One-pot synthesis of 5-(substituted-amino)pyrazoles

Tetrahedron Letters

Volumn 45, Issue 22, 2004, Pages 4265-4267

  Dodd, Dharmpal S ^a,b   Martinez, Rogelio L ^b  

^a Bristol Myers Squibb   (United States)

^b New Leads Chem Appl Biotechnology   (United States)

Author keywords

ketoamides; 5 Alkylaminopyrazoles; 5 Aminopyrazoles

Indexed keywords

ALKYL GROUP; AMIDE; AMINO ACID; HYDRAZINE; LAWESSONS REAGENT; PYRAZOLE DERIVATIVE; REAGENT; UNCLASSIFIED DRUG;

ARTICLE; CYCLIZATION; HEATING; SYNTHESIS;

EID: 2342666647     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2004.04.017     Document Type: Article

References (25)

1. For some recent reports see: Sakya S.M., Rast B. Tetrahedron Lett. 44:2003;7629
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11. Method described in Ref. 3 requires the reaction of β-ketoamide with mono-substituted hydrazines under very harsh acidic conditions and/or very high temperatures to accomplish the cyclization in poor to moderate yields
12. Method outlined in Refs. [2a, b, c], though very useful, is limited by the necessity of starting hydrazones that must be conjugated to an electron withdrawing group, to yield 5-(N-alkylamino)pyrazoles with electron-withdrawing groups at the C-4 position
13. The method described in Refs. [1b, c, d] takes advantage of the reaction between a 2-oxocarbo-thioamides (β-ketothioamides) with mono-substituted hydrazines to afford 5-(N-alkylamino)pyrazoles in good yield
14. Some useful methods for the preparation of β-ketoamides include: Miriyala B., Williamson J.S. Tetrahedron Lett. 44:2003;7957
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16. Witzemanard J.S., Nottingham W.D. J. Org. Chem. 56:1991;1715
17. ++H)
18. 15N HMQC/HMBC as well as COSY and PSNOESY NMR experiments
19. Reactions also proceeded without the use of pyridine, but it was noticed that yields were slightly higher when pyridine was used as an additive, particularly for sluggish reactions. Dioxane can be substituted for THF
20. The formation of the corresponding 5-pyrazolones 4 are monitored by LCMS
21. 8
22. Increasing reaction temperature did not enhance the yield. In fact, in some cases a decreased yield was observed due to an increase in the formation of the corresponding 5-pyrazolone 4
23. The hydrazones 3 were apparent by LCMS. Conversions to the thioamide intermediates were not observed
24. It was noticed that the initial hydrazone intermediates 3 that are formed from 2m are extremely stable (particularly those formed from phenylhydrazine). The reaction took >48 h at 60°C to go to completion and resulted in a significant amount of the corresponding 5-pyrazolones 4. Increasing the reaction temperatures (using 1, 4-dioxane as the solvent) did not enhance the yield
25. The reactivity of both electron rich and electron deficient hydrazines and β-ketoamides have also been examined. Though there were some combinations of hydrazines and β-ketoamides that were not compatible, on the whole most electronically diverse reagents were tolerated and gave reasonable yields and purity. The regioselectivity was independent of the electronic nature of the reactants