Central Chiral Ferrocene Derivatives

Asymmetric induction in ring closure reactions of central chiral ferrocene derivatives has been reported. Moderate diastereoselectivity was found in the ring closure of the enantiomeric 4-ferrocenyl-2-methyl-2-phenyl-butanoic acids by treatment with trifluoroacetic anhydride (Fig. 4-211) [10]. The diastereoisomeric ketones could be separated by chromatography. A higher induction was observed in an asymmetric Pictet — Spengler type cyclization of a reactive imine formed from enantiomerically pure 2-ferrocenyl-2-propylamine and formaldehyde, as only one isomer of the product was detected (Fig. 4-21 g) [135, 136]. 

Fig. 4-7. Synthesis of racemic central chiral ferrocene derivatives.

Ferrocene behaves like an aromatic compound activated for electrophilic substitution reactions. Thus, only minor modifications of experimental procedures developed for aromatics are necessary to obtain ferrocene derivatives (a useful review on general methods is given by Schldgl and Falk [42]). For central chiral ferrocenes, resolution of the racemate is a frequently applied technique. Traditionally, resolutions are best achieved by salt formation between a chiral acid or base and the... 

Ferrocene reacts with acetyl chloride and aluminum chloride to afford the acylated product (287) (Scheme 84). The Friedel-Crafts acylation of (284) is about 3.3 x 10 times faster than that of benzene. Use of these conditions it is difficult to avoid the formation of a disubstituted product unless only a stoichiometric amount of AlCft is used. Thus, while the acyl substituent present in (287) is somewhat deactivating, the relative rate of acylation of (287) is still rapid (1.9 x 10 faster than benzene). Formation of the diacylated product may be avoided by use of acetic anhydride and BF3-Et20. Electrophilic substitution of (284) under Vilsmeyer formylation, Maimich aminomethylation, or acetoxymercuration conditions gives (288), (289), and (290/291), respectively, in good yields. Racemic amine (289) (also available in two steps from (287)) is readily resolved, providing the classic entry to enantiomerically pure ferrocene derivatives that possess central chirality and/or planar chirality. Friedel Crafts alkylation of (284) proceeds with the formation of a mixture of mono- and polyalkyl-substituted ferrocenes. The reaction of (284) with other... 

A word of caution should be added with respect to Chemical Abstracts, as far as chirality assignments of homoannular substituted ferrocene derivatives are concerned. Until the 8th collective index, only (-f) and (—) are found as chirality indicators. For quite a long time, no descriptors were given at all, only the remark stereoisomer , followed by the registry number, which does not allow identification of a compound easily. This fact is in sharp contrast to the claims of Chemical Abstracts Service authors that they would consequently use Schlogl s central descriptors [20, 21]. Since volume 114, the (R, S ) nomenclature for ferrocene derivatives begins to appear, but its application is not very consequent, at least at the time where the book was written, and it is advisible to examine the orginal article rather than trust Chemical Abstract s descriptors. 

Fig. 4-8. Some synthetically important ferrocene derivatives with central chirality.

Ugi has coined the term stereorelating synthesis for the sequence lithiation/reac-tion with electrophiles [62,118], and used this technique as a method for the chemical correlation of the structure and for the determination of the enantiomeric purity of many 1,2-disubstituted ferrocene derivatives obtained either by resolution or by asymmetric synthesis (for a compilation, see [118]). It is important to note that all stereochemical features discussed above for central chiral compounds, such as retentive nucleophilic substitution, remain valid when more substituents are present at the ferrocene ring and the conversion of functional groups in planar chiral ferrocenes can be achieved by the same methods as described. 

Planar chiral compounds should also be accessible from the chiral pool. An example (with limited stereoselectivity) of such an approach is the formation of a ferrocene derivative from a -pinene-derived cyclopentadiene (see Sect. 4.3.1.3 [81]). A Cj-symmetric binuclear compound (although not strictly from the chiral pool, but obtained by resolution) has also been mentioned [86]. Another possibility should be to use the central chiral tertiary amines derived from menthone or pinene (see Sect. 4.3.1.3 [75, 76]) as starting materials for the lithiation reaction. In these compounds, the methyl group at the chiral carbon of iV,iV-dimethyl-l-ferrocenyl-ethylamine is replaced by bulky terpene moieties, e.g., the menthane system (Fig. 4-2 le). It was expected that the increase in steric bulk would also increase the enantioselectivity over the 96 4 ratio, as indicated by the results with the isopropyl substituent [118]. However, the opposite was observed almost all selectivity was lost, and lithiation also occurred in the position 3 and in the other ring [134]. Obviously, there exists a limit in bulkiness, where blocking of the 2-position prevents the chelate stabilization of the lithium by the lone pair of the nitrogen. 

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