Active arylation

The carbonyiation of o-diiodobenzene with a primary amine affords the phthalimide 501 [355,356]. Carbonyiation of iodobenzene in the presence of (9-diaminobenzene (502) and DBU or 2,6-lutidine affords 2-phenylbenzimida-zole (503)[357, The carbonyiation of aryl iodides in the presence of pentaflnor-oaniline affords 2-arylbenzoxazoles directly, 2-Arylbenzoxazole is prepared indirectly by the carbonyiation of (9-aminophenol[358j. The optically active aryl or alkenyl oxazolinc 505 is prepared by the carbonyiation of the aryl or enol triflates in the presence of the opticaly active amino alcohol 504, followed by treatment with thionyl chloride[359]. 

The terminal amino group of 2-hydrazino-4-phenylthiazole is also the reactive center in reactions with activated aryl halides such as 288. A solution of the product (289) obtained from this reaction when shaken with PbOj gives a deeply colored radical, whose structure has been studied by ESR (Scheme 173) (532. 533). 

Replacement of an aromatic fluorine atom by a carbon nucleophile is facihtated by the presence of electron-withdrawmg groups [82] (equation 44) Replacement of an activated aryl hydrogen can occur in preference to a nonactivated aryl fluorine [Si] (equation 45) in reactions known as vicarious subsututions. 

Heterocyclic bases which readily form quaternary salts with the more usual reagents will also react with suitably activated aryl and heterocyclyl halogen compounds, the classic case being the salt formed from pyridine and l-chloro-2,4-dinitrobenzene. Reactions of this type have been studied by Chapman et Salt formation between... 

A new method for the synthesis of 1,2,5-thiadiazoline 5,5-dioxides 231 was achieved by reacting activated aryl nucleophiles to the C=N double bond of the corresponding thiadiazoles 230 in the presence of AlClj as a catalyst at room temperature (00MI4). The yields of 4-aryl-derivatives ranged from 38 to 92%. 

Since these adducts undergo reductive desulfuration with Raney nickel, optically active aryl methyl sulfoxides are versatile reagents for the conversion of imines to optically active amines. 

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. 

HECK COUPLINGS OF ACTIVATED ARYL CHLORIDES AT ROOM TEMPERATURE... 

The method is quite useful for particularly active alkyl halides such as allylic, benzylic, and propargylic halides, and for a-halo ethers and esters, but is not very serviceable for ordinary primary and secondary halides. Tertiary halides do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and elimination predominates. The reaction can also be applied to activated aryl halides (such as 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, " and to activated alkenes such as acrylonitrile. The latter is a Michael type reaction (p. 976) with respect to the alkene. 

Other sulfur nucleophiles also react with activated aryl halides ... 

As mentioned in the discussion of the reaction mechanism for this transformation, the active species is a dicoordinate Pd(0) complex, and it is unclear whether an associative or a dissociative process is operative for oxidative addition. In this context, different NHC complexes containing only one carbene ligand have been tested in the Mizoroki-Heck reaction. The most successful are those prepared by Beller, which were able to perform the Mizoroki-Heck reaction of non-activated aryl chlorides with moderate to good yields in ionic liquids (Scheme 6.13). The same compounds have also been applied to the Mizoroki-Heck reaction of aryldiazonium... 

Scheme 6.13 Mizoroki-Heck reaction of non-activated aryl chlorides and diazo compounds using Seller s catalytic systems...

In the context of NHC/metal catalysed cross-coupling reactions, the only example of a Hiyama reaction was reported by Nolan using an in situ protocol by mixing Pd(OAc)j and IPr HCl for the formation of the catalyst. Activated aryl bromides and chlorides, such as 2-chloropyridine, were coupled with phenyl and vinyl-trimethoxysilane in good yields [123] (Scheme 6.39). 

Scheme 6.39 Hiyama coupling between activated aryl bromides/chlorides and phenyl/vinyl-trimethoxysilane...

The first examples of NHC-Pd complexes applied to the Sonogashira reaction were reported to show a limited scope in the coupling of aryl iodides and activated aryl bromides with acetylene [23,33,52]. However, the use of A-carbamoyl-substituted heterocyclic carbene Pd(ll) complexes expanded the use to alkyl-acetylenes and deactivated aryl iodides and bromides [124] (Scheme 6.40). 

More recently, a study with di- and mono-carbene Pd(II) complexes has demonstrated that the Sonogashira coupling of activated and non-activated aryl iodides can be carried out in an aqueous, aerobic medium and in the absence of amines. These results suggest that the moisture-sensitive copper-acetylide may not be present in this particular transformation, and that a Pd-acetyhde could be formed by deprotonation of the coordinated alkyne instead of transmetallation [130]. 

The stereospecific conversion of menthyl arenesulphinates into chiral aryl methyl sulphoxides may also be achieved by means of methyllithium . The reaction of methyllithium with diastereoisomerically or enantiomerically pure arenesulph-inamides 283 was found to give optically active aryl methyl sulphoxides 284 (equation 156). The preparation of optically active sulphoxides 285 and 286, which are chiral by virtue of isotopic substitution (H - D and - respectively), involves the reaction of the appropriate non-labelled menthyl sulphinates with fully deuteriated methyl magnesium iodide (equation 157) and with benzylmagnesium chloride prepared from benzyl chloride labelled with carbon (equation 158). 

The catalytic activity, however, is generally associated with leaching of the metal into solution, the reaction being most likely catalyzed by soluble active Pd species. Palladium leaching is generally caused by oxidative attack of the aryl halide on the metal nanoparticles, giving catalyt-ically active aryl halide Pd(II) species in solution [30]. 

A short and practical synthesis of glucokinase activator 1 was developed utilizing a convergent strategy involving an SNAr coupling of the activated aryl fluoride 11 with hydroxypyridine 9. 

Treatment of [IrCl(CO)2(/ -toluidene)] with azine phosphines of type Z, -PPh2CH2C( Bu) =N-N=C(Q)R, Q = H, Me, R = an organic group, activates aryl, heterocyclic, alkenyl, or aliphatic C—H bonds to give cyclometalated Ir111 hydrides.339... 

The pincer-type palladacycle (120) (R = 1Pr), which is actually a derivative of a dialkylphos-phinous acid (themselves excellent ligands see Section 9.6.3.4.6) was shown to allow the crosscoupling of aryl chlorides with terminal acetylenes ((120), ZnCl2, Cs2C03, dioxane, 160 °C). However the high reaction temperature may be prohibitive for the actual application of this catalytic system, as acetylenes are known to be thermally sensitive.433 The same palladacycle (R = Ph) is effective in the Suzuki-Miyaura reaction with aryl bromides and activated aryl chlorides (K2C03, toluene, 130 °C). 

A similarly high performance has been reported for oxime-derived (125) and benzylsulfide-derived (126) palladacycles.438 These precatalysts are effective in the cross-coupling of arylboronic acids,438,439 organotin compounds,440 and terminal acetylenes441 with aryl iodides and bromides, and of activated aryl chlorides. SC-palladacycles can effect the Suzuki-Miyaura reaction even at room temperature. 

Activated aryl chlorides, which are close in reactivity to unactivated aryl bromides, underwent reaction with the original P(o-tol)3-ligated catalyst.58 Nickel complexes, which catalyze classic C—C bond-forming cross-couplings of aryl chlorides, 9-64 also catalyzed aminations of aryl chlorides under mild conditions.65,66 However, the nickel-catalyzed chemistry generally occurred with lower turnover numbers and with a narrower substrate scope than the most efficient palladium-catalyzed reactions. 

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... 

Low-valent cobalt pyridine complexes, electrogenerated from CoCl2 in DMF containing pyridine and associated with a sacrificial zinc anode, are also able to activate aryl halides to form arylzinc halides.223 This electrocatalytic system has also been applied to the addition of aryl bromides containing an electron-withdrawing group onto activated alkenes224 and to the synthesis of 4-phenylquinoline derivatives from phenyl halides and 4-chloroquinoline.225 Since the use of iron as anode appeared necessary, the role of iron ions in the catalytic system remains to be elucidated. 

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