Lithium diisopropylamide basicity

Ring protons of 1,2,3-thiadiazoles are known to undergo rapid deuterium exchange under basic conditions, yet to date there have been no published estimates or experiments to determine the pA of these protons. Few attempts have even been made to metalate and alkylate this heterocycle. One study <85S945> found that metalation of 5-phenyl-1,2,3-thiadiazole (25) with methyllithium gives 4-lithio-5-phenyl-l,2,3-thiadiazole, which is stable and reacts with aldehydes and ketones in high yields (Equation (11)). Also, treatment of 4-phenyl-1,2,3-thiadiazole with lithium diisopropylamide, in the presence of TMS-Cl, affords 4-phenyl-5-trimethylsilyl-1,2,3-thiadiazole. 

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). 

Sometimes this equilibrium mixture of enolate and base won t work, usually because the base (hydroxide or alkoxide) reacts with the electrophile faster than the enolate does. In these cases, we need a base that reacts completely to convert the carbonyl compound to its enolate before adding the electrophile. Although sodium hydroxide and alkoxides are not sufficiently basic, powerful bases are available to convert a carbonyl compound completely to its enolate. The most effective and useful base for this purpose is lithium diisopropylamide (LDA), the lithium salt of diisopropylamine. LDA is made by using an alkyllithium reagent to deprotonate diisopropylamine. 

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 third method (Route C Eq. 23) engages the autoxidation of a-enolate car-boxylates. Since the latter are prepared from the corresponding carboxylic acids by deprotonation with lithium diisopropylamide (LDA) or n-butyllithium (BuLi), obviously very strong basic conditions, the autoxidation step and the subsequent protonation must be executed under strictly controlled low temperature (< — 78°C) conditions. Otherwise, the base- and acid-sensitive a-hydroperoxy acids are destroyed during their preparation. Undoubtedly, this method is the most convenient and most general of the three listed in Eq. 23. 

The base used here is LDA (lithium diisopropylamide) made by deprotonating -Pr2NH with BuLi. LDA is very basic (pKg about 35) but too hindered to be nucleophilic—ideal for promoting E2 elimination. 

Oppositely, a compound having a very high basicity, such as lithium diisopropylamide, is called a superbase. ... 

Continuing with the direct metallation of glycals, 2-phenylsulfinyl derivatives have found utility. Their formation and subsequent lithiation, shown in Scheme 3.1.4, is accomplished on reaction of glycals with phenylsulfenyl chloride under basic conditions. Subsequent oxidation with mCPBA yields the sulfinyl compound ready for lithiation on treatment with lithium diisopropylamide. Advantageous to the formation of this species is the stabilization of the anion by chelation of the sulfoxide to the metal. This procedure reported by Schmidt, et al.,5 was utilized in the preparation of C-disaccharides, discussed in Chapter 8. 

NaNH2 is a powerful basic reagent which was widely used in chemical laboratories until lithium diisopropylamide was discovered and became more commonly used as it is much more soluble in classical solvents such as ether and tetrahydrofuran. NaNH2 is also a powerful reagent when associated with potassium t-butoxide to become a "complex base" (not described here) as shown by the research work of Caubere and co-workers (ref. 62). 

The thermodynamically more stable lithium enolate of phenylacetone, regioselectively prepared in situ with lithium diisopropylamide (LDA) at 0 °C, reacted with arylnitrile oxides giving 5-hydroxy-2-isoxazolines 19. The adducts were dehydrated under basic conditions to afford 3-aryl-5-methyl-4-phenylisoxazoles 20 in 38-73% overall yields. The phenyl and 5-chloro-2-furyl derivatives 20 are selective cyclooxygenase-1 (COX-1) inhibitors <04JMC4881>. 

The idea of kinetic versus thermodynamic control can be illustrated by a brief discussion of the formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and is discussed more fully in Chapter 6 and in Section 1.1.2 in Part B. Most ketones can give rise to more than one enolate. Many studies have shown that the ratio among the possible enolates that are formed depends on the reaction conditions. " This can be illustrated for the case of 2-hexanone. If the base chosen is a strong, sterically hindered one, such as lithium diisopropylamide, and the solvent is aprotic, the major enolate formed is 3 in the diagram below. If a protic solvent or a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Under these latter conditions, equilibration can occur by reversible formation of the enol. Enolate 3 is the kinetic enolate, but 2 is thermodynamically favored. 

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. 

Successful application of the Mitsonobu epimerization procedure to an eudesmanic alcohol 44 to bring about inversion of configuration at C(l) is the crucial step in the Harapanhalli synthesis of erivanin (50) from santonin (Scheme 7) [16]. Reduction of enone 43, prepared from santonin in 10 steps, with sodium borohydride furnished the )8-alcohol 44 as the sole product. This product results from the approach of the hydride anion from the less hindered Of-face of the molecule. The chemical modification of the C(3)-C(4) double bond to give a 3a-hydroxy-A4-i4 rnoiety was accomplished via the epoxide 46 and its rearrangement in a basic medium. Epoxidation of 44 with MCPA yielded only one product without any directing effect exerted by the homoallylic alcohol. Treatment of 46 with lithium diisopropylamide (EDA) afforded l-e/>/-erivanin (47). For the synthesis of erivanin (50), epimerization at C(l) prior to the A -modification sequence was required. Attempts to epimerize this carbon atom in 44 by acetolysis of the tosyl derivative 45 were unsuccessful as they led to eliminated product 13 (Scheme 3). 

Lithium diisopropylamide (known as LDA) is comparable to sodium amide (NaNH2) in basicity, but, unlike NaNH2, is too sterically hindered to undergo competing nucleophilic addition to the carbonyl group. 

The enolate ion is nucleophilic at the alpha carbon. Enolates prepared from aldehydes are difficult to control, since aldehydes are also very good electrophiles and a dimerization reaction often occurs (self-aldol condensation). However, the enolate of a ketone is a versatile synthetic tool since it can react with a wide variety of electrophiles. For example, when treated with an unhindered alkyl halide (RX), an enolate will act as a nucleophile in an Sn2 mechanism that adds an alkyl group to the alpha carbon. This two-step a-alkylation process begins by deprotonation of a ketone with a strong base, such as lithium diisopropylamide (LDA) at -78°C, followed by the addition of an alkyl halide. Since the enolate nucleophile is also strongly basic, the alkyl halide must be unhindered to avoid the competing E2 elimination (ideal RX for Sn2 = 1°, ally lie, benzylic). 

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