Amines reactions with arynes

There has been a summary of the use of insertion reactions of arynes into a-bonds to prepare nrt/io-disubs tituted arenes. A key to the success of these processes is the ability to generate benzyne under mild conditions by the reaction of readily available o-(trimethylsilyl)phenyl triflate with fluoride ions.61 Reaction of amines and their derivatives with benzynes generated in this way has been shown to be an efficient method for the production of N-arylated derivatives, as illustrated in Scheme 8. The method also works well in the O-arylation reactions of phenols and carboxylic acids 62... 

Aryl halides in which electron-withdrawing groups activate the halogen atom to nucleophilic displacement react directly with ammonia to produce amines. Non-activated aryl halides yield amines on reaction with sodamide through the intermediacy of an aryne intermediate (see Chapter 9). 

Thus, reaction of 6-bromo-4-phenylpyrimidine (316) with lithium isopropylamide in isopropylamine proceeds via 317 to the ring-opened product 318 to eventually give 6-isopropylamino-4-phenylpyrimidine (319) in 70% yield. Since these particular aminations have been reviewed (78ACR462), they will not be discussed further. Nor will nucleophilic aminations proceeding via aryne-type intermediates (65AG557, 65AHC121) be a topic of this review. 

Observation of Scheme 54 shows a close analogy between these results and the ones obtained in arynic condensations. Thus we observe the formation of normal ketones 138, transposed ketones 139 or 140, and methylene cyclobutanols 141. However, we met large difficulties with the mechanism. Indeed, starting from the hypothesis of cyclohexyne being the intermediary (what is consistent with our works on amine condensations) and by analogy with arynic condensations, the reaction should be written as in Scheme 55. 

The use of sodium amide or potassium amide in liquid ammonia with bromo- or chlorobenzene leads inevitably to the capture of benzyne by its reaction with ammonia. However, the utility of bromo- or chlorobenzene as a benzyne precursor is extended to ethereal solvent systems by employing the conjugate base of a hindered secondary amine (diisopropylamine, 2,2,6,6-tetramethylpiperidine) which can be formed in situ from the amine and alkyllithium. Alternatively, butyllithium itself is used with the halogeno-benzene, and pentafluorobenzene and butyllithium are the usual source of tetrafluorobenzyne. In all of these reactions the aryne is generated by decomposition of an o-halogenoaryl anion at temperatures below 0°C. 

Aryne complexes of late transition metals are very reactive towards both nucleophiles (amines, alcohols, water) and electrophiles (iodine). They also undergo insertion reactions with CO, alkenes and alkynes,but while the behaviour of ruthenium complexes is somewhat similar to that of titanium or zirconium complexes, the reactivity of nickel complexes is rather different [6,8]. Examples of these reactions that are particularly interesting for the purposes of this chapter are shown in Schemes 8 and 9. Ruthenium complex 33 undergoes insertion of a molecule of benzonitrile,benzaldehyde or di(p-tolyl)acetylene to yield met-allacycles 40,41 and 42, respectively (Scheme 8). Further insertion of a second unsaturated molecule into these metallacycles has not been observed [25,27]. 

Yoshida et al. have shown the potential of CO as a Cj source in aryne MCR developing a straightforward access to benzoxazinones 73 nsing imines as the nncleophUic component (Scheme 12.38) [63]. The same authors have used aminosilanes for the three-component coupling with arynes and aldehydes, including sulfonylimines, to provide 2-aminobenzhydrols and 2-aminobenzhydryl amines 74. Benzoic acid plays a vital role in the reaction, probably favoring the formation of an amine from the aminosilane (Scheme 12.38) [64]. 

Reactions with Benzyne. A-Methylimidazole reacts with benzyne to generate either Al-methyl-Al-arylimidazolium salts or aryl amines containing anthracene. The product generated depends on the reaction stoichiometry using a 3 1 ratio of NMI to aryne gives aryl amines, whereas a 1 3 ratio produces salts (eqs 11 and 12). 

Arynes combine with all kinds of polar compounds such as lithium halide, alcohols, primary, secondary or tertiary amines, phosphines, and boranes. Of practical, even technical, importance are their reactions with metal hydroxides and alkoxides. The conversion of chlorobenzene by sodium hydroxide at 350 °C into sodium phenolate, an industrial process, obeys the elimination/addition mechanism. Again arynes can be postulated as plausible intermediates. Regardless of which isomer of bromophenol or of bromophenyl benzenesulfonate is heated with sodium hydroxide, resorcinol is always isolated as the main or sole product after neutralization. 

Some palladium-catalyzed reactions of organotins, such as carbostannylations, are not related to the Stille cross-coupling. The history of the transition-metal-cata-lyzed carbostarmylation [148] began with alkynylstannylation of alkynes catalyzed by a palladium-iminophosphine complex [149]. Thus, alkynylstannanes added to a carbon-carbon triple bond of various acetylenes, conjugated ynoates and propar-gyl amines and ethers in the presence of a catalytic amount of a palladium-iminophosphine complex [150]. The reaction also proceeded with arynes to afford ortho-substituted arylstannanes, which could further be converted into 1,2-substituted arenes via carbon-carbon bond-forming reactions [151]. 

Arynes are intermediates in certain reactions of aromatic compounds, especially in some nucleophilic substitution reactions. They are generated by abstraction of atoms or atomic groups from adjacent positions in the nucleus and react as strong electrophiles and as dienophiles in fast addition reactions. An example of a reaction occurring via an aryne is the amination of o-chlorotoluene (1) with potassium amide in liquid ammonia. According to the mechanism given, the intermediate 3-methylbenzyne (2) is first formed and subsequent addition of ammonia to the triple bond yields o-amino-toluene (3) and m-aminotoluene (4). It was found that partial rearrangement of the ortho to the meta isomer actually occurs. 

In connection with the substituent effects, the kinetic stability of benzyne is suggested to be increased by electron withdrawal (-/) and decreased by electron release (+/).73 However, the inference cannot be extrapolated to selectivity of substituted arynes in general. For example, in additions involving competition between phenyllithium and lithium piperidide, the methyl substituents (+/) on benzyne increase its selectivity, whereas methoxy groups (-/) decrease it (Scheme 6). On the other hand, in reactions of car-banions derived from acetonitrile in alkylamine solvents both +/ and -/ benzyne substituents lower selectivity and cause predominant amination. Thus, the method was found unsuitable for preparation of many substituted benzyl nitriles.74 In symmetrically disubstituted arynes there is partial cancellation of polarization, and in fact acceptable yields of acetonitrile adducts could be obtained from 3,6-dimethoxy-benzyne.75 The selectivity of substituted arynes varies with the set of nucleophiles in the competition and no comprehensive theory or simple generalization is available on this point. 

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