Phosphoramidite ligands substitution

The X-ray structure of the Cut complex 21 of phosphoramidite 14 provides additional insight into a possible mechanism for stereocontrol (Fig. 7.3). The formation of the L2CuEt-enone complex involves substitution of the iodide in 21 for the alkyl moiety and of one of the ligands for the -coordinated enone. Coordination of RZnX results in the bimetallic intermediate 19 (Fig. 7.3). The absolute configuration of the two phosphoramidite ligands and the pseudo-C2-symmetric arrangement dictate the formation of (S)-3-ethyl-cyclohexanone. 

The moderate ees obtained with the copper arenethiolate ligands discussed above prompted a search for new chiral ligands for use in asymmetric allylic substitution reactions. The binaphthol-derived phosphoramidite ligand 32, used successfully by Feringa et al. in copper-catalyzed 1,4-addition reactions [37], was accordingly tested in the reaction between 21 and n-BuMgl. 

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 phosphoramidite ligands that are the focus of the remainder of this chapter have prompted the investigation of ligands containing related structures. Iridium complexes of aspartic acid-derived P-chirogenic diaminophosphine oxides (DlAPHOXs) catalyze the amination [62] and alkylation [63] of aUyhc carbonates (Scheme 6). With BSA as base and catalytic amounts of NaPFs as additive, branched amination and alkylation products were obtained from cinnamyl carbonates in excellent yields and enantioselectivities. However, the yields and enantios-electivities were lower for the reactions of alkyl-substituted aUyhc carbonates. Added LiOAc increased the enantioselectivities of aUyhc alkylation products. 

Although the combination of [Ir(COD)Cl]2 and LI was shown to catalyze the alkylation, amination, and etherification of allyiic esters to form the branched substitution product in high yield and enantioselectivity, the identity of the active catalyst in these reactions had not been identified. The combination of [Ir(COD) Cl]2 and LI forms the square-planar [Ir(COD)(Cl)Ll] (4) (Scheme 11) [45]. However, this complex does not react with allyiic carbonates to form an appreciable amount of an aUyl complex, and the absence of this reactivity suggested that the mechanism or identity of the active catalyst was more complex than that from simple addition of the allyiic ester to the square-planar complex containing a k -phosphoramidite ligand. 

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... 

The configuration of the chiral BlNOLate backbone of the phosphoramidite ligand affects the rates and enantioselectivities of allylic substitution reactions. Hartwig and coworkers found that allylic substitution conducted with a catalyst derived from the simplified ligand (5a,/ )-L4 occurred more slowly than that conducted with a catalyst derived from (/ a,/ )-L4 [74]. Complexes of the mismatched (5a,/ )-L4 undergo cyclometalation slowly. The products formed from reactions catalyzed by complexes of (5a,/ )-L4 and (/ a,/ )-L4 have the opposite absolute configuration. 

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). 

TABLE 9. Asymmetric allylic substitution using a Cu/phosphoramidite ligand... 

A new phosphoramidite ligand (1 Y = OMe), gives high enantioselectivities (92-99% ee) and regioselectivities (99% S 2 ) in iridium-catalysed allylic substitution reactions of carbonates and acetates with carbanion or primary amine nucleophiles.6 The new ligand also leads to a faster rate of reaction than other phosphoramidite ligands. 

Several papers on allylic and vinylic substitution have been published. The effect of seven different phosphoramidite ligands (1) on the [IrCODCl]2 catalyst used in the Sn reaction between allylic esters and either benzylamine or sodium dimethylmalonate was studied.3 The best ligand, which gave a 99% yield of the S 2 product that was 99% ee in both reactions, had an o-methyl group on each aromatic ring. 

In another study,4 the substituents on the phosphoramidite ligand on the [IrCODClh catalyst were altered from aryl groups to 1-naphthyl groups. This led to higher yields (>94%), and greater regio- and enantio-selectivities in the 5 2 reaction between several substituted allylic carbonates and amines or phenoxides. The S 2 /S 2 product ratios were >91 9 with the new catalyst. 

Preparative Methods the phosphoramidite ligand can be prepared by the nucleophilic substitution of phosphory 1 chloride (formed from the reaction of PCI3 and (S)-2,2 -binaphthol in presence of triethylamine) with (R,R)-bis(l-phenylethyl)amine. Purification recrystallization from diethyl ether/dichloro-methane. 

Scheme 9.11 Rh catalyzed asymmetric hydrogenation of ortho substituted arylenamides with a triphosphorus bidentate phosphine phosphoramidite ligand 49.

Leitner and coworkers disclosed new phosphine phosphoramidite ligands con taining two elements of chirality, which can be prepared via a modular approach. These ligands proved to be very efficient for asymmetry of 2 substituted quino lines [22]. The hydrogenation reaction proceeded smoothly with up to 97% ee and full conversion (Scheme 10.16). 

Hydrogenation Easily prepared monodentate phosphoramidite ligands containing a BINOL residue are employed in conjunction with (cod)2RhBp4 in asymmetric hydrogenation of dehydroamino acid derivatives and a-substituted acrylic esters (ee > 99% reachable). 

Scheme 6.81 Ir-catalyzed allylic substitution reactions and chiral phosphoramidite ligands.

---