2- aryl bromides

Many organolithium compounds may be prepared by the interaction of lithium with an alkyl chloride or bromide or with an aryl bromide in dry ethereal solution In a nitrogen atmosphere ... 

Carbonylation of halides in the presence of primary and secondary amines at I atm affords amides[351j. The intramolecular carbonylation of an aryl bromide which has amino group affords a lactam and has been used for the synthesis of the isoquinoline alkaloid 498(352], The naturally occurring seven-membered lactam 499 (tomaymycin, neothramycin) is prepared by this method(353]. The a-methylene-d-lactam 500 is formed by the intramolecular carbonylation of 2-bromo-3-alkylamino-l-propene(354]. 

Aryl, heteroaryl, and alkenyl cyanides are prepared by the reaction of halides[656-658] or triflates[659,660] with KCN or LiCN in DMF, HMPA, and THF. Addition of crown ethers[661] and alumina[662] promotes efficient aryl and alkenyl cyanation. lodobenzene is converted into benzonitrile (794) by the reaction of trimethylsiiyl cyanide in EtiN as a solvent. No reaction takes place with aryl bromides and chlorides[663]. The reaction was employed in an estradiol synthesis. The 3-hydroxy group in 796 was derived from the iodide 795 by converting it into a cyano group[664]. 

A Pd-cataly2ed reaction of amines with halides is expected, but actually little is known about the reaction. The CDE ring system of lavendamycin (805) has been constructed by the intramolecular reaction of aryl bromide with aniline derivative in 804, but 1.2 equiv, of Pd(Ph3P)4 is required[679]. 

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]. 

The allylstannane 474 is prepared by the reaction of allylic acetates or phosphates with tributyltin chloride and Sml2[286,308] or electroreduction[309]. Bu-iSnAlEt2 prepared in situ is used for the preparation of the allylstannane 475. These reactions correspond to inversion of an allyl cation to an allyl anion[3l0. 311], The reaction has been applied to the reductive cyclization of the alkenyl bromide in 476 with the allylic acetate to yield 477[312]. Intramolecular coupling of the allylic acetate in 478 with aryl bromide proceeds using BuiSnAlEti (479) by in situ formation of the allylstannane 480 and its reaction with the aryl bromide via transmetallation. (Another mechanistic possibility is the formation of an arylstannane and its coupling with allylic... 

Although It IS possible to prepare aryl chlorides and aryl bromides by electrophilic aromatic substitution it is often necessary to prepare these compounds from an aromatic amine The amine is converted to the corresponding diazonmm salt and then treated with copper(I) chloride or copper(I) bromide as appropriate... 

Sandmeyer reaction using cop per(l) bromide is applicable to the conversion of primary arylamines to aryl bromides... 

Diazotization of a primary arylamine followed by treatment of the diazo mum salt with copper(l) bromide or copper(l) chloride yields the corre spending aryl bromide or aryl chloride... 

Sandmeyer reaction (Section 22 17) Reaction of an aryl dia zonium ion with CuCl CuBr or CuCN to give respec tively an aryl chloride aryl bromide or aryl cyanide (nitrile)... 

Aryl bromides were also perfluoroethylated under these conditions [205] The key to improved yields was the azeotropic removal of water from the sodium perfluoroalkylcarboxylate [205] Partial success was achieved with sodium hepta-fluorobutyrate [204] Related work with halonaphthalene and anthracenes has been reported [206 207] The main limitation of this sodium perfluoroalkylcarboxylate methodology is the need for 2 to 4 equivalents of the salt to achieve reasonable yields A trifluoromethylcopper solution can be prepared by the reaction of bis(tri-fluoromethyl)mercury with copper powder in /V-methylpyrrolidone (NMP) at 140 °C [208] (equation 138) or by the reaction of N-trifluoromethyl-A-nitro-sotnfluoromethane sulfonamide with activated copper in dipolar aprotic solvents [209] This trifluoromethylcopper solution can be used to trifluoromethylate aro matic [209], benzylic [209], and heterocyclic halides [209]... 

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

Bromoquinolines behave in the Suzuki reaction similarly to simple carbocyclic aryl bromides and the reaction is straightforward. Examples include 3-(3-pyridyl)quinoline (72) from 3-bromoquinoline (70) and 3-pyridylboronic acid (71) (91JOC6787) and 3-phenyl-quinoline 75 from substituted 3,7-dibromoquinoline 73 and (2-pivaloylaminophenyl)boronic acid 74 (95SC4011). Notice that the combination of potassium carbonate and ethanol resulted in debromination at the C(7) position (but the... 

Bromoquinoline (70), behaving similarly to a simple carbocyclic aryl bromide, was coupled with phenylethyne 121 to provide disubstituted ethyne 122 in 50% yield (2001JCS(P1)978). 

Remarkably, balogeti-magnesium exdiatige can also be extended to aryl and beteroaryl bromides [24, 25]. Tlius, tlie functionalized aryl bromides 28 and 29 iSdieme 2.7) were converted, at 0 C and at -30 C, respectively, into tlie corte-sponding Grignatd reagents. After treatment witli CuCN, tlie copper derivative 30 and 31 were obtained. Subsequent treatment witli typical electropb des sudi as benzoyl bromide or aliyl bromide fiirnisbed tlie products 32 and 33, in 70 and 8096 yields. 

Cradally, dais allows orgatiozitic reagents to be prepared from less reactive aryl bromides and secondary or tertiary alkyl bromides.. Alternatively, orgatiozitic iodides can be prepared by means of a paliadiurniOj-catalyzed reaction between alkyl iodides and Et2Zn iSdaeme 2.25) [53-56],... 

For the in situ preparation of the required arenediazonium salt from an aryl amine by application of the diazotization reaction, an acid HX is used, that corresponds to the halo substituent X to be introduced onto the aromatic ring. Otherwise—e.g. when using HCl/CuBr—a mixture of aryl chloride and aryl bromide will be obtained. The copper-(l) salt 2 (chloride or bromide) is usually prepared by dissolving the appropriate sodium halide in an aqueous solution of copper-(ll) sulfate and then adding sodium hydrogensulfite to reduce copper-(ll) to copper-(1). Copper-(l) cyanide CuCN can be obtained by treatment of copper-(l) chloride with sodium cyanide. 

An interesting free radical carbon-carbon bond formation with concomitant elimination of a /5-thio substituent was achieved during the course of Boger s impressive synthesis of CC-1065.26-27 In the event, treatment of aryl bromide 70 (see Scheme 13) with tri-n-... 

The -elimination of a thiyl radical (RS ) terminated a remarkably productive tandem radical bicyclization in Parker s formal total syntheses of ( )-codeine and ( )-morphine (see Scheme 14).29 Subjection of aryl bromide 72 to the conditions indicated generates transient aryl radical 73, an intermediate which engages the substi-... 

Saito has recently reported high yields and enantioselectivities in aziridine synthesis through reactions between aryl- or vinyl-substituted N-sulfonyl imines and aryl bromides in the presence of base and mediated by a chiral sulfide 122 (Scheme 1.41) [66]. Aryl substituents with electron-withdrawing and -donating groups gave modest transxis selectivities (around 3 1) with high enantioselectiv-... 

Palladium(II) complexes provide convenient access into this class of catalysts. Some examples of complexes which have been found to be successful catalysts are shown in Scheme 11. They were able to get reasonable turnover numbers in the Heck reaction of aryl bromides and even aryl chlorides [22,190-195]. Mechanistic studies concentrated on the Heck reaction [195] or separated steps like the oxidative addition and reductive elimination [196-199]. Computational studies by DFT calculations indicated that the mechanism for NHC complexes is most likely the same as that for phosphine ligands [169], but also in this case there is a need for more data before a definitive answer can be given on the mechanism. 

The palladium-catalyzed cross-coupling of alkenylsilanols has been extensively studied with respect to the structure of both the silicon component and the acceptor halide. The preferred catalyst for coupling of aryl iodides is Pd(dba)2 and for aryl bromides it is [allylPdCl]2. The most effective promoter is tetrabutylammonium fluoride used as a 1.0M solution in THF. In general the coupling reactions occur under mild conditions (room temperature, in 10 min to 12 hr) and some are even exothermic. 

Pd/P(t-Bu)., in the presence of Cy2NMe, is an unusually mild and versatile catalyst for Heck reactions of aryl chlorides (Tables 1 and 2) (as well as for room-temperature reactions of aryl bromides).21 22 23 Example A, the coupling of chlorobenzene with butyl methacrylate, illustrates the application of this method to the stereoselective synthesis of a trisubstituted olefin a-methylcinnamic acid derivatives are an important family of compounds that possess biological activity (e.g., hypolipidemic24 and antibiotic25) and serve as intermediates in the synthesis of pharmaceuticals (e.g., Sulindac, a non-steroidal anti-inflammatory drug26). Example B, the coupling of 4-chlorobenzonitrile with styrene, demonstrates that Pd/P(t-Bu). can catalyze the Heck reaction of activated aryl chlorides at room temperature. 

PdCl2(PPh3)2 and Cul in a mixture of Et2NH and DMF at 120 °C for 5-25 min were found to be suitable as a general protocol. For less reactive (hetero)aryl bromides and 2-chloropyridine, extra triphenylphosphine was added to improve the stability of the palladium catalyst (Scheme 49). 

A microwave-assisted Cu-catalyzed Sonogashira-type protocol on aryl iodide substrates without the involvement of a palladium catalyst has also been published (Scheme 54) [71]. Reactions were executed using Cut and CS2CO3 in NMP at 195 °C. The application seems to be fairly limited since there are indications that only (hetero)arylacetylenes are suitable coupHng partners for this protocol. In addition, aryl bromides react more sluggishly than aryl iodides. Moreover, even on aryl iodides the reaction times required are on the order of hours. 

Leadbeater described the use of Ni(CN)2 for the microwave-assisted cyanation of (hetero)aryl bromides [81]. The use of 0.6equiv of Ni(CN)2 was found to be optimal. Unfortunately, the heteroaryl bromides reported in the study gave relatively low yields due to significant decomposition (Scheme 70). 

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