Benzyne cyclization

Synthesis of Functionalized Indole- and Benzo-Fused Heterocyclic Derivatives through Anionic Benzyne Cyclization... 

Attachment of a crotonate chain to the alcohol (78), through a mixed carbonate ester, sets up the intramolecular Diels-Alder reaction in the synthesis of podophylotoxin.111 The starting benzocyclobutenol (78) was procured by the sequence of steps shown in Scheme 16. A similar route using a carboxylic ester, in place of the nitrile (76), for the benzyne cyclization gave a mixture of cis- and fra/u-benzocyclo-butenes but ester hydrolysis led to the pure trans acid (77).112... 

Benzyne cyclization of the side chain nitriles or carboxylic esters has also been employed for constructing other rings as shown in the synthesis of /V-methylisoindole (79) and the lysergic acid precursor... 

A major initial limitation of the benzocyclobutene approach to o-quinodimethanes was the lack of efficient, large-scale syntheses for many specifically substituted derivatives. Fortunately, recent developments have lemov much of this impediment. Q>nceptually, the synthesis of benzocyclobutenes from aromatic precursors can be envisaged in only a limited number of ways. These include [2 -i- 2] cycloadditions involving benzynes and alkenes, intramolecular cyclization on to a benzyne, cyclizations involving arene anions, and electrocyclic closure of o-quinodimethanes. Benzocyclobutene derivatives can also be prepared by aromatization of bicyclo[4.2.0]octanes. Detailed discussion of variations to these approaches can be found in the cited reviews. The cobalt catalyzed co-oligomerization of 1,5-hexadiynes with al-kynes, especially bis(trimethylsilyl)acetylene, has also been employed for the preparation of specifically substituted benzocyclobutenes. In the latter case the cyclobutenes are often not isolated but converted directly to o-quinodimethanes and subsequent products. ... 

The Kametani group has made considerable use of the intramolecular trapping of benzynes by pendant carbanion centers. The nitrile (133) is a key and versatile intermediate in many of the K etani studies, including the preparation of optically pure estradiol. The ester of the benzocyclobutenecarboxylic acid (134) was prepared by a similar benzyne cyclization. The acid (134) was converted via oxidative decarboxylation and HCl hydrolysis to the very labile tra/t5-2-arylbenzocyclobutenol (135), which was used in the preparation of p ophyllotoxin. ... 

Xie and Qiu have reported the first example of the [2+2+2] carboannulation of arynes, activated alkenes, and arynes. Whereas Pd catalysts promote the two-component benzyne-alkene-benzyne cyclization, under Ni catalysis the three-component reaction is favored leading to 1,2-dihydronaphthalenes 108 from readily available materials. In this case, the catalytic cycle is likely initiated by oxidative coupling of aryne and alkene on Ni to form a nickelacycle that undergoes subsequent insertion of the alkyne into the Ni-C(aryl) bond to give a seven-membered intermediate (Scheme 12.54) [95]. 

Treatment of the o-chlorobenzylamine derivative (333) with potassium amide in liquid ammonia yields, inter alia, the isoindole (334) by benzyne cyclization. The stable fluorescent isoindole (335) is formed from phthalaldehyde, t-butyl mercaptans, and propylamine. The base-induced elimination of methanesul-phinic acid from compound (336) affords the bis-isoindole (337) the benzo[l,2-f> 4,5-c ]dipyrrole (338) has been prepared in two steps from 5,6-dibenzoyl- 1 -methylindole. ... 

---