Dithiocarbamates
(DTCs) are ligands known to chelate with Cu and
other transition metals to form insoluble complexes. Wastewater treatment
protocols have utilized DTCs to remove trace (ppb) metals from waste
streams. We have extended the applicability of DTCs to a protocol
that readily enables control of the residual Cu in isolated material
in a quick and cost-effective manner. Formation of the chelate complex
typically results in purging of Cu and a variety of other metals in
an array of reaction media to ≤10 ppm. Furthermore, the simplicity
of the method makes it very attractive for large-scale applications
late in a synthetic sequence because of the low toxicity and efficient
removal of the metal complex by filtration.
We describe the development and scale-up of a nickel-catalyzed reductive cross-electrophile coupling reaction between a substituted 2-chloropyridine and ethyl 3-chloropropanoate using manganese dust as the terminal reductant. Several additives were screened for the activation of the manganese reductant in situ, and chlorotriethylsilane (TESCl) was found to provide the optimal conversion. A focused beam reflectance measurement (FBRM) probe was utilized to monitor particle attrition as well as manganese activation during the reaction. Modeling was employed to garner an understanding of mixing requirements that would ensure effective suspension of the manganese during scale-up. The process was successfully demonstrated on a 7 kg scale and afforded 2 in 64% yield.
A one-pot tandem Pd-catalyzed hydrostannylation/Stille coupling protocol for the stereoselective generation of vinyltins and their subsequent union, employing only catalytic amounts of tin, is described. By recycling the organotin halide Stille byproduct back to organotin hydride, a hydrostannylation/cross-coupling sequence can be carried out with catalytic amounts of tin. Such a process is most effective with Me(3)SnCl serving as the tin source. This protocol allows a 94% reduction of the tin requirement, while maintaining good yields (up to 90%) for a variety of Stille products. Furthermore, since one cycle requires the tin to undergo at least four transformations, each moiety of trialkyltin is experiencing a minimum of 60 reactions over the course of the hydrostannylation/Stille sequence.
We have found that either Bu 3 SnCl/PMHS/KF (aq) or the combination of tributyltin fluoride, PMHS, and catalytic quantities of tetrabutylammonium fluoride can serve as in situ sources of tributyltin hydride for both free radical and palladium-catalyzed hydrostannylation reactions. These methods are tolerant of a variety of functional groups, including silyl ethers. Furthermore, Me 3 SnCl is also reduced under these conditions, providing a relatively convenient and safe manner by which Me 3 -SnH can be formed and reacted. We have also observed that the Bu 3 SnCl/siloxane/fluoride combination offers improvements over the existing protocols for transforming 1-bromoalkynes into trans-1-(tributylstannyl)-1-alkenes. Specifically, the KF/PMHS methodology allows the 1-bromoalkyne to be formed and reacted in a single pot and with substoichiometric amounts of tin. Finally, alternative reductants such as Red-Sil are also amenable to the method.
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