Enamine Robinson annelation

Robinson annelation s. Enamine Robinson annelation Rose Bengal s. under Sensitizers... 

Similarly, methyl vinyl ketone has been added to enamines derived from aldehydes (3,321,324-327) and ketones (3,328), providing a useful extension of the Robinson annelation reaetion. Condensations of enamines with other a, 3-unsaturated ketones can give a variety of diketones (329). 

Answer The cyclohexenone is a clue to a Robinson annelation disconnection reveals symmetrical amino ketone (26) as starting material (see page T 147 ior its synthesis). An enamine is again the best control. Ana lysis... 

Control is best exercised by forming the enamine of the aldehyde. The reaction goes to (16) in one step and is a Robinson annelation (p T 175 ). 

The utilization of the Robinson annellation method for the synthesis of cory-nanthe-type alkaloids has been thoroughly investigated by Kametani and coworkers (149-152). The tetracyclic ring system was efficiently formed via the Michael addition of dimethyl 3-methoxyallylidenemalonate (247) to the enamine derived from 3,4-dihydro-1 -methyl-(3-carboline (150). Alkylation of 248, followed by hydrolysis and decarboxylation, resulted in a mixture of stereosiomeric enamides 250 and 251. Hydrogenation of 250 afforded two lactams in a ratio of 2 1 in favor of the pseudo stereoisomer 253 over the normal isomer 252. On the other hand, catalytic reduction of 251 gave 254 as the sole product in nearly quantitative yield. Deprotection of 254, followed by lithium aluminum hydride reduction, yielded ( )-corynantheidol (255) with alio relative configuration of stereo centers at C-3, C-15 and C-20. Similar transformations of 252 and 253 lead to ( )-dihydrocorynantheol and ( )-hirsutinol (238), respectively, from which the latter is identical with ( )-3-epidihydrocorynantheol (149-151.). 

The reaction of A2-piperideine (115) with methyl vinyl ketone to give (124) is another example of how initial electrophilic attack on the enamine double bond can be used in heterocyclic synthesis (77ACR193). This overall process is an enamine analog of the Robinson annelation and is a useful approach to the perhydroquinoline ring system. 

Enamines Art good enol equivalent for Robinson annelation... 

X -.".e third case, cyclopentanone has self-condensed and ignored the enone to which it was to add in a conjugate fashion and continue with a Robinson annelation (p. 761). The liiis - - again is to use a specific enolate such as an enamine though the simplest here is a keto-ester can be easily prepared by intramolecular Claisen ester condensation (p. 727). 

An impressive example19 is the Robinson annelation of the unsaturated aldehyde 98 where neither aldol reaction nor double bond migration in the enamine 99 interferes. The 1,5-dicarbonyl compound 100 cyclises spontaneously to the enone 101. 

Just to make the point that chemistry has surprises even for the best informed, the rather similar Robinson annelation of dihydrocarvone 105 again using the pyrrolidine enamine 106 goes on the less substituted side 107 when one molecule of enone is used, but on the more substituted side 108 if a large excess (fivefold) of the enone is used.38 Both reactions are of course very useful but an affront to our orderly instincts we shall meet other examples where only experiment can lay down the ground rules of selectivity. 

Acetone, the component that must enolise, is present in large excess but the achievement is considerable. The reaction involves formation of the proline enamine of acetone 91 which then attacks the aldehyde through a chair-like transition state 92 held together by the acidic proton of proline s carboxylic acid. This gives the imine salt 93 hydrolysed to the product with regeneration of proline. The intermediates are like those in the Robinson annelation enamines and imines. Organic catalysis with amines relies on equilibria between these intermediates and carbonyl compounds. 

A tandem sulfide-contraction and Robinson annelation reaction was used for the synthesis of a me-sembrine analog, A -mesembrenone (133). The aryl-substituted thiobutyrolactam (130) was treated with chloromethyl vinyl ketone followed by diisopropylethylamine to afford A -mesembrenone (133) in good yield (Scheme 29). The reaction probably proceeds through initial sulfide contraction to the intermediate vinyl enaminone (131), which tautomerized to the enamine (132) and underwent intramolecular Michael closure to produce (133). 

The synthesis can be completed either by activating aldehyde (9) as an enamine and eliminating to give (10) before combining the two in a Robinson annelation (synthesis 2), or by the lazy man s method of simply using no control at all —with good results in this case (synthesis 3). 

The catalyst we will use Is the amino acid L-proline—no derivatization or protection required. It was actually back in 1971 that it was first noted that L-proline will catalyse asymmetric aldols, but until the year 2000 examples were limited to this one cyclization. Treatment of a triketone with proline leads to selective cyclization onto one of the two enantiotopic carbonyl groups. A molecule of proline must condense with the least hindered ketone, and in this case an enamine (rather than an iminium ion) can form. The chiral enamine can select to react with only one of the two other carbonyl groups, and it turns out that it chooses with rather high selectivity the one coloured green in the scheme below. Cyclization, in the manner of a Robinson annelation, and hydrolysis of the resulting iminium ion follow on, releasing the molecule of L-proline to start another catalytic cycle. The isolated product is the bicyclic ketone, in 93% ee. 

The initial version of the reaction (as illustrated by entry 1) used an in situ source of methyl vinyl ketone. The quaternary salt of 4-dimethylamino-2-butanone decomposes easily to the unsaturated ketone. In more recent procedures—for example, entries 2-4—the a,j8-unsaturated ketone is added directly. Entry 3 illustrates the use of the enamine of a ketone as the reactive nucleophile in a Robinson annelation. 

In a sequence which actually represents an anomalous Robinson annelation. Konst et al. have shown that enamines of either (134) or (136) are alkylated by MVK at the most substituted a-positions, affording bicyclic enones(135)and(137). 

The 4-(chloromethyl)isoxazole 13, which is readily accessible from 3,5-dimethyloxazole, serves as a C4-building-block in annulations to cycloalkanones (isoxazole annelation according to Stork). The primary step is alkylation leading to product 14, a masked triketone. On hydrogenation, the isoxazole ring is reductively opened and cyclization via the enaminone 15 leads to the enamine 16. On treatment with sodium hydroxide, this is converted into the bicycloenone 17 by hydrolysis, acid fission of the y dicarbonyl system and an intramolecular aldol condensation (analogous to a Robinson annu-lation) ... 

---