Iridium-Catalyzed Enantioselective Allylation Reactions

Carreira has reported a conceptually different class of chiral ligands for iridium-catalyzed allylic displacement reactions (Equation 6) [87]. The use of chiral diene 89 in combination with Ir(I) led to kinetic resolution of racemic allylic carbonates. The resulting allylic ethers (cf 90) and recovered starting allylic carbonates are obtained with high enantioselectivity. The modular chiral diene ligands, exemplified by 89, are readily available by a short synthetic sequence starting from carvone. 

Activated cyclometalated catalyst complex identified by Hartwig [18] 

Direct preparation of chiral allylic alcohols reported by Carreira [10]  

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A related rhodium catalyzed enantioselective reductive coupling of acetylene to N arylsulfonyl imines leads to the formation of (Z) dienyl allylic amines (Scheme 1.28) [105]. The scope of the reaction is comparable to that demonstrated for the analogous iridium catalyzed process. The reaction between the acetylene and rhodium leads to the oxidative dimerization of acetylene to form a cationic rhoda cyclopentadiene that then reacts with the imine to generate the product after the protolytic cleavage and reductive elimination. 

In 2010, Ueda and Hartwig reported on an iridium-catalyzed asymmetric allylation of sodium sulfinates 345 to branched allylic sulfones 348 with high regioselectivities and enantioselectivities (Scheme 46.40). Notably, the reaction proceeded with a broad range of acyclic allylic carbonates 346 and aryl and alkyl sodium sulfinates 345. Most recently, Zhao et al. developed the catalytic asymmetric allylic alkylations of acyclic allylic carbonates 346 using sodium thiophenoxide and alkyl thiolates 348 to give good-to-excellent selectivities for branched products 350 with excellent enantioselectivities. 

Palladium remains the most widely recognized transition metal to effect stereoselective allylic alkylation reactions. Consequently, diastereoselective and enantioselective Pd-catalyzed processes are extensively discussed in Sections 14.2 and 14.3. More recent advances in the field of metal-catalyzed al-lylation reactions include the use of chiral iridium complexes, dealt with in Section 14.4 [33, 34]. Section 14.5 describes selected stereoselective copper-catalyzed SN2 -allylation reactions [33, 35-37], while a brief presentation of allylation reactions with other transition metals including Mo and Rh is given in Section 14.6 [8, 13, 33, 38, 39]. The closing Section 14.7 deals with selected methods for asymmetric ring-opening reactions of unsaturated heterocycles [38, 40, 41]. 

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... 

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. 

The use of ethylene adduct lb is particularly important when the species added to activate catalyst la is incompatible with one of the reaction components. Iridium-catalyzed monoallylation of ammonia requires high concentrations of ammonia, but these conditions are not compatible with the additive [Ir(COD)Cl]2 because this complex reacts with ammonia [102]. Thus, a reaction between ammonia and ethyl ciimamyl carbonate catalyzed by ethylene adduct lb produces the monoallylation product in higher yield than the same reaction catalyzed by la and [Ir(COD)Cl]2 (Scheme 27). Ammonia reacts with a range of allylic carbonates in the presence of lb to form branched primary allylic amines in good yield and high enantioselectivity (Scheme 28). Quenching these reactions with acyl chlorides or anhydrides leads to a one-pot synthesis of branched allylic amides that are not yet directly accessible by metal-catalyzed allylation of amides. 

More recently, Hartwig and coworkers reported iridium-catalyzed, asymmetric aminations of allylic alcohols in the presence of Lewis acid activators [103]. The addition of molecular sieves and Nb(OEt)5 or catalytic amounts of BPh3 activated the allylic alcohol sufficiently to allow allylic amination reactions to occur in high yield, branched-to-linear selectivity, and enantioselectivity (Scheme 29). Without the activators, only trace amounts of product were observed. 

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). 

Many diastereoselective allylations form a new stereocenter at one of the allylic carbons and at the nucleophilic carbon. For example, an iridium complex containing a phosphite ligand catalyzes enantioselective and diastereoselective formation of products containing two stereocenters, one at the original nucleophile and one at the original allyl electrophile (Equation 20.58). In another example shown in Equation 20.59, Trost s palladium catalyst leads to the reaction of allylic esters with chiral azlactone pronucleophiles with high diastereomeric and enantiomeric excess, as does the related molybdenum catalyst. In these cases, the metal appears to control the new stereocenter at the allyl group, as well as the relationship between this stereocenter and the new stereocenter formed at the nucleophile. 

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. 

In accessing chiral allyl vinyl ethers for Claisen rearrangement reactions, Nelson et al. employed the iridium-mediated isomerization strategy. Thus, the requisite enantioenriched diallyl ether substrate 28 was synthesized via a highly enantioselective diethylzinc-aldehyde addition protocol10 (Scheme 1.1k). The enantioselective addition of Et2Zn to cinnamaldehyde catalyzed by (—)-3-exo-morpholinoisobomeol (MIB 26)11 provided an intermediate zinc alkoxide (27). Treatment of 27 with acetic acid followed by 0-allylation in the presence of palladium acetate delivered the 28 in 73% yield and 93% ee. Isomerization of 28 with a catalytic amount of the iridium complex afforded the allyl vinyl ether... 

Much effort has been devoted to developing catalysts that control the enantioselectiv-ity of these substitution reactions, as well as the regioselectivity of reactions that proceed through unsymmetrical allylic intermediates. A majority of this effort has been spent on developing palladium complexes as catalysts. Increasingly, however, complexes of molybdenum, tungsten, ruthenium, rhodium, and iridium have been studied as catalysts for enantioselective and regioselective processes. In parallel with these studies of allylic substitution catalyzed by complexes of transition metals, studies on allylic substitution catalyzed by complexes of copper have been conducted. These reactions often occur to form products of Sj 2 substitution. As catalylic allylic substitution has been developed, this process has been applied in many different ways to the synthesis of natural products. ... 

Enantioselective Reactions of Unsymmetrical Allylic Esters Catalyzed by Molybdenum, Ruthenium, Rhodium, and Iridium... 

Up to date, numerous examples of nucleophilic substitution reactions on diverse allylic substrates catalyzed by Ir complexes have been published. Allylic or dienylic esters, carbonates, and phosphates are used as typical allyl donors. As an iridium source, no precatalyst better suited than [Ir(cod)Cl]2 (cod, 1,5-cyclooctadiene) has emerged, despite considerable work of several groups. The first Ir-catalyzed allylation was reported by Takeuchi in 1997 [146]. The first asymmetric version was then published by Janssen and Hebnchen (Scheme 12.64) [147]. Since then many further chiral ligands have been developed, providing regioselective access to branched substitution products with excellent enantioselectivities (Figure 12.4). 

As an alternative, iridium complexes show exciting catalytic activities in various organic transformations for C-C bond formation. Iridium complexes have been known to be effective catalysts for hydrogenation [1—5] and hydrogen transfers [6-27], including in enantioselective synthesis [28-47]. The catalytic activity of iridium complexes also covers a wide range for dehydrogenation [48-54], metathesis [55], hydroamination [56-61], hydrosilylation [62], and hydroalkoxylation reactions [63] and has been employed in alkyne-alkyne and alkyne - alkene cyclizations and allylic substitution reactions [64-114]. In addition, Ir-catalyzed asymmetric 1,3-dipolar cycloaddition of a,P-unsaturated nitriles with nitrone was reported [115]. 

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