Ferrocene aminomethylation

Contemporaneously with Snieckus, Uemura and coworkers showed that ferrocene 369 bearing an aminomethyl group may also be lithiated enantioselectively by alkyllithi-ums to give 370 in these cases, better results are obtained with the C2-symmetric amine 368 than with (—)-sparteine (Scheme 157). 

Togni s synthetic route to a planar chiral (trimethylsilyl group on ferrocene) and central chiral (asymmetric carbon in the NHC-Cp alkyl linker) carbene ligand starts from a central chiral aminomethyl ferrocene (see Figure 5.29) [9]. Lithiation and subsequent reaction with trimethylsilyl chloride introduces planar chirality on ferrocene. Quartemisation of the dimethylamino group with methyl iodide enables reaction with imidazole to the double Fc substituted imidazolium salt which can then be deprotonated to the free carbene with potassium rerf-butylate. 

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... 

As mentioned above, ruthenocene is susceptible to electrophilic substitution in a manner similar to ferrocene. Thus, common reactions for activated aromatics, such as acylation (RCOCFAICI3), sulfonation (SO3 in dioxane), aminomethylation (CH2(NMe2)2), Vilsmeier-Haack formy-lation (DMF/POCI3), arylation via diazonium salts, as well... 

Preparation. [(i )-a-(2-Naphthyl)aminomethyl]ferrocene was prepared in three steps from ferrocenyl 2-naphthyl ketone featuring an asymmetric CBS reduction with >99% ee (eq 1). After protection of the secondary hydroxyl group with an acetyl group, a nucleophilic displacement of the acetoxy group with an amino group proceeded with retention of stereochemistry. A range of different variations of [(i )-a-(2-naphthyl)aminomethyl]ferro-cene could be prepared using this sequence with similar efficiency. 

Modifications. A diverse array of chiral ligands related to [(R)-a-(2-naphthyl)aminomethyl]ferrocene was screened (see those mentioned in eq 1).4 It was found that when the 2-naphthyl group was replaced with the 3,5-di-rert-butyl phenyl group, the ee s improved from 82% to 92% in the case of cinnamyl chloride when Zn(neo-pentyl)2 was used. It is equally significant to note that the temperature could be elevated to —30°C (eq 4).4... 

University of Minnesota, Minneapolis, MN, USA [(/ )-a-(2-Naphthyl)aminomethyl] ferrocene... 

Electrophilic attack on coordinated cyclopentadienyl rings, particularly those in ferrocene, is well established. This process occurs in a similar fashion to electrophilic attack on arenes and was used to establish the binding mode of the Cp ligand in ferrocene (see Equation 3.88). These reactions of the Cp ligand with electrophiles are described in more detail in Chapter 12, which covers electrophilic attack on coordinated ligands. Friedel-Crafts acylation, formylation, aminomethylation, and mercuration are all known. - ... 

Lactones from carboxylic acid amides via — s. 19, 738 of terf-aminomethyl compounds s. 19, 738 ferrocene derivatives s. Am. Soc. 87, 1241 (1965)... 

Ferrocenyhnethylamine 52, which is commercially available, gives 2-dimethyl-aminomethyl formyl ferrocene by metallation and formylation. This aldehyde 53 is converted to an oxime, then reduced to a primary amine 54. An S jAr reaction between this amine and 4,7-dichloroquinoline yields the expected ferroquine 45 in the form of a yellow solid. Finally, the free base 45 is converted by L(+) tartaric acid or H Cl to the salt 5 5 which is water-soluble and thus more convenient for use. 

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]. 

The dimethylaminomethylferrocene obtained by aminomethylation is shown in eq. (15.13), the metalation at the 2-position eorresponding to the orthometalation of benzene is liable to proceed [26-30], for example, as shown in eq. (15.16) and Scheme 15.1. The metalation at the 2-position is able to proceed selectively and the metal is able to be exchanged easily with other substituents. Further, as the dimethylaminomethyl group is easily able to be exchanged with a variety of functional groups such as methyl, methylol and formyl. So the dimethylaminomethylferrocene is used as the raw material for the synthesis of ferrocene derivatives [27,29]. 

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],... 

Ferrocene undergoes a large number of typical ionic aromatic substitution reactions that include Friedel-Crafts acylation, alkylation, metalation, sulfonation, and aminomethylation. Figure 6-1 outlines some of the more... 

Aminomethylation of ferrocene is significant because of the large number of ferrocene derivatives that can be prepared from the quarternary ammonium salt, some of which are illustrated in Fig. 6-4. 

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