Iridium Catalyst Allylation

A polymer-supported iridium catalyst 4 has been prepared and used in the isomerization of the double bonds in aryl allyl ethers and aryl allylic compounds with excellent trans-scIcctivity and without conventional workup procedures (Scheme 45).73... 

Bis-allylic oxidation of 23 and related cyclohexa-1,4-dienes provides a convenient and general preparation of cyclohexa-2,5-dien-l-ones (Scheme 7). These cross-conjugated die-nones are substrates for a variety of photochemical rearrangement and intramolecular cycloaddition reactions. Amide-directed hydrogenations of dienones 24a and 24b with the homogeneous iridium catalyst afford cyclohexanones 25a and 25b, containing three stereogenic centers on the six-... 

As demonstrated in recent work by Obora and Ishii, alkynes serve as allyl donors in carbonyl allylations from the alcohol oxidation level [277]. Specifically, upon exposure to an iridium catalyst generated in situ from [lr(OH)(cod)]2 and P( -Oct)3, l-aryl-2-methylalkynes couple to primary alcohols to furnish homoallylic alcohols with complete branched regioselectivity and excellent levels of diastereoselectivity (Scheme 17). 

New catalytic allylation methodologies continue to emerge. For example, iridium-catalyzed transfer hydrogenation of a-(trimethylsilyl)allyl acetate in the presence of aldehydes mediated by isopropanol and employing the iridium catalyst... 

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. 

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. 

Thus, a catalyst for allylic substitution that is highly active and selective for the formation of products from addition to the more substituted terminus from a variety nucleophiles and allylic esters was unknown. Iridium catalysts have now been developed that begin to fill this void. 

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... 

Iridium-Catalyzed Allylic Etherification with Catalysts Derived from LI... 

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. 

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... 

Nitroalkanes react with allylic carbonates in the presence of iridium catalysts [83]. However, nitroalkanes are prochiral, and products are formed with poor diastereo-selectivity. Nitroalkanes and other prochiral nucleophiles are discussed further in Sect. 6. 

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,... 

Al-allylation of indoles and other azoles in the presence of iridium catalysts has been reported recently and is discussed in Sect. 5.3. 

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... 

Scheme 22. The rate equation for this mechanism is described in (1). The authors determined that the reaction is first-order in allylic carbonate, aniline and catalyst, and inverse first-order in allylamine product. These results are consistent with the proposed mechanism. Thus, iridium-catalyzed allylic substitution is inhibited by product. In addition, the formation of the allyliridium intermediate is disfavored.

Hartwig and coworkers reported an approach to address this limitation involving tandem catalytic reactions. In this tandem process, sequential palladium-catalyzed isomerization of the branched isomer to the linear isomer, followed by iridium-catalyzed allylic substitution leads to the branched product with high enantiomeric excess [105]. More specifically, treatment of branched allylic esters with catalytic amounts of the combination of Pd(dba)2 and PPhs led to rapid isomerization of the branched allylic ester to the linear isomer, and the linear isomer underwent allylic substitution after addition of the iridium catalyst and nucleophile (Scheme 31). 

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). 

Takeuchi s initial report on iridium-catalyzed allylic substitution demonstrated that the allylation of carbon nucleophiles forms branched, racemic substitution products. Chiral catalysts were quickly developed that led to methods to prepare the... 

In contrast to reactions with vinyl epoxides and palladium catalysts, the reactions with rhodium retain the stereochemistry of the alkene fragment during the reaction [20]. This is illustrated by the reactions of trans-37a/h and cis-37a/b, which give only one product possessing the same olefin geometry as the starting epoxides (Eqs. 4 and 5). The retention of olefin stereochemisty has also been documented in allylic functionalizations with iridium catalysts, indicating that similar modes of action may be present [21, 22]. 

Catalytic hydrogenation of the double bond of the allylic alcohol with either Pd/C or an iridium catalyst would lead to reduction also of the terminal olefinic linkage. 

The iridium catalyst [lr(COD)py(PCy )PFA] is utilized in substrate-controlled hydrogenations of allylic alcohols of the type 34, 36, and 38.25 The catalyst coordinates with the hydroxy group in the molecule, so hydrogenation occurs on ) from one side. 

Regioselective polycondensations with transition-metal catalysts were also reported. Nomura et al. developed palladium-catalyzed allylation polycondensation, in which nucleophile predominantly reacted with jt-allyl palladium at the terminal allylic carbon to give fi-linear products [122,123]. On the other hand, polymerization with an iridium catalyst selectively proceeded at the internal allylic carbon to yield branched polymers with pendant vinyl groups (Scheme 30). These polycondensations demonstrate that polymers having different structures can be synthesized from the same monomers by changing the catalyst [124],... 

Combinations of eight different ligands and twelve different metal salts were screened for their efficiency to catalyze the allylation of /i-dicarbonyl compounds. The assay identified not only the well known catalyst system Pd(OAc)2 combined with a phosphine ligand but also the combination [ IrCl(cod) 2] and iPr-pybox or 1,10-phenanthroline as efficient catalysts. These are the first examples of non-phosphane iridium catalysts capable of allylic alkylations. 

Allylic amination of 70 using iridium catalyst has also been reported recently using a chiral phophoramidite ligand. The reaction produced the branched product 72 over the linear monoalkylated and dialkylated products and the amines... 

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