Iridium-Catalyzed Allylic Substitution

Iridium-catalyzed allylic substitution was first investigated after many years of development of allylic substitution reactions catalyzed by a variety of complexes of other metals, particularly those containing palladium. While iridium-catalyzed... 

Most allylic substitution reactions catalyzed by other metals are selective for the formation of branched products. Although this had been demonstrated for a large portion of the d-block before Takeuchi s work with iridium, most of the progress in this area was restricted to stabilized enolate nucleophiles. 

One notable deviation from this trend of increased branched selectivity with increased 7i-accepting character has been reported. Nomura and coworkers reported allylic substitution reactions catalyzed by [lr(COD)Cl]2 and triphenylpho-sphine to form polymers linked by branched l,l -(l,4-phenylene)diprop-2-enyl units [49]. Despite this exception, most iridium-catalyzed allylic substitution... 

Isolation and Study of Intermediates in Allylic Substitution Reactions Catalyzed by Metalacyclic Iridium-Phosphoramidite Complexes... 

Allylic substitution reactions catalyzed by metalacyclic iridium-phosphoramidite complexes form branched products from linear allylic esters with high regioselec-tivity. However, reactions with racemic, branched allylic esters would be particularly valuable because they are readily accessible from a wide array of aldehydes and vinylmagnesium halides. However, iridium-catalyzed allylic substitution reactions of branched allylic esters have so far occurred with low enantioselectivities [45, 75]. 

Good fortune and design in the discovery of iridium-catalyzed asymmetric allylic substitution. 

A fourth focus of catalytic chemistry in our laboratory has been iridium-catalyzed asymmetric allylic substitution. Dr. Toshimichi Ohmura had been studying additions to rhodium and iridium allyl and benzyl complexes in hopes of developing... 

It is noteworthy that ZnEt2 has been used as a base in enantioselective allylic substitutions. A remarkable increase in ee was observed when ZnEt2 was used instead of KH, NaH, LiH, LDA, or BuLi in the Pd-catalyzed alkylations of allylic acetates by enolates of malonic esters and related compounds.403 In contrast, application of ZnEt2 was not as very effective as in similar iridium-catalyzed allylic alkylations.404... 

Scheme 27 Enantioselective allylation, crotylation, and lert-prenylation of substituted isatins via iridium-catalyzed transfer hydrogenation...

Asymmetric Iridium-Catalyzed Allylic Substitution A Survey of Ligands. 177... 

Diastereoselectivity of Iridium-Catalyzed Allylic Substitution Reactions. ..202... 

A wide range of carbon, nitrogen, and oxygen nucleophiles react with allylic esters in the presence of iridium catalysts to form branched allylic substitution products. The bulk of the recent literature on iridium-catalyzed allylic substitution has focused on catalysts derived from [Ir(COD)Cl]2 and phosphoramidite ligands. These complexes catalyze the formation of enantiomerically enriched allylic amines, allylic ethers, and (3-branched y-8 unsaturated carbonyl compounds. The latest generation and most commonly used of these catalysts (Scheme 1) consists of a cyclometalated iridium-phosphoramidite core chelated by 1,5-cyclooctadiene. A fifth coordination site is occupied in catalyst precursors by an additional -phosphoramidite or ethylene. The phosphoramidite that is used to generate the metalacyclic core typically contains one BlNOLate and one bis-arylethylamino group on phosphorus. 

This chapter describes the development of iridium-catalyzed, enantioselective allylic substitution. It is organized to focus on how modifications to the catalyst, combined with mechanistic insights, have provided the foundation for a steady... 

Scheme 1 Asymmetric allylic substitution catalyzed by metaiacyciic iridium-phosphoramidite complexes...

The first iridium catalysts for allylic substitution were published in 1997. Takeuchi showed that the combination of [fr(COD)Cl]2 and triphenylphosphite catalyzes the addition of malonate nucleophiles to the substituted terminus of t -allyliridium intermediates that are generated from allylic acetates. This selectivity for attack at the more substituted terminus gives rise to the branched allylic alkylation products (Fig. 4), rather than the linear products that had been formed by palladium-catalyzed allylic substitution reactions at that time [7]. The initial scope of iridium-catalyzed allylic substitution was also restricted to stabilized enolate nucleophiles, but it was quickly expanded to a wide range of other nucleophiles. 

The first examples of iridium-catalyzed allylic substitution [1] occurred between stabilized carbon nucleophiles and both alkyl- and aryl-substituted allylic alcohol derivatives with exceptional selectivity for the branched substitution product. 

The first enantioselective, iridium-catalyzed allylic substitution was reported by Helmchen and coworkers soon after the initial report by Takeuchi. Helmchen studied catalysts generated from phosphinooxazoline (PHOX) ligands and [Ir(COD)Cl]2 for the reactions of sodium dimethylmalonate with cinnamyl acetates (Scheme 2) [50]. The alkylation products were isolated in nearly quantitative yield and were formed with ratios of branched-to-Unear products up to 99 1 and with enantioselectivities up to 95% ee. In this and subsequent studies with PHOX ligands [51,52], Helmchen et al. demonstrated that the highest yields and selectivities were obtained with a PHOX ligand containing electron-withdrawing substituents and... 

Although Helmchen et al. showed that asymmetric iridium-catalyzed allylic substitution could be achieved, the scope of the reactions catalyzed by iridium complexes of the PHOX ligands was limited. Thus, they evaluated reactions catalyzed by complexes generated from [lr(COD)Cl]2 and the dimethylamine-derived phosphoramidite monophos (Scheme 8) [45,51]. Although selectivity for the branched isomer from addition of malonate nucleophiles to allylic acetates was excellent, the highest enantiomeric excess obtained was 86%. This enantiomeric excess was obtained from a reaction of racemic branched allylic acetate. The enantiomeric excess was lower when linear allylic acetates were used. This system catalyzed addition of the hthium salts of A-benzyl sulfonamides to aUylic acetates, but the product of the reaction between this reagent and an alkyl-substituted linear aUylic acetate was formed with an enantiomeric excess of 13%. 

Concurrent with studies on cyclometalation, studies on the effects of the structure of phosphoramidite ligand had been conducted. Several groups studied the effect of the stmcmre of ligand on the rate and selectivity of these iridium-catalyzed allylic substitutions. LI contains three separate chiral components - the two phenethyl moieties on the amine as well as the axially chiral BINOL backbone. These portions of the catalyst structure can control reaction rates by affecting the rate of cyclometalation, by inhibiting catalyst decomposition, or by forming a complex that reacts faster in the mmover-limiting step(s) of the catalytic cycle. 

Additional studies were conducted to determine how further modifications to the amine portion of the phosphoramidite ligand affect iridium-catalyzed allylic substitution. One arylethyl moiety is necessary for the formation of metalacyclic active catalyst, but it was unclear how changes to the structure of the second substituent on nitrogen would affect reactivity and selectivity. A stereocenter on this second... 

---