Mannich-cyclization

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... 

An oxidative Mannich cyclization methodology allowed the synthesis of indolizidine skeletons. The oxidation of the a-silylamide 140 with ceric ammonium nitrate (CAN) formed in situ an iV-acylaminium cation, which cyclized to afford the bicyclic compound 141 (Scheme 35) <1998JOC841>. 

Deng and Overman [74] employed their aza-Cope rearrangement-Mannich cyclization reaction as the key step in an approach to both (+)-and (-)-preussin. 

Organoaluminum-promoted Beckmann rearrangement/methylation of cyclohexanone oxime mesylate, followed by allylation of ketimine 40a and Mannich cyclization of the intermediate iminium-allylsilane, provides piperidine 40b possessing cxo-unsaturation (08BKC1669). 

Three years later, Chisholm and Van Vranken reported the first total synthesis of AT2433-A1 (339) using their acid-promoted Mannich cyclization methodology (785). 

An extension of this methodology led to another indolo[2,3-fl]carbazole, AT2433-B1 (341). For this synthesis, the required bisindolylsuccinimide (1455) was obtained through a catalytic hydrogenation of the readily available N-methylarcyriarubin A (1454). TFA-promoted Mannich cyclization of 1455 afforded the hexacyclic... 

Padwa et al. (187,188) concisely summarized his domino cycloaddition/ A -acyliminium ion cyclization cascade process, which involves sequentially the generation of an isomiinchnone 1,3-dipole, intramolecular 1,3-dipolar cycloaddition reaction, 77-acyliminium ion formation, and, hnally, Mannich cyclization. Kappe and co-workers (189) utilized Padwa s cyclization-cycloaddition cascade methodology to construct several rigid compounds that mimic the putative receptor-bound conformation of dihydropyridine-type calcium channel modulators. 

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. 

The use of a cationic aza-Cope rearrangement in concert with a Mannich cyclization has also been applied to the total synthesis of enantiomerically pure (—)-crinine (359) (205). In the event, nucleophilic opening of cyclopentenoxide with the aluminum amide that was formed on reaction of (/ )-a-methylbenzyl-amine and trimethylaluminum gave the amino alcohol 485 together with its (15,25) diastereomer. Although there was essentially no asymmetric induction in this process, the diastereomeric amino alcohols were readily separated by chromatography, and the overall procedure therefore constitutes an efficient means for the preparation of enantiomerically pure 2-amino alcohols from epoxides. When the hydrochloride salt derived from 485 was treated with paraformaldehyde and potassium cyanide, the amino nitrile 486 was formed. Subsequent Swem oxida-... 

Mannich cyclization. Reaction of the alkynylamine 1 with formaldehyde, sodium iodide (3 equiv.), and camphorsulfonic acid (CSA, 1 equiv.) results directly in the piperidine 2 in 81-90% yield. In the absence of Nal, no cyclization is observed even after a reaction at 100° for 3 hours. The vinylic iodide group is useful for elaboration to exocyclic tetrasubstituted double bonds. 

To control the equilibrium position of the rearrangement, Overman and others introduced a nucleophilic hydroxyl group at the C2 position to capture the rearranged iminium ion2 (Scheme 1.6b). Although the levels of diastereoselecti-vity for the formation of pyrrolidines 6a and 6b are low, the tandem cationic aza-Cope-Mannich cyclization provides a variety of substituted 3-acylpyrrolidines in high yields under mild reaction conditions. The first step in the reaction is the... 

Such a Mannich cyclization worked for fused piperidines, as demonstrated by the isolation of pyrrolo-diazocine 196 derived from 322 with methylamine and formaldehyde <1999J(P1)3623> (Scheme 60). Good results were also obtained when arylaldehydes were reacted with ethyl acetoacetate in the presence of NH4OAc in refluxing EtOH to produce carbonyl-bridged diazocines <2005MRC479>. 

Fig. 47. Mannich cyclization of symmetrical bis-amincs with formaldehyde.

Fig. 68. Tandem cationic aza-Cope rcarrangenient-Mannich cyclization.

Fig. 72. Racemizalion of an optically x tive aminic substrate upon Mannich cyclization with formaldehyde.

Jacobsen. E. J., l evin, J and Overman, L. E, 5icopc and mechanism of tandem cationic aza-Cope rcanangemcnt-Mannich cyclization reactions, / Am. Chem. Soc., 110, 4329, 1988. 

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