Organic Chemistry Frontiers Blog

Metal-assisted asymmetric catalysis has proved to be one of the most efficient strategies to obtain high stereoselectivities in organic synthesis. High levels of chiral induction in a chemical transformation, together with high turn-overs of the catalyst, arise from the best match between the transition metal and the ligand. The widespread use of N-containing ligand precursors, as enantiopure building blocks, facilitates the synthesis of a broad scope of heterocyclic ligands, such as (bis)oxazolines, salens, and NHCs. The strong chelation properties of the bipyridine core with various metal ions made chiral 2,2′-bipyridines a very promising class of ligand to be used in asymmetric catalysis.

A first N₂O₂ tetradentate 2,2′-bipyridinediol was first synthesized in the early 90’s by Bolm and efficiently used in asymmetric catalysis. Later, the stability of Lewis acid complexes with this ligand was highlighted in highly enantioselective reactions run in aqueous media, where easily hydrolysable metal salts were transformed into water-compatible metal-complexes. With the objective of optimizing chiral inductions, tremendous efforts have been invested to design new C₂-symmetric 2,2′-bipyridinediol derivatives.

Recently, the group of Thierry Ollevier and collaborators of Laval University in Québec, Canada, have disclosed the total synthesis of 2,2′-bipyridinediol (S,S)-1 in seven steps starting from commercially available 2-bromo-5-methylpyridine, with 25% overall yield and stereoselectivities up to 99% de and >99.5% ee (Scheme). The most crucial step for high levels of stereoenrichment of the ligand was demonstrated to be the oxidative homocoupling reaction, where the physical properties of the 2,2′-bipyridine N,N′-dioxides allowed removal of undesired diastereoisomers by silica gel column chromatography. X-ray studies revealed a favored complexation of (S,S)-1 that reaches heptacoordination of Fe^II.

The potential of (S,S)-1 for asymmetric induction for the Fe^II-catalyzed Mukaiyama aldol and thia-Michael reactions was highlighted. An increase of the chiral induction was demonstrated using the Fe^II catalyst made from newly synthesized ligand vs Bolm’s ligand.

Thierry Ollevier

Laval University

Thierry Ollevier is currently Full Professor in the Department of Chemistry at Laval University in Québec, Canada. He obtained his B.Sc. (1991) and Ph.D. (1997) at the Université of Namur (Belgium), and was post doctorate fellow at the Université catholique de Louvain (Belgium), under István E. Markó (1997), NATO postdoctorate fellow at Stanford University under Barry M. Trost (1998–2000), then post doctorate fellow at the Université de Montréal under André B. Charette (2000–2001). Current research in his group aims at designing novel catalysts, developing catalytic reactions and applying these methods to chemical synthesis. He is active in the areas of iron catalysis, diazo chemistry, asymmetric catalysis, and synthetic green chemistry. He is the author of more than 70 articles indexed by SCI and cited more than 2000 times.

http://www2.chm.ulaval.ca/tollevier/

Efficient stereoselective synthesis of chiral 3,3′-dimethyl-(2,2′-bipyridine)-diol ligand and applications in Fe^II-catalysis 

S. Lauzon, L. Caron and T. Ollevier, Organic Chemistry Frontiers 2021.

https://doi.org/10.1039/D1QO00188D 

Hole-mediated PhotoRedox Catalysis: Tris(p-substituted)biarylaminium Radical Cations as Tunable, Precomplexing and Potent Photooxidants.

Processes involving visible light photoinduced electron transfer (PET) are at the forefront of contemporary organic synthesis and allow access to reactive intermediates unavailable from conventional chemical reactivity. The selective delivery of photon energy to visible light-active photocatalysts which engage visible light-inactive molecules in PET is now an established synthetic technology known as PhotoRedox Catalysis (PRC). PRC is broadly-applicable, selective, proceeds under exceedingly mild conditions and is changing the way we do organic synthesis. However, PRC suffers some key limitations. Firstly, excess sacrificial chemical oxidants (O₂) or reductants (trialkylamines) are needed to turn over the ‘spent’ photocatalyst which can (or whose by-products, such as peroxides, can) interfere with subsequent chemical processes and need separation from desired products. Secondly, the scope of redox processes is fundamentally restricted by the energy of visible light photons (400-700 nm; 1.8-3.1 eV) and not all of this photon energy provided to the photocatalyst can be harnessed synthetically. Although high energy visible photons (400-450 nm) can temporarily populate excited states higher than the first excited state, Kasha’s rule dictates that relaxation to the first excited state is faster than typical diffusion-controlled photochemistry. This limits the applications of PRC in challenging redox processes.

Nature overcomes photon energy limitations by accumulating multiple photons for challenging chemical processes; several red photons are required for transfer of electrons to CO₂ in biological photosynthesis. With some exceptions, harnessing of multiple photon energies in PRC to access super-oxidizing or super-reducing excited states has largely eluded researchers. The fusion of photochemistry and electrochemistry provides an innovative solution to all issues above. Electroactivation of a catalyst to a colored radical ion, followed by its photoexcitation, exceeds the accessible excited state redox potentials of PRC alone (>3.0 eV). Some examples of this concept, coined ‘electrochemically-mediated PhotoRedox Catalysis’ (e-PRC), have emerged in the literature. A question that has eluded researchers is how excited radical ions (typically doublet states) could ever engage in photochemistry, given their typical picosecond lifetimes forbid diffusion. Moreover, while catalyst ‘tunability’ is well established in PRC, it is yet to be established in synthetic photoelectrochemistry.

Figure 1. Triarylamines (TAAs) as tunable e-PRCats developed by the Barham grou.; A. SET activation of challenging arenes and C-N bond formation with N-heterocycles. B. Experimental setup showing electroactivation of TAAs and photoexcitation of TAA^.+s in a divided cell.

Recently, the group of Joshua Philip Barham and collaborators at Universität Regensburg, Technische Universität München and the Central European Institute of Technology introduced triarylamines (TAA) as a new family of tunable electroactivated photoredox catalyst (e-PRCat). The group demonstrated that facile tuning of the e-PRCat accessed record-breaking excited state potentials of E^p_ox = +4.4 V vs SCE. This allowed PET super-oxidations of very challenging arenes, like polychloroarenes, polyfluoroarenes and trifluorotoluene, resulting overall in C-N bond formation with pyrazole partners. Catalyst power could be tuned down to access moderately challenging arenes (alkylbenzenes, benzene) with higher selectivity. Of key importance is the discovery of p-stacking dispersion precomplexation between the radical ion e-PRCat (TAA^.+) and substrate to rationalize, for the first time, the photochemistry of excited state radical ions. The study sets the scene for dispersive precomplexation as a novel control element in photochemistry, which allowed the group to:

1) circumvent of ultrashort lifetimes of radical ion excited states (*TAA^.+, t < 10 ps) for use in PET,

2) override Kasha’s rule and access to higher order excited states, to harness the full power of the visible photon’s energy (E^p_ox *TAA^.+ > 4.0 V vs. SCE),

3) overturn conventional thermodynamic redox selectivity (1,4- > 1,2-disubstituted arenes) by steric/electronic factors involved in precomplexation (1,2- > 1,4-disubstituted arenes).

Figure 2. Proposed mechanism of hole-mediated photoredox catalytic super-oxidation of arenes, involving dispersive precomplexation via a T-p interaction, supported by DFT calculations and changes in EPR spectroscopy of the TAA^.+ in the presence of arene substrates following a shift in spin density (increasing triplet representation of the signal).

Joshua Philip Barham

Universität Regensburg

Joshua Philip Barham is a Sofja Kovalevskaja Group Leader in the Faculty of Chemistry and Pharmacy at the University of Regensburg (Germany), where he investigates photo-, electro-, photoelectro- and flow chemistry as enabling technologies in organic synthesis. He received his industry-based Ph.D in Chemistry in 2017 under the supervision of Prof. John Murphy at the University of Strathclyde (U.K.) and Dr. Matthew John at GlaxoSmithKline (U.K.). His postdoctoral studies with Prof. Yasuo Norikane and Prof. Yoshitaka Hamashima at the National Institute of Advanced Industrial Science and Technology and the University of Shizuoka (Japan) specialized in photoredox catalysis and microwave flow chemistry. In addition to his authorship of 20 articles indexed by SCI which have been cited ~450 times, he has authored a book chapter, a patent, an industrial press release and various blogs/webinars. For a complete list of publications, see: http://www-oc.chemie.uni-regensburg.de/barham/page_417_en.php

https://scholar.google.co.uk/citations?user=fBgXhboAAAAJ&hl=en

Photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes with N-hydroxyphthalimide

Intermolecular olefin hydroamination is an efficient strategy to form C-N bonds and then construct high-value amines. Traditional olefin hydroamination methods mainly provide Markovnikov products. Thus, it is interesting and challenging to realize anti-Markovnikov olefin hydroamination.

In 2019, Yang’s group reported a visible-light-induced strategy to achieve N-OH bond cleavage of strained cyclobutanone oxime, which is able to activate the N-O bond directly to construct various cyano/gemdifluoroalkene-containing scaffolds via synergistic effects between visible light and phosphoranyl radical cation (Org. Lett. 2019, 21, 2658-2662). Recently, this group designed a visible-light photoredox-catalysed hydroamination of unactivated alkenes using N-hydroxyphthalimide (NHPI) to generate anti-Markovnikov product exclusively based on previous work (Scheme 1). The high versatility and mild conditions of this strategy allow a facile access to various amines using cheap and easily available reagents.

Scheme 1 Photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes with N-hydroxyphthalimide

Cyclohexene 1a and NHPI were chosen as model substrates. Optimization of reaction conditions shows that the highest yield (82%) could be obtained when using [Ir(dFCF₃ppy)₂dtbbpy]PF₆ and P(OEt)₃ as catalyst and MeCN as solvent at room temperature in 24 hours. A wide variety of unactivated alkenes could be tolerated, including cyclic and acyclic aliphatic olefins. Moreover, aliphatic olefins substituted with halogen or trimethylsilyl group could also provide the corresponding products in moderate yields (Table 2).

Table 2 Substrate Scope of Unactivated Olefinsa

^aConditions: olefin 1 (0.6 mmol, 3.0 equiv.), N‑hydroxyphthalimide (0.2 mmol, 1.0 equiv.), P(OEt)₃(0.3 mmol, 1.5 equiv.), [Ir(dFCF₃ppy)₂dtbbpy]PF₆ (2 mol%), MeCN (4 mL), 30 w blue LED, rt, argon atmosphere, 24 h, isolated yield.

Scheme 2. Control experiments

To gain mechanistic insights into this reaction, several control experiments were then carried out. Product formation was inhibited, when radical trapping agents such as 2,2,6,6-tetramethyl-1-piperdinyloxy (TEMPO) or benzoyl peroxide(BPO) were added under the standard reaction conditions, suggesting a radical process was involved possibly. On/off experiments demonstrate the corresponding product is formed upon irradiation, as well as in the dark, which supports a chain-propagation-type radical reaction (Scheme 2).

Scheme 3. potential energy surface of the plausible reaction pathway.

Furthermore, DFT calculations were performed to understand the catalytic mechanism.Initially, the [Ir(III)]isexcited to *[Ir(III)] under the irradiation of visible light. Then, NHPI and P(OEt)₃are able to oxidatively quench *[Ir(III)] via a PCET-mediated activation of O-H bond to afford the corresponding PINO radical. The key PINO radical undergoes a radical addition with P(OEt)₃ to deliver phosphoranyl radical I via TS1. Subsequently, N-centred radical intermediate II is formed through β-scission fragmentation of radical I, releasing triethyl phosphate. This step is calculated to possess a Gibbs free energy barrier of 7.8 kcal/mol and is highly irreversible with a driving force as large as 49.5 kcal/mol. In the presence of alkene, a radical addition occurs facilely to generate radical intermediate III. Finally, this resulting radical intermediate III promotes a hydrogen atom transfer from NHPI to deliver the desired product 3a and simultaneously regenerate the PINO radical, which would react with P(OEt)₃ to initiate another radical reaction. Notably, this chain-propagation-type mechanism agrees well with our control experiments and Schmidt’s results.
In summary, this group successfully developed a visible-light photoredox-catalysed hydroamination of alkenes using N-hydroxyphthalimide (NHPI) with exclusive anti-Markovnikov selectivity. High synthetic efficiency and mild reaction conditions would endow this protocol with potentials and flexibility in building various aliphatic amines.

Corresponding author

Professor Hua Yang at College of Chemistry and Chemical Engineering Central South University has a great interest in organic synthesis, asymmetric catalysis, visible-light catalysis and total synthesis of chiral drug molecules. Professor Yang developed an excellent organic catalyst-“Hua Cat”. And this patented reagent was commercialized by Sigma-Aldrich, and has been widely applied in asymmetric synthesis.

Hao-Yue Xiang, is an associate professor at College of Chemistry and Chemical Engineering, Central South University. Dr. Xiang received his PhD degree from Shanghai Institute of Materia Medica, Chinese Academy of Sciences and has made great progresses in the construction of heterocyclic compound library and the discovery of lead compounds. Dr Xiang’s current research focus is on fluorine chemistry, boron chemistry and radical chemistry.

Dr Kai Chen, at College of Chemistry and Chemical Engineering, Central South University.mainly work in computational organic chemistry, designof autocatalytic system, and computer-aided drug design. Chen received his PhD at Peking University in 2014, and then moved to South China University of Technology. Since 2019, Chen worked at Central South University.

Peng-Ju Xia, is lecturer of School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University.Xia mainly work inresearch field ofphotocatalytic/electrochemical organic catalysis and and 1, 3-dipole cyclization.