Efficient solid-phase synthesis of disubstituted 1,3-dihydro-imidazol-2- ones

Article abstract of DOI:10.1055/s-2004-831316

A bromoacetal linker was used to achieve the synthesis of ureas on a solid support. The resulting ureido acetals were treated with TFA and were converted in an intramolecular cyclization via N-acyliminium ion to disubstituted 1,3-dihydro-imidazol-2-ones.

Full text of DOI:10.1055/s-2004-831316

LETTER
2167
Efficient Solid-Phase Synthesis of Disubstituted 1,3-Dihydro-imidazol-2-ones
Synthesis of
D
isub
é
stituted 1, 3
r
-Dihydr
a
r2-ones d Rossé,* Julie Strickler, Marcel Patek
Chemistry Department, Aventis Combinatorial Technologies Center, Tucson, AZ 85737, USA
E-mail: gerard.rosse@aventis.com
Received 9 July 2004
to give the desired products. The ureido-acetal resin 3 was
Abstract: A bromoacetal linker was used to achieve the synthesis
of ureas on a solid support. The resulting ureido acetals were treated
with TFA and were converted in an intramolecular cyclization via
N-acyliminium ion to disubstituted 1,3-dihydro-imidazol-2-ones.
obtained by reacting resin 2 in NMP at 70 °C with either
isocyanates or with amines, which were pretreated with
N,N¢-carbonyldiimidazoles (CDI). The activation of ali-
phatic or aromatic amines with CDI represented a simple
and inexpensive method for the formation of ureas when
the desired isocyanates were not commercially available.
Key words: heterocycles, acetals, solid-phase synthesis, nucleo-
philes, cyclizations
The synthesis of heterocyclic ring systems on solid sup-
port to rapidly generate collections of small molecules
useful in medicinal chemistry programs is of considerable
interest.1 In the search for novel methodologies, we inves-
tigated the application of intramolecular cyclization via
N-acyliminium ion2 on solid support.3 An important side
reaction in N-acyliminium ion chemistry is the formation
of enamides.4 We report herein the solid-phase synthesis
of 1,3-dihydro-imidazol-2-ones using this strategy.
Substituted 1,3-dihydro-imidazol-2-ones are found in
many synthetic compounds that exhibit for example activ-
ities as central nervous system depressant5 as well as
properties desirable in the treatment of thrombosis,6
Alzheimer disease7 and obesity.8 Due to their broad bio-
logical activities several synthetic procedures have been
reported.9 The synthetic strategy using bromoacetalde-
hyde dimethylacetal as starting material is especially at-
tractive. Following this strategy, 1,3-dihydro-imidazol-2-
ones are obtained in a three step synthesis involving the
displacement of the bromine with primary amines, their
conversion to ureido-acetals and an acidic treatment to
generate the oxonium functionality. The activated alde-
hyde then reacts spontaneously with the urea to form an
N-acylimium ion, which in the absence of nucleophiles
deprotonates to form the 1,3-dihydro-imidazol-2-one. To
be successful, this synthetic pathway requires the purifica-
tion of each intermediates and is therefore not appropriate
for the preparation of combinatorial libraries. A solid-
phase synthesis strategy will avoid the purification steps.
Since we have made a bromoacetal resin available,3a we
realized that this three-step synthetic pathway is ideally
suited for a solid-phase synthesis.
Scheme 1 (i) R1-NH2, DMSO–NMP 1:1, 80 °C; (ii) R2-NCO or R2-
NH2–CDI, NMP, 70 °C; (iii) TFA, 16 h.
Table 1 N-Acyliminium Cyclization Yielding 4a–k
R1
Bn
Bn
R2
Ph
Product Yield (%)a
4a
4b
37
77
5-tert-butyl-1H-3-
aminopyrazole
Bn
Et
4c
4d
4e
4f
25
53
42
24
11
89
76
73
71
Bn
Bn
Me
4-Cl-Ph
Me
Ph
(Ph)2CH
Et
4g
4h
4i
The synthesis started with the reaction of bromoacetal res-
in 110 with primary amines in a mixture of DMSO–NMP
at 80 °C to afford the amino acetal resins 2 (Scheme 1).
Whilst the reaction proceeded well with non-aromatic
amines, the nucleophilic substitution with anilines failed
(CH3)2N-CH2CH2-
(CH3)2N-CH2CH2-
(CH3)2N-CH2CH2-
(CH3)2N-CH2CH2-
4-Cl-Ph
Ph
3,4,5-(MeO)3-Ph
Bn
4j
4k
SYNLETT 2004, No. 12, pp 2167–2168
Advanced online publication: 31.08.2004
DOI: 10.1055/s-2004-831316; Art ID: G26404ST
© Georg Thieme Verlag Stuttgart · New York
0
1
.1
0
.2
0
0
4
a Yields in % of purified products are based on the initial loading of
bromoacetal resin (1.6 mmol/g). A purity >90% was observed for all
examples described as determined by LC-MS, detecting at 220 nm.

2168
G. Rossé et al.
LETTER
(9) (a) Wang, P. C. Heterocycles 1985, 23, 3041. (b) Lee, Y.
Treatment of the ureido-acetal resin 3 with TFA afforded
the 1,3-dihydro-imidazol-2-ones 4. The monitoring of the
final cleavage step by LC-MS analysis showed a rapid
cleavage of the compounds from the resin and a subse-
quent slow intramolecular cyclization, which required 16
hours for completion. The compounds 4 were purified by
preparative reverse-phase LC-MS and obtained in good
yields (Table 1). All new compounds were characterized
by LC-MS, 1H- and 13C NMR analysis.11
S.; Kim, C. S.; Park, H. Heterocycles 1994, 38, 2605.
(c) Cheng, J. F.; Kaiho, C.; Chen, M.; Arrhenius, T.; Nadzan,
A. Tetrahedron Lett. 2002, 43, 4571. (d) Cheng, J. F. WO
Patent 2002020493A2, 2002; see also ref.5–8
.
(10) Bromoacetal resin has been prepared as described in ref.3a.
Bromoacetal linker attached on TentaGel or polystyrene
resin is now commercially available from Novabiochem
(www.novabiochem.com), Rapp Polymers (www.rapp-
polymer.com) and LCC Technologies (http://
www.chemsupply.ch).
In summary, we have developed an expedient and
straightforward approach to synthesize disubstituted 1,3-
dihydro-imidazol-2-ones. The use of high loading resin
was particularly useful for rapidly preparing combinatori-
al libraries of 4 in good quality and sufficient amounts for
biological, physicochemical and eADME evaluation.
(11) The synthesis of 4a and 4b are representative of the
procedure used for the parallel synthesis of the libraries.
Benzyl-amino-acetal Resin (2a): Bromoacetal LCC-
Dynosphere polystyrene resin (100 mg, 0.16 mmol, 203 m,
batch#F-BAS/270-F146.1, 1.6 mmol/g as determined by
elemental analysis, from LCC Engineering, Switzerland)
was swollen once with NMP (5 mL). A mixture of DMSO–
NMP 1:1 (2 mL) was added followed by benzylamine (257
mL, 2.4 mmol). The reaction mixture was shaken for 16 h at
80 °C, filtered off, washed three times with DMF (3 mL),
three times with i-PrOH (3 mL) and four times with DMF (3
mL) each. A sample of the resin was washed five times with
i-PrOH (3 mL) and dried under high vacuum: 94%
conversion based on elemental analysis. Anal. Found: N,
2.03; Br, 0.33.
Acknowledgment
We gratefully thank Harald Schroeder for the NMR data.
References
(1) (a) Hermkens, P. H. H.; Ottenheijm, H. C. J.; Rees, D.
Tetrahedron 1996, 52, 4527. (b) Hermkens, P. H.;
Ottenheijm, H. C.; Rees, D. C. Tetrahedron 1997, 53, 5643.
(c) Obrecht, D.; Villalgordo, J. M. Solid-Supported
Combinatorial and Parallel Synthesis of Small-Molecular-
Weight Compound Libraries; Elsevier Science Ltd: Oxford,
1998. (d) Bunin, B. A.; Dener, J. M.; Livingston, D. A.
Annu. Rep. Med. Chem. 1999, 34, 267. (e) Guillier, F.;
Orain, D.; Bradley, M. Chem. Rev. 2000, 100, 2091.
(f) Franzen, R. G. J. Comb. Chem. 2000, 2, 195.
(2) (a) Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41,
4367. (b) Maryanoff, B. E.; Zhang, H.-C.; Cohen, J. H.;
Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431.
(3) (a) Vojkovsky, T.; Weichsel, A.; Patek, M. J. Org. Chem.
1998, 63, 3162. (b) Eguchi, M.; Lee, M.; Nakanish, H.;
Stasiak, M.; Lovell, S.; Kahn, M. J. Am. Chem. Soc. 1999,
121, 1204. (c) Kohn, W. D.; Zhang, L. Tetrahedron Lett.
2001, 42, 4453. (d) Eguchi, M.; McMillan, M.; Nguyen, C.;
Teo, J. L.; Chi, E. Y.; Henderson, W. R. Jr.; Kahn, M. Comb.
Chem. High Throughput Screening 2003, 6, 611.
(4) Lee, Y. S.; Kim, C. S.; Park, H. Heterocycles 1994, 38, 2605.
(5) Wright, W. B. Jr.; Brabander, H. J.; Hardy, R. A. Jr. J. Med.
Chem. 1966, 9, 858.
(6) Himmelsbach, F.; Pieper, H.; Austel, V.; Linz, G.; Guth, B.;
Mueller, T.; Weisenberger, J. Eur. Pat. Appl. EP 0612741
A1, 1994.
(7) Moon, M. W.; Chidester, C. G.; Heier, R. F.; Morris, J. K.;
Collins, R. J.; Russell, R. R.; Francis, J. W.; Sage, G. P.;
Sethy, V. H. J. Med. Chem. 1991, 34, 2314.
1-Benzyl-3-phenyl-1,3-dihydro-imidazol-2-one (4a):
NMP (2 mL) and phenylisocyanate (285 mL, 2.4 mmol) were
successively added to resin 3a (0.16 mmol). The reaction
mixture was shaken for 7 h at 70 °C, filtered off, washed
three times with DMF (3 mL), three times with i-PrOH (3
mL) and five times with CH2Cl2 (3 mL) each. After drying
the resin for 30 min under vacuum (ca. 20 mbar house
vacuum), TFA (3 mL) was added and the reaction mixture
was shaken for 17 h. This eluate and one subsequent wash
with TFA (2 mL) were collected and combined. The solvent
was evaporated and the residue was purified by preparative
LC-MS with a Waters Fractionlynx system (YMC Pack Pro
C18 column, 5 m, 120Å, 50 × 20 mm) using a gradient of H2O
and MeCN (in 7 min from 5% MeCN to 85% MeCN, in 0.1
min from 85% MeCN to 95% MeCN, 1.2 min at 95%
MeCN, in 0.1 min from 95% MeCN to 5% MeCN, flow: 35
mL/min, an autoblend method was used to ensure a
concentration of 0.1% TFA throughout the complete run).
Compound 4a: 21 mg (37%). ESI-MS: m/z (%) = 251.1
(100) [M + H]+. 1H NMR (300 MHz, DMSO-d6): d = 7.65 (d,
J = 2.6 Hz, 2 H), 7.23–7.47 (m, 8 H), 6.59 (d, J = 1.0 Hz, 1
H), 6.28 (d, J = 1.0 Hz, 1 H), 6.40 (s, 1 H), 4.90 (s, 2 H). 13
NMR (150 MHz, DMSO-d6): d = 151.1, 137.3, 137.1,
128.7, 128.3, 126.7, 121, 112.2, 109.8, 66.1.
C
1-Benzyl-3-(5-tert-butyl-1H-pyrazol-3-yl)-1,3,-dihydro-
imidazol-2-one (4b): 5-tert-butyl-1H-3-aminopyrazol (334
mg, 2.40 mmol) was dissolved in NMP (2.4 mL). CDI (389
mg, 2.40 mmol) was dissolved in NMP (2.4 mL) and then
added to the aminopyrazole solution. The solution was
shaken for 10 min and added to the resin 3a (0.16 mmol).
The reaction mixture was shaken for 7 h at 70 °C and filtered
off. Washing of the resin, cleavage of the compound from
the resin and purification using LC-MS were performed as
described for 4a. Compound 4b: 51 mg (77%). ESI-MS:
m/z (%) = 297.2 (100) [M + H]+. 1H NMR (600 MHz,
DMSO-d6): d = 7.34–7.36 (m, 2 H), 7.27–7.30 (m, 3 H), 6.91
(d, J = 1.0 Hz, 1 H), 6.72 (d, J = 1.0 Hz, 1 H), 6.40 (s, 1 H),
4.78 (s, 2 H), 1.28 (s, 9 H). 13C NMR (150 MHz, DMSO-d6):
d = 150.4, 137.7, 128.5, 127.4, 119.5, 112.5, 107.6, 91.1,
46.1. 30.7, 29.8.
(8) (a) Naylor, E. M.; Parmoo, E. R.; Colandres, V. J.; Perkins,
L.; Brockunier, L.; Candelore, M. R.; Cascieri, M. A.;
Colwell, L. F. Jr.; Deng, L.; Foeney, W. P.; Forrest, M. J.;
Hom, G. J.; MacIntyre, D. E.; Strader, C. D.; Tote, L.; Wang,
P.-R.; Wyvratt, M. J.; Fisher, M. H.; Weber, A. E. Bioorg.
Med. Chem. Lett. 1999, 9, 755. (b) Schwink, L.; Stengelin,
S.; Gossel, M.; Boehme, T.; Hessler, G.; Rosse, G.; Walser,
A. WO Patent 2004011438A1, 2004.
Synlett 2004, No. 12, 2167–2168 © Thieme Stuttgart · New York