Mannich salts

The ring nitrogens react with electrophiles to afford either 1,3,4-thiadiazolium salts or l,3,4-thiadiazol-2(37/)-ones depending on the tautomerisability of the substituents at the C-2 or C-5 positions. While N-alkylation is the most common electrophilic reaction of 1,3,4-thiadiazoles, reactions with acyl and cyanogen halides as well as Mannich salts have also been reported. 

To get conjugate addition we might use a -ketoester 18 or an enamine for the enolate and we might carry out the reaction using the Mannich salt 19 so that the elimination will be caused by the same base that makes the enolate. Ester hydrolysis and decarboxylation of 20 would give 1. 

Notice that both substitutions 104 and 108 occurred next to nitrogen. Indoles on the other hand react very selectively at C-3 113 with electrophiles such as Vilsmeier and Mannich salts.15 This is probably because reaction at C-2 116 would disrupt the benzene ring as well as the pyrrole ring. As you have seen, substituents at C-2 are easy to put in during indole synthesis, so this is no great handicap. 

A more common method of ensuring that the conjugate addition step is free from side-reactions is to use the method Robinson himself invented—replace the enone by the Manmch base or Mannich salt as we have discussed already in this chapter. This ensures that the enone need have only a very short lifetime in the reaction mixture. 

In steps 5 and 6 of Scheme 6.1 the torand backbone is built up from two molecules of ketone 9 via Mannich salt 10. Together these reactions constitute the most efficient method known so far for the synthesis of fused pyridines from cyclic ketones. The key intermediates involved in the transformation of 9 to 11 are shown in Scheme 6.7. In Protocol 5, ketone 9 reacts with /V,/V-dimethyl(methylene)ammonium chloride in acetonitrile.21 The HC1 salt of the resulting Mannich compound 10 precipitates from this solvent and the relatively pure product is isolated from the reaction mixture by filtration. 

C—C—S—C, C—C—C—N torsional parameters for thianes, piperidines, and 1,4-thiazines Gallego 1993 Mannich salts... 

Amides or alkenes. Mannich salts undergo fragmentation on reaction with sodamide. The major products obtained from the salts derived from ketones are primary amides, but those derived from aldehydes are alkenes. 

There is nothing new in reactions occurring in many steps all in the same pot. The Robinson annelation is a classic where conjugate addition and intramolecular aldol reactions follow each other without as break. An extreme example would be the reaction of a Mannich salt 5 with the 1,3-diketone 6 to give the enone 7 on treatment with base... 

Related Mannich reactions have been reported by Holy and Wang. These chemists generated the silyl enol ethers under either thermodynamic or kinetic control, but cleaved the ether with methyllithium to the same lithium enolate and then added the Mannich salt. Product distributions demonstrated that the addition reaction is regiospecific. They also found that the reaction can be conducted by the trapping technique of conjugate addition of dimethylcopper-lithium to cyclohexenone followed by addition of the immonium salt (equation I.)... 

Poulter et al in the case of cyclohexanone generated the enolate with potassium hydride addition of the Mannich reagent gave an 88% yield of 2-dimethyl-aminomethylcyclohexanone. In the case of esters and lactones, they used LDA for generation of the enolate, to which the Mannich salt was then added. The yield of -methylene-y-butyrolactone by this procedure was about the same as that obtained with the silyl enol ether. 

MeSiCH cleaves the ether linkage of gem-aimno ethers to form dialkyl(methylene)ammonium chloride (Mannich-type salts) in excellent yields (eq 9). This procedure is much more convenient, efficient, economical, and less dangerous compared to earlier methods. The Mannich salts were also prepared in situ for electrophUic substitution of nucleophilic aromatic compounds (eq 10).2 - =... 

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