Naphthalene C-H Bond Functionalization: New Methodologies and Total Synthesis Application – NaFMeTS

Development of catalytic conditions allowing the regioselective functionnalization of 1-carbonylnaphthalenes. Optimizations on the directing groups as well as on the catalytic systems have been carried out.

Different groups have been introduced at position 8 of 1-carbonyl naphthalenes through palladium-catalyzed C-H activation reactions. For example, fluorinated groups have been successfully added, as well as a hydroxyl function. This latter oxygenation reaction enabled the formation of the naphtholactone scaffold in a single step.

In a second phase, a regioselective halogenation reaction of naphthaldehydes was optimized. Using palladium as a catalyst, naphthaldehydes selectively halogenated at position 2 or 8 were synthesized. These products allowed access to numerous natural product scaffolds in very few steps.

Furthermore, DFT calculations were carried out to explain the observed regioselectivity. This methodology was applied to the synthesis of a library of naphtholactams as well as the total synthesis of aspergillin F.

The future objectives of the project are to develop amination and alkynylation reactions in position 8 while trying to use less expensive metals as catalysts. In addition, other C-H bonds of naphthalenes will be targeted.

1) Berrou, C.; Prévost, S. Adv. Synth. Catal. 2021, 363, 4091-4095.

Nowadays the notion of “green chemistry” has emerged as an important domain of interest and becomes a crucial aspect of chemistry. In particular, the reduction of waste to develop environmentally friendly syntheses is a major concern for chemists. In this contest, direct functionalization of C-H bonds is of paramount interest due to the reduction of functional group manipulations. The NaFMeTS proposal presents, in a first part, the development of new regioselective C-H activation reactions of naphthalenes. In a second part,these C-H activation methods will be applied to the synthesis of natural products and they will especially been combined with bio-inspiration strategy to achieve the synthesis of an aromatic polyketide family, the corymbiferans.