Lithium diisopropylamide enolate formation with

Enolate alkylation can be difficult to carry out with simple aldehydes and ketones. It is not always possible to limit the reaction to monoalkylation, and aldol condensation competes with alkylation, especially with aldehydes. The formation of regioisomeric alkylation products is an issue with unsymmetrical ketones but can be minimized by selecting reaction conditions that favor either kinetic or thermodynamic control of enolate formation. The kinetic enolate of 2-methylcyclohexanone, for example, was prepared by deprotonation with lithium diisopropylamide then treated with benzyl bromide to give predominantly 2-benzyl-6-methylcyclohexanone,... 

Because carbonyl compounds are only weakly acidic, a strong base is needed for enolate ion formation. If an alkoxide such as sodium ethoxide is used as base, deprotonation takes place only to the extent of about 0. l% because acetone is a weaker acid than ethanol (pKa - 16). If, however, a more powerful base such as sodium hydride (NaH) or lithium diisopropylamide ILiNO -CjHy ] is used, a carbonyl compound can be completely converted into its enolate ion. Lithium diisopropylamide (LDA), which is easily prepared by reaction of the strong base butyllithium with diisopropylamine, is widely used in the laboratory as a base for preparing enolate ions from carbonyl compounds. 

When 2-lithio-2-(trimethylsilyl)-l,3-dithiane,9 formed by deprotonation of 9 with an alkyllithium base, is combined with iodide 8, the desired carbon-carbon bond forming reaction takes place smoothly and gives intermediate 7 in 70-80% yield (Scheme 2). Treatment of 7 with lithium diisopropylamide (LDA) results in the formation of a lactam enolate which is subsequently employed in an intermolecular aldol condensation with acetaldehyde (6). The union of intermediates 6 and 7 in this manner provides a 1 1 mixture of diastereomeric trans aldol adducts 16 and 17, epimeric at C-8, in 97 % total yield. Although stereochemical assignments could be made for both aldol isomers, the development of an alternative, more stereoselective route for the synthesis of the desired aldol adduct (16) was pursued. Thus, enolization of /Mactam 7 with LDA, as before, followed by acylation of the lactam enolate carbon atom with A-acetylimidazole, provides intermediate 18 in 82% yield. Alternatively, intermediate 18 could be prepared in 88% yield, through oxidation of the 1 1 mixture of diastereomeric aldol adducts 16 and 17 with trifluoroacetic anhydride (TFAA) in... 

When the enolate of an ,) - or a /j,y-unsatunited amide is used, it can react in an a or in a y fashion with a,/i-unsaturated esters, however, in most cases only a-selectivity is observed. Using l-(l-oxo-2-butenyl)pyrrolidine and lithium diisopropylamide at — 78 °C in a THF/HM-I A mixture (1 1), high. syn-selective formation of 3-alkyl-5-oxo-5-(l-pyrrolidinyl)-4-vinylpen-tanoates is achieved78,381 382. Related syn- or anti-selective additions of a vinylogous urethane also are known79. 

When 2,2-dimethylpropanal is used to prepare the azomethine moiety, the corresponding azaallyl anion may be obtained when l,8-diazabicyclo[5.4.0]undec-7-ene/lithium bromide is used as base. The subsequent addition to various enones or methyl ( )-2-butenoate proceeds with anti selectivity, presumably via a chelated enolate. However, no reaction occurs when triethylamine is used as the base, whereas lithium diisopropylamide as the base leads to the formation of a cycloadduct, e.g., dimethyl 5-isopropyl-3-methyl-2,4-pyrrolidinedicarboxylate using methyl ( )-2-butenoate as the enone84 89,384. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

The most direct route towards functionalized aliphatic polyesters is based on the functionalization of polyester chains. This approach is a very appealing because a wide range of functionalized aliphatic polyesters could then be made available from a single precursor. This approach was implemented by Vert and coworkers using a two-step process. Eirst, PCL was metallated by lithium diisopropylamide with formation of a poly(enolate). Second, the poly(enolate) was reacted with an electrophile such as naphthoyl chloride [101], benzylchloroformate [101] acetophenone [101], benzaldehyde [101], carbon dioxide [102] tritiated water [103], ot-bromoacetoxy-co-methoxy-poly(ethylene oxide) [104], or iodine [105] (Fig. 26). The implementation of this strategy is, however, difficult because of a severe competition between chain metallation and chain degradation. Moreover, the content of functionalization is quite low (<30%), even under optimized conditions. 

To obtain complete conversion of ketones to enolates, it is necessary to use aprotic solvents so that solvent deprotonation does not compete with enolate formation. Stronger bases, such as amide anion ( NH2), the conjugate base of DMSO (sometimes referred to as the dimsyl anion),2 and triphenylmethyl anion, are capable of effecting essentially complete conversion of a ketone to its enolate. Lithium diisopropylamide (LDA), which is generated by addition of w-butyllithium to diisopropylamine, is widely used as a strong... 

The alkylations are performed in the usual way. Deprotonation is achieved with a strong base, usually lithium diisopropylamide or sometimes butyllithium, added to the amide 1 in tetrahydrofuran at low temperature, usually —78 C7. Sometimes a mixture of solvents is used. To ensure complete enolate formation, warming to 20 °C is usually employed. An excess of alkylating agent is added at —78 or — 20 °C and the products 2 and 3 are isolated in the conventional way (see Tables 7 and 8). 

The lithium diisopropylamide solution prepared above is transferred dropwise, via a cannula, into the bicyclic lactam solution. The dry ice/acetone bath is replaced by an ice-water bath, where the reaction mixture is kept for 40 min to complete formation of the lithium enolate. The reaction mixture is cooled again (30 min) with a dry ice/acetone bath. Freshly distilled ethyl iodide (25.8 g, 13.4 mL, 165.4 mmol) (Note 9) is added slowly, via syringe, to the mixture and stirring is continued for 55 min in a... 

The formation of ( )-enolates is favored in tetrahydrofuran alone, whereas addition of metalchelating solvents such as hexamethylphosphoric triamide, A,A, /V, Ar-tetranncthylcthylenedi-amine or l,4-dimethyltetrahydro-2(l//)-pyrimidinone reverses the enolate configuration to the (Z)-product. The best seleetivities were obtained with 45% l,3-dimethyltetrahydro-2(l//)-pyrimidinone. In comparison to lithium diisopropylamide in 23% hexamethylphosphoric triamide. slightly bulkier bases, i.e., lithium hexamethyldisilanazide, have proved to be more E selective256. 

Lithium diisopropylamide. 13, 163-164 15, 188-189 16, 196-197 17, 165-167 Ester enolates. Procedures for the preparation of ( )- and (Z)-ketene silyl acetals are well developed. Enolates have been generated from conjugate esters by way of Michael addition, and when a remote halide is present, they are quenched by cyclization. Chiral Michael donors such as carbanions of the SAMP/RAMP hydra-zones initiate formation of trani-2-(2 -oxoalkyl)cycloalkanecarboxylic esters with excellent diastereomer excess and enantiomer excess. 

When the preparation of alkali metal enolates derived from alkanoylphosphonates was attempted by treatment with strong anhydrous bases such as lithium diisopropylamide or sodium hydride, the formation of phosphate phosphonate-type products was observed. This was interpreted in terms of fragmentation of the enolate formed in the first step to ketene and dialkyl phosphite anion (equation 75), and addition of the latter to the carbonyl group of an unreacted acylphosphonate molecules to form a bisphosphonate. Such molecules are known to rearrange to phosphate phosphonates ... 

Similarly, formation of the enolate (173 231) with lithium diisopropylamide (LDA, see sec. 9.2.B) should be facile due to relief of transannular strain for formation of the planar enolate moiety. A subsequent alkylation step (231 - 232, see sec. 9.3.A) may be sluggish, however, since the methyl group in 232 will introduce more strain in the product than in the original unsubstituted cyclooctanone (173). 

Liebeskind and Welker reacted 720 with lithium diisopropylamide (sec. 9.2.A) and propanal, showing the enantioselectivity in the final P-hydroxy acids (722 and 723) to be dependent on the conditions used to form the enolate. If diisobutylaluminum chloride (i-Bu2AlCl) was used, a 5.2 1 mixture of 722 and 723 was reversed (to 1 11.6) in 66% yield. Good enantioselectivity was observed in this reaction also. The acyl iron derivative behaves essentially as a protected acid, where the iron group is a chiral auxiliaryThe chiral iron moieties are useful variation of enolate condensation chemistry (sec. 9.4.B). In addition to the formation of the condensation product, the high asymmetric induction will prove valuable. 

To conduct the first carbon-carbon bond formation at the a-carbon of the lactone 195, the lithium diisopropylamide (LDA) generated enolate was trapped with methyl iodide providing a-methylated lactone 196 as a sole product in an excellent yield. As anticipated, the electrophile attacked... 

Regioselective enolate formation using kinetic deprotonation of an unsymmetri-cal ketone has been discussed in Section 1.1.1. The specihc enolate can react with aldehydes to give the aldol product, initially formed as the metal chelate in aprotic solvents such as THF or EtiO. Thus, 2-pentanone, on deprotonation with lithium diisopropylamide (LDA) and reaction of the enolate with butanal, gave the aldol product 44 in reasonable yield (1.56). 

Cleavage of enol trimethylsilyl ethers or enol acetates by methyllithium (entries 1 and 2, Scheme 1.3) as a route to specific enolate formation is limited by the availability of these materials. Preparation of the enol trimethylsilyl ethers and enol acetates from the corresponding ketones usually affords a mixture of the two possible derivatives, which must be then separated. It is sometimes possible to find conditions that favor the formation of one isomer for example, reaction of 2-methyl-cyclohexanone with lithium diisopropylamide and trimethylchlorosilane affords the less highly substituted enol ether preferentially by 99 1 over the more highly substituted one (kinetically controlled conditions). ... 

The formation of lithium enolates using lithium diisopropylamide furnishes a useful way of alkylating ketones in a regioselective way. For example, the lithium enolate formed from 2-methylcyclohexanone can be methylated or benzylated at the less hindered a carbon by allowing it to react with LDA followed by methyl iodide or benzyl bromide, respectively ... 

Another related method uses the anion of nitroalkanes in a reaction with halo-esters. Nitromethane reacted with lithium diisopropylamide to form the nitro enolate and then with methyl 3-chloropentanoatc to give 4.110. Reduction of the nitro group with ammonium formate gave methyl 2-phenyl-3-aminopropanoate, 4.111. 

Chlorination of ketones can be achieved via kinetic formation of enolate, using lithium diisopropylamide, followed by treatment with p-toluenesulfonyl chloride, acting as a source of Cl+. ... 

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