Metalacyclic iridium-phosphoramidite

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

The scope of allylic electrophiles that react with amines was shown to encompass electron-neutral and electron-rich ciimamyl methyl carbonates, as well as furan-2-yl and alkyl-substituted allylic methyl carbonates. An ort/io-substituted cinnamyl carbonate was found to react with lower enantioselectivity, a trend that has been observed in later studies of reactions with other nucleophiles. The electron-poor p-nitrocinnamyl carbonate also reacted, but with reduced enantioselectivity. Allylic amination of dienyl carbonates also occur in some cases with high selectivity for formation of the product with the amino group at the y-position over the s-position of the pentadienyl unit [66]. Arylamines did not react with allylic carbonates under these conditions. However, they have been shown to react in the presence of the metalacyclic iridium-phosphoramidite catalysts that are discussed in Sect. 4. 

Scheme 11 Formation of the active metalacyclic iridium phosphoramidite catalyst...

Unstabilized enolates react with allylic carbonates in the presence of metalacyclic iridium-phosphoramidite catalysts. Although ketones and aldehydes have not yet been used directly as pronucleophiles with this catalyst system, silyl enol ethers [80] and enamines [81] react with linear allylic carbonates to form, after workup, p-branched, y-8 unsaturated ketones (Scheme 13). Both methods form products in high yield, branched selectivity, and enantioselectivity for a range of cinnamyl and alkyl-substituted allylic carbonates. However, the silyl enol ethers derived from aliphatic ketones reacted in lower yields than enamines derived from the same ketones. 

Nitrogen heterocycles undergo C-allylation in the presence of metalacyclic iridium-phosphoramidite catalysts. Recently, Yu and coworkers reported the C-allylation of indoles with the iridium catalyst derived from LI [86] and from phosphoramidites containing 2-methylindoline- and 2-methyl-l,2,3,4-tetrahydro-quinoline as the amino group (Table 4) [87]. No N-allylation was reported. However,... 

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... 

Scheme 22 Catalytic cycle for the reaction of aniline with methyl cinnamyl carbonate catalyzed by a metalacyclic iridium-phosphoramidite complex...

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]. 

Scheme 34 The reaction of highly substituted allylic carbonates have not been catalyzed by metalacyclic iridium-phosphoramidite complexes...

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. 

Reactions of allylic electrophiles with stabilized carbon nucleophiles were shown by Helmchen and coworkers to occur in the presence of iridium-phosphoramidite catalysts containing LI (Scheme 10) [66,69], but alkylations of linear allylic acetates with salts of dimethylmalonate occurred with variable yield, branched-to-linear selectivity, and enantioselectivity. Although selectivities were improved by the addition of lithium chloride, enantioselectivities still ranged from 82-94%, and branched selectivities from 55-91%. Reactions catalyzed by complexes of phosphoramidite ligands derived from primary amines resulted in the formation of alkylation products with higher branched-to-linear ratios but lower enantioselectivities. These selectivities were improved by the development of metalacyclic iridium catalysts discussed in the next section and salt-free reaction conditions described later in this chapter. 

The synthesis of pure metalacycle la from [Ir(COD)Cl]2 and LI requires only amine base and heat, followed by precipitation and removal of amine hydrochloride. However, this complex was typically generated in situ during early studies by the treatment of a combination of [lr(COD)Cl]2 and LI with an amine base, such as uPrNH2, l,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), or l,8-diazabicyclo[5.4.0] undec-7-ene (DBU). If a 1 1 ratio of iridium to ligand is used, a mixture of la and [Ir(COD)Cl]2 is produced. Helmchen et al. have reported that catalyst activation in the presence of tetrahydrothiophene (THT) prevents coordination of the k -phosphoramidite [71]. 

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... 

In contrast, reactions catalyzed by la were typically conducted with added [Ir (C0D)C1]2 to trap the K -phosphoramidite ligand after dissociation, and thereby, to leave the unsaturated active catalyst. Under these conductions, as much as half of the iridium in the system is present in an inactive acyclic species. In contrast, when ethylene adduct lb is used as the catalyst, all of the iridium belongs to the active metalacyclic species. Hartwig and coworkers have recently taken advantage of the increased availability of the active catalyst generated from lb to develop new allylic substitution reactions. These new processes include the reactions of carbamates, nitrogen heterocycles, and ammonia. 

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). 

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