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Synthesis 2003(11): 1683-1692
DOI: 10.1055/s-2003-40888
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Practical Oxone®-Mediated, High-Throughput, Solution-Phase Synthesis of Benzimidazoles from 1,2-Phenylenediamines and Aldehydes and its Application to Preparative Scale Synthesis

Pierre L. Beaulieu*, Bruno Haché, Elisabeth von Moos
Boehringer Ingelheim (Canada) Ltd., Research and Development, 2100 Cunard Street, Laval (Québec) H7S 2G5, Canada
Fax: +1(450)6828434; e-Mail: pbeaulieu@lav.boehringer-ingelheim.com;
Further Information

Publication History

Received 31 March 2003
Publication Date:
25 July 2003 (online)

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Abstract

Addition of oxone® to a mixture of a 1,2-phenylenediamine and an aldehyde in wet DMF at room temperature results in rapid formation of benzimidazoles under very mild conditions. The reaction is applicable to a wide range of substrates including aliphatic, aromatic and heteroaromatic aldehydes, and is not significantly affected by steric or electronic effects. In most cases, crude products are isolated in good to excellent yields (59-95%) and homogeneities (86-99%) by simple precipitation or extraction from the reaction mixture and do not require additional purification. Limitations to the scope of this methodology were encountered in cases where aldehydes were sensitive to oxone® under the acidic reaction conditions. The features of this methodology make it particularly well suited for the high-throughput, solution-phase synthesis of benzimidazole libraries. The low cost and simplicity of this procedure makes it equally attractive for preparative-scale syntheses where safety and environmental issues are of greater concern.

Key words

benzimidazoles - heterocycles - aldehydes - amines - oxone - combinatorial chemistry

    References

  • 1a Spasov AA. Yozhitsa IN. Bugaeva LI. Anisimova VA. Pharm. Chem. J.  1999,  33:  232 
    Google Scholar
  • 1b Preston PN. Chem. Heterocycl. Compd.  1980,  40:  531 
    Google Scholar
  • 2a Evans BE. Rittle KE. Bock MG. DiPardo RM. Freidinger RM. Whitter WL. Lundell GF. Veber DF. Anderson PS. Chang RSL. Lotti VJ. Cerino DJ. Chen TB. Kling PJ. Kunkel KA. Springer JP. Hirshfield J. J. Med. Chem.  1988,  31:  2235 
    CrossrefGoogle Scholar
  • 2b Mason JS. Morize I. Menard PR. Cheney DL. Hulme C. Labaudiniere RF. J. Med. Chem.  1999,  42:  3251 
    CrossrefGoogle Scholar
  • See for example:
  • 3a Chi Y.-C. Sun C.-M. Synlett  2000,  591 
    Google Scholar
  • 3b Huang W. Scarborough RM. Tetrahedron Lett.  1999,  40:  2665 
    Google Scholar
  • 3c Wu Z. Rea P. Wickham G. Tetrahedron Lett.  2000,  41:  9871 
    Google Scholar
  • 3d Thomas JB. Fall MJ. Cooper JB. Burgess JP. Carroll FI. Tetrahedron Lett.  1997,  38:  5099 
    Google Scholar
  • 3e Phillips GB. Wei GP. Tetrahedron Lett.  1996,  37:  4887 
    Google Scholar
  • 3f Sun Q. Yan B. Bioorg. Med. Chem. Lett.  1998,  8:  361 
    Google Scholar
  • 3g Smith JM. Krchák V. Tetrahedron Lett.  1999,  40:  7633 
    Google Scholar
  • 3h Mayer JP. Lewis GS. McGee C. Bankaitis-Davis D. Tetrahedron Lett.  1998,  39:  6655 
    Google Scholar
  • 4 Brain CT. Brunton SA. Tetrahedron Lett.  2002,  43:  1893 
    CrossrefGoogle Scholar
  • 5a White AW. Almassy R. Calvert AH. Curtin NJ. Griffin RJ. Hostomsky Z. Maegley K. Newell DR. Srinivasan S. Golding BT. J. Med. Chem.  2000,  43:  4084 
    Google Scholar
  • 5b Hendrickson JB. Hussoin MS. J. Org. Chem.  1987,  52:  4137 
    Google Scholar
  • 5c Dunwell DW. Evans D. Smith CE. Williamson WRN. J. Med. Chem.  1975,  18:  692 
    Google Scholar
  • 5d Güngör T. Fouquet A. Teulon J.-M. Provost D. Cazes M. Cloarec A. J. Med. Chem.  1992,  35:  4455 
    Google Scholar
  • 5e Barni E. Savarino P. J. Heterocycl. Chem.  1979,  16:  1583 
    Google Scholar
  • 6a Smith JG. Ho I. Tetrahedron Lett.  1971,  38:  3541 
    CrossrefGoogle Scholar
  • 6b Jonas R. Klockow M. Lues I. Prücher H. Schliep HJ. Wurziger H. Eur. J. Med. Chem.  1993,  28:  129 
    CrossrefGoogle Scholar
  • 7a Blettner CG. König WA. Rühter G. Stenzel W. Schotten T. Synlett  1999,  307 
    Article in Thieme ConnectGoogle Scholar
  • 7b Sun Q. Gatto B. Yu C. Liu A. Liu LF. LaVoie EJ. J. Med. Chem.  1995,  38:  3638 
    Article in Thieme ConnectGoogle Scholar
  • 7c Ben-Alloum A. Bakkas S. Soufiaoui M. Tetrahedron Lett.  1998,  39:  4481 
    Article in Thieme ConnectGoogle Scholar
  • 7d Satz AL. Bruice TC. Bioorg. Med. Chem. Lett.  1999,  9:  3261 
    Article in Thieme ConnectGoogle Scholar
  • 7e Rangarajan M. Kim JS. Sim S.-P. Liu A. Liu LR. LaVoie EJ. Bioorg. Med. Chem.  2000,  8:  2591 
    Article in Thieme ConnectGoogle Scholar
  • 7f Black DSt.C. Kumar N. Wong LCH. Synthesis  1986,  474 
    Article in Thieme ConnectGoogle Scholar
  • 8a Denny WA. Rewcastle GW. Baguley BC. J. Med. Chem.  1990,  33:  814 
    CrossrefGoogle Scholar
  • 8b Dang Q. Brown BS. Erion MD. Tetrahedron Lett.  2000,  41:  6559 
    CrossrefGoogle Scholar
  • 8c Singh MP. Sasmal S. Lu W. Chatterjee MN. Synthesis  2000,  1380 
    CrossrefGoogle Scholar
  • 8d Gravatt GL. Baguley BC. Wilson WR. Denny WA. J. Med. Chem.  1994,  37:  4338 
    CrossrefGoogle Scholar
  • 9a Vanden Eynde JJ. Delfosse F. Lor P. Van Haverbeke Y. Tetrahedron  1995,  51:  5813 
    CrossrefGoogle Scholar
  • 9b Hopkins KT. Wilson WD. Bender BC. McCurdy DR. Hall JE. Tidwell RR. Kumar A. Bajic M. Boykin DW. J. Med. Chem.  1998,  41:  3872 
    CrossrefGoogle Scholar
  • 9c Lombardy RL. Tanious FA. Ramachandran K. Tidwell RR. Wilson WD. J. Med. Chem.  1996,  39:  1452 
    CrossrefGoogle Scholar
  • 10 Chikashita H. Nishida S. Miyazaki M. Morita Y. Itoh K. Bull Chem. Soc. Jpn.  1987,  60:  737 
    CrossrefGoogle Scholar
  • 11 Pätzold F. Zeuner F. Heyer Th. Niclas H.-J. Synth. Commun.  1992,  22:  281 
    CrossrefGoogle Scholar
  • 12a Ridley HF. Spickett RGW. Timmis GM. J. Heterocycl. Chem.  1965,  2:  453 
    CrossrefGoogle Scholar
  • 12b Göker H. Kus C. Boykin DW. Yildiz S. Altanlar N. Bioorg. Med. Chem.  2002,  10:  2589 
    CrossrefGoogle Scholar
  • 13 Yukawa H. Nagatani T. Torisawa Y. Okaichi Y. Tada N. Furuta T. Minamikawa J.-I. Nishi T. Bioorg. Med. Chem. Lett.  1997,  7:  1267 
    CrossrefGoogle Scholar
  • 14a Narsaiah AV. Synlett  2002,  1178 
    CrossrefGoogle Scholar
  • 14b For other uses of oxone® in organic synthesis, see for example: Lee K.-J. You H.-W. Synlett  2001,  105 ; and references cited therein
    CrossrefGoogle Scholar
  • 14c After submission of this manuscript, Borhan et al. reported on the use of oxone® for the oxidation of aldehydes to carboxylic acids: Travis BR. Sivakumar M. Hollist GO. Borhan B. Org. Lett.  2003,  5:  1031 ; it appears that formation of benzimidazoles under the present reaction conditions is faster than oxidation of the aldehyde substrate to the corresponding carboxylic acid. It is possible however that this latter pathway can become competitive for less reactive substrates and account for some of the lower yields
    CrossrefGoogle Scholar
  • 15 For an alternative reduction of nitro groups with stannous chloride, see for example: Bellamy FD. Ou K. Tetrahedron Lett.  1984,  25:  839 
    CrossrefGoogle Scholar
  • The formation of an intermediate formate ester from the starting aldehyde through a Baeyer-Villiger oxidation is inferred from detection of the corresponding alcohol. Precedent for this kind of process can be found in the literature, but usually involves organic peracids as oxidant. See for example:
  • 16a Yeager GW. Schissel DN. Synthesis  1991,  63 
    CrossrefGoogle Scholar
  • 16b Krow GR. Org. React.  1993,  43:  251 
    CrossrefGoogle Scholar
  • 16c Occurrence of an oxone®-promoted Baeyer-Villiger process has been proposed in the literature: Wu X.-Y. She X. Shi Y. J. Am. Chem. Soc.  2002,  124:  8792 ; see also earlier reference (Ref. 14c)
    CrossrefGoogle Scholar
  • 17 DMF alone or its dimethyl acetal can also promote conversion of 1,2-phenylenediamines to 2H-benz-imidazoles, but this usually requires elevated temperatures and is not suspected to occur under the present oxone®-promoted reaction conditions: Mataka S. Shimojyo Y. Hashimoto I. Tashiro M. Liebigs Ann.  1995,  10:  1823 
    Google Scholar
  • It is very likely that the quenched reaction mixtures still retain some oxidizing potential and should be disposed of appropriately to avoid hazardous decompositions. It has been reported for example that oxone® will lose active oxygen slowly under alkaline conditions, see:
  • 19a Kennedy RJ. Stock AM. J. Org. Chem.  1960,  25:  1901 
    Google Scholar
  • 19b Ball DL. Edwards JO. J. Am. Chem. Soc.  1956,  78:  1125 
    Google Scholar
  • 20a Chang J. Zhao K. Pan S. Tetrahedron Lett.  2002,  43:  951 ; and references cited therein
    CrossrefGoogle Scholar
  • 20b Hari A. Karan C. Rodrigues WC. Miller BL. J. Org. Chem.  2001,  66:  991 
    CrossrefGoogle Scholar
18

The ratio of 14 to 15 did not vary significantly upon prolonged reaction times indicating that under the reaction conditions, equilibration of the diamine 15 to benzamidine 3 and eventually to product 14 did not occur.