Ferrocene derivatives, synthesis

Other interesting synthetic applications of the ketone-derived enamine alkylation are found in the monomethylation of steroid enamines (249), extension of the benzylation reaction (250) to a ferrocene derivative (251), the use of a-bromoesters (252) and ketones (252) or their vinylogues (25J), in the syntheses of alantolactone (254-256), isoalantolactone (257), and with a bridged bis-enamine (258). The use of bifunctional alkylating agents is also seen in the introduction of an acetylenic substituent in the synthesis of the characteristic fragrant constituent of jasmine (259), the synthesis of macrocyclic ketolactones (260), the use of butyrolactone (261), and the intermolecular or intramolecular double alkylations of enamines with dihalides (262). 

As the latter were not easily accessible by chemical synthesis at that time, new methods of preparing these ferrocene derivatives were developed and introduced in 1969. It was then proved that the U-4CRs of chiral a-ferrocenyl-alkylamines can form diastereomeric a-aminoacid derivatives stereo-selectively, and it was further shown that after the reaction the a-ferrocenyl groups of the products can be replaced by protons, thus resynthesizing the chiral a-ferrocenyl-alkylamines simultaneously." Later, the development of this ferrocene chemistry was given up since such syntheses cannot form the products in sufficient quantity and stereoselective purity. ... 

The above product is an important intermediate in the synthesis of several ferrocene derivatives. 

The ubiquitous electrochemical behavior of ferrocene and its relative chemical stability have made this organometallic complex a useful group for the preparation of redox-active devices. The incorporation of ferrocene-modified amino acids into larger polypeptide structures can therefore lead to electrochemically active de novo designed proteins. In addition, the attachment of ferrocene derivatives to peptides make them electroactive and eligible to electrochemical detection. Hence, it is not surprising that the first synthesis of a ferrocene-modified amino acid dates back to the 1950s. 

Chung et al. reported the enantioselective synthesis of chiral NHCs, such as 6, using a chiral ferrocene derivative (Scheme 8) [28]. The nucleophilic substitution of the hydroxy function by an imidazole in an acidic medium gives the imidazolium salt with retention of the configuration at the chiral C-atom. 

Ferrocene derivatives coupled with heterocyclic systems have attracted special attention in recent years because of their interesting organic and inorganic properties. Recently, an efficient and rapid route for the synthesis of 4-aryl-2-ferrocenyl-quinolines 70 has been described by Tu and co-workers [116] through a microwave-assisted MCR of acetylferrocene with an aromatic aldehyde and dimedone in the presence of ammonium acetate in DMF. This novel procedure provides the target hetero-metallic compounds in excellent yields without the need of any purification (Scheme 54). 

Ferrocenoyl chloride (318), ethyl ferrocenecarboxylate (319), and cyanoferrocene (320) are all used as starting materials for the synthesis of 2-ferrocenyloxazolines (321) (Scheme 87). Chirality may be incorporated into the oxazoline ring, and these important chiral compounds have been used to prepare a great number of ferrocene derivatives that are used as catalysts in asymmetric synthesis." " ... 

Optically active ferrocene derivatives, particularly ferrocenyl phosphines, have hitherto been utilized as chiral ligands for a wide range of asymmetric synthesis. We have now revealed that the ferrocene moiety can easily be incorporated in amino alcohol ligands instead of phosphinic ligands. The preparative methods for several types of ferrocenylamino alcohols were developed and they were successfully used to catalyze enantioselective addition of dialkylzinc to aldehydes with high enantio-selectivity. In particular, 1,2-disubstituted ferrocenyl amino alcohols with planar... 

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

If an achiral ferrocene derivative is converted to a chiral one by chiral reagents or catalysts, this may be called an asymmetric synthesis. All asymmetric syntheses of ferrocene derivatives known so far are reductions of ferrocenyl ketones or aldehydes to chiral secondary alcohols. Early attempts to reduce benzoylferrocene by the Clemmensen procedure in (5)-l-methoxy-2-methylbutane as chiral solvent led to complex mixtures of products with low enantiomeric excess [65]. With (25, 3R)-4-dimethylamino-l,2-diphenyl-3-methyl-2-butanol as chiral modifier for the LiAlH4 reducing agent, the desired alcohol was formed with 53% ee (Fig. 4-9 a) [66]. An even better chiral ligand for LiAlH4 is natural quinine, which allows enantioselective reduction of several ferrocenyl ketones with up to 80% ee [67]. Inclusion complexes of ferrocenyl ketones with cyclodextrins can be reduced by NaBH4 with up to 84% enantioselectivity (Fig. 4-9 b) [68 — 70]. 

A chiral C2-symmetric bridged ferrocene was constructed from a synthetic ligand containing two cyclopentadiene units (Fig. 4-12d). The key step in the synthesis of the ligand is a diastereoselective Diels — Alder reaction of anthracene with bis[(S)-l-ethoxycarbonylethyl]fumarate. When oxidized to the ferrocinium salt, the ferrocene derivative has Lewis acid properties and catalyzes Diels — Alder reactions with some enantioselectivity [85]. 

Fig. 4-13. Ferrocene derivatives by asymmetric synthesis or from the chiral pool.

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. 

A chiral auxiliary is a compound that is incorporated into a larger molecule, where it transmits its chirality information to newly formed chiral elements. It is cleaved from the target molecule in a later step of the reaction sequence and should in principle be recycled, to avoid loss of the precious chiral material. Among the ferrocene derivatives, chiral primary amines are typical auxiliaries for their synthesis, see Section 4.3.3. All applications involve the intermediate formation of imines with carbonyl compounds. 

Considering the industrial importance of cyclopropanes in the pesticide field, it is not surprising that chiral ferrocenylphosphines have been applied as control ligands for the palladium-catalyzed enantioselective formation of cyclopropanes from the dicarbonate of 2-butene-1,4-diol and malonates, leading to 70% ee (Fig. 4-32e) [179]. Ferrocenylphosphines also induce chirality in the reaction of sulfonyl-substituted propenyl carbonates and acrylic esters to methylenecyclopentanes (up to 78% ee (Fig. 4-321)) [180], with potential applications in natural product synthesis. These examples show that the synthetic potential of chiral ferrocene derivatives is not yet fully exploited, and one may look forward to new applications. 

Synthesis of Ferrocene Derivatives Bearing Heteroelement Substituents... 

Scheme 5-3. Useful intermediates for the synthesis of ferrocene derivatives containing heteroatoms (a) Lithiation (generally with nBuLi) (b) mercuration with Hg(OAc)2, followed by reaction with LiCl or KCl (c) borylation with B(OnBu)3, followed by hydrolysis (d) CUCI2 (e) CuBr2 (f) compounds containing reactive bromo substituents, e.g., BrCX2 -CX2Br (X = F, Cl) or tosyl bromide (g) A-bromo succinimide (h) I2 (i) Br2.

The bifunctional ferrocene derivative fc(SH)2 has been tested as a component in the synthesis of macromolecules [84, 93, 94]. However, the reaction (1 1) of fc(SH)2 with norbornadiene (in the presence of AIBN) leads to oligomers containing only disulfide-bridged ferrocene units in the main chain [93,95] the diolefin appears solely in the form of norbornenyl or nortricyclyl terminations (Scheme 5-18). The preferred formation of disulfide linkages can be explained by the stability of the ferrocenyl thiyl radicals (Fc-S ), which live long enough to terminate the chain growth by radical combination [94]. 

Scheme 5-48. Synthesis of trinuclear ferrocene derivatives containing two terminal [3]ferroceno-phane units [224].

There have been reports of the synthesis of organometallic arylidene polyesters containing ferrocene derivatives in the main chain. Interfacial polymerization of... 

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