A Sequential Approach is Possible

When a new reaction is explored, it is known beforehand whether it will be necessary to precisely locate the optimum conditions. If sometimes happens that the initial experiments reveal that the reaction does not afford the desired result. In such cases, the most probable decision is to turn to more promising projects. If, on the other hand, the screening experiments indicate the the reaction merits further studies, the next step would be to more precisely locate the optimum conditions. 

A standard method for enamine synthesis from aldehydes or ketones is to heat the carbonyl compound and the secondary amine in benzene or toluene and remove the water formed by azeotropic distillation. This method cannot, however, be used the preparation of enamines from methyl ketones which undergo self-condensation under these conditions. A procedure which overcomes these difficulties has been given by White and Weingarten [31]. The method employs anhydrous titanium tetrachloride as water scavenger. In the original procedure by White and Weingarten, titanium tetrachloride is added dropwise to a cooled 

The experimental design and the yields obtained after 15 min are shown in Table 7. The quadratic response surface model fitted to the experiments in Table 7 was  

From the three-dimensional projection of the response surface in Fig. 7 it is seen that there is a maximum point on the surface within the explored domain. At this maximum point, the tangential plane to the surface has a zero slope in all 

The maximum point corresponds to the following molar ratios of the reagents TiCl4/ketone = 0.83 and morpholine/ketone = 6.5. Experiments carried out under these conditions afforded quantitative yields (98 2%) within 15 min and this confirmed the optimum conditions. 

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