Ethynylpyrazoles, acidity

The hydration of 5-amino-3-cyano-l-(2,6-dichloro-4-trifluoromethylphenyl)-4-ethynylpyrazole was performed with p-toluenesulfonic acid monohydrate in acetonitrile (2 h, room temperature) to give the corresponding 4-acetyl derivative. An alkyl substituent at the triple bond decreases the rate of hydration the conversion of 5-amino-3-cyano-l-(2,6-dichloro-4-trifiuoromethylphenyl)-4-(prop-l-yn-l-yl) pyrazole to the 4-propanoylpyrazole was completed after 18 h (98INP9804530 99EUP933363). 

A comparison between the values of the acidity of ethynylpyrazoles and the energies of heterocyclic cleavage of the C—H bond calculated by the CNDO-2 method (75KGS821) has revealed a correlation between these values (Fig. 2). 

The effect of substituents in the ring on the mobility of a methyne proton can be followed from the series of 5-substituted l-methyl-4-ethynylpyrazoles and 1,3-dimethyl-4-ethynylpyrazoles. In both structural series, the acidity of compounds increases with a change in the character of substituents in the following order CH3 < H < CH2NH2 < Cl. 

The increasing CH acidity in the ethynylpyrazole series points to the advantageous inductive nature of this influence. Although the data are rather scarce, some correlation is observed between the ethynyl group values and (T constants of substituents in heterocycles (Fig. 3). 

Five membered heterocycles, containing more than 1 heteroatom were also used in Sonogashira reactions. 4-Iodopyrazole, protected in the form of its ethyl vinyl ether adduct (6.51.) was reacted with a series of acetylenes and the acidic workup of the crude product led to 4-ethynylpyrazole derivatives in good yield.77... 

The high acidity of ethynylpyrazoles (pATa 24.0-30.4 92IZV507) determines the high reactivity of the terminal acetylenes and offers the possibility of obtaining a great number of the functionally substituted pyrazolylacetylenes. 

The acidity of 4-acetylenenylpyrazoles increases by 0.3-0.7 log units on introducing CH2NH2 group into position 5 of the ring. Chlorine atoms have the greatest acidifying effect. Chlorine atom in position 5 increases the acidity of l-methyl-3-ethynylpyrazole. 

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