Reactions Mannich

The Mannich reaction is an excellent method for the synthesis of P-amino carbonyl compounds and their derivatives, and unmodified primary amino acids were found to be enormously useful for this important reaction. Cdrdova et al. [42] reported the first primary amino acid-promoted three-component Mannich reaction of ketone, p-anisidine, and aldehydes primary amino acids, such as L-alanine and L-vahne, were excellent catalysts and led to the formation of Mannich products with up to 99% ee. Barbas and coworkers [31] also showed L-tryptophan catalyzed the direct three omponent Mannich reaction of hydroxyacetone, p-anisidine, and aromatic aldehydes good yields, high diastereoselectivity, and excellent ee were attainable. 

L-Threonine-derived catalysts were also found to be useful in direct asymmetric Mannich reactions. Lu and coworkers [43] demonstrated that O-silylated threonine 

The Mannich reaction is an excellent route to polynitroaliphatic amines and their derivatives. /3-Nitroalkylamines are formed from the reaction of an amine and aldehyde in the presence of a nitroalkane (Equations 1.4 and A large number of these reactions 

Primary and secondary nitroalkanes, dinitromethane, and terminal em-dinitroaliphatic compounds like 1,1-dinitroethane, all contain acidic protons and have been used to generate Mannich products. Formaldehyde is commonly used in these reactions although the use of other aliphatic aldehydes has been reported. The nitroalkane component is frequently generated in situ from its methylol derivative, a reaction which also generates formaldehyde. Ammonia, aliphatic amines, hydrazine, and even urea have been used as the amine component of Mannich reactions. 

The powerful explosive, bis(2,2,2-trinitroethyl)urea (160) (DiTeU), is synthesized from the reaction of 2,2,2-trinitroethanol (159) with urea, or from the direct reaction of nitroform with formaldehyde and urea. Bis(2,2,2-trinitroethyl)amine (161) has been synthesized from the reaction of 2,2,2-trinitroethanol with ammonia and also from the reaction of nitroform (112) with formaldehyde and ammonia, or hexamine.  

Frankel and Klager have reported using the Mannich reaction for the condensation of 2,2-dinitroalkanols with ammonia and hydrazine. This method was used to synthesize 2,2,6,6-tetranitro-4-azaheptane (100%) and bis(2,2-dinitropropyl)hydrazine (162) (73%) from the reaction of 2,2-dinitropropanol (25) with ammonia and hydrazine hydrate respectively. This work was later extended to using polynitroaliphatic amines and diamines.  

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. 

The Mannich reaction is a useful reaction for the synthesis of [3-aminocarbonyl compounds including (3-amino acids, [3-lactams, and related compounds.24 Because the synthesis of chiral compounds is required for biological study, asymmetric versions of this reaction are in high demand. Several approaches to achieve asymmetric Mannich reactions have been reported. 

The Mannich reaction, historically, has involved the condensation of formaldehyde, a primary or secondary amine, and an enolizable carbonyl compound. The resultant P-amino-carbonyl compound, or Mannich base, requires protic solvents and high reaction temperatures for its formation. 

Over the years with the advent of milder and more controlled reaction conditions, the aldehyde component has increased in its diversity with a concomitant increase in functional group inter-compatibility. These changes also have enabled the extension of the nature of the active hydrogen (nucleophilic) species beyond enols. More recently, the utility of the Mannich reaction has been enhanced with enantioselective and catalytic variations. 

The mechanistic details of the Mannich reaction have been the focus of considerable attention. In principle, one could conceive of two possible 

Experimental evidence has lead to the conclusion that option a does not occur. Kinetic effects, pH dependencies, stoichiometry, and solvent polarity all led to the second option, b, as being the actual mechanistic pathway. Under basic conditions, the key reactive intermediate is the hydroxymethyl amine species 6. The Mannich base 5 is produced through a nucleophilic displacement by the corresponding anion (enolate) of the active hydrogen species 1. As the pH shifts to more acidic conditions, the relative proportions of the reactive intermediates also shift. The hydroxymethyl amine 6 becomes protonated and, with loss of an equivalent of water, generates iminium ion 7. Subsequently, this species can react directly with the active hydrogen species 1 or via the methylene bis-amine 8, formed by the addition of a second equivalent of amine 3 to iminium ion 7 (under conditions of excess amine). 

The shortcomings of the classical version of the Mannich reaction stems from the high reaction temperatures and extended reaction times which leads to side reactions and diminished yields. However, there are examples of 

Phase-transfer-catalyzed direct Mannich reaction of glycine Schiff base 2 with a-imino ester 79 was achieved with high enantioselectivity by the utilization of N-spiro chiral quaternary ammonium bromide le as catalyst (Table 5.14) [42], 

In 2009, the chiral phosphoric acid 6b-catalyzed multicomponent Mannich reaction involving enecarbamates 8 as nucleophiles was described by Dagousset et al. 

Phosphoric acid can catalyze electron-demanding aza-Diels-Alder reaction smoothly between hydroxyaniline-derived imine 10 and 2,3-dihydro-2//-furan 11 to afford enantioenriched 8-hydroxytetrahydroquinolines as reported by Akiyama et al. [6]. Interestingly, Rueping and Lin disclosed that in the presence of A-triflylphosphoramide 

SCHEME 2.3 Phosphoric acid-catalyzed three-component Mannich reactions. 

SCHEME 2.4 Enecarbamate-involved asymmetric multicomponent Mannich reactions. 

SCHEME 2.5 Phosphoric acid-catalyzed Mannich-ketalization reaction. 

Primary amines were readily obtained in 60-83% yield after 15 min of microwave irradiation under solvent-free conditions, when using ammonium chloride as the amine source (R=H). When substituted amine hydrochlorides were used, the reaction failed under solvent-free conditions however, when performed in ethanol once more high yields were obtained (80-83%). In both cases, no traces of side-product formation were found. 

Direct three-component Mannich reaction OCH3 

Entry Product Ri R Time (s) Eq. iminium salt Yield (%) 

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Colourless solid m.p. 132-134 C. An important intermediate for preparing indole derivatives, produced by treating indole under Mannich reaction conditions with methanal and dimethylamine. 

The Mannich Reaction involves the condensation of formaldehyde with ammonia or a primary or secondary amine and with a third compound containing a reactive methylene group these compounds are most frequently those in which the methylene group is activated by a neighbouring keto group. Thus when acetophenone is boiled in ethanolic solution with paraformaldehyde and dimethylamine hydrochloride, condensation occurs readily with the formation of... 

Indole (I) condenses with formaldehyde and dimethylamine in the presence of acetie acid (Mannich reaction see Section VI,20) largely in the 3-position to give 3 dimethylaminomethylindole or gramine (II). The latter reaets in hot aqueous ethanol with sodium cyanide to give the nitrile (III) upon boiling the reaction mixture, the nitrile undergoes hydrolysis to yield 3-indoleaeet-amide (IV), part of which is further hydrolysed to 3-indoleacetic acid (V, as sodium salt). The product is a readily separable mixture of 20 per cent, of (IV) and 80 per cent, of (V). 

Knoevenagel reaction Knorr pyrrole synthesis. Kolbe>Schmitt reaction Leuckart reaction Mannich reaction... 

Mannich Reaction - a,p-unsaturated carbonyls (a-methylene carbonyls)... 

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

In another attempt to achieve efficient coordination, we have used a strongly chelating diamine (4.43) in the Mannich reaction with 4.39 (Scheme 4.12). The reaction was performed in aqueous ethanol, producing 4.44-2HC1 in 64% yield. 

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

Finally, in the last step, the chelating auxiliary had to be removed Ideally, one would like to convert 4.54 into ketone 4.55 via a retro Mannich reaction. Unfortunately, repeated attempts to accomplish this failed. These attempts included refluxing in aqueous ethanol under acidic and basic conditions and refluxing in a 1 1 acetone - water mixture in the presence of excess paraformaldehyde under acidic conditions, in order to trap any liberated diamine. Tliese procedures were repeated under neutral conditions in the presence of copper(II)nitrate, but without success. 

Apparently, 4.54 is extremely reluctant to undergo a retro Mannicli reaction. Riviere demonstrated that this behaviour is not unusual for (3-amino ketones. From the study of a large number of Mannich adducts. Riviere concludes that the retro Mannich reaction requires an aromatic group next to the carbonyl functionality. Qearly, 4.54 lacks this arrangement. 

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). 

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Reaction takes place on nitrogen when the electrophilic center is an sp carbon, particularly if it is charged. Thus Mannich reaction yields the N-substituted compound (71 and 72) (Scheme 34) (54. 157-159). The same reaction is reported with piperidine, o-toluidine. and methylaniline (158). 

The Mannich reaction can be realized with formaldehyde and secondary amines. 

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