Titanium tetrachloride enamine synthesis

In 1967, White and Weingarten64 presented a new enamine synthesis. In their method, titanium tetrachloride was used as a catalyst and also as a water scavenger. This made it possible to synthetize enamines from acyclic ketones, such as methyl ketones65-73, which had previously been difficult to make by conventional methods. This method fails in the case of several branched acyclic ketones. An optimization of this procedure has been reported74. In this modified procedure the ketone is added to a preformed complex between the amine and titanium tetrachloride. The method permits the synthesis of enamines from sterically congested ketones, for which the original procedure has failed. 

The conditions for optimal synthesis of morpholine enamines from alkyl methyl ketones (alkyl = isopropyl, isobutyl, t-butyl) were studied by using molecular sieves or titanium tetrachloride as the water scavengers56. 

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... 

A standard method for enamines synthesis from carbonyl compounds is to heat the parent aldehyde or ketone and a secondary amine in benzene or toluene and to remove the eliminated water by azeotropic distillation. However, this method fails with methyl ketone substrates which are prone to self-condensation imder these conditions. These difficulties could be overcome by a procedure using anhydrous titanium tetrachloride as water scavenger.[6] In the original procedure, titanium tetrachloride was added dropwise to a cold solution of the ketone and the amine, followed by prolonged stirring at room temperature. It was later found that the reaction time could be considerably shortened by a modified procedure, in which the... 

The synthesis of enamines by the modified titanium tetrachloride method was discussed in Chapter 12. The final yield and the rate of enamine formation depend on the molar ratios of TiCl4/substrate and amine/substrate. The optimum conditions with regard to these variables were determined by response surface technique and/or simplex technique for a series of carbonyl compounds. The results obtained for the morpholine enamines are summarized in Fig. 14.2. It is seen that the more crowded substrates require an excess of the reagents. The use of standardized conditions would have led to the wrong conclusions as to the utility of the method. For instance, when the optimum conditions for synthesis of the morpholine enamine from methyl isobutyl ketone were applied to diisopropyl ketone a yield of 12 % was obtained after 4 h. Under optimized conditions yields > 70 % could be obtained. 

Nelson disclosed a powerful three-component Diels-Alder/alkylation reaction sequence for the synthesis of several nitrogen-containing heterocycles. For example, treatment of enamine 29 with titanium tetrachloride yields electron poor imminium ion diene 30 that reacts with unactivated cyclohexene to furnish imminium ion cycloadduct 31. Introduction of allyltrimethylsilane into the reaction mixture leads to alkylation of the reactive imminium ion and production of... 

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