Microwave Assisted Asymmetric Catalytic Synthesis

Since the first application in mid 1980s of microwaves (MW) as alternative and efficient heating source, the technique has been firmly established as a powerful way to achieve reaction rate acceleration compared to the conventional heating with oil baths, isomantles or hot plates. The possibility to consistently reduce both times and energy [4] required for full conversions of substrates through MW irradiation has been advantageously exploited in organic and combinatorial synthesis with a great impact in drug discovery [5-8] and these aspects are also relevant in the field of ''green chemistry'' [9]. The ability of solvents or reactants to absorb MW energy at 2.45 GHz, the frequency assigned for heating applications, results in the direct heating of the chemical species through the walls of vessels that are at lower temperature than the reaction mixture, due to the transparency of common borosilicate glass to microwave radiation. Wall effects, that in the conductive heat transfer can be responsible for decomposition of reactants/ products over the time, are hence minimized under MW irradiation and usually high yields and cleaner reactions are observed. The efficiency with which MW radiation is converted into heat is expressed by the dissipation factor tand that is proportional to the polarizability and electric conductivity of the absorbing chemical species. Polar and ionically conducting solvents (tand >0.1) are well-suited for microwave-assisted synthesis but also solvents lacking permanent dipole moments, as dioxane, carbon tetrachloride or benzene, or solvents with tand < 0.1 can be used if substrates, reagents or catalysts are strongly polar and therefore MW absorbing. In domestic ovens, used in the pioneering experiments in microwave assisted organic synthesis (MAOS), the MW radiation is reflected by the walls within the oven cavity generating non-coherent multiple 3D wave patterns, called "modes", responsible of areas with different field strength referred as ''hot and cold spots''. In consequence of this and in conjunction with the low-quality of magnetrons, the resultant fields were quite inhomogeneous and the lack of reproducibility was a serious drawback in MAOS. Technological advances have today made available new instrumentation with ''single-mode'' cavity, also equipped with devices for the control of pressure and temperature inside the sample, able to provide uniform heating pattern and higher reproducibility of the results.

It has been often claimed that interactions between the MW field and the material could also generate ''not purely thermal'' effects [10, 11] as a contributing factor for reaction rate enhancement. Such effects should lead to decreased activation energy or increased Arrhenius pre-exponential factor in consequence of the induced rapid molecular mobility, but their experimental evidence as well as their rationalization and role in predictive models are still a controversial matter.

In the field of asymmetric synthesis reduction of reaction times by heating is usually detrimental, since enantioselectivity is directly determined by the energy difference between the diastereoisomeric transition states leading to opposite enantiomers and this value decreases with raising temperature according to the relation

However, highly selective reactions can be performed under MW irradiation and favourable reduction in catalyst loadings has been sometimes evidenced. Operationally, MW-assisted reactions have been performed following three protocols: (1) at constant MW power, that results in a rapid heating of the whole mixture at a temperature mainly dependent on the nature of solvent; (2) at constant temperature, so that the MW source is powered on-off during the reaction in order to maintain the fixed temperature and can act as a ''flash-heating'' source, really delivering low levels of MW power in the sample when solvents with high values of tand are employed; (3) at constant MW power or temperature with simultaneous external cooling, a technique that allows higher level of MW power administered to the reaction mixture but prevents overheating by continuously removing the heat [12].

(*) = conventional heating

[Pd(îi3-C3H5)- |iCl]2 (2%mol) (S)-1a or (S)- 1b (4% mol)

(*) = conventional heating


[Pd(îi3-C3H5)- |iCl]2 (2%mol) (S)-1a or (S)- 1b (4% mol)

MeO2C^CO2Me Ph^^Th




Scheme 4.1 Microwave-assisted reactions with transition-metal catalysis

An impressive example of rate acceleration was reported for Pd-promoted allylic alkylation of (±)-1,3-diphenylallyl-1-acetate with dimethyl malonate in the presence of phosphinooxazoline catalysts 1a or 1b, in which >99% substrate conversion was reached in only 30 s under 120 W MW irradiation. In comparison with the reference conditions (56% conversion after 6 h at 29 °C conventional heating) TOF substantially increased from 3 to 3,500 while the same excellent enantioselectivity (ee > 99%) was maintained [13] (Scheme 4.1a). MW-assisted addition of low reactive Me2Zn to aromatic aldehydes at 75 °C in the presence of catalyst 2 required only 1 h (vs several hours or days) to give high substrate conversion and the corresponding alcohols were obtained with slightly lower optical purities compared to standard conditions, but the same catalyst activity was also observed at reduced loading (5% mol) [14] (Scheme 4.1b). In the synthesis of diarylmethanols with aziridine catalyst 3, 300 W MW irradiation at 60 °C markedly accelerated both the formation of zinc reagents from boronic acids and the addition to aldehydes (10 min vs 12 h for each step) without loss of enanti-oselectivity [15] (Scheme 4.1c). The addition of dialkylzinc to phosphinoylimines in the presence of prolinol ligands [16] and the synthesis of chiral binapthalenes

R = H, OMe, i-Pr 15W, 46 °C, 2.5h 71-96%, 97-98% ee (21 °C, 21-26h)* 40-58%, 95-98% ee

O Ph



MW, -25 °C, 0.5h 91%, 98% ee, de 97% (-78 °C, 48h)* 49%, 98% ee, de 98%




(*) = conventional heating

Scheme 4.2 Examples of rate acceleration in organocatalysis under microwave irradiation

via Suzuki-Miyaura or Negishi cross-coupling reactions with a ferrocenyl-Pd catalyst have been also performed with MW heating and improved yields and satisfactory enantioselectivities were reported [17].

Proline-promoted Mannich reactions have sometimes displayed temperature tolerance but usually require long reaction times and high catalyst loading (>10% mol); however, when the reaction was performed in DMSO with constant 15 W MW power and simultaneous air-cooling excellent stereoselectivities and good product yields were achieved within few hours with even 0.5% mol of catalyst [18] (Scheme 4.2a). The same reaction was also carried out in water at 130 °C under MW heating for the stereoselective preparation of a serie of b-aminoketones from different combinations of substrates [19]. In a specific study Kappe and coworkers [20] emphasized that a careful monitoring of the internal reaction temperatures with a fiber-optic probe is essential for the correct comparison of catalytic performances under conventional and MW heating and in Mannich condensation of a-iminoethylglyoxylate and acetone at 60 °C the authors evidenced the same reaction outcome regardless of the heating methodology.

The aldol reaction originally developed by List (4-nitrobenzaldehyde and acetone in DMSO and 30% mol of proline) showed sensible rate enhancement (from 4 h to 15 min) and unchanged selectivity under 10 W MW irradiation with simultaneous air-cooling. Under the same MW heating protocol, Michel addition of various donors to b-nitrostyrene with bipyrrolidine catalyst 4 in CHCl3 gave slightly increased selectivity in remarkably shortened times and the occurrence of a non-thermal effect was suggested taking into account the transparency to MW of the used solvent [21] (Scheme 4.2b). In opposition to the above discussed examples, condensation of triethylpyruvate with ketones in the presence of proline required subzero temperatures in order to proceed with satisfactory selectivity and in a test reaction with cyclohexanone the adduct 5 was obtained with 98% ee and 49% yield after 48 h at -78 °C. Interestingly, by controlling the temperature with external cooling, the beneficial effects of MW irradiation were found operative also at -25 °C, so that 5 could be obtained in 91% yield and 98% ee after 30 min. Consistent results were also achieved with a variety of ketone substrates, but the origin of such MW activation was not further investigated [22] (Scheme 4.2c).

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