Aryl halides SRNI substitution reactions

Simple aryl halides undergo substitution reactions with very strong bases such as -NH2. Neither the addition-elimination mechanism nor the SrnI mechanism seems very likely for this pair of substrates. 

A second general reaction that proceeds by an SrnI mechanistic pattern involves aryl halides. Aryl halides undergo substitution by eertain nueleophiles by a ehain mechanism of the SrnI class.Many of the reactions are initiated photochemically, and most have been conducted in liquid ammonia solution. 

The report by Bunnett and coworkers107 of substitution of halide by MeCOCth" or PhS- ions in vinyl bromides or iodides appears to be the only synthetic application of the SrnI reaction at vinylic sites. The reactions, particularly with benzenethiolate ion, are slower than those of aryl halides and the yields are not as good. Tautomers or mixtures of products result in the reactions with MeCOCH2 (e.g. equation 32). 

The SrnI reactions are grouped according to the attacking element in the nucleophilic species, i.e. according to the new aryl-element bond being formed. These reactions are convenient one-step substitution reactions leading from aryl halides (or arenes with appropriate nucleofuges) to a variety of classes of aromatic compounds. 

Just as in aryl halides, the halogen can be replaced by hydrogen and by a metal, or be involved in transition metal-catalyzed processes (covered in Section 3.2.3.11.2). Three of the mechanisms of such nucleophilic substitutions are familiar from benzene chemistry via arynes, SrnI processes, and Pd(0)-catalyzed sequences. However, of the two further mechanisms of nucleophilic replacement, the ANRORC (Addition of Micleophile, Ring Opening, Ring Closure) is unique to heterocycles, and Sae reactions occur only with strongly activated benzenoid systems. 

Unactivated aryl halides will undergo nucleophilic displacement via electron transfer in the initial step the so-called SrnI mechanism. It is now clear that in the case of heteroaromatic compounds, nucleophilic substitution by the SRN process often competes with the additionelimination pathway. SRN reactions are radical chain processes and are usually photochemically promoted. For example, ketone 913 is formed by the SRN1 pathway from 2-chloroquinoxaline 912. 

Copper(I) salts such as CuCN and ROCu undergo aromatic substitution reactions very readily with ordinary aryl halides. The mechanism has not been established with certainty. One reasonable possibility is an SrnI mechanism. Another reasonable possibility involves oxidative addition of Ar X to N=C Cu(I) to give a Cu(III) complex, followed by reductive elimination of Ar-CN to give CuX. 

There is good evidence that some nucleophilic substitution reactions do involve a single electron transfer, but the best established use a slightly different mechanism. These are the SrnI reactions, with the subscript RN standing for radical nucleophilic. Examples are the reaction of the nitronate anion 4.14 with p-nitrobenzyl chloride 4.15, 251 and the reaction of the pinacolone enolate 4.16 with bromobenzene.252 The former might have been a straightforward SN2 reaction, but actually takes the S l pathway because the nitro groups make the electron transfer exceptionally easy. The latter cannot take place by a conventional Sn2 reaction, because aryl (and vinyl) halides are not susceptible to direct displacement, and the S l pathway overcomes this difficulty. 

Biologically important heteroarenes are readily prepared by the reaction of ketone, ester or amide enolates with ortho-substituted aryl halides [11]. The ortho-substituent can subsequently be used for further synthetic manipulations. For example, the reaction of o-iodo or o-bromoaniline with enolates generated from aliphatic or aromatic ketones under SrnI conditions provides 2,3-disubstituted indoles in moderate to excellent yields (Equation 13.2) [12, 13]. 2,3-Disubstituted isoquinolin-l-ones (Equation 13.3) and isoquinolines are readily prepared using o-iodobenzamide and o-iodobenzylamine as radical precursors by the same approach [14]. 

EtO)2P and Ph2P are good nucleophiles in aromatic SrnI reactions and react with aryl halides to yield the substitution products with acceptable to excellent yields. Moreover, Ar-1 reacts efficiently with PhS", substituted thiophenolates and... 

In the field of (hetero)aromatic photochemistry substitution reactions are also quite useful. The two most useful classes are the SrnI reaction [16] and SnI reaction [17], involving respectively the aromatic radical anion and the aryl cation as the key intermediates. In the former case, (generally photoinduced) electron transfer generates the radical anion of an aryl halide. With less strongly bonded derivatives (usually iodides) the intermediate cleaves to an aryl radical that gives the new product via a chain process (see Scheme 2.6). 

---