Mannich bases reverse

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

Mannich bases (see 16-15) and p-halo carbonyl compounds can also be used as substrates these are converted to the C=C—Z compounds in situ by the base (16-15, 17-12). Substrates of this kind are especially useful in cases where the C=C—Z compound is unstable. The reaction of C=C—Z compounds with enamines (12-18) can also be considered a Michael reaction. Michael reactions are reversible. 

Mannich bases derived from polynitroalkanes are usually unstable because of the facile reverse reaction leading to stabilized nitronate anions. The nitration of Mannich bases to nitramines enhances their stability by reducing the electron density on the amine nitrogen through delocalization with the nitro group. The nitration of Mannich bases has been exploited for the synthesis of numerous explosives, some containing both C-NO2 and N-NO2 functionality. Three such compounds, (163), (164) and (165), are illustrated below and others are discussed in Section 6.10. 

Examples of such surfactants are detergents which include calcium and magnesium sulfonates (RSOO)2M2+, phenates (RC6H40)2M2+, carboxylates (RCOO )2M2+, phosphonates RPO/M2 and carbonate-sulfonate hard-core reverse micelles (RMs). Ashless dispersants are the most widely used types, such as the substituted polyisobutylene amine succinimides (mono-substituted, m-PIBS and bis-substituted, b-PIBS), succinate esters, Mannich bases, and phosphorus types, see Chapter 2.2 for formulas (Inoue and Watanabe, 1983 Papke and Rubin, 1992 Vipper and Watanabe, 1981). 

The poor conversion may be accounted for, at least in part, by the apparent reversibility of this reaction. This was demonstrated by heating 2-hydroxy-3-tert-butyl-5-methylbenzyl-N,j V-dimethyl dithiocarbamate in diethylene glycol dimethyl ether whereupon the Mannich base XVIII was formed. 

Fig. 81) may occur on either the substrate (a) or the amine (b) side, thus affording deaminomethylation or deamination, respectively. Although the possibility of simultaneous reaction exists, one process usually prevails over the other, - depending on the chemical nature of the base. In general, C-Mannich bases, particularly the kctonic ones, arc more stable toward deaminomethylation, the reverse occurring with X-Mannich bases. There are, however, important exceptions to this behavior. 

Besides highlighting the reversible nature of the Mannich reaction, dcaminomethy-lation implies as a consequence the reduced possibility of storing some types of Mannich bases, particularly when they are in the free base form, both neat and in solution. The acid salt derivatives are u,sually more stable, although hygroscopic to a greater or lesser extent the hydrochlorides, however, arc preferable to the carboxyacid salts, which appear in some cases to favor the decomposition of the Mannich base. 

Hence, depending on the conditions, elimination reactions of Mannich bases follow irreversible or reversible kinetics. When the leaving amine is practically completely protonated as soon as it is formed, it cannot add to the double bond and the reaction becomes irreversible. Only when the pH-value is sufficiently high, so that the amines are present predominantly in the free base form, is the rate of addition comparable to that of elimination, and reversible kinetics are observed. 

Ketonic and phenolic Mannich bases react with sec. amines by amine exchange. The process is reversible and occurs without appreciable side reactions.— E a-Dimethylaminomethyl- -naphthol refluxed ca. 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

Actually, the reactions of AN with bases produce reversibly carbanions A, which are the major intermediates in the classical reactions of AN (Henry, Michael, and Mannich reactions). The reactions of AN with acids afford iminium cations B (also reversibly), which are the key intermediates in the Nef reaction... 

The related Mannich reaction is not common. Under the usual acidic reaction conditions TV-substitution occurs, but this is a reversible reaction in the presence of base. Therefore, in basic medium, C- substituted products accumulate, and all positions can be substituted. 2-Methylimidazole gives 1,4,5-tri, 4,5-di- and 4-mono-substituted products. The observation that with formaldehyde and hydrochloric acid histamine gave (98) is at variance with the apparent requirement for basic medium. Since 1-substituted imidazoles do not react it is likely that the imidazole conjugate base is the reactive species. Unless imidazoles contain activating substituents they are not very susceptible to reaction with aldehydes (except HCHO) and ketones. An exception appears to be the product (99) of interaction between imidazole and hexane-2,4-dione. An activated compound such as 4-methylimidazoline-2-thione gives the 5-dimethylamino compound (100) imidazoline-2-thione gave only the (V-hydroxymethyl product under the same reaction conditions. Imidazolin-4-ones with a free 5-position readily form benzylidene derivatives (B-76MI40701). 

Ishihara developed a highly diastereo- and enantioselective direct Man-nich-type reaction of aldimines with 1,3-dicarbonyl compounds using chiral lithium binaphtholate salts as effective Lewis-acid-Bronsted-base catalysts (Scheme 2.5). ° The stereoselectivity of the Mannich products anti-S and syn-7 ) was reversed when the nucleophile was changed from acyclic 1,3-dicarbonyl compound 4 to cyclic compound 6. The molecular flexibility and acidity of the nucleophiles 4 and 6 would be the major factor in differentiating the two reaction pathways. 

The reversibility problem in 1,2-additions is alleviated when imines bearing an electron-poor protecting group at nitrogen (sulfonyl, aeyl, ear-bamoyl) are employed as aeceptor partners, rendering possible even the use of 1,3-dicarbonyl compounds as donors. For example, Sehaus and eoworkers reported the highly enantioselective Mannich reaction of acetoacetates and cyclic 1,3-dicarbonyl compounds with N-carbamoyl imines derived from benzaldehydes and cinnamaldehydes catalysed by the natural Cinchona alkaloid cinchonine (CN) (Scheme 14.15). On the basis of the obtained results they developed a model that accounts for the observed diastereo- and enantioselectivity based on the bifunctional nature of the catalyst, which acts simultaneously as a hydrogen-bond donor and acceptor. 

Cationic Carbamoyi Poiymors. Poly(acrylamide) reacts with formaldehyde [50-00-0], CH2O, and dimethylamine [124-40-3], C2H7N, to produce aminomethylated polyacrylamide (a Mannich reaction). This reaction has been studied extensively (110-114). A wide range of substitution can be produced in solution or in water-in-oil emulsion. nmr studies (114) have verified that the Mannich substitution reaction follows second-order kinetics. The formation of the formaldehyde-dimethylamine adduct is very rapid. The high rate of Mannich substitution at high pH indicates a fast base-catalyzed condensation mechanism. The Mannich reaction is reversible and pH dependent. At low pH, the rate of substitution is very slow. 

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