5-Iodo-3-ethoxypyrazoles: an entry point to new chemical entities.

Sandrine Guillou, Yves L Janin

Index: Chemistry 16(15) , 4669-77, (2010)

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Abstract

Our program, which has focused on the preparation of new pyrazole derivatives, has led us to report here an original and simplified preparation of ethyl 3-ethoxy-1H-pyrazole-4-carboxylate. This is based on the reaction of hydrazine monohydrochloride and diethyl 2-(ethoxymethylene)malonate. Further transformations of this key compound allowed the preparation of the two possible iodinated isomers, namely, 3-ethoxy-4-iodo- and 3-ethoxy-5-iodo-1H-pyrazole. These compounds have opened the way to a quick access to many original pyrazole series. As an illustration, we report here on the selectivity of N-arylation, by using the Lam and Cham method, the C4- and C5-arylation of some of these 3-ethoxypyrazole derivatives by using the Suzuki-Miyaura reaction, and C5-benzylation reactions by means of the Negishi reaction. This was followed by hydrolysis of the ethoxy group, which led to the corresponding pyrazol-3-one derivatives. As a conclusion of this work, we conducted an investigation into the regiochemistry of the condensation between diethyl 2-(ethoxymethylene)malonate and the hydrochloride salts of methyl, benzyl, or phenyl hydrazine. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.