Ketones Mannich addition

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

Vinyl Ketone-C=X (X=0, NR) Coupling (Reductive Aldol and Mannich Additions)... 

As mentioned in the previous sections, silyl enolates are excellent enolate components in the Mannich-type reactions with imines. Alternatively, it was found that vinyl ethers also reacted with imines smoothly in the presence of a catalytic amount of Ln(OTf)3 to afford the corresponding b-amino ketones. In addition, the reactions proceeded smoothly by the combination of aldehydes, amines, and vinyl ethers in aqueous media [55]. 

Scheme 19.71 Secondary amine-thiourea mediated Mannich addition reactions of ketones and aldehydes to preformed or in situ generated imines.

The mechanisms of the primary amine-thiourea-catalyzed Michael additions of ketones to nitroolefins [184] and of Mannich additions of ketones to A -benzoyl hydrazones [185] have been theoretically studied by Tsogoeva and co-workers. While in the first case the calculations support a transition state according to the conceptual framework of Figure 2.42, involving an enamine intermediate (Figure 2.44A), in the second one the calculations provide evidence in favor of a nonconventional enol mechanism (Figure 2.44B) [186]. 

FIGURE 2.44. Transition state models for (A) the primary amine-thiourea-catalyzed Michael additions of ketones to nitroolehns and (B) Mannich additions of ketones to A-benzoyl hydrazones. 

Mannich addition of ketones to chalcogenazines with excellent enantioselectivi-ties has been recently reported (Scheme 24.5c) [133]. The presence of an equal amount of water greatly accelerated the reaction, which was accomplished in just... 

A number of chiral catalysts originally devised for aldol reactions (see Chapter 4) have also successfully been deployed in enantioselective Mannich additions. One such example is the dinuclear zinc complex 220 developed by Trost (Equation 18) [154]. The complex is generated in situ from Et2Zn and the corresponding chiral diamino triol ligand derived from prolinol. Excellent enantio- and diastereoselectivity were obtained in reactions with a-hydroxyketones such as 218. From imine 219, the syn a-hydroxy-/l-amino ketone 221 was isolated in > 99% ee and > 15 1 dr. Additional investigations revealed that appropriate choice of the N-substituent on the imine could selectively provide either the anti or the syn a-hydroxy- -amino ketones [155]. 

In a second attempt to extend the scope of Lewis-acid catalysis of Diels-Alder reactions in water, we have used the Mannich reaction to convert a ketone-activated monodentate dienophile into a potentially chelating p-amino ketone. The Mannich reaction seemed ideally suited for the purpose of introducing a second coordination site on a temporary basis. This reaction adds a strongly Lewis-basic amino functionality on a position p to the ketone. Moreover, the Mannich reaction is usually a reversible process, which should allow removal of the auxiliary after the reaction. Furthermore, the reaction is compatible with the use of an aqueous medium. Some Mannich reactions have even been reported to benefit from the use of water ". Finally, Lewis-acid catalysis of Mannich-type reactions in mixtures of organic solvents and water has been reported ". Hence, if both addition of the auxiliary and the subsequent Diels-Alder reaction benefit from Lewis-acid catalysis, the possibility arises of merging these steps into a one-pot procedure. 

Other modifications of the polyamines include limited addition of alkylene oxide to yield the corresponding hydroxyalkyl derivatives (225) and cyanoethylation of DETA or TETA, usuaHy by reaction with acrylonitrile [107-13-1/, to give derivatives providing longer pot Hfe and better wetting of glass (226). Also included are ketimines, made by the reaction of EDA with acetone for example. These derivatives can also be hydrogenated, as in the case of the equimolar adducts of DETA and methyl isobutyl ketone [108-10-1] or methyl isoamyl ketone [110-12-3] (221 or used as is to provide moisture cure performance. Mannich bases prepared from a phenol, formaldehyde and a polyamine are also used, such as the hardener prepared from cresol, DETA, and formaldehyde (228). Other modifications of polyamines for use as epoxy hardeners include reaction with aldehydes (229), epoxidized fatty nitriles (230), aromatic monoisocyanates (231), or propylene sulfide [1072-43-1] (232). 

Addition of ( )-enamines 3, derived from aldehydes and ketones, to various benzylideneimini-um salts 2 has been investigated. The reaction exclusively gives the Mannich bases anti-4 in good to excellent yield (72-94%). Therefore, this method provides an efficient and highly stereoselective route to /i-amino ketones and aldehydes1415. 

Addition of enantiomerically pure cnamines derived from (.Y -jmethoxymethyfipyrrolidine (SMP) and ketones (cyclohexanone, cycloheptanone, propiophenone) to AGY-dimethylmethylene-iminium tetrachloroaluminate11,42 give the corresponding Mannich bases in moderate to good yields (56 -79%) and low to moderate enantioselectivities (30-66% ce)12, l3. The (-)-isomer is the major enantiomer in each case. The absolute configuration of the major enantiomer has not been determined. The auxiliary can be recovered. 

The addition product of ethyl acetoacetate and methyl a-methoxyacrylate was hydrolyzed, and the resulting dicarboxylic acid was treated with dimethylamine hydrochloride and aqueous formaldehyde. The product of the Mannich reaction was decarboxylated, reesterifed, and finally treated with methyl iodide to supply quaternary salt 469 as the main product. During the above one-pot process, elimination also took place, yielding unsaturated ketone 470, which was later utilized as its hydrogen bromide adduct 471. Reaction of 3,4-dihydro- 3-car-boline either with 469 or 471 furnished the desired indolo[2,3-a]quinolizine derivative 467 as a mixture of two diastereomeric racemates. 

The reaction of different substituted hydrazines (or hydroxylamines) with the a,/3-unsaturated ketones 210 gives pyrazolines 211 (or isoxazolines 212), as the result of a Michael addition reaction followed by an intramolecular Mannich reaction (Scheme 12) <2001FAR32>. 

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

These a,/l-unsaturated ketones and aldehydes are used as reactants in Michael additions (Section 1.10) and Robinson annulations (Section 2.1.4), as well as in a number of other reactions that we will encounter later. Entries 8 and 9 in Scheme 2.11 illustrate Michael reactions carried out by in situ generation of a,/ -unsaturated carbonyl compounds from Mannich bases. 

Dixon reported that saturated BINOL 45 sufficiently activates various N-Boc aryl imines toward Mannich reaction with acetophenone-derived enamines to yield P-amrno aryl ketones in good yields and enantioselectivities (Scheme 5.62) [116]. The same group applied a BINOL-derived tetraol catalyst to the addition of meth-yleneaminopyrroHdine to N-Boc aryl imines. Interestingly, appendage of two extra diarymethanol groups to the BINOL scaffold resulted in a marked increase in enantiomeric excess [117]. 

Mannich Reaction This reaction takes place between an amine, an aldehyde (or ketone) and a highly nucleophilic carbon atom. The reaction is the addition of a nucleophilic carbon to an imonium ion intermediate. 

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