Iridium-catalyzed alkylation

Scheme 15 Iridium-catalyzed hydrogen-mediated coupling of alkyl-substituted alkynes to activated ketones and aldehydes. Conditions a ligand = BIPHEP, solvent = toluene, T = 80 °C b ligand = DPPF, solvent = toluene, T = 60 °C c ligand = BIPHEP, solvent = DCE,...

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... 

The most fundamental reaction is the alkylation of benzene with ethene.38,38a-38c Arylation of inactivated alkenes with inactivated arenes proceeds with the aid of a binuclear Ir(m) catalyst, [Ir(/x-acac-0,0,C3)(acac-0,0)(acac-C3)]2, to afford anti-Markovnikov hydroarylation products (Equation (33)). The iridium-catalyzed reaction of benzene with ethene at 180 °G for 3 h gives ethylbenzene (TN = 455, TOF = 0.0421 s 1). The reaction of benzene with propene leads to the formation of /z-propylbenzene and isopropylbenzene in 61% and 39% selectivities (TN = 13, TOF = 0.0110s-1). The catalytic reaction of the dinuclear Ir complex is shown to proceed via the formation of a mononuclear bis-acac-0,0 phenyl-Ir(m) species.388 The interesting aspect is the lack of /3-hydride elimination from the aryliridium intermediates giving the olefinic products. The reaction of substituted arenes with olefins provides a mixture of regioisomers. For example, the reaction of toluene with ethene affords m- and />-isomers in 63% and 37% selectivity, respectively. 

Ligand 19 performs excellently with the wide variety of l,l -disubstituted olefins reported. Substrates 61a-m are efficiently reduced at 1 bar of hydrogen in high enantioselectivity with very little dependence on the bulk of the alkyl substituents. Strongly coordinating olefins such as 611 and 61m tyqrically perform poorly in iridium-catalyzed hydrogenations, but reduction with 19 clearly breaks this rule and the substrates are reduced in excellent selectivity and yield. 

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%. 

Iridium-Catalyzed Asymmetric Allylic Alkylation with Catalysts Derived from LI... 

Scheme 10 Iridium-catalyzed allyiic alkylation catalyzed by [Ir(COD)Ci]2 and LI...

The cationic iridium complex [Ir(cod)(PPh3)2]OTf, when activated by H2, catalyzes the aldol reaction of aldehydes 141 or acetal with silyl enol ethers 142 to afford 143 (Equation 10.37) [63]. The same Ir complex catalyzes the coupling of a, 5-enones with silyl enol ethers to give 1,5-dicarbonyl compounds [64]. Furthermore, the alkylation of propargylic esters 144 with silyl enol ethers 145 catalyzed by [Ir(cod)[P(OPh)3]2]OTf gives alkylated products 146 in high yields (Equation 10.38) [65]. An iridium-catalyzed enantioselective reductive aldol reaction has also been reported [66]. 

The formation of a branched chiral product from the alkylation of monosubstituted substrates is not limited to the catalysis of metals described thus far. Allylic alkylation reactions catalyzed with rhodium [211] and iridium [212] complexes have been shown to occur at the more... 

McFarland JM, Francis MB. Reductive alkylation of proteins using iridium catalyzed transfer hydrogenation. J. Am. Chem. Soc. 2005 127 13490-13491. 

In the 1990s, BP re-examined the iridium-catalyzed methanol carbonylation chemistry first discovered by Paulik and Roth and later defined in more detail by Forster [20]. The thrust of this research was to identify an improved methanol carbonylation process using Ir as an alternative to Rh. This re-examination by BP led to the development of a low-water iridium-catalyzed process called Cativa [20]. Several advantages were identified in this process over the Rh-catalyzed high-water Monsanto technology. In particular, the Ir catalyst provides high carbonylation rates at low water concentrations with excellent catalyst stability (less prone to precipitation). The catalyst system does not require high levels of iodide salts to stabilize the catalyst. Fewer by-products are formed, such as propionic acid and acetaldehyde condensation products which can lead to low levels of unsaturated aldehydes and heavy alkyl iodides. Also, CO efficiency is improved. 

Saidi O, Blacker AJ, Lamb GW et al (2010) Borrowing hydrogen in water and ionic liquids iridium-catalyzed alkylation of amines with alcohols. Org Process Res Dev 14(4) 1046-1049... 

Fig. 10.3-11 Reductive alkylation of proteins using iridium catalyzed transfer hydrogenation, (a) The iridium(lll) catalyst shown reacts with formate ion to form a water-stable hydride. This species reduces imines formed in situ, (b) This reduction process proceeds readily on proteins, affording multiple alkylated products.

Yang H, White PS, Brookhart M. Scope and mechanism of the iridium-catalyzed cleavage of alkyl ethers with triethybilane. J Am Chem Soc 2008 130 17509-18. 

The analogous anionic iridium complex reacts with methyl iodide 150 times faster than the rhodium complex. The iridium complex also reacts 140-200 times faster than the rhodium analog with higher alkyl iodides/ but competing radical mechanisms appear to occur during the addition of the higher alkyl iodides. More details on the mechanism of rhodium and iridium-catalyzed carbonylation of methanol are provided in Chapter 17. 

Other indole syntheses of this type include the iridium-catalyzed hydrogen transfer of amine-substituted benzylic alcohols (130L3876), the intramolecular dehydrative coupling of tertiary amines with ketones (13OL6018), and the sequential alkylation/cyclization/isomerization of 3-(o-tri luoroacetamidoaryl)-l-propargylic esters (13T9494). 

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