Formaldehyde equivalent, , «■ 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. 

The mechanism of the reaction is considered in Section 6.12.7, p. 1050, where acetophenone, which can only enolise in one direction, reacts with the formaldehyde equivalent (17) formed from formaldehyde and dimethylamine hydrochloride, to give the Mannich base (18), which in this case is isolated as the hydrochloride. The free Mannich bases are obtained by treatment with base and solvent extraction or crystallisation (e.g. gramine, Expt 6.147). 

We need a formaldehyde equivalent that is less electrophilic than formaldehyde itself and will therefore add only once to enol(ate)s. The solution is the Mannich reaction.7 Formaldehyde is combined with a secondary amine to give an iminium salt that adds 47 to the enol of the aldehyde or ketone in slightly acidic conditions to give the amino ketone (or Mannich base ) 48. If the product of the aldol reaction 50 is wanted, alkylation on nitrogen provides a good leaving group and ElcB elimination does the trick. 

The imine and iminium functional groupings are, of course, the nitrogen equivalents of carbonyl and O-protonated carbonyl groups, and their reactivity is analogous. The Mannich reaction of pyrrole produces dialkylaminomethyl derivatives, the iminium electrophile being generated in situ from formaldehyde, dialkylamine and acetic acid. There are only a few examples of the reactions of imines themselves with pyrroles the condensation of 1-pyrroline with pyrrole as reactant and solvent is one such example. N-Tosyl-imines react with pyrrole with Cu(OTf>2 as catalyst. ... 

The evidence described above thus indicates that the structure of macralstonine is almost certainly XLIa b, and it is presumably formed in the plant by a Michael reaction between alstophylline and macroline, or alternatively, by a Mannich reaction involving alstophylline, the hydroxyketone XLIII, and a formaldehyde equivalent. The acid fission of macralstonine to alstophylline and macroline or to alstophylline, XLIII, and formaldehyde is thus seen to be the reverse of these reactions (10). 

We need a formaldehyde equivalent which is less reactive than formaldehyde itself. The most popular method is the Mannich reaction " in which formaldehyde reacts with the enolic component and a secondary amine. The mtermediate (41) is first formed this adds to the enol to form the Mannich base (42). 

Shibata and Tom used this strategy for a highly enantioselective mono-fluoromethylation by an asymmetric Mannich reaction using 1-fluorobi-s(phenylsulfonyl)methane (FBSM) with quinidine-derived catalyst 49c and subsequent removal of the sulfonyl group by treatment with magnesium powder (99% enantiomeric excess). Palomo and coworkers used sulfonyl acetonitrile as a synthetic equivalent of acetonitrile and obtained the optically active p-aminonitriles 97 (76% enantiomeric excess). Bernard , Ricci, and coworkers also introduced the same strategy to synthesise N-protected p -amino acid esters 98 (R = Ph, 92% enantiomeric excess) and a-alkylidene-p-aminoesters 99 (R = Ph, 91% enantiomeric excess) by an asymmetric Mannich reaction of sulfonylacetate followed by the subsequent reductive removal of the sulfonyl moiety and olefination with formaldehyde, respectively (Scheme 16.32). ... 

On treatment of 1 with equimolar quantities of formaldehyde and piperidine, morpholine or diethylamine in acetic acid, the Mannich bases 182a-c were synthesized in good yield. Their analogue, 182d, was obtained in the reaction of 1 with one equivalent of bis(dimethylamino)methane in AcOH or with A,A-dimethylmethyleneimmonium chloride in dry acetonitrile (yields are 79 and 47%, respectively)193. The introduction of the second dialkylaminomethyl group into compounds 182 is discussed in Section IV.D. 

Dimethylamine hydrochloride (1 equivalent) was prepared by evaporation of a mixture of aqueous dimethylamine (45 g, 1.0 mol, as 25% aqueous solution) and excess concentrated hydrochloric acid under reduced pressure. To the solid residue was added an aqueous solution of the cyclohexanone (224 g, 2.0 mol) and formaldehyde (30 g, 1.0 mol, 40% aqueous solution). The two-phase mixture was heated carefully (reaction is exothermic) to boiling under a long reflux condenser, boiled for about 5 min, and then cooled to room temperature. Water (200 mL) was added, the layers separated, the aqueous layer saturated with sodium chloride, washed with ether (4 x 50 mL), and then made basic with 30% aqueous potassium hydroxide (1.3 equivalents). The Mannich base separated as a yellow upper layer with a strong amine odor. The layers were separated, the aqueous layer extracted with ether (5 x 100 mL), the combined organic layer and ether extracts dried over magnesium sulfate, and the solvent was distilled to provide the amino ketone (118 g, 70%). 

Quite recently, benzoylhydrazones derived from a-functionalized aldehydes and formaldehyde have been prepared as stable equivalent of unstable imines, and successftdly used in Mannich-type reactions (Manabe et al. 2000). 

One of the limitations of the Mannich-type reaction for the preparation of aminometh-ylenephosphonic adds is that primary amines treated with 1 equivalent of formaldehyde and phosphorous acid yield a mixture of mono- and bis(methylenephosphonic) acids. A further limitation appears to be in the choice of carbonyl compounds. 

A combination of resorcinarene, formaldehyde and secondary amines results to tertiary amines or tetrakis-aminoalkylated resorcinarenes through a Mannich condensation reaction. When primary amines are used, the resulting secondary amine 2 reacts intramolecularly with one of the phenolic hydroxyl groups and a second equivalent of formaldehyde, forming tetrabenzoxazines 3 (Fig. 11.3) [20-23]. 

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