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Pd(II)-catalyzed direct Csp3-H functionalization of amines: a new platform for the synthesis of privileged molecules

Final Report Summary - HINDAMINE (Pd(II)-catalyzed direct Csp3-H functionalization of amines: a new platform for the synthesis of privileged molecules.)

The Gaunt group at the University of Cambridge has gained a world-class reputation for the discovery of innovative chemistry over the years. One of the main focuses of the group is the development of new methods that enable the practical and selective functionalization of traditionally unreactive aliphatic C–H bonds which has important synthetic applications in fields that range from drug discovery to advanced materials.
Aliphatic amines are central to the function of many biologically active molecules as evidenced by their prevalence in numerous pharmaceutical agents. Primary amines such as α-amino alcohols are among the most versatile of such structures and this basic motif is present in many functional molecules. However, their efficient synthesis is limited to a relatively small number of strategies. A streamlined synthetic solution to this problem could involve a catalyst capable of transforming simple, readily available fully substituted amino alcohols into complex variants via selective functionalization of C–H bonds. Recently, we discovered that a specific class of highly hindered, secondary aliphatic amine can successfully direct palladium-catalysed C–H activation through a novel four-membered ring cyclopalladation pathway. Inspired by these discoveries, we questioned whether a new strategy could be designed for the functionalization of primary aliphatic amines by transiently converting these substrates into hindered secondary amines to facilitate C–H activation. In this context, we recognized three factors that should guide our C–H activation blueprint: first, that the sterically controlling component should not be a permanent aspect of the amine substrate; second, that a broad range of C–H transformations would be amenable to the C–H activation strategy; and third, that the starting amines should have well-established synthetic utility, such that the products of C–H activation could be used to streamline the synthesis of biological and pharmaceutically important molecules.
Central to our design was a simple ketone, deployed temporarily to bridge the oxygen and nitrogen atoms of the amino alcohol forging a sterically hindered N,O-ketal motif and masking the primary amine function. We predicted that this extremely hindered secondary amine would bind to the palladium catalyst in such a way that the complexation would be accompanied by the formation of a hydrogen bond between the acetate ligand on the palladium and the free(N–H) of the amine. This non-covalent interaction would serve two important purposes: first, to orient the amines substituents in the bis-amine palladium(II) complex in such a way that steric interactions between the aliphatic groups would be intensified, enabling amine dissociation to form the 2-bound acetate intermediate empirically required for C–H bond cleavage; and second, to lock the conformation of the amine with respect to the palladium center, thereby projecting the targeted C–H bond into an optimal trajectory for activation. Reaction of the carbon-palladium bond in can be achieved via the action of a number of external reagents, forming functionalized products. To test this hypothesis it was plan to develop a new selective Csp3-H carbonylation of masked amino alcohols and ketones to afford interesting heterocyclic scaffolds such us -lactams by means of a palladium (II)/palladium (0) redox manifold.
The scope of the carbonylations reaction proved to be general and provided good yields of pyrrolidinone products containing a variety of useful functionality. In addition to the routine alkyl substituents we found that amino-alcohol derivatives displaying aryl, protected hydroxyl and amino motifs all worked well in the C–H carbonylation process; the reaction proceeded diastereoselectively when presented with the choice of two methyl groups. The process also displayed an exquisite selectivity in the case that the palladium has to choose between a four and five-membered ring cyclopalladation and we observe that the reaction proceeds through the larger ring pathway. Although the reaction is less efficient when there is a strongly electron-withdrawing group adjacent to the amine function, useful yields of the desired product can still be obtained. In all of these cases, we observe a small amount of the -unsaturated pyrrolidinone product that we believe originates from C(sp2)–H activation of an allylic amine derivative formed from -hydride elimination of a cyclopalladation intermediate. This product can be readily processed to the saturated pyrrolidinone by direct hydrogenation of the reaction mixture. The intermediacy of the allylic amine was confirmed by selective carbonylation of the sp2 hybridized C–H bond to give the expected unsaturated pyrrolidinone product in excellent yield.
In a final venture to establish the generality of this activation strategy, we sought to address a traditionally challenging carbon-carbon forming process based on a C–H alkenylation strategy. Although examples of this coupling reaction have recently emerged for aliphatic systems, combining C(sp3)–H bonds with alkenes remains an important goal. Guided by our experience with the C–H carbonylation, we first assessed the reaction of our hindered amines with trifluoroethyl acrylate in the presence of palladium acetate and silver acetate. Pleasingly, we observed the formation of the corresponding pyrrolidine that formed from the C–H alkenylation reaction followed by intramolecular aza-Michael addition. The desired pyrrolidine derivatives were isolated in high yields as a single diastereoisomer. Again, we observed a small amount of an unsaturated pyrrolidine product derived from the corresponding allylic amine and so the reaction mixture was directly hydrogenated to form the saturated pyrrolidine. We showed that the reaction displayed a broad substrate scope and supported the presence of different useful functional groups. We also noticed a modest improvement in yield when the size of the alkyl substituent increases, suggesting a further link between the reactivity and the steric hindrance around the aliphatic amine. In some cases, however, we found that the acetone derived N,O-ketal performed better than the corresponding cyclohexyl group, highlighting the subtle steric balance at work in this process. In addition to the coupling with acrylates, we were also able to show that vinyl sulfones also work well in the C–H alkenylation process, providing useful products with opportunities for further elaboration via well-established methods.
The advances outlined here demonstrate that manipulating the steric properties of aliphatic amines can lead to a remarkably broad strategy for the C–H functionalization of amino alcohols and ketones. The proof of concept presented in this report opens the door to the application of this new strategy to other prevalent amine-containing structural motif prevalent in nature and also, to the discovery and development of new palladium catalyzed C-H functionalisation reactions. This will be beneficial to the synthesis of complex amines with both established and unexplored biological properties and be of widespread utility to chemists in both academic and industrial institutions.