In the Mannich reaction

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. 

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael reactions, for example acetylenecarboxylic esters and acrylonitrile readily form the expected addition products. Styrene oxide gives rise, for example, to 1-styrylimidazoles (76JCS(P1)545). Benzimidazole reacts with formaldehyde and secondary amines in the Mannich reaction to give 1-aminomethyl products. 

The dialkylaminomethyl ketones formed in the Mannich reaction are useful synthetic intermediates.184 Thermal elimination of the amines or the derived quaternary salts provides a-methylene carbonyl compounds. 

Figure 4.23 Examples of active-hydrogen-containing compounds that can participate in the Mannich reaction. The points of reactivity are shown by the hydrogen atoms.

To increase the yield of conjugated hapten using this procedure, cBSA is used as the carrier protein in the method described below (see Section 2.1, this chapter for additional information on this carrier). The greater density of amine groups on cBSA available for participation in the Mannich reaction over that available on native proteins provides better results in coupling active-hydrogen-containing haptens. 

Silyl Nitronates in the Mannich Reaction The Mannich reaction with SENAs (Scheme 3.194) was also modified (459). This reaction in nonpolar solvents produced previously unavailable 3-nitroamines (331), which are unstable in water and other protic solvents. 

We have an aldehyde, an amine, and a ketone. As in part (b), the amine reacts first to give an imine, and this behaves as a carbonyl analogue, which in the Mannich reaction is then the electrophile for an enolate anion equivalent. How can we remember the sequence of events The most common mistake is to react the aldehyde and ketone via an aldol reaction, but this then leads to an alcohol and one is faced with a substitution reaction to incorporate the amine. It is the mild acidic conditions that help us to avoid wrong... 

Dicarbonyl donors bearing a thioester has been applied in the Mannich reaction to A -tosyl imines. Ricci presented an enantioselective decarboxylative addition of malonic half thioester 37 to imine 38. In the Mannich-type addition, catalyst 36 deprotonates the malonic acid thioester followed by decarboxylation to generate a stabilized thioacetate enolate. This stabilized anion reacts with facial selectivity to the imine due to steric-tuning from 36 [47] (Scheme 8). 

Systematic investigations of the catalyst structure-enantioselectivity profile in the Mannich reaction [72] led to significantly simplified thiourea catalyst 76 lacking both the Schiff base unit and the chiral diaminocyclohexane backbone (figure 6.14 Scheme 6.88). Yet, catalyst 76 displayed comparable catalytic activity (99% conv.) and enantioselectivity (94% ee) to the Schiff base catalyst 48 in the asymmetric Mannich reaction of N-Boc-protected aldimines (Schemes 6.49 and 6.88) [245]. This confirmed the enantioinductive function of the amino acid-thiourea side chain unit, which also appeared responsible for high enantioselectivities obtained with catalysts 72, 73, and 74, respectively, in the cyanosilylation of ketones (Schemes 6.84 and 6.85) [240, 242]. 

In contrast to the results obtained by Jacobsen et al. when utilizing Schiff base catalyst 42, the decrease of reaction temperature to -40 °C reduced the yield as well as enantioselectivity of the resulting Mannich adduct (Scheme 6.175) [201]. Catalyst 198 found to be less effective in the Mannich reaction in terms of yield and enantiomeric induction due to reduced basicity of the N-acylamine and weaker hydrogen-bonding interactions compared to the more basic Strecker substrates (Scheme 6.174). 

JCS1641). The ease of deprotonation is in the order 4>2>3, but, possibly for steric reasons, the 2-methyl substituent is found to be the more reactive, as condensation of 2,4-dimethylquinoline with 2,4-dinitrobenzaldehyde rapidly gives the 2-styryl derivative the 2,4-distyryl compound is formed only on prolonged reflux. Quinaldine will take part in the Mannich reaction to give /3-aminoethylquinoline derivatives. Examples of the above reactions are shown in Scheme 42. 

For earlier use of preformed iminium ions in the Mannich reaction, see Ahond Cav6 Kan-Fan Husson de Rostolan Potier J Am. Chem. Soc. 1968, 90, 5622 Ahond Cav6 Kan-Fan Potier Bull. Soc. Chim. Fr. 1970, 2707 Ref. 188. 

It combines with the electrophilic component (acetone in this case) to make it even more electrophilic. We met this previously in the Mannich reaction (frames 248-250). 

---