A convenient synthesis of imidazolidin-4-ones via domino reactions

Article abstract of DOI:10.1002/hlca.200900010

A series of imidazolidin-4-one derivatives was synthesized via a domino reaction of aldiminoesters and dialkylzinc. Chiral ligands were also examined in this reaction to obtain optically active products.

Full text of DOI:10.1002/hlca.200900010

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Helvetica Chimica Acta – Vol. 92 (2009)
A Convenient Synthesis of Imidazolidin-4-ones via Domino Reactions
by Xueming Chen, Hui Wei, Yunyun Chen, and Xingshu Li*
School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou 510006, P. R. China
(phone: þ 86-20-39943050; fax: þ 86-20-39943050; e-mail: lixsh@mail.sysu.edu.cn)
A series of imidazolidin-4-one derivatives was synthesized via a domino reaction of aldiminoesters
and dialkylzinc. Chiral ligands were also examined in this reaction to obtain optically active products.
Introduction. – Domino reactions, which can rapidly generate complex molecules in
a controlled and predictable manner, have attracted great attention in organic synthesis
because of the formation of two or more CꢀC bonds without isolation or purification
of any intermediates [1]. Especially, the novel ways of proceeding for the synthesis of
heterocyclic systems have been well explored [2]. Padwaꢀs rhodium carbenoid-initiated
dipolar cycloadditions [3], Denmarkꢀs nitroalkene [4 þ 2]/[3 þ 2]-cycloadditions
[1d][4], Overmanꢀs aza-Cope/Mannich cascade [5], and Grubbsꢀs ring-closing meta-
thesis chemistry [6] have all matured into significant synthetic tools.
Imidazolidin-4-one derivatives are found in a large spectrum of biological activities,
ranging from essential antibacterial activity [7a], cell inhibitor [7b – d], antimalarial
agents [7e – l], antiproliferative activity for melanoma [7m], selective inhibitor of the
glycine transporter 1 (GlyT1) [7n], and anticancer activity [7o – s]. They were also used
as efficient organocatalysts by MacMillan and co-workers for a variety of asymmetric
reactions [8][9].
Consequently, several synthetic methodologies have been developed for the
synthesis of imidazolidin-4-one and its derivatives in the past decades. The main
method toward these target products is the condensation of a-amino amide and CO
compounds (Scheme 1) [8 – 10]. The other well-established procedure for imidazoli-
dines are dipolar cycloadditions between azomethine ylides and imines [11]. However,
to the best of our knowledge, there have been limited reports in the literature on the
formation of imidazolidin-4-ones by domino reactions [12]. Herein, we report a
convenient procedure for the synthesis of imidazolidin-4-ones via condensation of a-
aldiminoesters and dialkylzinc reagents.
Scheme 1. Main Method toward the Synthesis of Imidazolidin-4-ones
ꢁ 2009 Verlag Helvetica Chimica Acta AG, Zꢂrich

Helvetica Chimica Acta – Vol. 92 (2009)
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Results and Discussion. – In our study of the alkylation of PMP (para-
methoxyphenyl)-protected aldimino ester with ZnMe2, we found that the reaction
gave two products after a period of 5 h, namely, minor amounts of 1,2-addition product
1 (26% yield) and the major product, imidazolidin-4-one 2a (64% yield). However, the
1,2-addition product 1 was fully converted to imidazolidin-4-one in 85% yield (after
isolation) when the reaction was continued at room temperature for 18 h (Scheme 2).
Scheme 2. Reaction of PMP-Protected Aldiminoester with Dimethylzinc
The single crystal of imidazolidin-4-one 2a was obtained, and the structure was
characterized by X-ray diffraction analysis (Fig. 1)1). This results was much different
from the literature reports, which revealed that Zn-mediated additions of iminoester
mainly produced 1,2-addition products [12][13]. On the other hand, the cis
configuration of 2a was proved by crystallographic analysis, which is in coincidence
with the results in literature [12].
Fig. 1. ORTEP Presentation of Imidazolidin-4-one 2a at 50% Probability
The possible mechanism for the formation of imidazolidin-4-ones is shown in
Scheme 3. A first molecule of the aldimino ester reacts with ZnMe2 to give the 1,2-
addition product A. The subsequent reaction of A with another molecule of the
1
)
CCDC-707059 contains the supplementary crystallographic data for this work. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif.

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Helvetica Chimica Acta – Vol. 92 (2009)
aldiminoester gives the intermediate B. Finally, the intramolecular cyclization leads to
the imidazolidin-4-one products.
Scheme 3. Possible Mechanism for the Formation of Imidazolidin-4-ones
Other solvents, such as CH2Cl2 or THF for the domino reaction were also
investigated, and the results indicated that toluene was the best solvent for the reaction
(Table 1).
Table 1. Synthesis of Imidazolidin-4-ones via Domino Reactions in Various Solvents
Entry
Solvent
Yield [%]a)b)
1
2
3
4
Toluene
CH2Cl2
THF
85
80
35
50
Et2O
b
a) Yield of isolated material. ) Single diastereoisomer, as determined by 1H-NMR and HPLC.
The reactions of a variety of aldimino esters and ZnMe2 under the optimal reaction
conditions are summarized in Table 2. It was clearly observed that both the electronic
and steric effects of the substrate were substantially important for the yield of
imidazolidin-4-ones. For example, the aldimino esters derived from 4-methoxy- or 4-
methylaniline gave products with higher yields than those from 4-chloro- or 4-
bromoaniline; on the other hand, besides the aldiminoester derived from 3-methylani-
line, which gave moderate yield, the aldiminoesters derived from 3-chloro- and 3-
methoxyaniline only gave precipitated by-products which could not be dissolved in
organic solvents and H2O. Diethylzinc was also used for the domino reaction with the

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Table 2. Synthesis of Imidazolidin-4-ones via Domino Reactions
Entry
ZnR2
R1
Product
Yield [%]a)b)
1
2
3
4
5
6
7
8
9
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnMe2
ZnEt2
4-MeOC6H4
4-MeC6H4
4-ClC6H4
4-BrC6H4
Ph
3-MeC6H4
3-MeOC6H4
3-ClC6H4
PhCH2
2a
2b
2c
2d
2e
2f
2g
2h
2i
85
72
68
58
75
63
by-product
by-product
by-product
76
10
4-MeOC6H4
2j
b
a) Yield of isolated material. ) Single diastereoisomer as determined by 1H-NMR and HPLC.
aldiminoester derived from 4-methoxyaniline as the substrate, and the results showed
that it was not as favorable as dimethylzinc for the reaction.
We also investigated the asymmetric synthesis of chiral imidazolidin-4-ones in the
presence of a series of readily available chiral ligands 3 – 12 in toluene at room
temperature. The results are shown in Fig. 2. Among the various chiral ligands tested,
the amide ligand 9, which is derived from camphor-10-sulfonic acid, gave the target
product with 21% ee; BINOL (10), the versatile chiral ligand in many asymmetric
catalytic reactions, provided 13% ee in this reaction.
The enantioselectivity of the reaction with the ratio of chiral ligand to substrate was
examined. With ligand 9, there was not much difference in enantioselectivity when the
amount of the ligand was increased (Table 3, Entries 1 – 3). On the other hand, when
BINOL was used as ligand, the ee value increased as the molar ratio of the ligand
increased. When the ligand/substrate ratio reached about 40%, the product ee values
came to a plateau (Table 3, Entries 4 – 7).
The temperature effect was insignificant in the range of 08 to room temperature.
When the reaction was carried out at 08 with BINOL as ligand, the enantioselectivity
was not improved. These results indicated that the use of chiral ligands presents a
possibility for the performance of asymmetric domino reactions, but the modification
of the ligands has still to be improved for better enantioselectivities.
Conclusions. – In conclusion, a series of imidazolidin-4-ones was synthesized via a
domino reaction of aldimino esters and dialkylzinc. Asymmetric induction with chiral
ligands was also explored but gave only low enantioselectivity. The development of
more stereoselective catalysts for the simple domino reactions is currently underway.
We thank the financial support from the Science & Technology Foundation of Guangzhou
(07A8206031) and the National Science Foundation of China (20472116).

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Helvetica Chimica Acta – Vol. 92 (2009)
Fig. 2. Asymmetric Induction in Imidazolidin-4-one Formation
Experimental Part
General Procedure for the Preparation of Imines. To a flask containing amine (10 mmol) and anh.
Na2SO4 (50 mmol) in 20 ml of toluene was added ethyl glyoxalate (12 mmol) slowly with stirring at r.t.
The stirring was continued for 1 h until the reaction was completed (monitored by TLC). Na2SO4 was
removed by filtration, and toluene was distilled off under reduced pressure to get the crude imine (95%
yield) which was used for the next step without purification.
General Procedure for the Synthesis of Imidazolidine Derivatives. To a flask containing imine
(1.0 mmol) in toluene (2 ml) was added Me2Zn soln. (1.2 mmol, 1.2m in toluene) at r.t. After completion
of the reaction (18 h, monitored by TLC), H2O (5 ml) was added. The mixture was diluted with AcOEt
and filtered through Celite. The collected phases were separated, and the aq. phase was extracted with
AcOEt (3 ꢁ 3 ml). The combined org. phases were washed with brine and dried over Na2SO4. After
removal of the solvent under reduced pressure, the crude product was purified by flash column
chromatography (FC; AcOEt/petroleum ether (PE) 1:5) to afford the desired imidazolidin-4-one
1
products. All the products were characterized by H- and 13C-NMR, and selected data as follows.
General Procedure for the Asymmetric Synthesis of Imidazolidin-4-one (2a). To a flask containing
imine (1.0 mmol) and chiral ligand (0.1 mmol) in toluene (2 ml) was added Me2Zn soln. (1.2 mmol, 1.2m
in toluene) at r.t. After completion of the reaction (monitored by TLC), H2O (5 ml) was added. The
mixture was diluted with AcOEt and filtered through Celite. The collected phases were separated, and
the aq. phase was extracted with AcOEt (3 ꢁ 3 ml). The combined org. phases were washed with brine

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Table 3. Asymmetric Synthesis of Imidazolidin-4-one 2a via Domino Reactions
Entry
Ligand
Ligand Ratio [%]
Yield [%]a)
ee [%]b)
1
2
3
4
5
6
7
9
9
9
10
10
10
10
5
10
20
10
20
40
50
93
91
90
89
96
91
92
18
21
22
13
18
31
26
a) Yield of material. b) Enantiomeric excesses were determined using an Agilent 1100 HPLC with UV
detection at 254 nm and Daicel Chiralpak OD column.
and dried over Na2SO4. After removal of the solvent under reduced pressure, the crude product was
purified by FC (AcOEt/PE 1:5) to afford imidazolidin-4-one 2a. Enantiomeric excesses were measured
using an Agilent 1100 HPLC system with UV detection at 254 nm and a Daicel Chiralpak OD column.
Ethyl 1,3-Bis(4-methoxyphenyl)-4-methyl-5-oxoimidazolidine-2-carboxylate (2a). White solid. M.p.
97 – 988. HPLC (Chiralpak OD; 1.0 ml/min, hexane/i-PrOH 95 :5): tR (R,R) ¼ 45 min, tR(S,S) ¼ 60 min;
the configuration was assigned by comparing the retention time of its homologue, ethyl 4-ethyl-1,3-bis(4-
1
methoxyphenyl)-5-oxoimidazolidine-2-carboxylate [12]. H-NMR (CDCl3, 300 MHz): 1.18 (t, J ¼ 6.9,
3 H); 1.68 (d, J ¼ 6.0, 3 H); 3.79 (s, 3 H); 3.82 (s, 3 H); 4.15 (q, J ¼ 6.9, 2 H); 4.35 (q, J ¼ 6.6, 1 H); 5.67 (s,
1 H); 6.75 (d, J ¼ 9.0, 2 H); 6.93 (d, J ¼ 9.0, 4 H); 7.39 (d, J ¼ 9.0, 2 H). 13C-NMR (CDCl3, 75 MHz):
14.36; 18.07; 55.79; 56.11; 57.15; 62.42; 76.94; 113.05; 114.80; 115.56; 125.30; 128.90; 138.61; 153.21;
159.92; 169.42; 171.88. HR-MS: 407.1580 ([M þ Na]þ, C21H24N2NaO5þ ; calc. 407.1583).
Ethyl 4-Methyl-1,3-bis(4-methylphenyl)-5-oxoimidazolidine-2-carboxylate (2b). White solid. M.p.
107 – 1088. 1H-NMR (CDCl3, 300 MHz): 1.18 (t, J ¼ 6.9, 3 H); 1.71 (d, J ¼ 6.0, 3 H); 2.33 (s, 3 H); 2.38 (s,
3 H); 4.15 (q, J ¼ 6.9, 2 H); 4.42 (q, J ¼ 6.6, 1 H); 5.79 (s, 1 H); 6.76 (d, J ¼ 9.0, 2 H); 7.05 – 7.24 (m, 4 H);
7.41 (d, J ¼ 6.0, 2 H). 13C-NMR (CDCl3, 75 MHz): 14.40; 17.93; 20.78; 21.52; 56.99; 62.52; 76.95; 111.81;
123.01; 128.48; 130.19; 130.49; 132.69; 137.01; 141.91; 169.35; 171.84. HR-MS: 375.1680 ([M þ Na]þ,
C21H24N2NaOþ3 ; calc. 375.1685).
Ethyl 1,3-Bis(4-chlorophenyl)-4-methyl-5-oxoimidazolidine-2-carboxylate (2c). Yellow oil. 1H-NMR
(CDCl3, 300 MHz): 1.25 (t, J ¼ 5.1, 3 H); 1.45 (d, J ¼ 6.0, 3 H); 4.16 (q, J ¼ 5.1, 2 H); 4.35 (q, J ¼ 6.6, 1 H);
5.74 (s, 1 H); 6.49 (d, J ¼ 9.0, 2 H); 6.72 (d, J ¼ 9.0, 1 H); 7.08 (d, J ¼ 9.0, 2 H); 7.25 (d, J ¼ 9.0, 2 H); 7.35
(d, J ¼ 9.0, 1 H); 7.52 (d, J ¼ 9.0, 1 H). 13C-NMR (CDCl3, 75 MHz): 14.38; 17.61; 61.62; 62.94; 75.96;
113.01; 114.66; 122.92; 123.48; 124.36; 129.34; 129.73; 129.84; 132.27; 133.92; 142.37; 145.39; 168.68;
174.50.
Ethyl 1,3-Bis(4-bromophenyl)-4-methyl-5-oxoimidazolidine-2-carboxylate (2d). White solid. M.p.
149 – 1508. 1H-NMR (CDCl3, 300 MHz): 1.15 (t, J ¼ 4.5, 3 H); 1.64 (d, J ¼ 6.0, 3 H); 4.15 (q, J ¼ 4.5, 2 H);
4.32 (q, J ¼ 5.1, 1 H); 5.74 (s, 1 H); 6.42 (d, J ¼ 9.0, 2 H); 7.19 (d, J ¼ 9.0, 2 H); 7.47 (m, 4 H). 13C-NMR
(CDCl3, 75 MHz): 14.37; 17.52; 56.87; 62.90; 75.74; 111.55; 113.51; 115.14; 120.02; 123.55; 132.62; 134.53;
142.77; 168.57; 171.22.

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Ethyl 4-Methyl-5-oxo-1,3-diphenylimidazolidine-2-carboxylate (2e). White solid. M.p. 94 – 958.
1H-NMR (CDCl3, 300 MHz): 1.14 (t, J ¼ 6.9, 3 H); 1.72 (d, J ¼ 6.0, 3 H); 4.15 (q, J ¼ 6.9, 2 H); 4.45
(q, J ¼ 6.6, 1 H); 5.84 (s, 1 H); 6.87 – 6.92 (m, 3 H); 7.27 – 7.44 (m, 5 H); 7.56 (d, J ¼ 9.0, 2 H). 13C-NMR
(CDCl3, 75 MHz): 14.37; 17.82; 56.93; 62.65; 76.39; 111.80; 119.31; 122.73; 127.06; 129.64; 130.03; 135.34;
143.98; 169.12; 171.73.
Ethyl 4-Methyl-1,3-bis(3-methylphenyl)-5-oxoimidazolidine-2-carboxylate (2f). White solid. M.p.
189 – 1908. 1H-NMR (CDCl3, 300 MHz): 1.18 (t, J ¼ 7.2, 3 H); 1.71 (d, J ¼ 6.6, 3 H); 4.17 (q, J ¼ 7.2, 2 H);
4.42 (q, J ¼ 6.6, 1 H); 5.83 (s, 1 H); 6.61 (d, J ¼ 6.9, 2 H); 6.71 (d, J ¼ 7.5, 1 H); 7.09 (d, J ¼ 7.2, 1 H); 7.21 –
7.35 (m, 3 H); 7.44 (s, 1 H). 13C-NMR (CDCl3, 75 MHz): 14.34; 17.84; 21.90; 22.30; 56.94; 62.46; 77.01;
109.05; 112.55; 119.83; 120.17; 123.55; 127.84; 129.34; 129.85; 135.35; 139.54; 139.88; 144.15; 169.22;
171.74. HR-MS: 375.1680 ([M þ Na]þ, C21H24N2NaO3þ ; 375.1685).
Ethyl 4-Ethyl-1,3-bis(4-methoxyphenyl)-5-oxoimidazolidine-2-carboxylate (2j). White solid. M.p.
110 – 1118. 1H-NMR (CDCl3, 300 MHz): 1.12 – 1.18 (m, 6 H); 2.08 – 2.12 (m, 2 H); 3.78 (s, 3 H); 3.80 (s,
2 H); 4.14 (q, J ¼ 7.2, 2 H); 4.26 (t, J ¼ 5.1, 1 H); 5.63 (s, 1 H); 6.82 – 6.92 (m, 6 H); 7.37 (d, J ¼ 9.0, 2 H).
13C-NMR (CDCl3, 75 MHz): 9.85; 14.37; 25.48; 55.79; 62.09; 62.45; 76.97; 114.19; 114.72; 115.33; 125.39;
127.99; 129.85; 139.91; 153.55; 158.42; 169.39; 171.15. HR-MS: 398.1830 (Mþ, C22H26O5N2þ ; 398.1841).
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Received January 12, 2009