Solid-phase synthesis of 5-substituted amino pyrazoles

Journal of Combinatorial Chemistry

Volumn 7, Issue 4, 2005, Pages 584-588

  Dodd, Dharmpal S ^a   Martinez, Rogelio L ^a   Kamau, Muthoni ^a   Ruan, Zheming ^a   Van Kirk, Katy ^a   Cooper, Christopher B ^a   Hermsmeier, Mark A ^a   Traeger, Sarah C ^a   Poss, Michael A ^a  

^a BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMINE; PYRAZOLE DERIVATIVE;

ARTICLE; CHEMICAL STRUCTURE; CHEMISTRY; COMBINATORIAL CHEMISTRY; SYNTHESIS;

AMINES; COMBINATORIAL CHEMISTRY TECHNIQUES; MOLECULAR STRUCTURE; PYRAZOLES;

EID: 22844447080     PISSN: 15204766     EISSN: None     Source Type: Journal    
DOI: 10.1021/cc049814s     Document Type: Article

References (11)

1. (a) For a recent reviews, see: (a) Dolle, R. E. J. Comb. Chem. 2004, 6, 623-679.
2. (b) Ley, S. V.; Baxendale, I. R. Nat. Rev. Drug Discovery 2002, 1, 573-586.
3. Dodd, D. S.; Martinez, R. L. Tetrahedron Lett. 2004, 45, 4265-4267.
4. 3) position, such as esters, ketones, and cyano groups.
5. (a) Raillard, S. P.; Chen, W.; Sullivan, E.; Bajjalieh, W.; Bhandari, A.; Baer, T. A. J. Comb. Chem. 2002, 4, 470-474.
6. (b) Witzeman, J. S.; Nottingham, W. D. J. Org. Chem. 1991, 56, 1713-1715.
7. For a comprehensive list of methods for the synthesis of β-carboxamides, see: Miriyala, B.; Williamson, J. S. Tetrahedron Lett. 2003, 44, 7957-7959.
8. 2 were not prepared. From our previous solution-phase study, we had found that ketoamides of this type were not very reactive in the subsquent 5-aminopyrazole synthesis step (see ref 2).
9. (a) THF can be substituted for 1,4-dioxane. Pyridine is not necessary for all substrates. Reactions involving a C-2-unsubstituted β-ketoamide (i.e., 2a-d, Table 1), intermediates proceed equally well without pyridine. Pyridine appears to be necessary in reactions involving hindered, C-2-substituted β-ketoamide intermediates (i.e., 2e-h, Table 1) for decent product recovery. Reaction temperature (50-55 °C) also appears to be critical, again more so for the C-2 substituted β-ketoamide intermediates. Reaction temperatures >60°C are detrimental and result in lower yields, presumably due to the premature formation of the corresponding 5-pyrazolone 11, which undergoes cyclative cleavage from the resin. The rates for the sluggish reactions could not be enhanced by heating at higher temperatures without compromising yields, (b) Intermediates of type 9 were also identified when the reactions were carried out in solution phase (see ref 2).
10. 15N HMQC/HMBC, as well as COSY and PSNOESY NMR experiments.
11. 3 on β-ketoamides were examined in library format. Though there were some combinations of hydrazines and β-ketoamides that were not compatible, on the whole, many electronically diverse reagents were tolerated, giving reasonable yields and purities. For example, simple hydrazine is incompatible under these reaction conditions. We also noticed that certain heteroarylhydrazines, as an example, 2-hydrazinopyridine, failed to give appreciable products with 2. We also observed that sterically hindered substrates also played a role in reaction rates and product recovery. β-Ketoamides 2 containing sterically encumbered groups at the C-3 position generally required longer reaction times (>36 h) for complete reaction. In some instances, the reactions could not be pushed to completion. Similar trends were seen with ortho-substituted arylhydrazines, but to a much lesser extent. The combination of sterically encumbered C-3-substituted β-ketoamides and ortho-substituted arylhydrazines gave poor recovery of pyrazoles 1, and mostly starting β-ketoamides were isolated after TFA-mediated cleavage from the resin. In all cases, the regioselectivity was independent of the electronic nature of the reactants.