Ketones, methyl vinyl Robinson annulation

The reaction of a cyclic ketone—e.g. cyclohexanone 1—with methyl vinyl ketone 2 resulting in a ring closure to yield a bicyclic a ,/3-unsaturated ketone 4, is called the Robinson annulation This reaction has found wide application in the synthesis of terpenes, and especially of steroids. Mechanistically the Robinson annulation consists of two consecutive reactions, a Michael addition followed by an Aldol reaction. Initially, upon treatment with a base, the cyclic ketone 1 is deprotonated to give an enolate, which undergoes a conjugate addition to the methyl vinyl ketone, i.e. a Michael addition, to give a 1,5-diketone 3 ... 

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. 

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]. 

Catalytic asymmetric methylation of 6,7-dichloro-5-methoxy-2-phenyl-l-indanone with methyl chloride in 50% sodium hydroxide/toluene using M-(p-trifluoro-methylbenzyDcinchoninium bromide as chiral phase transfer catalyst produces (S)-(+)-6,7-dichloro-5-methoxy-2-methyl-2--phenyl-l-indanone in 94% ee and 95% yield. Under similar conditions, via an asymmetric modification of the Robinson annulation enqploying 1,3-dichloro-2-butene (Wichterle reagent) as a methyl vinyl ketone surrogate, 6,7 dichloro-5-methoxy 2-propyl-l-indanone is alkylated to (S)-(+)-6,7-dichloro-2-(3-chloro-2-butenyl)-2,3 dihydroxy-5-methoxy-2-propyl-l-inden-l-one in 92% ee and 99% yield. Kinetic and mechanistic studies provide evidence for an intermediate dimeric catalyst species and subsequent formation of a tight ion pair between catalyst and substrate. 

A variant of the Robinson annulation, where bulky amines such as pyrrolidine are used, making the conjugate addition to methyl vinyl ketone (MVK) take place at the less hindered side of two possible enamines. 

Robinson Annulation The addition of a methyl vinyl ketone (or derivative) to a cyclohexanone to form an a, 5-unsaturated ketone containing a six-membered ring. 

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. 

The copper-catalyzed conjugate addition of methyl magnesium iodide to cyclohexenone and trapping the enolate as its trimethylsilyl enol ether, followed by a trityl hexachloro-antinomate-catalyzed Mukaiyama reaction, is apphed to / -(—jcarvone. C-2, C-3 functionalized chiral cyclohexanones are converted into their a-cyano ketones, which are submitted to Robinson annulation with methyl vinyl ketone. Highly functionalized chiral decalones are obtained that can be used as starting compounds in the total synthesis of enantiomerically pure clerodanes (equation 70). 

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... 

This is a modification of the Robinson annulation in which l,3-dichIoro-c -2-butene is used in place of methyl vinyl ketone. 

A much more generally useful process was developed by Robinson to prepare cyclohexenones from ketones and methyl vinyl ketone or its derivatives. Again, because good compilations of the Robinson annulation exist,8 only a few examples are given here. The first step of this process, the Michael addition, is carried out by normal base catalysis, while the second step, the aldol condensation, is best accomplished by the use of a secondary amine to form the enamine of the acyclic ketone, which then cyclizes... 

The use of a-thiophenyl enones (106 Scheme 12) allows the preparation of phenols such as (107) from cyclic ketones (18).30 The same product can also be obtained by normal Robinson annulation of methyl vinyl ketone (30) and the p-keto sulfoxide (lOS).30 Acceptors other than a, 3-unsaturated carbonyls have been used in both the Michael reaction and the Robinson annulation process. For example, nu-... 

Keywords 2-formylcycloalkanone, methyl vinyl ketone, proline, Robinson annu-lation, asymmetric annulation, spiro compound... 

This is an example of a Robinson annulation. The mechanism for the Robinson annulation involves a sequence of conjugate addition reactions and aldol condensations. As illustrated, the first step is deprotonation of cyclohexanedione with sodium hydride. The resulting anion then participates in a 1,4-addition to methyl vinyl ketone. The resulting enolate anion then tautomerizes through... 

Formation of a cyclohexenone ring by condensation of methyl vinyl ketone (MVK) or a substituted MVK derivative with a ketone. Robinson annulation proceeds by Michael addition to MVK, followed by an aldol condensation with dehydration, (p. 1088)... 

The Stork reaction of methyl vinyl ketones and enamines (e.g. 74) is a complementary procedure to the Robinson annulation method (equation 14)49. With this procedure, products from attack of the most reactive less substituted form of the enamine to the... 

On the basis of distribution of products obtained in these reactions with the change of solvents, temperature and molar ratio of reactants, a mechanism has been suggested for the anomalous annulation which does not involve an initial attack of the tetrasub-stituted isomer of the enamine (equation 16)51. Alkylation of the more stable cis isomer of the enamine (80) with methyl vinyl ketone (MVK) would afford zwitterion 81 (attack by the other side of the enamine leads to strong steric interactions in the transition state). Reaction of the thermodynamically less favorable trans isomer 83 gives rise to zwitterions 84 and 89 (both without axial-axial interactions), and ion 84 is sterically able to undergo intramolecular proton shift to afford enamine 85. Zwitterionic intermediates 81 and 89 can be stabilized by conversion to dihydropyrans 82 and 90, or protonated to immonium ions. The pair 81-82 will lead to enamine 85, while the pair 89-90 will afford enamine 91. Then, cyclization of 85 or 91 will afford the enone expected from the normal enamine version of the Robinson annulation. 

The well-known Robinson annulation reaction (Section 2.3.3) exploits a similar synthetic utilization of methyl vinyl ketone as an isomeric bipolar... 

Since both oxidative splitting of the double bond and aldol condensation represent reliable and general reactions, their sequence serves as an efficient route for the transformation of readily available cyclohexene systems e.g. formed via the Diels-Alder reaction or Robinson annulation) into functionalized cyclopentene derivatives. This standard operational mode is extensively used in total syntheses. One of the numerous examples, the synthesis of helminthosporal 463, the sesquiterpenoid toxin of fungi, is shown in Scheme 2.150. In the initial phases of the synthesis, commercially available (—)-carvomenthone 464 was transformed into 465 via Michael reaction with methyl vinyl ketone to give 466 and subsequent intramolecular aldol condensation. 

Asymmetric Robinson Annulation. 2-Propyl-1-indanone undergoes Robinson annulation with the catalyst and methyl vinyl ketone (eq 6). Higher ee values were achieved using 1,3-dichloro-2-butene (Wichterle Reagent) as an MVK surrogate for the Michael addition and overall Robinson annulation (eq 9)... 

Using (2) as catalyst provided the (R) enantiomer in 99% yield, 78% ee. The key introduction of asynunetry during the synthesis of (+)-podocarp-8(14)-en-13-one was the phase-transfer-catalyzed Robinson annulation of 6-methoxy-l-methyl-2-tetralone with ethyl vinyl ketone. The authors carried out a comparative study of the A/-(4-trifluoromethyl)benzyl derivatives of cinchonine, cinchonidine, dihydrocinchonine, and dihydrocinchonidine and found that (5) produced the highest ee of the desired (S) enantiomer at —45 °C using toluene and 60% aq KOH (eq 10). ... 

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. 

Dibutyltin bis(triflate), Bu2Sn(OTf)2, is a mild Lewis acid which catalyzes clean Michael addition of enol silyl ethers [148]. The new catalyst enables use of various labile acceptors such as methyl vinyl ketone and 2-cyclopentenone which do not undergo smooth reaction with conventional Lewis acids. A variety of enol silyl ethers are also employable and thus 2-(trimethylsiloxy)propene, the simplest of this class of compounds, can be used. The adducts of enol silyl ethers of cycloalkanones with vinyl ketones are readily cyclized to give the desired annulated enones free of isomers. Consequently, a practical version of the Robinson annulation has been realized. 

This very useful reaction resulted from a failed attempt to introduce a new protected methyl vinyl ketone equivalent for the all important Robinson annul-lation reaction. This failure turned out to be quite rewarding, for it allowed for a fast, simple, mild, and high yielding construction of a-alkylidene ketones, esters, and nitriles, as well as /3-methylenebutyrolactones, a family of compounds with several representatives among the tumor growth inhibitors. The method, unfortunately, has its own limitations, which will be discussed after exposing probable mechanisms. 

Therefore several reactions were subjected to various antibody catalyses, e. g., ester and enol ether cleavage, transesteiification, ketone reduction. Cope rearrangement, ring closure via epoxide opening, or Diels-Alder cycloaddition [74, 75]. An exceptional reaction is the antibody-catalyzed Robinson annulation of triketone 28 to the Wieland-Miescher ketone 29 on a preparative scale. Surprisingly, even the alkylation of diketone 27 with methyl vinyl ketone was catalyzed by the same antibody, but at moderate rates (Scheme 15) [76]. 

The Hajos-Parrish reaction can be regarded as the enantioselective version of the Robinson annulation. In the early stages of the synthetic effort targeting the mixed polyketide-terpenoid metabolite (-)-austalide B, L.A. Paquette and co-workers used this transformation to prepare the key bicyclic precursor in enantiopure form. Ethyl vinyl ketone was reacted with 2-methyl-1,3-cyclopentanedione in the presence of catalytic amounts of L-valine to afford the bicyclic diketone with a 75% ee. 

Several new synthetic routes to acorane sesquiterpenoids have been published during the past year cf. Vol. 8, p. 76). In the first of these routes spiroannulation of the pyrrolidine enamine (201) derived from cyclopentene aldehyde (200) provided an enone (202) which was subsequently converted into (-)-acorenone (203) (Scheme 19). In an alternative synthetic route,Robinson annulation of the aldehyde (204) with methyl vinyl ketone provided a spiro-ketone (205) which served as a common intermediate in the synthesis of (-)-acorenone (203) and (-)-acorenone-B (211) (Scheme 20) cf. Vol. 7 pp. 63, 64). To explain the conversion of (206) into (209), it has been suggested that the intermediate 1,2-borane borate (207) undergoes elimination followed by hydroboration. 

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