Synthesis of 2-Alkylpyrazole-1-oxides: A Facile Access to 1-Alkyl-5-halopyrazoles

Abstract

Selective N-alkylation of 1-hydroxypyrazole 1 into the corresponding 2-alkyl-pyrazole-1-oxides 2a-f has been achieved by treatment with alkyl bromides in the absence of base. Subsequent deoxygenation/halogenation into 1-alkyl-5-halopyrazoles 3a-d and 4a-d using phosphorus oxyhalides is described.

Key words

pyrazoles - alkylations - halogenation - deoxygenation - N-oxides

References

• 1 Begtrup M. Larsen P. Vedsø P. Acta Chem. Scand.  1992,  46:  972 
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• 3 Begtrup M. Vedsø P. Acta Chem. Scand.  1996,  50:  549 
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• 6 Rodríguez-Franco MI. Dorronsoro I. Hernández-Higueras AI. Antequera G. Tetrahedron Lett.  2001,  42:  863 ; and references cited therein
• 7 5-Iodo-1-methylpyrazole has been prepared in 67% yield using C-5 lithiation of 1-methylpyrazole (hampered by competitive deprotonation at the N-methyl group) followed by reaction with I₂, see: Effenberger F. Krebs A. J. Org. Chem.  1984,  49:  4687 
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4

Note that the numbering in the pyrazole ring changes upon reduction.

8

We previously described the preparation of 5-chloro- and 5-bromo-1-benzylpyrazole via selective chlorination/bromination of 2-benzylpyrazole-1-oxide and subsequent deoxygenation using POCl₃, for details see ref. 1.

10

5-Chloro-1-methylpyrazole and 5-chloro-1-benzylpyrazole have been prepared by treatment of the corresponding
5-hydroxy-1-alkylpyrazoles with POCl₃ at 155 °C, for details see ref. 12.