Reaction auxiliaries

Functional group Extent of Reaction Auxiliary variables... 

In situ preparation of carbohydrazide and cyclization with isobutyronitrile in the presence of a suitable tin compound as reaction auxiliary [93]. 

J-INTERMOLECULAR HOMO-CYCLOADDITIONS (DIELS-ALDER REACTIONS) - AUXILIARY ON THE DIENOPHILE... 

V-EASI Monitoring an enzymatic reaction (auxiliary method) Hu et al. [136]... 

Asymmetric DieJs-Alder Reactions - Chiral Auxiliaries... 

The merits of (enantioselective) Lewis-acid catalysis of Diels-Alder reactions in aqueous solution have been highlighted in Chapters 2 and 3. Both chapters focused on the Diels-Alder reaction of substituted 3-phenyl-1-(2-pyr idyl)-2-prop ene-1-one dienophiles. In this chapter the scope of Lewis-acid catalysis of Diels-Alder reactions in water is investigated. Some literature claims in this area are critically examined and requirements for ejfective Lewis-acid catalysis are formulated. Finally an attempt is made to extend the scope of Lewis-acid catalysis in water by making use of a strongly coordinating auxiliary. 

Scheme 4.6. Schematic representation of the use of a coordinating auxiliary for Lewis-acid catalysis of a Diels-Alder reaction.

This goal might well be achieved by introducing an auxiliary that aids the coordination to the catalyst. After completion of the Diels-Alder reaction and removal of the auxiliary the desired adduct is obtained. This approach is summarised in Scheme 4.6. Some examples in which a temporary additional coordination site has been introduced to aid a catalytic reaction have been reported in the literature and are described in Section 4.2.1. Section 4.2.2 relates an attempt to use (2-pyridyl)hydrazone as coordinating auxiliary for the Lewis-acid catalysed Diels-Alder reaction. 

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

Clearly, the use of diamine 4.43 as a coordinating auxiliary is not successful. However, we anticipated that, if the basicity of the tertiary amine group of the diamine could be reduced, the elimination reaction will be less efficient. We envisaged that replacement of the tertiary amine group in 4.43 by a pyridine ring might well solve the problem. 

Finally, in the last step, the chelating auxiliary had to be removed Ideally, one would like to convert 4.54 into ketone 4.55 via a retro Mannich reaction. Unfortunately, repeated attempts to accomplish this failed. These attempts included refluxing in aqueous ethanol under acidic and basic conditions and refluxing in a 1 1 acetone - water mixture in the presence of excess paraformaldehyde under acidic conditions, in order to trap any liberated diamine. Tliese procedures were repeated under neutral conditions in the presence of copper(II)nitrate, but without success. 

In summary, we have demonstrated that it is possible to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, by employing a chelating auxiliary. We envisage that analogues of 4.39 capable of undergoing a Mamrich reaction with 4.50 can be treated with reactive dienes in the presence of a Lewis-acid catalyst in water. 

Chiral 2-oxazolidones are useful recyclable auxiliaries for carboxylic acids in highly enantioselective aldol type reactions via the boron enolates derived from N-propionyl-2-oxazolidones (D.A. Evans, 1981). Two reagents exhibiting opposite enantioselectivity ate prepared from (S)-valinol and from (lS,2R)-norephedrine by cyclization with COClj or diethyl carbonate and subsequent lithiation and acylation with propionyl chloride at — 78°C. En-olization with dibutylboryl triflate forms the (Z)-enolates (>99% Z) which react with aldehydes at low temperature. The pure (2S,3R) and (2R,3S) acids or methyl esters are isolated in a 70% yield after mild solvolysis. 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

Specifying operating conditions, control methods, and auxiliary equipment to meet the technological and economic needs of the reaction process... 

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