A traceless solid-phase synthesis of 2-imidazolones

Article abstract of DOI:10.1016/S0040-4039(02)00897-3

A traceless solid-phase synthesis of 2-imidazolones has been developed. Polymer-bound glycerol resin was reacted with bromoacetaldehyde diethyl acetal to give the cyclic acetal bromide on the solid support. Amination of the resin-bound acetal bromide followed by urea formation by reaction with isocyanates afforded the resin-bound urea acetals. The aldehyde urea intermediate, which was released from the resin upon treatment with TFA, immediately cyclized to afford the desired 2-imidazolones in good yield and purity.

Full text of DOI:10.1016/S0040-4039(02)00897-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4571–4573
A traceless solid-phase synthesis of 2-imidazolones
Jie-Fei Cheng,* Christopher Kaiho, Mi Chen, Thomas Arrhenius and Alex Nadzan
Department of Chemistry, Chugai Pharma USA, LLC, 6275 Nancy Ridge Dr., San Diego, CA 92121, USA
Received 10 April 2002; accepted 10 May 2002
Abstract—A traceless solid-phase synthesis of 2-imidazolones has been developed. Polymer-bound glycerol resin was reacted with
bromoacetaldehyde diethyl acetal to give the cyclic acetal bromide on the solid support. Amination of the resin-bound acetal
bromide followed by urea formation by reaction with isocyanates afforded the resin-bound urea acetals. The aldehyde urea
intermediate, which was released from the resin upon treatment with TFA, immediately cyclized to afford the desired
2-imidazolones in good yield and purity. © 2002 Elsevier Science Ltd. All rights reserved.
Construction of heterocyclic ring systems on solid sup-
port continues to be of considerable interest in combi-
natorial organic synthesis. In this context, developing
useful method for building heterocyclic systems without
leaving a linker trace. Herein we describe a convenient
synthesis of 2-imidazolones using this strategy.
3
1
methodologies that provide access to these heterocyclic
systems without leaving any trace of the linker used for
tethering the starting building blocks to the solid sup-
2
-Imidazolones have long been known to possess some
4
interesting biological activities. Several synthetic proce-
dures have been reported in the literature. The most
convenient one is the intramolecular N-acyliminium ion
cyclization. It is well known that N-acyliminium ions
spontaneously deprotonate to afford the enamides in
2
5
port is one of the greatest challenges. As part of our
program to develop heterocyclic systems using solid
phase organic synthesis (SPOS), we found the
intramolecular cyclization of N-acyliminium ions of
acetal amides (or ureas) on the solid support to be a
6
the absence of any nucleophiles. This chemistry has
been successfully used to prepare 2-imidazolones and
3
related compounds in the solution phase. We envi-
Table 1. 2-Imidazolones via traceless solid-phase synthesis
sioned that if the acetal functionality was mounted onto
a polymer, the latter could serve as both a solid support
and a protecting group. Upon deprotection of the
polymer-bound acetal functionality under acidic condi-
tions, the released amide (or urea) aldehyde intermedi-
ate would spontaneously undergo cyclization to form
an N-acyliminium ion that would deprotonate to afford
the desired 2-imidazolones.
Entry
R1
R2
Ph
m-CF Ph
m-MeOPh
Et
Ph
n-Bu
m-CF Ph
m-MeOPh
Ph
Yielda
1
2
3
4
5
6
7
8
9
PhCH CH
PhCH CH
PhCH CH
PhCH CH
n-Bu
Ph
n-Bu
n-Bu
Bn
55
46
62
61
60
10
61
56
55
62
61
2
2
2
2
2
2
3
2
2
3
We investigated several previously reported approaches
7
to polymer-bound acetal functionalities, including
Wang resin and glycerol-resin based acetals. Although
Wang resin gave similar results as glycerol resin (vide
infra), it is not as good as glycerol resin in terms of
product purity and yields. IR analysis indicated the
presence of unreacted hydroxyl groups in the case of
Wang resin was used, probably due to incomplete
conversion. Therefore the reaction was conducted using
1
1
0
1
Bn
Bn
Et
m-MeOPh
a
Isolated yield based on the starting glycerol resin (Aldrich, loading
.38 mmol/g). All products were purified by preparative TLC and
gave satisfactory H NMR and ESIMS data.
1
1
8
glycerol resin. Acetal exchange of bromoacetaldehyde
Keywords: 2-imidazolone; traceless linker; solid-phase organic synthe-
diethyl acetal under acidic condition with polymer-
bound glycerol afforded the polymer-bound bromide
(2). The following acids were tested: camphorsulfonic
sis.
*
Corresponding author. Tel.: +1 858 535 5903; fax: +1 858 535 5994;
e-mail: jcheng@chugaibio.com
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00897-3

4
572
J.-F. Cheng et al. / Tetrahedron Letters 43 (2002) 4571–4573
Scheme 1. A traceless solid-phase synthesis of 2-imidazolones.
8
acid (CSA), p-toluenesulfonic acid (PTS) and pyri-
dinium p-toluenesulfonate (PPTS). CSA was the most
efficient and gave the cleanest product. IR analysis and
General procedure: Glycerol resin (250 mg, 1.38 mmol/
g) was suspended in dichloromethane (3 mL) in a 10
mL tube with frit and screw cap. Camphor sulfonic
acid (1 equiv.) was added followed by 2-bromoacetalde-
hyde diethyl acetal (10 equiv.). The suspension was
shaken in a shaker at room temperature for 12 h. The
solvent was drained, and the resin was washed with
DMF (3×6 mL), MeOH (3×6 mL) and CH Cl (3×6
9
weight change of the resin confirmed the formation of
bromide on the solid support. Amination of the inter-
1
0
mediate bromide with primary amine afforded the
desired amine (3) on the solid support. IR analysis
showed the appearance of NH absorption.
2
2
mL) and dried under vacuum at room temperature. The
dried resin was suspended in DMSO (3 mL). Benzyl-
amine (6 mmol) was added, and the reaction suspen-
sion was heated in an oven shaker at 80°C for 6–16 h.
The solvent was drained and the resin was washed and
dried as described above to give the resin-bound amine.
To the polymer-bound amine suspended in toluene (3
mL) was added m-methoxyphenylisocyanate (10 equiv.)
and DMAP (1 equiv.). The suspension was heated to
60°C in the oven shaker for 6 h. After washing and
drying, the resin was cleaved with 20% TFA in
Reaction of the resin-bound amine 3 with isocyanates
gave the desired urea (4) under a variety of conditions.
The reaction went smoothly in THF, CH Cl or toluene
2
2
and in the presence or absence of bases as evidenced by
the successful formation of the final products. In order
to ensure the complete reaction with relatively unreac-
tive isocyanates or sterically hindered amines, the reac-
tion was conducted at 60°C in toluene in the presence
of DMAP or DIPEA. Finally, treatment of the acetal
urea (4) with 20% TFA in CH Cl released the alde-
2
2
hyde, which spontaneously cyclized to give 2-imida-
dichloromethane followed by 50% TFA in H O
2
zolones 5 in good yields and purity (Table 1).
afforded the crude product. Further purification by
preparative TLC (30% ethyl acetate in hexanes) gave
The reaction sequence toward 2-imidazolones shown in
Scheme 1 is extremely simple. The overall yield seems
to be affected only by the efficiency of formation of
resin-bound acetal, not by amination or urea forma-
tion. While a variety of aliphatic amines and all iso-
cyanates worked well under these conditions, aromatic
the N-benzyl-N%-(3%-methoxylphenyl)-2-imidazolone in
1
61% yield. H NMR (CDCl ) l 7.5 (d, 1H), 7.3 (m,
3
6H), 7.0 (m, 2H), 6.4 (d, 1H), 6.2 (d, 2H), 4.8 (s, 2H),
3.8 (s, 3H). ESIMS: m/z 281 (M+H), C H N O .
17
16
2
2
amines (R =Ar) were not as efficient as aliphatic
Acknowledgements
1
amines. For example, when aniline (R =Ph) reacted
1
with resin-bound bromide 2 followed by reaction of the
resulting amine with n-BuNCO, only a small amount of
the desired product N-butyl-N%-phenyl-2-imidazolone
We would like to thank Dr. Peter Simms and Ms.
Cynthia Jeffries for HPLC and mass spectrometric
analysis and Dr. Mark Wilson for his helpful comments
on the manuscript.
(
Table 1, entry 6) was obtained (ca. 10% yield).
Although the same product was obtained in 60% yield
Table 1, entry 5) simply by switching the reagents, the
(
current condition may not the best for preparing N,N%-
diarylimidazolones.
References
In summary, a new and straightforward traceless solid-
phase synthesis of 2-imidazolones has been developed.
The reaction conditions are amenable to the synthesis
of large combinatorial libraries and the purity of the
final product is excellent.
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