Robinson ring-forming reaction

A unique reaction that produces a new ring containing an ,p-unsaturated ketone is the Robinson reaction. When an enolate derived from a ketone reacts with methyl 

A further interesting and synthetically useful reaction of carbanions and of organometaUic compounds acting as sources of negative carbon is addition to the very weak electrophile CO, to form the corresponding carboxylate anion in what 

Oxidation of carbanions by molecular oxygen is also an important reaction. Equation (3.10) shows the oxidation of the anion of triphenylmethane by molecular oxygen in a solution composed of 80% DMF and 20% t-butyl alcohol. Addition of water to the reaction mixture allowed isolation of triphenylmethyl hydroperoxide in high yields (e.g., 87%). When the reaction was carried out in 80% DMSO-20% 

The triphenyhnethyl carbanion is oxidized slowly by air to give the triphenyl-methyl free radical (Eq. (3.11))  

P-Halocarbonyl compounds can be rather unstable the combination of a good leaving group and an acidic proton means that ElcB elimination is extremely easy. The rate of the reaction depends on the stability of the carbanion. The presence of 

---

The sequence that follows illustrates how a conjugate aldol addition (Michael addition) followed by a simple aldol condensation may be used to build one ring onto another. This procedure is known as the Robinson annulation (ring forming) reaction (after the English chemist Sir Robert Robinson, who won the Nobel Prize in Chemistry in 1947 for his research on naturally occurring compounds). 

The Robinson annulation is a ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction. Like the other reactions in Chapter 24, it involves enolates and it forms carbon-carbon bonds. The two starting materials for a Robinson annulation are an a,P-unsaturated carbonyl compound and an enolate. 

Robinson annulation (Section 24.9) A ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction to form a 2-cyclohexenone. 

In an aldol addition, the enolate of an aldehyde or a ketone reacts with the carbonyl carbon of a second molecule of aldehyde or ketone, forming a j8-hydroxyaldehyde or a jS-hydroxyketone. The new C—C bond forms between the a-carbon of one molecule and the carbon that formerly was the carbonyl carbon of the other molecule. The product of an aldol addition can be dehydrated to give an aldol condensation product. In a Claisen condensation, the enolate of an ester reacts with a second molecule of ester, eliminating an OR group to form a j8-keto ester. A Dieckmann condensation is an intramolecular Claisen condensation. A Robinson annulation is a ring-forming reaction in which a Michael reaction and an intramolecular aldol addition occur sequentially. 

We have seen that Michael reactions and aldol additions both form new carbon-carbon bonds. The Robinson annulation is a reaction that puts these two carbon-carbon bond-forming reactions together in order to form an a,j8-unsaturated cychc ketone. Annulation comes from annulus, Latin for ring, so an annulation reaction is a ring-forming reaction. The Robinson annulation makes it possible to synthesize many complicated organic molecules. 

A Robinson annulation is a ring-forming reaction in which a Michael reaction and an intramolecular aldol condensation occur sequentially. 

A rather nice example of enolate anion chemistry involving the Michael reaction and the aldol reaction is provided by the Robinson annulation, a ring-forming sequence used in the synthesis of steroidal systems (Latin annulus, ring). 

The Robinson annelation is by no means the only ionic reaction that makes six-membered rings. Six-membered rings form easily so trapping a Nazarov intermediate (chapter 35) makes good sense. The Friedel-Crafts-like disconnection 18 suggests a most unlikely cation 19 until we realise that it would be formed in the Nazarov cyclisation of the dienone 20 whose synthesis is discussed in the workbook. 

This sequence of reactions consists of an alkylation of a 1,3-diketone, followed by a Robinson annulation. The carbon-carbon double bond appears where the second carbonyl group of the diketone used to be and is the site of the ring-forming aldol reaction. A Michael reaction between the diketone and the Michael acceptor 3-buten-2-one adds the carbon atoms used to form the second ring, and an alkylation with CH3I adds the methyl group. 

Four ring forming transforms have been considered at length by the LHASA development group - the Diels Alder addition, the Robinson Annelation, the Simmons-Smith reaction, and iodo-lactonization. The first three of these have been fully implemented in LHASA and the fourth is completely flow charted and awaits only coding into the chemistry data base language. 

Another representative example is the preparation of (3A,5/ ,7a/ )-5-(benzotriazol-l-yl)-3-phenyl[2,l-A oxazolopyr-rolidine 238 that was synthesized from benzotriazole, (A)-phenylglycinol, and 2,5-dimethoxy-tetrahydrofuran at room temperature. This reaction entailed the formation of two heterocyclic rings and two new chiral centers in one step (Equation 33) by double Robinson-Schopf condensation of the dialdehyde with the amino group and benzotriazole intercepting the initially formed iminium ion (Equation 36) <1999JOC1979>. 

Enolate D of Figure 13.71 can undergo an aldol reaction with the C=0 double bond of the ketone. The bicyclic compound A is formed as the condensation product. It is often possible to combine the formation and the consecutive reaction of a Michael adduct in a one-pot reaction. The overall reaction then is an annulation of a cyclohexenone to an enolizable ketone. The reaction sequence of Figure 13.71 is the Robinson annulation, an extraordinarily important synthesis of six-membered rings. 

Q Predict the products of conjugate (Michael) additions, and show how to use these reactions in syntheses. Show the general mechanism of the Robinson annulation, and use it to form cyclohexenone ring systems. 

The intramolecular interaction between an enolate and a carbonyl electrophile to form a six-membered ring is a well-known and general method (e.g. the Robinson annulation, see Section 2.3.3). This and related cyclization reactions involving interactions between 1,5-dicarbonyl moieties proceeds with high selectivity (A), and the alternative option, the formation of a four-membered ring (B), is much less favorable and rarely observed (Scheme 2.108). The usefulness of this method for the preparation of compounds containing the cyclohexenone moiety is abundantly documented in the literature. 

The mechanism of the Robinson annulation consists of two parts a Michael addition to the a,p-unsaturated carbonyl compound to form a 1,5-dicarbonyl compound, followed by an intramolecular aldol reaction to form the six-membered ring. The mechanism is written out in two parts (Mechanisms 24.7 and 24.8) for Reaction [2] between methyl vinyl ketone and 2-methyl-1,3-cyclohexanedione. 

Retrosynthetic analysis of six-membered ringformation almost always boils down to a Diels-Alder reaction176) or a Robinson annelation 177) (or variations thereof) as the crucial C—C bond forming step. Both methods have in common that more than one carbon—carbon bond is formed in a one pot reaction which allows a rapid and efficient construction of complex organic molecules from rather simple building blocks. No such general tool exists for the formation of carbocyclic five-membered rings. 

The reaction is AdN2 addition to the polarized multiple bond (Adj, then p.t.). This reaction is easy to predict because the most stable product is formed under these equilibrium conditions. HSAB theory predicts that the combination of the two softest sites is favored. This conjugate addition is often called a Michael addition and forms the first step in the Robinson annotation diagramed in Figure 8.9. The later steps are an aldol addition (AdN2) to form the new ring followed by elimination by ElcB to give the bicyclic product. 

---