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Organocatalytic synthesis of fluorine compounds. Development of new methodologies for the enantioselective introduction of fluorine building blocks via CH activation of sp3 carbon

Final Report Summary - CSP3OCF (Organocatalytic synthesis of fluorine compounds. Development of new methodologies for the enantioselective introduction of fluorine building blocks via CH activation of sp3 carbon)

During this grant the fellow has demonstrate the possibility to use nucleophilic fluorine building blocks to functionalize tertiary amines through a Cross Dehydrogenative Coupling process catalysed by organic dyes and light.
The fellow developed the fluoromalonate addition to tertehydroisoquinolines with good yields after optimization of the reaction conditions with a good substrate scope. He did the Proof of concept of the use of CDC reactions with fluorine building blocks.
We also developed a cascade reaction catalysed by dye and light consisting in the addition of 1-fluoro-1-nitro(phenylsulfonyl)methane to tetrahydroisoquinolines and subsequent desulfonylation. This methodology allow us to formally report the fluoronitromethane addition to Tetrahydroisoquinolines that is difficult to achieve due the inestability of the fluoronitromethane.
Finally he developed the addition of fluoroacetone to tetrahydroisoquinolines using the same approach achieving good yields and moderate diastereo- and enantioselectivities. This is the first time, to the best of my knowledge, that fluorine building blocks have been reported in an enantioselective addition to tetrahydroisoquinolines using a CDC approach with Organic dyes as catalysts.

Proof of concept: development of enantioselective CDC reactions with fluorine building blocks such as fluoroacetone.

The fellow studied the developed reactions with highly functionalised substrates (tetrahydroisoquinolines bearing electron withdrawing, electron donating, halogens etc...) showing that this approach is compatible with high degrees of substitution/functional groups presence.
Proof of concept development of CDC reactions with fluorine building blocks in highly substituted tetrahydroisoquinolines.
Finally the fellow have applied the concepts of Flow chemistry to the addition of fluoroacetone to tetrahydroisoquinolines with good results.
Main results: Proof of concept: development of CDC reactions with fluorine building blocks in flow reactors.

During this period the fellow also developed a side reaction discovered during the work with organic dyes consisting in the reaction of phosphites with primary amines leading to the synthesis ofphosphoramidates. This type of compounds are highly valuable for their applications in chemicalbiology, mass spectra, as catalysts and can be found in several blockbuster products as flame retardants. However their synthesis is usually tedious and require the use of toxic reagents or catalysts (transition metals, halogenated compounds, etc...) and the use of expensive purification techniques (column chromatography, HPLC, etc...). They found that the reaction could be simply
catalysed by light with the use of an organic dye that renders the phosphoramidate in excellent yields and purity without the use of column chromatography or any other purification technique.

Main Result: Development of a green phosphoramidation based in CDC coupling reactions

During this studies we have developed and builded a Photoreactor from simple pieces that increase the success of the reactions. We also build a flow system for the addition of fluorosulfones based in LED lights and a syringe pump.

The impact of this work is clearly in its early stage. But the fellow demonstrated (proof of concept) that the cross dehydrogenative coupling of amines can be used for the preparation of fluorine compounds using common fluorine building blocks such as fluromalonates, fluoronitromethylenesulfones and fluoroacetone. This proof of concept opens a new way for the later stages fluoro-functionalisation of compounds that will have an immediate impact in pharma or agrochemistry, where the use of fluorine compounds is quite common. We also proved that this concept can be used in highly functionalised compounds like tetrahydroisoquinolines bearing OMe, Cl, F, Br, functional groups and we prove that this type of reactions can be achieved using flow chemistry.

In conclusion in this grant the major objectives have been achieved. The fellow apply a CDC process catalysed by organic dyes/light for the addition of fluoro nucleophiles to tertiary amines with good yields and moderate diastereo- and enantioselectivities. This new reactions open a new gate for the discovery of new reactions based in the concept of activation of tertiary amines with organic dyes/light a greener approach to the ones reported before. Moreover, the fellow show that this combination organic dyes light can be used for other reactions such as the phosphoramidation reported. This would led to the development of new methodologies significantly greener, and more effective. Finally, with this works we are confident to demonstrate that this approach could be used in late stage modifications and will benefit the pharma- agrochemical industry which have been shown a huge interest in the development of new reactions for the introduction of fluorine in their hits to improve pharmacological or pharmacokinetic properties.

Part of this work have been published in peer review journals:

“Organophotocatalytic synthesis of phosphoramidates” Marta Meazza, Agnieszka Kowalczuk, Luke Shirley, Hao Guo* and Ramon Rios* Adv. Synth. Catal. 2016, 358, 719-723.

“Organocatalytic Cross Dehydrogenative copling for Synthesis of Fluorinated Compounds” Luke Shirley, Victor Ceban, Marta Meazza and Ramon Rios* ChemistrySelect 2016, 1, 13-15.
And more publications are in preparation.

This grant allow the fellow to build some strong connections/collaborations with other academics interested in the field of photocatalysis which produced some interesting results and established the fellow in this field. Some publications from this collaboration but not diurectly related with the grant are:

“Photoinduced intramolecular Haloarylation and Hydroarylation of alkynes” Dawen Xu, Ramon Rios, Feifei Ba, Dongmei Ma, Guangxin Gu, Ishun Ding, Yunyan Kuang, Hao Guo; Asian J. Org. Chem. 2016, 5, 981-985

“Catalyst-Free Photocyclopropanation of Dibromomalonates with Alkenes: An Approach to Multisubstituted Cyclopropanes” Yanbin Zhang, Yong An, Jing Sun, Aishun Ding, Yu Wang,* Ramon Rios,* and Hao Guo*; Tetrahedron Lett. 2015, 56, 6499-6502