Mannich reaction classical

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. ... 

Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2 show the preparation of typical Mannich bases from a ketone, formaldehyde, and a dialkylamine following the classical procedure. Alternatively, formaldehyde equivalents may be used, such as l>is-(di methyl ami no)methane in Entry 3. On treatment with trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive electrophile. lV,A-(Dimethyl)methylene ammonium iodide is commercially available and is known as Eschenmoser s salt.192 This compound is sufficiently electrophilic to react directly with silyl enol ethers in neutral solution.183 The reagent can be added to a solution of an enolate or enolate precursor, which permits the reaction to be carried out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich bases using Eschenmoser s salt in reactions with preformed enolates. 

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... 

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. 

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 is an important biosynthetic route to natural products, mainly alkaloids, and some of these routes have been duplicated in the laboratory. A classic example is the synthesis of tropinone (17) by Robinson in 1917. Robinson synthesized tropinone by a Mannich reaction involving succindialdehyde, methylamine, and acetone 183... 

In the Mannich reaction, a carbonyl component usually formaldehyde, a secondary amine and a CH-acidic compound react together to form 3-aminoketones. The classical method for the formation of (3-aminoketones suffers from many disadvantages such as drastic reaction conditions, formation of undesired side products, little or no stereo-or regioselectivity and low yields. In 2000, Gadhwal and co-workers developed the first microwave-assisted Mannich protocol24 (Scheme 5.10). 

Most reports in this category deal with asymmetric processes. For example, classic Mannich reaction of unmodified ketones, aqueous formaldehyde, and aromatic amines produces a-aminomethylation of the ketones in >99% ee, using L-proline as catalyst. 24 Methyl ketones regioselectively reacted on the methylene carbon. The method is simple, using wet solvents in the presence of air. 

In conclusion, this new organocatalytic direct asymmetric Mannich reaction is an efficient means of obtaining optically active //-amino carbonyl compounds. It is worthy of note that besides the enantioselective process, enantio- and diastereose-lective Mannich reactions can also be performed, which makes synthesis of products bearing one or two stereogenic centers possible. Depending on the type of acceptor or donor, a broad range of products with a completely different substitution pattern can be obtained. The range of these Mannich products comprises classic / -amino ketones and esters as well as carbonyl-functionalized a-amino acids, and -after reduction-y-amino alcohols. 

As in the classical reaction that it resembles, the Petasis Reaction also involves a large number of interdependent equilibrium steps, some of them identical to those in me Mannich Reaction. 

Regardless of how it does take place, the fact that this addition is irreversible certainly imparts a clear advantage. In the classical Mannich, the reversibility of the final step limits the number of cases where the yields are synthetically useful. By comparison, the Boronic Acid Mannich Reaction permits a much broader scope of conversions to be carried out. 

The classical Mannich aminomethylation is one of the most important ionic carbon-carbon bond forming reactions in organic chemistry [35]. However, only substituents with electron-withdrawing groups are suitable for the ionic addition. Electron-donating groups directly bonded to the carbon-centered radical favor nucleophilic radical addition to methylene-iminium salts. Thus, the radical-type Mannich reaction provides products which are complementary to those obtained with the classical ionic reaction. 

Proline and its derivatives also catalyze the classical asymmetric Mannich reaction between aqueous formaldehyde, anilines, and ketones. This was the first successful direct catalytic a-hydroxymethylation of ketones, and the corresponding a-aminomethyl ketones were isolated in excellent yields with up to >99 % ee (Scheme 4) [34]. 

Scheme 4. Direct catalytic asymmetric classical Mannich reactions.

Pyrrolidines can also be prepared by Mannich reactions a classical example is the synthesis of tropinone 43 from succindialdehyde, methylamine, and acetone dicarboxylic acid (Scheme 32) <1917JCS762> reactions of this type are involved in alkaloid biogenesis. 

The great importance of nonproteinogenic amino acids including a-substituted derivatives led to numerous investigations of modified amino acid enolates as nucleophiles in both classical alkylation or Mannich reactions and palladium-catalyzed allylic alkylations. 

Utilization of preprepai ed A,A-dimethylmethyleneammonium iodide (Eschenmoser salt) or chloride gives higher yields of (3-amino ketones than does the classical Mannich reaction. Silyl enol ethers also react with the Eschenmoser salt to give Mannich bases, as exemplified below. 

The classical Mannich reaction converts phenols to aminomethylated phenols. The reaction involves the addition of phenols to C=N bonds of imines or iminium salts formed from formaldehyde and primary or secondary amines, respectively . Recent modifications employ the reaction of an aminal in the presence of SO3, which gives a sulfonate ester, followed by o-aminomethylation (equation Sc(OTf)3 catalyzed... 

The original Mannich reaction is the acid-catalyzed aminomethylation of enohz-able ketones with non-enolizable aldehydes and ammonia, primary amines, or secondary amines, which involves nucleophilic addition of ketone enols to iminium salts generated in situ from the aldehydes and the nitrogen compounds [183]. This three-component coupling reaction provides a powerful tool for carbon-carbon bond formation and introduction of nitrogen functionality. The classical Mannich reaction has some drawbacks in reaction efficiency, regioselectivity, and appli-... 

Even more complicated reactions can be used to racemise during a resolution. The amino ketone 102 is needed for the synthesis of the analgesic and useful asymmetric reagent (see chapter 24) DARVON. Classical resolution with dibenzoyl tartaric acid 9 succeeds in crystallising the (+) enantiomer and racemising the mother liquors by reverse Mannich reaction.25... 

Since salts of the type of (1) have been considered to be the actual reagents in Mannich reactions, the French chemists1 treated various ketosteroids with solutions of (1) and obtained the products of a Mannich reaction in higher yield than that obtained by the classical procedure. 

Table 8 highlights some versatile applications of the Mannich reaction of enol silanes, providing Mannich bases that in some cases are very difficult, if not impossible, to obtain using the classical method. Regiocontrol is observed in the preparation of the two Mannich bases of 2-methylcyclohexanone from the corresponding regioisomeric enol silane derivatives (entries 1 and 2)P Aminomethylation of the enol... 

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