摘要：

Aryl ketones containing substituents at both ortho-positions are found in a variety of natural products with many interesting biological activities. For the construction of these sterically hindered aryl ketones, the Friedel-Crafts acylation has been successfully used, albeit with a little difficulty. In addition, a nucleophilic addition-elimination reaction with acyl electrophiles has been the most frequently utilized for the preparation of the ketones. To perform this strategy, cross-coupling reactions of organometallic reagents with the appropriate carbonyl compounds such as acid chlorides, esters, anhydrides, nitriles, and amides have mostly been executed in the presence of a transition metal catalyst. Despite the numerous outstanding methods for the preparation of simple aryl ketones, there are few examples, providing hindered aryl ketones. Martin and co-workers reported a convenient synthesis of sterically hindered aryl ketones utilizing the carbonylative cross-coupling reaction of ortho-disubstituted aryl iodides with aryl boronic acids in the presence of carbon monoxide. In addition, the rhodiumcatalyzed oxidative arylation of aldehydes was also proposed. More recently, a selective synthetic route to hindered unsymmetrical diaryl ketones was reported by Lockhart. In their study, arylstannes were coupled with aroyl chlorides under three different reaction conditions. However, as described above, a very limited number of organometallics have been employed for the preparation of highly hindered ketones. Accordingly, there is still need to develop a new efficient protocol especially for the synthesis of ketones bearing especially multiple substituents in ortho-positions. Herein, we report our results of utilizing organozinc reagents for the preparation of highly hindered ketones. During the course of our ongoing research utilizing organozinc reagents, we found a reliable synthetic protocol for the preparation of the highly desirable aryl ketones. To explore the potential applicability of organozinc reagents toward the synthesis of hindered diaryl ketones, two representative organozinc reagents were chosen in the crosscoupling reactions: 2,6-dimethylphenylzinc iodide (a) and 2methoxyphenylzinc iodide (b). For the corresponding coupling partners, we used 2,6-dimethoxybenzoyl chloride (1), 2,4,6-trimethylbenzoyl chloride (2), 2,6-difluorobenzoyl chloride (3) and 1-naphthanoyl chloride (4), all of which contain substitutents at both ortho-positions. Additionally, since we have found that a readily available Ni-catalyst can be effectively employed in the cross-coupling reaction of organozincs with relatively uncrowded aroyl chlorides under mild conditions, this reaction conditions was directly applied to the preparation of the titled compounds in this study. The cross-coupling reactions were carried out in THF at room temperature in the presence of 2 mol % of Ni(acac)2 and the results are summarized in Table 1. We first coupled the organozinc reagent a bearing two methyl groups at both ortho-positions with 2,6-dimethoxybenzoyl chloride (1). Under the conditions described in Table 1, the coupling reaction was completed in 2.0 h at room temperature resulting in the formation of the corresponding tetra-ortho-substituted ketone in 43% isolated yield (entry 1, Table 1). By employing the same organozinc reagent, more examples of the tetra-ortho-substituted diaryl ketones (1b and 1c) were obtained (entries 2, 3, Table 1). As shown in Table 1, higher product yield was observed with more sterically demanding 2,4,6-trimethylbenzoyl chloride (entry 2, Table 1) than 2,6-difluorobenzoyl chloride (entry 3, Table 1). The coupling reaction of a with 1-naphthoyl chloride (4) was also successfully carried out in THF at room temperature for 30 min and the expected coupling

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