Lithium 2,2,6,6-tetramethylpiperidide diisopropylamide

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... 

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 McCoy method also allows the preparation of cyclopropylacylsilanes 33. Treatment of a-haloacylsilanes with lithium diisopropylamide (LDA) or with lithium tetramethylpiperidide (LUMP) affords enolates which combine with a variety of electrophilic olefins to produce cyclopropane derivatives33. The major diastereomers formed in the reactions of 2-chloro-l-(/er/-butyldimethylsilyl)ethanone are usually the civ-compounds, while the corresponding a-bromo acylsilane exhibits a higher degree of trans selectivity. 

LDA = lithium diisopropylamide LICA = lithium isopropylcyclohexylamide LHMDS = lithium hexamethyldisilazide LTMP = lithium tetramethylpiperidide... 

The presence of a sulfonyl group in 1-azulenyl p-tolylsulfone directs lithiation, by lithium tetramethylpiperidide, to ortho-positions. " Regioselective lithiation, at the 2- and 6-positions, has also been observed in the reaction of l-chloro-3-(trifluoromethyl)benzene with lithium diisopropylamide in tetrahydrofuran (THF). The metalation involves a rate-limiting deaggregation process with a dimer-based transition state. In the presence of lithium chloride, monomer-based pathways are favoured. ... 

Lithium cyclohexylisopropylamide Lithium diisopropylamide Lithium hexamethyl disilazide Lithium 2,2,6,6-tetramethylpiperidide Methylaluminum I ij-(4-bromo-2,6-di-tert-butylphenoxide) I (s-(2,6-di-t-butyl-4-methylphenoxy)methyl aluminum mefa-Chloroperoxybenzoic acid Methyl... 

The metallation, especially the lithiation, of pyridazines, mentioned briefly in CHEC-II(1996) <1996CHEC-11(6)1 >, has been developed extensively since 1995 by Queguiner and co-workers for the derivatization of pyridazines and benzopyridazines. The bases of choice are usually lithium 2,2,6,6-tetramethylpiperidide (LTMP) and lithium diisopropylamide (EDA). Special efforts have been made to achieve regioselective lithiations. 

Although the regioselectivity of the alkylation reaction is independent of the nature and the steric bulk of the electrophile, it is dependent on the steric bulk of the base used for deprotonation. Lithium diisopropylamide (LDA) is superior for endo deprotonation, whereas exo dcprotonation is best achieved with the sterically hindered lithium 2,2,6,6-tetramethylpiperidide (LTMP)11,16. 

The lithium enolate generated using lithium diisopropylamide [4111-54-0], lithium 2,2,6,6-tetramethylpiperidide [58227-87-1], or lithium hexamethyldisilazide [4039-32-17 is a chemical reagent that reacts with other reactants to give a variety of products (37). In the quest for improved stereospecificity, enolates with different cations such as silicon, aluminum, boron, and zinc have also been used (38). In group transfer polymerization, ketene silyl acetals, eg, (CH3)2C=C [OSi(CH3)3] (OCH3) are employed as initiators (39). 

Due to the importance of azines and diazines in pharmaceutical industry and biorganic chemistry, the development of selective and efficient metallation protocols for substituted compounds has been the object of deep investigations.1 - The main difficulty in this context is that the 7r-deficient heteroaromatics undergo a facile nucleophilic addition to the azomethine bond with alkyllithiums.184-186 For this reason sterically hindered non-nucleophilic lithium amides (lithium diisopropylamide and lithium 2,2,6,6-tetramethylpiperidide)181 182 are usually employed in the selective deprotonation of heterocyclic compounds. In some cases the use of both unimetallic183 and... 

The dihydro-1,2-azaboroles 4 <1996CHEC-II(3)753>, 2,5-dihydro-l,2-oxaboroles 14 <20040M5088>, and dihydro-1,2-thiaboroles 19-21 <20000M4681, 20000M4935> can be deprotonated by strong, bulky bases as in Equation (6), the most widely used bases being lithium diisopropylamide (LDA), lithium 2,2,6,6-tetramethylpiperidide (LTMP), and KN(SiMe3)2. 

In order to introduce groups which cannot effect the elimination reaction, sterically hindered non-nucleophilic bases such as lithium diisopropylamide , lithium 2,2,4,4-tetramethylpiperidide or even t-BuO" can be used. Employing this technique, Szeimies and coworkers introduced thio and amino groups into the bridgehead position of bicyclobutane derivatives ... 

The commonly used lithium dialkylamides are LDA (lithium diisopropylamide), LTMP (lithium 2,2,6,6-tetramethylpiperidide), and LHMDS (lithium hexamethyldisi-lazide). They are available by reacting the appropriate amine with an organolithium reagent in Et20 or in THF solvent, as shown for the preparation of LDA. ... 

Deprotonation of carbonyl compounds by lithium dialkylamide bases is the single most common method of forming alkali enolates. Four excellent reviews have already been published. " Sterically hindered amide bases are employed to retard nucleophilic attack on the carbonyl group. The most common and generally useful bases are (i) lithium diisopropylamide (LDA 5) (ii) lithium isopropylcyclo-hexylamide (LICA 6) (iii) lithium 2,2,6,6-tetramethylpiperidide (LITMP 7) (iv) lithium hexamethyldisilylamide (LHMDS 8) and (v) lithium tetramethyldiphenyldisilylamide (LTDDS 9). Bases that are not amides include sodium hydride, potassium hydride and triphenylmethyllithium. 

These techniques will be discussed in Section 9.2, but an example is conversion of 3-pentanone to a 77 23 mixture of ( )- and (Z)-enolates by reaction with lithium diisopropylamide. When the enolate was formed by treatment with lithium 2,2,6,6-tetramethylpiperidide (LTMP), only slightly greater amounts of the ( ) -enolate were observed (86 14 E/Z). Addition of HMPA) to this reaction medium, however, led to a reversal of selectivity, favoring the (Z)-enolate (8 92). Under the best conditions, this ( /Z)-mixture will lead to a similar mixture of diastereomers in the products formed by reaction of the enolates. Some isomerization can occur in the deprotonation or condensation steps, and the product may isomerize under the reaction conditions. ... 

Lithium diisopropylamide (LiN(i-Pr)2 LDA) is the most widely used lithium amide but lithium 2,2,6,6-tetramethylpiperidide (LiTMP) is rather more basic and less nucleophilic - it has found particular use in the metallation of diazines. Alkyllithiums are stronger bases than the lithium amides, but usually react at slower rates. Metallations with the lithium amides are reversible so for efficient conversion, the heterocyclic substrate must be more acidic ( > 4 pAT units) than the corresponding amine. 

Hexamethylphosphoramide (Me3N)3P=0 Hexamethylphorous triamide (Me3N)3P Isopropyl — CH(CH3)2 Lithium cyclohexylisopropylamide Lithium diisopropylamide LiN(iPr)2 Lithium hexamethyl disilazide LiN(SiMe3)2 Lithium 2,2,6,6-tetramethylpiperidide meta-Chloroperoxybenzoic acid Methyl — CH3... 

Related Reagents. Lithium Amide Lithium Hexamethyl-disilazide Lithium Diethylamide Lithium Piperidide Lithium Pyrrolidide Lithium 2,2,6,6-tetramethylpiperidide Potassium Diisopropylamide. 

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