Lithium keto esters

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

Reaction with Carbon Nucleophiles. Unactivated a2iddines react with the lithium salts of malonates or p-keto esters in the presence of lithium salts to yield 3-substituted pyttohdinones (56—59), where R = alkyl and aryl, and R = alkoxyl, alkyl, and aryl. 

This procedure illustrates a new method for the preparation of 6-alkyl-a,g-unsaturated esters by coupling lithium dialkylcuprates with enol phosphates of g-keto esters. The procedure for the preparation of methyl 2-oxocyclohexanecarboxylate described in Part A Is based on one reported by Ruest, Blouin, and Deslongcharaps. Methyl 2-methyl-l-cyc1ohexene-l-carboxylate has been prepared by esterification of the corresponding acid with dlazomethane - and by reaction of methyl 2-chloro-l-cyclohexene-l-carboxyl ate with lithium dimethylcuprate. -... 

The formation of g-alkyl-a,g-unsaturated esters by reaction of lithium dialkylcuprates or Grignard reagents in the presence of copper(I) iodide, with g-phenylthio-, > g-acetoxy-g-chloro-, and g-phosphoryloxy-a,g-unsaturated esters has been reported. The principal advantage of the enol phosphate method is the ease and efficiency with which these compounds may be prepared from g-keto esters. A wide variety of cyclic and acyclic g-alkyl-a,g-unsaturated esters has been synthesized from the corresponding g-keto esters. However, the method is limited to primary dialkylcuprates. Acyclic g-keto esters afford (Zl-enol phosphates which undergo stereoselective substitution with lithium dialkylcuprates with predominant retention of stereochemistry (usually > 85-98i )). It is essential that the cuprate coupling reaction of the acyclic enol phosphates be carried out at lower temperatures (-47 to -9a°C) to achieve high stereoselectivity. When combined with they-... 

Alternatively, Cushman has devised a facile route to pyrroles by the reaction of Boc-a-amino aldehydes or ketones 14 with the lithium enolates of ketones 15 to afford aldol intermediates 16 which cyclize to pyrroles 17 under mild acidic conditions <96JOC4999>. This method offers several advantages over the Knorr since it employs readily available Boc-a-amino aldehydes or ketones and utilizes simple ketones instead of the p-diketo compounds or p-keto esters normally used in the Knorr. 

The phosphonate (176) has been used for the addition to aldehydes of a masked jS-keto-ester function and applied in the synthesis of ( )-7(f),9(t)-trisporic acid B methyl ester. The isomerically pure phosphonate (177) has been used in a synthesis of dehydro-Cig juvenile hormone," the anion being generated by treatment with lithium di-isopro-pylamide in THF-HMPT at - 65 °C for 1 min. 

Reactions with Carboxylic Acid Esters Alkyl nitrones can be metallized upon treatment with phenyl lithium in ether solution. The Li-derivatives react with carboxylic acid esters to give 3-oxo nitrones (305)- the analogs of 3-diketones and j3-keto esters (545). With the help of the 13C NMR method it has been found that 3-oxo nitrones (305) exist as an equilibrium mixture... 

P-Keto esters.2 In the presence of a trace of tertiary amine, an acid reacts with 1 in THF at 0° to form a 2-acyl-3,5,dioxo-l,2,4-oxadiazolidine (2). This activated form of an acid reacts with the lithium enolate of an ester in THF at - 75°... 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

The reason why the carbonyl group in -santonin remained intact may be that, after the reduction of the less hindered double bond, the ketone was enolized by lithium amide and was thus protected from further reduction. Indeed, treatment of ethyl l-methyl-2-cyclopentanone-l-carboxylate with lithium diisopropylamide in tetrahydrofuran at — 78° enolized the ketone and prevented its reduction with lithium aluminum hydride and with diisobutyl-alane (DIBAL ). Reduction by these two reagents in tetrahydrofuran at — 78° to —40° or —78° to —20°, respectively, afforded keto alcohols from several keto esters in 46-95% yields. Ketones whose enols are unstable failed to give keto alcohols [1092]. 

Another way of avoiding reduction of the keto group in a keto ester is protection by acetalization. Ketals are evidently not reduced by lithium... 

In spite of the fact that the only a-protons with respect to the carbonyl group in the tricyclic y-keto esters 231 are at bridgehead positions and thus no real enolates can be formed [118], compounds 231 with R = OR could easily and selectively be deprotonated at C-7, and the resulting lithium derivative then substituted with various electrophiles (Scheme 66). 

An amount of 4.1 equiv of lithium diisopropyl amide (LDA) is absolutely necessary for this reaction to go to completion. An equilibrium exists between the formation of the second anion of the B-keto ester and the formation of lithium diisopropyl amide from diisopropylamine. 

Spiroannelation. A new method for intramolecular spirocyclizalion involves decarboxylation of w-halogeno-j8-keto esters with lithium chloride in HMPT at 125— 140°. The method appears to be fairly general.1 Examples ... 

A novel entry to decahydrocyclopentacyclooctene derivatives via the intramolecular photocycloaddition of fused a,/3-unsaturated y-lactones has been developed (80CC1011). Irradiation of the butenolide (153) in acetone solution gave both the fused and bridged photoadducts (154) and (155) (2-3 1). The major adduct was hydrolyzed, oxidized and esterified to afford (156). Reductive cleavage of the unsaturated keto ester (156) with lithium in ammonia afforded a five-component mixture of a,/3- and /3,y-unsaturated esters. Equilibration with 0.1M sodium methoxide in methanol converted the mixture into a single a,j8-unsaturated ester (157 Scheme 34). This annelative two-carbon ring expansion method may find application in the synthesis of ophiobolin and ceroplastol sesterterpenes. 

CuCl-catalyzed decomposition of iodonium ylides prepared from /3-keto esters and diacetoxyiodobenzene, has been developed (equation 151)331. 1-Methylbenzvalene is obtained in a good yield by treating a mixture of lithium cyclopentadienide and 1,1-dichloroethane with butyllithium332. The tandem cyclization substitution in l-selenyl-5-hexenyllithiums derived from corresponding selenacetals via selenium/lithium exchange produces bicyclo[3.1.0]hexane derivatives333. 

Lithium enolates and the like are not good choices but enamines are excellent. The morpholine enamine 18 is cleanly alkylated by the bromoester 15 and hydrolysis gives1 the keto-ester 11. 

The a-protons of a ketone like propanone are only weakly acidic and so a powerful base (e.g. lithium diisopropylamide) is required to generate the enolate ion needed for the alkylation. An alternative method of preparing the same product by using a milder base is to start with ethyl acetoacetate (a [3-keto ester) (Fig.G). The a-protons in this structure are more acidic because they are flanked by two carbonyl groups. Thus, the enolate can be formed using a weaker base like sodium ethoxide. Once the... 

---