Enolates synthesis from carbonyl compounds

Tetrahydropyranyl (THP) protection of the hydroxy group of 48 yields a useful reagent for the Horner-Wadsworth-Emmons synthesis of enol ethers from carbonyl compounds.103 104... 

A cheap and efficient method for synthesis of 2-triniethylsilyloxy-l,3-butadiene from methyl vinyl ketone was desired. The method had to be practical for molar scale preparations. Although a number of methods for the synthesis of silyl enol ethers from carbonyl compounds are known, none of them were applicable for this conversion. They were either too expensive for use on larger scale, or afforded poor yields on attempted synthesis. 

The carbonyl group is one of the most prevalent of the functional groups and is involved in many synthetically important reactions. Reactions involving carbonyl groups are also particularly important in biological processes. Most of the reactions of aldehydes, ketones, esters, carboxamides, and the other carboxylic acid derivatives directly involve the carbonyl group. We discussed properties of enols and enolates derived from carbonyl compounds in Chapter 6. In the present chapter, the primary topic is the mechanisms of addition, condensation and substitution reactions at carbonyl centers. We deal with the use of carbonyl compounds to form carbon-carbon bonds in synthesis in Chapters 1 and 2 of Part B. 

P 55] Before synthesis, a micro-mixing tee chip micro reactor (Figure 4.85) (with two mixing tees and four reservoirs) was primed with anhydrous tetrahydrofuran (THF). A 40 gl volume of a 0.1 M solution of tetrabutylammonium fluoride trihydrate in anhydrous THF is filled into one reservoir of a micro-mixing tee chip reactor [15], 40 gl of a 0.1 M solution of 4-bromobenzaldehyde in anhydrous THF is added to a second reservoir, 40 gl of a 0.1 M solution of the silyl enol ether (masking the enolate of a carbonyl compound such as cyclohexanone) in anhydrous THF is added to a third reservoir and anhydrous TH F is filled into the fourth collection reservoir. Electrical fields of417,455,476 and 0 V cm are applied to transport the reaction species from the respective reservoirs. The reaction is carried out at room temperature. 

Another way to synthesize cyclic acetals uses enol ethers (not carbonyl compounds) as starting materials Draw a stepwise mechanism for the following synthesis of an acetal from an enol ether and ethylene glycol. 

Until about 30 years ago, hydrazones derived from carbonyl compounds were not used in organic synthesis. They were used only for analytical purposes , and as protecting groups of aldehydes and ketones ". Corey investigated dimethylhydrazones of ketones and aldehydes with a-hydrogens, and found that they undergo deprotonation with LDA or BuLi in THF at the a-carbons to the hydrazonic moiety in 90-100% yield. The formed lithium compounds, used as enolate anion equivalents, create new carbon-carbon bonds in their reaction with different electrophiles such as alkyl halides or oxiranes, ketones and aldehydes (equation 21). 

Another approach of regioselective Mizoroki-Heck reactions in ionic liquids is the synthesis of carbonyl compounds [51, 52]. Allylic alcohols (e.g. 12) react with iodoben-zene (5, X = I) via an enolic intermediate (e.g. 13) to the arylated carbonyl product 14 (Scheme 15.4 [52]), which was separated from the reaction mixture by extraction with diethyl ether. However, when choosing the appropriate reaction conditions (solvent and base), the corresponding allylic alcohols were obtained. If Pd(OAc)2 was applied in tetra-butylammonium acetate (as solvent and base) in the coupling of l-octen-3-ol with bromo-or iodobenzene, then selective formation (96 4) of allylic alcohols was achieved in 94% yield in 30 min reaction time at 70 °C [53]. 

Conventional asymmetric aldol reactions have been performed by using chiral enolates and achiral carbonyl compounds. A chiral boron enolate generated from a chiral oxazolidone derivative (26 and 28), dialkylboron tri-fiate, and diisopropylethylamine reacts stereoselectively with aldehydes to afford the corresponding syn aldol adducts (27 and 29) in good yields with excellent diastereoselectivity (Eqs. (8) and (9)) [12]. The opposite sense of asymmetric induction is achieved by changing the chiral auxiliary. Several other chiral auxiliaries have also been developed for highly diastereoselec-tive synthesis of syn aldol adducts (Eqs. (10)-(13)) [13]. 

In a chiral aldehyde or a chiral ketone, the carbonyl faces are diastereotopic. Thus, the addition of an enolate leads to the formation of at least one stereogenic center. An effective transfer of chirality from the stereogenic center to the diastereoface is highly desirable. In most cases of diastereoface selection of this type, the chiral aldehyde or ketone was used in the racemic form, especially in early investigations. However, from the point of view of an HPC synthesis, it is indispensable to use enantiomerically pure carbonyl compounds. Therefore, this section emphasizes those aldol reactions which are performed with enantiomerically pure aldehydes. 

Still another possibility in the base-catalyzed reactions of carbonyl compounds is alkylation or similar reaction at the oxygen atom. This is the predominant reaction of phenoxide ion, of course, but for enolates with less resonance stabilization it is exceptional and requires special conditions. Even phenolates react at carbon when the reagent is carbon dioxide, but this may be due merely to the instability of the alternative carbonic half ester. The association of enolate ions with a proton is evidently not very different from the association with metallic cations. Although the equilibrium mixture is about 92 % ketone, the sodium derivative of acetoacetic ester reacts with acetic acid in cold petroleum ether to give the enol. The Perkin ring closure reaction, which depends on C-alkylation, gives the alternative O-alkylation only when it is applied to the synthesis of a four membered ring ... 

Mannich and related readions provide one of the most fundamental and useful methods for the synthesis of p-amino carbonyl compounds, which constitute various pharmaceuticals, natural products, and versatile synthetic intermediates.1271 Conventional protocols for three-component Mannich-type readions of aldehydes, amines, and ketones in organic solvents indude some severe side reactions and have some substrate limitations, espedally for enolizable aliphatic aldehydes. The dired synthesis of P-amino ketones from aldehydes, amines, and silyl enolates under mild conditions is desirable from a synthetic point of view. Our working hypothesis was that aldehydes could read with amines in a hydro-phobic reaction fidd created in water in the presence of a catalytic amount of a metal triflate and a surfactant to produce imines, which could then read with hydrophobic silyl enolates. 

Heterocycles.—The phosphonium salt (59) is an effective three-carbon synthon, as demonstrated by its reaction with enolates of /9-keto-esters (Scheme 20) to give cyclopentenyl sulphides via an intramolecular Wittig reaction.63 Ylides are also intermediates in the synthesis of dihydrofurans (60) from the cyclopropylphos-phonium salt (61) and sodium carboxylates (Scheme 21).64 Cumulated ylides are very useful for the synthesis of heterocyclic compounds, e.g. (62), from molecules which contain both an acidic Y—H bond and a carbonyl or nitroso-function, as shown in Scheme 22.65... 

Diethyl [(2-tetrahydropyranyloxy)methyl]phosphonate is useful in the Wlttig-Horner synthesis of enol ethers, which are intermediates in one-carbon homologations of carbonyl compounds. This procedure is an adaptation of a general method for making dialkyl hydroxymethylphosphonates. An 0-tetra-hydropyranyl derivative also has been made from dibutyl hydroxymethyl -phosphonate, and diethyl hydroxymethylphosphonate has been O-silylated with tert-butylchiorodimethylsilane and imidazole. Another useful congener in this series has been prepared by an Arbuzov reaction of methoxyethoxymethyl (HEM) chloride and triethyl phosphite. 

Apart from the diols examined so far there are other bis-O nucleophiles that also react with carbonyl compounds following the mechanisms discussed, as illustrated by Figure 9.21. The result is acetal analogs such as the compounds D (from hydroxy carboxylic acid A), E (from enol carboxylic acid wo-B) or F ( Meldrum s acid from malonic acid). Each of these acetal analogs is used as a reagent in organic synthesis. 

The synthesis of dihydrofuran derivatives such as 177 has been performed to explore scope and limitations of the Lewis acid promoted hydroxyalkylation of siloxycyclopropanes. Table 6 shows that aromatic as well as aliphatic ketones can efficiently be incorporated. Enolization of ketones does not occur and a 1-methyl group at the cyclopropane is no obstacle for the reaction, which now binds the carbonyl compound to a quartemary center with surprisingly high efficiency (entry 5). Albeit there are some restrictions with regard to the substitution pattern of the cyclopropanes, bicyclic siloxycyclopropanes also give good yields (e.g. entry 6 and Eq. 76). Further examples of the tetrahydrofuran synthesis from intermediate y-lactols with... 

When the Wittig reaction was introduced (Chapter 14) we saw it simply as an alkene synthesis. Now if we look at one group of Wittig reagents, those derived from a-halo-carbonyl compounds, we can see that they behave as specific enol equivalents in making unsaturated carbonyl compounds. 

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