Dienolate anions

A difference in the reactivities and selectivities between tetra-n-butylammonium borohydride and sodium borohydride in the reduction of conjugated ketones is well illustrated with A1-9 2-octalone (Scheme 11.3) [17], Reduction with the sodium salt in tetrahydrofuran is relatively slow and produces the allylic alcohol (1) and the saturated alcohol (2) in a 1.2 1 ratio whereas, in contrast, tetra-n-butylammonium borohydride produces the non-conjugated alcohol (3) (50%) and the saturated alcohol (2) (47%), with minor amounts of the ketone (4), and the allylic alcohol (1) [16]. It has been proposed that (3) results from an initial unprecedented formation of a dienolate anion and its subsequent reduction. 

Angular methylation at positions 8a, 9a and 14a has been carried out with the unsaturated keto steroids (16),158,159 (18), (20)160 and (21).161,162 The observed result is due to the presence of the double bond which controls the direction of enolization. Proton abstraction results in the formation of a conjugated dienolate anion which is alkylated from the less hindered side at the most electronegative carbon atom. 

The final type of carbon nucleophile that is discussed in this chapter is a dianion. In some cases, treatment of an anion with a very strong base can remove a second proton to form a dianion. As an example, the reaction of 2,4-pentanedione with one equivalent of base removes a proton from the carbon between the two carbonyl groups. If this anion is treated with a second equivalent of a strong base, such as potassium amide, a second proton can be removed to form a dienolate anion ... 

Looking back on the history of ketone dianion chemistry, one soon notices that dianion species, derived from / -keto esters, have been in continuous steady use in organic synthesis3,4, as shown in Scheme 2. Thus, ethyl acetoacetate can be converted to the corresponding ketone o a -chainon via consecutive proton abstraction reactions. The resulting dienolate anion reacts with a variety of alkyl halides to give products, resulting from exclusive attack at the terminal enolate anions. 

The use of a relatively soluble base such as CS2CO3 allows good product yield. No products are formed via carbopalladation. Therefore the reaction is considered to occur on a dienolate anion generated from the enal to give an aryl(7r-allyl)palladium intermediate. The regioselectivity seems to be determined in the reductive elimination of the product. Treatment of aliphatic aldehydes with aryl bromides brings about aldol condensation followed by y-aryla-tion to afford 2 1 coupling products (Eq. 27). Note that y-arylation products are also produced in the arylation of a tin-masked dienolate [65,66]. 

Whatever the explanation, the effect of acids is less marked than the selectivffy in alkaline solutions, where a attack is largely suppressed. The effect of alkali may depend upon the formation and selective reduction of enolate anions. The A2 4-dienolate anion, which is the major product of kinetically-controlled enolisation by bases (see p. 156) is seen from a molecular model to have a somewhat "folded conformation of the A/B ring system (ii). The convex / -face of the A/B ring system and the absence of an axial 2jS-proton should favour approach to the catalyst from this direction, whereas the a-face of the A -bond is severely hindered by the axial hydrogens at C(7) and C<9>. 

The lithium dienolate anions derived from 2-bromocrotonates undergo addition to aldehydes and some ketones to furnish vinyloxiranes 1 at low temperature. ... 

As a result of the relatively low values for the pKaS of the substrate/product and its stability due to the absence of competing side reactions, the dienolate anion intermediate can be chemically prepared by treatment of substrate/product with strong base and, after rapid neutralization, can be supplied to KSI as a substrate to allow an evaluation of the kinetics of processing of the intermediate to substrate/ product [55]. Preparation of the enediolate intermediate in the TIM-catalyzed reaction is impossible because of its facile propensity to eliminate inorganic phosphate with the concomitant formation of methylglyoxal. 

The likely importance of strong hydrogen bonding in stabilizing the dienolate anion intermediate was prominent in the formulation of both the Gerlt-Gassman and Cleland-Kreevoy proposals, even prior to the availability of high resolution... 

Experiments reported by Pollack and his coworkers allow the conclusion that the dienolate anion intermediate is approximately isoenergetic with the more unstable unconjugated enone substrate/product, as proposed by Knowles and Albery in their theory for understanding optimization of catalytic efficiency [9]. Thus, based on the value of the rate constant for proton abstraction from the unconjugated enone, 1.7 x 10 s Pollack and coworkers calculated that the value of the Glint for proton abstraction from carbon is 10 kcal mol, a modest reduction from that expected ( 13 kcal mol ) for the nonenzymatic reaction. 

Various aspects of the reaction coordinate for the KSI-catalyzed reaction have been subjected to computational examination [62-64]. These are in accord with the experimental results, i.e., Tyr 14 and Asp 99 independently stabilize the dienolate anion intermediate via a hydrogen bond. Although the strengths of these hydrogen bonds each increase by 5 kcal mol as the anionic intermediate is formed, the hydrogen bonds are asymmetric with the protons associated with the donors. 

Both the 1,1-proton transfer reaction catalyzed by mandelate racemase (MR) and the dehydration catalyzed by enolase require Mg + for activity. The values of the pK s for mandelate and 2-phosphoglycerate, the substrates for the MR- and enolase-catalyzed reactions, are estimated as 29 and 32, respectively [1]. The values of the pKaS of the general basic Lys residues are 6 and 9 in MR [6] and enolase [73], respectively. Thus, formation of a dienolate anion intermediate is extremely endergonic, unless the active site can stabilize the intermediate which is the obvious function of the essential Mg. The rate accelerations for the MR- and enolase-catalyzed reactions are 10 as a direct result of the values of the pKaS of the a-protons (Table 6.1). 

The reaction of Vilsmeier reagents with 3,5-dienolate anions has been used to introduce 4-dimethylaminomethylene-, hydroxymethylene-, and cyano-groups into cholest- and androst-4-en-3-ones. A number of 2,3-trans- and 16a,17a-cis-halogeno-urethanes have been prepared from their parent halohydrins. ... 

An elegant route to quinazoline-2,4-diones (251) starts, unusually, from substituted uracils (249) other dienophiles e.g. methyl vinyl ketone and dimethyl fumarate) also cyclo-add to the dienolate anions (250) (Scheme 100)." ... 

The dienolate anion of 190 generated with potassium r-amyloxide was alkylated with 191 to yield the mixture 192 (R = OCH2CH2O) in 54% yield. Acid-catalyzed hydrolysis gave the crystalline mixture of ketones. The stereochemistry at C-1 was assigned on the basis of previous observation,and the benzene induced shifts of methyl signals in the nmr spectrum, confirmed by the X-ray structure determination. 

The Michael addition of the dienolate anion (90), readily generated from 1-trimethylsilyloxybuta-1,3-diene, to suitable acceptors provides an attractive alternative to the Diels-Alder reaction (Scheme 22). ... 

An aryne-based Diels-Alder reaction between tetrabromobiphenyl ether 169 and the dienolate anion generated from a,P-unsaturated amide 170 has been reported by Ruchirawat et al. in the synthesis of diospyrol derivatives, where the biphenyl ether 169 was converted to binaphthyl ether 171 in the presence of the sterically hindered base LiTMP (Scheme 12.49) [92],... 

A new four-carbon annulation procedure is shown in Scheme 14, whereby the dienolate anion of an unsaturated carboxylic acid (99) is added to a ketone to give an acid which upon rearrangement at... 

Acyl, Homoenolate, Acylvinyl, and Dienolate Anion Equivalents... 

In practice, isoquinuclidene 196 was prepared, protected as the N-benzenesulfonyl derivative and hydrolyzed to give the Buchi-oxygenation substrate 206 (Scheme 3.31) (43). Interestingly, oxygenation of 206 under Buchi s conditions did not yield the desired hydroxy ketone 207 but rather gave a substance tentatively characterized as the bicyclic azetidine 208. Presumably, under the basic reaction conditions, isoquinuclidene 206 forms a dienolate anion by a pathway involving nitrogen elimination and readdition to the intermediate dienone. 

Cis/trans double bond isomerization in enones is also possible if there is a suitable proton available to be removed to give the dienol/dienolate. So if 17.22 is treated with base, a proton is removed from the y-position to give the dienolate anion (Figure 17.13). In this intermediate, the bond between the a- and p-carbon atoms is a single bond and so may rotate freely the position of the equilibrium will depend on the relative stabilities of the two species, in this case determined by steric factors. 

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