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
1a
Lenz GR.
Nash HM.
Jindal S.
Drug Discovery Today
2000,
5:
145
1b
Falb D.
Jindal S.
Curr. Opin. Drug Discovery Dev.
2002,
5:
1367
2a
Dolle RE.
Mol. Diversity
1996,
2:
223
2b
Dolle RE.
Nelson KH.
J. Comb. Chem.
1999,
1:
235
2c
Dolle RE.
J. Comb. Chem.
2000,
2:
383
2d
Dolle RE.
J. Comb. Chem.
2001,
3:
477
2e
Dolle RE.
J. Comb. Chem.
2003,
5:
693
For a review see:
3a
Sun CM.
Comb. Chem. High Throughput Screening
1999,
2:
299
3b
Toy PH.
Janda KD.
Acc. Chem. Res.
2000,
33:
546
3c
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
4
Franzén R.
J. Comb. Chem.
2000,
2:
195
5
Shey JY.
Sun CM.
Tetrahedron Lett.
2002,
43:
1725
Microwave-assisted solid-phase combinatorial synthesis:
6a
Stadler A.
Kappe CO.
J. Comb. Chem.
2001,
3:
624
6b
Lew A.
Krutzik PO.
Hart ME.
Chamberlin RA.
J. Comb. Chem.
2002,
4:
95
6c
Al-Obeidi F.
Austin RE.
Okonya JF.
Bond DRS.
Mini-Rev. Med. Chem.
2003,
3:
459
6d
Blackwell HE.
Org. Biomol. Chem.
2003,
1:
1251
7a
Kohara Y.
Kubo K.
Imamiya I.
Wada T.
Inada Y.
Naka T.
J. Med. Chem.
1996,
39:
5228
7b
Roth T.
Morningstar ML.
Boyer PL.
Hughes SH.
Buckheit RW.
Micheda CJ.
J. Med. Chem.
1997,
40:
4199
7c
Porcari AR.
Devivar RV.
Kucera LS.
Drach JC.
Townsend LB.
J. Med. Chem.
1998,
41:
1252
7d
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
7e
Gua Z.
Zhou D.
Schultz PG.
Science
2000,
288:
2042
8
Singh AK.
Lown JW.
Anti-Cancer Drug Design
2000,
15:
265
9a
Mann J.
Baron A.
Boahen YO.
Johansson E.
Parkinson G.
Kelland LR.
Neidle S.
J. Med. Chem.
2001,
44:
138
9b
Rastogi K.
Chang JY.
Pan WY.
Chen CH.
Chou TC.
Chen LT.
Su TL.
J. Med. Chem.
2002,
45:
4485
10
Jin S.
Kim JS.
Sim SP.
Lin A.
Pilch DS.
Liu LF.
LaVoie EJ.
Bioorg. Med. Chem. Lett.
2000,
10:
719
11
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
12 Solid phase synthesis of 5-(benzimidazol-2-yl)benzimidazoles: Mazurov A.
Bioorg. Med. Chem. Lett.
2000,
10:
67
13a
White S.
Szewczyk JW.
Turner JM.
Baird EE.
Dervan PB.
Nature
1998,
391:
468
13b
Kielopf CL.
White S.
Szewczyk JW.
Turner JM.
Baird EE.
Dervan PB.
Rees DC.
Science
1998,
282:
111
13c
Dervan PB.
Bürlj RW.
Curr. Opin. Chem. Biol.
1999,
3:
688
MW-assisted reactions on soluble polymer support:
14a
Blettner CG.
König WA.
Stenzel W.
Schotten T.
J. Org. Chem.
1999,
64:
3885
14b
Bendale PM.
Sun CM.
J. Comb. Chem.
2002,
4:
359
14c
Wu CY.
Sun CM.
Synlett
2002,
10:
1709
14d
Lin MJ.
Sun CM.
Tetrahedron Lett.
2003,
44:
8739
15 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.
16
Morita S.
Kitano K.
Matsubara J.
Ohtani T.
Kawano Y.
Otsubo K.
Uchida M.
Tetrahedron
1998,
54:
4811
17 Ohemeng KA, and Nguyen VN. inventors; US Patent 5,942,532.
