A remarkably simple and efficient benzannulation reaction.

Whereas the application of atom-transfer radical cyclization reactions (ATRC reactions) to the synthesis of g-butyrolactams and g-butyrolactones is now reasonably well established, the same cannot be said of this approach to the synthesis of medium-sized rings. Previously we had shown that the trichloroacetate 1 (Scheme 1) undergoes sequential 5-exo, 6-exo ATRC reactions to provide rapid access to the 2-oxabicyclo[4.3.0]nonane ring system. Alternate modes of cyclization (by 9-exo or 10-endo pathways) were not observed. As a continuation of our interest in this area we investigated the cyclization of trichloroacetate 3 (Scheme 1) under ATRC conditions. The synthesis of benzoxocins by radical cyclization reactions has received scant attention, and at the outset we wished to determine if ATRC of 3 would occur by a 7-exo or 8-endo pathway and whether structural features could be incorporated into the substrate to modify the regiochemical outcome of the reaction. Furthermore, we also believed that this potentially problematic cyclization reaction would also serve as a suitable test case for the development and evaluation of more efficient catalysts for ATRC reactions. Cyclization (CuCl, 5 mol%; 2, 13] 5 mol%; toluene; reflux) of the readily available ester 3 proved to be rather sluggish (95% completion after 48 h) and afforded the labile lactone 4 through an 8-endo-trig reaction. This cyclization was also accompanied by the formation of a minor, wholly aromatic, by-product whose generation lagged behind the formation of lactone 4. Repeating the ATRC reaction of 3 for 120 h in refluxing toluene resulted in the total consumption of both ester 3 and the lactone 4, and the formation of 1chloronaphthalene (6), which was isolated in 23% yield after column chromatography. Moreover we were delighted to observe that irradiation of a solution of the ester 3 in 1,2-dichloroethane containing our standard catalyst system in a microwave reactor afforded 6 in 84% yield after a much reduced reaction time of two hours (Scheme 1). Wishing to establish the synthetic generality of this reaction, we subjected a variety of readily available aryl trichloroacetates (8, 10, 12a–12 f ; Scheme 2) to the same experimental protocol and found that, in each case, benzannulation proceeded smoothly over two hours at 200 8C to produce their respective naphthalene derivatives. The requisite ortho-allyl phenols used in this study are themselves readily available from an ortho-Claisen rearrangement of their respective allyl aryl ethers, a process which in many cases can also be efficiently accomplished in a microwave reactor. Of note is the observation that the benzannulation reaction proceeds with complete regiochemical control to afford an aryl chloride as a single regioisomer in each case. For example, subjecting the isomeric naphthyl esters 8 and 10 separately to our standard reaction conditions affords the known chlorophenanthrenes 9 and 11 as the sole benzannulation products, an observation which is in agreement with the supposition that the aryl–oyxgen bond of the ester undergoes ipso substitution by Ca during the course of the benzannulation sequence. The incorporation of potentially reactive, yet useful, functionality (esters, enolizable ketones) is also accommodated (Scheme 2). Generally speaking both electron-releasing and electron-withdrawing substituents are tolerated in the cyclization sequence, although the lower yield in the case of 12e (55%) may be attributed to a competing deacylation reaction during the course of the benzannulation. Scheme 1. ATRC and benzannulation sequences catalyzed by CuCl in the presence of ligand 2. a) 2 (5 mol%), CuCl (5 mol%), DCE, 80 8C, 3.5 h; b) SiO2, CH2Cl2, 75%; c) 2 (5 mol%), CuCl (5 mol%), DCE, 80 8C, 48 h, quantitative; d) 2 (5 mol%), CuCl (5 mol%), DCE, microwave, 200 8C, 2 h, 84%. DCE=1,2-dichloroethane.