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© Fagnou Research Group - 2008

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

What we do

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Despite their widespread presence, the C-H bonds of organic molecules have been historically ignored by organic chemists. This lack of attention can be ascribed to their high strength (e.g. 105 kcal/mol for the C-H bonds of methane, and 110 kcal/mol for benzene) making them inert to most common organic reagents. Despite this challenge, the ability to achieve and control reactivity at C-H bonds has undergone significant growth, particularly in the last decade where the leap from stoichiometric transition metal mediated processes to catalytic ones have increasingly become within reach.

Within the field of arene functionalization, the majority of work has focused on the use of electron-rich arenes and on arenes possessing a basic directing group that can enable the crucial catalyst-substrate interactions leading to C-H bond cleavage. In 2003, we chose to target the use of simple arenes (such as benzene itself) and electron-deficient arenes. To achieve this goal, we initiated a concerted methodological, mechanistic and computational research program to determine if a previously unidentified mechanistic entry point for such substrates could be uncovered. We and others have demonstrated the presence of a concerted metallation-deprotonation pathway that appears to prefer to react at electron-deficient arenes. This knowledge, in conjunction with further innovations, enabled us to not only achieve direct arylations of electron deficient benzenes, but also examples that can occur with completely unactivated arenes such as with benzene, itself.


Heterocyclic arenes simultaneously constitute one of the most important building blocks in medicinal chemistry and one of the most challenging molecular scaffolds to functionalize. Our mechanistic knowledge lead us to consider the use of N-oxides, a line of investigation that has lead to the resolution of a long-term problem in arene cross-coupling methodology. With traditional techniques, arene coupling at the 2-positions of azines and diazines is fraught with low yields and irreproducibility. These problems are coupled with inaccessible or very expensive starting materials. In 2005, we reported that these problematic reagents can be replaced by inexpensive, easily prepared, and bench-stable azine N-oxides that effectively allow for the replacement of the organometallic component in traditional palladium-catalyzed cross-couplings. We later showed that diazine N-oxides can be use and are currently evaluating the use of azole substrates with tremendous success. This technology has already been adopted at several Canadian, US and European pharmaceutical companies for use in the preparation of new medicinal compounds.

An even more efficient strategy for the construction of the biaryl carbon-carbon bond would involve the direct coupling of the two different arenes without recourse to activating groups. For such a reaction to succeed, the catalyst must avoid the generation of unwanted arene homo-coupling that would consume starting material and give wasteful product mixtures. To do so, the catalyst must first react with one arene and then invert its selectivity and react exclusively with the second arene. Our work in direct arylation led us to believe that the crucial reactivity/selectivity inversion for selective arene cross-couplings was an achievable goal. Building on our mechanistic knowledge, we succeed in achieving the first examples of high yielding arene oxidative cross-coupling reactions. The reactivity, the value of the products, and the new catalytic behaviour underlying these novel transformations should lay the foundation for a new strategy for the preparation of industrially and medicinally important biaryl molecules, an objective which we are actively pursuing.

Ongoing research efforts include the continuation of our work in direct arylation. This includes work aimed at broadening the scope of arenes that can participate in these transformations and applying our reactions in the total synthesis of complex natural products and medicinal compounds, both of which are rare despite the advances that this field has witnessed in recent years. Our initial report dealing with oxidative arene cross-couplings is just the tip of the iceberg. In addition to establishing reaction scope, issues of regioselectivity and ideally regiocontrol must be addressed. Furthermore, we intend to replace the use of stoichiometric metal co-oxidants with the use of cleaner alternatives such as peroxides or oxygen. In addition to the above research that is focussed on the functionalization of arenes at C-H bonds, we have also initiated a research program directed at alkane functionalization. This is a more challenging goal than sp2 functionalization since the crucial catalyst-substrate interactions leading to C-H bond cleavage are less understood and defined. Our aim is to apply the same approach that has been successful with arene functionalization to both understand and advance the use of alkane functionalization as a tool in organic synthesis.

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