Halogenation of arenes

The two mam methods for the preparation of aryl halides halogenation of arenes by electrophilic aromatic substitution and preparation by way of aryl diazomum salts were described earlier and are reviewed m Table 23 2 A number of aryl halides occur natu rally some of which are shown m Figure 23 1... 

Halogenation (Sections 4 14 and 12 5) Replacement of a hy drogen by a halogen The most frequently encountered ex amples are the free radical halogenation of alkanes and the halogenation of arenes by electrophilic aromatic substitution... 

One of the most important reactions in arene synthesis is the halogenation of arenes. Conventionally, these reactions are performed directly by bromine or chlorine [7]. However, on the laboratory scale chlorine is not easily manageable and is a toxic gas. Therefore, it is not often used in academic research. For iodinations normally a strong oxidizing agent is required. In halogenations, often unintentional side-chain... 

Much of the research on the SbCls-catalyzed halogenation of arenes has focused on the chlorination and bromination of perfluoroalkyl-substituted aromatics [14]. The reaction of organic disulfides with electron-rich aromatic compounds under catalysis with SbCls and AgSbFg affords unsymmetrical aryl sulfides in modest yields [15a]. Electrophilic sulfinylation and sulfonation can be similarly effected by SbCls [15a-c]. Alkyl- and halobenzenes give thiocyano derivatives when treated with a mixture of SbCls and Pb(SCN)2 in CCI4 [16],... 

In HF-SbFs solution 4-aIkyl- and 2,6-dialkylphenols and their methyl ethers (anisoles) are converted to the O-protonated forms, which react with Br2 to afford m-bro-mophenol derivatives selectively (Scheme 14.35) [83, 84]. In HF-SbFs o- and p-bro-mophenols isomerize to m-bromophenol by a 1,2-Br shift in fhe protonated forms [85], When NaBr or KBr is used instead of Br2, the meta selectivity is reduced [86]. ElectrophiUc halogenation of arenes can also be performed with Ar SeCl [87]. 

Similarly, chelation-assisted palladium-catalyzed oxidative functionalizations of C—H bonds with, for example, hypervalent iodine(III) reagents turned out to be particularly valuable. These protocols allowed for, inter alia, regioselective acetoxyla-tion or etherification of aromatic and aliphatic C— H bonds [17-19], and also halogenations of arenes (Scheme 9.3) [20, 21]. 

Ionization potential. See Ionization energy a- and p-lonone, 1049 lonophore, 624,1023 Iron, reduction of nitroarenes by, 878 Iron(III) salts as catalysts in halogenation of arenes, 446, 448—450 Isoamyl acetate, in bananas, 85, 788 Isobutane, 57. See also 2-Methylpropane Isobutene. See 2-Methylpropene... 

The above reactions appear to have synthetically significant advantages, being able to be carried out without stoichiometric metalation of nucleophilic substrates or halogenation of arenes. Since we surveyed these direct methods for preparing aromatic fine chemicals [5], further impressive progress has been achieved. Consequently, an updated summary of the direct reactions is described herein. 

Aromatic compounds can react with Pd(II) species, typically Pd(OAc)2, via cleavage of their C-H bonds to give arylpalladium(II) species (Scheme 1, mechanism D). Therefore, the arylation of alkenes can be performed directly using arenes and aromatic heterocycles [10, 11]. In this arylation, halogenation of arenes can be omitted, but an oxidizing reagent for the reoxidation of Pd(0) to Pd(II) should be added to make the reaction catalytic. 

Iodine in combination with [bis(acyloxy)iodo]arenes is a classical reagent combination for the oxidative iodination of aromatic and heteroaromatic compounds [99], A typical iodination procedure involves the treatment of electron-rich arenes with the PhI(OAc)2-iodine system in a mixture of acetic acid and acetic anhydride in the presence of catalytic amounts of concentrated sulfuric acid at room temperature for 15 min [100,101]. A solvent-free, solid state oxidative halogenation of arenes using PhI(OAc)2 as the oxidant has been reported [102]. Alkanes can be directly iodinated by the reaction with the PhI(OAc)2-iodine system in the presence of f-butanol under photochemical or thermal conditions [103]. Several other iodine(in) oxidants, including recyclable hypervalent iodine reagents (Chapter 5), have been used as reagents for oxidative iodination of arenes [104-107]. For example, a mixture of iodine and [bis(trifluoroacetoxy)iodo]benzene in acetonitrile or methanol iodinates the aromatic ring of methoxy substituted alkyl aryl ketones to afford the products of electrophilic mono-iodination in 68-86% yield [107]. 

It is well documented [95] that direct halogenation of arenes, bromination in particular, is one of the most selective electrophilic reactions yielding almost exclusively para-substituted products. Evidently, however, the use of cyclometalated compounds might drastically change the selectivity in favor of ort/io-halogenated compounds, as shown in Eq. (7.43) [76, 96]. This halogenation is also widely applied as a regioselective reaction method, as shown below in Eq. (7.44) [97]. 

Related strategies have been successfully applied to the halogenation of aliphatic and aromatic C-H bonds. Yu reported iodination of alkyl chains attached to an oxazoline that binds the palladium catalysts (Equation 18.19a). In this iodination, the combination of PhI(OAc)j and are used as the reagents to effect iodination and oxidation. The use of directing groups on arenes has also made possible the regioselective halogenation of arenes. As illustrated by the catalyzed and uncatalyzed processes in Equation 18.19b, the palladium-catalyzed process can occur faster than the uncatalyzed process to form a product directed by the catalyst, rather than the electronic properties of the arene. Under microwave conditions, directed fluorination of arene C-H bonds can also occur (Equation 18.19c). ... 

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