Aldehydes reaction with Mannich bases

Diastereoselective Mannich reaction.13 Mannich bases can be prepared by addition of a lithium dialkylamide to a nonenolizable aldehyde to form a lithium aikoxide. Trans-metallation provides a trichlorotitanium aikoxide, which reacts with a lithium enolate to form a Mannich base. 

Acdve methylene compounds ranging in acidity from -keto esters, malonates and nitroalkanes pK = 9-13) to ketones (pATa = 16-20) can be used in the Mannich reaction. The lack of examples using simple unactivated esters (p/iTa = 25) appears to be due to their weaker acidity or to transamination and/or hydrolysis side reactions. Enolizable aldehydes have also been used in certain instances however, side products arising from subsequent aldol condensation of the resulting -amino aldehyde often occur. Best results are achieved with a-branched aldehydes, which produce Mannich bases without enolizable protons. 

The Stetter procedure [22, 23] is an excellent route to 1,4-diketones. Here, cyanide anion, or more often a thiazolium ylide, catalyses the addition of an aldehyde to an a,p-unsaturated ketone or a precursor thereof, e.g. a Mannich base. For example, the reaction of pyridine-4-carbaldehyde with Mannich base 11, catalysed by the ylide from 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide 12, produces the 1,4-diketone 13, from which the central thiophene ring of 14 can be constructed (Scheme 12) [24]. Comparable thiazolium yUde catalysis... 

Sulphone syntheses based upon sulphinic acids include addition to activated alkenes, " condensation of salts RSOz Na" with Mannich bases or with an aldehyde and a urea or a thiourea in a Mannich-type reaction, and reaction with a diazoalkane benzhydryl p-tolyl sulphone is formed... 

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). 

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). 

Reactions of 6-aminouracils with various 2-substituted cyclohexanones such as the aldehyde (264) give reduced pyrimido[4,5-f ]quinolines (265) (57BRP774095, 58JA3449), and other cyclohexanone derivatives used include the 2-dimethylaminomethyl (Mannich) bases (78AP542) and the 5-benzylidenedimedones (266) formed in situ from dimedone and aldehydes (67KGS395, cf. 67KGS406). 

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. 

Mannich Reaction The reaction of a compound with a reactive hydrogen with aldehydes (non-enol forming) and ammonia or a primary or secondciry amine to form a Mannich base (ciminomethylated compound). 

Aminochromans also arise from the reaction of phenolic Mannich bases with enamines (70JHC1311). The route is attractive for a number of reasons the starting materials are readily available its scope is considerable since the enamines may be aldehyde or ketone based and the Mannich bases may be aromatic or heteroaromatic and the products themselves are precursors of hydroxychromans and 4//-chromenes. Mechanistically, the synthesis proceeds through a quinone methide followed by addition to the enamine and cyclization, which may be a concerted process (Scheme 71). 

We need a formaldehyde equivalent that is less electrophilic than formaldehyde itself and will therefore add only once to enol(ate)s. The solution is the Mannich reaction.7 Formaldehyde is combined with a secondary amine to give an iminium salt that adds 47 to the enol of the aldehyde or ketone in slightly acidic conditions to give the amino ketone (or Mannich base ) 48. If the product of the aldol reaction 50 is wanted, alkylation on nitrogen provides a good leaving group and ElcB elimination does the trick. 

Route a in Fig. 8 represents the case of modification in the substrate moiety caused by the presence of another reactive species, such as the solvent, participating in the reaction. An example of such an occurrence is afforded by aldehydes acting as substrates, which give the corresponding acetals 8 and 9 (Fig. 9) by reaction with ethanol, the solvent mainly used in Mannich synthesis. The expected Mannich base can however be obtained by further treatment of the acetal 9. - ... 

Reagents of type 251 (Fig. 94) are aldehydes or phosphoranes which, by reaction with kctonic and indolic Mannich bases, allow the production of p-diketones 252 or phosphoranes 253, respectively. In the former case, the conversion of aldehyde to ketone is thus made possible, - - and in the latter, the formation of unsaturated derivatives by subsequent reaction of the PPh3 residue with carbonyl compounds is allowed. - ... 

The prochirality of aldehydes other than formaldehyde is frequently exploited in order to obtain asymmetric Mannich bases 99A and B, as the reaction with substrate may occur from either side of the double bond plane of the aminomethylating agent (Fig. 38). 

In the reaction of butyllithium or lithium di-isopropylaminc with the Mannich bases derived from hydrogen cyanide, phosphine oxides, and phosphorous esters, as well as from phenols, jhc metal atom is prevalently bound to the CH2—N moiety (313 in big. 119, route b). This intermediate is then allowed to react with halides, epoxides, and other alkylating reagents in order to link an alkyl group to methylene. Under proper conditions, aldehydes, ketones and enamines can be prepared by this method. 

Although formaldehyde has been most common, other aldehydes have also been used successfully for the formation of iminium ion. The Mannich reaction also proceeds with the other activated hydrogen compounds such as indole, furan, pyrrole and phenols. When primary amine is used, the Mannich base formed is a secondary amine and may undergo further condensation to yield tertiary amine. The Mannich base may eliminate an amine... 

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