Syntheses Mannich bases

Von Strandtman, M., Cohen, M. P., Puch-alski, C., and Shavel J.. Jr., Reaction of phos-phoranes with Mannich bases. Synthesis of a-substituted-P-arylacrylic acids via the Wittig reaction, J. Org. Chem., 33, 4306, 1968. 

Tramontini, M. 1973. Advances in the chemistry of Mannich bases. Synthesis 703-775. 

Diinethoi iisphthaleiie (I) is reduced with sodium and alcohol to the ketone (II), methylated with methyl iodide, and then subjected to the Robinson-Mannich base synthesis yielding the phenanthrene derivative (III). Demethylation, reduction of the a,j3-unsaturated ketone system, and partial acetylation produces IV, which is then hydrogenated under... 

Messinger P, Kusuma K. Alkylation of active methylene group of sulfones with Mannich-bases. Synthesis 1980 (7) 565-566. 

Synthesis Though we could follow the stepwise pattern of the disconnections, it is easier to add an activating group to the acetone molecule so that our starting materials are two molecules of acetoaeetate and formaldehyde. It turns out that Hagemann s ester can be made in two steps without having to alkylate the Mannich base ... 

Chloral forms well-crystallized adducts (126) with diaziridines containing at least one NH group (B-67MI50800). Carbonyl addition products to formaldehyde or cyclohexanone were also described. Mixtures of aldehydes and ammonia react with unsubstituted diaziridines with formation of a triazolidine ring (128). Fused diaziridines like (128) are always obtained in ring synthesis of diaziridines (127) from aldehyde, ammonia and chloramine. The existence of three stereoisomers of compounds (128) was demonstrated (76JOC3221). Diaziridines form Mannich bases with morpholine and formaldehyde (64JMC626), e.g. (129). 

The synthesis of a large number of y-pyrones and y-pyranols from enamines has been brought about through the use of a wide variety of bifunctional molecules. These molecules include phenolic aldehydes (126,127), phenolic Mannich bases (128), ketal esters (129), and diketene (120-132). All of these molecules have an electrophilic carbonyl group and a nucleophilic oxygen center in relative 1,4 positions. This is illustrated by the reaction between salicylaldehyde (101) and the morpholine enamine of cyclohexanone to give pyranol 102 in a quantitative yield (127). 

The condensation reaction of a CH-acidic compound—e.g. a ketone 3—with formaldehyde 1 and ammonia 2 is called the Mannich reaction, the reaction products 4 are called Mannich bases. The latter are versatile building blocks in organic synthesis, and of particular importance in natural products synthesis. 

Because of their manifold reactivity, Mannich bases 4 are useful intermediates in organic synthesis. For example the elimination of amine leads to formation of an o ,/3-unsaturated carbonyl compound 8 ... 

The reaction of enamines with iminium salts provides an alternative route to Mannich bases which are an attractive class of compounds, since they have found many applications (synthesis of drugs, pesticides, synthetic building blocks, etc.). This methodology has several basic advantages compared to the classic aminomethylation procedure15-18-24 ... 

Myers, T.C., Harvey, R.G., and Jensen, E.V., Phosphonic acids. II. Synthesis of y-ketophosphonic acids from methyl ketones via Mannich bases, /. Am. Chem. Soc., 77, 3101, 1955. 

The key step of the synthesis, which involved a classical Mannich condensation in the synthesis by Evans and Scott (as well as in the biogenesis of alkaloids in general [10]), is substituted by a 1,3-dipolar cycloaddition of a nitrone to a carbon-carbon double bond [11] which provides an alternative route for the formation of a new C(l)-C(2) bond with the concomitant creation of a 1,3-consonant relationship between an oxygen atom and a dialkylamino group. In order to arrive at a typical Mannich base two more steps are, however, necessary. The similarity between the two processes is shown is Scheme 13.2.7 ... 

A method of synthesis which has been used generally in this series employed a Fischer reaction at an early stage to form the tetrahydrocarbazolone nucleus [59] (Scheme 7.2). We devised a second route employing the Fischer method in which the key intermediate was the cyclohexenone (22) (Scheme 7.3). This was readily prepared by treating the enolate of the methyl enol ether (21) with dimethyl(methylene)ammonium iodide [60] to form the Mannich base which was then condensed with 2-methylimidazole to give (22). 

Mannich bases derived from polynitroalkanes are usually unstable because of the facile reverse reaction leading to stabilized nitronate anions. The nitration of Mannich bases to nitramines enhances their stability by reducing the electron density on the amine nitrogen through delocalization with the nitro group. The nitration of Mannich bases has been exploited for the synthesis of numerous explosives, some containing both C-NO2 and N-NO2 functionality. Three such compounds, (163), (164) and (165), are illustrated below and others are discussed in Section 6.10. 

The condensation between an aldehyde, an amine and an active methylene compound, named after Carl Mannich, was first published in 1912 [4]. The products of the reaction, a-amino ketones or Mannich bases are important compounds with numerous applications in the synthesis of pharmaceuticals and of natural products [7]. 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

A Mannich reaction is the reaction of formaldehyde with a primary or secondary amine and a compound with an active hydrogen atom. The product, an amine with a y-carbonyl, is called a Mannich base, useful in a number of synthesis reactions. An example is in Figure 15-23, and the mechanism is in Figure 15-24. 

A very versatile tool for the synthesis of monomeric aza[60]fullerene derivatives 32 is the Mannich fimctionalization (Scheme 12.11), where 2 is typically treated in ODCB with an excess of the carbonyl compoimd and 40 equiv. TsOH at 150 °C in a constant stream of O2 [21, 22, 26]. After 15 min the conversion is usually completed and the Mannich bases are formed in good yield and complete regioselectivity. 

The products of the Mannich reaction (Mannich bases) are useful intermediate on organic synthesis e.g. 

M. Tramontini, Synthesis 1973, 703-775 . .Advances in the Chemistry of Mannich Bases". 

After the successful asymmetric synthesis of a-substituted P-amino ketones (R)-14, we envisaged the diastereo- and enantioselective synthesis of a,P-disubstituted Mannich bases. As shown in Scheme 1.1.4, we were able to use benzaldehyde-N-phenylimine [11] as well as a-alkoxycarbonylaminosulfones [12] as Mannich electrophiles to synthesize in good overall yields and high de- and ee-values the anti-configured P-amino ketones (R,S)-15 and (R,S)-16, respectively [13]. 

Scheme 1.1.4 Asymmetric synthesis of tmti-configured Mannich bases.

The nature of the aromatic substituents is apparently not critical for SSRI activity, as indicated by the structure of duloxetine (23-5), where one ring is replaced by thiophene and the other by naphthalene. The synthesis starts as above by the formation of the Mannich base (23-1) from 1-acetyl thiophene with formaldehyde and dimethyl-amine. Treatment of that intermediate with the complex from lithium aluminum hydride and the 2R,3S entantiomer of dimethylamino-l,2-diphenyl-3-methyl-butane-2-ol gives the S isomer (23-2) in high enantiomeric excess. Treatment of the aUcoxide from (23-2) and sodium hydride with 1-fluoronaphthalene leads to the displacement of halogen and thus the formation of ether (23-2). The surplus methyl group is then removed by yet another variant of the von Braun reaction that avoids the use of a base for saponifying the intermediate urethane. Thus, reaction of (23-3) with trichloroethyl formate leads to the A -demethylated chlorinated urethane (23-4). Treatment of that intermediate with zinc leads to a loss of the carbamate and the formation of the free secondary amine duloxetine (23-5) [23]. 

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