Mannich ring closure

At slightly elevated temperatures (40—60 °C) catharanthine. b-oxide (219) undergoes a facile [2,3]-sigmatropic rearrangement with quantitative conversion into the isoxazolidine derivative (220), whose structure was established by the X-ray method. Oxidation at to C-3, followed by Mannich ring-closure, affords an... 

As a result of the cisitrans geometry of the imines, either 26-cis or 26-trans could be afforded, with 26-cfr being at a higher energy state. Intermediate 27a would afford the cfr-isomer by a Mannich ring closure and similarly intermediate 27b would afford the rrons-isomer. The positioning of the geminal diester should enable the retro-Mannich process to take place, which would leave a reasonable pathway for the less stable tram isomer to be converted to the more stable cis isomer. 

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 . 

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... 

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. 

The Mannich reaction l and the related a-aminoalkylations of nucleophilic anions of weak acids are also examples of MCRs of type I,t whereas ring closures to heterocycles, e.g. the Hantzschf l and Radziszewkit l reactions, correspond to MCRs of type II. The Asinger reactiont sometimes belongs to type I and in some other cases to type II MCRs. 

The Tadano group extended the use of the sugar-based chiral templates for the l 8-methyl carbapenem synthesis. As concerns the chemical synthesis of 1/3-methyl carbapenems such as 1 /S-methyl thienamycin, the most common approach is a late-stage ring closure for bicyclic skeleton construction using a C-4 functionalized azetidin-2-one, such as 113, namely (35, 45)-3-[(R)-l-(r-butyldimethylsilyloxy)ethyl]-4-[(R)-l-carboxyethyl]azetidin-2-one, which may be constructed via the Mannich-like reaction of commercial (3R,4R)-4-acetoxy-3-[(R)-l-(r-... 

A number of Mannich-type cyclizations that proceed in an exocyclic mode with respect to the allylsi-lane terminator have been reported. In this way, five-, six-, seven- and eight-membered azacycles are accessed in good yields. In keeping with Baldwin s suggestion concerning ring closure aptitudes, the iminium ion derived from amine (113) could not be cyclized (Scheme 41). 

Quaternary Mannich bases react like, / -unsaturated ketones under the conditions of a Michael addition. The vinyl ketone is formed from the Mannich base in a sufficiently reactive state to add to simple ketones under the influence of sodamide and not to require the usual 1,3-dicarbonyl compound then ring closure follows immediately ... 

Arylethanamines react with aldehydes easily and in good yields to give imines. 1,2,3,4-Tetrahydroisoquinolines result from their cyclisation with acid catalysis. Note that the lower oxidation level imine, versus amide, leads to a tetrahydro- not a dihydroisoquinoline. After protonation of the imine, a Mannich-type electrophile is generated since these are intrinsically less electrophilic than the intermediates in Bischler-Napieralski closure, a strong activating substituent must be present, and appropriately sited on the aromatic ring, for efficient ring closure. 

Hydrogenation was carried out at O to minimize decarboxylation of the saturated 3-keto acid product 18. Mannich reaction proceeded with in situ decarboxylation to afford a-methylene ketone 19, which on Michael reaction with ketal 3 keto ester 20 -" yielded adduct 21. Saponification, B ring closure, and decarboxylation then led to ketalenone 23 in high yield, which was converted into ( + )-19-nortestosterone 24 and thence to ( + )-19-norandrostenedione 25 in 50% yield from 18 or 27% overall yield from 12. However, ketal hydrolysis, A ring closure, oxidation at C-17, and isomerization by the Roussel procedure (acetyl bromide-acetic anhydride in methylene chloride at 20°) should yield (-f )-estrone 26 efficiently. 

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