Willgerodt-Kindler reaction, possible

Complete multi-level factorial designs would usually yield too large a number of test systems for a first approach to new reaction systems. It is possible to reduce the number of test systems and yet achieve a selection which covers a large part of the entire reaction space. This can be achieved by a selection made from a two-level fractional factorial design. The principles are illustrated by an example provided by the Willgerodt-Kindler reaction. 

It is impossible to evaluate all possible combinations of substrates, reagents, and solvents by experiments. It is quite cumbersome, even to run a complete factorial design with selected substrates, reagents and solvents, as was described in the examples above. To achieve a more manageable number of test systems, it is possible to use the principles of fractional factorial designs to select test systems by their principal properties To illustrate this, we shall once more make use of the Willgerodt-Kindler reaction. 

Yet another example on the Willgerodt-Kindler reaction is shown.[9] It also illustrates that a stepwise approach to the study of discrete variations is possible by PLS. 

Reichardt (2003, p. 504) presents a table of solvents recommended as replacements for more hazardous ones. Total avoidance of solvent is sometimes a possibility. An example was mentioned in Chapter 1. Scott (2003) discusses the scope of solvent-free methods and considerations of mutual solubility of reactants and of control, including exothermic reactions. A recent application is the solvent-free synthesis by Valdez-Rojas et al. (2012) of thioamides and alpha-ketothioamides through the Willgerodt-Kindler reaction. Scheme B. 

Morpholine is well suited to the Kindler version of the Willgerodt reaction it is cheap, and its boiling point (128°) makes possible the use of open apparatus in place of an autoclave or bomb tube. 

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