Base-Catalyzed Alkylation

In contrast to acid-catalyzed alkylation of arenes, where alkylation of the aromatic nucleus occurs, the base-catalyzed reaction of alkylarenes leads to alkylation of the side chain.231-234 Alkenes (straight-chain 1-alkenes, isobutylene), conjugated 

Sodium and potassium are the two most frequently used alkali metals in side-chain alkylation. Sodium usually requires a promoter (o-chlorotoluene, anthracene) to form an organosodium intermediate that is the true catalyst of the reaction. A temperature range of 150-250°C is usually required for alkylation with monoolefins, whereas dienes and styrenes are reactive at lower temperatures. 

The reaction of alkylbenzenes with ethylene in the presence of sodium occurs with successive replacement of one or two benzylic hydrogens to produce mono-and diethylated compounds.235 Propylene reacts to form isomeric products with the preponderance of the branched isomer236 [Eq. (5.61)]. When potassium is used as catalyst, indan derivatives can also be formed237 [Eq. (5.62)]  

Alkylnaphthalenes are more reactive than alkylbenzenes and react at temperatures as low as 90°C. Sodium is a selective catalyst for side-chain monoalkylation. More elevated temperatures and prolonged reaction times allow the replacement in ethylation of all a-hydrogen atoms of alkylnaphthalenes with high selectivity.238 

3-Dienes react quite readily with alkylbenzenes to form monoalkenylbenzenes under controlled experimental conditions. Sodium and potassium deposited on calcium oxide were found to be very suitable catalysts for these alkenylation reactions.240 Naphthalene-sodium in tetrahydrofuran is a very effective catalyst 

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Chemoselective C-alkylation of the highly acidic and enolic triacetic acid lactone 104 (pAl, = 4.94) and tetronic acid (pA, = 3.76) is possible by use of DBU[68]. No 0-alkylation takes place. The same compound 105 is obtained by the regioslective allylation of copper-protected methyl 3,5-dioxohexano-ate[69]. It is known that base-catalyzed alkylation of nitro compounds affords 0-alkylation products, and the smooth Pd-catalyzed C-allylation of nitroalkanes[38.39], nitroacetate[70], and phenylstilfonylnitromethane[71] is possible. Chemoselective C-allylation of nitroethane (106) or the nitroacetate 107 has been applied to the synthesis of the skeleton of the ergoline alkaloid 108[70]. 

A cyclic borate can be used to protect a catechol group during base-catalyzed alkylation or acylation of an isolated phenol group the borate ester is then readily hydrolyzed by dilute acid. ... 

The direct base-catalyzed alkylation of 3-keto steroids is generally not a very satisfactory method for the preparation of monoalkylated products. However, under optimum conditions (short reaction time with methyl iodide, a Modest excess of potassium t-butoxide in boiling t-butanol) modest yields of... 

Benzoxazine, an heterocycle present as structural subunit in many naturally occurring and synthetic bioactive compounds, was prepared under microwave irradiation from a mixture of 2-aminophenol 218 and an a-bromoester 219 (Scheme 80). The reaction proceeded through an initial base-catalyzed alkylation of the phenoUc OH followed by spontaneous amidation. Yields from 44 to 78% were reported for 17 different benzoxazines 220 [ 141]. 

Silyl enol ethers and silyl ketene acetals also offer both enhanced reactivity and a favorable termination step. Electrophilic attack is followed by desilylation to give an a-substituted carbonyl compound. The carbocations can be generated from tertiary chlorides and a Lewis acid, such as TiCl4. This reaction provides a method for introducing tertiary alkyl groups a to a carbonyl, a transformation that cannot be achieved by base-catalyzed alkylation because of the strong tendency for tertiary halides to undergo elimination. 

Coughing is a useful physiologic device utilized to clear the respiratory tract of foreign substances and excessive secretions. Coughing, however, does not always serve a useful purpose but can rob the patient of sleep. A number of agents are available to suppress this. Many of these are narcotic and have an undesirable abuse potential. One of the agents available which is claimed to be nonnarcotic is amicibone (45). The synthesis involves base-catalyzed alkylation of benzyl cyclohexan-ecarboxylate (44) with p-hexamethyleneiminoethyl chloride a reaction which may go through an aziridinium intermediate. 

Sodium is the metal which has been studied most for base-catalyzed alkylations. The use of it results in the most selective reactions. 

Of the olefins, ethylene has been most extensively studied (19, 21, 23-26, 36) it reacts most readily in base-catalyzed alkylations. In general temperatures of 150-200 are used with relatively low ethylene pressures (0-70 atm.). Benzylic hydrogens are replaced by ethyl groups i.e., toluene yields n-propylbenzene. Additional substitution on the a-carbon may yield 3-phenylpentane and 3-ethyl-3-phenylpentane [Reaction (3)]. 

Alkylpyridines have been shown to undergo base-catalyzed alkylations similar to those of alkylbenzenes These compounds are included in... 

Simple monoolefins and cycloolefins react in the presence of base catalysts under conditions similar to those used for base-catalyzed alkylation. The... 

The mechanism of reaction of monoolefins resembles that for base-catalyzed alkylation. An example is the reaction of isobutylene (32a, b, c). 

Acetoacetic Ester Synthesis The formation of a substituted acetone through the base-catalyzed alkylation or arylation of a (3-keto ester. 

The intermediacy of an anhydro base (57) was referred to in Scheme 46. Analogous anhydro bases (pyridone methides) can be formed by deprotonation of quaternary salts of 2- and 4-benzylpyridines and the like. The pyridone methides are usually highly reactive and not readily isolable some stable examples are shown in Scheme 49. Pyridine methides are intermediates in the base-catalyzed alkylation and acylation reactions of pyridinium salts at the exocyclic carbon. Compounds of type (60) have been estimated to have 25-30% dipolar character. Protonation of (60) occurs at the 2 - and 3 -positions in the ratio 4 1 respectively (70JCS(C)800). 

Reaction of the 2-acetoxy-3(2//)-furanones (526) with monosubstituted hydrazines gives good yields of the pyridazinium-5-olates (527) together with varying amounts of isomeric products. Alkyl derivatives (527 R = alkyl) have also been prepared by base-catalyzed alkylation (Mel, Me2SO4, PhCH2Cl) of 3-methyl-6-phenyl-5-ethoxycarbonyl-4( 1 //)-pyridazinone. Reduction of the diphenyl compound 527 (R = Ar = Ph) by zinc and hydrochloric acid gives 3-ethoxycarbonyl-5-hydroxy-5-methyl-l,2-diphenyl-2-pyrrolin-4-one (528 R = Ar = Ph) (Scheme 21... 

Base-catalyzed carbanionic alkylation, isomerization, polymerization reactions are of major significance. Base-catalyzed alkylation of alkylarenes, in contrast to acid-catalyzed ring alkylation, leads to alkylation of the side chain in the benzylic position [Eq. (1.28) see also Chapter 5] of particular interest is the alkylation of toluene to ethylbenzene (for styrene production). 

The higher stability of primary anion 37 as compared to secondary anion 38 explains the predominant formation of branched isomers. The high reactivity of conjugated dienes and styrenes compared with that of monoolefins is accounted for by the formation of new resonance-stabilized anions (39 and 40). Base-catalyzed alkylation with conjugated dienes may be accompanied by telomerization. The reason for this is that the addition of a second molecule of diene to the 39 monoadduct anion competes with transmetallation, especially at lower... 

The base-catalyzed alkylation of oxindoles favors C-alkylation, and O-alkylation is observed with halides only for particularly favorable intramolecular alkylations (B-70MI30614). Triethyloxonium tetrafluoroborate, on the other hand, gives the O-alkylated... 

Unfortunately, alkylation reactions analogous to the base-catalyzed alkylation of carbonyl compounds generally are not useful for the synthesis of higher nitro compounds, because C-alkylation of the conjugate bases of primary nitro compounds is slower than O-alkylation. 

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