Alkyl derivatives enolate compounds

The chiral A/ -propionyl-2-oxazolidones (32 and 38) are also useful chiral auxiliaries in the enantioselective a-alkylation of carbonyl compounds, and it is interesting to observe that the sense of chirality transfer in the lithium enolate alkylation is opposite to that observed in the aldol condensation with boron enolates. Thus, whereas the lithium enolate of 37 (see Scheme 9.13) reacts with benzyl bromide to give predominantly the (2/ )-isomer 43a (ratio 43a 43b = 99.2 0.8), the dibutylboron enolate reacts with benzaldehyde to give the (3R, 25) aldol 44a (ratio 44a 44b = 99.7 0.3). The resultant (2R) and (25)-3-phenylpropionic acid derivatives obtained from the hydrolysis of the corresponding oxazolidinones indicated the compounds to be optically pure substances. 

A mechanistic study of acetophenone keto-enol tautomerism has been reported, and intramolecular and external factors determining the enol-enol equilibria in the cw-enol forms of 1,3-dicarbonyl compounds have been analysed. The effects of substituents, solvents, concentration, and temperature on the tautomerization of ethyl 3-oxobutyrate and its 2-alkyl derivatives have been studied, and the keto-enol tautomerism of mono-substituted phenylpyruvic acids has been investigated. Equilibrium constants have been measured for the keto-enol tautomers of 2-, 3- and 4-phenylacetylpyridines in aqueous solution. A procedure has been developed for the acylation of phosphoryl- and thiophosphoryl-acetonitriles under phase-transfer catalysis conditions, and the keto-enol tautomerism of the resulting phosphoryl(thiophosphoryl)-substituted acylacetonitriles has been studied. The equilibrium (388) (389) has been catalysed by acid, base and by iron(III). Whereas... 

Intramolecular diastereoselective alkylation of the exocyclic enolate derived from compound 6 results in cyclization yielding bicyclic 7 in 94%. 

Steric control elements are also important for the diastereoselectivity in alkylations of mono-cyclic cyclohexanone enolates. However, electronic control becomes more evident in these systems compared to monocyclic cyclopentanone enolates The flexibility of the six-membered ring system, and the large number of possible ring conformations, makes predictions of the diastereoselectivity difficult. In general, one may conclude that the diastereoselectivity in alkylations of enolates derived from monocyclic cyclohexanones is not as high as in alkylations of cyclopentanone enolates. The syntheses of compounds 21-27 demonstrate the effect of substitution in each position of the six-membered ring49,61 -7°. 

Several enolates derived from the diastereomeric mixtures of 11 and 12 can be diastereoselec-tively alkylated with bulky electrophiles31. One example of this is provided by the alkylation of the enolate derived from compound 13 with benzyl bromide which mainly gives the diastereomer 14 (d.r. 14 epimer 95 5). 

The alkylation of enolates from 1-acyl-2-pyrrolidinemethanols is not limited to compounds carrying two a-hydrogens. An example of an interesting type of dianion is that derived from the a-oxoamide 17, which is then alkylated with iodomethane to give a 87 13 ratio of diastereomers, as determined by NMR7. 

With multigram quantities of compounds (181) and (182) in hand, attention was turned to the stereoselective alkylation of their derived enolates. The lactones (181) were smoothly transformed to their corresponding dianions which subsequently suffered alkylation favoring the expected trans product (183a)185>. 

In chapter 10 we compared C-C disconnections with related two-group C-X disconnections, mainly at the alcohol oxidation level. In this chapter we deal more fully with carbonyl compounds, chiefly aldehydes and ketones, by two related disconnections. We start by comparing the acylation of heteroatoms by acid derivatives such as esters (a 1,1-diX disconnection 1 that can also be described as a one-group C-X disconnection) with the acylation of carbon nucleophiles and move on to compare the 1,2-diX disconnection 3 with the alkylation of enolates 6. Here we have reversed the polarity. We mention regioselectivity—a theme we shall develop in chapter 14. 

Phenylthioalkylation of silyl enol ethers. Silyl enol ethers of ketones, aldehydes, esters, and lactones can be alkylated regiospecifically by a -chloroalkyl phenyl sulfides in fhe presence of a Lewis acid. Zinc bromide and titanium(IV) chloride are the most effective catalysts. The former is more satisfactory for enol ethers derived from esters and lactongs. ZnBr2 and TiCL are about equally satisfactory for enol ethers of ketones. The combination of TiCL and Ti(0-f-Pr)4 is more satisfactory for enol ethers of aldehydes. Since the products can be desulfurized by Raney nickel, this reaction also provides a method for alkylation of carbonyl compounds. Of more interest, sulfoxide elimination provides a useful route to a,B-unsaturated carbonyl compounds. 

Classic synthetic methods based upon the alkylation of enolates were therefore limited to cases where especially stable enolates could be generated. Usually )S-dicarbonyl compounds such as acetoacetic ester or malonic ester were used as precursors in these reactions. For example, alkylation of the stable enolate derived from malonic ester served as a routine and totally reliable method to achieve C2 chain elongation, as shown in the standard sequence below ... 

W-Alkylidene derivatives of glycine esters are the preferred starting compounds for the synthesis of unnatural amino acids via the deprotonation/alkylation procedure. Enolate formation is achieved with a strong base (LDA, BuLi, or phosphazene bases such as 2- tert-butylimino)-2-(ethylamino)-l,3-dimethyl-l,3,2-diazaphosphinane) or by phase-transfer catalysis (tetraalkylammonium salts with NaOH or the latter method allows... 

Acrylonitrile alkylates the enolate anion derived from a pregn-17(20)-en-21-al (226), or similar compounds, to give 16-cyanoethyl derivatives (227), which... 

In addition to their reactions with trlmethylsilyl enol ethers, (propargyl1um)Co2(C0)g complexes react with a variety of other mild carbon nucleophiles including activated aromatic compounds, g-dicarbonyl compounds, other enol derivatives (enol acetates and ketones directly), allylsilanes, and alkyl- and alkynyl-aluminum reagents. These reactions provide a flexible means to introduce the synthetically versatile propargyl function. Key features of propargylations using these complexes are 1) ready... 

The a-alkylation of carbonyl compounds by their conversion into nucleophilic enoiates or enolate equivalents and subsequent reaction with electrophilic alkylating agents provides one of the main avenues for regio- and stereo-selective formation of carbon-carbon a-bonds. " Classical approaches to a-alkylation typically involve the deprotonation of compounds containing doubly activated methylene or methine groups and having p/iTa values of 13 or below by sodium or potassium alkoxides in protic solvents. Since these conditions lead to monoenolates derived from deprotonation only at the a-site of the substrate, the question of the regioselectivity of C-alkylation does not arise (however, there is competition between C- and 0-alkylation in certain cases). In more recent years, dienolates of p-dicarbonyl compounds have been utilized in -alkylations with excellent success. 

This chapter will provide coverage of the scope and limitations of alkylations of metal enolates of saturated and unsaturated ketones, aldehydes and carboxylic acid derivatives, together with a discussion of alkylations of various enols and enolate equivalents. Where applicable, the utility of these reactions for the diastereoselective and enantioselective synthesis of a-substituted carbonyl compounds will be described. Inevitably, the coverage of a vast research area such as this will be incomplete and in part will reflect the author s interests. However, it is hoped that most of the useful methods of carbon-carbon o-bond formation by alkylations of enolates and enols will be included. 

Alkylation of enolate anions usually gives C-alkylation and is therefore not suitable for the preparation of enol ethers. The exception is when triethyloxonium tetrafluoroborate is used as the alkylating agent in a dipolar aprotic solvent. 0-Alkylation can be regioselectiveiy achieved if the enolate anion is derived from acetoacetate or a similar compound. On the other hand, 0-acylation of enols or enolate anions is quite common. Enol esters can therefore be prepared readily from the parent carbonyl compounds. For... 

For the alkylation of enolates, chromium tricarbonyl complexes of aromatic compounds (benchrotrenes) are useful, as they make simple aromatic compounds chiral. Thus, enantiomer-ically pure (indanone)tricarbonylchromium (2R)-25 has been prepared by resolution of the racemic benchrotrene derivative with cinchonidine and oxidation of the alcohol to the ketone with manganese dioxide60. The chiral ketone is alkylated diastereoselectively via the enolate, leading to the f.vo-2-methyl derivative (2/ )-25 which has been used in enolate alkylations and annulation reactions (Section D.1.5.2.4.). If necessary, complete isomerization to the endo-methyl compound can be achieved by treatment with base. 

Another technique is to block one of the a-positions by introduction of a removable substituent which prevents formation of the corresponding enolate. Selective alkylation can be performed after acylation with ethyl formate and transformation of the resulting formyl (or hydroxymethylene) substituent into a group that is stable to base, such as an enamine, an enol ether or an enol thioether. An example of this procedixre is shown in Scheme 1.16, in the preparation of 9-methyl-1-decalone from rra 5-1-decalone. Direct alkylation of this compound gives mainly the 2-alkyl derivative, whereas blocking the 2-position allows the formation of the required 9-alkyl-1-decalone (as a mixture of cis and trans isomers). 

Arylthallium bis(trifluoroacetate)s are converted by successive treatment with KF and BF3 into aryl fluorides.Thallium(iii) nitrate (TTN) readily oxidizes dialkyl sulphides and selenides to the corresponding sulphoxides or selenoxides, and 2-(alkylthio)-l-arylethanones (37) into compounds (38) in methanolic solution.In a modification of the TTN oxidative conversion of aryl alkyl ketones into arylacetic acids, enol ethers derived from the ketones are used instead of the ketones themselves. This reduces the formation of side products. Cyclic aralkyl ketones (39) may be ring-expanded and alkylated to give compounds (40) via treatment of their Wittig-derived alkenes with TTN/ an extrapolation of the basic reaction discovered previously. 

---