Solid-phase synthesis of substituted benzimidazoles

Tetrahedron Letters

Volumn 40, Issue 34, 1999, Pages 6185-6188

  Tumelty, David ^a   Schwarz, Matthias K ^a   Cao, Kathy ^a   Needels, Michael C ^a  

^a AFFYMAX RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BENZIMIDAZOLE DERIVATIVE;

ARTICLE; CHEMICAL ANALYSIS; CHEMICAL REACTION; CHEMICAL STRUCTURE; CYCLIZATION; REACTION ANALYSIS; SYNTHESIS;

EID: 0033588074     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0040-4039(99)01299-X     Document Type: Article

References (13)

1. Recent reviews include, (a.) Fauchere, J.-L.; Boutin, J. A.; Henlin, J.-M.; Kucharczyk, N.; Ortuno, J.-C. Chemom. Intell. Lab. Syst. 1998, 43, 43-68.
2. (b.) Brown, R.C.D. J. Chem. Soc., Perkin Trans I 1998, 3293-3320.
3. (c.) Gallop, M.A.; Barrett, R.W.; Dower, W.J.; Fodor, S.P.A.; Gordon, E.M. J. Med. Chem. 1994, 37, 1233-1251.
4. Tumelty, D.; Schwarz, M. K.; Needels, M. C. Tetrahedron Lett. 1998, 39, 7467-7470.
5. (a) Mayer, J. P.; Lewis, G. S.; McGee, C.; Bankaitis-Davis, D. Tetrahedron Lett. 1998, 39, 6655-6658.
6. (b) Lee, J.; Gauthier, D.; Rivero, R. A. Tetrahedron Lett. 1998, 39, 201-204.
7. (c) Phillips, G. B.; Wei, G. P. Tetrahedron Lett. 1996, 37, 4887-4890.
8. Obviously, the R1 amine, the amino acid component, the o-halo-nitroarene (providing R2) and the R3 aldehyde can each be varied to provide combinatorial diversity.
9. We determined separately that heating above 50°C during either of the reduction (ref. 2) or cyclization steps (ref. 3(c)) was the major contributing factor to reduced product yields using these methods.
10. Presumably, the products were first cleaved by acid then cyclized in solution. This further illustrates the propensity of intermediate 5 for cyclization as shown in Scheme 2. Glycine was, in fact, chosen for optimization studies as it could be expected to present the most problematical example in terms of these cyclative losses.
11. 2O (x5) then dried overnight in vacuo prior to acidolysis.
12. We postulate that the intermediate imine formed by aldehyde addition under neutral conditions protects the reduced intermediate 5 from the previously observed cyclative losses, allowing subsequent benzimidazole formation via thermal cyclization (at 50°C).
13. +).