Robinson-Mannich base

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... 

Robinson-Mannich base procedure— Ring closure with ester hydrolysis and... 

Cyclohexenone ring from -aminoketones Robinson-Mannich base procedure Ring closure... 

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. 

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 forward synthetic sequence would therefore involve the Michael reaction of 2-methylcyclopentane-l,3-dione with methyl vinyl ketone to give (20), followed by cyclisation to the hydroxyketone (19), and then dehydration to the target molecule (13a). The overall process of addition and cyclisation is known as the Robinson annelation reaction.3 In this preparative example (Expt 7.6) the methyl vinyl ketone is used directly under conditions which minimise its polymerisation 48 it should be noted, however, that many literature examples of the annelation reaction use Mannich bases or the corresponding methiodides as an in situ source of the a, /J-unsaturated carbonyl component (see Section 5.18.2, p. 801). 

A more common method of ensuring that the conjugate addition step is free from side-reactions is to use the method Robinson himself invented—replace the enone by the Mannich base or Mannich salt as we have discussed already in this chapter. This ensures that the enone need have only a very short lifetime in the reaction mixture. 

Steroid synthesis. In developing a method of cyclization which has been of immeasurable -walue in the total synthesis of steroids, Robinson at first experimented with the condensation of ketones with methyl vinyl ketone itself, but encountered difficulties associated with the tendency of the ketone to polymerize. He then turned to possible prectnsors and met with some success with methyl /3-chloroacetyl ketone, CHsCOCHzCH CI. Still better, however, was the methiodide (2) of the Mannich base (1), l-diethylamino-3-butanone. Treated with a strong base such as sodamide in... 

In preparation for a Robinson annelation, it is often advantageous to increase the reactivity of the position adjacent to the carbonyl group by introduction of a substituent that can later be removed. Thus Turner et al." found direct condensation of 7-methoxy-l-tetralone (1) with methyl vinyl ketone or the corresponding Mannich base to show little promise. They then converted (1) into the 2-hydroxymethylene... 

A different approach to the problem of morphine synthesis was made by Ghosh and Robinson [41], who built up the hydrogenated-phenan-threne nucleus from a /3-tetralone by the now familiar addition of a Mannich base mothiodide. The tetralono [oxxxv, R = Cl] was con-... 

Annelation. The Robinson annelation of (—)-dihydrocarvone (1) to give the ketol (2) was originally carried out using the Mannich base 1 -diethylamino-3-pentanone methiodide and sodamide in ether-pyridine.3 Halsall1 improved the... 

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. 

Officially, the history of MCRs dates back to the year 1850, with the introduction of the Strecker reaction (S-3CR) describing the formation of a-aminocyanides from ammonia, carbonyl compounds, and hydrogen cyanide [4]. In 1882, the reaction progressed to the Hantzsch synthesis (H-4CR) of 1,4-dihydropyridines by the reaction of amines, aldehydes, and 1,3-dicarbonyl compounds [5], Some 25 years later, in 1917, Robinson achieved the total synthesis of the alkaloid tropinone by using a three-component strategy based on Mannich-type reactions (M-3CR) [6]. In fact, this was the earliest application of MCRs in natural product synthesis [7]. 

Strategies based on two consecutive specific reactions or the so-called "tandem methodologies" very useful for the synthesis of polycyclic compounds. Classical examples of such a strategy are the "Robinson annulation" which involves the "tandem Michael/aldol condensation" [32] and the "tandem cyclobutene electrocyclic opening/Diels-Alder addition" [33] so useful in the synthesis of steroids. To cite a few new methodologies developed more recently we may refer to the stereoselective "tandem Mannich/Michael reaction" for the synthesis of piperidine alkaloids [34], the "tandem cycloaddition/radical cyclisation" [35] which allows a quick assembly of a variety of ring systems in a completely intramolecular manner or the "tandem anionic cyclisation approach" of polycarbocyclic compounds [36]. 

There is nothing new in reactions occurring in many steps all in the same pot. The Robinson annelation is a classic where conjugate addition and intramolecular aldol reactions follow each other without as break. An extreme example would be the reaction of a Mannich salt 5 with the 1,3-diketone 6 to give the enone 7 on treatment with base... 

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