Mannich bases, alkylation

Thus many compounds arc obtained (250, Table 24), which may be considered to be derived from C-alkylation of the nucleophilic reagent by the Mannich base. Alkyl ketonic and phenolic bases arc mostly involved in this reaction, which exhibits many analogies with aminomethylation, particularly concerning chemo- and regioselectivity on aromatic and heteroaromatic derivatives. Ring activation by means of hydroxy and amino substituents in the alkylation of pyridine and pyrimidine derivatives is also required. 

Synthesis Though we could follow the stepwise pattern of the disconnections, it is easier to add an activating group to the acetone molecule so that our starting materials are two molecules of acetoaeetate and formaldehyde. It turns out that Hagemann s ester can be made in two steps without having to alkylate the Mannich base ... 

Under appropriate conditions 2-amino-4-alkylthiazoles are alkylated in the 5-position 2-acetylamino-4-methylthiazole reacts with dimethyl-amine and formaldehyde to afford the corresponding Mannich base (113) (372). 2-Amino-4-methyl-thiazole is alkylated in the 5-position by heat-... 

Although connection of polyalkylene or poly(alkylene oxide) groups to the polyamine is most commonly by the succinimide linkage, a different linking group is employed in another important class of ashless dispersants— the Mannich bases. They are prepared on a commercial scale by reaction of an alkylphenol with formaldehyde and a polyamine (173—177). The alkyl and polyamine moieties are similar to those used in the succinimide products. 

Furthermore, a substitution of the amino group is possible. An important application of Mannich bases 4 is their use as alkylating agents ... 

In this reaction, methyl groups are cleaved in preference to other saturated alkyl groups. A similar reaction takes place between a Mannich base (see 16-15) and a secondary amine, where the mechanism is elimination-addition (see p. 430). See also 19-5. 

Alkylation of acetylacetone chelates is generally unsuccessful, but carbon—methylene bonds can be formed by chloromethylation,279 reaction with ethyl diazoacetate,287 reaction with thioacetals288 (equations 64, 65 and 66) and by the Mannich reaction (Scheme 73).279 The Mannich base can be quatemized with methyl iodide and converted by cyanide ion into a cyanomethyl-substituted chelate. 

Cyclocondensation of aminoazoles and a,(3-unsaturated carbonyl compounds or Mannich bases is the most common method for the synthesis of dihydroa-zolopyrimidines [99, 155, 156, 157]. Various alkyl- and aryl-substituted dihy-dropyrimidines were prepared in this way. For example, cyclocondensation of 3-amino-1,2,4-triazole 147 with chalcones 148 leads to 5,7-diaryl-4,7-dihydro-l,2,4-triazolo[l,5-a]pyrimidines 149 [158], while reaction with hydrochlorides of Mannich bases 150 leads to heterocycles 151 (Scheme 3.46). 

We need a formaldehyde equivalent that is less electrophilic than formaldehyde itself and will therefore add only once to enol(ate)s. The solution is the Mannich reaction.7 Formaldehyde is combined with a secondary amine to give an iminium salt that adds 47 to the enol of the aldehyde or ketone in slightly acidic conditions to give the amino ketone (or Mannich base ) 48. If the product of the aldol reaction 50 is wanted, alkylation on nitrogen provides a good leaving group and ElcB elimination does the trick. 

Alkylation of the product (a Mannich Base A) gives a compound (B) which gives the required vinyl ketone on elimination in base. This last step is usually carried out in the basic medium of the Michael reaction itself so that the reactive vinyl ketone (TM122) need never be isolated. 

Under appropriate conditions activated thiazoles are alkylated at the 5-position 2-amino 4-methylthiazole is alkylated in the 5-position by heating with /-butyl alcohol in sulfuric acid (24). Under similar conditions 4-methyl-2-phenylthiazole is alkylated by cyclohexanol. 2-Acetylamino-4-methylthiazole reacts with dimethylamine and formaldehyde to afford the corresponding Mannich base (25). 2-Hydroxy-4-methyIthiazole fails to react when submitted to Friedel-Crafts benzoylation conditions whereas it reacts normally in Gatter-mann and in Reimer-Tiemann formylation reactions yielding the 5-formyl derivative (26). 2,4-Dimethylthiazole undergoes perfluoroalkylation when heated at 200 °C for 8 h in a sealed tube with perfluoropropyl iodide and sodium acetate (27). 

This nucleophilic reactivity of 2-aminothiazoles has been used to prepare biheterocyclic compounds. Thus 2-aminothiazole reacts with chlorovinyl methyl ketone yielding 5-methyl-thiazolo[3,2-a]pyrimidinium chloride (Scheme 109). In the presence of formaldehyde, aminothiazoles react with ends affording condensation products, through the intermediacy of Mannich bases (Scheme 110). In acidic medium and at higher temperatures, condensation of 4-aryl-2-aminothiazole with benzaldehyde takes place at the C-5 position (Scheme 111). The same orientation is observed when 2-amino-4-methylthiazole is alkylated by secondary or tertiary alcohols in 85% sulfuric acid (Scheme 112). 

The most reliable method for making the enone is to alkylate the Mannich base with Mel and then treat the ammonium salt with base. Enolate ion formation leads to an ElcB reaction rather like the dehydration of aldols, but with a better leaving group. 

Enones like this, with two hydrogen atoms at the end of the double bond, are called exo-methylene compounds they are very reactive, and cannot easily be made or stored. They certainly cannot be made by aldol reactions with formaldehyde alone as we have seen. The solution is to make the Mannich base, store that, and then to alkylate and eliminate only when the enone is needed. We shall see how useful this is in the Michael reaction in Chapter 29. 

The electron-dona ting power of thye indole and pyrrole nitrogens is never better demonstrated than in the use to which these Mannich bases (the products of the reaction) are put. You may remember that normal Mannich bases can be converted to other compounds by alkylation and substitution (see p. 758). No alkylation is needed here as the indole nitrogen can even expel the Me2N group when NaCN is around as a base and nucleophile. The reaction is slow and the yield not wonderful but it is amazing that it happens at all. The reaction is even easier with pyrrole derivatives. 

C-Alkylated Products by Amino Group Replacement of Mannich Bases... 

An anomalous behavior may be observed in 254 (Fig. 95), as the cleavage of the reagent molecule occurs in the course of the replacement reaction prtxiucing, simultaneously, C-alkylation of one fragment by the phenolic Mannich base and hydroxy group... 

When two molecules of a Mannich base react together with the formation of a methylenc-bis-derivative (255, Fig. 96), a particular type of C-alkylation lakes place, simultaneously involving deaminomethylation and amine replacement, which could be defined as a self-condensation of the Mannich base. 

The replacement reaetion by poly functional nitrogen-containing derivatives, in particular, makes it possible to introduce multiple RCH2 groups into the same molecule. Thus, the reaction of indole Mannich bases with ammonia y ields bis- and tris-(3-indolyl) amines. Likewise, primary amines, hydrazine, and hydroxylamine can be bis-alkylated by several Mannich bases. 

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