Palladium-catalysed anti-Markovnikov selective oxidative amination

Abstract

In recent years, the synthesis of amines and other nitrogen-containing motifs has been a major area of research in organic chemistry because they are widely represented in biologically active molecules. Current strategies rely on a multistep approach and require one reactant to be activated prior to the carbon-nitrogen bond formation. This leads to a reaction inefficiency and functional group intolerance. As such, a general approach to the synthesis of nitrogen-containing compounds from readily available and benign starting materials is highly desirable. Here we present a palladium-catalysed oxidative amination reaction in which the addition of the nitrogen occurs at the less-substituted carbon of a double bond, in what is known as anti-Markovnikov selectivity. Alkenes are shown to react with imides in the presence of a palladate catalyst to generate the terminal imide through trans-aminopalladation. Subsequently, olefin isomerization occurs to afford the thermodynamically favoured products. Both the scope of the transformation and mechanistic investigations are reported.

Figure 1:. Current strategies for anti-Markovnikov oxidative amination of simple alkenes.

a, Use of activated alkenes gives rise to stabilized alkyl-Pd intermediates, providing a basis for anti-Markovnikov selectivity. b, Allylic C–H bond activation can afford a π-allyl intermediate, which can be intercepted by a nucleophile to afford allylic amines. c, A tethered directing group can direct functionalization at the terminal position through formation of a more stable metallacyclic intermediate. d, Use of a palladate catalyst with sterically encumbered nucleophiles can kinetically favor anti-Markovnikov functionalization in stoichiometric studies and in the present work.

Figure 2:. Mechanistic investigation of the anti-Markovnikov oxidative amination through reagent order determination and Hammett plot analysis.

a, Determination of the order in all reagents for the anti-Markovnikov selective oxidative amination of 1a, showing first order kinetics for alkene, non-integer 1.4 order for catalyst, and zero order for nucleophile. b, Determination in the order of [Pd] when no Bu₄NOAc is added, indicating first order in catalyst with lower acetate equivalence and implicating palladium oligomerization. c, Hammett investigation for the effect of electronics on the aryl ring on the rate of the oxidative amination reaction, demonstrating the rate enhancement of electron withdrawing groups, even several bonds from the reactive alkene. Error bars represent the standard deviation of the measured values across multiple independent runs.

Figure 3:. Deuterium labelling studies as probes to distinguish between multiple mechanistic pathways.

a, Potential C–H activation and aminopalladation mechanisms. b, Isotopic labeling experiments to test the two possible mechanisms, showing full deuterium retention and no kinetic isotope effect as evidence for aminopalladation and against C–H activation. c, Possible outcomes for cis- and trans-aminopalladation pathways. d, Isotopic labeling study to probe the mechanism of aminopalladation, showing predominately deuterium retention at the terminal carbon and thereby indicating an anti-aminopalladation pathway (see Supplementary Figure 32).

Figure 4:. A catalytic cycle proposal based upon the mechanistic studies undertaken.

The order in reagents implicates the involvement of the alkene and catalyst at or before the rate determining step, while excluding the involvement of the phthalimide. This suggests that alkene binding through associative ligand dissociation is the rate determining step, and that nucleophilic attack upon the bound olefin is fast relative to this. The requirement of some catalytic quantity of acetate suggests its involvement in this process, and its function as a catalytic base is proposed, to generate a nucleophilic anionic phthalimide. Subsequent β-hydride elimination and olefin isomerization generates the most stable olefin isomer, and the resultant Pd–H is then oxidized aerobically to regenerate the palladate.