A simple and efficient synthesis of 2-imidazolin-2-ones

Article abstract of DOI:10.1039/b502719e

We report on the reactions of diazenes 1 and 2 with 1,3-dicarbonyl compounds. The first step involves a regioselective attack of the diazene on the active methylene group, giving the Michael adducts 3 or 4, and can be performed either in the presence of sodium acetate or DBN (1,5-diazabicyclo[4.3. 0]non-5-ene). The Michael adducts underwent ring-closure leading to 2-imidazolidinones 5 or 6 which were isolated in some cases. We found that 5 or 6 easily eliminated water in the presence of an acid to give imidazolin-2-ones 7 or 8 as the final products. The rate-determining step of this last mentioned process depends on the stereochemistry at C4 and C5 of the initial 2-imidazolidinone. A one-pot procedure to produce 7 or 8 directly from the diazene and the appropriate dicarbonyl partner is also described. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2005.

Full text of DOI:10.1039/b502719e

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P A P E R
A simple and efficient synthesis of 2-imidazolin-2-ones
ꢀ
Sergeja Bombek, Franc Pozgan, Marijan Kocevar and Slovenko Polanc*
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Asˇkercˇeva 5, SI-1000
Ljubljana, Slovenia. E-mail: slovenko.polanc@fkkt.uni-lj.si; Fax: þ386-1-24-19-271;
Tel: þ386-1-24-19-236
Received (in Montpellier, France) 22nd February 2005, Accepted 26th April 2005
First published as an Advance Article on the web 9th June 2005
We report on the reactions of diazenes 1 and 2 with 1,3-dicarbonyl compounds. The first step involves a
regioselective attack of the diazene on the active methylene group, giving the Michael adducts 3 or 4, and
can be performed either in the presence of sodium acetate or DBN (1,5-diazabicyclo[4.3.0]non-5-ene). The
Michael adducts underwent ring-closure leading to 2-imidazolidinones 5 or 6 which were isolated in some
cases. We found that 5 or 6 easily eliminated water in the presence of an acid to give imidazolin-2-ones 7 or
8 as the final products. The rate-determining step of this last mentioned process depends on the
stereochemistry at C4 and C5 of the initial 2-imidazolidinone. A one-pot procedure to produce 7 or 8
directly from the diazene and the appropriate dicarbonyl partner is also described.
of diazene 1 with 1,3-dicarbonyls A–F gave the Michael
adducts 3a–3f (Scheme 2).
Introduction
The imidazole ring is of therapeutic interest as it is widely
recognized to be an important pharmacophore.1 Its activity is
often connected to its hydrogen bond donor–acceptor capabil-
ity2 or with high affinity for the metals that are present in many
protein-active sites.3 These characteristics make imidazole
derivatives attractive targets in organic synthesis. Imidazolin-
2-ones represent an important part of the imidazole family that
possess functional motifs found in biologically active mole-
cules.
As a part of our continuing interest in hydrazides4 and other
NꢀN-containing compounds,5 we recently described the
ZrCl4-mediated treatment of substituted aminocarbonyldiaze-
necarboxylates with 1,3-diketones or b-ketoesters leading to
highly functionalized imidazolin-2-ones.6 In some cases we
noticed the formation of the corresponding Michael adducts
as the initial products that were further transformed to imida-
zolin-2-ones in the final step. The overall process takes place
under mild reaction conditions and is regioselective with
respect to both partners.
Similar products were isolated on reaction of diazene 2 with
selected 1,3-dicarbonyl partners which is demonstrated by the
preparation of the adducts 4a, 4e and 4f. The synthesis of any
adduct requires an application of the appropriate catalyst. The
best results were obtained using either sodium acetate or DBN
(1,5-diazabicyclo[4.3.0]non-5-ene) as a promoter (Table 1).
The above Michael adducts 3 and 4 were isolated and fully
characterized. Proton NMR spectra of most of the adducts
exhibit a singlet for the enolic OH group in the range 14.5–16.4
ppm from TMS which is in agreement with the proposed
structures.8 This is not the case for 3b and 3d, which exist in
solution in the diketo form. Although adducts are stable under
neutral conditions at room temperature, ring closure to the
corresponding 2-imidazolidinones 5 and 6 can occur in the
presence of either an acid or a base. In most cases, 2-imidazo-
lidinones 5 and 6 were not isolated, but they could be detected
in crude reaction mixtures. They easily eliminate water in the
presence of an acid to generate imidazolin-2-ones 7 and 8 in
excellent yields (Table 2).
In contrast, 2-imidazolidinones were isolated when N-phe-
nylacetoacetamide (F) was employed as a dicarbonyl partner.
The reaction of diazene 1 with F in the presence of DBN led to
a mixture of 5f0 and 5f00. Similarly, the mixture of isomers 6f0
and 6f00 was obtained by the treatment of the diazene 1 with the
same ketoamide. The products 5f0 and 6f0 were the predomi-
nant diastereoisomers, probably due to hydrogen bond forma-
tion between the enolic OH group and the neighbouring amido
moiety. Each of the above mixtures was easily transformed to
the corresponding imidazolin-2-one in methanolic solution in
the presence of the ion-exchange resin Dowexs 50WX2-100.
Therefore, imidazolin-2-one 7f was prepared from the mixture
of 5f0 and 5f00, and the product 8f was achieved from the
mixture of 6f0 and 6f00. A successful separation of both mixtures
resulted in 5f0, 5f00, 6f0 and 6f00, respectively, as diastereomeri-
cally pure isomers. The arrangement of the groups at C4 and
C5 of the 2-imidazolidinone ring was supported by NOESY
experiments, which showed a strong correlation between hy-
drogen at 4.15 ppm and OH at 6.60 ppm in the case of 5f00,
compared to a weak correlation between hydrogen at 3.95 ppm
and OH at 6.13 ppm in 5f0. Furthermore, a strong correlation
Results and discussion
Here we report on a detailed investigation of the above-
mentioned sequence and provide some additional evidence
for the reaction pathway. Two alkyl aminocarbonyldiazene-
carboxylates 1 and 2 were used in the present study. Both
diazenes are easily produced by adding methyl carbazate to the
appropriate isocyanate, followed by oxidation of the corres-
ponding 1,4-disubstituted semicarbazide using NBS in pyridine
(Scheme 1).
1,3-Diketones (A–C), b-ketoester (D) and b-ketoamides (E,
F) were employed as 1,3-dicarbonyl partners. Although the
reaction of a selected diazene with a 1,3-dicarbonyl compound
could give two Michael adducts, due to the presence of two
electrophilic nitrogens only one product was always observed,
i.e., the nitrogen atom adjacent to the amide functionality
seems to be more electrophilic than the nitrogen attached to
the ester group. The same regioselectivity was recently ob-
served in studies that involved an electrophilic amination of
aromatic substrates with similar diazenes.7 Thus, a treatment
T h i s j o u r n a l i s & T h e R o y a l S o c i e t y o f C h e m i s t r y a n d t h e
C e n t r e N a t i o n a l d e l a R e c h e r c h e S c i e n t i f i q u e 2 0 0 5
948
N e w J . C h e m . , 2 0 0 5 , 2 9 , 9 4 8 – 9 5 4

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The isolation of Michael adducts 3 and 4, as well as 2-
imidazolidinones 5 and 6 can be avoided, as demonstrated by a
one-pot synthesis of imidazolin-2-ones 7 or 8 from diazenes
and the appropriate 1,3-dicarbonyl partners. The desired pro-
ducts were isolated in good to excellent yields (Table 3).
Conclusion
We have developed a new, simple and mild route to produce
highly substituted imidazolin-2-ones. The initial steps which
involve a regioselective addition of alkyl aminocarbonyldiaze-
necarboxylates 1 or 2 to the various 1,3-dicarbonyl compounds
and further cyclization of Michael adducts into 2-imidazolidi-
nones 5 and 6 take place either under basic or under acidic
conditions. The dehydration of the 2-imidazolidinones to give
the final products was carried out in the presence of an acid.
The rate-determining step of the last process seems to depend
on the steric hindrance around the tertiary OH group at
position 4 in 2-imidazolidinones and on the formation of the
hydrogen bond between this OH and the amide group at the
vicinal position. It should be noted that an application of
b-keto amides E and F in the above studies is particularly
important from the point of view of the growing interest in
various biologically active imidazole carboxamides11 as our
method offers a new, mild and direct route to these com-
pounds. Furthermore, our method for the synthesis of
2-imidazolidinones may serve as a simple approach to various
new chiral auxiliaries12 and catalysts.13
Scheme 1
between hydrogen at 4.25 ppm and OH at 6.74 ppm in
2-imidazolidinone 6f00, and a weak correlation between hydro-
gen at 4.06 ppm and OH at 6.37 ppm in 6f0, are also in
agreement with the arrangement of the groups at C4 and C5.
The structure of 5f0 was also supported by X-ray analysis.9
The elimination of water, either from the mixture of 5f0 and
5f00 or from 6f0 and 6f00, was studied by 1H NMR spectroscopy.
Each mixture was dissolved in DMSO-d6 and treated with 10
equivalents of CF3CO2D at 29 1C. The isomer 5f00 disappeared
from the reaction mixture within 26 min, whereas 5f0 reacted
completely after 48 min to give 7f as the only product.
Similarly, the isomer 6f00 required 63 min, compared with 105
min for 6f0 to produce 8f. The above results indicate that the
elimination of water from 2-imidazolidinone to obtain the final
product depends on stereochemistry at C4 and C5. A plausible
reaction pathway is depicted in Scheme 3.
Experimental
It is well known that tertiary alcohols dehydrate in the
presence of an acid by the E1 mechanism.10 The first step,
i.e., the deuteration of the OH group, seems to be the rate-
determining step for the entire process. Here, the deuteration
of 5f00 (or 6f00) is obviously less hindered than that of 5f0 (or 6f0)
which can result, after a smooth elimination of HOD, in a
straightforward transformation of the corresponding carboca-
tion. The latter is stabilized by the contribution of an acylimi-
nium resonance structure due to the participation of the
lone-pair of the adjacent nitrogen as shown in Scheme 3.
Elimination of the proton from this carbocation leads to the
final imidazolin-2-one 7f (or 8f). The fact that the intramole-
cular hydrogen bond between the tertiary OH group and
the amido functionality is possible only in the case of 5f0
(or 6f0) is also in agreement with the faster elimination of
HOD from 5f00 (or 6f00).
General methods
Melting points were determined on a Kofler micro hot stage
and are uncorrected. IR spectra were measured as KBr pellets
with a Bio-Rad FTS 3000MX spectrometer. NMR spectra
were recorded on a Bruker Avance DPX 300 spectrometer at
300.13 for 1H NMR and 75.5 MHz for 13C NMR, using TMS
as the internal standard. Mass spectra were obtained on a VG-
Analytical AutospecQ instrument. Elemental analyses (C, H,
N) were performed on Perkin Elmer 2400 CHN Analyzer. TLC
was carried out on Fluka silica gel TLC plates (F254). Radial
chromatography was carried out with a Harrison Research
instrument, model 7924 T, employing Merck silica gel 60
PF254. Dicarbonyl compounds A–F were purchased from
commercial sources (Fluka, Merck, Aldrich) and used without
further purification. The diazene 2 was prepared as described
Scheme 2
N e w J . C h e m . , 2 0 0 5 , 2 9 , 9 4 8 – 9 5 4
949

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Table 1 The synthesis of Michael adducts
Table 2 Ion-exchange resin-promoted cyclization of Michael adducts
Reaction
time/h
Yieldb
(%)
Adducta
Reaction time/h
Product
Yieldb (%)
Reactantsa
Promoter (mol%)
Product
3a
3b
3c
3d
3e
3f
4a
4e
4f
a
18
13
17
4c
7a
7b
7c
7d
7e
7f
95
90
1 þ A
1 þ B
1 þ C
1 þ D
1 þ E
1 þ F
2 þ A
2 þ E
2 þ F
a
AcONa (10)
AcONa (10)
AcONa (20)
AcONa (20)
DBN (10)
23
22
2
10c
1
3a
3b
3c
3d
3e
3f
78
95
96
65d
99
93
89
92
91
99
100
99
2
20
22
4.5
15.5
100
100
100
100
AcONa (40)
AcONa (10)
DBN (10)
5
8a
8e
8f
4
4a
4e
4f
1
24
AcONa (10)
Reactions were carried out at r.t. in methanol in the presence of
b
Dowexs 50WX2-100 (Aldrich; cat. No. 21744-1). Isolated yields are
Reactions were carried out in CH2Cl2 at r.t.; THF was used as a
b
c
given. Under reflux.
solvent for 1 þ C, ethyl acetate for 2 þ E. Isolated yields are
c
d
given. Under reflux. After radial chromatography using petroleum
ether–ethyl acetate (5 : 1).
NBS (587 mg, 3.25 mmol) was slowly added at room
temperature to a stirred suspension of methyl cyclohexylami-
nocarbonylhydrazinecarboxylate (430 mg, 2 mmol) and pyr-
idine (325 mL, 4 mmol) in dichloromethane (10 mL). After 30
min, the reaction mixture was treated with HCl (1 : 1, 10 mL)
and two layers were separated. The dichloromethane solution
was washed first with aqueous solution of Na2S2O3 (5%, 10
mL), then with a saturated solution of NaHCO3 (10 mL), dried
over anhydrous Na2SO4 and evaporated to dryness to achieve
the diazene 1 (388 mg, 91% yield): mp 48–50 1C (petroleum
ether–toluene); IR (KBr): 3298, 2934, 2856, 1771, 1709, 1557,
earlier.5a. Petroleum ether corresponded to the fraction of
bp 60–80 1C.
Synthesis of methyl
cyclohexylaminocarbonyldiazenecarboxylate (1)
A solution of cyclohexyl isocyanate (629 mg, 5 mmol) in
dichloromethane (5 mL) was added dropwise to a stirred
solution of methyl hydrazinecarboxylate (450 mg, 5 mmol) in
dichloromethane (5 mL) at 0 1C. The reaction mixture was
stirred at 0 1C for 30 min and then at room temperature for an
additional 30 min. The solid material was filtered off and rinsed
with diethyl ether (5 mL) to give methyl cyclohexylaminocar-
bonylhydrazinecarboxylate (969 mg, 90% yield): mp 144–145 1C
(ethanol); IR (KBr): 3330, 3265, 2945, 1735, 1655, 1525, 1440,
1265, 1225, 1055 cmꢀ1; 1H NMR (DMSO-d6): d 1.18 (m, 5H),
1.62 (m, 5H), 3.33 (m, 1H), 3.57 (s, 3H), 6.06 (d, J ¼ 9 Hz, 1H),
7.53 (s, 1H), 8.71 (broad s, 1H); 13C NMR (acetone-d6): d 26.5,
27.0, 34.8, 50.2, 53.2, 159.1, 159.2; MS (FAB) m/z (%) 216 (M1
þ H, 45), 91 (100). Anal. for C9H17N3O3 (215.25): calc.: C
50.22, H 7.96, N 19.52; found: C 50.05, H 8.06, N 19.33%.
1
1523, 1437, 1260, 1229 cmꢀ1; H NMR (DMSO-d6): d 1.15–
1.33 (m, 5H), 1.56–1.86 (m, 5H), 3.56 (m, 1H), 4.02 (s, 3H),
9.03 (d, J ¼ 2.7 Hz, 1H); 13C NMR (CDCl3): d 24.4, 25.0, 32.2,
50.2, 55.1, 157.8, 161.9; MS (FAB) m/z (%) 214 (M1 þ H,
100), 90 (18), 83 (24), 55 (10). Anal. for C9H15N3O3 (213.23):
calc.: C 50.69, H 7.09, N 19.71; found: C 51.00; H 7.20, N
19.79%.
Preparation of Michael adducts
Typical procedure. Methyl cyclohexylaminocarbonyldiazene-
carboxylate (1, 213 mg, 1 mmol) was slowly added at room
Scheme 3
950
N e w J . C h e m . , 2 0 0 5 , 2 9 , 9 4 8 – 9 5 4

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Table 3 A one-pot synthesis of 2-imidazolin-2-ones from diazenes and 1,3-dicarbonyl compounds
Reactants
Promotera
Reaction time/h
Method
Product
Yieldb (%)
1 þ A
1 þ B
1 þ C
1 þ D
1 þ E
1 þ F
2 þ A
2 þ B
2 þ C
2 þ D
2 þ E
2 þ F
a
ZrCl4; Dowex
ZrCl4; Dowex
CF3COOHe
4;c 17d
4;c 13d
18
II
7a
7b
7c
7d
7e
7f
86
90
87
92
86
94
73
93
83
84
78
83
II
III
II
ZrCl4; Dowexf
CF3COOH
2;c 3d
120
III
IV
II
AcONa; Dowex
ZrCl4; Dowex
ZrCl4
7;c 20d
4;c 13d
10
8a
8b
8c
8d
8e
8f
I
CF3COOH
18
2;c 96d
10
2;c 48d
III
IV
IV
IV
AcONaf; Dowex
AcONa; Dowex
AcONa; Dowex
b
c
Reactions were carried out at r.t. unless stated otherwise. Isolated yields are given. Reaction time for treatment of the reaction mixture with the
d
e
f
first promoter. Reaction time required for the second promoter that was applied after the first one to give the final product. At 0 1C. Under
reflux.
1
temperature to a stirred suspension of dibenzoylmethane (B,
224 mg, 1 mmol) and sodium acetate (8.2 mg, 0.1 mmol) in
dichloromethane (6 mL). Stirring was continued for 22 h, the
reaction mixture was then evaporated to dryness, the residue
was washed with water (10 mL) and diethyl ether (10 mL) to
produce the adduct 3b (415 mg; 95% yield). Other details for
the synthesis of adducts 3 and 4 are given in Table 1.
1665, 1644, 1520, 1235, 1210, 1184 cmꢀ1; H NMR (DMSO-
d6): d 1.17 (t, J ¼ 7.1 Hz, 3H), 1.19 (m, 5H), 1.58 (m, 5H), 3.36
(m, 1H), 3.55 (s, 3H), 4.15 (q, J ¼ 7.1 Hz, 2H), 6.11 (broad s,
1H), 6.68 (d, J ¼ 8.1 Hz, 1H), 7.52 (m, 2H), 7.65 (m, 1H), 8.02
(m, 2H), 8.89 (broad s, 1H); 13C NMR (DMSO-d6): d 13.8,
24.8, 25.1, 32.5, 32.6, 49.5, 52.0, 61.2, 128.3, 128.5, 133.4, 135.5,
155.8, 156.1, 167.0, 190.5; MS (FAB) m/z (%) 406 (M1 þ H,
100), 281 (66), 105 (67), 55 (56). Anal. for C20H27N3O6
(405.45): calc.: C 59.25, H 6.71, N 10.36; found: C 59.15, H
6.49, N 10.44%.
Methyl 2-(1-acetyl-2-hydroxypropen-1-yl)-2-(cyclohexylamino-
carbonyl)hydrazinecarboxylate (3a). Mp 136.8–140 1C (ethyl
acetate); IR (KBr): 3360, 3222, 1727, 1661, 1630, 1558, 1519,
1
1449, 1259,1205 cmꢀ1; H NMR (DMSO-d6): d 1.18 (m, 1H),
Methyl 2-(1-aminocarbonyl-2-hydroxypropen-1-yl)-2-(cyclo-
hexylaminocarbonyl)hydrazinecarboxylate (3e). Mp 142–
147 1C (petroleum ether–ethyl acetate); IR (KBr): 3377,
1.24 (m, 4H), 1.55 (m, 1H), 1.67 (m, 4H), 2.14 (s, 6H), 3.39 (m,
1H), 3.60 (s, 3H), 6.55 (s, 1H), 9.38 (s, 1H), 16.09 (s, 1H); 13C
NMR (DMSO-d6): d 22.1, 25.1, 25.2, 32.8, 49.6, 51.9, 78.5,
117.7, 155.2, 192.8; MS (FAB) m/z (%) 314 (M1 þ H, 100),
189 (65), 114 (77), 76 (43). Anal. for C14H23N3O5 (313.35):
calc.: C 53.66, H 7.40, N 13.41; found: C 53.93, H 7.46,
N 13.35%.
3204, 2855, 1733, 1665, 1531, 1451, 1329, 1252, 998 cmꢀ1
;
1H NMR (DMSO-d6): d 1.05 (m, 1H), 1.21 (m, 4H), 1.60 (m,
5H), 1.88 (s, 3H), 3.37 (m, 1H), 3.64 (s, 3H), 6.40 (d, J ¼ 8.1
Hz, 1H), 7.50 (s, 1H), 7.73 (s, 1H), 9.47 (s, 1H), 15.42 (s, 1H);
13C NMR (DMSO-d6): d 18.1, 25.1, 25.2, 32.7, 49.6, 52.3,
106.9, 155.0, 158.8, 173.2, 176.0; MS (FAB) m/z (%) 315
(M1 þ H, 90), 190 (98), 185 (63), 93 (100). Anal. for
C13H22N4O5 (314.34): calc.: C 49.67, H 7.05, N 17.82; found:
C 49.42, H 7.21, N 17.53%.
Methyl 2-(1-benzoyl-2-oxo-2-phenylethyl)-2-(cyclohexylamino-
carbonyl)hydrazinecarboxylate (3b). Mp 191–194 1C (methanol
–DMF); IR (KBr): 3340, 3311, 2930, 2854, 1755, 1695, 1668,
1
1597, 1536, 1449, 1440, 1270, 1247 cmꢀ1; H NMR (DMSO-
d6): d 1.01–1.24 (m, 5H), 1.52–1.66 (m, 5H), 3.37 (m, 1H), 3.63
(s, 3H), 6.72 (d, J ¼ 7.7 Hz, 1H), 7.10 (broad s, 1H), 7.16 (s,
1H), 7.52 (m, 4H), 7.65 (m, 2H), 8.02 (m, 4H); 13C NMR
(DMSO-d6): d 24.1, 25.1, 32.6, 47.6, 53.6, 69.4, 128.66, 128.70,
133.8, 135.1, 156.1, 156.9, 193.3; MS (EI) m/z (%) 437 (M1,
0.4), 312 (14), 105 (100), 77 (51). Anal. for C24H27N3O5
(437.49): calc.: C 65.89, H 6.22, N 9.60; found: C 65.89, H
6.41, N 9.46%.
Methyl 2-(1-anilinocarbonyl-2-hydroxypropen-1-yl)-2-(cyclo-
hexylaminocarbonyl)hydrazinecarboxylate (3f). Mp 173–
176 1C (ethyl acetate–methanol); IR (KBr): 3350, 3196, 2937,
1732, 1659, 1629, 1556, 1489, 1446, 1252, 901 cmꢀ1; 1H NMR
(DMSO-d6): d 1.04 (m, 1H), 1.21 (m, 4H), 1.60 (m, 5H), 1.94 (s,
3H), 3.37 (m, 1H), 3.71 (s, 3H), 6.73 (d, J ¼ 8.1 Hz, 1H), 7.10
(m, 1H), 7.33 (m, 2H), 7.45 (m, 2H), 9.82 (s, 1H), 10.27 (s, 1H),
14.51 (s, 1H); 13C NMR (DMSO-d6): d 25.0, 25.7, 29.8, 31.0,
51.2, 52.3, 71.0, 84.4, 119.3, 123.7, 128.7, 138.1, 157.0, 157.1,
165.0; MS (FAB) m/z (%) 391 (M1 þ H, 30), 298 (43), 266
(68), 174 (72), 55 (100). Anal. for C19H26N4O5 (390.43): calc.: C
58.45, H 6.71, N 14.35; found: C 58.44, H 6.69, N 14.55%.
Methyl
2-(1-benzoyl-2-hydroxypropen-1-yl)-2-(cyclohexyl-
aminocarbonyl)hydrazinecarboxylate (3c). Mp 116–120 1C
(diethyl ether); IR (KBr): 3348, 3297, 2931, 2856, 1761, 1661,
1602, 1530, 1451, 1331, 1235, 1099 cmꢀ1; 1H NMR (CDCl3): d
1.07–1.24 (m, 3H), 1.31–1.49 (m, 2H), 1.63–1.80 (m, 3H), 1.92–
2.06 (m, 2H), 2.47 (s, 3H), 3.64–3.78 (m, 1H), 3.67 (s, 3H), 5.19
(broad, 1H), 5.71 (broad s, 1H), 7.42–7.58 (m, 5H), 16.36
(broad s, 1H); MS (FAB) m/z (%) 376 (M1 þ H, 77), 251
(100), 176 (64), 105 (85). Anal. for C19H25N3O5 ꢁ 0.4 Et2O:
calc.: C 61.08, H 7.22, N 10.37; found: C 61.20, H 7.44, N
10.43%.
Methyl 2-(1-acetyl-2-hydroxypropen-1-yl)-2-(2-chloroethyl-
aminocarbonyl)hydrazinecarboxylate (4a). Mp 167.2–171.5 1C
(petroleum ether–ethyl acetate); IR (KBr): 3400, 3251, 1749,
1
1670, 1531, 1244 cmꢀ1; H NMR (DMSO-d6): d 2.18 (s, 6H),
3.34 (m, 2H), 3.60 (m, 2H), 3.61 (s, 3H), 7.15 (s, 1H), 9.51 (s,
1H), 16.16 (s, 1H); 13C NMR (DMSO-d6): d 22.1, 42.2, 43.5,
51.9, 78.5, 117.5, 155.9, 193.1; MS (FAB) m/z (%) 294 (M1
H, 14), 189 (13), 71 (99), 55 (100). Anal. for C10H16ClN3O5
(293.70): calc.: C 40.89, H 5.49, N 14.31; found: C 40.64, H
5.53, N 14.09%.
þ
Methyl 2-(1-benzoyl-2-ethoxy-2-oxoethyl)-2-(cyclohexylamino-
carbonyl)hydrazinecarboxylate (3d). Mp 104–108.3 1C (petro-
leum ether–ethyl acetate); IR (KBr): 3320, 2930, 1760, 1735,
N e w J . C h e m . , 2 0 0 5 , 2 9 , 9 4 8 – 9 5 4
951

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organic phase was dried over anhydrous Na2SO4 and evapo-
rated to dryness. The residue was purified by radial chromato-
graphy using petroleum ether–ethyl acetate (5 : 3) to give 293.7
mg of 6f0 (53% yield), 140.9 mg of 6f00 (25% yield) and 65.4 mg
of the adduct 4f (12% yield).
Methyl 2-(1-aminocarbonyl-2-hydroxypropen-1-yl)-2-(2-chloro-
ethylaminocarbonyl)hydrazinecarboxylate (4e). Mp 205–207 1C
(methanol); IR (KBr): 3347, 3252, 1732, 1668, 1630, 1559,
1
1526, 1445, 1325, 1256 cmꢀ1; H NMR (DMSO-d6): d 1.92 (s,
3H), 3.36 (m, 2H), 3.57 (m, 2H), 3.65 (s, 3H), 7.03 (s, 1H), 7.57
(s, 1H), 7.78 (s, 1H), 9.61 (s, 1H), 15.52 (s, 1H); 13C NMR
(DMSO-d6): d 18.2, 42.2, 43.3, 52.4, 106.6, 155.6, 158.9, 173.1,
176.6; MS (FAB) m/z (%) 295 (M1 þ H, 30), 154 (58), 71 (75),
55 (100). Anal. for C9H15ClN4O5 (294.69): calc.: C 36.68, H
5.13, N 19.01; found: C 36.60, H 5.03, N 18.78%.
6f0. Mp 150–155 1C (dichloromethane–methanol); IR (KBr):
3327, 3236, 1733, 1723, 1664, 1600, 1549, 1453, 1437, 1410,
1265 cmꢀ1; 1H NMR (DMSO-d6): d 1.60 (s, 3H), 3.46 (m, 2H),
3.65 (s, 3H), 3.71 (m, 2H), 4.06 (s, 1H), 6.37 (s, 1H), 7.09 (m,
1H), 7.34 (m, 2H), 7.64 (m, 2H), 9.49 (s, 2H); 13C NMR
(DMSO-d6): d 25.6, 41.2, 41.8, 52.5, 70.7, 83.9, 119.3, 123.8,
128.7, 138.1, 157.0, 158.2, 164.5; MS (EI) m/z (%) 370 (M1, 2),
352 (94), 228 (64), 93 (100), 63 (65); HRMS for C15H19ClN4O5:
calc.: 370.1044; found: 370.1055. Anal. for C15H19ClN4O5:
calc.: C 48.59, H 5.16, N 15.11; found: C 48.84, H 5.31, N
14.96%.
Methyl 2-(1-anilinocarbonyl-2-hydroxypropen-1-yl)-2-(2-chloro-
ethylaminocarbonyl)hydrazinecarboxylate (4f). Mp 157–162 1C
(dichloromethane–methanol); IR (KBr): 3345, 3196, 1730,
;
1665, 1628, 1597, 1561, 1524, 1450, 1328, 1256 cmꢀ1 1H
NMR (DMSO-d6): d 2.00 (s, 3H), 3.38 (m, 2H), 3.60 (t, J ¼
6.4 Hz, 2H), 3.73 (s, 3H), 7.11 (m, 1H), 7.36 (m, 3H), 7.57 (m,
2H), 9.96 (s, 1H), 10.33 (s, 1H), 14.61 (s, 1H); 13C NMR
(DMSO-d6): d 18.3, 42.3, 43.5, 52.9, 107.8, 119.7, 124.0, 128.9,
137.7, 155.7, 159.9, 168.9, 176.6; MS (EI) m/z (%) 370 (M1, 7),
291 (14), 222 (68), 93 (100). Anal. for C15H19ClN4O5 (370.79):
calc.: C 48.59, H 5.16, N 15.11; found: C 48.71, H 5.29, N
15.02%.
6f00. Mp 109–113 1C (dichloromethane); IR (KBr): 3359,
3316, 3212, 1749, 1721, 1707, 1651, 1601, 1539, 1488, 1437,
1229 cmꢀ1; 1H NMR (DMSO-d6): d 1.39 (s, 3H), 3.44 (m, 2H),
3.63 (s, 3H), 3.67 (m, 2H), 4.25 (s, 1H), 6.74 (s, 1H), 7.10 (m,
1H), 7.34 (m, 2H), 7.64 (m, 2H), 9.47 (s, 1H), 9.99 (s, 1H); 13
C
NMR (DMSO-d6): d 22.1, 40.7, 41.6, 52.3, 72.1, 84.7, 119.7,
124.0, 128.8, 138.0, 156.6, 156.7, 165.6; MS (EI) m/z (%) 370
(M1, 2), 352 (93), 228 (70), 93 (100), 63 (65); HRMS for
C15H19ClN4O5: calc.: 370.1044; found: 370.1053. Anal. for
C15H19ClN4O5 ꢁ 0.75H2O: calc.: C 46.88, H 5.38, N 14.58;
found: C 46.67, H 5.60, N 14.43%.
Formation of 2-imidazolidinones
Isomers 5f0 and 5f00. The diazene 1 (319.8 mg, 1.5 mmol) was
slowly added to the solution of N-phenylacetoacetamide (265.5
mg, 1.5 mmol) and DBN (18.7 mg, 0.15 mmol) in dichloro-
methane (5 mL). The reaction mixture was stirred at room
temperature for 1.5 h and evaporated to dryness. The residue
was purified by radial chromatography using petroleum ether–
ethyl acetate (5 : 2) to give 410 mg of 5f0 (70% yield), 40 mg of
5f00 (4% yield) and 57 mg of the adduct 3f (10% yield).
Cyclization of Michael adducts
An ion-exchange resin Dowexs 50WX2-100 (Aldrich; cat.
No. 21744-1; 650 mg) was added to the selected adduct (0.25
mmol) in methanol (5 mL) and the reaction mixture was stirred
at room temperature for 2–22 h (see Table 2 for details). The
resin was filtered off and the filtrate was evaporated to dryness
to produce the corresponding imidazolin-2-one 7 or 8 with an
excellent yield.
5f0. Mp 140–143.5 1C (petroleum ether–ethyl acetate); IR
(KBr): 3267, 2937, 2854, 1749, 1726, 1682, 1599, 1549, 1493,
1446, 1375, 1319, 1271, 1258, 764 cmꢀ1; 1H NMR (DMSO-d6):
d 1.16 (m, 3H), 1.58 (s, 3H), 1.68 (m, 5H), 2.02 (m, 2H), 3.14
(m, 1H), 3.64 (s, 3H), 3.95 (s, 1H), 6.13 (s, 1H), 7.08 (m, 1H),
7.33 (m, 2H), 7.64 (m, 2H), 9.29 (s, 1H), 9.45 (s, 1H); 13C NMR
(DMSO-d6): d 25.0, 25.5, 29.7, 31.0, 51.2, 52.3, 70.9, 84.4,
119.3, 123.7, 128.7, 138.1, 157.0, 157.1, 164.9; MS (FAB) m/z
(%)391 (M1 þ H, 32), 373 (100), 280 (27), 254 (92), 172 (40).
Anal. for C19H26N4O5 ꢁ 0.6 EtOAc: calc.: C 57.98, H 7.00, N
12.64; found: C 58.23, H 7.01, N 12.49%.
One-pot procedure for the preparation of imidazolin-2-ones
7 and 8
The reactions of diazenes (1, 2) with various 1,3-dicarbonyl
compound (A–F) were carried out using the appropriate (see
Table 3) method described below, which led to the formation
of imidazolin-2-ones 7 or 8.
5f00. Mp 137–140 1C (diethyl ether); IR (KBr): 3328, 2926,
2855, 1732, 1700, 1678, 1602, 1555, 1502, 1445, 1259, 1250, 757
cmꢀ1; 1H NMR (DMSO-d6): d 1.04–1.31 (m, 3H), 1.32 (s, 3H),
1.52–1.76 (m, 5H), 2.04 (m, 2H), 3.10 (m, 1H), 3.63 (s, 3H),
4.15 (s, 1H), 6.59 (s, 1H), 7.11 (m, 1H), 7.33 (m, 2H), 7.64 (m,
2H), 9.35 (s, 1H), 9.82 (s, 1H); 13C NMR (DMSO-d6): d 22.1,
25.0, 25.7, 25.8, 29.6, 30.8, 50.5, 52.2, 72.5, 85.0, 119.7, 123.9,
128.7, 138.0, 155.3, 157.1, 165.9; MS (EI) m/z (%) 390 (M1,
1.1), 372 (79), 215 (23), 197 (33), 93 (86), 55 (100); MS (FAB)
m/z (%) 391 (M1 þ H, 9.2), 373 (6.6), 154 (80), 136 (66), 69
(60), 55 (100); HRMS for C19H26N4O5: calc.: 390.1903; found:
390.1913. Anal. for C19H26N4O5: calc.: C 58.45, H 6.71, N
14.35; found: C 58.31, H 6.81, N 14.23%.
Method I. A solution of the diazene 2 (213 mg, 1.1 mmol)
and dibenzoylmethane (B, 224.3 mg, 1 mmol) in CH2Cl2
(7 mL) was added dropwise to a stirred suspension of ZrCl4
(1.1 mmol) in CH2Cl2 (5 mL) at 20 1C under argon. The
reaction mixture was stirred at the same temperature for 10 h,
quenched with water (5 mL) and neutralized with saturated
aqueous NaHCO3. The two phases were separated, and the
aqueous solution was extracted with CH2Cl2 (4 ꢂ 10 mL). The
combined CH2Cl2 extracts were dried over anhydrous Na2SO4
and evaporated to dryness to give 8b (372.1 mg, 93%).
Method II. The diazene 1 (352 mg, 1.65 mmol) and diben-
zoylmethane (336.5 mg, 1.5 mmol) reacted in the presence of
ZrCl4 (385 mg, 1.65 mmol) as described in method I (reaction
time: 4 h). The residue, obtained after the evaporation of the
combined CH2Cl2 extracts, was treated with the ion-exchange
resin Dowexs 50WX2-100 (200 mg) in methanol (10 mL) for
13 h at room temperature. Next, the resin was filtered off and
the filtrate was evaporated to dryness to produce 568.5 mg of
7b (90% yield).
Isomers 6f0 and 6f00. The diazene 2 (290.3 mg, 1.5 mmol) was
slowly added to the solution of N-phenylacetoacetamide (265.5
mg, 1.5 mmol) and DBN (18.7 mg, 0.15 mmol) in dichloro-
methane (5 mL). The reaction mixture was stirred at room
temperature for 2 h. Dichloromethane (15 mL) was added to
the reaction mixture at 30 1C and then the solution was treated
successively with 5% HCl (1.5 mL) and water (1.5 mL). The
952
N e w J . C h e m . , 2 0 0 5 , 2 9 , 9 4 8 – 9 5 4

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Method III. A mixture of acetoacetamide (E, 151.7 mg, 1.5
mmol), diazene 1 (319.8 mg, 1.5 mmol) and trifluoroacetic acid
(1.53 mL, 20 mmol) in dichloromethane (10 mL) was stirred at
room temperature for 120 h. The reaction mixture was evapo-
rated to dryness, dissolved in dichloromethane (10 mL) and
treated successively with saturated NaHCO3 (5 mL) and with
water (2 ꢂ 7 mL). The dichloromethane solution was dried
over anhydrous Na2SO4 and evaporated to dryness to give 7e
(384.8 mg, 86% yield).
Methyl 5-acetyl-3-(2-chloroethyl)-4-methyl-2-oxo-2,3-dihy-
dro-1H-imidazol-1-ylcarbamate (8a), methyl 5-benzoyl-3-(2-
chloroethyl)-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-ylcarba-
mate (8b), methyl 5-benzoyl-3-(2-chloroethyl)-4-methyl-2-
oxo-2,3-dihydro-1H-imidazol-1-ylcarbamate (8c) and ethyl
1-(2-chloroethyl)-3-methoxycarbonylamino-2-oxo-5-phenyl-2,3-
dihydro-1H-imidazole-4-carboxylate (8d). See ref. 6.
Methyl 5-aminocarbonyl-3-(2-chloroethyl)-4-methyl-2-oxo-
2,3-dihydro-1H-imidazol-1-ylcarbamate (8e). Mp 215–218 1C
(ethyl acetate–methanol); IR (KBr): 3411, 3208, 1753, 1686,
1658, 1587, 1522, 1447, 1400, 1378, 1341, 1250 cmꢀ1; 1H NMR
(DMSO-d6): d 2.33 (s, 3H), 3.66 (broad, 3H), 3.81 (t, J ¼ 5.9
Hz, 2H), 3.95 (t, J ¼ 5.9 Hz, 2H), 7.12 (broad, 2H), 9.92 (s,
1H); 13C NMR (DMSO-d6): d 9.6, 42.0, 42.3, 52.6, 114.0,
124.8, 151.2, 155.8, 160.0; MS (EI) m/z (%) 276 (M1, 35),
217 (14), 202 (100), 185 (15), 152 (79). Anal. for C9H13ClN4O4
(276.68): calc.: C 39.07, H 4.74, N 20.25; found: C 39.20, H
4.88, N 19.95%.
Method IV. A mixture of the diazene 1 (213.2 mg, 1 mmol),
N-phenylacetoacetamide (F, 177 mg, 1 mmol) and sodium
acetate (35.2 mg, 0.4 mmol) in dichloromethane (5 mL) was
stirred at room temperature for 7 h. Next, dichloromethane
was added (10 mL) and the mixture was washed with water (7
mL). The organic phase was dried over anhydrous Na2SO4 and
evaporated to dryness. The residue was dissolved in methanol
(7 mL), an ion-exchange resin was added (250 mg) and the
reaction mixture was stirred for 20 h at room temperature. The
resin was filtered off and the filtrate evaporated to dryness to
give the product 7f (353.7 mg, 94% yield).
Methyl 5-anilinocarbonyl-3-(2-chloroethyl)-4-methyl-2-oxo-
2,3-dihydro-1H-imidazol-1-ylcarbamate (8f). Mp 152–154 1C
(petroleum ether–ethyl acetate); IR (KBr): 3308, 3241, 1740,
;
1712, 1654, 1526, 1445, 1410, 1281, 756 cmꢀ1 1H NMR
Characterization of imidazolin-2-ones 7 and 8
Methyl
5-acetyl-3-cyclohexyl-4-methyl-2-oxo-2,3-dihydro-
1H-imidazol-1-ylcarbamate (7a) and methyl 5-benzoyl-3-cyclo-
hexyl-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-ylcarbamate
(7b). See ref. 6.
(DMSO-d6): d 2.32 (s, 3H), 3.63 (s, 3H), 3.84 (t, J ¼ 6.1 Hz,
2H), 4.00 (t, J ¼ 6.1 Hz, 2H), 7.08 (m, 1H), 7.32 (m, 2H), 7.61
(m, 2H), 9.78 (s, 1H), 10.04 (s, 1H); 13C NMR (DMSO-d6): d
10.0, 42.0, 42.5, 52.5, 115.0, 119.6, 123.6, 124.0, 128.7, 138.6,
151.2, 155.8, 156.7; MS (FAB) m/z (%) 353 (M1 þ H, 20), 260
(10), 135 (70), 71 (55), 55 (62). Anal. for C15H17ClN4O4
(352.77): calc.: C 51.07, H 4.86, N 15.88; found: C 51.09, H
5.06, N 15.77%.
Methyl 5-benzoyl-3-cyclohexyl-4-methyl-2-oxo-2,3-dihydro-
1H-imidazol-1-ylcarbamate (7c). Mp 169.8–172.0 1C (petro-
leum ether–ethyl acetate); IR (KBr): 3150, 2910, 1750, 1690,
1
1560, 1250 cmꢀ1; H NMR (DMSO-d6): d 1.15 (m, 1H), 1.32
(m, 2H), 1.62 (m, 1H), 1.76 (m, 4H), 1.96 (s, 3H), 2.16 (m, 2H),
3.56 (s, 3H), 3.77 (m, 1H), 7.50 (m, 2H), 7.62 (m, 3H), 9.89 (s,
1H); 13C NMR (DMSO-d6): d 11.1, 24.7, 25.3, 29.2, 52.2, 53.8,
119.2, 128.5, 128.6, 129.8, 132.4, 138.9, 151.0, 155.7, 183.6; MS
(FAB) m/z (%) 358 (M1 þ H, 100), 275 (11), 201 (10), 105 (64).
Anal. for C19H23N3O4 (357.40): calc.: C 63.85, H 6.49, N 11.76;
found: C 64.19, H 6.44, N 11.72%.
Acknowledgements
The Ministry of Higher Education, Science and Technology of
the Republic of Slovenia is gratefully acknowledged for its
financial support (P1-0230-103). We would like to thank Dr
Bogdan Kralj and Dr Dusan %igon (Mass Spectrometry Cen-
ꢀ
ter, Jozef Stefan Institute, Ljubljana, Slovenia) for recording
the mass spectra.
Ethyl 1-cyclohexyl-3-(methoxycarbonylamino)-2-oxo-5-phe-
nyl-2,3-dihydro-1H-imidazole-4-carboxylate (7d). See ref. 6.
References
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hydro-1H-imidazol-1-ylcarbamate (7e). Mp 207–210 1C (ethyl
acetate–methanol); IR (KBr): 3185, 2928, 1742, 1698, 1665,
1
1585, 1450, 1316, 1224, 1079 cmꢀ1; H NMR (DMSO-d6): d
1.14 (m, 1H), 1.31 (m, 2H), 1.64 (m, 3H), 1.77 (m, 2H), 2.10 (m,
2H), 2.31 (s, 3H), 3.64 (s, 3H), 3.73 (m, 1H), 7.06 (broad d,
2H), 9.79 (s, 1H); 13C NMR (DMSO-d6): d 9.8, 24.7, 25.4, 29.5,
52.5, 53.2, 113.8, 124.6, 150.8, 155.9, 160.2; MS (EI) m/z (%)
296 (M1, 80), 214 (82), 197 (99), 169 (73), 140 (100), 55 (89).
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found: C 52.81, H 6.92, N 18.70%.
2
3
(a) S. Wendeborn, T. Winkler and I. Foisy, Tetrahedron Lett.,
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dihydro-1H-imidazol-1-ylcarbamate (7f). Mp 182–183.5 1C
(petroleum ether–ethyl acetate); IR (KBr): 3334, 2932, 1742,
1697, 1661, 1599, 1538, 1397, 1442, 1249, 758 cmꢀ1; 1H NMR
(DMSO-d6): d 1.16 (m, 1H), 1.34 (m, 2H), 1.65 (m, 3H), 1.79
(m, 2H), 2.14 (m, 2H), 2.29 (s, 3H), 3.62 (s, 3H), 3.78 (m, 1H),
7.07 (m, 1H), 7.31 (m, 2H), 7.60 (m, 2H), 9.74 (s, 1H), 9.92 (s,
1H); 13C NMR (DMSO-d6): d 10.3, 24.7, 25.4, 29.5, 52.5, 53.4,
115.0, 119.4, 123.5, 123.7, 128.7, 138.7, 150.8, 155.9, 156.9; MS
(EI) m/z (%) 372 (M1, 65), 215 (43), 197 (57), 93 (100), 55 (56).
Anal. for C19H24N4O4 (372.42): calc.: C 61.28, H 6.50, N 15.04;
found: C 61.56, H 6.41, N 14.81%.
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(a) F. Pozgan, S. Polanc and M. Kocevar, Synthesis, 2003, 2349;
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7
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S. Bombek, R. Lenarsic, M. Kocevar and S. Polanc, Synlett, 2001,
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The details will be published elsewhere.
ꢀ
4429; (f) V. Kepe, F. Pozgan, A. Golobic, S. Polanc and M.
9
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ꢀ
5
(a) S. Bombek, F. Pozgan, M. Kocevar and S. Polanc, J. Org.
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954
N e w J . C h e m . , 2 0 0 5 , 2 9 , 9 4 8 – 9 5 4