Aryl bromides and iodides

Another method for the hydrogenoiysis of aryl bromides and iodides is to use MeONa[696], The removal of chlorine and bromine from benzene rings is possible with MeOH under basic conditions by use of dippp as a ligand[697]. The reduction is explained by the formation of the phenylpalladium methoxide 812, which undergoes elimination of /i-hydrogen to form benzene, and MeOH is oxidized to formaldehyde. Based on this mechanistic consideration, reaction of alcohols with aryl halides has another application. For example, cyclohex-anol (813) is oxidized smoothly to cyclohexanone with bromobenzene under basic conditions[698]. 

Electrolysis, [Ni(bipy)3](BF3), Mg anode, DMF, rt, 40-99% yield.Aryl bromides and iodides are reduced under these conditions. 

Scheme 6.24 Selected pre-catalysts used for the Suzuki coupling between aryl bromides and iodides with boronic acids...

The reaction has a broad scope and is currently being widely applied in fine chemicals manufacture. One limitation is that the arylating agent is largely limited to relatively expensive aryl bromides and iodides (see, however, Reetz et al, 1998), while the process... 

It has been found that a number of bidentate ligands greatly expand the scope of copper catalysis. Copper(I) iodide used in conjunction with a chelating diamine is a good catalyst for amidation of aryl bromides. Of several diamines that were examined, rra s-yV,yV -dimethylcyclohexane-l,2-diamine was among the best. These conditions are applicable to aryl bromides and iodides with either ERG or EWG substituents, as well as to relatively hindered halides. The nucleophiles that are reactive under these conditions include acyclic and cyclic amides.149... 

With the exception of intramolecular amination reactions, all of the early aryl halide aminations were catalyzed by palladium complexes containing the sterically hindered P(o-tol)3. In papers published back-to-back in 1996, amination chemistry catalyzed by palladium complexes of DPPF and BINAP was reported.36,37 These catalysts allowed for the coupling of aryl bromides and iodides with primary alkyl amines, cyclic secondary amines, and anilines. 

In 1978 and 1980 the coupling of aryl bromides and iodides with both aliphatic and aromatic thiols was first reported in the presence of NaO-t-Bu and Pd(PPh3)4 (Equation (35)).118,119 In contrast to aryl halide aminations and etherifications, the thiation reactions did not require unusual catalysts. Yet, reactions that form aryl alkyl sulfides from alkyl thiols occurred in modest yields in many cases ... 

Vinyl and Aryl Halides and Triflates. The organosilane reduction of aryl halides is possible in high yields with triethylsilane and palladium chloride.195 The reaction is equally successful with aryl chlorides, bromides, and iodides. Aryl bromides and iodides, but not chlorides, are reduced with PMHS/Pd(PPh3)4 in moderate to excellent yields.199 This system also reduces vinyl bromides.199 p-Chlorobenzophenone is reduced to benzophenone with yym-tetramethyldisilo-xane and Ni/C in excellent yield (Eq. 59).200 There is a report of the organosilane reduction of aryl and vinyl triflates in very high yields with the combination of Et3SiH/Pd(OAc)2/dppp (l,3-bis(diphenylphosphino)propane) (Eq. 60).201... 

The ring closure to form butenolides by palladium(O) catalysis can be combined with C,C bond linking, as shown by Ma and co-workers. If using tetrakis (triphenyl -phosphane)palladium(O), the products 272 are obtained from 268 (R1 = alkyl, R2 = H) and vinyl iodides or aryl bromides and iodides R3X [304]. The authors assume that... 

An unusual palladium-catalyzed arylative fragmenation process of /3-hydroxy-substituted allenes was observed by Oh et al. [59]. Compounds such as 8 reacted with aryl bromides and iodides in the presence of Pd(PPh3)4 and K2C03 as base to give 1,3-dienes 120 and aldehydes 121 as second fragment (Scheme 14.28). The initially expected cyclization product, dihydropyran 122 (Scheme 14.29), was usually not formed. 

The difference in the reactivity of benzylic versus aromatic halogens makes it possible to reduce the former ones preferentially. Lithium aluminum hydride replaced only the benzylic bromine by hydrogen in 2-bromomethyl-3-chloro-naphthalene (yield 75%) [540]. Sodium borohydride in diglyme reduces, as a rule, benzylic halides but not aromatic halides (except for some iodo derivatives) [505, 541]. Lithium aluminum hydride hydrogenolyzes benzyl halides and aryl bromides and iodides. Aryl chlorides and especially fluorides are quite resistant [540,542], However, in polyfluorinated aromatics, because of the very low electron density of the ring, even fluorine was replaced by hydrogen using lithium aluminum hydride [543]. 

Alternative chemical reactions are available for tire generation of phenyl a-radicals. These include the diazonium salt reactions mentioned earlier and also reaction of aryl bromides and iodides with tributyltinhydride or triphenyltinhydride in the presence of a radical initiator [174], Electrogeneration of the tin radical by... 

Palladium(o) triphenylphosphine complexes catalyse the reduction of aryl bromides and iodides in a divided cell to give the diaryl [230]. The catalytic species... 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

Although aryl bromides and iodides reacted well without any additive (Scheme 32), tetrabutylammonium bromide (TBAB) was effective at improving the reactivity of aryl triflates under these conditions (Scheme 33). 

Scheme 32 Cross-coupling reaction of Ar3Bi with aryl bromides and iodides...

Very high regioselectivities (> 99.5% iso) were obtained, using PdCl2(PhCN)2 in combination with (+)-neomethyldiphenylphosphine and toluene-j9-sulfonic acid, under mild conditions (70 °C and 10 bar). More recently, the palladium-catalyzed alkoxycarbonylation and amido-carbonylation of aryl bromides and iodides in [bmim][BF4] and [bmim][PF6] has been described. Enhanced reaction rates were observed compared to conventional media and the ionic liquid-catalyst could be recycled. 

The arylation reaction is not applicable to aryl bromides and iodides. Another line of experimental evidence also indicates that an arylpalladium halide complex, instead of an arylpalladium triflate complex, is not electrophilic (Lewis acidic) enough to cleave the cyclopropane ring. 

An alternate approach for the 1-arylation of pyrroles is offered by their copper catalyzed coupling with aryl bromides and iodides, as depicted in 6.68. The process, run in the presence of trans-N,N -dnnethyl-cyclohcxane-diamine, was also efficient in the A-arylation of pyrazole, imidazole, triazoles and indazole, giving a mixture of isomers in the latter case.100... 

Aryl halides are often susceptible to photochemical degradation. As described in Chapter 10 later in this book, cleavage of the C-X bond occurs with low quantum yield for aryl chlorides (132), higher quantum yields for aryl bromides and iodides (133), and high quantum yields for some aryl fluorides (e.g., fluoroquinolones) (134). Aryl chlorides are photolabile to homolytic and/or heterolytic dechlorination (43). For sertraline hydrochloride, decomposition of the aryl dichloride moiety occurs in solution when exposed to light (ultraviolet and fluorescent conditions). As shown in the following proposed mechanism, the major photochemical decomposition products include mono-chloro- and des-chloro-sertraline via homolytic cleavage (Fig. 91) (86). 

The approach from Nicolaou [13] is similarly based on the activation of an aryl halide. Aryl bromides and iodides substituted with ortho-triazene react smoothly with phenols at 80 °C in the presence of K2CO3 and CuBr-Me2S to afford diaryl ethers in good yields (Scheme 2b). The use of this procedure requires the preformation of the requisite triazenes and the subsequent removal or transformation of this functional group. 

One of our initial forays into Mo(CO)6-promoted carbonylations included the investigation of intermolecular reactions using amines as nucleophiles to form secondary and tertiary aromatic amides from aryl bromides and iodides [27]. Subsequent work using the activating preligand f-Bu3PHBF4 has allowed for the extension of this chemistry into examples using aryl chlorides as substrates (Scheme 1) [30]. 

In 2005, very similar reactions were shown to proceed smoothly in continuous flow reactors (Scheme 45). The yield of couplings with aryl bromides and iodides were overall high, although the authors noted that it was not clear exactly how long a sample was irradiated due to uncertainties regarding the focus of the irradiation over the capillary column [119]. 

The development of catalytic systems using neat water as solvent is of high importance to industrial and environmentally friendly applications. In this respect, water is perhaps the ultimate solvent because of its lack of toxicity and ready availability. Leadbeater has published several papers where the Suzuki-Miyaura reaction has been optimized for aqueous conditions [9,120]. Aryl bromides and iodides were coupled and the corresponding products isolated in good yields with an attractive ligandless protocol. Some reactions gave increased yields with the addition of tetrabutylammonium bromide (TBAB) [121], Recently, an application for a scaled-up Suzuki-Miyaura synthesis in water using an automated batch stop-flow apparatus was also published (Scheme 46) [89]. 

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