Regiospecific enolization

While we are on the subject of specificity and control in substitution adjacent to a carbonyl, there is another contribution, which I would like to mention because it has turned out to be very important. It is what I refer to as regiospecific enolate formation and trapping. It made possible the introduction of an electrophile, including a carbon chain, on one or the other a-methylenes of a ketone. 

The reduction of a. -unsaturated carbonyls with lithium in ammonia is a versatile reaction of great utility. The advantage of this method is that regiospecific enolates are obtained that are sometimes not accessible by other routes. This technique finds important applications in steroid-like systems (equation 15). °... 

Problems of regio- and chemoselectivity are all answered by the use of specific enol equivalents—that is reagents which behave as the regiospecific enol of one particular carbonyl compound. 

The enol acetates of aldehydes (but not ketones) are obtained in high yield with acetic anhydride and triethylamine with 4-JV,JV-dimethylaminopyridine. Regiospecific enol acetates (95) are obtained by nucleophilic ring opening of cyclopropyl ketones [equation (60)]. ... 

Basis and Example of Use. This reagent acts as the alkyla-tive equivalent of 3-buten-2-one (methyl vinyl ketone), permitting regiospecific enolate alkylation under nonequilibrating conditions. As a vinylsilane it can be converted, via the corresponding a,/3-epoxy silane, into a 3-oxobutyl moiety, and hence used in an alkylative equivalent of Robinson annulation. Application of such methodology can be seen (eq 1) in the preparation of bicyclodecenones via the alkylation of dihydrocarvone with this reagent. Apart from this application, and its use in combination with potassium iodide, it has seen little use so far. 

During a synthesis of pederol dibenzoate, a key step required formation of a regiospecific enol silyl ether in a highly oxygenated and base-sensitive substrate. The reaction was uniquely achieved by a rhodium(i)-catalysed hydrosilylation sequence (Scheme 47). ... 

Enolates and their Equivalents. The generation of regiospecific enolates is another problem of considerable synthetic importance. Use of lithium bis(2-propyl)amide as base at low temperature is recommended "- for formation of trilithio derivatives of 2,4,6-triketones and for synthesis with little loss of optical activity of the enolate of (14). The highly hindered base (15) is even better for carrying out in situ crossed aldol reactions between methyl ketones and aldehydes. 

The decarboxylation-allylation of allyl enol carbonates proceeds smoothly[450]. The isomeric enol carbonates 699 and 701 of the enone 698 undergo regiospecific allylation, giving the regioisomers 700 and 702 selectively. 

Ailyl enol carbonates derived from ketones and aldehydes undergo Pd-cat-alyzed decarboxylation-elimination, and are used for the preparation of a, /3-unsaturated ketones and aldehydes. The reaction is regiospecific. The regio-isomenc enol carbonates 724 and 726, prepared from 723, are converted into two isomeric enones, 725 and 727. selectively. The saturated aldehyde 728 can be converted into the a,/3-unsaturated aldehyde 730 via the enol carbonate 729[459]. 

Silylated cyanohydrins have also been prepared via silylation of cyanohydrins themselves and by the addition of hydrogen cyanide to silyl enol ethers. Silylated cyanohydrins have proved to be quite useful in a variety of synthetic transformations, including the regiospecific protection of p-quinones, as intermediates in an efficient synthesis of a-aminomethyl alcohols, and for the preparation of ketone cyanohydrins themselves.The silylated cyanohydrins of heteroaromatic aldehydes have found extensive use as... 

In a manner analogous to classic nitrile iinines, the additions of trifluoro-methylacetonitrile phenylimine occur regiospecifically with activated terminal alkenes but less selectively with alkynes [39], The nitnle imine reacts with both dimethyl fumarate and dimethyl maleate m moderate yields to give exclusively the trans product, presumably via epimenzation of the labile H at position 4 [40] (equation 42) The nitrile imine exhibits exo selectivities in its reactions with norbornene and norbornadiene, which are similar to those seen for the nitrile oxide [37], and even greater reactivity with enolates than that of the nitnle oxide [38, 41], Reactions of trifluoroacetomtrile phenyl imine with isocyanates, isothiocyanates, and carbodiimides are also reported [42]... 

An important stage in the synthesis has been reached. It was anticipated that cleavage of the trimethylsilyl enol ether in 18 using the procedure of Binkley and Heathcock18 would regiospecifically furnish the thermodynamic (more substituted) cyclopentanone enolate, a nucleophilic species that could then be alkylated with iodo-diyne 17. To secure what is to become the trans CD ring junction of the steroid nucleus, the diastereoisomer in which the vinyl and methyl substituents have a cis relationship must be formed. In the... 

Kuwajima (75) has provided full details of the regiospecific monoalkylation of carbonyl compounds via their silyl enol ethers, using stoichiometric amounts of fluoride ion. Noyori (76) has given more information on the use of the complex fluoride source (2) (Chapter 18)... 

Rhodium-catalysed addition (10) of hydridosilanes (Chapter 17) to a/3-unsaturated carbonyl compounds can be performed regioselectively, to afford either the product of 1,2-addition, or, perhaps more usefully, that of 1,4-addition, i.e. the corresponding silyl enol ether this latter process is an excellent method for the regiospecific generation of silyl enol ethers. Of all catalyst systems investigated, tris(triphenylphosphine)rhodium(l) chloride proved to be the best. 

The role of the trimethylsilyl group is to stabilize the enolate formed in the conjugate addition. The silyl group is then removed during the dehydration step. Methyl 1-trimethylsilylvinyl ketone can be used under aprotic conditions that are compatible with regiospecific methods for enolate generation. The direction of annulation of unsymmetrical ketones can therefore be controlled by the method of enolate formation. 

Formal isomerization of the double bond of testosterone to the 1-position and methylation at the 2-position provides yet another anabolic/androgenic agent. Mannich condensation of the fully saturated androstane derivative 93 with formaldehyde and di-methylamine gives aminoketone 94. A/B-trans steroids normally enolize preferentially toward the 2-position, explaining the regiospecificity of this reaction. Catalytic reduction at elevated temperature affords the 2a-methyl isomer 95. It is not at all unlikely that the reaction proceeds via the 2-methylene intermediate. The observed stereochemistry is no doubt attributable to the fact that the product represents the more stable equatorial isomer. The initial product would be expected to be the p-isomer but this would experience a severe 1,3-diaxial non-bonded interaction and epimerize via the enol. Bromination of the ketone proceeds largely at the tertiary carbon adjacent to the carbonyl (96). Dehydrohalogenation... 

These reactions were proposed to proceed via electrophilic attack on the enol by the SN reagents at N followed by cyclization either via a second enol as in compound 151 or by cyclization onto the more reactive carbonyl <1997J(P1)2831>. Unsymmetrical 1,3-diketones can give a mixture of regioisomers if both carbonyls have similar reactivities however, aroylacetones react regiospecifically to afford only the 3-aroyl-4-alkyl-l,2,5-thiadiazoles 154 (R = Me). 

Regiospecific mono-C-alkylation (60-90%) of trimethylsilyl enol ethers is promoted by benzyltriethylammonium fluoride [34, 35]. A similar alkylation of tin(IV) enolates is aided by stoichiometric amount of tetra-n-butylammonium bromide and has been utilized in the synthesis of y-iminoketones [36]. Carbanions from weakly acidic carbon acids can be generated by the reaction of their trimethylsilyl derivatives with tetra-n-butylammonium triphenyldifluorosilicate [37] (see also Section 6.3). Such carbanions react readily with haloalkanes. Tautomeric ketones in which the enol form has a high degree of stabilization are O-alkylated to form the enol ether, e.g. methylation of anthrone produces 9-methoxyanthracene [26],... 

The products are triazolines with the amino or alkoxy function in the 5-position Addition is regiospecific. In some cases the triazolines aromatize spontaneously more usually, aromatization is effected by heating the compounds alone (for enol ether adducts) or with acid or base. 

For a recent discussion of regiospecific synthesis of trimethylsilyl enol ethers see G. M. Rubottom, R. 

---