Active hydrogen Mannich reaction

Mannich reaction is the condensation between formaldehyde, ammonia, or a primary or secondary amine (preferably as the hydrochloride), and a compound containing at least one active hydrogen atom... 

The Mannich reaction consists in the condensation of formaldehyde with ammonia or a primary or a secondary amine and a compound containing at least one hydrogen atom of pronounced reactivity the active hydrogen atom may be derived from a methylene group activated by a neighbouring keto group, or from a nitroparaffin, or it may be the o- or p-hydrogen atoms in phenols. Thus when acetophenone is boiled in alcoholic solution with formaldehyde and dimethylamine hydrochloride, the Mannich base P-dimethylamino-propiopbenone hydrochloride (I) is readily formed ... 

The Mannich reaction consists of the condensation of an active hydrogen-containing compound with an amine-containing compound in the presence of formaldehyde. See Section 5.4 (this chapter) for addition details. 

Figure 4.22 The Mannich reaction occurs between an active-hydrogen-containing compound (phenol) and an amine-containing molecule in the presence of an aldehyde (formaldehyde). The condensation reaction forms stable crosslinks.

The Mannich reaction can be used for the immobilization of certain drugs, steroidal compounds, dyes, or other organic molecules that do not possess the typical nucleophilic groups able to participate in traditional coupling reactions (Hermanson et al., 1992). It also can be used to conjugate hapten molecules to carrier proteins when the hapten contains no convenient nucleophile for conjugation (Chapter 19, Section 6.2). In this case, the carrier protein contains the primary amines and the hapten contains at least one sufficiently active hydrogen to participate in the condensation reaction. 

To obtain acceptable yields, the Mannich reaction must be done at elevated temperatures. Incubation at 37-57°C for at least 2-24 hours usually is required to complete the reaction. Addition of formaldehyde is done by adding an aliquot of a 37 percent solution to the reaction to obtain about a 10- to 100-fold molar excess over t he amount of active-hydrogen-containing... 

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.

It is obvious that the Mannich reaction pathway and the immonium ion mechanism may occur simultaneously, especially at conditions of room temperature or greater. Formaldehyde-facilitated crosslinking reactions between molecules that both contain nucleophiles probably occur primarily by the immonium ion pathway, since the Mannich reaction proceeds at a slower rate. In addition, the Mannich reaction will cause nondescript polymerization between molecules that possess both active hydrogens and amine groups. It is best to utilize the Mannich reaction only when one of the molecules contains no nucleophilic groups but at least one active hydrogen, and the other molecule contains a primary or secondary amine. 

In its simplest form, the Mannich reaction consists of the condensation of formaldehyde (or sometimes another aldehyde) with ammonia, in the form of its salt, and another compound containing an active hydrogen. Instead of using ammonia, however, this reaction can be done with primary or secondary amines, or even with amides. An example is illustrated in the condensation of acetophenone, formaldehyde, and a secondary amine salt (the active hydrogens are shown underlined) ... 

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. 

The yield of conjugation using the Mannich reaction is dependent on the reactivity of active hydrogens within the hapten molecule. It is often difficult to predict the relative reactivity of any given compound in this reaction. Thus, trial and error may be necessary to determine the suitability of the Mannich procedure. 

Multicomponent reaction systems are highly valued in solid-phase organic synthesis because several elements of diversity can be introduced in a single transformation.1 The Mannich reaction is a classic example of a three-component system in which an active hydrogen component, such as a terminal alkyne, undergoes condensation with the putative imine species formed from the condensation of an amine with an aldehyde.2 The resultant Mannich adducts contain at least three potential sites for diversification specifically, each individual component—the amine, aldehyde, and alkyne—can be varied in structure and thus provide an element of diversity. 

Although imines are less electrophilic than carbonyl compounds, they are also more readily activated by acids or hydrogen bonding. For this reason, Mannich reactions are often faster than the corresponding aldol reactions. It is not even necessary to use preformed imines. In a typical three-component Mannich reaction, the acceptor imine is generated from an aromatic or otherwise protected primary amine. 

A Mannich reaction is the reaction of formaldehyde with a primary or secondary amine and a compound with an active hydrogen atom. The product, an amine with a y-carbonyl, is called a Mannich base, useful in a number of synthesis reactions. An example is in Figure 15-23, and the mechanism is in Figure 15-24. 

Shortly thereafter, Terada demonstrated that the Mannich reaction between several N-Boc aryl imines and acetoacetone was effectively catalyzed by only 2 mol% of le (Scheme 5.2) [4]. In view of AMyama s work, this study is particularly significant because it suggested that le may act as a bifunctional catalyst [9] not only to form a chiral ion pair with the electrophile but also to activate the nucelo-phile through hydrogen bonding of the a-proton with Lewis basic phosphoryl oxygen. 

Pyrrole-containing thiourea derivatives 52 and 53 were developed and optimized for hydrogen-bonding activation of N-acyliminium ions [76] in the acyl-Pictet-Spengler [202, 205] (Schemes 6.50 and 52) and acyl-Mannich reaction [204] (Scheme 6.51). List et al. extended the applicability of this thiourea type to... 

Reaction between aldehydes, ammonia or amines, and an active hydrogen compound (Mannich)... 

---