Unsaturated from Mannich bases

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. 

The elimination reaction can be followed only for pH > (pKvm — 2). The rate of the side reaction of the a,(i-unsaturated ketone increases with increasing pH and for phenylvinyl ketone becomes of importance at pH values above about 9. To study the elimination process unaffected by the hydration of the a,[3-unsaturated ketone generated, it was necessary to find a Mannich base the elimination of which would take place at pH << 9, i.e. with a.pKjtB 9. 3-Morpholinopropiophenone proved to be a suitable model (27) this compound has a pK B value of 6.8, so that constants ke and kaa at pH < 9 can be quantitatively evaluated without any effect from cleavage of the a,(3-unsaturated ketone. The validity of the kinetic equations corresponding to scheme (13) was proved both for the elimination of p-aminoketones (27) and for the addition of primary and secondary amines to a, (3-unsaturated ketones (28). 

Pyrazolines may be obtained readily from a,j3-unsaturated aldehydes or ketones and aliphatic diazo compounds.44,349 Convenient syntheses have been worked out using Mannich bases,488-494 by the cyclization of aldehydo- and keto-azines.495-499 The conversion of a number of 4- and 5-substituted pyrazolines to the corresponding pyrazoles by frams-elimination was noted above. The 4-amino-pyrazolines with the appropriate configuration (41) readily eliminate... 

The Mannich reaction of an aldehyde enol (example Formula C in Figure 12.14) or a ketonic enol (example Formula C in Figure 12.15) often proceeds beyond the hydrochloride of a /l-aminocarbonyl compound or the Mannich base. The reason is that the secondary amine or its hydrochloride, which has previously been incorporated as part of the iminium ion, is relatively easy to eliminate from these two types of product. The elimination product is an a,fi-unsaturated aldehyde (example Formula E in Figure 12.14) or an a,/l-unsaturated ketone (example Formula D in Figure 12.15)—that is, an a,/l-unsaturated carbowyl compound. Figure 13.51 will show how the Mannich reaction of a carboxylated lactonic enol provides access to an a-methylene lactone, that is, an a,/l-unsaturated carboxyl compound. 

The hydrogenolysis product of the Mannich base is also obtained through the formation of a suitable intermediate, in some cases not isolated or purified, which is subsequently subjected to hydrogenation. This may be an unsaturated derivative (R=CH2) produced by deamination of Mannich base, - - or the R—CH2—X (X = 0-Acyl or S-Alkyl -) product deriving from amino group replacement. 

Deamination is the most commonly performed reaction of steroid Mannich bases. It is usually carried out by heating the base in the presence of acetic acid/acctic anhydride, - by column chromatography on silica gel, by heat decomposition of the corresponding hydrochloride or iodomethylate, or under suitably modified reaction conditions leading directly to the unsaturated final pnxluct starting from the usual Mannich reactants (Chap. II, A.2). 

When the unsaturated substrate is an acetylene derivative, furans - or benzo-furans- may be produced. For instance, 2-aminoethyl-benzofuran 190 (Fig. 67) is obtained at pH 7 from the acetylenic alcohol 189 instead of the expected Mannich base, which is produced at a higher pH value. 

In a manner similar to that indicated in Table 23, the unsaturated products 245 can be directly obtained from Mannich synthesis, or by allowing the prepared base to react, or by converting the Mannich base into the corresponding, more reactive io-domethyl derivative. - ... 

In the benzoin condensation, one molecule of aldehyde serves as an electrophile. If a carbanion is generated from protected cyanohydrins, a-aminonitriles or dithioacetals, it can react with electrophiles such as alkyl halides, strongly activated aryl halides or alkyl tosylates to form ketones. Amongst other electrophiles which are attacked by the above carbanions are heterocyclic A -oxides, carbonyl compounds, a,p-unsaturated carbonyl compounds, a,3-unsaturated nitriles, acyl halides, Mannich bases, epoxides and chlorotiimethyl derivatives of silicon, germanium and tin. 

Hence the rate of the elimination reaction can be determined either from the decrease in Mannich base concentration or from the increase in concentration of the a,j8-imsaturated ketone. Because the wave of the unsaturated ketone was at more positive potentials, it was possible to measure it with a greater accuracy and, if not otherwise stated, the measurement of this wave was preferred. Moreover the time-change of this wave indicated the presence of consecutive reactions. 

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. 

Quaternary Mannich bases react like, / -unsaturated ketones under the conditions of a Michael addition. The vinyl ketone is formed from the Mannich base in a sufficiently reactive state to add to simple ketones under the influence of sodamide and not to require the usual 1,3-dicarbonyl compound then ring closure follows immediately ... 

The Robinson annulation is the reaction of alkali metal derivatives of cyclohexanones with a-,p>unsaturated methyl ketones to produce cycloketones and polycycloketones. The standard method for Robinson annulation is exemplified in the mechanism shown above. For the synthesis of the 1,5-diketone side chain, the enolate nucleophile reacts with a Michael acceptor this Michael acceptor is usually a substituted vinyl ketone or the parent methyl vinyl ketone (MVK), although the latter gives low yield due to its propensity to polymerize under the standard reaction conditions. To overcome the drawbacks for using MVK, Robinson, McQuillin and Du Feu introduced the Robinson-Mannich variation of the annulation reaction. This modification uses a quatemized Mannich base formed from the vinyl entity the Maimich base is made in situ and acts as a methyl vinyl ketone precursor after it is converted to its methiodides. The formed methiodides of the Mannich adduct 4-(trimethylamino-2-butanone) is condensed with sodioderivatives of ketones or with the parent ketone in the presence of sodium ethoxide. 

Preparation of vinyl ketones via a Mannich reaction overcomes many of the drawbacks of the procedures described above. The a,p-unsaturated ketones are obtained in high yields under mild conditions from readily available starting materials (Table 7). Thus this is the best technique for laboratory preparation [333]. The Mannich base, which is formed by heating equimolar quantities of ketone, formaline, and diethylamine hydrochloride for Ih at 95 °C, is isolated and pyrolyzed at 150 to 210 °C under reduced pressure. The a,p-unsaturated ketone is distilled from the reaction mixture the... 

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... 

Another approach to 1,4-dicarbonyl products is also quite versatile and powerful. It involves the conjugate addition of a carbonyl anion equivalent derived from an aldehyde to an a,p-unsaturated carbonyl compound, using either cyanide or thiazolium ion catalysis (Stetter reaction). In the scheme shown (Scheme 14), it is also possible to have R3 = H, by using vinyl ketones or their Mannich base equivalents (225). 

Deprotonation of 379,381 and 383 can be accomplished with EtONa in ethanol, NaH in toluene or DMF, or with tetramethylguanidine in dichloromethane. Alkyl/benzyl bromides are usually employed as alkylation agents chlorides and iodides are less commonly used. In a few cases Mannich bases have been used ". Also, Michael additions using a,)3-unsaturated carbonyl compounds and esters are feasible, as documented with the synthesis of (7 /S)-[2- C]homoserine (from acrolein) and [2- C]- and glutamic acid (from... 

Methylthiocoumarin has been prepared by treating thiophenol with diketen followed by cyclization of the resulting thiol ester with polyphos-phoric acid. 4-Hydroxythiocoumarins undergo Michael additions with a/3-unsaturated ketones, and also form Mannich bases (64), from which the pyranothiocoumarin derivative (65) has been prepared. ... 

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