Ethers reactions with arynes

The preceding reactions dealt with the use of chiral auxiliaries linked to the electrophilic arene partner. The entering nucleophile can also serve as a chiral controller in diastereoselective SjjAr reactions. This approach was successfully employed for the arylation of enolates derived from amino acids. To illustrate the potential of the method, two examples have been selected. Arylation of Schollkopf s bislactim ether 75 with aryne 77 as electrophilic arylation reagent was demonstrated by Barrett to provide substitution product 81 with good yield (Scheme 8.18) [62, 63]. Aryne 77 arises from the orf/jo-lithiation of 76 between the methoxy and the chlorine atom followed by elimination of LiCl. Nucleophilic attack of 77 by the lithiated species 78 occurs by the opposite face to that carrying the i-Pr substituent. Inter- or intramolecnlar proton transfer at the a-face of the newly formed carbanion 79 affords the anionic species 80. Subsequent diastereoselective reprotonation with the bulky weak acid 2,6-di-f-butyl-4-methyl-phenol (BHT) at the less hindered face provides the syn product 81. Hydrolysis and N-Boc protection give the unnatural arylated amino acid 82. The proposed mechanism is supported by a deuterium-labeling experiment. Unnatural arylated amino acids have found application as intermediates for the construction of pharmaceutically important products such as peptidomi-metics, enzyme inhibitors, etc. [64, 65]. 

As mentioned in the introductory section, arynes behave as soft acids . Therefore, the relative reactivity of a nucleophile should be governed by basicity as well as polarizability. The following gradations, established through competitive reactions of arynes with different nucleophiles, are more or less in line with this expectation.1 (i) BuLi > PhSLi > PhNMeLi > PhGaCLi > ROLi > ArOLi, for 9,10-phe-nanthryne in ether (ii) PhS- > Ph3C > PhC=C > enolates > PhO- > RO" > I, CN, for benzyne in liquid ammonia (iii) I- > Br > Cl- > EtOH for benzyne in alcohol. 

Ethers do not exhibit marked nucleophilicity towards arynes but readily enter into reaction with more electrophilic halogenated analogs like (121). In the betaine derived from (121) and ethyl ether, a proton... 

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. 

Arynes react readily with simple alkenes to give either benzocyclobutenes or substituted benzenes (Scheme 7.31). The formation of benzocyclobutenes by [2+2] cycloaddition reaction of the aryne to the alkene proceeds best for strained and electron-rich carbon-carbon (C=C) double bonds. For example, dicyclopentadiene reacts to give the ex o-isomer of the corresponding four-membered ring in good yield. The addition to cyanoethene (acrylonitrile) and the reaction with the electron-rich ethoxyethene (ethyl vinyl ether) gives the cyano- and ethoxy-benzocyclobutenes in 20% and 40% yields, respectively. The latter reaction almost certainly involves nucleophilic addition of the enol ether to the electrophilic aryne followed by coUapse... 

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]. 

The cleavage of thio-ethers suggested that the breakdown of the ylide derived from the reaction of an aryne with tetrahydrothiophen... 

Displacement reactions in the benzo ring can also occur via aryne intermediates. Treatment of 6-choroquinoline with a fourfold excess of potassium amide in ether at -33 °C... 

Isobenzofurans are especially useful dienes toward arynes. 1,3-Diphenylisobenzofuran has long been used as a trap for benzynes, but only recently has the utility of this reaction been demonstrated through the generation of simpler isobenzofurans and their trimethylsilyl derivatives d47 Treatment of acetal 258 with one equivalent of MeLi and a catalytic amount of diisopropylamine in ether gave solutions of259, and subsequent addition of 0-... 

Poly(ethylene glycol)s (PEG) and their dimethyl ethers have been used as phase-transfer catalysts for the reaction of aryl halides with diphenylamine. Since mixtures of triarylamines were obtained from a single aryl bromide (for example, u-bromotoluene gave both 0- and m-tolyldiphenylamine), arynes are intermediates. A kinetic study led the authors to propose the following mechanism ... 

Arynes can be added under mild conditions and rapid reaction times to azides through fluoride-promoted o-elimination. The addition of arynes to azides has been already shown by Huisgen and Wittig, respectively. Recently, 0-(trimethylsilyl)phenyltriflate and various fluoride sources in combination with a complementary crown ether were used for the [3 + 2]-cycloaddition with functionalized azides (Scheme 9.5). ... 

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