Mannich reactions, conversion

An important method for construction of functionalized 3-alkyl substituents involves introduction of a nucleophilic carbon synthon by displacement of an a-substituent. This corresponds to formation of a benzylic bond but the ability of the indole ring to act as an electron donor strongly influences the reaction pattern. Under many conditions displacement takes place by an elimination-addition sequence[l]. Substituents that are normally poor leaving groups, e.g. alkoxy or dialkylamino, exhibit a convenient level of reactivity. Conversely, the 3-(halomethyl)indoles are too reactive to be synthetically useful unless stabilized by a ring EW substituent. 3-(Dimethylaminomethyl)indoles (gramine derivatives) prepared by Mannich reactions or the derived quaternary salts are often the preferred starting material for the nucleophilic substitution reactions. 

Conversion of Graft Polyacrylamide to Amines via the Hofmann and Mannich Reactions... 

NaOH/10% NaCl solution. After 24 hours, the capacity had fallen to 0.44 meq/g (82% loss) and after twelve days no capacity remained. The conversion of PAM grafts to useful anion exchangers clearly requires a much more inert linkage than that introduced by the Mannich reaction. 

After the initially performed aldol condensations and the process optimisation, the scope of the reaction was further extended to an enantiomeric Mannich reaction. The authors started from A-PMP-protected ot-imino ethyl glyoxylate and cyclohexanone in the presence of 5% catalyst loading. In 10 min at 60°C, the conversions were complete and the p-aminoketone was obtained in 91% yield and >95% ee after purification on column. 

The quaternary salts produced by the Mannich reaction undergo a number of conversions useful in synthesis. For example, although stable at room temperature they eliminate an amine hydrochloride on heating to yield an a,/J unsaturated ketone (e.g. the conversion of dimethylaminopropiophenone to phenyl vinyl ketone, Expt 6.147). 

Regardless of how it does take place, the fact that this addition is irreversible certainly imparts a clear advantage. In the classical Mannich, the reversibility of the final step limits the number of cases where the yields are synthetically useful. By comparison, the Boronic Acid Mannich Reaction permits a much broader scope of conversions to be carried out. 

Enantioselective silver-catalyzed aza-Diels-Alder reactions have also been described. Whereas the use of BINAP as the chiral ligand gave only unsatisfactory enantioselectivities,367,367a Hoveyda etal 6 used the peptidic phosphine 373 which has already been used for silver-catalyzed asymmetric Mannich reactions (see Scheme 108) in the efficient Ag(i)-catalyzed cycloaddition of arylimines 449 with Danishefsky s diene (Scheme 135). After acidic work-up, the chiral pyridones 450 were obtained with excellent yields and enantioselectivities. The presence of isopropanol as a proton source is essential for obtaining high conversions and stereoselectivities. Similar to the Mannich reactions, the cycloaddition is not affected by the presence of air or the use of undistilled THF. 

Deng and Overman employed the aza-Cope-Mannich reaction in the enantios-elective total synthesis of (+)-preussin (21), a potent antifungal agent possessing a pyrrolidine skeleton8 (Scheme 1.6h). Conversion of the amino alcohol 22 to the oxazolidine derivative 23 was readily accomplished by reacting with decanal in hot benzene with removal of water using a Dean-Stark trap. Treatment of... 

Intramolecular Mannich reactions have also been used in the synthesis of piperidines. An intramolecular Mannich reaction was applied as the key step in the synthesis of the piperidine A ring of cylindrospermopsin <07SL1446> and in the high yielding diastereoselective conversion of 3-amino acids to 2,6-yy -disubstituted piperidinones <07JOC10287>. 

Gall, M Kamdar, B. V., Lipton, M. F Chi-dester, C. G., and DuChamp, D. J., Mannich reactions of heterocycle,s with dimeth-yI(mcthylene)ammonium chloride A high yield, one-step conversion of estazolam to ad-inazolam, J. Heterocycl. Chem., 25, 1649,... 

Recovery of industrial by-products—Mannich reactions may help in the conversion of process by-products or residues into more valuable materials, as is evidenced in the cellulose industry, where the recovery of Ca-lignin sulfonate involves employing the aminomethylation reaction to give the Mannich bases of lignin (482 in Chap. IV and 579 in Sec. A.2), which are then used for various applications. ... 

Benzimidazoles, benzimidazolinones and benzimidazolinethiones react with formaldehyde and secondary amines in a Mannich reaction to form AC-aminomethyl derivatives. The conversion of benzimidazoles into l-(2-hydroxyethyl) derivatives with ethylene oxide is well known. 

A number of years ago Armesto and his colleagues reported the photochemical Mannich reactions of the dienes (92) in the presence of perchloric acid. This reaction brought about conversion into the isoquinolinones (93) efficiently via the photocyclization of the protonated species (94). The mechanism for the transformation was proposed to involve an intramolecular SET process as a key event in the reaction. The present report gives details of quantum yield measurements on a series of derivatives that support this mechanistic postulate. Kojima and coworkers have studied the dicyanobenzene-sensitized reactions of the dienes (95) and (96) in acetonitrile/water/ammonia systems. Products (97) and (98) are... 

A phase-transfer-catalyzed direct Mannich reaction of glycinate Schiff base 5 with a-itnino ester 78 was achieved with high enantioselectivity by the use of N-spiro chiral quaternary ammonium bromide 9e as catalyst (Scheme 11.21) [62]. This method enabled the catalyhc asymmetric synthesis of differentiatly protected 3-aminoaspartate, a nitrogen analogue of dialkyl tartrate, the utility of which was demonstrated by the conversion of product (sy -79) into a precursor (80) of strep-tohdine lactam. 

Conversely if the target is a vinyl ketone, then the aldol disconnection removes only one carbon atom - not much of a simplification Even so, the aldol and its modifications such as the Mannich reaction are often used for such syntheses. An extreme example comes in Corey s synthesis of antheridic acid5 where an aldol disconnection of an advanced intermediate 21 removes just one carbon atom but makes the remainder 22 of this complex molecule much easier to synthesise. 

The loss of acetaldehyde from voacristine (143) when it was heated in acetic acid may well proceed by way of (144), produced by a reverse Mannich reaction cf. Scheme 28) note that (144) is an intermediate of the type necessary for the conversion of an iboga type into (132) by an ionic route. 4,20-Dehydro voacangine (145) was also produced in this reaction. 

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