Solid-phase synthesis of disubstituted 1,3-dihydro-2H-imidazol-2-ones

Article abstract of DOI:10.1055/s-2005-868476

An efficient and straightforward solid-phase synthesis of sulfonylimidazolones 2a-g is described. Our design was directed toward obtaining molecules for a general library development and incorporates functionalities that fulfill lead-like criteria. The synthesis was realized with the use of SPOS in fair to good yields and purity. Monitoring and quantitation of intermediates and final products were performed by the use of LCMS and NMR spectroscopy.

Full text of DOI:10.1055/s-2005-868476

1
322
LETTER
Solid-Phase Synthesis of Disubstituted 1,3-Dihydro-2H-imidazol-2-ones
S
M
olid-Phase
S
ynthesis
.o f Substitute
P
d Imidazolone
a
s
tek,* A. S. Weichsel, B. Drake, M. Smrcina
Sanofi-Aventis Center for Combinatorial Technologies, 1580 E. Hanley Blvd., Tucson, Arizona 85737, USA
Fax +1(520)5758283; E-mail: Marcel.Patek@sanofi-aventis.com
Received 23 February 2005
O
O
Abstract: An efficient and straightforward solid-phase synthesis of
R2
R1
R2
R1
sulfonylimidazolones 2a–g is described. Our design was directed
toward obtaining molecules for a general library development and
incorporates functionalities that fulfill lead-like criteria. The syn-
thesis was realized with the use of SPOS in fair to good yields and
purity. Monitoring and quantitation of intermediates and final prod-
ucts were performed by the use of LCMS and NMR spectroscopy.
N
N
N
N
O
O
R3
R4
S
1
2
Ar
Figure 1
Key words: imidazolones, solid-phase synthesis, acyliminium ion,
nucleophiles, combinatorial chemistry
zole, thus suggests its inclusion in the general category of
drug-like structures’.
Known approaches to the solution-phase synthesis of
,5-substituted imidazolones are generally based on
‘
A major challenge in combinatorial chemistry today is the
development of new methods and synthetic strategies for
efficient formation of carbon–carbon and carbon–hetero-
atom bonds with the prospect of synthesizing new com-
pounds of potential biological and therapeutic value.
Small heterocyclic scaffolds, such as 2-imidazolones 1,
become a popular choice for the construction of libraries
4
condensation of ureas with carbonyl compounds and in-
clude reaction of (i) a-amino carbonyl compounds with
isocyanates followed by thermal or acid-catalyzed de-
4,9
hydration, (ii) reaction of ureas with acyloins, a-keto-
10
aldehydes, or a-bromoketones and (iii) N-carbamoyl-
iminium ion formation followed by inter/intramolecular
1
for general screening. The imidazolone scaffold appears
11a–c
cyclizations in the presence of internal
nucleophiles.
or external
in a diverse array of biologically active compounds of
both natural (e.g. biotin, hydantoins) and synthetic origin
and has received extensive attention in medicinal chemis-
11d–f
As part of our program on the combinatorial synthesis of
small organic molecules, we have adapted the above-men-
tioned tandem N-carbamoyliminium ion formation–nu-
cleophilic addition reaction sequence to the solid-phase
conditions for direct access to the substituted imidazolo-
nes 2.
2
try (Figure 1). Imidazolone’s diverse portfolio of biolog-
ical activities, including inhibition of phosphodiesterase
3
4
IV (PDE4), selective agonism of b adrenergic receptor,
3
5
inhibition of protein kinase C, selective antagonism of
6
7
dopamine D4 receptor, antagonism of angiotensin II,
and inhibition of CoA-independent transacylase (CoA- The corresponding synthetic approach that we have devel-
8
IT), as well as its close structural relationship to imida- oped toward the target structures 2 is shown in Scheme 1.
Scheme 1
SYNLETT 2005, No. 8, pp 1322–1324
1
7.
0
5.
2
0
0
5
Advanced online publication: 21.04.2005
DOI: 10.1055/s-2005-868476; Art ID: S02305ST
©
Georg Thieme Verlag Stuttgart · New York

LETTER
Solid-Phase Synthesis of Substituted Imidazolones
1323
The initial studies have centered on brief examination of to form the ureas 4. After the treatment with glyoxal and
the urea formation on the Novagel Rink and PS-PAL res- the corresponding sulfinic acids, cleavage was initiated
12
ins using isocyanates. Resin-bound ureas 4a–g were ob- 80% TFA in CH Cl . In all cases, the imidazolones were
2
2
tained in a classic one-step procedure involving the linker formed in >50% purity (HPLC analysis, UV detection at
treatment with ten equivalents of isocyanate in dry DMF 220 nm) and isolated by MS triggered preparative HPLC.
at room temperature for five hours. To establish a general
protocol for the preparation of imidazolones 2a–g, we
have investigated the reaction of urea substituted resin 4
with glyoxal and sulfinic acids in different conditions
In conclusion, we have developed an efficient method to
synthesize substituted imidazolones with direct C-SO2
bond connections. To exemplify the utility of this solid-
phase synthesis, a small set of substituted imidazolones
varying solvents (HCOOH, AcOH, dioxane), acid cata-
was synthesized and products were fully characterized.
lysts, reaction times (2–24 h), and concentration of sulfin-
The general availability of isocyanates and sulfinic acids
ic acid. Acetic acid used as a solvent and proton source
further enhances the utility of this reaction in the construc-
was found to be superior to other solvent systems. Our op-
tion of combinatorial libraries containing imidazolone
timized reaction conditions utilize 20 equivalents of gly-
scaffolds.
oxal and 10 equivalents of sulfinic acid (or its sodium salt)
in AcOH (0.5 M concentration of the sulfinic acid) at ei-
Acknowledgment
ther room temperature (16 h) or at 80 °C (30 min). Final
cleavage from the resins was accomplished by 80% TFA/
CH Cl in the presence of 4% i-Pr SiH. In general, we
We thank Harald Schroeder for the supporting NMR data.
2
2
3
have obtained better yields of the products when using the
Rink linker with aliphatic isocyanates and the PAL linker
with arylisocyanates. Poor yields were observed when
heteroarylisocyanates were used to form ureas 4. Addi-
tionally, only arylsulfinic acids provided expected imida-
zolone products. Overall, under the optimized reaction
conditions, the isolated yields were in the range of 20–
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R1
Ar
Yield (%) Ratio C4/C5
a
b
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Et
4-Me-C H
62
25
23
24
24
30
35
1:8
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4
4-EtO-C H4
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1:10
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t-Bu
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NA
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6
6
5
5
g
H
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6
In accordance with literature data,11f the reaction regio-
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rates of cleavage from the resin were observed for each of
the regioisomers, the 4-regioisomer being cleaved first
(
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(
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(
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1
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1
1f
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(
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Synlett 2005, No. 8, 1322–1324 © Thieme Stuttgart · New York

1
324
M. Patek et al.
LETTER
(
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2
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(
1
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mmol). The suspension was shaken for 16 h at r.t. or for 30
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(
2
2
(
2
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product 9 that was further purified by preparative LCMS.
Synlett 2005, No. 8, 1322–1324 © Thieme Stuttgart · New York