¼366.1454 (MHþ); nmax (KBr)
3253, 3094, 2983, 1744, 1700, 1637, 1584, 1505, 1439, 1346, 1256,
128.9, 132.8,137.2, 151.1,155.7, 158.9, 183.0. (C20H19N3O5 requires: C,
62.99; H, 5.02; N, 11.02. found C, 62.72; H, 4.99; N, 11.09); EI-HRMS:
m/z¼382.1419 (MHþ); C20H20N3O5 requires: m/z¼382.1403 (MHþ);
nmax (KBr) 1745, 1709, 1634, 1575, 1517, 1433, 1401, 1330, 1256, 1180,
1055, 940, 895, 831, 778, 738, 704 cmꢂ1
.
1167, 1053, 990, 896, 841, 748, 716 cmꢂ1
.
5.5.9. Ethyl
(5-benzoyl-3-(3-nitrophenyl)-2-oxo-2,3-dihydro-1H-
5.5.5. Ethyl (5-benzoyl-2-oxo-3-phenyl-2,3-dihydro-1H-imidazol-1-
yl)carbamate (7e). Prepared from aniline hydrochloride (5e)
(129.0 mg, 1.0 mmol), t1¼48 h, t2¼24 h, chromatography (ethyl
acetate/petroleum ether¼1:2). Crystallised from ethyl acetate/pe-
troleum ether; yield: 260 mg (74%) of white solid. Mp
imidazol-1-yl)carbamate (7i). Prepared from m-nitroaniline (5i)
(138.0 mg, 1.0 mmol), 4 drops of concd HCl, t1¼24 h, t2¼24 h,
chromatography (ethyl acetate/petroleum ether¼1:1). Crystallised
from ethyl acetate/petroleum ether; yield: 337 mg (85%) of white
solid.
153.4e154.6 ꢀC 1H NMR (CDCl3, 300 MHz):
d
1.28 (3H, t, J¼7.2 Hz,
CH3); 4.23 (2H, t, J¼7.2 Hz, CH2); 7.13 (1H, s, CH); 7.31e7.36 (1H, m,
Ph); 7.42e7.51 (4H, m, Ph); 7.55e7.63 (4H, m, PhþNH); 7.82e7.85
5.5.10. Ethyl
(5-benzoyl-3-(4-nitrophenyl)-2-oxo-2,3-dihydro-1H-
imidazol-1-yl)carbamate (7j). Prepared from p-nitroaniline (5j)
(138.0 mg, 1.0 mmol), 4 drops of concd HCl, t1¼24 h, t2¼48 h,
chromatography (ethyl acetate/petroleum ether¼1:2). Crystallised
from ethyl acetate/petroleum ether; yield: 268 mg (68%) of yellow
(2H, m, Ph). 13C NMR (CDCl3, 75.5 MHz):
d 14.4, 63.0, 121.8, 122.3,
122.7, 127.7, 128.9, 129.0, 129.7, 133.1, 135.9, 137.3, 151.0, 155.6, 183.3.
(C19H17N3O4 requires: C, 64.95; H, 4.88; N, 11.96. found C, 64.90; H,
4.76; N, 11.99); EI-HRMS: m/z¼352.1290 (MHþ); C19H18N3O4 re-
quires: m/z¼352.1297 (MHþ); nmax (KBr) 3220, 2987, 1745, 1705,
1639, 1576, 1525, 1505, 1435, 1396, 1326, 1254, 1240, 1053, 895, 822,
solid. Mp 185.3e187.6 ꢀC 1H NMR (CDCl3, 300 MHz):
d 1.24 (3H, t,
J¼7.2 Hz, CH3); 4.19 (2H, t, J¼7.2 Hz, CH2); 7.26 (1H, s, CH);
7.48e7.53 (2H, m, Ph); 7.61e7.66 (1H, m, Ph); 7.84e7.87 (4H, m, Ph);
7.97 (1H, br s, NH); 8.25e8.28 (2H, m, Ph). 13C NMR (CDCl3,
757, 707 cmꢂ1
.
75.5 MHz): d 14.7, 63.4, 119.6, 122.2, 123.6, 125.5, 129.3, 129.4, 133.8,
5.5.6. Ethyl (5-benzoyl-2-oxo-3-(m-tolyl)-2,3-dihydro-1H-imidazol-
1-yl)carbamate (7f). Prepared from m-toluidine (5f) (108.2 L,
137.1, 141.3, 146.2, 150.9, 155.8, 183.6. (C19H16N4O6 requires: C,
57.58; H, 4.07; N, 14.14. found C, 57.87; H, 3.91; N, 13.98); EI-HRMS:
m/z¼397.1133 (MHþ); C19H17N3O4 requires: m/z¼397.1148 (MHþ);
nmax (KBr) 1748, 1712, 1677, 1584, 1527, 1504, 1431, 1394, 1384, 1327,
m
1.0 mmol), 4 drops of concd HCl, t1¼48 h, t2¼24 h, chromatography
(ethyl acetate/petroleum ether¼1:2). Crystallised from ethyl ace-
tate/petroleum ether; yield: 261 mg (72%) of white solid. Mp
1241, 1217, 1177, 1112, 1052, 939, 895, 856, 811, 750 cmꢂ1
.
217.1e219.2 ꢀC 1H NMR (CDCl3, 300 MHz):
CH3); 2.39 (3H, s, CH3); 4.25 (2H, t, J¼7.2 Hz, CH2); 7.11 (1H, s, CH);
7.14e7.17 (1H, m, Ph); 7.32e7.39 (4H, m, 3PhþNH); 7.47e7.52 (2H,
m, Ph); 7.59e7.64 (1H, m, Ph); 7.83e7.85 (2H, m, Ph). 13C NMR
d
1.30 (3H, t, J¼7.2 Hz,
5.5.11. Ethyl (5-benzoyl-3-(4-bromophenyl)-2-oxo-2,3-dihydro-1H-
imidazol-1-yl)carbamate (7k). Prepared from p-bromoaniline (5k)
(172.0 mg, 1.0 mmol), 4 drops of concd HCl, t1¼48 h, t2¼72 h,
chromatography (ethyl acetate/petroleum ether¼1:2). Crystallised
from ethyl acetate; yield: 395 mg (92%) of white solid. Mp
(CDCl3, 75.5 MHz): d 14.5, 21.6, 63.0, 119.9, 122.2, 123.5, 128.7, 128.9,
129.1, 129.5, 133.1, 135.8, 137.3, 139.9, 155.6, 183.4. (C20H19N3O4 re-
quires: C, 65.74; H, 5.24; N, 11.50. found C, 65.43; H, 5.15; N, 11.43);
EI-HRMS: m/z¼366.1448 (MHþ); C20H20N3O4 requires: m/
167.6e169.7 ꢀC 1H NMR (CDCl3, 300 MHz):
CH3); 4.24 (2H, t, J¼7.2 Hz, CH2); 7.09 (1H, s, CH); 7.09 (1H, br s, NH);
d
1.30 (3H, t, J¼7.2 Hz,

ꢀ
J. Bezensek et al. / Tetrahedron 68 (2012) 516e522
521
7.45e7.53 (4H, m, Ph); 7.56e7.66 (3H, m, Ph); 7.82e7.86 (2H, m, Ph).
13C NMR (CDCl3, 75.5 MHz):
14.5, 63.0, 120.9, 121.1, 122.5, 124.0,
hydrochloride (5e) (258.2 mg, 2.0 mmol), t1¼48 h, t2¼48 h, chro-
matography (ethyl acetate/petroleum ether¼1:2). Crystallised from
ethyl acetate/petroleum ether; yield: 244 mg (39%) of white solid.
d
128.9, 129.0, 132.7, 133.2, 134.9, 137.1, 150.8, 155.6, 183.2.
(C19H16N3O4Br requires: C, 53.04; H, 3.75; N, 9.77. found C, 53.09; H,
3.51; N, 9.71); EI-HRMS: m/z¼430.0403 (MHþ); C19H17N3O4Br re-
quires: m/z¼430.0402 (MHþ); nmax (KBr) 3017, 1744, 1707, 1638,
1589, 1572, 1523, 1496, 1435, 1395, 1327, 1252, 1214, 1052, 1011, 895,
Mp 142.6e149.6 ꢀC 1H NMR (CDCl3, 300 MHz):
d 1.21 (6H, t,
J¼6.9 Hz, 2ꢁ CH3); 4.15 (4H, q, J¼4.15 Hz, 2ꢁ CH2); 7.23 (2H, s, CH);
7.25e7.28 (2H, m, Ph); 7.31e7.37 (4H, m, Ph); 7.49e7.51 (4H, m, Ph);
7.58 (1H, t, J¼7.7 Hz, Ph); 8.01 (2H, d, J¼7.7 Hz, Ph); 8.25 (3H, br s,
827, 758, 711 cmꢂ1
.
2ꢁ NHþPh). 13C NMR (CDCl3, 75.5 MHz):
d 14.3, 62.6, 121.7, 122.2,
122.4, 127.5, 128.9, 129.2, 129.4, 132.6, 135.4, 137.6, 150.7, 155.6,
181.8. (C32H28N6O8ꢁ0.5H2O requires: C, 60.66; H, 4.61; N, 13.26.
found C, 60.51; H, 4.50; N, 13.20); EI-HRMS: m/z¼625.2067 (MHþ);
C32H29N6O8 requires: m/z¼625.2047 (MHþ); nmax (KBr) 3240, 2982,
2925, 1719, 1637, 1596, 1577, 1499, 1438, 1400, 1329, 1252, 1216,
5.5.12. Diethyl (3,30-(1,2-phenylene)bis(5-benzoyl-2-oxo-2,3-
dihydro-1H-imidazole-3,1-diyl))dicarbamate (7l). Prepared from o-
diaminobenzene (5l) (54 mg, 0.5 mmol), 4 drops of concd HCl,
t1¼240 h, t2¼24 h, chromatography (ethyl acetate/petroleum
ether¼2:1). Crystallised from ethyl acetate/petroleum ether; yield:
214 mg (68%) of brownish solid. Mp 162.4e167.6 ꢀC 1H NMR (CDCl3,
1095, 1053, 966, 910, 829, 799, 763 cmꢂ1
.
300 MHz):
d
1.21 (6H, br s, 2ꢁ CH3); 4.16 (4H, br s, 2ꢁ CH2); 7.09
5.7. X-ray structure analysis for compound 7i
(2H, s, CH); 7.44e7.49 (6H, m, Ph); 7.53e7.58 (4H, m, Ph); 7.82 (2H,
br s, 2ꢁ NH); 7.89e7.91 (4H, m, Ph). 13C NMR (CDCl3, 75.5 MHz):
Single crystal X-ray diffraction data were collected at room
temperature on a Nonius Kappa CCD diffractometer (Mo Ka radia-
tion was used) using the Nonius Collect Software.25 DENZO and
SCALEPACK26 were used for indexing and scaling of the data. The
structures were solved by using SIR97.27 Refinement was per-
formed using the Xtal3.428 program package and crystallographic
plots were prepared with ORTEP III.29 Structures were refined on F
values using the full-matrix least squares procedure. The non-
hydrogen atoms were refined anisotropically in both cases, while
the positions of hydrogen atoms were geometrically calculated;
their positional and isotropic atomic displacement parameters
were not refined. Absorption correction was not necessary. Regina
weighting scheme was used in both cases.
d
14.3, 62.8, 122.2, 124.6, 128.5, 128.8, 129.3, 130.8, 132.8, 133.2,
137.3, 150.7, 156.2, 183.5. (C32H28N6O8 requires: C, 61.53; H, 4.52; N,
13.46. found C, 61.14; H, 4.42; N, 13.30); EI-HRMS: m/z¼625.2041
(MHþ); C32H29N6O8 requires: m/z¼625.2047 (MHþ); nmax (KBr)
3012, 1749, 1736, 1638, 1585, 1508, 1488, 1436, 1406, 1333, 1253,
1236, 1212, 1176, 1134, 1060, 935, 897, 824, 775, 715 cmꢂ1
.
5.5.13. Ethyl (5-benzoyl-2-oxo-3-(pyridin-2-yl)-2,3-dihydro-1H-imi-
dazol-1-yl)carbamate (7m). Prepared from o-aminopyridine (5m)
(94.1 mg, 1.0 mmol), 4 drops of concd HCl, t1¼24 h, t2¼24 h,
chromatography (ethyl acetate/petroleum ether¼1:2). Crystallised
from ethyl acetate/petroleum ether; yield: 174 mg (49%) of white
solid. Mp 118.9e119.7 ꢀC 1H NMR (CDCl3, 300 MHz):
d 1.24 (3H, t,
CCDC 834560 contains the supplementary crystallographic data
for structure reported in this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
J¼7.2 Hz, CH3); 4.21 (2H, t, J¼7.2 Hz, CH2); 7.19 (1H, ddd, J1¼0.9 Hz,
J2¼4.8 Hz, J3¼7.5 Hz, Py); 7.45e7.50 (2H, m, Ph); 7.56e7.62 (1H, m,
Ph); 7.79 (1H, ddd, J1¼1.8 Hz, J2¼7.5 Hz, J3¼8.4 Hz, Py); 7.85e7.88
(2H, m, Ph); 7.97 (1H, s, CH); 8.16 (1H, br s, NH); 8.36 (1H, ddd,
J1¼0.9 Hz, J2¼1.8 Hz, J3¼4.8 Hz, Py); 8.43 (1H, dt, J1¼0.9 Hz,
J2¼8.4 Hz, Py). 13C NMR (CDCl3, 75.5 MHz):
d 14.4, 62.7, 114.7, 118.9,
Acknowledgements
122.0, 122.2, 128.7, 129.0, 133.0, 137.0, 138.9, 148.0, 148.1, 150.6,
155.6, 183.6. (C18H16N4O4 requires: C, 61.36; H, 4.58; N, 15.90. found
C, 61.19; H, 4.42; N, 15.81); EI-HRMS: m/z¼353.1235 (MHþ);
C18H17N4O4 requires: m/z¼353.1250 (MHþ); nmax (KBr) 2977, 1734,
1646, 1636, 1577, 1506, 1472, 1441, 1395, 1327, 1248, 1209, 1175,
Financial support from the Slovenian Research Agency through
grants P0-0502-0103, P1-0179 and J1-6689-0103-04 are gratefully
acknowledged. We also thank the Krka d.d. (Novo mesto, Slovenia)
and Lek d.d., a Sandoz Company (Ljubljana, Slovenia) for financial
support.
1095, 1056, 944, 894, 781, 713 cmꢂ1
.
5.5.14. Ethyl
(5-benzoyl-2-oxo-3-(pyrazin-2-yl)-2,3-dihydro-1H-
References and notes
imidazol-1-yl)carbamate (7n). Prepared from o-aminopyrazine
(5n) (95.1 mg, 1.0 mmol), 4 drops of concd HCl, t1¼24 h, t2¼24 h,
chromatography (ethyl acetate/petroleum ether¼1:1). Crystallised
from ethyl acetate/petroleum ether; yield: 245 mg (69%) of white
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J¼7.2 Hz, CH3); 4.23 (2H, t, J¼7.2 Hz, CH2); 7.49e7.54 (2H, m, Ph);
7.61e7.66 (1H, m, Ph); 7.87e7.90 (4H, m, 2PhþCHþNH); 8.36 (1H,
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