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Synthesis 2009(11): 1876-1880  
DOI: 10.1055/s-0028-1088056
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

A Practical Synthesis of 3-Diethoxyphosphoryl-1,2-pyridazine Derivatives

Jean-Christophe Monbaliu, Jacqueline Marchand-Brynaert*
Unité de Chimie Organique et Médicinale, Département de Chimie, Université catholique de Louvain, Bâtiment Lavoisier, Place Louis Pasteur 1, 1348 Louvain-la-Neuve, Belgium
Fax: +32(10)474168; e-Mail: jacqueline.marchand@uclouvain.be;
Further Information

Publication History

Received 8 January 2009
Publication Date:
20 April 2009 (online)

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Abstract

Under microwave (MW) heating, 1-diethoxyphosphorylbuta-1,3-diene cycloadds to diethyl, diisopropyl and di-tert-butyl azodicarboxylates leading to the corresponding hetero Diels-Alder (HD-A) cycloadducts in excellent yields. Cycloaddition to the di-tert-butyl derivative is conveniently scaled up using a six-entry parallel synthesis rotor (>10 g scale). B3LYP/6-31G** calculations confirmed the concerted, but highly asynchronous character of this reaction. The di-tert-butyloxycarbonyl cycloadduct is compatible with orthogonal deprotection (i.e., selective N-deprotection without degradation of the phosphonate ester). Thus, reduction and dihydroxylation of the C=C bond of this cycloadduct, followed by TFA deprotection, gave 3-diethoxyphosphorylhexahydro-1,2-pyridazine and 3-diethoxyphosphoryl-4,5-dihydroxyhexahydro-1,2-pyrida­zine, respectively. This HD-A strategy offers a convenient entry towards phosphonate bioisosters of cyclic α-hydrazino acid and azafagomine derivatives in racemic series.

Key words

azo compounds - cycloadditions - Diels-Alder reactions - heterocycles - phosphorus

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23

In this case, we supposed that the Lewis acids were quenched by the phosphonate moiety of diene 1, preventing any activation of DTAD. Higher conversion yields observed for the blank than for the Lewis acid activated samples supported this hypothesis. Acids could also contribute to the decomposition of 2c by Boc deprotection.

24

A few drops of toluene were added to guarantee sufficient fluidity of the reaction mixture. Indeed, the cycloadduct 3c is a viscous oil that precludes stirring of the mixture.