Mannich-Eschenmoser methylenation

MANNICH - ESCHENMOSER Methylenation reagent Ammomethylation of activated methyl or methylene groups by in situ formed MeaN -CHR (Mannich) Me2N- -=CH2 X reagent for o methylenation (Eschenmoser)... 

MANNICH ESCHENMOSER Methyfenationreagent Ananomethylation of activated methyl or methylene groups by in situ formed Me2N+-CHR... 

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. 

Aminomethylation of lactone enolates with the Eschenmoser salt followed by neutralization (workup) yields the corresponding Mannich bases. Their conversion to quaternary ammonium iodides followed by treatment with DBU (1,5-diazabicy-clo[5.4.0]undec-5-ene) leads to a-methylene lactones. 

When preformed iminium salts are utilized in Mannich reactions, the reaction medium no longer needs to be a protic solvent, so the use of aprotic solvents allows the transformation of sensitive intermediates such as metal enolates. L.A. Paquette et al. carried out the highly regioselective introduction of an exo-methylene functionality during the total synthesis of (-)-O-methylshikoccin by reacting a potassium enolate with the Eschenmoser salt. The resulting p-A/,A/-dimethylamino ketone was converted to the corresponding quaternary ammonium salt and elimination afforded the desired a,p-unsaturated ketone (Eschenmoser methenylation). 

A(, -Dimethyl(methylene)iminium salts have been the most widely used class of preformed iminium salts, mainly due to their applications in the synthesis of a,p-unsaturated carbonyl compounds, normally accomplished by subjecting the /V, -dimethyl Mannich base to quatemarization followed by base-induced elimination. Table 3 outlines various counterion forms of /V, -dimethyl(methylene)iminium salts that have been used in Mannich reactions as well as their synthetic precursors. The crystalline iodide (30), known also as Eschenmoser s salt , has seen the most widespread use and is prepared by thermal fragmentation of (iodomethyl)trimethylammonium iodide or, more conveniently, by a variant of the... 

An alternative method for the formation of an a,(3-unsaturated carbonyl compound is the elimination of an initially formed Mannich product. The procedure is particularly effective for the formation of (3,(3-bis(unsubstituted) a, -unsaturated carbonyl compounds. The Mannich product 11 can be formed in the presence of a secondary amine and a non-enolizable aldehyde such as formaldehyde (2.12). The Mannich reaction is a useful carbon-carbon bond-forming reaction and the products have found application in the synthesis of, in particular, alkaloid ring systems. The Mannich product may eliminate under the reaction conditions, or can be alkylated to form the quaternary ammonium salt in order to induce elimination. A convenient variation of this method is the use of Eschenmoser s salt, H2C=NMe2 X. For example, Nicolaou s synthesis of hemibrevetoxin B used this salt in order to introduce the required methylene unit a- to the aldehyde 12 (2.13). The same transformation with the corresponding methyl ester, which is less acidic, requires prior enolization with a strong base (e.g. NaN(SiMe3)2) and subsequent quatemization of the tertiary amine with iodomethane and elimination using DBU. 

Imines are generally less electrophilic than the corresponding aldehyde but this diminished level of activity can be countered by suitable activation with Lewis acids. Formaldehyde imines are generally stable only at low temperatures and are best formed in situ. However, there are exceptions like Eschenmoser s salt 20. This methylene iminium salt is a relatively stable solid that is now commercially available. The utility of this reagent was illustrated in the Mannich reaction of corrin 19 with 20 to generated 21. 

A procedure in which the iminium salt shown, A, N-dimethyl(methylene) ammonium trifluoroacetate, is isolated and added separately to an enolate ion allows Mannich bases to be prepared by routes other than those involving acidic media. This procedure is exemplified by entry 4. N,iV-Dimethyl(methylene) ammonium iodide is commercially available as Eschenmoser s salt and is sufficiently electrophilic so as to react directly with enol silyl ethers in neutral media. Ketone enolates have been converted to Mannich bases with Eschen-moser s salt (entry 5). 

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