Sodium enolates

Ethyl M-butylcyanoacetate has been prepared by alkylation of the sodium enolate of ethyl cyanoacetate with butyl bromide and by condensation of capronitrile with ethyl carbonate, in addition to the method given above. ... 

Kinetics of the reaction of p-nitrochlorobenzene with the sodium enolate of ethyl cyanoacetate are consistent with this mechanism. Also, radical scavengers have no effect on the reaction, contrary to what would be expected for a chain mechanism in which aryl radicals would need to encounter the enolate in a propagation step. The reactant, /i-nitrophenyl chloride, however, is one which might also react by the addition-elimination mechanism, and the postulated mechanism is essentially the stepwise electron-transfer version of this mechanism. The issue then becomes the question of whether the postulated radical pair is a distinct intermediate. 

Lithium-ammonia reduction of l7a-ethyl-19-nortestosterone (68) using Procedure 8a (section V) affords the 4,5a-dihydro compound (69) in 85% yield after a reaction time of 12 minutes after a reaction time of 80 minutes, the yield of (69) is 76%. Lfsing sodium in the same reduction, the yields of compound (69) are 79 and 77 % after reaction times of 8 and 80 minutes respectively. Both the lithium and sodium enolates appear to be reasonably stable in liquid ammonia in the presence of alkali metal. Since the enolate salts are poorly soluble in ammonia, their resistance to protonation by it may be due in part to this factor. 

Alkylation of enamines with epoxides or acetoxybromoalkanes provided intermediates for cyclic enol ethers (668) and branched chain sugars were obtained by enamine alkylation (669). Sodium enolates of vinylogous amides underwent carbon and nitrogen methylation (570), while vicinal endiamines formed bis-quaternary amonium salts (647). Reactions of enamines with a cyclopropenyl cation gave alkylated imonium products (57/), and 2-benzylidene-3-methylbenzothiazoline was shown to undergo enamine alkylation and acylation (572). A cyclic enamine was alkylated with methylbromoacetate and the product reduced with sodium borohydride to the key intermediate in a synthesis of the quebrachamine skeleton (57i). 

A modification of the K-R reaction was introduced by Mozingo. This method involved reacting an o-hydroxyacetophenone with an ester in the presence of metallic sodium to form a 1,3-diketone. Treatment of the diketone with an acid then delivered the chromone via an intramolecular cyclization reaction. This method was applied to the preparation of 2-ethylchromone (21). 0-hydroxyarylketone 22 was allowed to react with ethyl propionate (23) in the presence of sodium metal.The resulting sodium enolate was then quenched with acetic acid to deliver the 1,3-diketone 24. Upon heating 24 in glacial acetic acid and hydrochloric acid, 2-ethylchromone (21) was delivered in 70-75% overall yield. 

The experimental conditions for the syntheses starting from acid chlorides of hydroxamic acids and from nitrile oxides are somewhat different. In the former case the other component of the reaction is organometallic, usually an organomagnesium derivative of an acetylene or, less frequently, a sodium enolate of a /8-diketone. Nitrile oxides condense directly with unsaturated compounds. 

Oxidation of the sodium enolate of 15b, prepared by using NaHMDS, with ( )-2-phenylsulfonyl-3-phenyloxaziridine yielded the desired 7-hydroxy derivative 23 (R = H) and its C(7) epimer with a very low... 

The synthesis of key intermediate 6 begins with the asymmetric synthesis of the lactol subunit, intermediate 8 (see Scheme 3). Alkylation of the sodium enolate derived from carboximide 21 with allyl iodide furnishes intermediate 26 as a crystalline solid in 82 % yield and in >99 % diastereomeric purity after recrystallization. Guided by transition state allylic strain conformational control elements5d (see Scheme 4), the action of sodium bis(trimethylsilyl)amide on 21 affords chelated (Z)-enolate 25. Chelation of the type illustrated in 25 prevents rotation about the nitrogen-carbon bond and renders... 

Carbanions of active methylene compounds also react with aziridine-2-car-boxylic esters to give ring-opened products [129]. The ring-opened intermediates usually cyclize spontaneously to pyrrolidones. Treatment of 190 (Scheme 3.70) with the sodium enolate of dimethyl malonate 191, for example, afforded pyrroli-done 192 in 15% isolated yield, together with 30% of the debenzoylated product 193. 

The quantitative and diastereoselective addition of the sodium enolate of te/7-buty] 5-methyl-3-oxohexanoate to the Michael acceptor 2 was used in the synthesis of 0-methyl pisiferic acid280. 

Chiral phosphinous amides have been found to act as catalysts in enantio-selective allylic alkylation. Horoi has reported that the palladium-catalyzed reaction of ( )-l,3-diphenyl-2-propenyl acetate with the sodium enolate of dimethyl malonate in the presence of [PdCl(7i-allyl)]2 and the chiral ligands 45 gave 46 in 51-94% yields and up to 97% ee (Scheme 38). It is notorious that when the reaction is carried out with the chiral phosphinous amide (S)-45a, the product is also of (S) configuration, whereas by using (R)-45b the enantiomeric (R) product is obtained [165]. 

The rate of alkylation of enolate ions is strongly dependent on the solvent in which the reaction is carried out.41 The relative rates of reaction of the sodium enolate of diethyl n-butylmalonate with n-butyl bromide are shown in Table 1.3. Dimethyl sulfoxide (DMSO) and iV,Ai-dimethylformamide (DMF) are particularly effective in enhancing the reactivity of enolate ions. Both of these are polar aprotic solvents. Other... 

For enolates with additional functional groups, chelation may influence stereoselectivity. Chelation-controlled alkylation has been examined in the context of the synthesis of a polyol lactone (-)-discodermolide. The lithium enolate 4 reacts with the allylic iodide 5 in a hexane THF solvent mixture to give a 6 1 ratio favoring the desired stereoisomer. Use of the sodium enolate gives the opposite stereoselectivity, presumably because of the loss of chelation.61 The solvent seems to be quite important in promoting chelation control. 

Preparation of XIII proceeded as described by Sih (8) and yields of about 85% (reported 93%) were obtained. The coupling step of XIII with the bromobutenolide (XIV) (see Figure 2) proceeded to form a mixture of strigol and epistrigol in approximately the yields reported by Sih (8). An attempt to use the sodium enolate with the... 

The literature preparation (11) of the two-ring analog of strigol (2-RAS) involved reacting the sodium enolate (XIX) with the mesylate (XX) to form 2-RAS (XXI). In our work we found it very difficult to prepare and purify the mesylate. Low yields of 2-RAS contaminated with XVIII resulted. 

In our experience, better results were obtained using the method of Cassady and Howie (17) than by the mesylate route. Thus the sodium enolate (XIX) is reacted with the bromobutenolide (XIV) in acetonitrile to form the 2-RAS (XXI) in 50-60% crude yields which after column chromatography provided 20-30% of XXI. Similar yields were obtained when tetrahydrofuran (THF) was used as the solvent,... 

Another two ring analog of strigol was prepared in a similar manner from the sodium enolate of a-valerolactone (XXII) and XIV. There is a methyl group at the 5-position of the ring which would correspond to the C-ring of strigol, so the shorthand for this compound is Me-2-RAS (XXIII). Johnson and co-workers (21) had... 

The final ring coupling reaction is usually an O-alkylation of the sodium enolate with a methyl sulfonate-, bromo-, or chloro-butenolide in acetonitrile or an ether solvent (8.22-24). Use of the methyl sulfonate derivative is least preferred because of its poor stability (9,24). The isolated hydroxymethylene lactone can be allowed to react with the bromobutenolide using potassium carbonate in hexamethylphosphoric triamide (caution a potential carcinogen). 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

The isolation of calycanthine (9) in 1888 by Eccles [28] and the subsequent proposition for its origins in the oxidative dimerization of tryptamine by Woodward [29] and Robinson [30] had prompted several key synthetic studies based on a biomimetic approach. Hendrickson was the first to experimentally verify the plausibility of forming the C3-C3 linked dimers through an oxidative radical dimerization strategy (Scheme 9.2a). He demonstrated that the sodium enolate of a tryptamine-derived oxindole could be oxidized with iodine to afford a mixture of three possible stereoisomers. The racemic product was isolated in 13 % yield, while the meso product was isolated in 8 % yield. Global reduction of the oxindole and carbamates afforded the first synthetic samples of chimonanthine (7) [9a],... 

A 2-1. three-necked flask is mounted on a steam bath and fitted with a reflux condenser, a separatory funnel, and an efficient sealed stirrer. In the flask is placed 600 cc. of absolute alcohol, and to this is added gradually 46 g. (2 gram atoms) of clean sodium cut into small pieces.1 The sodium ethoxide solution is stirred and cooled to room temperature, after which 267 g. (260 cc., 2.05 moles) of ethyl acetoacetate (Note 1) is added slowly through the separatory funnel. The reflux condenser is then replaced by a short still head, and the alcohol is removed by distillation at approximately room temperature and under the pressure of a water pump. When approximately half the alcohol has been removed, sufficient sodium enolate precipitates so that stirring has to be discontinued. When the residue appears dry (after about two hours) the last traces of alcohol are removed by heating for an hour on the steam bath under a pressure of 2 mm. The flask is allowed to cool to room temperature under reduced pressure. 

To the cooled residue of sodium enolate is added 600 g. (570 cc., 4 moles) of ethyl benzoate. The steam bath is replaced... 

TABLE 4-19. Diasteroselective Hydroxylation of Chiral Carboximide Sodium Enolates Using 2-(Phenylsulfonyl)-3-Phenyl-Oxaziridine (141) in THF at — 78°C... 

In contrast to the oxidation of prochiral esters and amides, which induces only moderate ee, sodium enolates of ketones give high stereoselectivity with (+)-147 or (—)-147 as the oxidant (Scheme 4-56 and Table 4-21). The highest stereoselectivity has been observed in the oxidation of the sodium enolate of deoxybenzoin 150, in which benzoin 149 can be obtained in over 95% optical purity. 

In the presence of catalytic amounts of sodium methoxide, dimethylketene /3-lactone dimer is polymerized at moderate temperature to a polyester.3 At higher temperatures (above 100°), disproportionation to the cyclic trimer, hexamethyl-1.3,5-cyclohexanetrione, takes place.9 Addition of a stoichiometric amount of sodium methoxide to the lactone dimer generates the sodium enolate of methyl 2,2,4-trimethyl-3-oxovalerate. This reaction provides a convenient entry into certain ester anion chemistry that formerly required the use of a strong base like tritylsodium.10... 

The stereoselective total synthesis of both ( )-corynantheidine (61) (170,171) (alio stereoisomer) and ( )-dihydrocorynantheine (172) (normal stereoisomer) has been elaborated by Szdntay and co-workers. The key intermediate leading to both alkaloids was the alio cyanoacetic ester derivative 315, which was obtained from the previously prepared ketone 312 (173) by the Knoevenagel condensation accompanied by complete epimerization at C-20 and by subsequent stereoselective sodium borohydride reduction. ( )-Corynantheidine was prepared by modification of the cyanoacetate side chain esterification furnished diester 316, which underwent selective lithium aluminum hydride reduction. The resulting sodium enolate of the a-formyl ester was finally methylated to racemic corynantheidine (171). 

Diazo transfer to these substrates is best effected by reaction of the sodium enolate of 2 with />-nitrobenzenesulfonyl azide. A typical diazocarboximide is obtained in 85% yield after a quench with a pH 7 phosphate buffer. 

A vat dye is a water-insoluble colorant containing two or more keto groups. It can thus be brought into aqueous solution by a reduction process (vatting), which converts the vat dye into its alkali-soluble enolic (leuco) form. As the soluble sodium enolate the leuco vat dye has substantivity for cellulose. The application of vat dyes to cellulosic fibres (virtually the only fibre type on which their outstanding fastness properties can be exploited) thus proceeds in four stages ... 

The rate of reduction of a vat dye depends partly on the intrinsic chemical properties of the dye and partly on the size and physical form of the dispersed particles undergoing this reaction. The physical factors are much less important than the chemical aspects [26]. The vatting process entails conversion of the insoluble keto form into the soluble sodium enolate (section 1.6.1). The reaction takes place in two stages at ambient temperature. Extremely rapid reduction to the hydroquinone is followed by slower dissolution in the alkaline solution. At higher temperatures, however, the dissolution rate approximates more closely to the rate of reduction. Temperature and dithionite concentration are the important variables and the rate of reduction is much less dependent on dye or alkali concentration. 

Caubere et al. [64, 65] also employed enolates as nucleophiles to intercept the intermediates produced from 32a and the mixture of sodium amide and a sodium enolate. Scheme 6.12 illustrates the results obtained by using the enolates of cyclohexanone and cyclopropyl methyl ketone. The former furnished only the ketone 43 in hexamethylphosphoric triamide as solvent, but almost exclusively the cyclobuta-... 

Scheme 6.12 Reactions of 1-chlorocyclohexene (32a) with complex bases from sodium amide and sodium enolates, according to Caubere and co-workers.

Scheme 6.98 Products of the reactions of 1-halocycloheptenes, for example 468a, with KOtBu, substituted sodium amides and sodium enolates.

Addition products 444 are obtained from 3-(l -hydroxy-2,2,2,-trifluoroethyl-idenyl)-l-methylpyrrolidin-2-one and acylallene. They may further react with the C=0 group connected to CF3 to afford bicyclic compound 445 via intramolecular nucleophilic attack of oxygen on the C=0 group connected to CF3 and 446 via protonation of sodium enolate 444 [200],... 

Vlhen the chiral methylation is carried out with 30% aqueous NaOH the indanone is deprotonated at the interface but does not precipitate as the sodium enolate (Figure 11). In this system there are 3 to 4 molecules of H2O per molecule of catalyst available while in the 50% NaOH reactions the toluene is very dry with only 1 molecule of H2O available per catalyst molecule thus forcing the formation of tight ion pairs. Solvation of the ion pairs in the toluene/30% NaOH system should decrease the ee which we indeed observe with an optimum 78% versus 94% in the 50% NaOH reaction. In the 30% NaOH reactions the ee decreases from 78% to 55% as the catalyst concentration increases from 1 mM to 16 mM (80 mM 5, 560 mM CH3CI, 20 C). Based on these ee s rates of formation of (-h)-enantiomer and racemic product can be calculated. When the log of these rates are plotted versus the log of catalyst concentrations (Figure 13) we find an order of about 0.5 in the catalyst for the chiral process similar to that found using 50% NaOH consistent with a dimer-monomer pre-equilibrium. The order in catalyst for the... 

Fluorination of the sodium enolate of 2-methyl-1-tetralone by (-)-A-tluoro-2,10-(3,3-dichlorocamphorsultam) gives (5 )-(- -)-2-iluoro-2-methyl-1-tetralone in 70% ee, which corresponds to the opposite asymmetric induction to that achieved using non-racemic (camphorsulfonyl)oxaziridines as closely related hydroxylation reagents. ... 

A NMR study of reactions of methyl 2-(bromomethyl)-but-2-enoate with the sodium enolate of methyl 2-methyl-3-oxobutanoate has been carried out to rationalize the observed solvent-dependent regioselectivity in terms of addition-eiimination sequences. ... 

---