Enolate equivalents for aldehydes

Among the best enol equivalents for aldehydes are enamines.19 They are stable compounds, easily made from aldehydes 95 and secondary amines, reacting with electrophiles in the same way as enols 96 to give iminium salts 97, hydrolysed to substituted aldehydes 98. 

According to Section 12.3 enamines are just one synthetic equivalent for enols that are not sufficiently represented in equilibrium with a carhonyl compound to allow for a-functional-izations. Enol ethers and silyl enol ethers, which are addressed in this section, are other synthetic equivalents for such enols. An enol ether, for example, is used as an enol equivalent for aldehyde enols, since several aldehydes do not form stable enamines. In addition, enol ethers or silyl enol ethers are usually employed as synthetic equivalents for the enols of ,/i-unsatu-rated carbonyl compounds. The attempt to react ce,/ -unsaturated carhonyl compounds with secondary amines to give a dienamine is often frustrated by a competing 1,4-addition of the amine. The combination of these factors turns the dienol ether B of Figure 12.23 into a species for which there is no analog in enamine chemistry. 

The best specific enol equivalents for aldehydes are enamines (75) and these are also very useful for ketones. They are easily made from the carbonyl compound and a secondary amine, are stable isolable compounds, and react... 

Summary specific enol equivalents for aldehydes and ketones ... 

The use of aldehyde enolates for conjugate additions is precluded by competing polymerization and al-dolization processes however, introduction of the OfeCHO moiety is accomplished with aldehyde enolate equivalents. For example, dianions of nitroethanes, e.g. 3-phenylnitroethane (165) or methyl 3-nitropropionate (166), add exclusively in the 1,4-mode to ot,3- nones.,36a-b Similarly, the dianion of 4-nitro-1-butene (167) adds in a 1,4-mode exclusively unlike typical dienolates (Section 1.2.2.2.2) which react at the ot-position, this dianion is formally equivalent to the crotonaldehyde >-enolate (Scheme 64).l36c... 

Among the enolates of carboxylic acid derivatives, esters are the most widely used. Ester enolates cannot be used in crossed aldols with aldehydes because the aldehyde is both more enolizable and more electrophilic than the ester. It will just condense with itself and ignore the ester. The same is true for ketones. A specific enol equivalent for the ester will therefore be needed for a successful ester aldol reaction. 

The enol content of simple aldehydes and ketones is low under standard acid-catalyzed conditions. Silyl enol ethers, often available free of regioisomers, are an important source of enol equivalents for nucleophilic addition reactions. The reaction of silyl enol ethers with carbonyl compounds in the presence of BF3 Et20, SnCl4, TiCl4 or InCl3 proceeds through an open transition state instead of a closed transition state and leads, after hydrolytic workup, to aldol products. 

We must use a spedflc enol equivalent for the aldehyde enolate to avoid self-condensation an enamine or a silyl enol ether would be fine. Since we must reduce the ester in the presence of the aldehyde, it makes sense to put the acetal in before we do this. 

Silyl enol ethers are other ketone or aldehyde enolate equivalents and react with allyl carbonate to give allyl ketones or aldehydes 13,300. The transme-tallation of the 7r-allylpalladium methoxide, formed from allyl alkyl carbonate, with the silyl enol ether 464 forms the palladium enolate 465, which undergoes reductive elimination to afford the allyl ketone or aldehyde 466. For this reaction, neither fluoride anion nor a Lewis acid is necessary for the activation of silyl enol ethers. The reaction also proceed.s with metallic Pd supported on silica by a special method[301j. The ketene silyl acetal 467 derived from esters or lactones also reacts with allyl carbonates, affording allylated esters or lactones by using dppe as a ligand[302]... 

Pyridinium p-toluenesulfonylmethylide 91 has been used as a formyl anion equivalent for conjugate addition to N-substituted maleimides to give the enol ethers 92, which were readily deprotected to give the aldehydes 93 (80TL705). 

Specific enol equivalents will be needed for both synthons (61) and (66), Since (61) is to give a double bond but (66) is to give an alcohol, the logical choices are a Wittig reagent - actually (67) - for (61) and a Reformatsky reagent for (66). The ester to aldehyde conversion (65 63) Is easiest by over-reduction and re-... 

When the 1,3-dicarbonyl substrate reacts twice via its activated methylene due to the presence of heteroatoms blocking the enolization process on other positions, spiranic systems are formed in the presence of two equivalents of aldehyde and an equivalent of urea (Scheme 15) [85]. The reaction can be promoted either in acetic acid as solvent or neat under microwave irradiations or in the presence of H3PW12O40 as catalyst. Finally, this technique for generating spiroheterocyclic products has been transferred to solid-supported methodology by immobilizing the 1,3-dicarbonyl partner onto a resin [86]. 

The conjugate addition of unstabilized enolates to various acceptors was conceptually recognized by early researchers however, complications were encountered depending on the enolates and acceptors employed. Reexamination of this strategy was made possible by the development of techniques for kinetic enolate formation. This discussion is divided into three enolate classes (a) aldehyde and ketone enolates, azaenolates or equivalents, (b) ester and amide enolates, dithioenolates and dienolates and (c) a,0-carboxylic dianions and a-nitrile anions, in order to emphasize the differential reactivity of various enolates with various acceptors."7 The a-nitrile anions are included because of their equivalence to the hypothetical a-carboxylic acid anion. 

Casey and coworicers have shown that ketone etiolates add efficiently to a,3-unsaturated vinyl carbene complexes (164), irrespective of 3,3-disubstitution on the complex or high substitution on the enol-ate 133 thus, contiguous 3 and y quaternary centers are easily assembled. When coupled with the ease of release of the carbene ligand from the complexes by either oxidation to the ester functionality1331 or elimination to the corresponding enol ether,133 the vinyl carbene complexes are synthetic equivalents for a,3-unsaturated esters or a,3-unsaturated aldehydes, respectively (Scheme 63). 

So if we want to make 9 we have a choice between adding an enolate equivalent of the aldehyde 7 to an unsaturated ester 8 or an enolate equivalent of the ester 11 to an unsaturated aldehyde 10. We prefer the first 9a as the unsaturated ester 8 is more likely to do conjugate addition. An enamine would be a good choice for 7. 

A simple example is the cyclopentenone 7 because the keto-aldehyde 8 can cyclise only one way as the aldehyde cannot enolise. The best 1,4-dicarbonyl disconnection is probably 8 giving some enolate equivalent 10 of isobutyraldehyde and a reagent for the unnatural synthon 9 such as the bromoketone 11. 

Tetrasubstituted pyrroles could be obtained by skeletal rearrangement of 1,3-oxazolidines, a reaction that is substantially accelerated by microwave irradiation. Dielectric heating of a 1,3-oxazolidine 7, absorbed on silica gel (1 g silica gel/mmol) for 5 min in a household MW oven (900 W power) cleanly afforded the 1,2,3,4-tetrasubstituted pyrrole 8 in 78% yield, thus reducing the reaction time from hours to minutes (Scheme 5) [24], 1,3-Oxazolidines are accessible in one-pot, two-step, solvent-free domino processes (see also Sect. 2.6). The first domino process, a multi-component reaction (MCR) between 2 equivalents of alkyl propiolate and 1 equivalent of aldehyde furnished enol ethers 9 (Scheme 5). Subsequent microwave-accelerated solvent-free reactions of enol ethers 9 with primary amines on silica support afforded intermediate 1,3-oxazolidines, which in situ rearranged to the tetrasubstituted pyrroles (2nd domino process). Performed in a one-pot format, these... 

The enol content of simple ketones is much lower than that of /1-ketoesters or /3-diketones. For a number of electrophiles it is often too low. Hence, functionalizations with the respective electrophile via the enol form do not succeed in these cases. This problem can be managed, though, by converting the ketone (Formula A in Figure 12.16) into an enamine D with the aid of a condensation with a secondary amine that is in line with Figure 9.29 and the mechanism given there. Enamines are common synthetic equivalents for ketonic and aldehyde enols. 

Silyl enolates react with acyl cation equivalents to give the C- and/or O-acylated products (Equation (90)).333 Fluoride-catalyzed reaction using acyl fluorides is valuable for O-acylation of silyl enolates derived from aldehydes and ketones.334 CuCl also promotes the 0-acylation with acyl chlorides.335 The CuCl-promoted reaction of ester silyl enolates results in exclusive (7-acylation. Combined use of BiCfl and Znl2 (or Nal) effects catalytic (7-acylation of ketone silyl enolates with acyl chlorides. 

---