Annulation reaction Robinson

Davis and co-workers have carried out the first examples of the Knoevenagel condensation and Robinson annulation reactions [61] in the ionic liquid [HMIM][PFg] (HMIM = l-hexyl-3-methylimidazolium) (Scheme 5.1-33). The Knoevenagel condensation involved the treatment of propane-1,3-dinitrile with a base (glycine) to generate an anion. This anion added to benzaldehyde and, after loss of a water molecule, gave l,l-dicyano-2-phenylethene. The product was separated from the ionic liquid by extraction with toluene. 

Carbonyl condensation reactions are perhaps the most versatile methods available for synthesizing complex molecules. By putting a few fundamental reactions together in the proper sequence, some remarkably useful transformations can be carried out. One such example is the Robinson annulation reaction for tire synthesis of polycyclic molecules. The word annulation comes from the Latin annulus, meaning "ring," so an annulation reaction builds a new ring onto a molecule. 

Figure 23.9 This Robinson annulation reaction is used in the commercial synthesis of the steroid hormone estrone. The nucleophilic donor is a /3-diketone.

Problem 23.21 What product would you expect from a Robinson annulation reaction of 2-methyl-1,3-cyclopentanedioiie with 3-buten-2-one ... 

Problem 23.22 How would you prepare the following compound using a Robinson annulation reaction between a jS-diketone and an, /3-unsaturated ketone Draw the structures of both reactants and the intermediate Michael addition product. 

The following molecule was formed by a Robinson annulation reaction. What reactants were used ... 

Robinson annulation reaction (Section 23.12) A synthesis of cyclohexenones by sequential Michael reaction and intramolecular aldol reaction. 

Michael reaction, 894-895 acceptors in, 895 donors in, 895 mechanism of. 894-895 Robinson annulation reactions and, 899-900... 

Scheme 2.11 shows some examples of Robinson annulation reactions. Entries 1 and 2 show annulation reactions of relatively acidic dicarbonyl compounds. Entry 3 is an example of use of 4-(trimethylammonio)-2-butanone as a precursor of methyl vinyl ketone. This compound generates methyl vinyl ketone in situ by (3-eliminalion. The original conditions developed for the Robinson annulation reaction are such that the ketone enolate composition is under thermodynamic control. This usually results in the formation of product from the more stable enolate, as in Entry 3. The C(l) enolate is preferred because of the conjugation with the aromatic ring. For monosubstituted cyclohexanones, the cyclization usually occurs at the more-substituted position in hydroxylic solvents. The alternative regiochemistry can be achieved by using an enamine. Entry 4 is an example. As discussed in Section 1.9, the less-substituted enamine is favored, so addition occurs at the less-substituted position. 

Methyl 1-phenylthiovinyl ketones can also be used as enones in kinetically controlled Robinson annulation reactions, as illustrated by Entry 6. Entry 7 shows a annulation using silyl enol ether as the enolate equivalent. These reactions are called Mukaiyama-Michael reactions (see Section 2.6.3). 

As already discussed for aldol and Robinson annulation reactions, proline is also a catalyst for enantioselective Mannich reactions. Proline effectively catalyzes the reactions of aldehydes such as 3-methylbutanal and hexanal with /V-arylimines of ethyl glyoxalate.196 These reactions show 2,3-syn selectivity, although the products with small alkyl groups tend to isomerize to the anti isomer. 

An alternate means of forming 96 arises from reaction of imine 97 with methylvinylketone in a variant of the Robinson annulation reaction. This... 

A procedure using a phase-transfer catalyst is employed to prevent the rapid polymerisation of crotonaldehyde dining the Robinson annulation reaction. 

One-pot syntheses of diaryl-a-tetralones by Michael condensation and subsequent Robinson annulation reactions of isophorone with chalcones were performed efficiently in a solvent-free PTC system under the action of MW irradiation. Compared with conventional heating substantial rate enhancements were observed, within very short reaction times, by use of microwaves (Eq. 59 and Tab. 5.31). They were far better than those achieved by the classical method (NaOEt in EtOH under reflux for 24 h 40-56%). 

In 1986, Puchot et al.104 studied the nonlinear correlation between the enantiomeric excess of a chiral auxiliary and the optical yield in an asymmetric synthesis, either stoichiometric or catalytic. Negative NLEs [(—)-NLEs] were observed in the asymmetric oxidation of sulfide and in [.S ]-proline-mediated asymmetric Robinson annulation reactions, while a positive NLE [(+)-NLEs]... 

Robatel extractor, 10 781 Robbins, Frederick, 11 10 Robinson Annulation Reaction, 24 571 Robinson, important experimental design text coverage compared to other texts, 8 395t... 

The Robinson annulation reaction of 7-methoxy-l-methyl-2-tetralone with methyl vinyl ketone in the presence of A,-(4-trifluoromethylbenzyl)cinchonidinium bromide produces the S-isomer of the tricyclic compound (Scheme 12.10) with an 81% conversion (81% ee) [8]. 

A particularly important example is the Robinson annulation, a procedure which constructs a new six-membered ring from a ketone.83 84 The reaction sequence starts with conjugate addition of the enolate to methyl vinyl ketone or a similar enone. This is followed by cyclization involving an intramolecular aldol addition. Dehydration frequently occurs to give a cyclohexenone derivative. Scheme 2.10 shows some examples of Robinson annulation reactions. 

Methyl 1-phenylthiovinyl ketones can also be used as enones in kinetically controlled Robinson annulation reactions, as illustrated by entry 7 in Scheme 2.10. 

Aldol reactions are often used to close five- and six-membered rings. Because of the favorable entropy (p. 211), such ring closures generally take place with ease, even where a ketone condenses with a ketone. An important example is the Robinson annulation reaction which has often been used in the synthesis of steroids and terpenes. In this reaction a cyclic ketone is converted to another cyclic ketone, with one additional six-membered ring containing a double bond. The substrate is treated with methyl vinyl ketone (or a simple derivative of methyl vinyl ketone) and a base.551 The enolate ion of the substrate adds to the methyl vinyl ketone in a Michael reaction (5-17) to give a diketone that undergoes or... 

Fig. 13.71. Tandem reaction I, consisting of a Michael addition and an aldol condensation Robinson annulation reaction for the synthesis of six-membered rings that are condensed to an existing ring.

Show the intermediate aldol product in the Robinson annulation reaction of ethyl 2-oxocyclohexanecarboxylate with 1 -penten-3-one. 

Show syntheses of these compounds using the Robinson annulation reaction ... 

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