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Fundamentally new strategy for coupling of secondary alkyl boronic esters for the formation of new C-C bonds

Final Report Summary - FUNTASTIC (Fundamentally new strategy for coupling of secondary alkyl boronic esters for the formation of new C-C bonds)


The main objective of this Marie Curie project has been the develop of new methodologies for the enantioespecific cross-coupling of secondary and tertiary boronic esters with aromatic rings which are nowadays not possible to achieve using existing methodologies. As well, we postulated the develop of a method which could perform the cross-coupling retaining the boron moiety in the aromatic ring increasing the atom economy of the reaction.

We were aiming to apply this methodology towards the total synthesis of biological active molecules.

-Comprehensive summary

Our proposed methodologies consist in the formation of a radical cation intermediate which allows the cross-coupling reaction. We postulated that this intermediate could be achieved by multi-electron oxidants or photochemical oxidation (Scheme 1). Initial results was confirming that this could be possible because we have got a high yielding reaction for the sp2-sp2 coupling using DDQ as oxidant in just 5min of reaction time (Scheme 2).

With this in hand, we move to the most interesting sp2-sp3 coupling. The reaction with enantionrich secondary boronic ester work in excellent yields with complete retention of the configuration. The scope can be extend to different enantionrich secondary boronic esters but the limitations came when we try to modify the furan ring for other aromatic rings, where the reaction seems to be very specific for this heteroaromatic ring. Different oxidants and reaction conditions where tried in order to overcome this limitation without succeed.

Prof Herbert Mayr reported last year that DDQ can react as electrophile. In this context, we envisage the possibility that DDQ where playing a role of electrophile instead to oxidant. A bench of electrophiles where tested in the reaction successfully and NBS show the best performance to the reaction. Mechanism of the reaction would proceed via electrophilic aromatic substitution, generating a cation on the aromatic ring, which allows to the alkyl moiety to migrate with complete retention of the configuration (Scheme 3). Theorical calculations corroborated that the coupling is successful when DDQ is acting as electrophile (Scheme 4).

Our group published the reaction of enantionrich secondary ate complexes with electrophiles, this reaction undergoes with complete inversion of the configuration. In this context, reaction on the sp3 carbon and in the sp2 were carried out in similar reaction conditions, this means that the aromatic ring and electrophile should be tailored in order to direct the reaction towards the aromatic ring instead to the sp3 carbon. We observed that reaction conditions, like solvent or temperature, have a large influence in the overcome of the selectivity being MeOH the most successful to achieve the coupling.

Substrate scope of the reaction is broad but we are still working in expanding it. In terms of boronic esters, we can perform the reaction with secondary and tertiary boronic esters, benzylics or non benzylics with excellent yields, overcoming the main problem of the traditional transition metal methods. In terms of aromatic partners, we can achieve this tranformation from electronrich heteraromatic rings to moderate electronrich six member ring. When we decrease the electronrichness of the aromatic ring lower than methylbenzene, bromination of the sp3 carbon is predominant (Scheme 5).

We discover that changing the reaction we can retain the boron in the final molecule after the cross-coupling. This reaction is synthetic useful when aromatic rings are less electronrich which can be obtain in yields up to xx% and the boron moiety can be further functionalize (Scheme 6).

- Conclusions and potential use

Cross-coupling reactions have been widely used for the industry towards the synthesis of fine products such as medicines or materials.

The methodology that we have been developing over this grant is unique and allow a number of cross-coupling reactions that haven't been possible before. The development of this new method, allow to expand the substrate scope of coupling reactions available and in consequence increase the number of products that can be generate. Consequently industrial synthesis can be shorter (economy) as well allows the discovery of new drugs and materials that could only be achieved using this method, having a direct impact in society.

The expected final results for this project is delivery a well establish new method for cross-coupling reactions that would be widely used in both academia and industry.