Mannich Intramolecular

One instance of an intramolecular Mannich reaction of an A -acyl-tryptamine has been reported. ... 

The Mannich reaction has been employed to obtain the pyr-N-substituted l,2,3,4-tetrahydro-j8-carboline 319, and intramolecular Mannich reactions at the pyr-N of suitably 1-substituted 1,2,3,4-tetrahydro-jS-carbohnes with formaldehyde 149,359-361... 

The second line of circumstantial evidence quoted in support of this hypothesis is the ready formation of l,2,3,4-tetrahydro-/3-carboline derivatives under pseudo-physiological conditions of temperature, pH, and concentration. Tryptamine and aldehydes, trypt-amine and a-keto acids, and tryptophan and aldehydes condense at room temperature in a Pictet-Spengler type intramolecular Mannich reaction in the pH range 5.2-8.0 (cf. Section III, A, 1, a). It was argued that experiments of this type serve as models for biochemical reactions and may be used in evidence. 

Intramolecular Mannich reactions of iminium 1 and acyliminium ions (see Section D.1.4.5.) with electron-rich double bonds are important reactions in the synthesis of naturally occurring alkaloids. In general, the iminium ions are not isolated but produced as intermediates. 

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. 

An intramolecular Mannich reaction of carboline derivative 352 afforded a complex bridged system containing an indolo[2,3-tf]quinolizidine moiety, as a mixture of two diastereomers. One of them, 353, was transformed into the alkaloid tacamonine 15 (Scheme 79) <2002T4969>. 

In the course of the first total synthesis of (+)-halichlorine <1999TL6513, 1999AGE3542>, the spiroquinolizidine unit 460 was constructed by a two-carbon chain extension in compound 458 through a crossed Claisen condensation, leading to 459, and an intramolecular Mannich reaction of this compound with formaldehyde (Scheme 109). 

The reaction of different substituted hydrazines (or hydroxylamines) with the a,/3-unsaturated ketones 210 gives pyrazolines 211 (or isoxazolines 212), as the result of a Michael addition reaction followed by an intramolecular Mannich reaction (Scheme 12) <2001FAR32>. 

Intramolecular Mannich type reaction of the conjugated iminium salt 426 should lead to ellipticine (228) via an intermediate 427. Alternatively, the conjugated iminium salt 426 could hydrolyze to afford the 2-vinylsubstituted indole 428, which, on cyclization through an intermediate 429, would lead to guatambuine (233). This alkaloid, on demethylation and dehydrogenation, should afford olivacine (238a) (375) (Scheme 3.11). 

L-metilionine to -adenosylmethionine. In this process a positively charged sulphur is produced and facilitates the nucleophilic reaction. By the activity of diamine oxidase, the A -methyl-A -pyrrolinium cation is formed and after that the first alkaloid, hygrine. From hygrine, by way of acetyl CoA, hydrolysis and intramolecular Mannich reactions, other pyrrolidine and tropane alkaloids are synthesized cuscohygrine, hyoscyamine or tropinone, tropine and cocaine. The Mannich reaction involves the combination of an amine, an aldehyde or a ketone with a nucleophilic carbon. This reaction is typical in alkaloid synthesis, and can be written as follows ... 

The enantiopure tricarbonyl(dienal)iron complex 61 suitably transfers chirality in the piperidine ring formation. Condensation to the Schiff base is followed by the intramolecular Mannich reaction catalyzed with p-TSA. The piperidine was converted to dienomycin C (62) in five additional steps <99EJOC1517>. 

Systematic bond disconnection of porantherine [151] with recognition of the double bond-carbonyl equivalence for synthesis generated a synthetic pathway which is based on two intramolecular Mannich reactions. The symmetrical nature of the amino diketone precursor identified by the retrosynthetic analysis facilitates its preparation and subsequent transformations. Moreover, all the hetero atoms (donors) are separated by odd-numbered carbon chains and such arrangements are most amenable to normal modes of assembly. 

More probable is the second route, because Overman was able to demonstrate that the cationic aza-Cupe rearrangement occurs more rapidly than cyclization. To this end, substrate 26 was treated with paraformaldehyde and camp hors ulfonic acid, which led not to the tetrahydropyridine 27, but rather to pyrrolidine 29, formed by intramolecular Mannich cyclization of allylsilaniminium ion 28. 

Tricyclic thiazepine derivatives were analogously prepared via an intramolecular Mannich-type reaction <1995JME2145, 2000JOC4269>. 

An intramolecular Mannich-type cyclization of l,3-dimethyl-6-(2-aminophenylthio)uracil (120) has been utilized for the synthesis of 5, 6-dihydropyrimido[4,5-b][ 1,5]benzothiazepine-2,4( 1H,3//)-diones (121) this synthesis was realized by reaction of 120 with an excess of formaldehyde, benzaldehyde, or p-nitro- or p-methoxybenzaldehyde in chloroform in the presence of a catalytic amount of p-toluenesulfonic acid under reflux for 4-10 hours. The thiazepine cyclization using aliphatic aldehydes other than formaldehyde did not give satisfactory results. In these cases the reaction resulted in the formation of a dimeric product that probably... 

Schemel.3. Retrosynthesis of lycopodine based on an intramolecular Mannich reaction [3],...

In the final example in Scheme 3.3 the starting material is the product of a formal intramolecular Mannich reaction. Accordingly, the C-C bond between the amino and the carboxyl group is particularly weak. Upon hydrogenolysis this bond is cleaved, whereby an imine or aldehyde is presumably formed as an intermediate which leads to the formation of a secondary amine as main product by reductive N-alkylation of 5-aminopentanoic acid. 

Chiral imines have been reported as undergoing intramolecular Mannich reaction to give 4-piperidones <2005JA8398>. Equation (47) illustrates the synthesis of the cis-Z,6-disubstituted 4-piperidone, which was a key step in the synthesis of (+)-abresoline <2005TL2669>. 

A novel reaction that transfers chirality from an enantiopure tricarbonyl(dienal)iron complex in a Schiff base condensation reaction is followed by an intramolecular Mannich reaction to yield a piperidine which was then manipulated in additional five steps to dienomycin C 40 (Equation 109) <1999EJO 517>. 

Aborine (28) and a large number of other 2-substituted quinazolines have been prepared by intramolecular Mannich reactions of N-methylanthranilamide with aldehydes and dehydrogenation of the resultant dihydroquinazolines (Scheme 5).28... 

Benzimidazole reacts with formaldehyde and secondary amines in a Mannich reaction to give 1-aminomethyl products. Intramolecular Mannich reactions at ring nitrogen can produce bicyclic products, for example, 131 in Scheme 23 <2005JHC173>. 

An intramolecular Mannich reaction is observed as well. In this way enaminones derived from 0-phenylendiamine are condensed to indenodiazepine36 (equation 23). 

Intramolecular Mannich reactions have also been used in the synthesis of piperidines. An intramolecular Mannich reaction was applied as the key step in the synthesis of the piperidine A ring of cylindrospermopsin <07SL1446> and in the high yielding diastereoselective conversion of 3-amino acids to 2,6-yy -disubstituted piperidinones <07JOC10287>. 

The principal advantage of the Mannich reaction is that it enables two different molecules to be bonded together in one step, as depicted in Eq. 1 (Fig. 3), whereas Eq. 2 stresses the alternatives connected with regioselectivity in polyfunctional substrates, which, on the other hand, also allow interesting cyclization or polymerization reactions to be performed. When the amino group is present in the substrate (Eq. 3), intramolecular Mannich reactions leading to cyclic products or to polymeric derivatives may occur. 

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