1
Electrophilic Alkylation of Arenes

1.1 General Aspects

For large-scale industrial organic syntheses, electrophilic alkylations of arenes are essential (Scheme 1.1). Their attractive features include the absence of waste when alcohols or olefins are used as electrophiles, the large scope of available starting materials, and the high structural complexity attainable in a single step. The main issues are low regioselectivity, overalkylations, and isomerization of the intermediate carbocations. Important products resulting from this chemistry include isopropylbenzene (cumene – starting material for phenol and acetone), ethylbenzene (starting material for styrene), methylphenols, geminal diarylalkanes (monomers for polymer production), trityl chloride (from CCl4 and benzene [1]), dichlorodiphenyltrichloroethane (DDT) (from chloral and chlorobenzene), and triarylmethane dyes.

Scheme 1.1 Mechanism of the Friedel–Crafts alkylation.

To obtain acceptable yields, careful optimization of most reaction parameters is often required. Because the reactivity of an arene increases upon alkylation (around 2–3-fold for each new alkyl group), multiple alkylation can be a problem. This may be prevented by keeping the conversion low, or by modifying the reaction temperature, the concentration, the rate of stirring, or the solvent used (e.g., to provide for a homogeneous reaction mixture). In dedicated plants, processes are usually run at low conversion if the starting materials can be recycled. In the laboratory or when working with complex, high-boiling compounds, though, electrophilic alkylations of arenes can be more difficult to perform.

Typical electrophilic alkylating reagents for arenes include aliphatic alcohols, alkenes, halides, carboxylic and sulfonic esters, ethers, aldehydes, ketones, and imines. Examples of alkylations with carbonates [2], ureas [3], nitroalkanes [4], azides [5], diazoalkanes [6], aminoalcohols [7], cyclopropanes [8], and thioethers (Scheme 1.14) have also been reported. Amines can be used as alkylating agents either via intermediate conversion to N-alkylpyridinium salts [9] or by transient dehydrogenation to imines [10]. Some examples of Friedel–Crafts alkylation are given in Scheme 1.2.

Scheme 1.2 Examples of Friedel–Crafts alkylations [11–17].

In most instances, the electrophilic alkylation of arenes proceeds via carbocations, and complete racemization of chiral secondary halides or alcohols is usually observed. Only if neighboring groups are present and capable of forming cyclic configurationally stable cations, arylations can occur with retention of configuration [18].

Stabilized carbocations (e.g., tertiary carbocations) are easy to generate, but they are less reactive (and more selective) than less stable cations. Thus, the trityl or tropylium (C7H7+) cations react with anisole but not with benzene. On the other hand, carbocations destabilized by a further positively charged group in close proximity will show an increased reactivity [7, 19]. Highly stabilized cations may even be generated and arylated under almost neutral reaction conditions [20].

1.1.1 Catalysis by Transition-Metal Complexes

Electrophilic alkylations of arenes by olefins or alkyl halides can be catalyzed by soft electrophilic transition metals, for example, by Pd, Rh, or Ru complexes (Scheme 1.3). Most of the reported examples proceed via aromatic metallation through chelate formation. With Ru-based catalysts, selective meta-alkylation can be achieved when using sterically demanding electrophiles (fifth equation in Scheme 1.3).

Scheme 1.3 Transitions-metal-catalyzed arene alkylations [21–26].

Reactions where carbocation formation is the slowest (rate-determining) step can be catalyzed by any compound capable of stabilizing the intermediate carbocation (and thereby promote its formation). This form of catalysis should be most pronounced in nonpolar solvents, in which free carbocations are only slightly stabilized by solvation. Some transition-metal complexes, for example, IrCl3 and H2[PtCl6], catalyze Friedel–Crafts alkylations with benzyl acetates, probably by transient formation of benzylic metal complexes (Scheme 1.4). Because racemization is also observed in these instances, the intermediate complexes are likely to undergo fast transmetallation. Ru-based catalysts have been developed that enable the preparation of enantiomerically enriched alkylbenzenes and alkylated heteroarenes from racemic alcohols [27] (Scheme 1.18).

Scheme 1.4 Catalysis of Friedel–Crafts alkylations [28].

1.1.2 Typical Side Reactions

The rearrangement of intermediate carbocations is a common side reaction in Friedel–Crafts chemistry (Scheme 1.5). Rearrangements can sometimes be avoided with the aid of transition-metal-based catalysts, because the intermediate complexes are less reactive than uncomplexed carbocations.

Scheme 1.5 Rearrangement of carbocations during Friedel–Crafts alkylations [29, 30].

Carbocations can also act as oxidants and abstract hydride from other molecules [31]. The newly formed carbocations may also alkylate arenes and lead to the formation of complex product mixtures (Scheme 1.6).

Scheme 1.6 Hydride abstraction by carbocations as side reaction during Friedel–Crafts alkylations [32].

When using noble metal halides as catalysts, or α-haloketones, α-haloesters (Section 1.3.5), or perhaloalkanes as electrophiles, arenes may undergo halogenation instead of alkylation (Scheme 1.7). Alkyl halides with the halogen bound to good leaving groups (positions where a carbanion would be stabilized) are electrophilic halogenating reagents.

Scheme 1.7 Halogenation of arenes by alkyl halides and by AuCl3 [30, 33, 34].

If the concentration of alkylating reagent is too low, arenes may undergo acid-catalyzed oxidative dimerization (Scholl reaction) [35]. This reaction occurs particularly easily with electron-rich arenes, such as phenols and anilines.

1.2 Problematic Arenes

1.2.1 Electron-Deficient Arenes

Yields of alkylations of electron-deficient arenes by carbocations are usually low. This is mainly because the reaction is too slow, and the carbocation undergoes rearrangement and polymerization before attacking the arene. If no alternative reaction pathways are available for the carbocation, though, high-yielding Friedel–Crafts alkylations of electron-deficient arenes can be achieved (Scheme 1.8).

Scheme 1.8 Friedel–Crafts alkylation of electron-deficient arenes [36–38].

Electron-deficient arenes can be alkylated by olefins or alkyl halides via intermediate arene metallation. Chelate formation is usually required and crucial for the regioselectivity of transition-metal-catalyzed reactions (Scheme 1.9). The Ru- and Rh-catalyzed ortho-alkylation of acetophenones and acetophenone-imines by alkenes can even proceed at room temperature [39]. With sterically demanding alkyl halides, Ru complexes can mediate meta-alkylations [24]. When conducted in the presence of oxidants, these reactions can yield styrenes instead of alkylbenzenes [40–42] (see also Section 2.3).

Scheme 1.9 Ru-, Rh-, and Pd-catalyzed, chelate-mediated alkylation of electron-deficient arenes [43–46].

The metals used as catalysts for this ortho-alkylation of acetophenones insert not only into C–H bonds but also at similar rates into C–O and C–N bonds (Scheme 1.10). The selectivity can sometimes be improved by the precise choice of the catalyst [47]. Another potential side reaction of the alkylations described above is aromatic hydroxylation, which can readily occur if oxidants are present in the reaction mixture [48, 49].

Scheme 1.10 Ru-catalyzed ortho-alkylation and -arylation of acetophenones [50, 51]. Further examples: [52, 53].

Some heteroarenes, such as pyridine N-oxides, thiazoles, or imidazoles, are strongly C–H acidic, and can be metallated catalytically even without chelate formation. In the examples in Scheme 1.11, the intermediates are, in fact, metal carbene complexes.

Scheme 1.11 Metallation and alkylation of C–H acidic heteroarenes [54–56].

Under forcing conditions, fluoro- or nitrobenzenes can also be metallated without chelate formation, and trapped in situ with a number of electrophiles, including aldehydes and ketones (Scheme 1.12). Owing to the competing Cannizzaro reaction and the potential cleavage of ketones by strong nucleophiles (e.g., Haller–Bauer reaction), these reactions may require a large excess of electrophile and careful optimization.

Scheme 1.12 Metallation and alkylation of C–H acidic arenes [57].

Electron-deficient arenes and heteroarenes, such as pyridinium salts, can react with carbon-centered, electron-rich radicals. These can be generated from alkanes, alkyl halides, carboxylic acids, and some diacylperoxides [58] (Scheme 1.13), or by oxidation of boranes [59]. The...