Use of polymer supported thiophenol for the synthesis and purification of a benzimidazol-2-one library

Article abstract of DOI:10.1016/S0040-4039(00)00185-4

An efficient solution phase synthesis of substituted benzimidazol-2-ones is described. Polymer-supported thiophenol is used to remove excess alkylating agents. A library of 24 mono- and di-substituted benzimidazol-2- ones has been prepared in 60-99% yield and 65-99% purity. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00185-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 2483–2485
Use of polymer supported thiophenol for the synthesis and
purification of a benzimidazol-2-one library
Monika Ermann,a Nadja M. Simkovsky,a Stanley M. Roberts,a,∗ David M. Parry,b
Andy D. Baxter b and John G. Montana b
aDept. of Chemistry, University of Liverpool, PO Box 147, Liverpool L69 3BX, UK
bCelltechChiroscience, Milton Road, Cambridge CB4 0WE, UK
Received 16 December 1999; accepted 25 January 2000
Abstract
An efficient solution phase synthesis of substituted benzimidazol-2-ones is described. Polymer-supported
thiophenol is used to remove excess alkylating agents. A library of 24 mono- and di-substituted benzimidazol-
2-ones has been prepared in 60–99% yield and 65–99% purity. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: molecular recognition; alkylation; supported reagents/reactions.
Recent trends in the search for novel pharmacological agents have focused on the preparation of chem-
ical libraries as potential sources of new lead compounds for drug discovery. Combinatorial chemistry
and parallel synthesis are the main strategies in creating a wide array of various pharmacophores and
optimising molecular diversity. The methodology in this area has utilised the advantages of solid phase
organic synthesis, such as separation of reagents from the product by filtration and the use of excess
starting materials to drive reactions to completion. Recently several purification strategies for solution-
phase combinatorial library synthesis have been reported.1–3 The method, described by Flynn,4 and
Parlow et al.,5 relies on the principles of complementary molecular reactivity and recognition (CMR/R)
using polystyrene beads bearing reactive groups complementary to those of reagents or byproducts requi-
ring resin sequestration. This approach is characterised by the following attributes: (1) library members
are synthesised in solution; (2) reactants, catalysts and reagents have inherent or artificially imparted
functional groups which enable their post-reaction sequestration; (3) removal of reactants, catalysts and
reagents is accomplished by incubation and filtration of the reaction mixture through resins containing
complementary molecular-reactivity or molecular-recognition functionalities; (4) purified products are
obtained by simple filtration.
Benzimidazol-2-ones and related urea derivatives exhibit a wide variety of interesting biochemical and
pharmacological properties.6,7 Several solution based8–10 and recently solid phase11,12 syntheses have
been reported.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00185-4
tetl 16465

2484
We report herein a significant improvement in the synthesis of 1,3-dihydro-benzimidazol-2-ones
compared to that originally described by Meanwell et al.13 In the latter work the heterocycle was alkylated
using a variety of alkyl halides. A deprotection step was necessary in order to give the desired product.
Using polymer-supported (PS) thiophenol14 we were able to bypass these additional purification and
isolation procedures by selective removal of excess alkylating agents. Subsequent hydrolysis of the
ethoxycarbonyl protecting group yielded the monofunctionalised urea derivatives in high yields and
purities (Scheme 1).
Scheme 1. Reagents and conditions. (i) R–X, K2CO3, KI, DMF, rt, 16 h; (ii) PS-thiophenol, DMF, rt, 6 h; (iii) K2CO3, EtOH,
rt, 6 h
Thus ethyl 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylate (1) was reacted with a range of alkyl
halides (1.1 equiv.) in dry DMF in the presence of powdered K2CO3 (1.2 equiv.) and a catalytic amount
of KI. PS-Thiophenol (3 equiv. to excess halide) was added to the reaction to remove any excess
electrophile. In situ hydrolysis of the carboxylic ester moiety using the same base (1 equiv.) in ethanol
followed by a simple work-up15 yielded the products 2a–p in high overall yields. Purities were assessed
by HPLC-MS (Table 1) and yields were corrected.
Table 1
Synthesis of 1-substituted 1,3-dihydro-benzimidazol-2-ones
In order to further explore the versatility of this methodology and increase the diversity of molecules
in the library the second, now unprotected urea nitrogen, was alkylated; the strategy is exemplified using
the N-benzyl compound 3 (Scheme 2). After quenching with polymer supported thiophenol, again the
key operation in the process, and an extractive work-up16 the bisfunctionalised heterocycles 4a–h were
obtained in good yields and excellent purities (Table 2).

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Scheme 2. Reagents and conditions. (i) R–X, K2CO3, KI, DMF, rt, 16 h; (ii) PS-thiophenol, DMF, rt, 6 h
Table 2
Synthesis of 1,3-disubstituted 1,3-dihydro-benzimidazol-2-ones
Acknowledgements
We thank Iain Reid at CelltechChiroscience for HPLC-MS data and CelltechChiroscience for the
provision of research studentships (for M.E. and N.M.S.).
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14. Supplied by Argonaut Technologies, San Carlos, CA 94070.
15. The resins were filtered off and the solvent evaporated. The residue was acidified with 1N HCl and the resulting precipitate
filtered off and dried in vacuo.
16. The resins were removed by filtration. The filtrate was diluted with water and extracted with Et2O:hexane (1:1). This solvent
switch was necessary to avoid DMF impurities. The combined organic extracts were washed with brine and dried (MgSO4).
Evaporation of the solvent yielded the bisalkylated heterocycles.