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44771-G1
Catalytic Diamination of Alkenes
As a result of the funding provided by the PRF, significant progress was made in understanding the basic mechanistic steps that will eventually lead to a successful diamination of alkenes. Other research in our laboratory had previously established that the use of a tridentate ligand on palladium was successful in inhibiting beta-hydride elimination. This led to the development of a catalytic intramolecular hydroamination of alkenes, which proceeded via nucleophilic addition of an amine nucleophile to a palladium-coordinated alkene to form a palladium-alkyl complex, followed by subsequent protonolysis of this species to form the hydroamination product.
In order to exploit this reactivity in the desired diamination reaction, the intermediate palladium alkyl complex must be intercepted by an appropriate source of electrophilic nitrogen. During the grant period, we investigated the reaction of the isolated palladium complex with numerous nitrogen electrophiles, such as PhI=NTs, N-halosuccinimides, N-haloacetamides, hydrazines, azodicarboxylates and nitroso compounds. None of these reactions resulted in the formation of a new carbon-nitrogen bond. Treatment with amines in the presence of oxidizing agents, like copper salts, also did not result in diamination. However, in the course of an attempted fluorination reaction, we discovered that treatment of the palladium-alkyl complex with N-fluorobenzenesulfonimide (NFBS) resulted in formation of a diamination product by transfer of the benzenesulfonimide group to the palladium-bound carbon.
Unfortunately, the reaction of the palladium-alkyl complex with NFBS also resulted in oxidation of the phosphine donors in the tridentate ligand, which prevented the reaction from proceeding under catalytic conditions. However, we quickly discovered that the diamination reaction proceeds using commercially available simple palladium precursors even in the absence of ligands, indicating that the amination of the palladium-alkyl complex is faster than beta-hydride elimination.
Further optimization of this diamination reaction is underway. We have found that incorporation of the counterions of the palladium source can be a complication, as well as palladium catalyzed isomerization of the alkene. Determining the effects of various additives on minimizing the formation of these byproducts is an ongoing goal. Preliminarily, it appears that radical scavengers such as TEMPO or BHT can help inhibit the isomerization reaction, and the addition of extra benzenesulfonimide can minimize counterion incorporation.
The palladium-catalyzed diamination reaction that we have discovered constitutes a significant advance in the construction of vicinal diamines. The reaction provides ready access to diamines that are differentially protected for future manipulations under mild conditions. This will be of great use in the construction of medicinally relevant compounds from petroleum-based starting materials. Future work will focus on extending the scope of the reaction and understanding the mechanistic details.
We anticipate that a communication detailing the development of the diamination reaction will be published in the next several months, and ongoing study of this reaction will lead to additional publications in the next few years. Other observations about the reactivity of NFBS under palladium-catalyzed conditions that were made during the course of this investigation are likely to lead to other types of oxidative aminations, which will also be published in the coming years. The support of the PRF in getting this research started was invaluable.
