BARTHOLOMÄUS PIEBER, C. OLIVER KAPPE*

*Corresponding author

Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, A-8010 Graz, Austria

Abstract

One of the rare alternative reagents for the reduction of carbon-carbon double bonds is diimide which can be generated in situ from hydrazine hydrate and oxygen. While this selective method is extremely clean and powerful it is rarely used as the rate-determining oxidation of hydrazine in the absence of a catalyst is relatively slow using conventional batch protocols. A continuous high-temperature/high-pressure methodology dramatically enhances the initial oxidation step, at the same time allowing for a safe and scalable processing of the hazardous reaction mixture. The continuous strategy not only allows the reduction of simple alkenes but can also be applied in semi-synthetic drug manufacturing as shown for the production of the artemisinin precursor dihydroartemisinic acid and a synthetic protocol towards hydrocodone.

INTRODUCTION

The reduction of unsaturated carbon-carbon bonds is arguably among the most important synthetic transformation known. In general, the majority of these reactions are carried out by using hydrogen gas and heterogeneous transition metal catalysts such as e.g. Pd/C, PtO₂, Rh/C or Raney Nickel (1). Alternatively, homogeneous transitions metal complexes can be utilized which also accesses asymmetric hydrogenation reactions (2). However, in certain cases these common strategies are accompanied by severe selectivity problems as several undesired side-reactions such as e.g. hydrogenolysis of protecting groups, reduction of other functionalities, alkene migration or racemization can occur.

One of the few alternatives is the use of diimide (N₂H₂) which has been used as transfer hydrogenation agent in synthetic organic chemistry for more than a century (3). This extremely labile hydrogen donor predominantly reduces unpolarized carbon-carbon double bonds avoiding the above mentioned side-reactions. Diimide is usually prepared in situ by decarboxylation of dipotassium azodicarboxylate or from sulfonylhydrazide ...