Aryl halide exchange reactions

Halogen exchanges in aryl halides are important for several reasons  

In drug optimization endeavors, a common practice is to introduce fluorine or chlorine in metabolically sensitive positions, because of their bioisosteric properties with hydrogen, thus blocking, for instance, hydroxylation by cytochrome P-450. 

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Reaction of aryl organometallic compounds with halogens Aryl halide exchange halo-denitration halo-dehydroxylation Reaction between diazonium salts and iodide ion Heating of diazonium fluoroborates (Schiemann)... 

Scheme 6.145 Halide-exchange reactions in aryl halides.

Halide exchange reactions ( transhalogenation or Finkelstein reaction) have been, until recently, of particular synthetic importance only in the synthesis of alkyl (and strongly activated aryl) fluorides or iodides, where thermodynamic stability (for the fluorides) and solubility differences (for the iodides) shift the reversible exchange processes in the desired direction. With the advent of phase transfer catalysis (PTC) and transition metal catalysis (mainly homogeneous) this important family of reactions has been extended to practically all aromatic and aliphatic halides. 

Scheme 4 Proposed mechanistic pathways for the copper-assisted halide exchange reactions in nonactivated aryl halides...

Ni(0) complexes were also employed in the halide exchange reactions in non-activated aryl halides. Both Ni powder and in-situ generated Ni(0) species (from Ni(ll) and Zn dust) provided good yields of the exchange products, which included aryl iodides from the corresponding aryl bromides and chlorides [28-30]. In some cases, the reactions were accompanied by the formation of considerable amounts of C-C coupling products. 

A novel route to prepare bifimctional initiating systems susceptible to anionic polymerization was recently devel-oped. For the synthesis of PMMA-PBd-PSt-PBd-PMMA, a bis(aryl halide) was metalated by a lithium/halide exchange reaction. The initiator that resulted was used to polymerize sequentially St, Bd, and MMA (Scheme 11). To ensure solubilization of the initiator in nonpolar organic media (benzene). 

It has been shown that the use of ionic liquids may be beneficial in aromatic fluorinations in protic solvents." Aryl fluorides may also be obtained using a copper-catalysed halide exchange reaction. The evidence suggests a redox Cu(I)/Cu(III) catalytic cycle involving oxidative addition of aryl halide at the copper(I) centre followed by halide exchange and reductive elimination." A mechanistic investigation of the palladium-catalysed conversion of aryl triflates to fluorides has shown that C-F reductive elimination from the palladium—arene complex does not occur when the aryl group is electron rich and requires in situ modification of the catalyst." ... 

The next series of fully-conjugated indeno[l,2-b]fluorenes synthesized by Haley et al. was 6,12-diarylindeno[l,2-b]fluorenes (Scheme 26) [77]. Similar to 96a-i, lithium-halogen exchange with the appropriate aryl halide and reaction with 22 afforded mixtures of stereoisomers 97a-i. Reduction using anhydrous SnCl2 at elevated temperatures provided 87a-j in 36-59% yield. The electron-withdrawing... 

The mechanism of action of the cyanation reaction is considered to progress as follows an oxidative addition reaction occurs between the aryl halide and a palladium(O) species to form an arylpalladium halide complex which then undergoes a ligand exchange reaction with CuCN thus transforming to an arylpalladium cyanide. Reductive elimination of the arylpalladium cyanide then gives the aryl cyanide. 

Silver salts are also employed to create more effective chiral catalysts by exchange of counter anions. For example, in the Mizoroki-Heck reaction of alkenyl or aryl halides, silver salts are employed to form effective chiral Pd intermediates by abstracting a halide group from the Pd11 precursor species (Scheme 53).227,228... 

In the direct synthesis of aryl terminal alkynes via Pd-catalyzed cross-coupling of aryl halides with ethynylmetals, formation of diarylethynes is one of the potential side reactions. Indeed, the Kumada coupling of 2-iodo-5-methylthiophene (29) with ethynylmagnesium chloride gave the desired 2-ethynyl-5-methylthiophene (30) in only 35% yield, along with 24% of bis(5-methyl-2-thienyl)ethyne (31) [29], The high propensity for H-Mg exchange reaction to occur was blamed for the diarylethyne formation. 

It can be assumed that the azoles are deprotonated by the interfacial exchange mechanism, but it is noteworthy that it has been suggested that the rate of alkylation of indole under liquiddiquid two-phase conditions decreases with an increase in the concentration of the sodium hydroxide [8]. The choice of catalyst appears to have little effect on the reaction rate or on the overall yields of alkylated azole. Benzyltriethylammonium chloride, Aliquat, and tetra-n-butylammonium hydrogen sulphate or bromide have all been used at ca. 1-10% molar equivalents (relative to the concentration of the azole) for alkylation reactions, but N-arylation of indole with an activated aryl halide requires a stoichiometric amount of the catalyst [8]. 

Because the free energy of the aryl halide/lithium exchange equilibrium is essentially equal to the enthalpy change of the reaction, we consider other reactions from the same source of the general type (equation 11),... 

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