Mannich closure

Reductive removal of the amide carbonyl with borane and Mannich closure of the middle ring give P-lycorane 72. A feature of this synthesis is that by changing the order of events and by adding ArLi with chelation control, all three lycoranes can be made selectively. 

Winkler and coworkers have coupled the photocycloaddition and retro-Mannich fragmentation of an acyclic vinylogous amide with a subsequent Mannich closure to produce perhydroindole structures as outlined in Scheme 2445. The acyclic secondary... 

A [2+2] cycloaddition/retro-Mannich fragmentation/Mannich closure cascade, conceptualised in Scheme 2, has been applied to the vinylogous amide (113) as a key step in the synthesis of the pentacyclic ring system found in the antileukaemia marine alkaloid manzamine... 

A distinct route was followed by Winkler et al. and included the application of the known vinylogous amide [2+2] photocycloaddition, refro-Mannich fragmentation, Mannich closure cascade (pharM) sequence. Two methodologies for the synthesis of the requisite pentacycle were described. The transannular photocyloaddition of an 18-membered amide and photocycloaddion of an acyclic vinylogous amide, followed by macrolactamization of the derived pharM closure product was used to generate the ABODE system (see Scheme 32) [95]. 

An Approach to the Synthesis of the Manzamine Alkloids via the Vinylogous Amide PhotocycloAddition/Retro-Mannich Fragmetation/Mannich Closure Cascade (pharM). Winkler, J. D. Stelmach, J. E. Siegel, M. G. Haddad, N. Axten, J. and Daily III, W. P. Isr. J. Chem. 1997, 37, 47. 

Retro-Mannich fragmentation of the cycloaddition product 40 (not isolated) resulted in the formation of the imine 41, which upon a new Mannich closure reaction produced the cyclohexanone derivative 42. Further manipulation of 42 resulted in the formation of 43, which had previously been reported as a precursor for vindorosine (44) [27, 28]. 

Ring closure to [l,2,4]triazolo[3,4- ][l,3,5]thiadiazines by utilizing the Mannich reaction has been published by a Chinese team <1999SC2027, 2001SC2841, 2001JF1C929> (Scheme 23). 5-Aryl-substituted 3-mercapto[l,2,4]tri-azoles 123 were treated with formaldehyde and primary amines under acidic conditions to yield the fused thiadiazines 124. The reaction was interpreted to proceed via formation of intermediate 125 upon the reaction of 123 with a... 

In 2003, we reported a multicomponent approach toward highly substituted 2H-2-imidazolines (65) [157]. This 3CR is based on the reactivity of isocyano esters (1) toward imines as was studied in detail by Schollkopf in the 1970s [76]. In our reaction, an amine and an aldehyde were stirred for 2 h in the presence of a drying agent (preformation of imine). Subsequent addition of the a-acidic isocyanide 64 resulted in the formation of the corresponding 2//-2-imidazolines (65) after 18 h in moderate to excellent yield. The mechanism for this MCR probably involves a Mannich-type addition of a-deprotonated isocyanide to (protonated) imine (66) followed by a ring closure and a 1,2-proton shift of intermediate 68 (Fig. 21). However, a concerted cycloaddition of 66 and deprotonated 64 to produce 65 cannot be excluded. 

Surprisingly, 3-(2-dialkylaminoethyl)-l,2-benzisoxazoles 207 can be easily obtained by direct cyclization of the corresponding Mannich bases oxime acetates 206 in refluxing benzene in the presence of anhydrous K2CO3 (equation 90). The known methods for ring closure to 1,2-benzisoxazole were ineffective for this class of pharmacologically relevant compounds . 

A preparation of yohimbenone [152] by closure of the D-ring with formaldehyde can be considered as a vinylogous Mannich reaction. 

In one route, tidopidine (1) was assembled via Sn2 displacement of 2-chlorobenzyl chloride (9) with 4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (8). " The nucleophile 8 was synthesized by heating 2-thiophen-2-yl-ethylamine (6) with 1,3-dioxolane in the presence of concentrated hydrochloric acid. 1,3-Dioxolone gave better yields than with formaldehyde, paraformaldehyde and 1,3,5-ttioxane. The interesting transformation 6 —> 8 first involved the formation of the corresponding Mannich base 7, which then underwent a Pictet-Spengler type reaction to afford the ring-closure product 8. It was of interest to note that a possible intramolecular aminomethylation did not take place. 

Mannich condensation of o-hydroxyphenylacetylene (227, R = H) leads to compound 228 heterocyclic ring closure of the latter gives the basic 2-substituted benzofuran 229. The diacetylenic derivative (227, R = C=CH) gives the corresponding 5-ethynylbenzofuran (229, R = C=CH).488... 

Scheme 27)48. Irradiation of 111 led to the formation of 112, which was formed by a sequence involving photoaddition and retro-Mannich fragmentation to the intermediate ketoimine, followed by tautomerization of the imine to enamine, transannular closure and dehydration. 

Oxadiazolc derivatives (sydnonimines) 328 and oxazolcs 329 (Fig. 126) can be synthesized from Mannich bases of hydrogen cyanide po.s.scssing a secondary amino group, as ring closure may take place by condensation with nitrous acid " or anhydride, respectively. Analogous. syntheses of spiroidantoins arc reported. ... 

Path a can be considered as a C-alkylation by the Mannich base of enamine or enol derivatives the latter acts in the presence, for example, of hydroxylamine, followed by intramolecular condensation leading to ring closure and formation of the aromatic nucleus 340. " By contrast, path b involves amino group replacement by arylamine (N-alkylation by the Mannich base) producing the P-arylaminoketone 341, directly obtainable also by Mannich synthesis. " ... 

Replacement of the amino group in the Mannich base is also applied to alkaloid synthesis. Thus, ellipticinc alkaloids are prepared by deamination of the intermediate indole Mannich base 457 (Fig. 174), which allows ring closure to the hcxa-atomic cycle evolving. subsequently toward the phenolic moiety (458) through the occurrence of tautomeric equilibria. 

Ring closure with concomitant amino group elimination is actually a replacement reaction, as depicted below, strictly connected with the replacement reaction described in Sec. B. Similarly, the cyclization mechanism may or may not involve the formation of a vinyl intermediate (vinylketone, methylcnequinone, etc.), originated by the deamination of the initial Mannich base, which then undergoes addition. 

When the o-amino nitroso derivative 363 is subjected to reaction with various N-indolic or phenolic Mannich bases, closure of the imidazole ring by the methylene moiety occurs, thus making it possible to obtain the interesting purine derivatives 364. 

Studies of nucleosides and the corresponding heterocyclic bases predominate, although nucleotides are also investigated. The synthesis of these compounds, based on the chemistry of Mannich bases, is reported by few papers, as in the case of the ring closure of imidazole (364 in Chap. II, E.2) however, the functionalization of nucleosides and nucleotides, using these molecules as substrates or amine reagents in aminomethylation reactions, is more diffusely reported. 

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