Arynes elimination methods

By far the most common and historically oldest aryne generation method involves the elimination of hydrogen halides from aryl halides (32a) in the presence of strong bases (Table 1). " In many cases o-haloarylanions (33) can be trapped as intermediates, although often the elimination of halide ion to the aryne (1) is either too rapid to allow their detection or perhaps concerted. The effect of halogen, metal, and substituents on this reaction has been well studied. ... 

Other Elimination Methods. Benzenediazonium-2-carboxylates, easily accessed by diazota-tion of the readily available anthranilic acids, have been widely used for generating arynes by loss of Nj and CO molecules upon heating [14]. HowevCT, the explosive nature of diazonium salts somehow limits the utility of this approach (Schane 12.8). 

Aromatic substitution reactions that proceed by the elimination-addition mechanism are not widely used synthetically, as a very strong base (pIsTb — 35) is required to generate the aryne intermediate by /3-elimination of HX. In addition, there is regiochemical ambiguity for unsymmetrical aryl halides. Even benzyne itself is much more readily prepared by several other methods. 

Scheme 7.5 summarizes the common methods of aryne generation, although the examples are limited to ortho-benzyne. Because of their extreme reactivity, arynes must be generated in situ. When an unactivated aryl halide is treated with a very strong base, an elimination reaction is possible, generating aryne. 

In 1983, Kobayashi developed a convenient approach to arynes by the fluoride-induced 1,2-elimination of o-(trimethylsilyl)aryl triflates (Equation 12.6) [5]. The mild reaction conditions involved in this protocol are compahble with a variety of reagents, substrates, functionalities and even transition metal catalysts. Today, this approach is the most widely used and the most efficient method for aryne generation. 

All practical methods of generating arynes involve either the concerted or stepwise loss of appropriately situated substituents from an aromatic precursor. Many different types of leaving groups have been utilized including those which are part of a second ring. If the elimination is stepwise several possible inter-... 

Considering the ainbiguities and suspicions raised above it is worthwhile to consider some of the methods which may be used to determine if a particular aryne adduct (148) is actually formed via an aryne. Since the most common alternative involves the addition-elimination mechanism [equation (23)] this could be tested for specifically. The isolation of the initial Diels-Alder adduct (150) and the demonstration that it goes on to the aryne adduct (148) under the conditions of alleged aryne formation, while not... 

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]. 

Vinylogous amides react with arynes to yield 2+2-cycloadducts at ambient temperatures. These cycloadducts rmdergo ring opening to produce orffto-quinodimethide intermediates. A new method for the selective formation of Catellani-Heck isomers from arynes with norbomene has been described. The use of a bulky P(Bu03 ligand on the catalyst accelerates the C-C reductive elimination from the key intermediate palladacycle. ... 

The benzyne created from 2-(trimethylsilyl)phenyl triflate was used in a highly diastereoselective aiyne Diels-Alder reaction with a diene bearing Oppolzer s sultam. This approach to cis-functionalized 1,4-dihydronaphthalenes was reportedly the first aryne Diels-Alder reaction to provide enantioenriched cyclo-adducts. An unusual route to /3-aminoketones involves the treatment of 2-(trimethylsilyl)phenyl triflate with TBAF and an asymmetric vinyldihydropyridone. The resultant aryne Diels-Alder cycloadduct undergoes aromatization/elimination to create the A -acyl-/3-aminoketone (eq 13). This method was featured in a multistep synthesis of an unnatural a-amino acid. 

Common methods for the generation of o-QDMs can be classified into four categories according to the precursors employed (1) thermolysis of benzo-cyclobutenes, (2) retro-Diels-Alder reaction or cheletropic reaction of benzo-fused heterocycles, (3) photoenolization of o-tolualdehydes, and (4) 1,4-elimination of a,a -substituted o-xylenes (Scheme 28.25). Similarly to the case with arynes,... 

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