Allylic substitutions iridium complexes

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... 

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. 

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

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... 

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. 

Scope of Allylic Substitution Catalyzed by Metalacyclic Iridium-Phosphoramidite Complexes... 

As previously discussed, activation of the iridium-phosphoramidite catalyst before addition of the reagents allows less basic nitrogen nucleophiles to be used in iridium-catalyzed allylic substitution reactions [70, 88]. Arylamines, which do not react with allylic carbonates in the presence of the combination of LI and [Ir(COD)Cl]2 as catalyst, form allylic amination products in excellent yields and selectivities when catalyzed by complex la generated in sim (Scheme 15). The scope of the reactions of aromatic amines is broad. Electron-rich and electron-neutral aromatic amines react with allylic carbonates to form allylic amines in high yields and excellent regio- and enantioselectivities as do hindered orlAo-substituted aromatic amines. Electron-poor aromatic amines require higher catalyst loadings, and the products from reactions of these substrates are formed with lower yields and selectivities. 

Protected primary allylic amines were generated from allylic carbonates and ammonia equivalents. Iridium-catalyzed allylic substitution has now been reported with sulfonamides [90, 91], imides [89, 91-93], and trifluoroacetamide [89] to form branched, protected, primary allylic amines (Table 5). When tested, yields and selectivities were highest from reactions catalyzed by complexes derived from L2. Reactions of potassium trifluoroacetamide and lithium di-tert-butyhminodi-carboxylate were conducted with catalysts derived from the simplified ligand L7. Reactions of nosylamide and trifluoroacetamide form singly-protected amine products. The other ammonia equivalents lead to the formation of doubly protected allylic amine products, but one protecting group can be removed selectively, except when the product is derived from phthalimide. 

Several types of intramolecular allylic substitution reactions of carbon, nitrogen, and oxygen nucleophiles catalyzed by metalacyclic iridium phosphoramidite complexes have been reported. Intramolecular allylic substitution is much faster than the competing intermolecular process when conducted in the presence of iridium catalysts. Thus, conditions involving high dilution are not required. Intramolecular... 

Markovic and Hartwig isolated and characterized the first intermediate in iridium-catalyzed allylic substitution [100]. They isolated the metalacyclic iridium-phosphor-amidite fragment containing COD and the olefinic portion ofN- l -phenylallyl)aniline, the product of the allylic substitution reaction between cinnamyl carbonate and aniline (5 in Scheme 22). This complex containing the product of allylic substitution was first detected by NMR spectroscopy during catalytic reactions. It was then isolated, prepared independently, and shown to be chemically and kinetically competent to be an intermediate in allylic substitutions. 

Additional mechanistic insights were gained when Hartwig and coworkers isolated and characterized the first 7t-allyl complexes that are chemically and kinetically competent to be intermediates in iridium-catalyzed allylic substitution [46]. These complexes were prepared independently from allylic electrophiles that are more reactive than allylic carbonates. The isolation and structural characterization of these species provided a detailed view into the origins of enantioselectivity. 

These recent mechanistic studies have provided the foundation for the most recent work that has expanded the scope of iridium-catalyzed allylic substitution. The synthesis and characterization of the ethylene-bound complex lb resulted directly... 

The scope of reactions catalyzed by metalacychc iridium-phosphoramidite complexes is remarkably broad, but reactions with some substrates, such as allylic alcohols, prochiral nucleophiles, branched allylic esters, and highly substituted allylic esters, that would form synthetically valuable products or would lead to simpler symthesis of reactants occur with low yields and selectivities. In addition, iridium-catalyzed allylic substitution reactions are sensitive to air and water and must be conducted with dry solvents under an inert atmosphere. Several advances have helped to overcome some, but not aU of these challenges. 

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]. 

No examples have been reported of enantioselective, iridium-catalyzed allylic substitutions of linear allylic esters to generate 1,1-disubstituted or 2-substituted 7i-allyl intermediates. Takeuchi published reactions in which the proposed allylir-idium intermediates are 1,1- or 1,3-disubstituted, but these substrates have not been shown to undergo reactions catalyzed by chiral iridium complexes. No reactions of 1,2-disubstituted substrates have been published (Scheme 34). 

Except for one recent example, all iridium-catalyzed allylic substitution reactions have been performed under an inert atmosphere with dry solvent and reagents. The iridium metalacycle is sensitive to protonation, which opens the metalacycle and results in the formation of a less-active complex containing a K -phosphoramidite ligand. A paper by Helmchen et al. addressed this issue [107]. Nearly all iridium catalysts used for allylic substitution consist of an iridium fragment chelated by COD. In the presence of a catalyst containing dibenzo[a,c]cyclooctatetraene (dbcot) in place of COD, allylic substimtion reactions occur in air with results that are comparable to those of reactions performed under an inert atmosphere (Scheme 35). 

Keywords Allylic substitution, Allylation, Allylic alkylation, Jt-Allyl complexes, Palladium, Molybdenum, Ruthenium, Iridium... 

Allylic substitution. The iridium complex of 2A is effective for catalyzing aUyUc substitution reactions, for example, in reaction of enamines with aUyUc carbonates to yield branched products. Chiral aUyUc ethers are similarly prepared. ... 

Gunter Helmchen of the Universitat Heidelberg took advantage (Chem. Comm. 2004, 896) of the substitutional flexibility of 7t-allyl iridium complexes to develop enantioselective cyclizations such as 3 to 4. Six-membered rings are also formed efficiently (88% ee). 

Even oxygen nucleophiles have been introduced with good enantioselectivity using both palladium- and iridium-based catalysts. The conditions of the reaction need to be sufficiently mild that the product does not become a substrate for the allylic substitution, since this will ultimately lead to racemisation. Pivalate ( BuC02 ) and phenols have been used as nucleophiles, in the presence of palladium catalysts, with good results, while linear allylic carbonates are converted into chiral branched products with high ee using phenolates, aUcoxides and also hydroxylamines with iridium complexes. Sulfur nucleophiles have also been used in enantioselective allylic substitution reactions. ... 

A related iridium complex has been used for the decarbo)grlative radical allylation of aminoacids and phenylacetic acids that occurs smoothly at room temperature in the presence of Pd(PPh3)4, irradiating by white LEDs. The proposed scheme (Scheme 6) is based on dual catalysis. Ruthenium tris(phenanthroline) dichloride has been used for visible light catalysis of the mild amidation of ketoacids by ort/zo-substituted anilines using ozygen as terminal oxidant (Scheme 7) ... 

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