60th Annual Report on Research 2015

The conversion of solar energy into chemical energy in photosynthesis has enthralled scientists for decades. Sunlight could be used as an inexpensive, green, and sustainable source of energy to induce the application of photochemistry in synthesis is therefore restricted.  In response to this limitation, several light- absorbing photocatalysts have been developed in an effort to mimic the light-harvesting abilities of bio-complexes found in natural processes, such as photosynthesis.  Increased attention is being placed on visible-light-mediated photoredox processes for the development of efficient and waste-minimizing processes of general applicability that should decrease our dependence on toxic chemical products. To mimic Nature's photosynthesis, chemists have developed a variety of photoredox complexes.  Among theses, polypyridine Ru(II) and Ir(III) complexes (1-3) possesses high-energy, long-lived and highly emissive excited states to be useful in organic synthesis (Figure 1). Although these photoredox catalysts (1-3) are able to cleave C-X bonds either by direct reduction from the catalyst excited state (oxidative quenching) or via two single electron transfer (SET) processes (reductive quenching), their reduction potentials (-1.31 V to -1.73 V versus SCE) limit the scope of the radical intermediates to precursors having activated or weak C-X bonds such as bromomalonate, electron deficient benzyl bromides, polyhalomethanes and C-I.  Typically, methods to generate carbon-centered radicals from unactivated C-X bonds require the use of hazardous radical initiators such as AIBN and Et₃B, and toxic organotin reagent as a source of hydrogen.

Figure 1

In late 2013, our group reported a UVA-enabled reductive radical reaction of unactivated alkyl and aryl bromides in the presence of a dimeric phosphine gold complex [Au₂(dppm)₂]Cl₂ as the photocatalyst (Figure 2).  UVA irradiation of [Au₂(dppm)₂]Cl₂ generates long-lived excited states which can undergo oxidative and reductive quenching cycle.  It was demonstrated that the applicability of this photoredox process is not limited to intramolecular processes, but that intermolecular transformations are also possible.  Although the mechanism was not completely understood, our results demonstrated the uniqueness of this transformation and the high synthetic potential.

Figure 2

Progress report

The goal of this grant is to accelerate the development of photoredox catalysis as an effective strategy for the construction of carbon-carbon bonds.  The use of photoexcited gold dinuclear complexes to generate radicals from unactivated carbon-halogen bonds provides a new plateform to perform radical reactions and design new transformations.  Early 2015, we reported a new protocol for the reductive deoxygenation of primary alkyl alcohols (Figure 3-A).  This method takes advantage of the unexpected light-mediated bromination with CBr₄ in DMF using UVA-LED and its compatibility with the photoredox process.  The high synthetic value of this transformation was demonstrated through the formation of alkyl radicals leading to reduction (deoxygenation) and cyclization products.  Taking advantage of the formation of the Vilsmeir-Haack reagent, we wanted to apply the photogeneration of Vilsmeier-Haack reagent in a one-pot procedure for the synthesis of amides from readily available carboxylic acids and amines.  As shown in Figure 3-B, this new process was conveniently applied to a simple one-pot synthesis of amides.  Several amides and anhydrides were obtained in high yields.  This study demonstrates the importance of photochemistry in developing fast, efficient and reagent minimizing methods in organic synthesis.

Figure 3

Later in 2015, we reported the use of photoredox catalyst [Au₂(dppm)₂]Cl₂ for the generation of organic free radicals in the functionalization of indoles (Figure 4).  Operating through an oxidative quenching cycle, this method proves to be highly efficient for the synthesis of substituted indoles.  This process allows for simple access of carbon-centered radicals not attained with popular photoredox catalysts and without the use of harsh conditions and toxic reagents. 

Figure 4

Part of the current PRF proposal, we have described the development of photoredox Minisci reaction.  Radical heteroaromatic additions like the Minisci reaction are important transformations for the chemical industry. We are pleased to report that the generation and addition of nucleophilic alkyl radicals to heteroarenes from unactivated bromoalkanes has been achieved for the first time on a photocatalytic platform.  We are currently developing a universal and efficient Csp³-Csp² coupling strategy for the direct C-H alkylation of heteroarenes using a dimeric gold(I) photoredox catalyst, [Au₂(dppm)₂]Cl₂ (Figure 5).  At the present time, we have produced more 30 examples in high yields ranging from 50 to 95% which include cross-polar radical addition. 

Figure 5

Future Plans and Outlook

In addition to developing new synthetic methods, we are currently establishing a thorough mechanistic investigation to determine the mode of action of the photoexcited dimeric gold complex.  In other words, does the oxidative or reductive quenching cycle operate in an inner or out-of-sphere mechanism?  Answer to these questions will not only be fundamental but help with the design of new dimeric gold complexes for specific reactivity to transform petroleum feedstock to important molecules.