Sixty-years ago, the serendipitous discovery of ferrocene opened a new area of research in organometallic chemistry. The following years have witnessed the emergence of the metallocene chemistry which culminated with the Nobel of Chemistry, shared between Ernst Otto Fischer and Geoffrey Wilkinson. Since that, ferrocene derivatives have found applications in nearly all areas of chemistry: from redox sensing to material science, from catalysis to medicinal chemistry.
However, these developments remain almost restricted to easily accessible monosubstituted, 1,1’- and 1,2-disubstituted ferrocene compounds. This results from the lack of easy syntheses of compounds featuring original substitution patterns although they are of main importance for specific applications. Indeed, due to their large angle between the two substituents (for 1,3-disubstituted and 1,2,4-trisubstituted ferrocenes) or due to the fine tuning of steric and electronic properties (for 1,2,3,4-tetra and 1,2,3,4,5-pentasubstituted compounds), they offer more degree of liberty than the usual compounds.
One main topic of our group is to develop synthetic tools to access ferrocene derivatives featuring original substitution patterns and to develop new methodologies to functionalize ferrocene derivatives. Another interest of the group is to incorporate ferrocene derivatives into biologically active compounds.
New routes toward original substitution patterns
One approach currently investigated is based on the halogen ‘dance’ reaction, a process able to deliver 3-halogenated derivatives by starting from its 2-halogenated isomer. If the reaction simply requires a directing group (DG), a heavy halogen (X = I, Br) and a lithium amide to initiate the isomerization process, its control is a lot more difficult to achieve.
We reported the first example of controlled H.D. reaction in the ferrocene series by using a bulky N,N-diisopropylcarboxamide as the directing group and subsequently studied how the resulting 1,3-disubstituted ferrocene derivative can deliver a wide diversity of original compounds.
Recognising that fluoroferrocene chemistry was the less explored in the haloferrocene families, we extended the chemical diversity available around this original compound. Therefore, by combining ortho-directed deprotometallation with electrophilic trappings, an original library of 1,2-disubstituted ferrocene derivatives was obtained.
Further deprotometallation next to the fluorine atom was found possible to reach a 1,2,3-trisubstituted derivative which was successfully converted into its original 1,2,4-isomer by using the halogen ‘dance’ reaction.
Enantioenriched ferrocene derivatives being of high interest, especially in catalysis, we recently reported the first example of asymmetric halogen ‘dance’ reaction by converting an original tetrasubstituted ferrocene (easily prepared from Ugi’s amine) into a hetero 1,2,3,4,5-pentasubstituted ferrocene, obtained as a single isomer.
Original methodologies in the ferrocene series
To access ferrocene derivatives in a greener fashion, our group is developing methodologies to perform asymmetric transformations, reduce step-numbers and optimise purification processes.
In this view, we reported the diastereoselective deprotometallation of ferrocenes containing carbohydrates as the chiral inducer by using the bimetallic combination developed in the group. Their subsequent transformation allows an access to chiral sensor, selective for (L)-glutamic acid.
Although of major interest, ferroceneboronic acid chemistry did not meet the success of the parent arene derivatives. This is partially due to lengthy or not user friendly syntheses and to the lack of important analytical data. We recently engaged a study dedicated to the synthesis and full characterization of ferrocene substituted by various borylated substituents. The reactivity of one compound in Ir- and Ru-catalyzed silylation and borylation was also evaluated.
Development of the halogen ‘dance’ reaction in the ferrocene series requires a robust supply of the starting 1,2-disubstituted ferrocene. We recently reported a chromatographic-free approach able to deliver more than 30g of 2-iodo-N,N-diisopropylferrocenecarboxamide in a single batch. Further functionalization by C-O and C-C bond formation was also studied.
Ferrocene-based biologically-active derivatives
Nitrogen containing heterocycles are usually endowed with biological activities. Recently, we prepared new ferrocene-isatine and -pyridine conjugates and we are currently extending this approach toward more complex compounds.
The shortest route toward protected 1’-aminoferrocene-1-carboxylic acids from commercially available ferrocene-1,1’-dicarboxylic acid by using a Curtius rearrangement was also described. Studies in order to incorporate this ferrocenic amino acid into bioactive compounds are currently ongoing.
