Mannich ring closure with

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. 

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... 

Robinson-Mannich base procedure— Ring closure with ester hydrolysis and... 

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 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. 

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. ... 

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. 

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). 

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. 

Block copolymer 2.34 with a low polydispersity of 1.1 was prepared by ring closure of 1,4-dicarbonyl precursor 2.33 using an excess of Lawesson s reagent (Scheme 1.8) [99]. The latter compound was synthesized by coupling of two equivalents of formylated a-terthiophene 2.32 endowed with a polystyrene chain at other a-terminus with the bis-Mannich base 5,5 -bis[3-(dimethylamino)propionyl]-2,2 5, 2 -terthiophene. TEM and scanning force microscopy (SFM) showed that 2.34 is self-assembled into spherical, micellar structures with average diameters of 12 nm, which corresponds to about 60 block copolymer molecules per aggregate. 

Oximes are useful in preparing isoxazolines and isoxazoles. Since some ring closures to produce these heterocycles may involve oxime anchi-merism, Scott and MacConaill " studied the reaction with a number of Mannich base oxime methiodides. They found that the oximate anion was a powerful nucleophile and that displacement of trimethylamine, as in (266), occurred stereospecifically. The oxime of structure (267) undergoes elimination rather than cyclization. 

Polymer (63) was produced in an 81% yield. This new condensation polymerization represents the first example of polymerization using the Stetter reaction. Since a variety of aromatic aldehydes and Mannich bases undergo the Stetter reaction, this procedure is useful for the preparation of new polymers. Ring closure of the polymer (63) by Lawesson s reagent gave the polymer (64), which showed a conductivity of 10 Scm after doping with AsFs. 

Note In the Pictet-Spengler reaction, P-arylethylamines undergo ring closure on condensation with an aldehyde or ketone. Usually an acid catalyst is employed and the reaction mixture heated, but some reactive compounds give good yields even at physiologic conditions. The Pictet-Spengler reaction can be considered a special case of the Mannich reaction [29, 30]. 

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