Mannich conditions

Carbocations stabilized by functional groups can also effect 3-alkylalion of indoles. From a synthetic point of view the most important are jV.jV-dialkyl-methyleneiminium ions which can be generated under Mannich conditions from formaldehyde and secondary amines[13]. The products, 3-(A/,A-dialkyl-aminornethyl)indoles, are useful synthetic intermediates (see Chapter 12). 

Aza-Diels-Alder reactions in aqueous soiutions cycioaddition of dienes with simpie iminium salts generated under Mannich conditions [22]... 

These results contrasted sharply with those obtained with a HHT that was relatively unstable to the reaction conditions. For example, the commercially available HHT of glycinonitrile 28 gave a very poor yield (6%) of coupled glyphosate product with diethyl phosphite because the reaction must be run with acid-catalysis at much lower temperatures (27,38). Somewhat higher yields were observed when 28 was used directly under the modified, acidic Mannich conditions to provide iV-phosphonomethylglycinonitrile 29, which was hydrolyzed direedy to GLYNa3 (39). 

Alkyl-3-hydroxy-4-pyridinones can be converted into analogues containing, e.g., anilino-, phenylthio-, or 2-hydroxyethylthio-substitu-ents by silver(I) oxidation (Ag20 in ethanol) followed by Michael addition (71). In aminomethylation of 3-hydroxy-4- and -2-pyridinones under Mannich conditions the position of substitution can be tailored, by reaction conditions to position C4 or C6, or by converting the OH into OMe, which directs substitution to C5 (72). 

The Mannich reaction is a particularly good method of introducing a reactive functional group into a sensitive aromatic nucleus. The reaction has been very useful in ferrocene chemistry. Treatment of chromium acetylacetonate under Mannich conditions yielded a tris-V,N-dimethylaminomethyl chelate (XXXIII). This remarkable substance was very difficult to purify because of its extreme solubility in all solvents ranging from n-heptane to water. The trisamino chelate (XXXIII) is a deep purple, hydroscopic oil and behaves like a typical organic amine. Reaction of this amine with methyl iodide afforded a trisquater-nary ammonium salt (XXXIV), soluble in water but insoluble in organic solvents. When this salt (XXXIV) was treated with cyanide ion, trimethylamine was lost and the cyanomethyl chelate (XXXV) was formed. 

Reaction with indoles,5 Reaction with N,N-dimethyl(methylene)ammonium chloride is superior to reaction under conventional Mannich conditions for functionalization of various indoles. 

The pyrrolopyrimidine-2,4-dione (27) alkylates under Mannich conditions at C-6 rather than C-5, probably by the mechanism shown, to give (28 R = CH2NMe2). In the absence of the C-2 carbonyl group, the normal C-5 derivative (29) is formed (74CPB2921). 

Larsen, S. D. and Grieco, P. A., Azui Diels-Aldcr reactions in aqueous solution Cyclocondensation of dienes with simple iminium salts generated under Mannich conditions, J. Am. Chem. Soc., 107, 1768, 1985. 

Several modifications of the Mannich reaction were tried with 5-azaindole, but no isolatable product could be obtained. Since the Mannich conditions are usually acidic (pH 5-7), it seems the difference in reactivity between 5- and 7-azaindole can be accounted for by the greater basic strength (pK 8.26 ) of the former compared to the latter (pK 4.59 ). As noted above, protonation of the pyridine nitrogen has the effect of lowering the electron availability at the 3-position. Under the conditions of the reaction 5-azaindole would exist almost entirely in the protonated form (101), which is stabilized by resonance with the pnra-quinonoid canonical form (102), thus lowering the electron density of the pyrrole ring further. Protonation of 7-azaindole would be only partial, with mostly neutral molecule present. Also, the orfAo-quinonoid form (104) of the protonated species (103) is unimportant (see Section V,B,2). 

A series of N-substituted (aminomethylene)diphenylphosphine oxides has been obtained from the reaction of diphenylphosphine oxide, paraformaldehyde, and a secondary amine under modified Mannich conditions . A route from the arylaminovinylphosphine oxides 224 to the quinolyl system 225 has been developed. The enaminophosphine oxides 226 have been obtained by addition... 

X = S) reacts with diazonium salts to form 5-arylhydrazones, and is 5-aminomethylated under Mannich conditions. The dioxo analogue, however, does not take part in the second two reactions <87MI 302-01) (Scheme 71). 2-Alkylideneimidazolidines take part in inverse Diels-Alder synthesis <87TL2681, 87TL6027>, and they are C-alkylated by alkyl halides in neutral media <94H(37)1233>. 

Exposure of imidazole to normal Mannich conditions leads to A-(dimethylaminomethyl)imidazole, presumably via attack at the imine nitrogen, followed by loss of proton from the other nitrogen. A-Arylation or A-vinylation of imidazoles or benzimidazole can be achieved efficiently with metal catalysis (see 4.2). 

The standard, acidic Mannich conditions do not allow simple C-substitutions of the imidazole, (cf. 24.1.1.2 for A-substitution), thiazole or oxazole systems. 

An example that illustrates the advantages that an enol ether can offer vis-d-vis the parent carbonyl compound in iminium ion cyclization is found in Overman and Goldstein s construction of the allopumi-liotoxin A alkaloid intermediate (32). A variety of Mannich conditions failed to produce (32) from amino ketone (28), but yielded only cyclopentaoxazolidine (29). However, intramolecular Mannich cyclization was accomplished in 52% yield at low temperature by treatment of the bicyclic trimethylsilyl enol ether (30) with 1.1 equiv. of trimethylsilyl trifluoromethanesulfonate (Scheme 15). Remarkably, (32) produced in this manner was racemic, a result ascribed to facile [3,3] sigmatropic rearrangement of intermediate (31). 

Cydoadditions of Iminium Salts Generated under Aqueons Mannich Conditions"... 

These systems are reported as cyclopentaoxazolidines and can be obtained by conventional azeotropic dehydration of aldehydes with amino alcohols <85TL5303> for example, (S)-5-Hydroxymethyl-2-pyrrolidinone (236) was condensed with benzaldehyde to obtain the corresponding chiral 5-oxo-2-phenylperhydropyrrolo[l,2-c]oxazole (237) in excellent yield <86JOC3140>. Similar treatment of enantiomerically pure amino ketone (238) with paraformaldehyde or formalin under a variety of Mannich conditions yielded (239) <84ja5360>. These reactions are shown in Scheme 41. 

Chromones and flavones show analogies in their reactions to 4i/-pyran-4-one, i.e. they behave as masked 1,3-dicarbonyl systems. Protonation and alkylation occur on oxygen. Electrophilic attack takes place at the deactivated pyran-4-one ring in the 3-position, e.g. aminomethylation can be brought about under Mannich conditions. 

Cydoaddidoils of Iminiom Salts Generated under Aqneoas Mannich Conditions ... 

Mannich Reaction. The IV-methylindole can realize nucleophilic addition on an iminium ion under classical Mannich conditions. The iminium ion can be formed by combining a secondary amine, formaldehyde, and some acid. The Mannich adduct can he isolated in 94% yield (eq 11). ... 

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