Solid-phase synthesis of 1,2,5-trisubstituted imidazolidin-4-ones

Article abstract of DOI:10.1016/j.tetlet.2008.11.030

A general solid-phase synthesis of 1,2,5-trisubstituted imidazolidin-4-ones is described. The key synthetic transformation incorporates a microwave-assisted condensation of an α-amino amide on solid support with an aldehyde in solution to give the corresp

Full text of DOI:10.1016/j.tetlet.2008.11.030

Tetrahedron Letters 50 (2009) 419–422
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Solid-phase synthesis of 1,2,5-trisubstituted imidazolidin-4-ones
a
a
a
b
b
Lan-Ying Qin a, , Andrew G. Cole , Axel Metzger , Linda O’Brien , Xiling Sun , Jin Wu ,
*
Yan Xu b, Kai Xu b, Ying Zhang b, Ian Henderson a
a Pharmacopeia, Inc., PO Box 5350, Princeton, NJ 08543, USA
b WuXi PharmaTech Co., Ltd, Building 1, 288 FuTe Zhong Lu, Shanghai, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2008
Revised 7 November 2008
Accepted 10 November 2008
Available online 14 November 2008
A general solid-phase synthesis of 1,2,5-trisubstituted imidazolidin-4-ones is described. The key syn-
thetic transformation incorporates a microwave-assisted condensation of an
a-amino amide on solid
support with an aldehyde in solution to give the corresponding resin-bound imidazolidin-4-one in a
simple one-pot procedure.
Ó 2008 Elsevier Ltd. All rights reserved.
Imidazolidin-4-ones represent an interesting class of com-
pounds with respect to biological activity.1,2 Through manipulation
of the substituents around the imidazolidin-4-one core, molecules
with a variety of biological properties have been discovered. Exam-
ples include compounds that exhibit antibacterial activity.3,4 Imi-
dazolidin-4-ones have also been reported to inhibit binding of
VCAM-1 to VLA-4, which are useful in treating inflammation asso-
ciated with chronic inflammatory diseases such as rheumatoid
arthritis, multiple sclerosis, asthma, and inflammatory bowel dis-
ease.5 The structural diversity of substituted imidazolidin-4-ones
makes this compound class versatile for drug discovery research
and necessitates the development of efficient and versatile synthe-
ses of such molecules.6,7 Previous work reported by Pospíšil and
din-4-ones under microwave-assisted conditions in a solvent-free
system.8 The work described here extends this methodology
to generate a diversified 1,2,5-trisubstituted imidazolidin-4-one
system (Fig. 1) on solid phase.
The aim of this project was to develop a general solid-phase
synthesis of imidazolidin-4-ones that allow diverse elements to
be incorporated at the N-1, C-2, and C-5 positions. This solid-phase
synthesis would subsequently be used to generate parallel and
combinatorial 1,2,5-trisubstituted imidazolidin-4-one compound
libraries.
A 2-nitrobenzyl-based photo-cleavable linker 3 was selected as
the basis for construction of the imidazolidin-4-one system.9 Ami-
nation of 4-(bromomethyl)-3-nitrobenzoic acid (1) with ammonia
in methanol provides primary amine 2, which was protected using
9-fluorenylmethyl chloride (Fmoc-Cl) to provide 3 (Scheme 1). This
linker allows photo-mediated cleavage of the substituted imidaz-
olidin-4-ones from solid phase, and is compatible with the chem-
istry required to conduct the synthesis.
ˇ
Potácek describes the formation of 1,2,3-trisubstituted imidazoli-
O
R
HN
Solid-phase synthesis was initiated by acylating aminomethyl-
terminated ArgogelÒ (4) with N-
a-N-e-bis-Fmoc-lysine followed
N
R
R
by Fmoc deprotection to generate 5 (Scheme 2). This increases
the loading capacity of the resin by doubling the number of amino
Figure 1. 1,2,5-Trisubstituted imidazolidin-4-one.
O
O
O
NO2
NH2
NO2
NHFmoc
NO2
HO
a
b
HO
HO
Br
1
2
3
Scheme 1. Reagents and conditions: (a) NH3, MeOH, 25 °C; (b) Fmoc-Cl, Na2CO3, THF, H2O, 25 °C.
* Corresponding author. Tel.: +1 609 452 3600x3216; fax: +1 609 655 4187.
E-mail address: lqin@pcop.com (L.-Y. Qin).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.030

420
L.-Y. Qin et al. / Tetrahedron Letters 50 (2009) 419–422
with ammonia to give 7. However, this solid-phase amination re-
O
sults in significantly diminished yields due to cross-linking of the
generated primary amine with unreacted benzyl bromide.
a,b
N
N
H
NH2
c,b
NH2
4
NH2
Acylation of 7 with an Fmoc-protected
9, which was then Fmoc deprotected to provide resin-bound
amino amide 10 (Scheme 4). A range of -amino acids 8 were suc-
a-amino acid 8 provided
4
5
a-
a
O
O
cessfully employed (Table 1). Glutamic acid, serine, and diamino-
propionic acid incorporated acid-labile protecting groups on their
side chains. Reaction of 10 with 1.0 M aromatic aldehyde 11 under
microwave-assisted conditions at 180 °C resulted in efficient
conversion to the diastereomeric imidazolidin-4-one 12.10 This
reaction is very rapid, going to completion in 10 min. The R1 sub-
stituent derived from the amino acid significantly influences the
cyclization. When R1 is not hydrogen, the reaction occurs readily
with clean conversion. However, when R1 is hydrogen, a less facile
cyclization occurs with formation of significant side products. One
possible explanation for this observation may be the ease of gener-
ation of the required reactive conformation for cyclization of the
putative imine intermediate. The energy required to adopt this
conformation from the extended non-reactive conformation may
be less when there is an R1 substituent. Employing the microwave
conditions, imidazolidin-4-one 12 formation was successfully
achieved with a set of electronically diverse aromatic aldehydes
11 (Table 1).
The imidazolidin-4-one 12 was further functionalized via N-
derivatization (Scheme 5). Initial experiments identified differing
levels of reactivity for the two imidazolidinone diastereomers. Un-
der mild acylation conditions, for example, using benzoic acid and
DIC, only the cis-diastereomer is acylated. When more forcing N-
derivatization conditions are applied, for example, using benzoic
acid and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl),
both diastereomers are benzoylated. Also, only the cis-diastereo-
mer reacts with less reactive electrophiles such as sulfonyl chlo-
rides. The higher reactivity of the cis-diastereomer is likely due
to the fact that one face of the five-membered ring is not subject
to steric hindrance by either the 2- or the 5-substituent. For the
trans-diastereomer, the approach of the electrophile to either face
of the five-membered ring is sterically hindered by one of these
substituents. This hypothesis is supported by the fact that the ex-
act nature of the R1 and Ar2 substituents also affects the N-deriva-
tization, which is more facile with smaller R1 and Ar2 groups. The
cis- and trans-stereochemistry was determined by NOE and 1H
NMR experiments. Also, in the cis-diastereomer, the R1 and Ar2
groups have restricted rotation due to steric interaction, and hence
exhibit rotamers in the 1H NMR spectrum. Using a combination of
relatively reactive electrophiles and/or forcing conditions, com-
plete N-derivatization of both the cis- and the less reactive trans-
diastereomers of 12 was achieved. Successful amide 13 formation
was performed with both benzoic acid and acetic anhydride, urea
14 formation with both phenyl isocyanate and 3-fluorophenyl iso-
NH2
NO2
NH2
N
H
4
H
NH
O
=
7
NO2
NH2
7
Scheme 2. Reagents and conditions: (a) N-a-N-e-bis-Fmoc-Lys, HOBt monohy-
drate, DIC, CH2Cl2, DMF, 25 °C; (b) piperidine, DMF, 25 °C; (c) 3, HOBt monohydrate,
DIC, CH2Cl2, DMF, 25 °C.
O
O
NO2
Br
O
4
N
H
N
H
4
a
NH
N
H
NH2
O
NH2
5
NO2
Br
6
O
O
NO2
NH2
N
H
N
H
4
NH
O
b
NO2
NH2
7
Scheme 3. Reagents and conditions: (a) 1, HOBt monohydrate, DIC, CH2Cl2, DMF,
25 °C; (b) 7 M NH3 in MeOH, THF, 25 °C.
groups for further functionalization. The double-loaded resin was
subsequently acylated with 3 followed by Fmoc deprotection to
provide resin-bound primary amine 7.
Formation of 7 can be achieved more directly through coupling
of 1 with 5 to provide 6 (Scheme 3). This is followed by amination
O
O
R1
R1
b
a
N
H
+
NH2
HO
Ar2
NHFmoc
NHFmoc
9
7
8
O
O
O
O
H
R1
NH2
11
c
R1
R1
N
N
H
N
NH
12
H
N
Ar2
Ar2
10
Scheme 4. Reagents and conditions: (a) HOBt monohydrate, DIC, CH2Cl2, DMF, 25 °C; (b) piperidine, DMF, 25 °C; (c) DMF, microwave, 180 °C.

L.-Y. Qin et al. / Tetrahedron Letters 50 (2009) 419–422
421
Table 1
1,2,5-Trisubstituted imidazolidin-4-ones synthesized on solid phase
O
R1
R3
HN
Ar2
N
Compound
R1
Ar2
R3
pmol per beada
274
Yieldb (%)
12
Purityc (%)
80
O
16a
OH
F
O
16b
930
38
84
OH
O
O
16c
16d
17a
17b
465
596
800
529
19
25
33
22
94
87
90
82
O
O
O
Cl
H
N
F
O
H
N
NH2
O
O
O
O
18a
678
572
28
24
88
88
Cl
O
18b
O
O
O
a
Based on comparison with an analytical reference.
Based on average loading per bead.
Based on HPLC analysis at 220 nm.
b
c
O
O
cyanate, and carbamate 15 formation with both phenyl chlorofor-
mate and 4-methoxyphenyl chloroformate.
R1
R1
d
a
b
N
HN
N
R3
O
N
All final products were generated on resin as a pair of diastereo-
mers with a ratio of approximately 1:1. The compounds incorpo-
rating acid-labile protecting groups were deprotected with TFA.
Release of the 1,2,5-trisubstituted imidazolidin-4-ones 16–18 from
the solid support was achieved by photolysis (Scheme 5).
To determine the yield in the photolysis, the combined eluent
from 20 beads of each compound was quantitatively analyzed
versus an analytically pure sample of the corresponding imidaz-
olidin-4-one. Released compound yields range from 12% to 38%
over eight steps (Table 1). The purity level of the crude substi-
tuted imidazolidin-4-one is exceptionally high. This is exemplified
in Figure 2, which shows the HPLC profile at 220 nm of the puri-
fied analytical standard of 16d in comparison to the crude bead
eluent.11
In conclusion, a general solid-phase synthesis of 1,2,5-trisubsti-
tuted imidazolidin-4-ones has been developed. The synthesis per-
forms well with a wide range of R1, Ar2, and R3 components, and
provides a high level of purity. This route provides an effective
and efficient method for the construction of both parallel and com-
binatorial 1,2,5-trisubstituted imidazolidin-4-one libraries.
Ar2
Ar2
O
O
16
R3
O
13
O
R1
N
d
d
R1
O
R1
O
N
HN
NH
Ar2
N
N
Ar2
Ar2
12
HN
HN
R3
R3
17
14
15
O
O
R1
O
R1
O
c
N
HN
N
N
Ar2
Ar2
O
O
R3
R3
18
Scheme 5. Reagents and conditions: (a) 0.25 M benzoic acid, BOPCl, DIEA, CH2Cl2,
or neat acetic anhydride, 25 °C; (b) 0.25 M isocyanate, CH2Cl2, 25 °C; (c) 0.25 M
chloroformate, DIEA, CH2Cl2, 25 °C; (d) TFA/H2O/isopropanol (3:20:80), h
325 nm wavelength), 50 °C.
m (265–

422
L.-Y. Qin et al. / Tetrahedron Letters 50 (2009) 419–422
Figure 2. (A) HPLC profile of the standard of 16d at 220 nm. (B) HPLC profile of the crude bead eluent of 16d at 220 nm.
6. Blass, B. E.; Coburn, K.; Fairweather, N.; Fluxe, A.; Hodson, S.; Jackson, C.;
Janusz, J.; Lee, W.; Ridgeway, J.; White, R.; Wu, S. Tetrahedron Lett. 2006, 47,
7497–7499.
References and notes
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ˇ
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10. Microwave reactions were performed using a EmrysTM Optimizer at 180 °C for
10 min.
11. Analytical HPLC analysis was conducted using a PDA-linked Waters Millenium
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