Hindered base

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

The direction of elimination is also affected by steric effects, and if both the base and die reactant are highly branched, steric factors may lead to preferential removal of the less hindered hydrogen. Thus, when 4-methyl-2-pentyl iodide reacts with very hindered bases such as potassium tricyclohexylmethoxide, there is preferential formation of the... 

LDA (Section 21.10) Abbreviation for lithium diisopropyl-amide LiN[CH(CH3)2]. LDA is a strong, sterically hindered base, used to convert esters to their enolates. 

The Bsmoc derivative is formed from the chloroformate or the A -hydroxy-succinimide ester. It is cleaved rapidly by a Michael addition with tris(2-aminoethyl)amine at a rate that leaves Fmoc derivatives intact. More hindered bases, such as A -methylcyclohexylamine or diisopropylamine, do not react with the Bsmoc group, but do cleave the Fmoc group, illustrating the importance of steric effects in additions to Michael acceptors. 

Together with a shift of the proton from the a-carbon to the alkoxide oxygen, the tertiary amine is eliminated from the addition product to yield the unsaturated product 3. Early examples of the Baylis-Hillman reaction posed the problem of low conversions and slow reaction kinetics, which could not be improved with the use of simple tertiary amines. The search for catalytically active substances led to more properly adjusted, often highly specific compounds, with shorter reaction times." Suitable catalysts are, for example, the nucleophilic, sterically less hindered bases diazabicyclo[2.2.2]octane (DABCO) 6, quinuclidin-3-one 7 and quinuclidin-3-ol (3-QDL) 8. The latter compound can stabilize the zwitterionic intermediate through hydrogen bonding. ... 

Both the malonic ester synthesis and the acetoacetic ester synthesis are easy to cany out because they involve unusually acidic dicarbonyi compounds. As a result, relatively mild bases such as sodium ethoxide in ethanol as solvent can be used to prepare the necessary enolate ions. Alternatively, however, it s also possible in many cases to directly alkylate the a position of monocarbonyl compounds. A strong, stericaliy hindered base such as LDA is needed so that complete conversion to the enolate ion takes place rather than a nucleophilic addition, and a nonprotic solvent must be used. 

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. 

To avoid side reactions, like the formation of diglycolic acid disodium salt, a reaction is described whereby instead of NaOH as base a so-called hindered base (e.g., tert-butoxide) is used [16]. 

Sterically hindered bases may greatly favor one enolate over the other. See, for example, Prieto, J.A. Suarez, J. Larson, G.L. Synth. Commun., 1988, 18, 253 Gaudemar, M. Bellassoued, M. Tetrahedron Lett., 1989, 30, 2779. 

This method has been made more general by use of modern reagents low temperatures and the strong hindered base i-Pr NLi allow the deprotonation of many nitriles and their capture by a variety of epoxides. Acid hydrolysis gives lactones,... 

There is no room for an activating group on (8) so we can either use the nitrile or simply the acid with the strong hindered base LDA. 

This is a very strained ketone but three-membered ring formation is kineticalJy favourable and the hindered base offers no cleavage reactions. Notice that the rings are added in order of size. 

Consider the elimination reaction below, which uses a strong, sterically hindered base (LDA). The product will be a double bond. This reaction will produce the Hoffmann product. Draw this product. 

However, there are many exceptions in which the Zaitsev product (the more-substituted alkene) is not the major product. For example, if the reaction above is performed with a stericaUy hindered base (rather than using ethoxide as the base), then the major product will be the less-substituted alkene ... 

In this case, the Hofmann product is the major product, because a sterically hindered base was used. This case illustrates an important concept The regiochemical outcome of an E2 reaction can often be controlled by carefully choosing the base. Below are two examples of sterically hindered bases that will be encountered frequently throughout your organic chemistry course ... 

ANSWER Let s first consider the expected regiochetnical outcome of the reaction. The reaction does not employ a sterically hindered base, so we expect formation of the more substituted alkene (the Zaitsev product) ... 

The Zaitsev product is generally favored over the Hofmann product, unless a sterically hindered base is used, in which case the Hofmann product will be favored. 

For the regiochemical outcome, we expect the Zaitsev product to be the major product, because the reaction does not utilize a sterically hindered base ... 

We can control which product we get by carefully choosing our base. If we use a strong base (like methoxide or ethoxide), then we will get the more substituted alkene. However, if we use a strong, sterically hindered base, such as tert-butoxide, then we will get the less substituted alkene. 

However, we must be careful to control the regiochemistry properly in each of these two steps. In the elimination step, we need to form the less substituted double bond (i.e., the Hofmann product), and therefore, we must use a stericaUy hindered base. Then, in the addition step, we need to place the Br on the less substimted carbon (anh-Markovnikov addition), so we must use HBr with peroxides. This gives us the following overall synthesis ... 

After we have converted the OH into a tosylate, then we can do our technique (using a strong, sterically hindered base to eliminate, followed by anti-Markovnikov addition of H and OH) ... 

We have also shown ( 8) that other bases stronger than CH-CX) (pK. 4.75) catalyse the decomposition of N -nitroso-2-pyrrolidone at o C. With the exception of imidazole, these reactions follow uncomplicated second order kinetics (Rate = kp[Substrate][Base]) and only products of deamination (hydrolysisT are obtained. Generally, values increase with the base strength of the catalyst and fit tne Br/e(nsted relationship withes 0.66. However, the absence of significant catalysis by sterically hindered bases 2,6-lutidine), the strong catalysis by imidazole relative to HPOi (k2(Imidazole)/k2(HP0J ) = 83) and by hydroxide ion relative to... 

Reversible O-silylation also enhances the electrophilicity of carbonyl dienophiles. For example, 10 mol % A-trimethylsilyl triflimide catalyzes the reaction of pent-3-en-2-one with cyclopentadiene. A hindered base, such as 2,6-/p/.S - -butyl-4-mclhylpyridinc improves the yield in cases in which the catalyst causes the occurrence of reactant degradation. 

A number of these alkylation reactions are illustrated in Scheme 9.2. Entries 1 and 2 are typical examples of a-halo ester reactions. Entry 3 is a modification in which the highly hindered base potassium 2,6-di-f-butylphenoxide is used. Similar reaction conditions can be used with a-halo ketones (Entries 4 and 5) and nitriles (Entry 6). Entries 7 to 9 illustrate the use of diazo esters and diazo ketones. Entry 10 shows an application of the reaction to the synthesis of an amide. 

When monomeric metaphosphate anion POf (102) is generated form the phos-phonate dianion 170 in the presence of the hindered base 2,2,6,6-tetramethylpiper-idine, it undergoes reaction with added carbonyl compounds147), Thus, it phosphoryl-ates acetophenone to yield the enol phosphate, whereas in the presence of acetophenone and aniline the Schiff base is formed from both compounds, probably by way of the intermediate C6H5—C(CH3) (OPO e) ( NH2C6HS). This reactivity pattern closely resembles that of monomeric methyl metaphosphate 151 (see Sect. 4.4.2). 

Primary halide Does not occur Highly favored Does not occur Occurs when strong, hindered bases are used... 

Monodehydrohalogenation of allylic halides is another classical method for diene synthesis24. This method is complementary to double dehydrohalogenation as both the 1,2-dihalides and allylic halides are readily accessed from alkenes. The commonly employed protocol for diene synthesis, particularly for cyclic 1,3-dienes, is through the allylic monobromination of the alkene with A-bromosuccinimide or related reagents followed by dehydrobromination with hindered bases such as DBN or DBU (equation l)25. 

The protonation of carbenes by acids has been studied by PAC. Using sterically hindered acids to prevent collapse of the ion pair, the heat of reaction can be obtained and used to determine the p as of the resultant carbocations (Fig. 4).56 The results indicate that deprotonation of the carbocations to generate carbenes should be possible with strong hindered bases. This method has only rarely been used in the literature.1-57... 

The reaction presumably involves a cis, syn elimination. As Eq. 34 illustrates, regioselectivity can be controlled by choice of base 49). The higher kinetic acidity of the benzylic position of 20 determines the regioselectivity with a- non-hindered base whereas, steric hindrance directs the base to the methyl group. 

Alkyl-4-hydroxybutenolides. This group is present in some marine sponges and is believed to arise from 3-alkylfurans. This transformation can be realized in vitro by singlet oxygen oxidation in the presence of a hindered base such as ethyl-diisopropylamine. ... 

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