Enolates reactions with arynes

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. 

If the moeity adding to the aryne carries a suitably placed electrophilic center, cyclization with the initially formed anion can occur as observed in the synthesis of dibenzothiophene (60).92 Of wider synthetic import in this context is enolate addition to arynes. Here, after the initial ring closure many types of products can be formed (Scheme ll).35 However, with some substrates, a particular reaction course can predominate 93 94 for example, reaction of cyclodecanone with bromobenzene provides an efficient method for benzo-annulation and ring expansion. Similarly, high yields of benzocyclobutenols can be obtained from the monoketals of ot-diketones.9s... 

The arynic condensation of 1,2-diketone monoacetal enolates with aryne (from bromobenzene and sodium amide) lead to IV/114. Depending on the reaction conditions, compound IY/1I4 can be transformed to two different enlargement products, IV/115 and IV/117. The mechanisms involved in these transformations are obvious [63] [64], Scheme IV/18. 

Various anions (ketones enolates for example) are able to react with arynes (Fig. 13) leading to the phenylated compound (refs. 80, 81). When the anion is generated from the starting material, the reaction leads to a cyclisation product (refs. 82-84). These reactions are also possible with other aromatic compounds (ref. 85). 

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... 

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]. 

IV.2.1.3.3. Polyhabgenobenzenes. We essentially studied the reactions of NaNH2-enolate or NaNH2 -f-BuONa-enolates with dialkylamino dichlorobenzenes 117 and 118 for which the corresponding generated arynes are 119 and 120 respectively. 

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