Simple and efficient copper-catalyzed approach to 2,4-disubstituted imidazolones

Article abstract of DOI:10.1021/ol1008813

(Figure Presented) Some imidazolone derivatives are biological and pharmaceutical active molecules and the chromophores of the fluorescent proteins. In this communication, a simple and efficient approach to 4-arylidene-2-alkyl-4,5-dihydro-1H-imidazol-5-ones (2,4-disubstituted imidazolones) has been developed, and the protocol uses readily available 2-bromo-3-alkylacrylic acids and amidines as the starting materials without addition of any ligand or additive. The reactions were performed under mild conditions. Therefore, the present method will be of wide application in organic chemistry and medicinal chemistry.

Full text of DOI:10.1021/ol1008813

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3128-3131
Simple and Efficient Copper-Catalyzed
Approach to 2,4-Disubstituted
Imidazolones
Xiaoyu Gong,† Haijun Yang,† Hongxia Liu,‡ Yuyang Jiang,‡ Yufen Zhao,† and
Hua Fu*,†
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry
of Education), Department of Chemistry, Tsinghua UniVersity, Beijing 100084, P. R.
China, and Key Laboratory of Chemical Biology (Guangdong ProVince), Graduate
School of Shenzhen, Tsinghua UniVersity, Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn
Received April 17, 2010
ABSTRACT
Some imidazolone derivatives are biological and pharmaceutical active molecules and the chromophores of the fluorescent proteins. In this
communication, a simple and efficient approach to 4-arylidene-2-alkyl-4,5-dihydro-1H-imidazol-5-ones (2,4-disubstituted imidazolones) has been
developed, and the protocol uses readily available 2-bromo-3-alkylacrylic acids and amidines as the starting materials without addition of any
ligand or additive. The reactions were performed under mild conditions. Therefore, the present method will be of wide application in organic
chemistry and medicinal chemistry.
The imidazolone motif appears in natural products. For
example, bis(indole) alkaloids rhopaladins A-D (Figure 1),
showing antibacterial activity against Sarcina lutea and
Corynebacterium xerosis and inhibitory activity against
cyclin-dependent kinase 4 and c-erbB-2 kinase, were isolated
from the Okinawan marine tunicate Rhopalaea sp.1 Imida-
zolones were applied as intermediates in the synthesis of
natural products, such as biotin,2 slagenins,3 axinohydanto-
ins,4 and oroidin-derived alkaloids.5 The imidazolone sub-
structures were found to act as the chromophores of the
fluorescent proteins, such as E6 and F7 for green fluorescent
protein (GFP), G for the Y66F mutant of GFP, H for cyan
fluorescent protein (CFP) representing the Y66W mutant of
GFP, I for blue fluorescent protein (BFP) representing the
Y66H mutant of GFP,7 and J for red fluorescent protein
(RFP) (Figure 1).8 Imidazolones show various biological and
pharmaceutical activities. For example, they are antagonists
of many receptors including the neurokinin-1 receptor,9 the
CGRP receptor,10 the dopamine receptors,11 the angiotensin
(6) Niwa, H.; Inouye, S.; Hirano, T.; Matsuno, T.; Kojima, S.; Kubota,
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(8) Gross, L. A.; Baird, G. S.; Hoffman, R. C.; Baldridge, K. K.; Tsien,
R. Y. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 11990.
† Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education).
(9) (a) Meurer, L. C.; Finke, P. E.; Owens, K. A.; Tsou, N. N.; Ball,
R. G.; Mills, S. G.; MacCoss, M.; Sadowski, S.; Cascieri, M. A.; Tsao,
K.-L.; Chicchi, G. G.; Egger, L. A.; Luell, S.; Metzger, J. M.; MacIntyre,
D. E.; Rupniak, N. M. J.; Williams, A. R.; Hargreaves, R. Bioorg. Med.
Chem. Lett. 2006, 16, 4504. (b) Finke, P. E.; Meurer, L. C.; Levorse, D. L.;
MacCoss, M.; Sadowski, S.; Cascieri, M. A.; Tsao, K.-L.; Chicchi, G. G.;
Metzger, J. M.; MacIntyre, D. E. Bioorg. Med. Chem. Lett. 2006, 16, 4497.
(10) Burgey, C. S.; Stump, C. A.; Nguyen, D. N.; Deng, J. Z.; Quigley,
A. G.; Norton, B. R.; Bell, I. M.; Mosser, S. D.; Salvatore, C. A.; Rutledge,
R. Z.; Kane, S. A.; Koblan, K. S.; Vacca, J. P.; Graham, S. L.; Williams,
T. M. Bioorg. Med. Chem. Lett. 2006, 16, 5052.
‡ Key Laboratory of Chemical Biology (Guangdong Province).
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10.1021/ol1008813  2010 American Chemical Society
Published on Web 06/18/2010

II receptor,12 and the ꢀ3-adrenergic receptor.13 They are also
used as potent PDE4 inhibitors14 and GABAA receptor
ligands.15 In addition, 2-imidazolones can be transferred into
imidazoles that display wide biological and pharmaceutical
activity.16 Herein, we are interested in preparation of
4-arylidene-2-alkyl-4,5-dihydro-1H-imidazol-5-ones (2,4-di-
substituted imidazolones) considering their wide applications
in life science and medicinal chemistry. Only several
approaches to 2,4-disubstituted imidazolones were reported
until now,7,17,18 and the protocols used reactions of oxazo-
lones with amines17,18a or ammonia18b and coupling of
imidates with amino acid esters.18c Recently, there has been
great progress in copper-catalyzed N-arylations,19 and the
N-arylation strategy has been used to make N-heterocycles.20
We have also developed some efficient methods for copper-
catalyzed cross couplings21 and synthesis of N-heterocy-
cles.22 In this communication, we report a simple and
efficient copper-catalyzed synthesis of 4-arylidene-2-alkyl-
4,5-dihydro-1H-imidazol-5-ones (2,4-disubstituted imidazo-
lones) without addition of any ligand or additive under mild
conditions.
(11) Carling, R. W.; Moore, K. W.; Moyes, C. R.; Jones, E. A.; Bonner,
K.; Emms, F.; Marwood, R.; Patel, S.; Fletcher, A. E.; Beer, M.; Sohal, B.;
Figure 1. 2,4-Disubstituted imidazolone motif occurring in the
natural products and the fluorescent proteins.
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L.; Feeney, W. P.; Forrest, M. J.; Hom, G. J.; MacIntyre, D. E.; Starader,
C. D.; Tota, L.; Wang, P.-R.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E.
Table 1. Copper-Catalyzed Cascade Synthesis of
(Z)-4-Benzylidene-2-methyl-4,5-dihydro-1H-imidazol-5-one (3a)
via Coupling of 2-Bromo-3-phenylacrylic Acid (1a) with
Acetamidine Hydrogen Chloride (2a): Optimization of
Conditionsa
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D.; Diels, G.; Megens, A.; Somers, M.; Wauwe, J. V.; Stoppie, P.; Cools,
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2002, 12, 653
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Stribling, D. S.; Shearman, L. P.; Strack, A. M.; Van der Ploeg, L. H. T.
temp
(°C)
yield
(%)b
entry
cat.
CuI
CuBr
CuCl
Cu2O
CuO
base
solvent
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(17) He, X.; Bell, A. F.; Tonge, P. J. Org. Lett. 2002, 4, 1523
.
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
dioxane
NMP
DMF
DMF
80
80
80
80
80
80
80
80
80
80
80
80
80
r.t.
60
35
27
32
53
15
26
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2001, 123, 7727. (b) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (c)
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Cu(OAc)2
-
tracec
37
43
trace
40
0
28
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
9
Na2CO3
K3PO4
10
11
12
13
14
15
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
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Ullmann-type couplings, see: (a) Martin, R.; Rivero, M. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2006, 45, 7079. (b) Evindar, G.; Batey, R. A. J.
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0
trace
a Reaction conditions: 2-bromo-3-phenylacrylic acid (1a) (0.7 mmol),
acetamidine hydrogen chloride (2a) (0.5 mmol), catalyst (0.1 mmol), base
(1 mmol), and solvent (2 mL) under nitrogen atmosphere. b Isolated yield.
c In the absence of copper catalyst.
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8107. (b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.sEur. J. 2006,
12, 3636. (c) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007,
72, 672. (d) Jiang, Q.; Jiang, D.; Jiang, Y.; Fu, H.; Zhao, Y. Synlett 2007,
72, 1836. (e) Guo, X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. AdV. Synth.
Catal. 2006, 348, 2197. (f) Zeng, L.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y.
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Chem.sEur. J. 2010, 16, 2366.
2-Bromo-3-phenylacrylic acid (1a) and acetamidine hy-
drogen chloride (2a) were first used as the model substrates
to optimize reaction conditions including optimization of the
catalysts, bases, solvents, and temperature under nitrogen
Org. Lett., Vol. 12, No. 14, 2010
3129

Table 2. Copper-Catalyzed Cascade Synthesis of 2,4-Disubstituted Imidazolonesa
a Reaction conditions: 2-bromo-3-alkylacrylic acid (1) (0.7 mmol), amidine hydrogen chloride (2) (0.5 mmol), Cu2O (0.1 mmol), Cs2CO3 (1 mmol), and
DMF (2 mL) under nitrogen atmosphere, reaction temperature of 80 °C, and reaction time of 12 h. b Isolated yield. c Reaction temperature of 100 °C. d 0.6
mmol of 2-bromo-3-(furan-2-yl)acrylic acid.
atmosphere. As shown in Table 1, six copper catalysts were
investigated at 80 °C using 2 equiv of Cs2CO3 as the base
(relative to amount of 2a) in DMF (entries 1-6), and Cu2O
showed the best activity (entry 4). Only a trace amount of
target product was found in the absence of copper catalyst
(entry 7). Other bases, K2CO3, Na2CO3, and K3PO4, were
tested, and Cs2CO3 was proven to be the most effective base
(compare entries 4 and 8-10). The effect of solvents was
3130
Org. Lett., Vol. 12, No. 14, 2010

also investigated (compare entries 4 and 11-13), and DMF
provided the highest yield (entry 4). Reaction temperature
was also changed, and 80 °C was the best choice (compare
entries 4, 14, and 15).
Scheme 1
.
Possible Formation Mechanism of 2,4-Disubstituted
Imidazolones
The scope of copper-catalyzed cascade reactions of
2-bromo-3-alkylacrylic acids with amidines was investigated
under optimized conditions (20 mmol % of Cu2O as the
catalyst, 2 equiv of Cs2CO3 as the base, DMF as the solvent
under nitrogen atmosphere). As shown in Table 2, all the
substrates examined provided moderate to good yields at 80
or 100 °C. For various substituted 2-bromo-3-alkylacrylic
acids, their reactivity did not show evident differences. In
general, aromatic amidines showed slightly higher reaction
activity than aliphatic ones. In addition, the cascade reactions
could tolerate ether (entries 11-15 and 19-22) and the
C-Cl bond (entries 16-18).
Since the suitable ortho-substituents could promote Ull-
mann-type couplings,22a,d,23 a possible formation mechanism
of 2,4-disubstituted imidazolones was proposed in Scheme
1 according to the results above. Coordination of 2-bromo-
3-alkylacrylic acid with a Cu(I) ion first forms I in the
presence of base (Cs2CO3). Oxidative addition of I and
following complex of copper with amidine gives II, and
reductive elimination of II provides III. Intramolecular
nucleophilic attack24 of amino to carbonyl in III affords 2,4-
disubstituted imidazolone (3) freeing the copper catalyst.
In summary, we have developed a simple and efficient
method for synthesis of 2,4-disubstituted imidazolones. The
protocol uses readily available 2-bromo-3-alkylacrylic acids
and amidines as the starting materials, and the corresponding
target products were obtained in moderate to good yields
without addition of any ligand or additive under mild
conditions. The 2,4-disubstituted imidazolones are biological
and pharmaceutical active molecules and the chromophores
of the fluorescent proteins, and therefore, the present method
will be of wide application in organic chemistry and
medicinal chemistry.
Acknowledgment. Financial support was provided by the
National Natural Science Foundation of China (Grant No.
20972083), Chinese 863 Project (Grant No. 2007AA02Z160),
and the Key Subject Foundation from Beijing Department
of Education (XK100030514).
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Supporting Information Available: Synthetic procedures,
characterization data, and 1H and 13C NMR spectra of these
synthesized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
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