1. C–H arylation project (Scheme 1)
First, stoichiometric reactions between a pre-formed amine cyclopalladation complex and various organoboron reagents were investigated. We found that the desired arylation reaction was observed with Ph-BPin in the presence of benzoquinone and Na2CO3. Based on these findings, we were able to render this transformation catalytic in Pd(OAc)2 by the addition of Ag2CO3 as terminal oxidant in combination with amino-acid-derived ligand, benzoquinone and Na2CO3. Then we found that a modest range readily available amines derivatives were suitable substrates for the C–H arylation. The reaction was also readily extended to a variety of arylboronic acid pinacol esters in good yields. Moreover, the products of the arylation can be advanced to complex polycyclic molecules by sequential C-H activation reactions. Finally, we investigated the potential for an asymmetric C–H arylation on the basis that the amino-acid-derived ligands can provide asymmetric induction. We screened a range of ligands and found that b-phenyl-phenylalanine combined with the bulky acyl side chain could give a 60% ee.
Overview of the results: a palladium-catalyzed C-H arylation of aliphatic amines with arylboronic esters is described, proceeding through a four-membered-ring cyclopalladation pathway. Crucial to the successful outcome of this reaction is the action of an amino-acid-derived ligand. A range of hindered secondary amines and arylboronic esters are compatible with this process and the products of the arylation can be advanced to complex polycyclic molecules by sequential C-H activation reactions.
2. C–H alkenylation project (Scheme 2)
The studies began with the investigation of a stoichiometric C–H alkenylation process using 3-ethyl-3,5,5-trimethylmorpholin-2-one. Its reaction with Pd(OAc)2 delivered a 3 : 1 mixture of palladacycles in favour of the 4-membered ring complex. When this mixture of palladacycles was treated with ethyl acrylate, we found that the bicyclic pyrrolidine product was formed; reaction of only the 5-membered ring palladacycle via sequential carbopalladation of the alkene, b-hydride elimination to a substituted acrylate and aza-Michael addition gave the pyrrolidine. Then we found that the use of ligand Ac-Gly-OH was reversing the cyclopalladation process, such that, in the presence of an alkene, the C–H alkenylation via the 5-membered ring palladacycle becomes a kinetic trap for the equilibrium, selectively forming pyrrolidine. So we were able to render this transformation catalytic in Pd(OAc)2 by the addition of AgOAc as terminal oxidant. Then we found that a range of functionalized a,a-disubstituted morpholinones underwent smooth ligand assisted C–H alkenylation. The reaction was also readily extended to a variety of acrylates in excellent yields. a,b-Unsaturated ketones, amides acrolein and even vinyl sulfone, vinyl phosphonate could also be incorporated into the pyrrolidine scaffold.
Overview of the results: the development of a ligand-assisted Pd-catalyzed C–H alkenylation of aliphatic amines is reported. Our studies indicated that an amino-acid-derived ligand renders the C–H bond activation step reversible and promotes the traditionally difficult alkenylation process. The C(sp3)–H alkenylation proceeds through a 5-membered-ring cyclopalladation pathway that allows access to complex aliphatic heterocycles that could be useful to practioners of synthetic and medicinal chemistry.
