Hydrogen TEAF system

The catalysts are best prepared in situ by mixing a half-equivalent of the di-chloro-metal aromatic dimer with an equivalent of the ligand in a suitable solvent such as acetonitrile, dichloromethane or isopropanol. A base is used to remove the hydrochloric acid formed (Fig. 35.3). If 1 equiv. of base is used, the inactive pre-catalyst is prepared, and further addition of base activates the catalyst to the 16-electron species. In the IPA system the base is conveniently aqueous sodium hydroxide or sodium isopropoxide in isopropanol, whereas in the TEAF system, triethylamine activates the catalyst. In practice, since the amount of catalyst is tiny, any residual acid in the solvent can neutralize the added base, so a small excess is often used. To prevent the active 16-electron species sitting around, the catalyst is often activated in the presence of the hydrogen donor. The amount of catalyst required for a transformation depends on the desired reaction rate. Typically, it is desirable to achieve complete conversion of the substrate within several hours, and to this extent the catalyst is often used at 0.1 mol.% (with SCR 1000 1). Some substrate-catalyst combinations are less active, requiring more catalyst (e.g., up to 1 mol.% SCR 100 1), in other reactions catalyst TONs of 10000 (SCR 10000 1) have been realized. 

The TEAF system can be used to reduce ketones, certain alkenes and imines. With regard to the latter substrate, during our studies it was realized that 5 2 TEAF in some solvents was sufficiently acidic to protonate the imine (p K, ca. 6 in water). Iminium salts are much more reactive than imines due to inductive effects (cf. the Stacker reaction), and it was thus considered likely that an iminium salt was being reduced to an ammonium salt [54]. This explains why imines are not reduced in the IPA system which is neutral, and not acidic. When an iminium salt was pre-prepared by mixing equal amounts of an imine and acid, and used in the IPA system, the iminium was reduced, albeit with lower rate and moderate enantioselectivity. Quaternary iminium salts were also reduced to tertiary amines. Nevertheless, as other kinetic studies have indicated a pre-equilibrium with imine, it is possible that the proton formally sits on the catalyst and the iminium is formed during the catalytic cycle. It is, of course, possible that the mechanism of imine transfer hydrogenation is different to that of ketone reduction, and a metal-coordinated imine may be involved [55]. 

The transfer hydrogenation methods described above are sufficient to carry out laboratory-scale studies, but it is unlikely that a direct scale-up of these processes would result in identical yields and selectivities. This is because the reaction mixtures are biphasic liquid, gas. The gas which is distilled off is acetone from the IPA system, and carbon dioxide from the TEAF system. The rate of gas disengagement is related to the superficial surface area. As the process is scaled-up, or the height of the liquid increases, the ratio of surface area to volume decreases. In order to improve de-gassing, parameters such as stirring rates, reactor design and temperature are important, and these will be discussed along with other factors found important in process scale-up. 

Rather surprisingly alcohols are poor at reducing imines, yet TEAF works well. During our studies we rationalized that the TEAF system was sufficiently acidic (pH approximately 4) to protonate the imine (pK l approximately 6) and that it was an iminium that was reduced to an ammonium salt [14]. When an iminium was used in the I PA system, it was reduced albeit with a low rate and moderate enan-tioselectivity. Quaternary iminium salts were also reduced to tertiary amines. Hydrogen will not reduce ketones or imines using the CATHy catalysts, but hydrides such as sodium borohydride have been shown to work. 

Fig. 7 Asymmetric transfer hydrogenation of 4-fluoroacetophenone using the TEAF system. The effect of bubbling nitrogen through the reaction mass.

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