Under Biphasic Conditions

Asymmetric transfer hydrogenation of ketones in the presence of soluble transition metal catalysts has been developed [8-10], enantioselectivities up to 99% ee being obtained using a ruthenium catalyst bearing mono-N-tosylated diphenyl-ethylenediamine as a ligand. Iridium complexes associated with fluorous chiral diimines 3a-3c or diamines 4a—4b have also been shown to be effective catalysts in hydrogen-transfer reduction of ketones [11,12]. 

Enantioselectivities up to 56% ee were obtained using [Ir(COD)Cl]2 associated with fluorous diimines 3a-3c at 70 °C in the reduction of acetophenone with isopropanol as the hydride source in the presence of Galden D-lOO (mainly n-perfluorooctane, b.p. 102 °C) as the fluorous solvent. The hydrogen-transfer reduction was extended to other ketones, enantioselectivity of 60% ee being obtained 

Takeuchi and collaborators reported the condensation of benzaldehyde with Et2Zn at 0 °C in the presence of the complex prepared in situ by mixing Ti(0-i-Pr)4 and fluorous BINOL 5 [15-17]. When the reaction was performed in a toluene/hexane/ 

Ligand Solvent Yield l%] (cycle) ee l%] (cycle) Recovery of ligand (%] (cycle) 

Chan et al. [19] used ligand fib in association with Ti(0-iPr)4 in the condensation of aromatic aldehydes with EtjAl in the biphasic hexane-perfluoro(methyldecalin) system at 53 °C [Eq. (2)]. Enantioselectivities in the range 76-88% ee and chemical yields of 77-82% were obtained during six consecutive runs when fresh titanium was added. When the reaction was extended to the electron-deficient 4-chlorobenzaldehyde, the yield was the same (59-88% for three runs) and the enantioselectivity a little lower (63-79% ee for three rrms) for the electron-rich 4-methoxybenzaldehyde, only 10% of product was obtained with an enantioselectivity of 38%. 

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Usually, iodides and bromides are used for the carbonylation, and chlorides are inert. I lowever, oxidative addition of aryl chlorides can be facilitated by use of bidcntatc phosphine, which forms a six-membered chelate structure and increa.scs (he electron density of Pd. For example, benzoate is prepared by the carbonylation of chlorobenzene using bis(diisopropylphosphino)propane (dippp) (456) as a ligand at 150 [308]. The use of tricyclohexylphosphine for the carbonylation of neat aryl chlorides in aqueous KOH under biphasic conditions is also recommended[309,310]. 

Singer and Scammells have investigated the y-Mn02 oxidation of codeine methyl ether (CME) to thebaine in the ionic liquid [BMIM][BF4] [63]. The ionic liquid was used in different ways and with mixed results (Scheme 5.1-35). For example, the oxidation of CME in the ionic liquid gave 38 % yield after 120 hours. A similar reaction under biphasic conditions (with diethyl ether) gave a 36 % yield of thebaine. This reaction gave a 25 % yield of thebaine when carried out in tetrahydrofuran... 

Table 7.2-4 Polymerization of isobutene to high molecular weight poly(isobutene)s in the ionic liquid [EMIM]CI/AICl3 under biphasic conditions [35].

A related study used the air- and moisture-stable ionic liquids [RMIM][PFg] (R = butyl-decyl) as solvents for the oligomerization of ethylene to higher a-olefins [49]. The reaction used the cationic nickel complex 2 (Figure 7.4-1) under biphasic conditions to give oligomers of up to nine repeat units, with better selectivity and reactivity than obtained in conventional solvents. Recycling of the catalyst/ionic liquid solution was possible with little change in selectivity, and only a small drop in activity was observed. 

Room temperature ionic liquids are air stable, non-flammable, nonexplosive, immiscible with many Diels-Alder components and adducts, do not evaporate easily and act as support for the catalyst. They are useful solvents, especially for moisture and oxygen-sensitive reactants and products. In addition they are easy to handle, can be used in a large thermal range (typically —40 °C to 200 °C) and can be recovered and reused. This last point is particularly important when ionic liquids are used for catalytic reactions. The reactions are carried out under biphasic conditions and the products can be isolated by decanting the organic layer. 

Table 1 Results of the alkene epoxidation reactions with fluorinated (salen)Mn complexes under biphasic conditions ...

Structurally, a carbene is the smallest member of the alkene family. As carbenes have no charge, they are expected to have a certain stability toward water. In fact, in some of the earliest work, carbenes were generated in aqueous medium under biphasic conditions via the reaction of chloroform with a strong base such as NaOH. 

Water-soluble dicationic palladium(II) complexes [(R.2P(CH2)3PR.2)Pd-(NCMe)2][BF4]2 proved to be highly active in the carbon monox-ide/ethene copolymerization under biphasic conditions (water-toluene). In the presence of an emulsifier and methanol as activator, the catalytic activity increased by a factor of about three. Also higher olefins could be successfully incorporated into the copolymerization with CO and the terpolymerization with ethene and CO.184... 

Ru3(CO)12(117)3] and [H4Ru4(CO)11(117)] as catalyst precursors in the hydrogenation of non-activated alkenes under biphasic conditions. Each cluster displays activity under moderate conditions, ca. 60 atm. H2 at 60 °C with catalytic turnovers up to ca. 500. The trinuclear clusters undergo transformations during reaction but can be used repeatedly without loss of activity.325... 

As part of a search for catalysts that can be used under biphasic conditions, zwitterionic Rh(sulphos)(cod) derivatives were studied. The isomerization of allyl alcohol proceeded within 1 h at 100 °C using only 1 mol% catalyst to give propanal in quantitative yield (Equation (12)).46 After separation of the product, the catalyst could be recycled three times with a slight deactivation after each run. 

Under biphasic conditions, the zwitterionic Rh1 complex Rh(cod)(sulphos) proved to be very efficient for the hydrogenation of quinoline to THQ (TOF = 20 at 160°C, 30 bar H2, water/n-heptane) [8c]. 

The in situ reduction of the precursor [lr(COD)Cl]2 dispersed in BMI-PF at 75 °C and under 4atm of H2 provided a suitable medium for the synthesis of lr(0) nanoparticles, and represents an ideal system for the biphasic hydrogenation reactions of several olefins (Table 15.3) [24]. Of note, the TOP observed for this system (6000 h at 1200 rpm and 75 °C) was considerably higher than those obtained under biphasic conditions by classical transition-metal catalyst precursors in ILs under similar reaction conditions [46-48]. 

Denmark and coworkers reported 4-oxopiperidinium salt 17 to be an effective catalyst under biphasic conditions (Fig. 6) [44, 45]. The choice of the alkyl groups on the nitrogen affects the lipophilicity of the ketone, thus influencing the partitioning... 

Scheme 2.14 Reductive amination of phenylpyruvic acid derivatives under biphasic conditions.

Using a similar approach, Chechik and Crooks (73), modified the PAMAM dendrimer-encapsulated palladium nanoparticles with perfluoropolyether tails utilizing non-covalent ion-pair interactions. The catalytic hydrogenation of six substrates under biphasic conditions (toluene/ perfluoro-2-butyltetrahydrofuran FC-75) was investigated. Allyl alcohol, methyl acrylate, vinyl isopropenyl ether, and... 

Related work was done with variously substituted acrylates in an ionic liquid 87). It was found that the solubility of both monomers and polymers depends on the chain length of the alkyl group linked to the ester. Methyl acrylate and its polymer are soluble in [BMIMJPF. However, butyl acrylate (BA) is only partially soluble, and the corresponding polymer is insoluble in the ionic liquid. The ATRP of BA in the ionic liquid proceeded under biphasic conditions with the catalyst, CuBr/pentamethyldiethylenetriamine, dissolved in the ionic liquid phase. Relatively low-molecular-weight polymer was formed. In this case, as the polymer was insoluble in the ionic liquid, it was spontaneously separated from the ionic liquid phase free of copper contamination. Furthermore, an undesirable side-reaction was significantly reduced in the ionic-liquid-phase ATRP 87). 

To circumvent the formation of ditelomers and to attempt recycling of the catalysts, the telomerization of polyols was studied in the presence of water using water soluble catalysts such as Pd/TPPTS (TPPTS = tris(m-sulfonato-phenyl) phosphine trisodium salt) [9, 12, 16, 17]. Behr et al. studied the telomerization of ethylene glycol under biphasic conditions. Under such reaction conditions, 80% of mono-telomer are formed and only traces of ditelomer and butadiene dimers are detected (Fig. 4). This is attributed to the solubility of the monomer in the catalyst phase. However, the catalyst is unstable and decomposes rapidly, leading to almost inactive catalyst after three runs. This is due to TPPTS oxidation during the work-up of the reaction and can be avoided by addition of 2.5 equiv. ligand in the solution prior to each run. 

In situ Pd(acac)2/IMes.HCl catalyst was evaluated under biphasic conditions. The activities of this catalyst are lower compared to those obtained under mono-phasic conditions (963 and 2,150/h respectively) because the catalytic system is... 

Fig. 4 Telomerization of butadiene with ethylene glycol under biphasic conditions reuse of the catalyst...

The establishment of the stereocenter in efavirenz provides a challenging goal for the synthetic chemist (Pierce et al., 1998 Thompson et al., 1995). The synthesis starts by treating 4-chloroaniline with pivaloyl chloride under biphasic conditions to provide the desired amide 10 (Scheme 6.2). Ortho metallation as directed by the amide is accomplished with two equivalents of n-butyllithium (or w-hexyllithium) in tetramethylethylene diamine (TMEDA) and MTBE. The resulting dianion is quenched with ethyl trifluoroacetate to provide pivaloylamide ketone 11 (Euhrer and Gschwend, 1979). The amide is hydrolyzed in situ to provide the trifluoroketone hydrate hydrochloride 12, which crystallizes from the reaction mixture (>98% pure). 

One of the early examples for organocatalysis is the asymmetric Weitz-Scheffer epoxidation of electron-deficient olefins, which can be effected either by organic chiral phase transfer catalysts (PTC) under biphasic conditions or by polyamino acids. This reaction has gained considerable attention and is of great synthetic use. 

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