Potassium enolates alkylation

Stork and his colleagues, working with nonsteroidal compounds, have shown that only lithium enolates may be alkylated successfully in ammonia or tetrahydrofuran. The more basic sodium and potassium enolates undergo... 

Electrostatic interactions can guide alkylation under certain conditions. Examine the electrostatic potential map of the potassium enolate of ethyl acetoacetate. Is carbon or oxygen more electron rich Are electrostatic interactions likely to favor addition of oxygen or carbon Examine atomic charges and electrostatic potential maps for diethylsulfate, ethyl chloride, ethyl bromide and ethyl iodide, pay attention to the backside of the electrophilic carbon. Order the systems from most to least electron poor. Which reaction is most likely to be guided by electrostatics Least likely Can the experimental results be fully explained on this basis ... 

Ester enolates are somewhat less stable than ketone enolates because of the potential for elimination of alkoxide. The sodium and potassium enolates are rather unstable, but Rathke and co-workers found that the lithium enolates can be generated at -78° C.69 Alkylations of simple esters require a strong base because relatively weak bases such as alkoxides promote condensation reactions (see Section 2.3.1). The successful formation of ester enolates typically involves an amide base, usually LDA or LiHDMS, at low temperature.70 The resulting enolates can be successfully alkylated with alkyl bromides or iodides. HMPA is sometimes added to accelerate the alkylation reaction. 

Alkylations of this type also proved to be sensitive to the cation. Good stereoselectivity (15 1) was observed for the lithium enolate, but the sodium and potassium enolates were much less selective.75 This probably reflects the weaker coordination of the latter metals. 

Diketones. Potassium enolates of some ketones can dimerize with incorporation of a methylene group from DMF to give 1,5-diketones. This novel reaction requires a rert-alkyl or phenyl group attached to the carbonyl group.2... 

This procedure for the acetylation of methyl alkyl ketones to form /3-diketones is a modification5 of an earlier procedure, which used boron trifluoride gas as the catalyst.6 3-n-Butyl-2,4-pentanedione has also been prepared by the acetylation of 2-heptanone catalyzed with boron trifluoride gas,7 by the thermal rearrangement of the enol acetate of 2-heptanone,7 and by the alkylation of the potassium enolate of 2,4-pentanedione with n-butyl bromide.8... 

A typical example is alkylation of the steroid ester 11. Treatment of 1 with LDA in tetrahydrofuran at —78 °C for 1 hour followed by addition of 4-bromo-2-methyl-2-butene in the presence of HMPA at —78 °C to —20 °C furnished an 87 13 mixture of the monoalkylated esters 3a and 3b. The potassium enolate 2 (KHMDS, THF, —78 °C, 1 h) has been hydroxylated with an oxaziridine reagent in 70% yield to give a 3 1 mixture of a-hydroxy derivatives. 

Polymer-supported reagent. HMPT supported on a polystyrene-type resin is a catalyst for SN2 reactions5-7 and for reduction of ketones by NaBIi4.7 It also has a marked effect on the alkylation of ethyl acetoacetate with diethyl sulfate. In the presence of solid HMPT the enolales undergo 60 70% O-alkylation. In the absence of HMPT, the lithium enolate does not react and the sodium and potassium enolates undergo C-alkylation (90-100%). There is some difference in the effect of solid and liquid I1MPT The solid HMPT increases the reactivity of the K. enolate more than the liquid form, whereas the reverse is true with the Li enolate.8... 

Nowick and Danheiser have employed the Horner-Emmons reaction of a-phosphon-oacyl silanes to prepare a,/l-unsaturated acyl silanes in 54-97% yields116. The a-phosphonoacetyl silane intermediate (21), prepared from a-iodoacetyl t-butyldimethylsilane through the Arbuzov reaction, undergoes enolate alkylation, for example using potassium t-butoxide and methyl iodide the alkylated products also underwent Horner-Emmons reaction (Scheme 53). 

C-Carboxylation of enolates.1 Carboxylation of potassium enolates generated from silyl enol ethers is not regioselective because of extensive enolate equilibration. Regiospecific C-carboxylation of lithium enolates is possible with carbonyl sulfide in place of carbon dioxide. The product is isolated as the thiol methyl ester. If simple esters are desired, transesterification can be effected with Hg(OAc)2 (8, 444). Carboxylation of ketones in this way in the presence of NaH and DMSO is not satisfactory because of competing alkylation of the enolate.2 Example ... 

Gill and Lubell have also reported a complementary 4-keto-L-proline alkylation procedure using the potassium enolate of ketone 55.50 In this instance, regiospecific alkylation using methyl bromoacetate gave a 91% yield of a 2 1 trans cis ratio of diastereoisomers of ketone 56 (Scheme... 

SCHEME 97. Hydroxypinan-3-one-directed alkylation of glycine lithium and potassium enolates and proposed stmcture for the dimer of the lithium enolate (S = solvent)475,476... 

The potassium enolate generated from 23 is regarded as an enantiomeric atropisomer. Recently non-biaryl atropisomers have been receiving more attention in asymmetric synthesis.19 Most of them employ atropisomers that are configurationally stable at room temperature, while attention in this chapter is focused on asymmetric reactions that proceed via chiral nonracemic enolate intermediates that can exist only in a limited time. An application of configurationally stable atropisomeric amide to a chiral auxiliary for stereoselective alkylation has been reported by Simpkins and co-workers (Scheme 3.10).20... 

Direct nucleophilic addition of potassium enolates derived from bis(trimethylsilyl)ketene acetals to aromatic chromium-complexed aromatic ethers affords meta substituted products (Scheme 124). A very high degree of asymmetric induction is obtained upon reaction of chiral arene chromium tricarbonyl complexes. For example, alkylation of complex (80)gave (81)afterdecomplexation(Scheme 125). ... 

Potassium enolates of aldehydes, Enolates of aldehydes are somewhat difficult to generate because of competing polymerization by base. They have been obtained recently in high yield by use of potassium hydride in THF at 0° and successfully alkylated, sulfenylated with diphenyl disulfide, and converted into o-iodo aldehydes by iodine. The last two reactions have not been observed previously. Sulfenylation of aldehydes has previously used indirectly generated lithium enolates and a reactive sulfenyl chloride. All three reactions are useful, however, for aldehydes with only one a-proton. Otherwise yields of monosubstituted aldehydes are low and largely by-products are obtained. 

Selective a-alkylalion of ketones Potassium enolates of ketones and an unhindered trialkylborane such as triethylborane form a potassium enoxytriethyl-borate, which undergoes selective a -monoalkylation with alkyl halides in high yield. Lithium enolates do not form the corresponding borates. In the absence of triethylborane dialkylated products are formed and some of the original ketone is recovered. 

The same chiral auxiliary has also been used for the stereoselective synthesis of arene-chromium complexes treatment of an aromatic aminal with chromium hexacarbonyl gives the corresponding complex with high diastereomeric excess. This protocol was recently applied in a total synthesis of (—)-lasubine (eq 4). A successful application of 1,2-diaminocyclohexane (as its IR,2R enantiomer) as a chiral auxiliary is illustrated by the di-astereoselective alkylation of the potassium enolate of bis-amide (3) with electrophiles such as benzyl bromide to give bis-alkylated products with excellent diastereoselectivity (eq 5). Lower levels... 

Alkylation of potassium enolates is not always fruitful, and so counterion exchange with lithium bromide prior to addition of the electrophile has been recommended. Reduction of aromatic esters instead of acids provides a number of potential advantages. The esters tend to be more soluble than carboxylate salts, hydrogenolysis of 2-alkoxy substituents does not appear to present the s me problem, and the products are more stable. This can be important when enol ether functions are generated, allowing the necessarily acidic work-up procedures for carboxylic acids to be avoided. Indeed, the hydrolysis of enol ether functions may be very slow in aqueous acid and is best achieved through catalysis by mercury(II) nitrate. ... 

An efficient synthetic sequence for the preparation of 2,4-b/s(trifluoromethyl)furan was developed by R. Filler and co-workers. " The potassium enolate of ethyl 4,4,4-trifluoroacetate was reacted with 3-bromo-1,1,1-trifluoroacetate in DMSO to afford 2,4-bis (trifluormethyl)-4-hydroxydihydro-3-furoate as a result of O-alkylation. Interestingly, under these conditions usually C-alkylation is preferred. Next, dehydration was performed to give the corresponding 2,4-bis (trifluoromethyl)-3-furoate in good yield. Finally, decarboxylation by heating with quinoline and CUSO4 yielded the target furan in excellent yield. 

An illustration of this behavior is provided in equation (1). A 67 33 mixture of the less- and more-substituted potassium enolates was produced upon treatment of 2-methylcyclohexanone with tritylpotassium in DME. However, the major product of alkylation of this mixture with methyl iodide was 2,2-dimethyl-cyclohexanone and significant amounts of tri- and tetra-methylcyclohexanone were also obtained. ... 

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