Cyclohexenones aldol cyclization

Carbonyl condensation reactions are widely used in synthesis. One example of their versatility is the Robinson anuulation reaction, which leads to the formation of an substituted cyclohexenone. Treatment of a /3-diketone or /3-keto ester with an a,/3-unsaturated ketone leads first to a Michael addition, which is followed by intramolecular aldol cyclization. Condensation reactions are also used widely in nature for the biosynthesis of such molecules as fats and steroids. 

A further example of the use of 2//-thiopyrans as surrogates for m-substituted dienes involves the use of the protected 3,4-dihydio-3-(3-oxobutyl)A//-thiopyranA-onc, 3-[2-(2-methyl-l,3-dioxolan-2-yl)ethyl]-4-[tris(l-methy-lethyl)silyl)oxy-2//-thiopyran 328 as an equivalent of l-ethenyl-2-methylcyclohexene in Diels-Alder reactions. The thiopyran reacted with various maleimides to yield the endo cycloadducts and with methyl propenoate to give the exo adduct under either thermal or Lewis-acid-catalyzed conditions. In the latter case concomitant release of the protected ketone functions occurs, acid-catalyzed cyclization of which generates a fused cyclohexenone ring (Scheme 67). Desulfurization, preferably before the aldol cyclization, leads to derivatives of 2,3,4,4a,5,6,7,8-octahy-dro-4a-methylnaphthalenes < 1997CJC681 >. 

Robinson annulation reaction (Section 23.12) a multistep sequence for building a new cyclohexenone ring onto a ketone. The sequence involves an initial Michael reaction of the ketone followed by an internal aldol cyclization. 

The third and fourth steps in the synthesis of Hagemann s ester from ethyl acetoacetate and formaldehyde (Problem 23.50) are an intramolecular aldol cyclization to yield a substituted cyclohexenone, and a decarboxylation reaction. Write both reactions, and show the products of each step. 

This complex transform can be envisaged by assuming that one equivalent of 3-8 attacks the enol lactone carbonyl group to afford the hydroxylactone 4-2 (Scheme 4.4). This unstable intermediate actually comprises a hemiacetal of an enol lactone. The reaction medium is sufficiently basic to cause the underlying diketone (4-3) to undergo aldol cyclization to form cyclohexenone 4-4. 

The preferred direction of base-catalysed aldol cyclization of 1,5-diones of the type MeCO(CH2)3COCH2R has been shown to depend on the nature of the group R (Scheme 38). Formation of the cyclohexenone (13) is favoured for R = Me formation of the cyclohexenone (14) is favoured when R is a straight-chain-alkyl group and this tendency becomes marked when R is a branched-chain alkyl group. ... 

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. 

In the majority of dehydration reactions, heterocyclic compounds are formed, rather than carbocyclic compounds. Many possibilities for formation of carbocyclic compounds exist, but these are important only if (a) the heterocyclic or acyclic tautomers cannot undergo further elimination reactions, or (b) the conditions of reaction greatly favor the formation of an acyclic tautomer capable of affording only the carbocyclic compound. Both five- and six-membered carbocyclic compounds have been isolated, with reductic acid being the compound most frequently reported. Ring closure occurs by an inter-molecular, aldol reaction that involves the carbonyl group and an enolic structure. Many examples of these aldol reactions that lead to formation of carbocyclic rings have been studied.47 As both elimination and addition of a proton are involved, the reaction occurs in both acidic and basic solutions. As examples of the facility of this reaction, pyruvic acid condenses spontaneously to a dibasic acid at room temperature in dilute solution, and such 8-diketones as 29 readily cyclize to form cyclohexenones, presumably by way of 30, either in acid or base. 

The simplest approach which can be envisaged to 4/f-pyrans involves the ring closure of 1,5-diketones. However, such molecules are frequently able to undergo a facile intramolecular aldol condensation leading to cyclohexenones, which competes successfully with cyclization to the pyran. 

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... 

Cycloalkenones. The nucleophilic at disubstituted 1,3-cycloalkanediones re Wadsworth reaction to give 3-substituted 2 The reaction of the same reagent wit phonates), which may undergo cyclization. rapid aldolization, permitting subsequent a 2-cyclohexenones. 

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