Abstract
The ortho-deprotonation of halide-substituted ferrocenes by treatment with lithium tetramethylpiperidide (LiTMP) has been investigated. Iodo-, bromo-, and chloro-substituted ferrocenes were easily deprotonated adjacent to the halide substituents. The synthetic applicability of this reaction was, however, limited by the fact that, depending on the temperature and the degree of halide substitution, scrambling of both iodo and bromo substituents at the ferrocene core took place. Iodoferrocenes could not be transformed selectively into ortho-substituted iodoferrocenes since, in the presence of LiTMP, the iodo substituents scrambled efficiently even at −78 °C, and this process had occurred before electrophiles had been added. Bromoferrocene and certain monobromo-substituted derivatives, however, could be efficiently ortho-deprotonated at low temperature and reacted with a number of electrophiles to afford 1,2- and 1,2,3-substituted ferrocene derivatives. For example, 2-bromo-1-iodoferrocene was synthesized by ortho-deprotonation of bromoferrocene and reaction with the electrophiles diiodoethane and diiodotetrafluoroethane, respectively. In this and related cases the iodide scrambling process and further product deprotonation due to the excess LiTMP could be suppressed efficiently by running the reaction at low temperature and in inverse mode. In contrast to the low-temperature process, at room temperature bromo substituents in bromoferrocenes scrambled in the presence of LiTMP. Chloro- and 1,2-dichloroferrocene could be ortho-deprotonated selectively, but in neither case was scrambling of a chloro substituent observed. As a further application of this ortho-deprotonation reaction, a route for the synthesis of 1,3-disubstituted ferrocenes was developed. 1,3-Diiodoferrocene was accessible from bromoferrocene in four steps. On a multigram scale an overall yield of 41% was achieved. 1,3-Diiodoferrocene was further transformed into symmetrically 1,3-disubstituted ferrocenes (1,3-R2Fc; R = CHO, COOEt, CN, CH=CH2).
Highlights
Ferrocene derivatives have found broad application in a number of different fields including catalysis, bioorganometallic chemistry, and material sciences, and all of these areas have been reviewed extensively.[1−4] For applications in catalysis, besides achiral 1,1′-heteroannularly substituted ferrocenes, chiral homoannularly 1,2-substituted derivatives are mainly used
The majority of these approaches make use of ortho-directing groups. Both N,N-dimethylaminomethylferrocene[5] and chloroferrocene[6] can be ortho-deprotonated by treatment with n-butyllithium, and the lithiated intermediates can be further reacted with electrophiles to afford 1,2disubstituted products (Scheme 1)
We subsequently showed that the ortho-deprotonation of bromoferrocenes can be significantly
Summary
Ferrocene derivatives have found broad application in a number of different fields including catalysis, bioorganometallic chemistry, and material sciences, and all of these areas have been reviewed extensively.[1−4] For applications in catalysis, besides achiral 1,1′-heteroannularly substituted ferrocenes, chiral homoannularly 1,2-substituted derivatives are mainly used. A huge number of methodologies have been developed for the synthesis of 1,2-disubstituted ferrocenes.1c,d The majority of these approaches make use of ortho-directing groups. We reported on biferrocene diphosphines as ligands for hydrogenation catalysts.[7] The ligand synthesis was achieved by a Negishi coupling reaction, and for this purpose racemic 2bromo-1-iodoferrocene was required. In this context we questioned whether this derivative could be synthesized in one step from commercially available bromoferrocene. We subsequently showed that the ortho-deprotonation of bromoferrocenes can be significantly
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