CE07 - Chimie moléculaire

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

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

Naphthalene is a key structural core in chemistry as shown by its presence in many bio-active compounds as well as in organic materials. However, reported synthesis are often steppy. The goal of this project is to develop new C-H activation reactions to introduce regioselectively different functionnal groups on naphthalene derivatives and to apply theses methods to natural products synthesis.

Regioselective fonctionalization of 1-carbonylnaphthalenes via C-H activation

The objective of this project is to develop regioselective functionalization reactions of 1-carbonylnaphthalenes via C-H activation. The carbonyl group will be used as directing group and is also very interesting for further reactions. The peri position of naphthalene will be mainly focused for the C-H activation reaction due to the possible transformations which give an access to natural product skeletons. In addition, this position has been very little studied and is more challenging that the ortho position.

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

Initially, an oxygenation reaction of naphthalenes in position 8 was developed using palladium as catalyst. Different directing groups were used in order to obtain the corresponding naphthols and, when the reaction was carried out with a Weinreb amide as directing group, naphtholactones were directly isolated.
Secondly, a regioselective halogenation reaction of naphthaldehydes was optimized. Still using palladium as catalyst, naphthaldehydes were selectively halogenated in position 2 or 8. These products have made it possible to have access to natural product skeletons in very few steps. In addition, DFT calculations to explain the observed regioselectivity were undertaken.

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.

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.

Project coordination

Sébastien Prévost (Laboratoire de Synthèse Organique)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

LSO Laboratoire de Synthèse Organique

Help of the ANR 199,216 euros
Beginning and duration of the scientific project: November 2020 - 48 Months

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