LDA as a base

A route for the asymmetric synthesis of benzo[3]quinolizidine derivative 273 was planned, having as the key step a Dieckman cyclization of a tetrahydroisoquinoline bis-methyl ester derivative 272, prepared from (.S )-phcnylalaninc in a multistep sequence. This cyclization was achieved by treatment of 272 with lithium diisopropylamide (LDA) as a base, and was followed by hydrolysis and decarboxylation to 273 (Scheme 58). Racemization could not be completely suppressed, even though many different reaction conditions were explored <1999JPI3623>. 

In symmetrical stractures such as cyclohexanone, ionization at a-positions occurs readily and allows the preparation of alkylated products. In unsymmet-rical stractures, the sheer size of LDA as a base may allow selectivity by preferential removal of... 

Trost and Latimer reported the clean generation of ketone ,/ -dianion of 6-methoxy-indanone. They used two equivalents of LDA as a base and THF as a solvent6. Alkylation with one equivalent of ethyl iodide gave 89% yield of 3-ethyl-6-methoxy-l-indanone. For the alkylation, the ambident character of the dianion was evident, although negligible, since the formation of 3-ethyl-3-hydroxy-6-methoxy-l-indene was confirmed (Scheme 11). 

Second, methyl ester 61 is subjected to crossed ester condensation with methyl formate and triphenyl methyl sodium 64 as base. Ester 61 is deprotonated and the resulting anion 65 adds lo methyl formate. The anion formed is stabilized by loss of methanolate yielding the desired product as its conjugated base. As a Claisen type ester condensation, all steps but the last are reversible since the resulting aldehydo ester 67 is more acidic than methanol therefore the last deprotonation step occurs iiTeversibly. The use of LDA as a base is also possible for this transformation. 

Cyanophosphates can be prepared from aromatic or a,p-unsaturated aldehydes with diethvl nhnsnhn. rocyanidate (DEPC, (EtO)2P(0)CN) in THF using LiCN or LDA as a base. Deprotonation of a cyanophosphate with Bu Li in the presence of tetramethylethylenediamine in THF at --78 C followed... 

The first synthesis of racemic LTA4 methyl ester, as a mixture with its cis isomer, was reported by Corey et al. as outlined in Scheme 3.19. Alcohol 45 was used as the synthon for the C-12 portion of the target structure and ( , )-2,4-hexadien-l,6-diol became C-6 to C-11. The functionality in the diol was differentiated by its transformation to 47, which then underwent a Wittig reaction with 46 to yield the 15-carbon alcohol 48. The formation of the mesylate of 48 and the reaction of sulfonium salt 49 with methyl 4-formylbutyrate using LDA as a base is also a difficult step and only modest yields of the target compounds are obtained. ... 

Alkylations. The use of LDA as a base in alkylations is almost universal. Listed here are some new examples perfluoroalkylation of A-acyloxazolidin-2-ones, alkylation of 2-cyanocycloalkanones via the SAMP derivatives, and alkylation of a-(p-toluenesulfinyl)alkanoic esters. The last of these reacts with A-tosylimines to generate adducts that are precursors of (i-amino esters. 

The Cs-phosphonate 39 is prepared by an Horner-Emmons reaction of triethyl-phosphonoacetate (11) with chloroacetone (40) in THE, with NaH or LDA as a base (yield 58%). The chloro product 47 is reacted with triethyl phosphite in an Arbusov reaction which gives, after distillation in vacuo, pure 39 in a yield of 81% [50] (Scheme 13). Similarly, diethyl cyanomethylphosphonate (3) is coupled to chloroacetone (40) in 72% yield and the coupling product 42 is converted into the C5-phosphonate 43 by reaction with triethyl phosphite. The yield after distillation is 89% [50]. 

Allylation of simple ketone is not possible under usual conditions, but the reaction can be carried out under selected conditions. Asymmetric allylation of the chiral racemic o -methylcyclohexanone 161 with allyl carbonate proceeded in the presence of LDA as a base with or without MesSnCl as a Lewis acid at room temperature to provide the allylated ketone 162 in very high yield with 82 % ee when (5,5)-Trost L-1 was used. The choice of base is crucial, and it was claimed that no reaction took place when Na or K bases were used in this reaction [57]. Asymmetric allylation of a-aryl and heteroaryl ketones has been carried out. Asymmetric allylation of 2-indolylcyclohexanone 163 took place at 0 C to give the the allyl ketone in 82 % yield with 84 % ee. In this reaction, NaHMDS was used as a base and Trost L-2 as chiral ligand [58]. Asymmetric allylation of the tetralone 164 with allyl acetate was carried out using Trost L-6 in the presence of CS2CO3 to provide the allylated ketone with 91 % ee in 90% yield [59]. 

The common method involves deprotonation of a thiocarbonyl compound and reaction of the intermediate enethiolate with an allyl halide (Scheme 9.8). This actually relies on two noticeable features of the sulfur series. (1) The proton located a to a thiocarbonyl group is much more acidic, by 7-10 pKa units, than the one of a carbonyl moiety [39, 41]. This may be related to the strong ability of the sulfur atom (polarizability) to stabilize the negative charge of the enethiolate. Presently, the preferred conditions involve LDA as a base for optimum deprotonation [42-45]. (2) The resulting anionic species are soft ambident nucleophiles. The... 

For the condensation reaction of 60, 66, and 71, the thermodynamic reaction conditions constitute the traditional method of doing a Claisen condensation. This reaction may be modified to use kinetic control conditions using LDA as a base and THF as the solvent. An example is the reaction of 74 with LDA to form the ester enolate. Under these kinetic control conditions, assume that is large and that the reaction will give primarily the enolate anion such that... 

Crossed aldol reactions can also be performed using LDA as a base. 

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. 

It is noteworthy that ZnEt2 has been used as a base in enantioselective allylic substitutions. A remarkable increase in ee was observed when ZnEt2 was used instead of KH, NaH, LiH, LDA, or BuLi in the Pd-catalyzed alkylations of allylic acetates by enolates of malonic esters and related compounds.403 In contrast, application of ZnEt2 was not as very effective as in similar iridium-catalyzed allylic alkylations.404... 

Cyclic thiourea derivatives like l,3,4,5-tetramethylimidazole-2(3H)-thione— prepared by condensation of substituted thioureas with a-hydroxyketones—can be converted into the corresponding imidazolin-2-ylidene by desulfurization with sodium or potassium [Eq. (23)]. This method was used to prepare and isolate l,3-bis-neo-pentylbenzimidazolin-2-ylidene with Na/K. With LDA as the base it is also possible to generate free benzimidazolin-2-ylidenes in solution. ... 

With C-2 substituents other than methyl, clean reaction occurs at C-5. Reaction in the presence of a 2-bromine atom has even been achieved using LDA as the base [86JOC1184 88CJC1617 92JCS(P1)215]. If the 2-... 

For the reaction of 1,3-dioxin -ones with electrophiles, activation by deprotonation of the side-chain alkyl group is required. Typically lithium diisopropylamide (LDA) is used as a base. The resulting lithium dienolates react with aldehydes <2002EJ0718> or with allyl bromides in the presence of Ar,Ar -dimethylpropyleneurea (DMPU) <2005AGE820, 2006CEJ2488> exclusively at the side-chain double bond, albeit in modest yields (Equation 25). 

Again for synthetic applications, thio- and dithioesters are particularly useful. Their enethiolates are easily generated [120]. Potassium and lithium amides and LDA can be conveniently used, and deprotonate the dithioesters quantitatively in THF at -78°C. Methyllithium under the same conditions also acts as a base and not as a nucleophile, and it has the advantage that its conjugate acid is the totally inert methane. 

Enolate ions can be formed from aldehydes and ketones containing protons on an a-carbon (Following fig.). Enolate ions can also be formed from esters if they have protons on an a-carbon. Such protons are slightly acidic and can be removed on treatment with a powerful base like lithium diisopropylamide (LDA). LDA acts as a base rather than as a nucleophile since it is a bulky molecule and this prevents it attacking the carbonyl group in a nucleophilic substitution reaction. 

In general, this effect is sufficient to allow selective kinetic deprotonation of methyl ketones, that is, where the distinction is between Me and alkyl. In this example, unusually, MeLi is used as a base LDA was probably tried but perhaps gave poorer selectivity. The first choice for getting kinetic enolate formation should always be LDA. 

The diisopropylamine formed when LDA acts as a base is much less acidic than the proton a to the nitro group (see Appendix C). Thus, protonation of the anion 3-54 must take place during workup. 

As with ketone enolate anions (see 16-34), the use of amide bases under kinetic control conditions (strong base with a weak conjugate acid, aprotic solvents, low temperatures), allows the mixed Claisen condensation to proceed. Self-condensation of the lithium enolate with the parent ester is a problem when LDA is used as a base, ° but this is minimized with LICA (lithium isopropylcyclohexyl amide).Note that solvent-free Claisen condensation reactions have been reported. ° ... 

The nucleophilic addition of a carbanion to an aldehyde or a ketone having a conjugated double bond and the subsequent dehydration sequence (Knoevenagei reaction) is a popular method for generating dienes and polyenes (equation 37). This reaction takes place efficiently and stereoselectively, when LDA is used as a base in the presence of chlorotrimethylsilane (equation 38). Knoevenagei condensation was a key reaction during many classical carotenoid syntheses. Recently, Seltzer and coworkers used the dimefiiyl acetal of acetylacetaldehyde for aldol condensation with a Cis-aldehyde, to generate the tetraenyl ketone acetal (equation 39). ... 

Lithium diisopropylamide (LDA) is easily prepared by reaction betweea butyliithium (BuLi) and diisopropyiamine and is widely used as a base fin preparing enolate ions from carbonyl compounds. LDA has nearly ideal properties ... 

The dilithio dianions of carboxylic acids can be prepared in THF-HMPA solution using LDA as the base. These dianions are more stable than a-ester anions but can still be readily C-alkylated. " ... 

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