Bases Lithium 2,2,6,6-tetramethylpiperidide

The most significant advance in the synthesis of cyclopropanes during the course of this Report has come from the work of Olofson and co-workers. By employing the arpoon base, lithium 2,2,6,6-tetramethylpiperidide (LiTMP) the stringent selectivity requirements for proton abstraction in chloromethyl esters and ethers are... 

Recently, optically active (+)-(R)-methy 1 tolyl sulfoxide 102, R = H was alkylated with a very high diastereoselectivity136. The sulfoxide was treated with either lithium diisopropy-lamide (LDA) or lithium tetramethylpiperidide (LTMP) to form the lithio-derivative, which upon subsequent reaction with lithium a-bromomethyl acrylate gave a mixture of two diastereomers of a-methylene-y-sulfinylcarboxylic acid 103. The use of the sterically highly hindered base, LTMP, gave the product with a higher diastereoselectivity. For example, the Sc4 Rc4 ratio was 95 5 when R was the methyl group. 

As first described by Krizan and Martin,6 the in situ trapping protocol, i.e., having the base and electrophile present in solution simultaneously, makes it possible to lithiate substrates that are not applicable in classical ortho-lithiation reactions.7 Later, Caron and Hawkins utilized the compatibility of lithium diisopropylamide and triisopropyl borate to synthesize arylboronic acid derivatives of bulky, electron deficient neopentyl benzoic acid esters.8 As this preparation illustrates, the use of lithium tetramethylpiperidide instead of lithium diisopropylamide broadens the scope of the reaction, and makes it possible to functionalize a simple alkyl benzoate.2... 

The analogous dimerization of alkynes over Fe(C0)5 is not applicable, so clearly a different route towards alkynylated derivatives of 25 was needed. Comparison of 25 to cymantrene suggests that metallation of the hydrocarbon ligand should be the route of choice for the synthesis of novel substituted cyclobutadienes. In the literature, addition of organolithium bases (MeLi, BuLi) to the CO ligands with concomitant rearrangement had been observed [25]. But the utilization of LiTMP (lithium tetramethylpiperidide, Hafner [26]) or sec-BuLi as effectively non-nucleophilic bases led to clean deprotonation of the cyclobuta-... 

Parts A and B of the procedure correspond to preparation of lithium tetramethylpiperidide, and its use in the in situ preparation and addition of dibromomethyllithium to the ester 1 producing tetrahedral intermediate 2. In Part C a mixture of lithium hexamethyldisilazide and lithium ethoxide is prepared for addition in Part D to the solution of 2. The silazide base serves to deprotonate the mono and dibromo ketones that are formed on initial warming of the reaction to -20°C, thus protecting them as the enolate anions 4 and 3. Addition of the sec-butyllithium in Part... 

D. Base and butyllithium addition. Ten minutes after the addition of lithium tetramethylpiperidide to the main reaction is complete, the cold (ca. -70°C) solution of... 

With heterocycles containing an sp--nitrogen atom, a totally different problem can occur, namely nucleophilic addition of the base to the azo-methine (C=N) bond. The use of very sterically hindered bases such as lithium tetramethylpiperidide (LiTMP) can prevent this type of addition in certain cases, but bases of this sort tend to be expensive and not suitable for general use. However, two different approaches to overcoming the problem of azomethine addition have been developed over the years, both relying on the fact that the addition is temperature dependent, and that by enabling metalation reactions to be performed at low temperatures, the desired carbanion formation can often be achieved. 

The choice of the base and the solvent is crucial for the yield of a-sulfinyl carbanion alkylation. A high diastereoselection (80%) was observed in the alkylation of an a-sulfinyl carbanion with a-bromoacrylate56. In this ease the choice of the base appears to be decisive the highest asymmetric induction is found when the metalation is carried out using highly hindered bases, e.g., lithium tetramethylpiperidide. An interesting asymmetric synthesis of chiral 5-alkyl(or phenyl)dihydro-3-methylene-2(3f/)-furanoncs is based on this reaction56. 

I-Alkynes from methyl ketones This reaction can be effected by conversion to Ihe enol phosphate followed by -elimination with LDA (equation I). In the case of a simple ketone such as 2-octanone the yield is low because of formation also of an allene. In such cases lithium tetramethylpiperidide is recommended as base. 

Metalloenolates derived from a, /9 -unsaturated a-diketones undergo a cyclization reaction with lithium tetramethylpiperidide (LiTMP) to give a -hydroxycyclopente-nones, the first example of a base-induced Nazarov reaction (Scheme 51).85 If these reactions represent conrotations, they are the first such reactions to be described for enolates. 

The use of lithium tetramethylpiperidide (LiTMP) as the base, followed by a quench with trimethylchlorosilane, has been shown to effectively silylate iV,iV-d i meth y I amides. With two equivalents of base the reaction occurs on the same methyl group, probably because the first trimethylsilyl group favors the formation of and stabilizes the anion on the same carbon atom.136 137 The process has been extended to thiobenzamide136 and aliphatic amides.137... 

Eliminations of epoxides lead to allyl alcohols. For this reaction to take place, the strongly basic bulky lithium dialkylamides LDA (lithium diisopropylamide), LTMP (lithium tetramethylpiperidide) or LiHMDS (lithium hexamethyldisilazide) shown in Figure 4.18 are used. As for the amidine bases shown in Figure 4.17, the hulkiness of these amides guarantees that they are nonnucleophilic. They react, for example, with epoxides in chemoselective E2 reactions even when the epoxide contains a primary C atom that easily reacts with nucleophiles (see, e.g., Figure 4.18). 

Hydrogen attached to ring carbon atoms of neutral azines, and especially azinium cations, is acidic and can be replaced by a metal formally being removed as a proton. Alkyllithiums can be used as bases for this purpose however, the reaction can be accompanied by addition of the alkyl anion to the ring C=N bond. To avoid this, sterically hindered bases with strong basicity but low nucleophilicity can be utilized. Among these are lithium tetramethylpiperidide (LiTMP) and lithium diisopropylamide (LDA). If the anion contains an ortho halogen atom, then this can be eliminated to form a pyridyne (see Section 3.2.3.10.1). 

The term amidolithium is the unambiguous name for the compounds RR NLi (R, R = alkyl, aryl, silyl, etc.) more often termed lithium amides. They derive their importance from the near-ubiquity of their bulkier members lithium diisopropy-lamide (LDA), lithium tetramethylpiperidide (LTMP), and lithium hexamethyldisilazide (LHMDS) in organic synthesis. Using such powerful but nonnucleophilic bases, many useful reactions may be performed, notably the enolization of ketones and esters, which can proceed both regio- and stereoselectively under kinetic control at low temperatures. ... 

Base-promoted isomerizations of oxiranes by way of oxirane C—H abstraction are less common. Lithium tetramethylpiperidide (LiTMP) has successfully been used for this purpose <94CC2103>. Monosubstituted oxiranes are isomerized with LiTMP to aldehydes. 

All attempts to metallate cyclopropyl silanes with strong bases such as alkyl-lithiums in THF 94> or sec BuLi and TMEDA in THF 82,98) as well as cyclopropyl selenides with non-nucleophilic bases such as LDA in THF39,94 , or lithium tetramethylpiperidide in THF 35,94) or in THF-HMPT35 (Scheme 12), meet with failure. 

Freshly prepared LDA has varying stability, being most stable in alkanes and 1 1 aIkanes THF. Homemade LDA should be stored cold to extend its shelf-life. The preparation of LDA is representative of other lithium amide bases, such as lithium tetramethylpiperidide and lithium hexamethyl disilylamide. 

What is needed for the alkylation is rapid conversion of the ester into a reasonably stable enolate, so rapid in fact that there is no unenolised ester left. In other words the rate of proton removal must be faster than the rate of combination of enolate and ester. These conditions are met when lithium enolates are made from esters with lithium amide bases at low temperature, often 78 °C. Hindered bases must be used as otherwise nucleophilic displacement will occur at the ester carbonyl group to give an amide. Popular bases are LDA (Lithium Di-isopropyl Amide, 66), lithium hexamethyldisilazide 67, and lithium tetramethylpiperidide 68, the most hindered of all. These bases are conveniently prepared from the amine, e.g. 65 for LDA, and BuLi in dry THF solution. 

In this style too, asymmetry has become a major concern.42 An asymmetric version 147 of this homoenolate was made from natural nor-ephedrine and could be alkylated stereoselectively using lithium tetramethylpiperidide (LiTMP) as base. The product could be hydrolysed to the bicyclic amide43 149. 

Ketene silyl acetals. The enolsilylation of esters is highly dependent on the bases used. Contrasting stereoselectivities in the silylation of methyl a-f-butyldi-methylsiloxyacetate are found with respect to the reaction conditions The ( )-isomer is obtained in the trimethylsilylation promoted by lithium tetramethylpiperidide, and the (Z)-isomer from the reaction with t-butyldimethylsilyl chloride in the presence of LHMDS and HMPA. 

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