Abstract
Combinatorial parallel synthesis of bis-benzimidazoles by focused (mono-modal) microwave
irradiation is described. Polymer immobilized o-phenylenediamines as a versatile template was synthesized under microwave irradiation.
The resulting PEG bound diamines was N-acylated with 4-fluoro-3-nitrobenzoic acid
selectively in primary aromatic amino moiety. Nucleophilic aromatic substitution of
the amide obtained was performed with different amines then cyclized to benzimidazole
in acidic condition. Successive reduction, cyclization with various aldehydes yielded
5-(benzimidazol-2-yl)benzimidazoles. The desired products were released from the polymer
support to afford the tri-substituted bis-benzimidazoles in good yields and purity.
Key words
bis-benzimidazole - combinatorial chemistry - liquid-phase method - solid-phase method
- scaffold
References
<A NAME="RS09203ST-1A">1a</A>
Lenz GR.
Nash HM.
Jindal S.
Drug Discovery Today
2000,
5:
145
<A NAME="RS09203ST-1B">1b</A>
Falb D.
Jindal S.
Curr. Opin. Drug Discovery Dev.
2002,
5:
1367
<A NAME="RS09203ST-2A">2a</A>
Dolle RE.
Mol. Diversity
1996,
2:
223
<A NAME="RS09203ST-2B">2b</A>
Dolle RE.
Nelson KH.
J. Comb. Chem.
1999,
1:
235
<A NAME="RS09203ST-2C">2c</A>
Dolle RE.
J. Comb. Chem.
2000,
2:
383
<A NAME="RS09203ST-2D">2d</A>
Dolle RE.
J. Comb. Chem.
2001,
3:
477
<A NAME="RS09203ST-2E">2e</A>
Dolle RE.
J. Comb. Chem.
2003,
5:
693
For a review see:
<A NAME="RS09203ST-3A">3a</A>
Sun CM.
Comb. Chem. High Throughput Screening
1999,
2:
299
<A NAME="RS09203ST-3B">3b</A>
Toy PH.
Janda KD.
Acc. Chem. Res.
2000,
33:
546
<A NAME="RS09203ST-3C">3c</A>
Sun CM.
Soluble Polymer-Supported Synthesis of Heterocyclic Libraries, In ‘Combinatorial Chemistry
Methods and Protocols’, Methods in Molecular Biology Series
Bellavance L.
The Humana Press Inc.;
New Jersey:
2002.
Chap. 10.
p.345-371
<A NAME="RS09203ST-4">4</A>
Franzén R.
J. Comb. Chem.
2000,
2:
195
<A NAME="RS09203ST-5">5</A>
Shey JY.
Sun CM.
Tetrahedron Lett.
2002,
43:
1725
Microwave-assisted solid-phase combinatorial synthesis:
<A NAME="RS09203ST-6A">6a</A>
Stadler A.
Kappe CO.
J. Comb. Chem.
2001,
3:
624
<A NAME="RS09203ST-6B">6b</A>
Lew A.
Krutzik PO.
Hart ME.
Chamberlin RA.
J. Comb. Chem.
2002,
4:
95
<A NAME="RS09203ST-6C">6c</A>
Al-Obeidi F.
Austin RE.
Okonya JF.
Bond DRS.
Mini-Rev. Med. Chem.
2003,
3:
459
<A NAME="RS09203ST-6D">6d</A>
Blackwell HE.
Org. Biomol. Chem.
2003,
1:
1251
<A NAME="RS09203ST-7A">7a</A>
Kohara Y.
Kubo K.
Imamiya I.
Wada T.
Inada Y.
Naka T.
J. Med. Chem.
1996,
39:
5228
<A NAME="RS09203ST-7B">7b</A>
Roth T.
Morningstar ML.
Boyer PL.
Hughes SH.
Buckheit RW.
Micheda CJ.
J. Med. Chem.
1997,
40:
4199
<A NAME="RS09203ST-7C">7c</A>
Porcari AR.
Devivar RV.
Kucera LS.
Drach JC.
Townsend LB.
J. Med. Chem.
1998,
41:
1252
<A NAME="RS09203ST-7D">7d</A>
Zarrinmayeh H.
Nunes AM.
Ornstein PL.
Zimmernan DM.
Arnold MB.
Schober DA.
Gackenheimer SL.
Bruns RF.
Hipskind PA.
Britton TC.
Cantrell BE.
Gehlert DR.
J. Med. Chem.
1998,
41:
2709
<A NAME="RS09203ST-7E">7e</A>
Gua Z.
Zhou D.
Schultz PG.
Science
2000,
288:
2042
<A NAME="RS09203ST-8">8</A>
Singh AK.
Lown JW.
Anti-Cancer Drug Design
2000,
15:
265
<A NAME="RS09203ST-9A">9a</A>
Mann J.
Baron A.
Boahen YO.
Johansson E.
Parkinson G.
Kelland LR.
Neidle S.
J. Med. Chem.
2001,
44:
138
<A NAME="RS09203ST-9B">9b</A>
Rastogi K.
Chang JY.
Pan WY.
Chen CH.
Chou TC.
Chen LT.
Su TL.
J. Med. Chem.
2002,
45:
4485
<A NAME="RS09203ST-10">10</A>
Jin S.
Kim JS.
Sim SP.
Lin A.
Pilch DS.
Liu LF.
LaVoie EJ.
Bioorg. Med. Chem. Lett.
2000,
10:
719
<A NAME="RS09203ST-11">11</A>
Yeung KS.
Meanwell NA.
Qiu Z.
Hernandez D.
Zhang S.
McPhee F.
Weinheimer S.
Clark JM.
Janc JW.
Bioorg. Med. Chem. Lett.
2001,
11:
2355
<A NAME="RS09203ST-12">12</A> Solid phase synthesis of 5-(benzimidazol-2-yl)benzimidazoles:
Mazurov A.
Bioorg. Med. Chem. Lett.
2000,
10:
67
<A NAME="RS09203ST-13A">13a</A>
White S.
Szewczyk JW.
Turner JM.
Baird EE.
Dervan PB.
Nature
1998,
391:
468
<A NAME="RS09203ST-13B">13b</A>
Kielopf CL.
White S.
Szewczyk JW.
Turner JM.
Baird EE.
Dervan PB.
Rees DC.
Science
1998,
282:
111
<A NAME="RS09203ST-13C">13c</A>
Dervan PB.
Bürlj RW.
Curr. Opin. Chem. Biol.
1999,
3:
688
MW-assisted reactions on soluble polymer support:
<A NAME="RS09203ST-14A">14a</A>
Blettner CG.
König WA.
Stenzel W.
Schotten T.
J. Org. Chem.
1999,
64:
3885
<A NAME="RS09203ST-14B">14b</A>
Bendale PM.
Sun CM.
J. Comb. Chem.
2002,
4:
359
<A NAME="RS09203ST-14C">14c</A>
Wu CY.
Sun CM.
Synlett
2002,
10:
1709
<A NAME="RS09203ST-14D">14d</A>
Lin MJ.
Sun CM.
Tetrahedron Lett.
2003,
44:
8739
<A NAME="RS09203ST-15">15</A>
All the microwave assisted polymer-supported reactions described here were performed
in a 50 mL round bottom flask (attached to the reflux condenser) with CEM Discover
Microwave System at a frequency of 2450 Hz (0-300 W).
A Typical Procedure for the Synthesis of 4:
A mixture of polyethylene glycol (MW χα. 6000, 0.1 mmol), DCC (N,N′-dicyclohexylcarbodiimide, 0.15 mmol), DMAP (5 µmol) and 4-fluoro-3-nitrobenzoic
acid (0.15 mmol) in CH2Cl2 (10 mL) was irradiated under microwave cavity with an output at 300 W for 5 min.
Upon completion of the reaction, Et2O (30 mL) was added to the reaction mixture in an ice-water bath to precipitate out
PEG-bound compound. The precipitate was then collected on sintered glass funnel and
thoroughly washed with Et2O (3 × 10 mL) following filtration. To 600 mg each of the above resin was added 3
equiv of primary amines and 10 mL CH2Cl2 at r.t. The reaction mixtures were irradiated in a microwave (300 W) for 5 min. After
completion, polymer bound product was purified by precipitation method and was redissolved,
precipitated twice and dried in vacuo. To 600 mg each of the above resin was added
zinc (2.0 mmol) and NH4Cl (0.56 mmol) in CH3OH (10 mL) at r.t. The reaction mixtures were irradiated in microwave cavity with
an output at 300 W for 6 min and the bright yellow color of the solution was observed
to disappear. The same work-up procedure has been followed by precipitation to separate
side products and desired polymer-supported diaminobenzene. The crude PEG product
4 was redissolved, precipitated twice and dried in vacuo for the next sequence.
<A NAME="RS09203ST-16">16</A>
Morita S.
Kitano K.
Matsubara J.
Ohtani T.
Kawano Y.
Otsubo K.
Uchida M.
Tetrahedron
1998,
54:
4811
<A NAME="RS09203ST-17">17</A>
Ohemeng KA, and
Nguyen VN. inventors; US Patent 5,942,532.