Directing groups, arenes with

A flexible means of access to functionalized supports for solid-phase synthesis is based on metallated, cross-linked polystyrene, which reacts smoothly with a wide range of electrophiles. Cross-linked polystyrene can be lithiated directly by treatment with n-butyllithium and TMEDA in cyclohexane at 60-70 °C [1-3] to yield a product containing mainly meta- and para-Iithiated phenyl groups [4], Metallation of noncross-linked polystyrene with potassium ferf-amylate/3-(lithiomethyl)heptane has also been reported [5], The latter type of base can, unlike butyllithium/TMEDA [6], also lead to benzylic metallation [7]. The C-Iithiation of more acidic arenes or heteroar-enes, such as imidazoles [8], thiophenes [9], and furans [9], has also been performed on insoluble supports (Figure 4.1). These reactions proceed, like those in solution, with high regioselectivity. 

There is some evidence that particular calixarene derivatives have direct therapeutic properties. The antitubercular action of 4-octylcalix[8]arenes with pendent polyether chains was determined by Cornforth s group in the early 1950s where the compound, then of unknown composition and called Macrocyclon, was shown to be generally non-toxic to mammals and yet more potent than streptomycin in the treatment of tubercular bacilli [32],... 

Simpkins and coworkers found increasing enantioselectivity with increasing size of alkoxy ortho-directing group. A 90% ee was achieved with R = z-Pr (Scheme 39)78,80, but no reaction occurred with the arene complex with R = Z-Bu. 

The most common mechanism of C-H bond cleavage in the arylation examples discussed above has been assumed to be electrophilic aromatic substitution involving reaction of an electrophilic palladium catalyst with an electron rich, nucleophilic aromatic ring. In order to effect direct arylation on simple, electron deficient arenes, a basic directing group or intramolecular reaction is usually necessary to enable formation of a metalocycle. As a brief introduction to the effect of this area on the functionalization of indoles and pyrroles, we provide an overview of the mechanistic... 

In the cross-coupling reaction, starting from the simple arene (with directing group), palladation by a Pd(II) salt would lead to the formation of the palladacyclic complex (Ar1Pd(II)L) (Scheme 3). After the transmetallation and reductive elimination processes, the biaryl product is obtained together with Pd(0). If the Pd(0) can be further oxidized to Pd(II) catalyst, a catalytic cycle will be formed. By accomplishing this, arenes (C-H) are used to replace the aryl halides (C-X). Similarly, arenes (C-H) can be used to replace the aryl metals (C-M). 

Intermolecular direct arylations of heteroarenes with aryl halides were thus far predominantly accomplished with palladium or rhodium complexes [31, 39,75, 76], Hence rhodium catalysts proved applicable to various electron-rich heteroarenes. In contrast, less expensive and more versatile palladium catalysts allowed for direct arylations of both electron-rich and electron-deficient substrates. Generally, the problem of achieving regioselectivities in direct arylation reactions of heteroarenes is less pronounced than it is for simple arenes, since in many cases the heteroatom can be considered as an endocyclic directing group. 

Shi and co-workers have developed various types of C—H bond functionalization and C—C bond formation. Recently, they reported a novel transformation to realize ortho-arylation of acetanilides with trialkoxyarylsilanes through direct C—H functionalization (Equation 11.34) [72]. Furthermore, they also demonstrated a novel method for the direct construction of biaryl C—C bonds via Pd(II)-catalyzed cross-coupling of (hetero)arenes and various arylboronic acids [73]. Various aromatic rings show good selectivity, even without directing groups, under mild conditions. 

Friedel—Crafts alkylation. Alkenes (styrenes and trisuhstituted alkenes) alkylate indoles at the 3-position in CH2CI2 containing 5 mol% of TfOH (or an Au(III) species). Benzyl trifluoromethyl carhinols are obtained from reaction of arenes with trifluoro-methyl epoxides. The direction of epoxide ring opening is determined by the electron-withdrawing trifluoromethyl group. ... 

Valuable ligand effects have been observed in oxidative Heck reactions. Arenes with weak directing groups benefit from the use of amino acid ligands such as acetylated isoleucine (Ac-Ile-OH), which promote C-H activation via proton... 

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