Synthesis of enamines

Synthesis of Enamines Utilizing Various Compounds of Phosphorus Titanium, Boron, Arsenic, and Mercury. ... 

The oxidation of amines by mercuric acetate is an old reaction (54) which up until recent years was employed primarily to modify alkaloid structures (55). A systemic study of the oxidizing action of mercuric acetate by Leonard and co-workers led to the development of a general method for the synthesis of enamines from cyclic tertiary amines. An observation made after a large number of compounds were oxidized, but which is worth noting at the onset, is that a tertiary hydrogen alpha to the nitrogen atom is removed preferentially to a secondary a-hydrogen. 

Most of the work on the C-N bond-forming crosscoupling reactions has concentrated on the formation of aromatic C-N bonds. Recent studies show that the application of cross-coupling reactions to alkenyl halides or triflates furnished enamines (Scheme 19) (for palladium-catalyzed reaction, see 28,28a-28d, and for copper-catalyzed reaction, see 28e-28g). Brookhart et al. studied the palladium-catalyzed amination of 2-triflatotropone 109 for the synthesis of 2-anilinotropone 110.28 It was found that the reaction of 109 proceeded effectively in the presence of racemic BINAP and a base. As a simple method for the synthesis of enamines, the palladium-catalyzed reactions of alkenyl bromide 111 with secondary amine were achieved under similar conditions.2841 The water-sensitive enamine 112 was isolated as pure compound after dilution with hexane and filtration through Celite. The intramolecular cyclization of /3-lactam 113, having a vinyl bromide moiety, was investigated by Mori s... 

The synthesis of enamines by the reaction of some ketones or aldehydes with a secondary amine can lead to saturated by-products when the enamine is heated in a nitrogen atmosphere with a catalytic amount of p-toluenesulfonic acid [48-50] (Eq. 10). 

The recorded reports of the synthesis of enamines which can exist as geometric isomers are generally characterized by the absence of discussion of the stereochemical constitution of the products. It is likely that, where possible, mixtures of stereoisomers are obtained when employing the general procedures, whose composition is the result of thermodynamic control. 

A consideration of the design of a stereospecific synthesis of enamines suggested that at least two requirements must be met. First, if the introduction of the double bond was to be the final step, it must be stereospecific in character and, second, the enamine, once formed, must retain its stereochemical integrity under the conditions employed in the double-bond-forming step. 

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. 

Mixtures of Z and E stereoisomers have been obtained in most syntheses. This undoubtedly holds in the presence of an acid catalyst. The tendency of the E-enamine to isomerize to the Z-enamine was readily observed on numerous occasions under unexpectedly mild conditions. Munk and Kim357 summarized the requirements for the stereospecific synthesis of enamines. First, if the introduction of the double bond is to be the final step of the synthesis, it must be stereospecific in character. Second, once the enamine is formed it must retain its stereochemical integrity under the conditions employed in the double-bond-forming step. The base-induced bimolecular -elimination reaction fulfills both these requirements. Indeed, treatment of the mesitoate esters of ( )-threo- (99) and ( )-erythro- (100) l-(4-morpholino)-l,2-diphenylethanol with... 

K. The Role of Phosphorus, Arsenic, Tin and Boron in the Synthesis of Enamines... 

The use of a nitrimino group instead of a carbonyl group in the synthesis of enamines has been reported515 (equation 33). 

Synthesis of enamines from amino acids has been described518. Van Tamelen and coworkers519 have described a useful method for the preparation of enamines by the oxidative decarboxylation of N,N-dialkyl-a-amino acids with sodium hypochlorite. Synthesis of enamines by the Babyan rearrangement-cleavage reaction has been described520. 

An unexpected synthesis of enamines has been observed. Treatment of hexahydro-benzazocinium halides 120 (R = H, Me R = Alkyl, R1 = Me, Et) with sodium in liquid ammonia gave 70-86% of E-4-aryl-l-(dialkylamino)-l-butenes (121)527. 

Enamines. A few years ago White and Weingarten- reported that TiCf can serve as the catalyst and water scavenger in the synthesis of enamines. The method is particularly useful in the case of enamines of acyclic ketones. Yields can be improved by addition of the ketone to a preformed complex between ihc amine and TiCf the ratio of amine to TiC should be at least 5 1. 

Prior to the discoveries that lithium and other less electropositive metal cations were valuable counterions for enolate alkylations, the Stork enamine reaction was introduced to overcome problems such as loss of regioselectivity and polyalkylation that plagued attempts to alkylate sodium or potassium enolates of ketones or aldehydes.Methods of synthesis of enamines by reactions of ketones and aldehydes with secondary amines have been thoroughly reviewed.Enamine alkylations are usually conducted in methanol, dioxane or acetonitrile. Enamines are ambident nucleophiles and C- and V-alkylations are usually competitive. Subsequent hydrolysis of the C-alkylated product (an iminium salt) yields an... 

Fig. 12B.1 Lambda plot in the Box-Cox transformation of the responses in tbe synthesis of enamine.

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. 

A versatile synthesis of enamines and dienamines has been developed from aldehydes via a-aminonitriles (equation 23). 

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