Organic Chemistry Frontiers Blog

Diborons can directly be transformed into diverse organoboron compounds of high synthetic significance via a variety of transition metal-catalyzed and -free borylation reactions. Besides commonly used symmetrical diborons such as (pin)B–B(pin), recently attention has also been paid to the use of unsymmetrical ones, especially those having different boron-Lewis acidities.

Numerous attention have been directed toward developing unsymmetrical diborons with different boron-Lewis acidities including (pin)B–B(aam) (aam = anthranilamidato), (neop)B–B(dan) (dan = naphthalene-1,8-diaminato) and (pin)B–B(mdan) (mdan = N,N′-dimethyl-naphthalene-1,8-diaminato), and their application in catalytic borylation reactions via σ-bond metathesis as a key elementary step; palladium-catalyzed Miyaura–Ishiyama-type borylation of aryl halides and the copper-catalyzed internal-selective hydroboration of terminal alkynes show the synthetic versatility of (pin)B–B(aam).

Recently, the group of Hiroto Yoshida from Hiroshima University has demonstrated that (pin)B–B(aam) can also be catalytically activated by oxidative addition to a platinum complex, leading to syn-diboration of terminal alkynes, and that a highly electron-deficient triarylphosphine developed by Korenaga, P(BFPy)₃, is effective for regiocontrol (Figure 1).

Figure 1 Pt-catalyzed diboration of alkynes with (pin)B–B(aam)

A broad substrate scope of the regioselective diboration has been demonstrated (Figure 2): a variety of aromatic and aliphatic terminal alkynes bearing an electron-donating or electron-withdrawing substituent smoothly underwent the diboration to afford the respective products in high yields without damaging the reactive functionalities. Internal alkynes participating in this reaction also gave syn-products with a high regiocontrol, whereas the reaction of 2-octyne (2x) led to the formation of a mixture of regioisomers (3x and 3′x). Finally, a conjugated diene (4) was also readily transformable into a 1,4-diborated product (5) in a stereoselective fashion.

Figure 2 Substrate scope of the diboration

The synthetic utility of the resulting diborylalkene was demonstrated by site-selective cross-coupling to construct a triarylalkene efficiently (Figure 3). In the plausible catalytic cycle, the present diboration could be initiated by the oxidative addition of the boron–boron bond of 1 to a Pt(0) catalyst (Figure 4). The resulting oxidative adduct (8) then accepts the insertion of an alkyne at the Pt–B (pin) bond and/or –B(aam) bond to provide an alkenyl platinum intermediate (9 and/or 9′), which finally affords the diboration product (3) through reductive elimination.

Figure 3 Chemoselective cross-coupling of the diboration product

Figure 4 A plausible catalytic cycle for the diboration

(pin)B–B(aam) with different boron-Lewis acidities can be activated by oxidative addition to a platinum(0) complex, leading to regio- and stereo-selective diboration of unsaturated carbon linkages including terminal alkynes, internal alkynes and a conjugated diene. Moreover, the use of a highly electron-deficient triarylphosphine ligand, P(BFPy)₃, is indispensable for the regiocontrol, and electron-deficiency in ligands has been proven to be closely correlated with the regioselectivity.

Corresponding Author:

Hiroto Yoshida graduated from Kyoto University in 1996 and received his Ph.D. from Kyoto University under the supervision of Professors Tamejiro Hiyama and Eiji Shirakawa in 2001. He then became an Assistant Professor in 2001 and an Associate Professor in 2006 at Hiroshima University. From 2020, he has been a Full Professor at the same University. His research interests include (1) development of new methods for synthesis of main group organometallics containing boron, tin or silicon, (2) carbon–carbon bond-forming reactions with the main group organometallics, and (3) aryne-based organic synthesis. He is the author of more than 110 articles indexed by SCI and cited more than 5200 times with an index H = 45.

Web of Science ResearcherID: B-7954-2011 (https://publons.com/researcher/1189090/hiroto-yoshida/)

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.

We are delighted to share with you a collection of articles from Organic Chemistry Frontiers to showcase the recent development in asymmetric synthesis.

You can read these articles for free until 30^th April.

Multi-catalyst promoted asymmetric relay reactions
Qiu-Ju Liang, Yun-He Xu and Teck-Peng Loh
Org. Chem. Front., 2018,5, 2765-2768
http://dx.doi.org/10.1039/C8QO00604K

Total synthesis of natural products via iridium catalysis
Changchun Yuan and Bo Liu
Org. Chem. Front., 2018,5, 106-131
http://dx.doi.org/10.1039/C7QO00664K

Lu’s [3 + 2] cycloaddition of allenes with electrophiles: discovery, development and synthetic application
Yin Wei and Min Shi
Org. Chem. Front., 2017,4, 1876-1890
http://dx.doi.org/10.1039/C7QO00285H

Catalytic asymmetric synthesis of hetero-substituted oxindoles
Renato Dalpozzo
Org. Chem. Front., 2017,4, 2063-2078
http://dx.doi.org/10.1039/C7QO00446J

Asymmetric Diels–Alder cycloadditions of benzofulvene-based 2,4-dienals via trienamine activatio
Jing-Fei Yue, Guang-Yao Ran, Xing-Xing Yang, Wei Du and Ying-Chun Chen
Org. Chem. Front., 2018,5, 1284-1287
http://dx.doi.org/10.1039/C8QO00653A

Diastereoselectivity in a cyclic secondary amine catalyzed asymmetric Mannich reaction: a model rationalization from DFT studies
Siwei Shu, Zhao Liu, Yukui Li, Zhuofeng Ke and Yan Liu
Org. Chem. Front., 2018,5, 2148-2157
http://dx.doi.org/10.1039/C8QO00424B

Copper-catalyzed asymmetric hydroboration of 1,3-enynes with pinacolborane to access chiral allenylboronates
Hui Leng Sang, Songjie Yu and Shaozhong Ge
Org. Chem. Front., 2018,5, 1284-1287
http://dx.doi.org/10.1039/C8QO00167G

Synthesis of trans-disubstituted-2,3-dihydrobenzofurans by a formal [4 + 1] annulation between para-quinone methides and sulfonium salts
Ying Zhi, Kun Zhao, Carolina von Essen, Kari Rissanen and Dieter Enders
Org. Chem. Front., 2018,5, 1348-1351
http://dx.doi.org/10.1039/C8QO00008E

1,6-Conjugated addition-mediated [4 + 1] annulation: an approach to 2,3-dihydrobenzofurans
Yang Wang, Yan Qiao, Donghui Wei and Mingsheng Tang
Org. Chem. Front., 2018,5, 623-628
http://dx.doi.org/10.1039/C7QO00846E

Computational study on NHC-catalyzed enantioselective and chemoselective fluorination of aliphatic aldehydes
Lina Liu, Zhenbo Yuan, Rui Pan, Yuye Zeng, Aijun Lin, Hequan Yao and Yue Huang
Org. Chem. Front., 2017,4, 1987-1998
http://dx.doi.org/10.1039/C7QO00436B

Asymmetric synthesis of CF₃– and indole-containing tetrahydro-β-carbolines via chiral spirocyclic phosphoric acid-catalyzed aza-Friedel–Crafts reaction
En Xie, Abdul Rahman and Xufeng Lin
Org. Chem. Front., 2017,4, 1407-1410
http://dx.doi.org/10.1039/C7QO00229G

Highly enantioselective nitro-Mannich reaction of ketimines under phase-transfer catalysis
Bin Wang, Tong Xu, Lei Zhu, Yu Lan, Jingdong Wang, Ning Lu, Zhonglin Wei, Yingjie Lin and Haifeng Duan
Org. Chem. Front., 2017,4, 1266-1271
http://dx.doi.org/10.1039/C7QO00124J

Asymmetric synthesis of trifluoromethyl-substituted 3,3′-pyrrolidinyl-dispirooxindoles through organocatalytic 1,3-dipolar cycloaddition reactions
Wei-Jie Huang, Qing Chen, Ning Lin, Xian-Wen Long, Wei-Gao Pan, Yan-Shi Xiong, Jiang Weng and Gui Lu
Org. Chem. Front., 2017,4, 472-482
http://dx.doi.org/10.1039/C6QO00723F

The synthesis of unsymmetric diamides through Rh-catalyzed selective C–H bond activation of amides with isocyanates
Xiaoli Yu, Duo-Sheng Wang, Zhaojun Xu, Bobin Yang and Dawei Wang
Org. Chem. Front., 2017,4, 1011-1018
http://dx.doi.org/10.1039/C6QO00793G