Pyridinyl- and Furanyl-methylzinc Chloride: Direct Preparation and Coupling Reactions

Abstract

Benzylic organometal reagents are highly relevant for the synthesis of organic complex molecules, especially for the homologation of organometallics. By utilizing these benzylmetallic reagents, the introduction of a diarylmethanemoiety presented in many natural compounds and biologically active materials has been successfully accomplished. To perform this strategy, a wide range of benzylic metal reagents have been used. Along with the presence of a simple benzylic moiety in many natural materials, a nonfunctionalized or functionalized heterobenzylic moiety is also found and considered as an important class in biologically active pharmaceutical products. For the synthesis of these active compounds, heterobenzylic halides were used mostly as a coupling partner of the corresponding organometallic reagents in the Stille, Suzuki and Negishi couplings. However, some of the heterobenzylic halides are very unstable in the transition metal-catalyzed coupling reactions. To alleviate this difficulty, heterobenzylic sulfonium salts have also been participated in Pd-catalyzed coupling reactions of organometalllics. As described above, each heterobenzylic compound was used as a very efficient coupling partner in the cross-coupling reactions. In addition to this approach for the preparation of compounds containing a heterobenzylic moiety, utilizing the corresponding heterobenzylic organometal reagents would be another way to synthesize various different types of heterobenzyl-moiety-containing derivatives. Nevertheless, to the best of our knowledge, there is no report on the direct preparation of the heterobenzylic organometal reagent and its application in organic synthesis. In our continuing effort to explore the utility of organozinc reagents, it was found that several heterobenzylzinc reagents were easily prepared and their subsequent cross-coupling reactions were also carried out under mild conditions with some limitations. We herein report our first results of utilizing heterobenzylic zinc reagents. For the preparation of heterobenzylzinc halides, readily available heterobenzyl halides such as 2-chloro-5-(chloromethyl)pyridine, 2-chloromethylpyridine, and 2-ethoxycarbonyl5-(chloromethyl)furan were chosen. The oxidative addition of active zinc was generally carried out in THF at room temperature. First attempt for the preparation of heterobenzylzinc was executed with 2-chloro-5-(chloromethyl)pyridine. In the presence of 2.0 equivalent of active zinc, the oxidative addition into the C-Cl bond of the benzylic position was completed in 4.0 h at room temperature to afford the corresponding organozinc reagent, (6-chloropyridin-3-yl)methylzinc chloride (A) without forming of any homocoupling product (Scheme 1). To investigate the applicability of the resulting organozinc reagent, we first examined the palladium-catalyzed crosscoupling reaction with a variety of acid chlorides. The results are summarized in Table 1. The reaction of A with benzoyl chloride was carried out in the presence of 1 mol % of Pd(PPh3)2Cl2 at room temperature within 30 min providing the ketone 1a in 65% isolated yield (entry 1, Table 1). During the coupling reaction, no detectable amount of homocoupling product of organozinc was observed. In addition, as we have developed a new catalytic system for the cross-coupling reaction of organozincs with acid chlorides, coupling reaction has also been tried with 2 mol % of Ni(acac)2-catalyst. Similar results were obtained in terms of yield and purity. Therefore, the rest of the reactions in this study were conducted using a Pd(II)-catalyst system. Not only bromobenzoyl chlorides (entries 2 and 3, Table 1) but chlorobenzoyl chloride (entry 4, Table 1) was successfully coupled with A under the Pd-catalyst system resulting in the formation of the ketones (1b, 1c, and 1d, Table 1) in moderate yields. Even higher yields were obtained from using benzoyl chlorides containing an electron-donating group. As depicted in Table 1, both 4-methyland 4-methoxybenzoyl chlorides reacted with A leading to ketones (1f and 1g, Table 1) in 76% and 82% isolated yields, respectively. The reaction of A with 4-chloromethylbenzoyl chloride gave the expected product 1h in 54% yield leaving benzyl chloride intact (entry 7, Table 1). By using heteroaromatic acid chlorides such as 2-furancarbonyl chloride and 2-thiophenecarbonyl chloride, the cross-coupling products (1i and 1j, Table 1) were obtained in moderate yield (entries 8 and 9). The alkyl carbonyl chlorides (entries 10 and 11) were also suitable for the Pd-catalyzed coupling reaction, furnishing the