Activated aryl halides

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). 

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 ... 

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]. 

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. 

Scheme 6.125 Nucleophilic aromatic substitutions of activated aryl halides.

Although sodium sulphide reacts readily with haloalkanes [2] and activated aryl halides (see Chapter 2) [e.g. 3-5] in the presence of a quaternary ammonium catalyst to form symmetrical thioethers (Table 4.1), a major side reaction results in the formation of disulphides owing to the oxidation of the intermediate thiols under the basic conditions. Consequently, little use has been made of this procedure for the synthesis of thioethers [3, 6], but the corresponding reaction of the a,(0-dihaloalkanes to yield cyclic thioethers has proved to be a valuable procedure for the synthesis of thietanes [7] (Table 4.2). The ring closure with the secondary dihaloalkanes is considerably more difficult to effect than is the reaction of the primary dihaloalkanes. 1,3-Dihydrobenzo[c]thiophene (89%) is produced in the reaction of 1,2-bis(bromomethyl)benzene with sodium sulphide (Scheme 4.1) [8]. The direct... 

Activated aryl halides react with thiols [e.g. 4] to produce aryl thioethers and thioethers, derived from non-activated aryl halides, can be synthesized via the Cr(CO), complexes of the haloarenes [29] (Scheme 4.2, see also Chapter 2). 

A superior and relatively versatile procedure for the synthesis of unsymmetrical dialkyl thioethers, which avoids the unattractive direct use of thiols, utilizes the stable l-alkylthioethaniminium halides, which are readily obtained from thioacet-amidc [32] (Scheme 4.4). The reaction has also been used for the synthesis of alkyl aryl thioethers from activated aryl halides [33], but it cannot be used for the synthesis of cyclic thioethers, as polymeric sulphides are formed from a,co-dihaloalkanes. A similar sequence to that which leads to the thioethers has been used for the synthesis of S-alkyl thioesters [34] (see 4.1.26). 

In the unconventional synthesis of thioethers (Scheme 4.11), cyanide ion is displaced from thiocyanates by carbanions [52, 53], which have been generated under phase-transfer catalytic conditions (cf. 4.1.12). Thiocyanates are readily obtained by a standard catalysed nucleophilic substitution reaction [4, 54-58] (see Table 4.19). Aryl thiocyanates are obtained from activated aryl halides [4, 57] (see Chapter 2). 

It can be assumed that the azoles are deprotonated by the interfacial exchange mechanism, but it is noteworthy that it has been suggested that the rate of alkylation of indole under liquiddiquid two-phase conditions decreases with an increase in the concentration of the sodium hydroxide [8]. The choice of catalyst appears to have little effect on the reaction rate or on the overall yields of alkylated azole. Benzyltriethylammonium chloride, Aliquat, and tetra-n-butylammonium hydrogen sulphate or bromide have all been used at ca. 1-10% molar equivalents (relative to the concentration of the azole) for alkylation reactions, but N-arylation of indole with an activated aryl halide requires a stoichiometric amount of the catalyst [8]. 

We initiated our work by examining nucleophilic aromatic substitution, a somewhat difficult reaction to effect in other than activated aryl halides as substrates. It occurred to us that if polyhaloaromatics could be made to suffer disubstitution under mild solid-liquid PTC conditions, then they might be used as comonomers with a variety of bisnucliophiles to prepare halogenated polyaryl-ethers, sulfides, sulfone-ethers as well as other interesting polymers which are at present synthesized only with some difficulty. 

Non-activated aryl halides react only moderately with sodinm tellnride prepared from the elements in inert solvents (DMF, iV-methyl-2-pyrrolidone (NMP), hexamethylphos-phoric acid triamide (HMPA)). " ... 

The arylation of organyl tellurolates, restricted first to aryl halides activated by electron-withdrawing groups,2 or requiring special conditions such as heating in HMPA in the presence of Cul, or photostimulation in liquid ammonia,ijggjj achieved successfully with non-activated aryl halides under normal conditions. ... 

Nucleophilic substitution of halogen atom in aromatic and heteroaromatic halides with a hydroxyamino group proceeds only in substrates that are activated by a strong electron-withdrawing substituent in the benzene ring (e.g. 27, equation 17). Despite this limitation this reaction is useful for synthesis of arylhydroxylamines and usually provides good yields of products. Along with activated aryl halides and sulfonates, activated methyl aryl ethers such as 28 can be used (equation 18). 

Hydroxamic acids undergo facile nucleophilic Ai-arylation with activated aryl halides such as 31 (equation 22). While hydroxamates are known to be ambident nucleophiles in alkylation reactions, arylation of hydroxylamines results exclusively in Ai-substituted hydroxamates of type 32 (equation 22)". ... 

The general approach to 0-arylation of hydroxylamines involves N-protection followed by O-arylation. Activated aryl halides and heteroaryl halides easily alkylate oxime salts (equation 25), N-aUcyl hydroxamic acids and N-hydroxysuccinimide . N-Hydroxyph-thalimide can be also 0-phenylated through a reaction with diphenyliodonium salt, although in lower yield . ... 

Tertiary and aromatic nitroso compounds react with aryl Grignard or aryl-lithium reagents giving the corresponding hydroxylamines . This reaction is useful for preparation of alkyl- and aiylhydroxylamines (e.g. 109, equation 80 and 110, equation 81) and can be considered as complementary to arylation of hydroxy lamines with activated aryl halides. It has been used for functionalization of cyclophanes with the hydroxy amino group. The main limitation of the reaction is the relatively restricted choice of available aliphatic nitroso components, so most of reactions were done with 2-nitroso-2-methylpropane. There is no literature data about the possibility of removal of the tert-butyl group from these compounds. 

BMIM]BF4 and [BMIMJPFg were used as catalysts to activate aryl halides for nucleophilic substitution reactions with secondary amines at room temperature. The corresponding arylamines were obtained in high yields (159). 

Alkylation (with dialkyl sulfates, alkyl tosylates, and alkyl halides) and arylation (with nitro-activated aryl halides) of the llf-naphtho[l,8-deltriazine (89) and of the structurally related 6,7-dihydro-lif-... 

As mentioned above, condensed 1,2,3-triazine derivatives can be arylated by treatment with nitro-activated aryl halides. The only other report of direct arylation of the 1,2,3-triazine system is due to McKillop and Kobylecki, who studied the reaction of l,2,3-benzotriazin-4-one (10, R = H) with diaryliodonium salts in the presence of base. Treatment of 10, R = H, with diphenyl- and di-p-bromophenyliodonium chloride results in exclusive arylation at N2 and gives the corresponding triazinium betaines (77, R = Ph, p-BrCjH4) in good yield. When di-p-tolyliodonium chloride is used, a mixture of the Nj-, Nj-, and 0-arylated... 

Arylation. Arylation of 2,4-diaryl-5(4//)-oxazolones 170 with activated aryl halides has been reported to proceed under phase-transfer conditions (Scheme 7.51). The yields of 2,4-diaryl-4-(2,4-dinitroaryl)-5(47/)-oxazolones 171 are often modest. Heteroarylation of 170 was accomplished using 2-chloro-3,5-dinitropyridine. Representative examples are shown in Table 7.19 (Fig. 7.21). 

Only activated aryl halides (e.g. 2,4-dinitrochlorobenzene and picryl chloride) react with pyridine, and the facility of these reactions is subject to much the same steric and electronic controls as alkylation. Picryl chloride forms characteristic yellow TV-picryl derivatives with pyridines. These have been used to help separate, purify and characterize particular liquid pyridines. Pyridine also undergoes quaternization with diphenyliodonium fluoroborate (equation 19). Treatment of pyridine 1-oxides with arenediazonium salts yields aryloxy quaternary salts (equation 20). 

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