Mannich reaction, intramolecular

Our initial improvement in the synthesis of pyrrolidine acid 3 relied on a racemic 1,3 dipolar cycloaddition followed by resolution. Attempts to devise asymmetric protocols of this reaction using chiral auxiliaries were not productive. The results from our laboratories were consistent with literature findings, with a moderate diastereoselectivity of 3 to 4 1 at best obtained even when double chiral auxiliaries were used. Several other approaches, such as Aza-Cope/Mannich reaction, intramolecular C-H insertion, and asymmetric aryl 1,4 addition, did not bear fruit. 

Perhaps the most important application of the Mannich reaction is in the synthesis of 3-dialkylaminoindoles. Intramolecular versions of this reaction are also possible, as illustrated by the formation of the /S-carboline (73). 

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. 

The aza-Cope/Mannich reaction takes advantage of the facility with which a y,<5-unsaturated itninium ion, such as 6, participates in a [3,3] sigmatropic rearrangement to give an isomeric species which is suitably functionalized for an intramolecular and irreversible Mannich cyclization (see intermediate 7). The aza-Cope rearrangement substrate 6 is simply an unsaturated iminium ion which can be fashioned in a number of ways from a homoallylic... 

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. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

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). 

A novel intramolecular photocycloaddition involving vinylogous amides and allenes led to an interesting type lb entry to functionalized pyrroles <060L4031>. For example, photolysis of allene 11 provided fused pyrrole 12 via a [2+2] cycloaddition and retro-Mannich reaction. 

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>. 

Mechanistically, the present transformation probably comprises two steps. Mannich reaction of in situ-generated cyclohexadienol 103 with iminium ion 104 is followed by an intramolecular aza-Michael reaction to furnish isoquinuclidine 102 (Scheme 41). Three stereogenic centers are created in this process. 

Sequential Mannich reaction of ester 210a or nitrile 210b, alkylation and displacement of quaternary ammonium salt affords azides 211. Further hydrogenation can be followed by intramolecular cyclization under basic conditions into pyrrolo-benzodiazepinone 212 (Scheme 44 (1994JHC1317, 1994S164)). 

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 groups of Rueping [25] and Gong [26] have developed the aza-hetero-Diels-Alder reaction of aryl imines and cyclohexenone to give isoquinuclidines in good endojexo selectivities and high yields and ee s by 1 and la, respectively (Scheme 5.13). In the presence of acid, cyclohexenone enolizes to afford the dienol which subsequently undergoes a Mannich reaction with the protonated aldimine followed by intramolecular aza-Michael addition to produce the formal Diels-Alder adducts. 

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>. 

Solid-phase library synthesis of triazolopyridazines via a [4+2] cycloaddition strategy has been accomplished <99TL619>. Intramolecular bis-Mannich reaction of 3-aryl-5-mercapto-13,4-triazole, formaldehyde and a-phenylethylamine yields chiral 5-aryltriazolo[3,4-ft]-[133]thiadiazine derivatives. These compounds have been screened for antibacterial activities and some of them show potent biological activity <99SC2027>. 

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. 

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