Mannich reaction methylene addition

As a further illustration of the reactivity of the 3 position toward electrophiles, the methoxyindole (25-1) readily undergoes Mannich reaction with formaldehyde and dimethylamine to afford the aminomethylated derivative (25-2). Treatment of that intermediate with potassium cyanide leads to the displacement of dimethylamine and the formation of the nitrile (25-3), possibly by an elimination-addition sequence involving a 3-exomethylene-indolenine intermediate. The protons on the methylene group adjacent to the nitrile are quite acidic and readily removed. Reaction of (25-3) with methyl carbonate in the presence of sodium methoxide gives the carbo-methoxylated derivative (25-4). Catalytic hydrogenation leads to reduction of the nitrile to a primary amine. There is thus obtained the antihypertensive agent indorenate (25-5) [26]. 

The classical Mannich aminomethylation is one of the most important ionic carbon-carbon bond forming reactions in organic chemistry [35]. However, only substituents with electron-withdrawing groups are suitable for the ionic addition. Electron-donating groups directly bonded to the carbon-centered radical favor nucleophilic radical addition to methylene-iminium salts. Thus, the radical-type Mannich reaction provides products which are complementary to those obtained with the classical ionic reaction. 

Tfce preferred synthetic route to these important intermediates is the Mannich reaction (Chapter 27), The compound is stored as the stable Mannich base and the unstable enone released by elimination of a tertiary amine with mild base, The same conditions are right for this elimination and for conjugate addition, Thus the aw-methylene compounds can be formed in the flask for immediate reaction with the enol(ate) nucleophile, The overall reaction from (3-amino carbonyl to 1,5-dicarbonyl appears to be a substitution but the actual mechanism involves elimination and conjugate addition,... 

Cyclic ketone with exo cyclic methylenes can be prepared in just the same way and used in situ. Morpholine is often used as a convenient secondary amine for the Mannich reaction and the resulting amino-ketones can be methylated and undergo elimination-addition reactions with stabilized enoUtes such as that derived from ethyl acetoacetate. This starting material wias prepared from natural menthone and the mixture of diastereoisomers produced is unimportant because the product is to be used in a Robinson annelation (see below). 

HCN, 193, 442 de-conjugation, 159 dehydrogenation, 189 enamine formation, 185-186 enolisation, 156 ei seq. epoxidation, 18, 201, 442 formation, 109, 189, 248, 337 hydroboration. So Mannich reaction (aminometh-ylation), 172 methylation, 168-171 methylene addition, 202 oxidation, Baeyer-VUliger, 349, 445... 

In addition to the Mannich reaction being a valuable method for preparing amino ketones,which are encountered in many drugs, the reaction is also important in organic synthesis in providing a stable equivalent of a conjugated exo-methylene moiety. Thus, addition of methyl iodide to the Mannich base converts it to the quaternary ammonium salt. Subsequent treatment with a base results in a [3-elimination of trimethylamine to generate the a-methylene ketone. 

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. 

Furthermore, this catalyst promotes asymmetric Mannich reactions [31] and Michael addition of active methylene compounds to a,p-unsaturated imides [32]. 

Explanation. The active H-atom of the methyl function in acetone, the H-atom of the secondary amine (dimethy amine) and the 0-atom of the aldehyde (formaldehyde) gets eliminated as one mole of water. Thus, the resulting aminomethylated product essentially possesses an additional methylene (—CH2—) moiety. In other words, in all Mannich reactions the carbon-chain shall be increased by one due to the —CH2— methylene function forming a part of the Mannich Base. 

Acetophenone reacts with dimethylamine hydrochloride along with one mole of formaldehyde (obtained from paraformaldehyde which is pol3rmerized formaldehyde) to 3rield the corresponding salt metamfepramone hydrochloride plus a mole of water. Most of the Mannich reactions, it is a practice to make use of the hydrochloride salt of the secondary amine, so that the reaction moves faster in the solubilized conditions and the resulting condensed product, with an additional methylene linkage (—CH2—) is also obtained as its HCL salt. 

The mechanism of thymidylate synthase in both its normal mode and when it is about to be blocked by the inhibitor involves attack of an enolate ion on an iminium cation. This process is closely analogous to the Mannich reaction discussed in Section 19.8. The enolate ion in this attack arises by ccnjugate addition of a thiol group from thymidylate synthase to the a,/3-unsaturated carbonyl group of the substrate. This process is analogous to the way an enolate intermediate occurs in a Michael addition. The iminium ion that is attacked in this process derives from the coenzyme A/, N °-methylenetet-rahydrofolate (A/ ,A/ °-methylene-THF). Attack by the enolate in this step forms the bond that oovalently links the substrate to the enzyme. It is this bond that cannot be broken when the fluorinated inhibitor is used. The mechanism of inhibition is shown at right. 

In addition, a chiral bis-thiourea was selected by Chen et al. among a series of various chiral organocatalysts to promote the enantioselective Mannich reaction of stabilised phosphorus ylides with A -Boc-protected aldimines. A subsequent reaction with formaldehyde provided a facile access to chiral A-Boc-p-amino-a-methylene carboxylic esters in good to excellent enantioselectivities of up to 96% ee (Scheme 3.19). 

The reaction between trialkylboranes and enones has found some interesting synthetic applications. An example is the preparation of prostaglandin precursors from exo-methylene cyclopentanone, generated in situ from a Mannich base. After dehydrogenation, a second conjugate addition of tri-octylborane was used to introduce the w-chain (Scheme 25) [70]. 

Treatment of the reduced intermediate (23-6) with butyl hthium leads to the anion from the removal of a proton on the methylene group reaction of that with methyl acetate affords the methyl ketone (24-1), which contains two of the three required side chain carbon atoms. The additional carbon atom and the basic function are incorporated by means of a Mannich condensation. Thus, reaction of (24-1) with A-methylpiperazine and formaldehyde leads to the aminoketone (24-2). The carbonyl group is then reduced with sodium borohydride and the resulting alcohol is dehydrated by reaction with phosphoms oxychloride in pyridine. In this case, too, the Z isomer is responsible for most of the activity. This is isolated from the resulting mixture of olefins to afford thiothixene (24-3) [25]. 

Either the tertiary amine or the quaternary ammonium salt can be stored as a stable equivalent of the exo-methylene compound. In our first example, the Mannich base with dimethylamine is first methylated with methyl iodide and then added to the conjugate addition reaction. Elimination of trimethylamine, which escapes from the refluxing ethanol as a gas, reveals the exo-methylene ketone in which the methylene group is exo to a chain. Fast conjugate addition of the stabilized enolate of diethyl malonate produces the product. 

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