Unactivated aryl halides

Unactivated aryl halides can be converted to amines by the use of NaNH2, NaNHR, or NaNR2. With these reagents, the benzyne mechanism generally operates, so cine substitution is often found. Ring closure has been effected by this type of reaction,for example. 

Unactivated aryl halides react with copper acetylides to give good yields of arylacetylenes Stephens-Castro coupling)P ... 

Direct aromatic substitution of unactivated aryl halides is slow and generally requires a catalyst to become a useful synthetic method. Copper reagents have been used in some cases in classical procedures for the formation of products from aromatic substitution. In many cases these copper-mediated reactions occur at high temperatures and are substrate dependent. Since the 1970s, transition metal catalysts have been developed for aromatic substitution. Most of the early effort toward developing metal-catalyzed aromatic substitution focused on the formation of... 

The first palladium-catalyzed formation of aryl alkyl ethers in an intermolecular fashion occurred between activated aryl halides and alkoxides (Equation (28)), and the first formation of vinyl ethers occurred between activated vinyl halides and tin alkoxides (Equation (29)). Reactions of activated chloro- and bromoarenes with NaO-Z-Bu to form /-butyl aryl ethers occurred in the presence of palladium and DPPF as catalyst,107 while reactions of activated aryl halides with alcohols that could undergo /3-hydrogen elimination occurred in the presence of palladium and BINAP as catalyst.110 Reactions of NaO-/-Bu with unactivated aryl halides gave only modest yields of ether when catalyzed by aromatic bisphosphines.110 Similar chemistry occurred in the presence of nickel catalysts. In fact, nickel catalysts produced higher yields of silyl aryl ethers than palladium catalysts.108 The formation of diaryl ethers from activated aryl halides in the presence of palladium catalysts bearing DPPF or a CF3-subsituted DPPF was also reported 109... 

With very strong bases, such as amide ion, NHj, unactivated aryl halides undergo substitution by an elimination-addition (benzyne) mechanism. 

Another series of monomers that was prepared began with the displacement of an unactivated aryl halide with phenate anion in the presence of a copper catalyst [113-115], Figure 46 outlines the basic route followed for the preparation of 114a. The sequence of reactions started with 4-bromobenzocyclobu-tene, 2 which was reacted with the phenate of p-acetamidophenol, 112a in the presence of copper (I) chloride as a catalyst, to afford the ether linked product 113a in a yield of 50-75%. 

The reaction of the cyanide ion with alkyl halides, using PTC, has been widely studied since the first example was reported by Starks.167 However, with unactivated aryl halides (e.g., chlorobenzene and dichlorobenzene) the reaction fails.229 On the other hand, chloropyrimidine reacts with tetra-ethylammonium cyanide in acetonitrile.230 Hermann and Simchen231 have described more generally the synthesis of cyano heterocycles, using tetra-ethylammonium cyanide. 

Very strong bases such as NaNH2 convert unactivated aryl halides into benzyne intermediates which react rapidly with nucleophiles to form the products of an apparently simple nucleophilic substitution. It is now clear that hetarynes are frequent intermediates in reactions of not too highly activated heteroaromatic halides. 

Unactivated aryl halides also undergo nucleophilic displacement via electron transfer in the initial step the so-called SRN1 mechanism. It is now clear that in the case of heteroaromatic compounds, nucleophilic substitution by the Srn process often competes with the addition-elimination pathway. The SRN reactions are radical chain processes, and are usually photochemically promoted. For example, ketone (895) is formed by the SRN1 pathway from 2-chloroquinoxaline (894) (82JOC1036). 

The point at which one can expect SN2 and E2 reactions to go faster than radical formation as the structures of the halides and the nature of the metal are changed is not yet clearly defined. However, it is becoming increasingly evident that there are substitution reactions of unactivated aryl halides that proceed without rearrangement by way of radical intermediates. The key step in these reactions is donation of an electron to one of the unfilled tt orbitals of the ring and subsequent ejection of a halide ion ... 

Parrish and Buchwald30 performed couplings with a polystyrene-supported biphenyl-phosphine palladium complex between aryl halides and either amines (entry 24) or boronic acids (entry 25). The resin-bound complex is analogous to the corresponding homogeneous compound and is effective for couplings to unactivated aryl halides, including aryl chlorides. The complex is air-stable and retains activity after recovery without apparent loss of palladium. 

Iron sulfate [82] and iron chloride [83] have also been reported as catalysts for the nucleophilic aromatic substitution of unactivated aryl halides. As solvents, liquid ammonia and DMSO at room temperature are used (Scheme 6.17). 

This method is useful for aryl-substituted malonates 27 where the normal alkylation of the malonate anion 26 is impossible as Sn2 reactions fail on unactivated aryl halides. For Ar = Ph reaction of 28 with NaH and diethyl carbonate gives3 27 Ar = Ph in 86% yield. 

This instant invention represents an improvement in the Ullman coupling reaction. This investigation represents the first general method for coupling electron deficient phenols and unactivated aryl halides (1,2,3,4). The basis of the improvement lay in the high solubility of (CuOTf)2 benzene and cesium phenolate or copper phenolate in the reaction solvent, toluene. 

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