Subject Mannich reactions

As with aldol and Mukaiyama addition reactions, the Mannich reaction is subject to enantioselective catalysis.192 A catalyst consisting of Ag+ and the chiral imino aryl phosphine 22 achieves high levels of enantioselectivity with a range of N-(2-methoxyphenyljimines.193 The 2-methoxyphenyl group is evidently involved in an interaction with the catalyst and enhances enantioselectivity relative to other A-aryl substituents. The isopropanol serves as a proton source and as the ultimate acceptor of the trimethyl silyl group. 

The amine-catalyzed Mannich reaction has also been a subject of special reviews [243, 244]. In general, yields and enantioselectivities of proline-catalyzed Mannich reactions are very high. Initially, the reactions were restricted to imines bearing an aromatic A-substituent, such as the p-methoxyphenyl (PMP) group. This restriction considerably limited the usefulness of the protocol, because relatively... 

The Mannich reaction proceeded in nearly quantitative yield for the pyrrolopyridines (1) and (4). A somewhat lower yield was obtained from the isomer (3). A number of derivatives of compound (1) have also been subjected to the Mannich reaction. The typical reaction conditions include treatment with excess paraformaldehyde and dimethylamine hydrochloride in butanol. Results are summarized in Table 41 <69TL1909>. 

The aldol reaction is one of the most fundamental tools in organic chemistry, and it still remains an open field for new ideas and developments504-509. Among the many reviews dedicated to this subject, the reader should refer, for a more referenced survey, to Heathcock7,11 and more recently to Braun s articles510 devoted specifically to the preformed metal enolates of group I—II. The Mannich reaction (the aza-equivalent of the aldol reaction) is a subject on its own and will be only partially treated here. 

More recently, some review artieles have appeared in which several applications of Mannich bases in the pharmaceutical field - and in other industries,such as those connected with maeromolccular chemistry, arc described. However, no general, complete overview of the widespread practical applications of Mannich bases has been published so far, despite their connections with important branches of industrial organic chemistry. Although the most relevant contribution of the Mannich reaction is still in pharmaceutical research (over 30% of the scientific papers published on this subject are found in journals dealing with pharmaceutical chemistry), Mannich bases have been found to have important uses in the manufacture of polymeric materials (resins and, in particular, surface coatings) and in the production of various additives and auxiliaries (for lubricants, textiles, paper, etc.) as well as, for example, in the production of water-treatment agents. 

When the aromatic ring is suitably activated by electron-donor substituents (NR2, OH, or alkoxy groups) for electrophilic attack, it can be easily subjected to Mannich reaction. 

The possibility of crosslinking natural macromoleculcs, such as cellulose and proteic materials, via the Mannich reaction has also been inve.stigatcd. Cellulose derivatives, however, are mostly subjected to the analogous amidomcthylation reaction, " usually employing bis-methylol amides (urea, oxalyl, adipoyl derivativas, etc.) capable of reacting with the cellulose hydroxy groups. 

Reactions of type (a) are among the most extensively studied, as they include the. synthesis of polyacrylamide Mannich bases, widely employed in water-purification processes. Many other polymeric substrates are, however, succe.ssfully subjected to Mannich reaction (Table 33). Moreover, some polymeric substances need to be suitably functionalized in order to undergo the aminomethylation reaction, as reported for polymeric ketones obtained by oxidation of polyenes." Further macromolecular carbonyl substrates could be provided by interesting vinyl monomers purposely designed to give polymers suitable for Mannich reaction." ... 

The aminoalkylation reactions applied to the synthesis of alkaloids arc mostly cycliyui-tions of the type described in Chap, I, C.4, usually involving CH substrates such as alkyl ketones. The analogous reactions on alkcncs arc frequently accompanied by more or less relevant modiheations of the substrate molecule (Chap. I, C.5). Activated aromatic substrates, particularly phenols and their alkylether derivatives, arc also subjected to Mannich reaction. 

The heterocyclic ring, also, has been subjected to aminomethylation, as reported for the reaction of the furane sub.strate 454 (Fig. 172) with dimethylamine and formaldehyde, which represents a key step in the synthesis of muscarines. This is one of the few examples in alkaloid chemistry of the Mannich reaction not involving cyclization. 

The crosslinking of polymeric materials by Mannich reaction includes the polycondensation of acetone with oligomeric polyalkyleneamines and aldehydes (see also 480, Chap. IV) and, more relevantly, polyamides (430, Chap. Ill) crosslinked with benzidine and formaldehyde. Macromolecular materials such as cellophane and polyglucosamine (Fig. 183), deriving from natural substances, are also subjected to the reaction. 

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. 

The present chapter deals with the application of Mannich aminomethylation or Mannich bases to the synthesis and modification of macromolecular compounds. As summarized in Fig. 150, a remarkable number of different combinations exist, as the Mannich reaction enables us (a) to perform polymerizations by using bifunctional substrate and amine as well as (d) to functionalize polymeric derivatives behaving, alternatively, as substrate or amine components of Mannich synthesis. On the other hand, the manifold reactivity of Mannich bases makes it possible (b) to produce polymers by amino group replacement with bifunctional nucleophiles or to polymerize suitable moieties (e.g., double bonds) present in the base. Furthermore (e), macromolecular compounds can be subjected to amino group replacement as well as to various other reactions given by Mannich bases. Finally (c), crosslinked derivatives are obtained from oligomeric or polymeric products through any of the above mentioned methods. 

Mostly phenols and phcnolethers are subjected to Mannich reaction, with hctcroaromatic substrates also employed. The first group of compounds has been thoroughly investigated (p. 374 in Ref. 2) mainly as far as intramolecular cyclization with the hydroxy-or alkoxy-activatcd aromatic ring of the tclrahydroisoquinolinc-dcrivcd methyleneim-monium sail is concerned (453, Fig. 171). 

The steroid skeleton is usually subjected to Mannich reaction in order to obtain derivatives possessing basic functionalities. Steroidal aminomethyl compounds arc used mostly for the synthesis of compounds having pharmacological activity. 

Various imidazo[4,5-fc]pyrazin-2-ones (228) have been subjected to a number of different reactions. Alkylation, acylation and the Mannich reaction all give 1,3-disubstituted derivatives (229). Halogenation of the 2-oxo compound (230) with bromine or chlorine in acetic acid or with sulfuryl chloride provided monohalo derivatives (231) (69FRP1578366, 71BRP1248146). The chlorine atom of (231) can be removed by catalytic hydrogenation. 

The Mannich reaction is an aldol reaction with an imine. It has been the subject of many excellent reviews. For example, see Arend, M. Westerman, B. Risch, N. Angew. Chem. Int. Ed. 1998, 37, 1044-1070. Asymmetric variants have also been reported see, for example, Notz, W. Tanaka, E Barbas, C. E, III Acc. Chem. Res. 2004, 37, 580-591. 

In addition to the side reactions mentioned above, deamination of Mannich bases can occur, especially at elevated temperature, to give a,p-unsaturated derivatives. This route of decomposition of Mannich bases has been exploited as a means of in situ generation of a,p-unsaturated ketones in the Michael reaction and for the direct synthesis of a,3-unsaturated ketones several reviews of the Mannich reaction have discussed aspects of these applications.Recently, a direct one-pot synthesis of a-methylene ketones has been reported involving condensation of ketones with formaldehyde and A -methylaniline tri-fluoroacetate in aptotic solvents. Also, a less direct method has been described in which Mannich bases prepared from 3-keto esters, formaldehyde and dimethylamine are subjected to quatemarization and thermal fragmentation to yield a-methylene ketones.This method is particularly useful for the regios-pecific synthesis of a-methylene ketones because the aminomethylation reaction always takes place at the most activated position flanked by the ketone and ester groups. 

A(, -Dimethyl(methylene)iminium salts have been the most widely used class of preformed iminium salts, mainly due to their applications in the synthesis of a,p-unsaturated carbonyl compounds, normally accomplished by subjecting the /V, -dimethyl Mannich base to quatemarization followed by base-induced elimination. Table 3 outlines various counterion forms of /V, -dimethyl(methylene)iminium salts that have been used in Mannich reactions as well as their synthetic precursors. The crystalline iodide (30), known also as Eschenmoser s salt , has seen the most widespread use and is prepared by thermal fragmentation of (iodomethyl)trimethylammonium iodide or, more conveniently, by a variant of the... 

The mechanism of the Mannich reaction was for a long time subject to discussion (83-86). It is most reasonably described by an aldehyde and an amine, which form an imminium ion in a first step, which then attacks the nucleophilic center of the C—H acidic component. With primary amines, the resulting secondary amine reacts further to yield a tertiary amine. 

Coumarins are known to react with amines to give various products, for example 2,3-dihydrobenzofurans. 3-Bromocoumarin has been shown to give the benzofuran (194) on heating with piperidine but coumarin itself gave 2 -hydroxycinnamic acid amides. The behaviour of coumarin-3-carboxylic acid with amines depends on the ratio of reactants and the temperature. When 8-acetyl-7-hy(iroxy-4-methylcoumarin was subjected to a Mannich reaction, the benzodipyran (195) was formed in 80% yield.Several other tricyclic products have been prepared from coumarins for example, the... 

Various 2-oxo compounds have been subjected to a variety of reactions. Alkylation and acylation result in the formation of 1,3-disubstituted products.Similarly the Mannich reaction with morpholine gives products such as the bis compound 107. Halogenation of the 0x0 compound 108 with bromine in acetic acid," or chlorine in acetic acid, ° or with sulfuryl chloride results in formation of the monohalo derivatives 109. The chlorine atom in 109 (R = Cl) can be removed by hydrogenation over palladium on charcoal. Nitration of the chloro compound 110 with a mixture of nitric and sulfuric acids provides the nitro derivative 111, which may be catalytically reduced to the amino compound 112. If the reduction is carried out in the presence of an aldehyde, the product is a substituted amino derivative (113). Alternatively the amine 112 can be condensed with an aldehyde and the resultant Schiff base reduced to give the product 113. 

Dichloro-phenoxy acetic acid undergoes Friedal-Craft s reaction with 4-butyryl chloride to yield the corresponding 4-butyryl analogue. This is subsequently subjected to Mannich reaction with formaldehyde and dimethylamino thereby introducing the methylene group caused by thermal decomposition, yields the official compound. 

When the 1,3-indanedione 1-phenylhydrazone (89) was subjected to a double Mannich reaction using benzylamine or methylamine and formaldehyde in the presence of a small amount of acetic acid, it afforded (60-65% yield) the indano-1,2,4-triazepines (90) (Scheme 14) <90ZN(B)80>. The NMR spectra indicate that (90) existed in solution as mixtures of keto and enol tautomers. Similarly,... 

Acylhydrazones, R CH=N-NHCOR , undergo stereoselective Mannich reactions with silyl ketene acetals to give j8-hydrazido esters, using activation by a chiral silicon Lewis acid. Alternatively, the use of silyl ketene imine gives a /3-hydrazido nitrile. Enantioselective (5)-l-amino-2-methoxymethylpyrrolidine (SAMP) hydrazone alkylation of aldehydes and ketones is the subject of a computational study, providing a useful screening method for possible new candidates. " ... 

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