Calorimetric Insight into Coupling between Functionalized Primary Alkyl Halide and Vinylic Organocuprate Reagent:Experimental Determination of Reaction Enthalpies in the Synthesis of (R)-Ethyl 3-(tert-butyldimethylsilyloxy) hex-5-enoate - a Key Lactonized Statin Side Chain Precursor

摘要

The first calorimetric study of coupling between organocuprate, derived from Grignard reagent (vinyl magnesium chloride), and primary alkyl halide (e.g. (S)-ethyl 3-(tert-butyldimethylsilyloxy)-4-iodobutanoate) has been conducted. This transformation is paramountly important for efficient preparation of (R)-ethyl 3-(tert-butyldimethylsilyloxy)hex-5-enoate - a key lactonized statin side chain precursor. The results obtained give thorough calorimetric insight into this complex low-temperature synthesis as well as a new understanding of the suggested reductive ehmination of the final intermediates in the coupling reaction. Namely, the surprising unexpected spontaneous three-step exothermal event has been observed during controlled progressive heating of the mixture of the final intermediates to the room temperature. This phenomenon confirms that coupling between functionalized primary alkyl halide and vinylic organocuprate reagent is not a simple S_N2 substitution reaction. The presented study provides among others the first reported values of reaction enthalpies and corresponding adiabatic temperature rises of reaction mixture for all exothermic events that occurred in the (R)-ethyl 3-(tert-butyldimethylsilyloxy)hex-5-enoate synthesis. The obtained results ensure consequential thermal process safety knowledge which can be incorporated into safe process scale-up as well as design of reactor system with sufficient cooling capacity for industrial production of (R)-ethyl 3-(tert-butyldimethylsilyloxy)hex-5-enoate. Moreover, the results provide a basic guidance for other organocuprate coupling reaction systems.