Dialkylation enolates

The Perkow reaction has been used to generate a wide range of vinyl phosphates. Reaction of trialkyl phosphites with a-halogeno-ketones provide vinyl phosphates.1-5 Alkenes are produced via reduction of the dialkyl enol phosphate using either sodium or lithium in liquid ammonia. 

Ketones, in which one alkyl group R is sterically demanding, only give the trans-enolate on deprotonation with LDA at —12°C (W.A. Kleschick, 1977, see p. 60f.). Ketones also enolize regioseiectively towards the less substituted carbon, and stereoselectively to the trans-enolate, if the enolates are formed by a bulky base and trapped with dialkyl boron triflates, R2BOSO2CF3, at low temperatures (D A. Evans, 1979). Both types of trans-enolates can be applied in stereoselective aldol reactions (see p. 60f.). 

Examples of the remaining potential 3,4-dihydroxy heterocycles are presently restricted to furan and thiophene. Although the parent 3,4-dihydroxyfuran apparently exists as the dioxo tautomer (86), derivatives bearing 2-alkyl or 2,5-dialkyl substituents prefer the keto-enol structure (87) (71T3839, 73HCA1882). The thiophene analogues also prefer the tautomeric structure (87), except in the case of the 2,5-diethoxycarbonyl derivative which has the fully aromatic structure (88) (71T3839). 

Enol ethers of 17-ketones are formed by pyrolysis of the corresponding dialkyl ketals and enol acetates are readily prepared by the exchange procedure.The latter derivatives are widely used as reactive intermediates for the introduction of substituents at C-16. 

Xenon difluoride [55], xenon difluoride complexed with dialkyl sulfides [59], and xenon difluoride intercalated with graphite [90] are all effective reagents for the fluonnalion of acids, enolates, or enols (Table 2)... 

In the alkylation of enolate anions, a mixture of mono- and polyalky lation produets is usually obtained, and when enolization of a di-a-methylene ketone is possible toward both sides, a mixture of di-a- and a,a -dialkylation products ean be expeeted. Thus the enamine alkylation sequenee beeomes partieularly attractive when eontrolled monoalkylation is imperative beeause of difficulties in separation of a mixture of alkylation produets. One of its first synthetie applications was in the reaetions of /8-tetralones with alkyl halides. Yields in exeess of 80% were usually found 238-243) in these reaetions, which make valuable intermediates for steroid and diterpene syntheses more aecessible. 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

Dialkyl-3-hydroxyselenophenes exist in a keto-enol equilibrium 82 83 (72CS9). Analysis of the ionization potentials showed that for these compounds both the keto and the enol form are important [75ACS(B)652]. 

The rate of the alkylation reaction depends on the enolate concentration, since it proceeds by a SN2-mechanism. If the concentration of the enolate is low, various competitive side-reactions may take place. As expected, among those are E2-eliminations by reaction of the alkyl halide 2 with base. A second alkylation may take place with mono-alkylated product already formed, to yield a -alkylated malonic ester however such a reaction is generally slower than the alkylation of unsubstituted starting material by a factor of about 10. The monoalkylation is in most cases easy to control. Dialkylated malonic esters with different alkyl substituents—e.g. ethyl and isopropyl—can be prepared by a step by step reaction sequence ... 

Ketones, esters, and nitriles can all be alkylated using LDA or related dialkyl-amide bases in THE. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. 

The chiral lithium enolate 2 reacts with symmetrical ketones to produce /(,/i-dialkyl-/l-hydroxy-acyl complexes 3 which serve as precursors to oc,/1-unsaturated iron complexes (see Section 1.3.4.2.5.1.1.). 

Silyi enol ethers can be dimerized to symmetrical 1,4-diketones by treatment with Ag20 in DMSO or certain other polar aprotic solvents." The reaction has been performed with R , R = hydrogen or alkyl, though best yields are obtained when r = r = H. In certain cases, unsymmetrical 1,4-diketones have been prepared by using a mixture of two silyi enol ethers. Other reagents that have been used to achieve either symmetrical or cross-coupled products are iodosobenzene-Bp3-Et20," ceric ammonium nitrate," and lead tetraacetate." If R =0R (in which case the substrate is a ketene silyi acetal), dimerization with TiCU leads to a dialkyl succinate (34, r =0R)." ... 

Phosphorylation of enolate ions by dialkyl or diaryl phosphorochlori-dates gives exclusive O-phosphorylation and it appears that the product geometry in acyclic systems is determined by the polarity of the solvent and... 

Asymmetric conjugate addition of dialkyl or diaryl zincs for the formation of all carbon quaternary chiral centres was demonstrated by the combination of the chiral 123 and Cu(OTf)2-C H (2.5 mol% each component). Yields of 94-98% and ee of up to 93% were observed in some cases. Interestingly, the reactions with dialkyl zincs proceed in the opposite enantioselective sense to the ones with diaryl zincs, which has been rationalised by coordination of the opposite enantiofaces of the prochiral enone in the alkyl- and aryl-cuprate intermediates, which precedes the C-C bond formation, and determines the configuration of the product. The copper enolate intermediates can also be trapped by TMS triflate or triflic anhydride giving directly the versatile chiral enolsilanes or enoltriflates that can be used in further transformations (Scheme 2.30) [110],... 

Note also that dialkyl ketones such as acetone and 3-pentanone are slightly more acidic than the simple alcohols in DMSO. Use of alkoxide bases in DMSO favors enolate formation. For the amide bases, -K b-h) << a(c-H)> and complete formation of the enolate occurs. 

Deprotonation of the corresponding carbonyl compound is a fundamental method for the generation of enolates, and we discuss it here for ketones and esters. An unsymmetrical dialkyl ketone can form two regioisomeric enolates on deprotonation. 

A careful study of the alkylation of several enolates of dialkyl malate esters has been reported.74 These esters form dianions resulting from deprotonation of the hydroxy... 

Summary of Facial Stereoselectivity in Aldol and Mukaiyama Reactions. The examples provided in this section show that there are several approaches to controlling the facial selectivity of aldol additions and related reactions. The E- or Z-configuration of the enolate and the open, cyclic, or chelated nature of the TS are the departure points for prediction and analysis of stereoselectivity. The Lewis acid catalyst and the donor strength of potentially chelating ligands affect the structure of the TS. Whereas dialkyl boron enolates and BF3 complexes are tetracoordinate, titanium and tin can be... 

Sekine, M., Kume, A., Nakajima, M., and Hata, T., A new method for acylation of enolates by means of dialkyl acylphosphonates as acylating agents, Chem. Lett., 1087, 1981. 

Two reports are available on the rearrangement of mixed vinyl phosphite esters to produce phosphonate diesters in moderate yield.94 95 In both instances, the vinyl phosphite esters were prepared by reaction of the dialkyl phosphorous chloride with highly enolized carbonyl compounds. The mixed ester products undergo thermal rearrangement to the phosphonate diesters (Figure 6.25). 

A similar method has been described by Badia and co-workers who used chiral amides derived from pseudoephe-drine.139 Moreover, a zirconium-mediated Claisen-aldol tandem reaction of an a,cr-dialkylated ester with several aldehydes has been reported (Scheme 39).140 After the initial Claisen condensation, zirconium enolate intermediate 92 reacts with various types of aldehydes through aldol-type reaction and subsequent lactonization, providing the corresponding pyran-2,4-diones. 

Dialkyl(trimethylsilyl)phosphines undergo 1,4-addition to a,/3-unsaturated ketones and esters to give phosphine-substituted silyl enol ethers and silyl ketene acetals, respectively. A three-component coupling reaction of a silylphosphine, activated alkenes, and aldehydes in the presence of a catalytic amount of GsF affords an aldol product (Scheme 76).290 291... 

Many of the reactions assembled in Scheme 5.4are of undiminished interest in modern allene chemistry when relatively simple alkyl derivatives are the preparative goal. For example, /3-eliminations of enolphosphates prepared from saturated ketones constitute a simple route to 1,3-dialkylated allenes. Thus 3-octanone (49), on LDA treatment followed by quenching the generated enolate ions with diethyl chlor-ophosphate, affords a mixture of the enolphosphates 50. When these are treated with further LDA in THF at low temperatures, 2,3-octadiene (51) is produced in 50% yield (Scheme 5.5) [15]. 

The calculation for dibenzylphosphoenolpyruvate assumes that the enol dibenzyl phosphate will have the same reactivity towards bimolecular attack by RCOOH as the dialkyl phosphate group of A.5.5. The comparison between A.5.3 and A.5.4 shows that the substitution of an alkoxy group by phenyl increases the reactivity by an order of magnitude towards COOH, and this factor allows us to put the phosphonate A.5.1 on the scale. The intrinsic reactivity of A.5.1 and A.5.2 are assumed the same b Gordon el al., 1964 Blackburn and Brown, 1969 c van Holst el al., 1974... 

A broad range of compounds can be O-alkylated with carbene complexes, including primary, secondary, and tertiary alcohols, phenols, enols, hemiaminals, hydroxylamines, carboxylic acids, dialkyl phosphates, etc. When either strongly acidic substrates [1214] and/or sensitive carbene precursors are used (e.g. aliphatic diazoalkanes [1215] or diazoketones) etherification can occur spontaneously without the need for any catalyst, or upon catalysis by Lewis acids [1216]. 

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