General Papers ARKIVOC 2014 (vi) 54-71
number of reports on successful application of cross-coupling in pyrazole chemistry increases, this field is not yet fully investigated.
2-Nitro-and 2-formylhetarylacetylenes are valuable intermediates of new heterosystems.12-15 Previous studies of intramolecular cyclisation or cycloisomerisation of 2-formylhetarylacetylenes has showed that the structure of products can vary depending on the nature of used materials.12,16 For further studies of cyclisation reactions 1-(1-ethoxyethyl)-3-(phenylethynyl)-1H-pyrazole-4carbaldehyde and 1-(1-ethoxyethyl)-3-nitro-4-(phenylethynyl)-1H-pyrazole were synthesized. Herewith the Sonogashira cross-coupling reaction of 1-(1-protected)-3-iodo-1H-pyrazole derivatives with phenylacethylene was investigated and applied for the synthesis of N-unprotected pyrazoles.
Results and discussion
As pyrazoles themselves are known as ligands for transition metals,4 protection of N-H group of 3iodo- 1H-pyrazole derivatives were necessary in our investigations of cross-coupling reactions. 1HPyrazoles 1-5 were protected using Boc anhydride and ethyl vinyl ether. N-ethoxyethyl (EtOEt) and N-Boc protected pyrazole derivatives (1a-5a and 1b-5b, respectively) were synthesized in good to excellent yields (Scheme 1) and used in reactions with lithium organic compounds and Sonogashira cross-coupling reactions. Unfortunately, Boc protecting group was not stable enough both in reactions with lithium organic compounds and during GC-MS analysis. Thus we have decided to focus our further experiments on EtOEt protected pyrazole derivatives.
Scheme 1. Protection of free N-H group in 1H-pyrazole derivatives 1-5.
According to literature reports, EtOEt protecting group can be easily introduced and removed from pyrazole ring in mild acidic conditions.17-19 Tetrahydropyran (THP) group is recommended for the synthesis of unsymmetrical pyrazole derivatives.20 Usually protection reaction of pyrazole ring with EtOEt or THP groups are performed by heating reaction mixture of starting pyrazoles with ethyl vinyl ether or dihydropyran and catalytic amount acid 40-50 °C. Deprotection in acidic conditions is reversible and the removal of ethyl vinyl ether or 3,4-dihydro-2H-pyran is necessary to complete this reaction. Due to lower boiling temperature ethyl vinyl ether appeared to be preferable.
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