Arynes annulation

Another interesting example reported by this group consists of the palladium-catalyzed carbocyclization of aryl iodides, bicyclic alkenes, and arynes. Annulated 9,10-dihydrophenanthrene derivatives 26 are obtained through a mechanism that involves C—H activation promoted by the fluoride anion as the key step [37], On the basis of the regio-chemistry of the products obtained and supported by the isolation of complexes similar to those involved in the process, the authors propose the catalytic cycle depicted in Scheme 3.18. 

This aryne annulation is likely to proceed via electrophilic attack of benzyne at the enamide 82 ( 86) followed by ring-closure and dehydration (86 87 83), thus representing a formal (4 + 2)-cycloaddition of 82 to the aryne. 

Aryne Annulation. Treatment of o-(trimethylsilyl)aryl triflates with TBAT results in the formation of ben-zyne intermediates. Fluoride-induced 1,2-eliminations of o-(trimethylsilyl)aryl triflates, which are readily prepared from phenols, have been shown to provide the respective aryne products, which, at room temperature, precipitously undergo cycloaddition in the presence of Diels-Alder adducts, including, but not limited to, tethered acyclic dienes, tethered enynes (eq 15), azomethine imines (eq 16),ene carbamates, and acetamidoacry-lates (eq 17). ... 

Rogness DC, Markina NA, Waldo JP, Larock RC (2012) Synthesis of pyrido[l,2-a]indole malonates and amines through aryne annulation. J Org Chem 6 2743-2755... 

Gilmore CD, Allan KM, Stoltz BM (2008) Orthogonal synthesis of indolines and isoquinolines via aryne annulation. J Am Chem Soc 130 1558-1559... 

SCHEME 19 Synthesis of pyrido[l,2-fl]indole derivatives through aryne annulations [44]. 

SCHEME 25 Synthesis of N-arylisatins using aryne annulation strategy [49]. 

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... 

Methyl thiosalicylate provides both electrophilic and nucleophilic sites for annulation of arynes generated from silylaryl triflates in the presence of CsF. An initial intermolecular nucleophilic coupling to afford a diaryl sulfide 529 is followed by an intramolecular electrophilic cyclization and thioxanthones result. The use of THF as solvent suppresses the competitive proton abstraction which leads to methyl 2-thiophenoxybenzoate (Scheme 211) <2005OL4273>. 

Both xanthones and thioxanthones are available through CsF-promoted coupling of arynes with salicylates and thiosalicylates. The synthesis proceeds through sequential intermolecular nucleophilic substitution and intramolecular electrophilic cyclisation (Scheme 39) <07JOC583>. The Pd-catalysed annulation of 3-iodoflavone with the same triflate results in the dibenzo[a,c]xanthone (Scheme 39) <07JOC223>. 

Zhu demonstrated that arynes (generated from 153 with fluoride) smoothly annulate 2-acyl-substituted tetrahydroisoquinolines in moderate to excellent yields at room temperature. The starting tetrahydroisoquinolines (e.g., 154) were prepared via a Lewis acid-catalyzed, three-component Povarov reaction (9 examples, 21-75% yield) (140L1756). 

Unsurprisingly due to their potential as medicinal agents there have been many reported synthetic routes to isoflavanones including the reduction of corresponding isoflavones, [12] benzylic oxidation of isoflavans, [13] gold-catalysed annulations, [14] addition of C-O bonds to arynes [15] and palladium catalysed a-arylation [16]. Despite the multitude of syntheses reported over the past 70 years few routes have been shown to be truly modular with respect to substituents on the isoflavanone skeleton and only one route was asymmetric, relying on the use of chiral auxiliaries [17]. 

Finally, the same group carried out a mono and a double annulation of arynes to synthesize fluoren-2-ones 60 and polycyclic aromatic systems 62 respectively [40]. These methods involve the in situ formation of highly reactive arynes by reaction of 2-(trimethylsilyl)aryl triflates 58 and CsF. In the presence of Pd(dba)2 (dba = dibenzylideneacetone), a crosscoupling and cyclization with a 2-halobenzaldehyde occur in the former case and C—H activation and cyclization occur in the latter case (Scheme 8.13). 

Scheme 3.18 Palladium-catalyzed annulation of acyloximes with arynes and alkynes via...

This palladium-catalyzed annulation has also been extended to arynes and 2-halobiaryls to synthesize fused polycyclic aromatic hydrocarbons (Equation 12.62) [130]. 

When one molecule of aryne precursor is replaced with a bicycUc alkene in the previous process, the carbocycUzation of an aryl iodide, a bicydic alkene and an aryne takes place, giving exclusively the eoco isomer of an annulated 9,10-dihydrophenanthrene 240 (Equation 12.65) [132]. 

In the last two decades transition metal catalyzed cyclization/annulation reactions have also been reported. In most cases alkynes are cyclized within a biphenyl-containing substrate. Different modes of action for the transition metal can be distinguished. In the first case the metal undergoes an oxidative addition into an aryl-halogen bond and then performs the carbometallation of the alkyne. Here, an example by Larock and coworkers is presented, in which an in situ formed aryne species is cyclized with an iodo biaryl substrate 136 (Scheme 34) [89]. 

Polycyclic Arenes. Trimethylsilylphenyl triflates have found widespread use as benzyne precursors in the preparation of polycyclic arenes. Triphenylenes are made via paUadium-catalyzed [2 + 2 + 2] cyclotrimerization of arynes, by paUadium-catalyzed annulation of the aryne and 2-halobiaryls, or via carbopalladation/carbocycUzation of arynes with substituted iodobenzenes (eq 2). All three approaches furnish substituted triphenylenes in high reported yields. Substituted phenanthrenes or naphthalenes are similarly prepared using 2-(trimethylsilyl) phenyl triflate as an aryne precursor. Treatment of the reagent with fluoride, a palladium catalyst, and a deactivated alkene, allyl halide, or internal aIk5Tie provides 9-substituted or 9,... 

The palladium-catalyzed annulation of arynes, derived from 2-(trimethylsilyl)phenyl triflate, by 2-halobenzaldehydes provides variably substituted fluoren-9-ones in good yields (eq 4). Catalytic dicobalt octacarbonyl under CO pressure furnishes anthraquinones in the presence of the ar5me derived from 2-(trimethylsilyl)phenyl triflate. ... 

When the nucleophilic and the electrophilic positions of the reagent confronted to the aryne are not c-bonded, a cascade intermolecular nucleophilic addition-intramolecular electrophilic cycUzation of arynes can take place. The fragmentation step, which is cmcial for the insertion reaction of arynes into a-bonds, is not involved in annulation processes because the intermediate obtained from the cyclization is usually a stable five- or six-membered ring system. 

Annulation Reactions. Larock et al. have described the synthesis of different heterocyclic systems using a [3+2] annulation approach. For instance, pharmaceutically important pyrido[l,2-fl]indole derivatives such as 93 are easily accessible from 2-substituted pyridines and aryne precursors (Scheme 12.48) [83]. More recently, the 1/f-indazole skeleton has been accessed through a [3+2] annulation from arynes and hydrazones. The reaction with Al-arylhy-drazones leads to 1,3-disubstituted indazoles 94 through an annulation-oxidation process (Scheme 12.48). The use of iV-tosylhydrazones also affords 3-substituted-Ai(H)-indazoles, although probably via a [3+2] cycloaddition (see Scheme 12.18) with in situ generated diazo compounds [84]. 

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