Mannich reaction examples

Tritiated formaldehyde is also useful in Mannich reactions. Examples of such applications include the preparation of the topoisomerase-1 inhibitor 364 by condensation of tritiated formaldehyde and dimethylamine with 10-hydroxycamptothecin 1363). the reaction with acetone and diethylamine to give 4-diethylamino-4-[ H2]butan-2-one 365 which was further converted upon heating with thebaine (366) to the morphine derivative 367 (specific activity of 46 Ci/mol). Furthermore, condensation of aqueous deuterated formaldehyde with allyltrimethylsilane to prepare the 2,6-doubly labeled piperidine 368. as indicated , would be expected to work equally well with tritiated formaldehyde. 

The well-known Mannich reaction is illustrated by the following example ... 

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 synthesis of tropinone 14, a precursor of atropine and related compounds, is a classical example. In 1917 Robinson has prepared tropinone 14 by a Mannich reaction of succindialdehyde 11 and methylamine 12 with acetone 13 better yields of tropinone were obtained when he used the calcium salt of acetonedicar-boxylic acid instead of acetone. Modern variants are aimed at control of regio-and stereoselectivity of the Mannich reaction. ... 

The three examples in Table 9 show Mannich reactions with 7V,A -dimethyl(methylene)im-inium salts. In the case of 5, a d.r. (exo/endo) 20 80 of the products was reported3 0. 

Example The lactone (8>, needed for a natural product synthesis, might be made from (6) via epoxide (7) and so a synthesis for (6) was required. Wittlg disconnection reveals a 1,5-dicarbonyl compound (9), best made by Michael addition of a substituted malonate (11) to enone (10). The enone was made by the simple but reliable Grignard route rather than risking a Mannich reaction of unknown regloselectivity. 

Lignin amines with high nitrogen content are water soluble at both alkaline and acidic pH values. The lignin amines have various useful properties. For example, they are active as flocculants, filtration aids, scale inhibitors, fluid loss additives, oil well cement additives, and corrosion inhibitors among other potential uses. The nitrogen is introduced into the lignins with the Mannich reaction [1570]. 

Mannich reactions, or a mechanistic analog, are important in the biosynthesis of many nitrogen-containing natural products. As a result, the Mannich reaction has played an important role in the synthesis of such compounds, especially in syntheses patterned after the biosynthesis, i.e., biomimetic synthesis. The earliest example of the use of the Mannich reaction in this way was Sir Robert Robinson s successful synthesis of tropinone, a derivative of the alkaloid tropine, in 1917. 

Entry 6 is analogous to a silyl ketene acetal rearrangement. The reactant in this case is an imide. Entry 7 is an example of PdCl2-catalyzed imidate rearrangement. Entry 8 is an example of an azonia-Cope rearrangement, with the monocylic intermediate then undergoing an intramolecular Mannich condensation. (See Section 2.2.1 for a discussion of the Mannich reaction). Entry 9 shows a thioimidate rearrangement. 

For example, Mannich reaction of N-methylpyrrole affords the corresponding dimethylaminomethyl derivative (2) and treatment with methyl iodide affords the quaternary salt (3). Displacement of the quaternary amine by means of cyanide leads to the substituted... 

A beautiful example of a domino [3+3]-sigmatropic rearrangement is the synthesis of the enantiopure antifungal antibiotic (-)-preussin (4-14) by Overman [5], which starts from the amine 4-10 and decanal to give the iminium ion 4-11 (Scheme 4.3). This undergoes a [3+3]-sigmatropic rearrangement to provide 4-12, followed by a Mannich reaction with the formation of 4-13. 

A domino Claisen/ene strategy was employed for the synthesis of (+)-9(l l)-dehy-droestrone [82] methyl ether, while an example of a domino aza-Cope rearrange-ment/Mannich reaction is the above-mentioned synthesis of (-)-preussin (4-14) [5]. 

More recently in 2001, Winkler and Kwak reported methodology designed to access the pyrrolidine core of the hetisine alkaloids via a photochemical [2+2], retro-Mannich, Mannich sequence (Scheme 1.3) [26]. In a representative example of the methodology, vinylogous amide 42 was photo-irradiated to give the [2+2] cycloaddition product 43. Heating cyclobutane 43 in ethanol provided enamine 44 via a retro-Mannich reaction. Exposure of enamine 44 to acidic conditions then effected a Mannich reaction, resulting in pyrrolidine 45. 

A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type lb entry to functionalized pyrroles <060L4031>. For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. 

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.

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) ... 

The procedure described is an example of a general reaction,1-2 the Mannich reaction, a review of which, from the experimental point of view, has recently been published. ... 

The Mannich reaction has been applied to the synthesis of a wide array of iV-aminomethyl-l,2,4-trialozethiones. For example, 1,2,4- triazolo-3-thione 52 reacts with iV-phenylpiperidine in the presence of 40% formalin to give the corresponding N-substituted l,2,4-triazolo-3-thione 53 in 77% yield (Equation 16) <2005PS(180)537, 2000PS(164)67>. 

Vainilavicius and co-workers studied the Mannich reaction of oxadiazolethiones in detail and reported several examples pointing to the importance of starting reagent stmctures and the reaction conditions on the course of the reaction <2002M 173, 2003CHE1364>. For example, aminomethylation and acylation of 5-(4,6-diphenyl-2-pyrimidinyl)-... 

Related catalytic enantioseiective processes Representative examples of other catalytic asymmetric Mannich additions are depicted in Scheme 6.31. In 1997, Tomioka demonstrated a Li-catalyzed synthesis of functionalized p-lactams that proceeds through a catalytic enantioseiective Mannich reaction (promoted by 103) [95], and a year later Lectka and his team published a series of reports concerning additions of silyl ketene acetals... 

Scheme 6.31. Representative examples of non-Zr-catalyzed enantioselective Mannich reactions.

Kobayashi and his team have utilized a catalytic system similar to that used in their development of a Zr-catalyzed Mannich reaction (Schemes 6.27—6.29) to develop a related cycloaddition process involving the same imine substrates as used previously (Scheme 6.35) [105]. As the representative examples in Scheme 6.35 demonstrate, good yields and enantioselectivities (up to 90% ee) are achieved. Both a less substituted version of the Danishefsky diene (—> 110) and those that bear an additional Me group (e. g.— 111) can be utilized. Also as before, these workers propose complex 89, bearing two binol units, to be the active catalytic species. 

Electrophilic attack at carbon is a well-documented reaction which occurs regioselectively at the C-3 position. It was illustrated by numerous examples, including nitrations, halogenations, acylations, and Mannich reactions in CHEC(1984) and CHEC-II(1996) <1996CHEC-II(8)249>. Table 1 reports some additional recent examples. It should be noted that all these synthetic transformations were carried out in the field of medicinal chemistry. 

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. 

Aromatic Mannich reactions have been reviewed290. Recent examples are the formation of 254 from p-cresol, paraformaldehyde and 1-methylpiperazine and of 255 from salicylaldehyde, aqueous formalin and 1-methylpiperazine291. 

Mannich reaction org chem Condensation of a primary or secondary amine or ammonia (usually as the hydrochloride) with formaldehyde and a compound containing at least one reactive hydrogen atom, for example, acetophenone. Also known as Mannich condensation reaction. man-ik re,ak-shon mannite See mannitol. ma,nlt ... 

One simple example was the hydrolysis of imines hack to carbonyl compoimds via nucleophilic attack of water. The Mannich reaction is only a special case of nucleophilic addition to iminium ions,... 

The Mannich reaction is best discussed via an example. A mixture of dimethylamine, formaldehyde and acetone under mild acidic conditions gives N,N-dimethyl-4-aminobutan-2-one. This is a two-stage process, beginning with the formation of an iminium cation from the amine and the more reactive of the two carbonyl compounds, in this case the aldehyde. This iminium cation then acts as the electrophile for addition of the nucleophile acetone. Now it would be nice if we could use the enolate anion as the nucleophile, as in the other reactions we have looked at, but under the mild acidic conditions we cannot have an anion, and the nucleophile must be portrayed as the enol tautomer of acetone. The addition is then unspectacular, and, after loss of a proton from the carbonyl, we are left with the product. 

The mechanism of imine formation is standard, as seen in the other examples. The cyclization reaction is then like the Mannich reaction, attack of an enol on to the iminium cation. This time though, the nucleophile is provided by the resonance effect from the phenol system. 

As a true testament to the potential long-term impact of H-bonding activation, a number of ureas, thioureas, and acid catalysts are now finding broad application in a large number of classical and modem carbon-carbon bond-forming processes. On one hand, Johnston s chiral amidinium ion 28 was elegantly applied to the asymmetric aza-Henry reactions (Scheme 11.12d). On the other hand, chiral phosphoric acids (e.g., 29 and 30), initially developed by Akiyama and Terada, have been successfully employed in Mannich reactions, hydrophosphonylation reac-tions, aza-Friedel-Crafts alkylations (Scheme 11.12e), and in the first example... 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

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