Traceless solid-phase synthesis of substituted benzimidazoles via a base-cleavable linker

Organic Letters

Volumn 3, Issue 1, 2001, Pages 83-85

  Tumelty, David ^a   Kathy, Cao ^a   Holmes, Christopher P ^a  

^a AFFYMAX RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINE; BENZIMIDAZOLE DERIVATIVE;

ARTICLE; CATALYSIS; CHEMICAL STRUCTURE; CHEMISTRY; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; MASS SPECTROMETRY; NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY; STRUCTURE ACTIVITY RELATION; SYNTHESIS;

AMINES; BENZIMIDAZOLES; CATALYSIS; CHROMATOGRAPHY, HIGH PRESSURE LIQUID; MAGNETIC RESONANCE SPECTROSCOPY; MASS SPECTROMETRY; MOLECULAR STRUCTURE; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 0035843328     PISSN: 15237060     EISSN: None     Source Type: Journal    
DOI: 10.1021/ol006801o     Document Type: Article

References (20)

1. (a) Tumelty, D.; Schwarz, M. K.; Cao, K.; Needels, M. C. Tetrahedron Lett. 1999, 40, 6185-6188.
2. (b) Tumelty, D.; Schwarz, M. K.; Needels, M. C. Tetrahedron Lett. 1998, 39, 7467-7470.
3. Mayer, J. P.; Lewis, G. S.; McGee, C.; Bankaitis-Davis, D. Tetrahedron Lett. 1998, 39, 6655-6658.
4. Sun, Q.; Yan, B. Bioorg. Med. Chem. Lett. 1998, 8, 361-364.
5. (e) Lee, J.; Gauthier, D.; Rivero, R. A. Tetrahedron Lett. 1998, 39, 201-204.
6. (f) Phillips, G. B.; Wei, G. P. Tetrahedron Lett. 1996, 37, 4887-4890.
7. (a) Mazurov, A. Bioorg. Med. Chem. Lett. 2000, 10, 67-70.
8. (b) Smith, J. M.; Krchnak, V. Tetrahedron Lett. 1999, 40, 7633-7636.
9. Huang, W.; Scarborough, R. M. Tetrahedron Lett. 1999, 40, 2665-2668.
10. In essence, this means that the benzimidazole products may lack the obligatory carboxyl/carboxamide group, which is usually left on the aromatic ring as a remnant of cleavage from acid-labile (or other) linkers.
11. (a) Brown, A. R. J. Comb. Chem. 1999, 1, 283-285.
12. (b) Brown, A. R.; Rees, D. C.; Rankovic, Z.; Morphy, J. R. J. Am. Chem. Soc. 1997, 119, 3288-3295.
13. Kroll, F. E. K.; Morphy, R.; Rees, D.; Gani, D. Tetrahedron Lett. 1997, 38, 8573-8576.
14. Morphy, J. R.; Rankovic, Z.; Rees, D. C. Tetrahedron Lett. 1996, 37, 3209-3212.
15. By quantitative ninhydrin test: Sarin, V. K.; Kent, S. B. H.; Tam, J. P.; Merrifield, R. B. Anal. Biochem. 1981, 117, 147-57. The amine was also reprotected using Fmoc-Cl/DIEA/DCM. the Fmoc removed with piperidine and quantified at 302 nm. The new loading was 0.35 mmol/g.
16. Of the many commercially available monomers of this type, around 20 proved to be useful in this synthetic scheme, some examples of which were used synthesize the final products shown in Table 1 and Scheme 2
17. Oxone (Aldrich) dissolves easily in water. Presolvation of the resin in MeOH aids its solvation by the aqueous solution. Previous oxidations of this type have also used MCPBA, e.g.: Garcia-Echeverria, C. Tetrahedron Lett. 1997, 38, 8933-8934.
18. Primary carboxamides or, with the appropriate linker, secondary carboxamides have been described tor previous solid-phase syntheses, where the carboxamide group was also the point of attachment to the linker/resin. With this new strategy, more diverse tertiary carboxamides are possible from the common resin intermediate, 6a, as the carboxyl group is no longer required to be the point of attachment to the resin.
19. The alternative route is derived from refs 1a-c, as well as the following: Tumelty, D.; Dong, L.-C.; Cao, K.; Le, Lanchi; Needels, M. C. Case Studs 4-3. In High Throughput Organic Synthesis; Sucholeiki, I., Ed.; Marcel Dekker: New York, in press; pp 93-107.
20. This acid was obtained by treating 3-fluoro-4-nitrotoluene with dichromate in aqueous sulfuric acid: Reynolds, D. W.; Cassidy, P. E.; Johnson, C. G.; Cameron, M. L. J. Org. Chem. 1990, 55, 4448-4454.