Solvent Free Reactions

The most obvious way to minimize the solvent waste is to not use solvent at all or to perform highly concentrated reactions and additional cost-saving benefits can derive from reduced reaction time, energy consumption and reactor size. Although this approach has been applied to different polymerization, radical, ionic and photochemical reactions and in less extent to asymmetric catalysis, thermal safety considerations can not be neglected due to the possible occurrence of a rapid overheating in absence of solvent. In asymmetric catalysis under solvent-free conditions the important parameters of catalyst concentration and nature of the solvent are not operative and the composition of reaction medium changes as reactants are converted into products with unpredictable influence on the

Ar^H

TMSO^

2) CF3COOH

(R)-3a/Ti/(R)-3a or (R)-3a/Ti/(R)-3b (0.01-0.1% mol) Ar

(CH2)4OTBS,

(CH2)3CHMe2

Ar Me

Scheme 3.1 Examples of asymmetric reactions performed in solvent-free conditions

enantioselectivity so that is not unusual that lower performances are observed in comparison with the standard conditions with solvents.

However, some transition-metal and organocatalyst promoted reactions work well in solvent-free conditions [4] and excellent examples were found in hetero-Diels-Alder [5] and carbonyl-ene reactions [6] catalyzed by Ti-complexes of homo- or hetero-combinations of BINOL-type ligands in extremely low concentration (Scheme 3.1a, b). Bis-sulfonamide 4-Ti complex was a very active catalyst for the addition of alkyl- and functionalized organozinc reagents to a range of aromatic and cycloalkylketones giving similar or better enantioselec-tivities compared to the reactions in solution with up to 40-fold decreased catalyst loading. The reaction afforded chiral tertiary alcohols with 80-99% ee and its combination with diastereoselective epoxidation in a one-pot procedure allowed to prepare syn-epoxyalcohols with three contiguous stereocentres in high yield also on a 5 g scale-up [7] (Scheme 3.1c, d).

A solvent-free aldol reaction with 10% mol of proline gave the anti-aldol adducts in high optical purities and moderate to good diastereoselectivity and sensible decrease in the reaction time was achieved mixing the reactants with ball milling technology using 5-mm diameter balls of chemically inert and non abrasive zirconium oxide [8]. Under the same experimental conditions better reaction rate and selectivity were obtained with (S)-proline-(S)-phenylalanine methylester as organocatalyst [9].

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