Abstract
We have developed a multi-step, microwave-assisted method for the bismuth chloride catalyzed synthesis of 1,2-disubstituted benzimidazoles. Biologically interesting benzimidazoles were readily assembled using a SN Ar reaction, reduction, and finally a bismuth(III)-mediated cyclization under microwave irradiation. The desired products were then liberated from the soluble matrix in excellent yield and purity after cleavage. Each step of the synthetic sequence was performed under microwave conditions.
Key words
bismuth chloride - combinatorial chemistry - liquid-phase method - microwave assisted synthesis - scaffold
References
1a
Dolle RE.
Mol. Diversity
1996,
2:
223
1b
Dolle RE.
Nelson KH.
J. Comb. Chem.
1999,
1:
235
1c
Dolle RE.
J. Comb. Chem.
2000,
2:
383
1d
Dolle RE.
J. Comb. Chem.
2001,
3:
477
1e
Dolle RE.
J. Comb. Chem.
2003,
5:
693
1f
Dolle RE.
J. Comb. Chem.
2004,
6:
623
Microwave-assisted combinatorial synthesis:
2a
Lew A.
Krutzik PO.
Hart ME.
Chamberlin RA.
J. Comb. Chem.
2002,
4:
95
2b
Al-Obeidi F.
Austin RE.
Okonya JF.
Bond DRS.
Mini-Rev. Med. Chem.
2003,
3:
459
2c
Blackwell HE.
Org. Biomol. Chem.
2003,
1:
1251
2d
Swamy KMK.
Yeh WB.
Lin MJ.
Sun CM.
Curr. Med. Chem.
2003,
10:
2403
2e
Kappe CO.
Angew. Chem. Int. Ed.
2004,
43:
6250
3a
Larhed M.
Hallberg A.
Drug Discov. Today
2001,
6:
406
3b
Wathey B.
Tierney J.
Lidström P.
Westman J.
Drug Discov. Today
2002,
7:
373
Reviews see:
4a
Sun CM.
Comb. Chem. High Throughput Screening
1999,
2:
299
4b
Toy PH.
Janda KD.
Acc. Chem. Res.
2000,
33:
546
4c
Sun CM.
Soluble Polymer-Supported Synthesis of Heterocyclic Libraries, In ‘Combinatorial Chemistry Methods and Protocols’ Methods in Molecular Biology Series
Bellavance L.
Humana Press Inc.;
New Jersey:
2002.
Chap. 10.
p.345-371
The progress of the liquid-phase synthesis reaction was monitored by regular 1 H NMR spectroscopy:
5a
Shey JY.
Sun CM.
Tetrahedron Lett.
2002,
43:
1725
5b
Yeh WB.
Lin MJ.
Lee MJ.
Sun CM.
Mol. Diversity
2003,
7:
185
6a
Preston PN.
Chem. Rev.
1974,
279
6b
Cedillo-Rivera R.
Munoz O.
J. Med. Microbiol.
1992,
37:
221
6c
Chavaz B.
Cedillo-Rivera R.
Martinez-Palomo A.
J. Protozool.
1992,
39:
510
6d
Fears SD.
O’Jare J.
Antimicrob. Agents Chemother.
1998,
32:
114
6e
Gabrial NV.
Roberto C.
Alicia HC.
Liian Y.
Francisco HL.
Juan V.
Raul M.
Rafael C.
Manuel H.
Rafael C.
Bioorg. Med. Chem. Lett.
2001,
11:
187
7a
Phillips GB.
Wei GP.
Tetrahedron Lett.
1996,
37:
4887
7b
Phillips GB.
Wei GP.
Tetrahedron Lett.
1998,
39:
179
7c
Lee J.
Gauthier D.
Rivero RA.
Tetrahedron Lett.
1998,
39:
201
7d
Smith JM.
Gard J.
Cummings W.
Kanizsai A.
Krchňák V.
J. Comb. Chem.
1999,
1:
368
7e
Tumelty D.
Cao K.
Holmes CP.
Org. Lett.
2001,
83
Combinatorial soluble polymer synthesis of heterocyclic libraries has been demonstrated in our laboratory:
8a
Chang WJ.
Yeh WB.
Sun CM.
Synlett
2003,
1688
8b
Lin M.-J.
Sun CM.
Synlett
2004,
663
8c
Tung CL.
Sun CM.
Tetrahedron Lett.
2004,
45:
1159
8d
Yeh WB.
Lin MJ.
Sun CM.
Comb. Chem. High Throughput Screening
2004,
7:
251
8e
Yeh WB.
Sun CM.
J. Comb. Chem.
2004,
6:
279
8f
Su YS.
Lin MJ.
Sun CM.
Tetrahedron Lett.
2005,
46:
177
9
Morita S.
Kitano K.
Matsubara J.
Ohtani T.
Kawano Y.
Otsubo K.
Uchida M.
Tetrahedron
1998,
54:
4811
10 The control reaction was also performed under normal thermal heating in refluxing chloroform (pre-heated oil bath) for four minutes, using identical stoichiometry. However, after cleavage we obtained only the unreacted compound 4 . The same reaction reached completion in two hours by conventional heating. Similar enhancement through microwave irradiation was also observed during the cleavage step. Compared to conventional thermal hearting, microwave irradiation decreased the reaction time on the support from several hours to several minutes.
11 All the microwave assisted polymer-supported reactions described here were performed in a CEM Discover Microwave System at a frequency of 2450 Hz (0-300 W).
12
Leonard NM.
Wieland LC.
Mohan RS.
Tetrahedron
2002,
58:
8373
13
Mohammedadpoor-Baltrok I.
Aliyan H.
Khosropour AR.
Tetrahedron
2001,
57:
5857
14
Sabiyha G.
Venkata Reddy E.
Maruthi CH.
Yadav JS.
Tetrahedron Lett.
2002,
43:
1573
15
Sabiyha G.
Venkata Reddy E.
Swapna R.
Reddy NM.
Yadav JS.
Synlett
2004,
1276