Subject Mannich

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. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

Figure 1.11 Tyrosine residues are subject to nucleophilic and electrophilic reactions. The unprotonated phe-nolate ion may be alkylated or acylated using a variety of bioconjugate reagents. Its aromatic ring also may undergo electrophilic addition using diazonium chemistry or Mannich condensation, or be halogenated with radioactive isotopes such as 12iI.

Katritzky offers a general one-pot alternative approach to polysubstituted pyrroles utilizing disubstituted olefins of which a wider variety is commercially available compared to acetylenes . Thus, thioamides 32 were subjected to Mannich condensation with aldehydes and BtH to yield functionalized thioamides 33 which were then treated with base... 

The potential utility of the Mannich-type phenolic bases makes the aminoalkyla-tion reaction of naphthol derivatives a subject of current chemical interest. But, because of the relatively low reactivity of 1-naphthol, the reaction gave only a moderate yield and displayed moderate diastereoselectivity [5]. 

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... 

Oxindole 89 was cleanly demethylated upon treatment with boron tribromide. The resulting oxindole 90 was subjected to the prenylation conditions, and the desired alkylated product 91 was obtained in 52% yield. The epoxidation/Lewis acid-mediated cyclization proved to be successful on this substrate. The epoxide product was directly treated with SnCl4 in THF to provided the desired 92. When oxindole 92 was treated with NaBHt (1.6 equivjand BF3 OEt2 (3.5 equiv) in THF, the desired 93 was obtained. The indole 93 was treated with TBDMSC1 and imidazole in DMF, to provide the required O-silylated indole, which was easily converted to the gramine 94 through the well known Mannich procedure. 

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. 

Similar applications of acetylene chemistry appear equally promising, but have been less intensively studied. In an early contribution to this subject, Islam and Raphael observed that the product of sequential acetylation and Mannich chain extension of cyclopentylethynyl alcohol did undergo cyclization when heated in a mixture of formic and phosphoric acids, although in low yield (7 %).49 Greater... 

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. 

The amidomethylation reaction is suitable for the same purpose, as NH atnide.s, whieh are well-known substrates of Mannich synthesis, can also behave like amine reagents. Thus, the resultant amidomethyl derivative 21 (Fig. 15) can be then subjected to hydrolysis by means of hydrazine to give the primary amine product. - By this method the 6-aminomethyl indole derivative 22 has been obtained. ... 

Compounds of lype 27 and analogous derivaiives such as sulfonamides are frequently used in condensation reactions (defined as amidomcthylations) with formaldehyde and substrates of the same type as those subjected to Mannich synthesis. Yet. the products obtained cannot be strictly considered as Mannich bases, due to their negligible basicity. 

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. 

Substrates containing all the three reactive moieties of Mannich synthesis, that is, substrate, amine, and aldehyde, such as 161 (Fig. 56) also have been subjected to cy-clization. - Two carbonyl functions are present in these molecules, which may produce intramolecular aminoalkylation. 

The Mannich bases subjected to the replacement reaction arc usually derivatives of alkyl ketones, phenols, and ferrocene. 

A very wide range of Mannich bases can be subjected to replacement reaction with —SH derivatives, including ketobases producing optically active y-ketosulfides [275, R = PhCO-CH(Me) , when the reaction is carried out in the presence of catalytic amounts of chiral amine of the cinchonidinc type. ... 

The hydrogenolysis product of the Mannich base is also obtained through the formation of a suitable intermediate, in some cases not isolated or purified, which is subsequently subjected to hydrogenation. This may be an unsaturated derivative (R=CH2) produced by deamination of Mannich base, - - or the R—CH2—X (X = 0-Acyl or S-Alkyl -) product deriving from amino group replacement. 

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." ... 

A variety of specific reactions are performed on polymeric amidic Mannich bases for instance, poly(maleimide), after aminomclhylation with aromatic amine, is subjected to a coupling reaction with a diazo derivative in order to obtain azo dyes, grafted onto the polymeric chain 439, which arc able to give colored chelates." ... 

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. 

II can be observed that a fair variety of classes of substrates is represented in the table. In addition to the most frequently employed alkyl ketones, particularly cycloalkyl ketones, quinonic, phenolic, and alkync subsn-ates have been subjected to Mannich... 

Steroidal aminomethyl derivatives have been subjected to some of the reactions typical of Mannich bases, described in Chap. II, usually with the aim of introducing structural modifications of the molecule by means, in particular, of deamination and hydrogen-olysis. The formation of a quaternary ammonium salt (mainly iodomethylatc) by N-alkylation of the base - is also performed to the same end in order to obtain unsaturated deaminated products. ... 

C-Mannich derivatives of uridine 467 and thymidine s or N-Mannich bases of cy-tidinc iododcrivatives arc yielded from nucleosides subjected to aminomethyla-(X = 0. NAIkyl) iof, presence of the glycoside moiety may favor the reaction at C-5 (arrow in 468) through the formation of a polycyclic structure bearing an electron-attracting group inserted at the adjacent position, C-6. ... 

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. 

Cyclic N-nitro-derivatives starting from hexamethylenetetraamine are similarly obtained. Acyclic Mannich ba.ses of methylmercaptan have also been subjected to nitration. - ... 

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