Tsuji–Trost reaction

The Tsuji–Trost reaction (also called the Trost allylic alkylation or allylic alkylation) is a palladium-catalysed substitution reaction involving a substrate that contains a leaving group in an allylic position. The palladium catalyst first coordinates with the allyl group and then undergoes oxidative addition, forming the π-allyl complex. This allyl complex can then be attacked by a nucleophile, resulting in the substituted product. The Tsuji–Trost reaction (also called the Trost allylic alkylation or allylic alkylation) is a palladium-catalysed substitution reaction involving a substrate that contains a leaving group in an allylic position. The palladium catalyst first coordinates with the allyl group and then undergoes oxidative addition, forming the π-allyl complex. This allyl complex can then be attacked by a nucleophile, resulting in the substituted product. This work was first pioneered by Jiro Tsuji in 1965 and, later, adapted by Barry Trost in 1973 with the introduction of phosphine ligands. The scope of this reaction has been expanded to many different carbon, nitrogen, and oxygen-based nucleophiles, many different leaving groups, many different phosphorus, nitrogen, and sulfur-based ligands, and many different metals (although palladium is still preferred). The introduction of phosphine ligands led to improved reactivity and numerous asymmetric allylic alkylation strategies. Many of these strategies are driven by the advent of chiral ligands, which are often able to provide high enantioselectivity and high diastereoselectivity under mild conditions. This modification greatly expands the utility of this reaction for many different synthetic applications. The ability to form carbon-carbon, carbon-nitrogen, and carbon-oxygen bonds under these conditions, makes this reaction very appealing to the fields of both medicinal chemistry and natural product synthesis. In 1962, Smidt published work on the palladium-catalysed oxidation of alkenes to carbonyl groups. In this work, it was determined that the palladium catalyst activated the alkene for the nucleophilic attack of hydroxide. Gaining insight from this work, Tsuji hypothesized that a similar activation could take place to form carbon-carbon bonds. In 1965, Tsuji reported work that confirmed his hypothesis. By reacting an allylpalladium chloride dimer with the sodium salt of diethyl malonate, the group was able to form a mixture of monoalkylated and dialkylated product. The scope of the reaction was expanded only gradually until Trost discovered the next big breakthrough in 1973. While attempting to synthesize acyclic sesquiterpene homologs, Trost ran into problems with the initial procedure and was not able to alkylate his substrates. These problems were overcome with the addition of triphenylphosphine to the reaction mixture. These conditions were then tested out for other substrates and some led to 'essentially instantaneous reaction at room temperature.' Soon after, he developed a way to use these ligands for asymmetric synthesis. Not surprisingly, this spurred on many other investigations of this reaction and has led to the important role that this reaction now holds in synthetic chemistry. Starting with a zerovalent palladium species and a substrate containing a leaving group in the allylic position, the Tsuji–Trost reaction proceeds through the catalytic cycle outlined below. First, the palladium coordinates to the alkene, forming a η2 π-allyl-Pd0 Π complex. The next step is oxidative addition in which the leaving group is expelled with inversion of configuration and a η3 π-allyl-PdII is created (also called ionization). The nucleophile then adds to the allyl group regenerating the η2 π-allyl-Pd0 complex. At the completion of the reaction, the palladium detaches from the alkene and can start again in the catalytic cycle. The nucleophiles used are typically generated from precursors (pronucleophiles) in situ after their deprotonation with base. These nucleophiles are then subdivided into 'hard' and 'soft' nucleophiles using a paradigm for describing nucleophiles that largely rests on the pKas of their conjugate acids. 'Hard' nucleophiles typically have conjugate acids with pKas greater than 25, while 'soft' nucleophiles typically have conjugate acids with pKas less than 25. This descriptor is important because of the impact these nucleophiles have on the stereoselectivity of the product. Stabilized or 'soft' nucleophiles invert the stereochemistry of the π-allyl complex. This inversion in conjunction with the inversion in stereochemistry associated with the oxidative addition of palladium yields a net retention of stereochemistry. Unstabilized or 'hard' nucleophiles, on the other hand, retain the stereochemistry of the π-allyl complex, resulting in a net inversion of stereochemistry. This trend is explained by examining the mechanisms of nucleophilic attack. 'Soft' nucleophiles attack the carbon of the allyl group, while 'hard' nucleophiles attack the metal center, followed by reductive elimination.