Ferrocene Mannich reaction

The Mannich reaction is a particularly good method of introducing a reactive functional group into a sensitive aromatic nucleus. The reaction has been very useful in ferrocene chemistry. Treatment of chromium acetylacetonate under Mannich conditions yielded a tris-V,N-dimethylaminomethyl chelate (XXXIII). This remarkable substance was very difficult to purify because of its extreme solubility in all solvents ranging from n-heptane to water. The trisamino chelate (XXXIII) is a deep purple, hydroscopic oil and behaves like a typical organic amine. Reaction of this amine with methyl iodide afforded a trisquater-nary ammonium salt (XXXIV), soluble in water but insoluble in organic solvents. When this salt (XXXIV) was treated with cyanide ion, trimethylamine was lost and the cyanomethyl chelate (XXXV) was formed. 

However, in contrast to benzene, ferrocene is sensitive to oxidation, and the ferrocenium cation, FeCpj, a paramagnetic 17-electron species, is readily formed in the presence of various oxidants. The ferrocenium cation is reluctant to undergo electrophilic substitution, and therefore reactions such as halogenation and nitration, which are important routes to substituted benzene derivatives, cannot be used for the synthesis of substituted ferrocenes. Only electrophilic substitution under nonoxidizing conditions (e.g., Friedel-Crafts acylation, Mannich reaction, borylation, lithiation or mercuration), and radical substitution are available as an entry into the chemistry of substituted ferrocenes. 

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 AICI3 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, Mannich 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... 

Ferrocene is an aromatic compound similar to benzene. As the aromatic rings of ferrocene are coordinated by iron, ferrocene shows a higher basicity than that of benzene. Then an electrophilic reaction is liable to proceed. For example, Friedel-Crafts acylation, Mannich reaction (aminomethylation) and lithiation easily proceeds as shown in eqs. (15.12)-(15.14) [26]. 

Ferrocenes are aromatic compounds similar to benzene, as they have a high basicity, electrophilic substitution reactions such as Friedel-Crafts acylation (eq. (15.12)), metalation (eqs. (15.14) and (15.16), Scheme 15.1), Mannich reaction (aminomethylation, eq. (15.13)) and formylation (Scheme 15.1) are liable to proceed as described above. These products also have a high reactivity and they are used as raw materials for other ferrocene derivatives as shown in Schemes 15.1 and 15.2. For example, if one bridged ferrocene is obtained from Scheme 15.1 to form another bridge, lithium diisopropylamide (EDA) is reacted, oxidized with CuCl2, and reduced with LiAlH4 to afford a two bridged ferrocenophane as shown in eq. (15.23) [50,69]. 

Aminomethylated compounds (eqs. (15.13) and (15.16), Scheme 15.1) obtained by the Mannich reaction yield various kinds of 2-metalated compounds. The aminomethylated compounds yield quaternary amine salts by the Menshutkin reaction with an alkyl halide, and a methylol derivative is prepared by adding alkali to the salt. Dihydrocholesterol (cholestanol) reacts with dimethylamino-methylferrocene in the presence of methyl iodide and acetone to afford the ferrocene derivatives as shown in Scheme 15.5 [76,77],... 

Ruthenocene has aromatic properties similar to ferrocene and its electrophilic substitution reactions are liable to proceed. For example, a Friedel-Crafts acylation, metalation, arylation, formylation, a Mannich reaction and sulfonation all readily proceed as shown in Scheme 16.2 [17]. 

Interestingly, TaniaPhos catalysts used in the asymmetric hydrogenations can be synthesized from the (7 )-Ugi amine 15 in two steps [14], The (/ )-Ugi amine can be synthesized via a Mannich reaction between ferrocene 12, dimethyl amine (13), and acetaldehyde (14) (Scheme 15.6) [15]. 

Hauser and Lindsay first showed that ferrocene undergoes a Mannich-type reaction with formaldehyde and dimethylamine to form dimethylaminomethyl-ferrocene (XXIV) (31). This amine is readily converted to a methiodide, and... 

The Vilsmeir reaction and the Mannich condensation are reactions which are shown by aromatic systems that are more reactive than benzene. It follows, therefore, that ferrocene is more aromatic than benzene. 

The Mannich bases subjected to the replacement reaction arc usually derivatives of alkyl ketones, phenols, and ferrocene. 

Nevertheless, in many cases, hydrogcnolysis docs not occur readily however, the ammonium salt of the Mannich base appears more suitable for a successful reaction. Thus, several ortho-phenolic Mannich bases arc hydrogenated as hydrochlorides, in order to avoid the presence of the intramolecular hydrogen bond between OH and N, which is responsible for the weak reactivity of the free Mannich base. ITie ferroccnyl Mannich base 282, containing both tertiary and quaternary amino groups, gives 2-di-methylaminomethyl-l-(2-methylferroccn-l-yl) ferrocene (283) upon reaction of the more reactive quaternary ammonium moiety. ... 

Dimethoxybenzene reacts with A -methylenemoipholinium chlwide in acetonitrile to afford the Mannich product, characterized as the hydrobromide, in 66% yield. The analogous reaction using the pyrrolidinium salt is shown in equation (21). Ferrocene gives low yields of products, for example with... 

The coordinated cyclobutadiene readily undergoes electrophilic substitution. It can be acylated under Friedel-Crafts conditions, sulphonated and mer-curated. Like ferrocene (p. 284) it performs the Vilsmeier reaction with PhN(Me)CHO/POClj giving the aldehyde (f -C H3CHO)Fe(CO)3 and the Mannich condensation with GHjO/Me NH giving (f/ -C H3CHjNMe3)Fe(CO), which occur... 

With formaldehyde and secondary amines, (Mannich condensation) ferrocene yields mpno-dialkylaminomethyl derivatives,. 8.2. The ability of ferrocene to react under Vilsmeier or Mannich conditions is further evidence of its high susceptibility to electrophilic substitution, as these reactions are observed in the benzene series only for reactive compounds such as phenol. 

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