Organic Chemistry Frontiers Blog

Cinammylamines and 3,3-diarylallylamines represent an important class of molecules for drug discovery, and can serve as intermediates thanks to their olefin functionality which can lead to further elaboration. However, there are numerous challenges in the application of organometallic methods to synthesize highly-functionalized 3,3-diarylallylamines. Historically these reactions required protecting groups, with the protecting group both limiting substrate decomposition as well as improving regioselectivity by imparting a directing effect (Scheme 1a). Recent efforts have established feasibility for direct free amine-directed reactions that avoid the need for protection and deprotection, but which suffer from selectivity issues due to the presence of different Pd species which promote different reaction pathways (Scheme 1b). Notably, β-protio allylamines undergo both Heck reactions to give trans-functionalised products as well as C–H activation to give the cis-functionalised products as mixtures. Meanwhile, β-substituted allylamines preferentially undergo a γ,γ’-diarylation reaction rather than the simple γ-monoarylation due to the reactivity of the in situ-formed Pd nanoparticles responsible for the reaction.

To solve the stereoselectivity challenge, the group of Prof. Michael C. Young at the University of Toledo has unveiled a new protocol for selective Mizoroki–Heck arylation of unprotected cinnamyl and allylamines (Scheme 1c). Compared with previous work, a pivotal change was to exploit an oxidative Heck reaction using aryl boronic acid as the coupling partner. By using the aryl boronic acid, the conditions could be made sufficiently mild to essentially shut down the C–H activation pathway, giving >20:1 selectivity in most cases.

Scheme 1. Approaches for the Mizoroki–Heck reaction of allyl and cinnamylamines.

The researcher team demonstrated the broad applicability of their approach by successfully synthesizing a range of unsymmetrical 3,3-diarylallylamine derivatives with overall good structural diversity. The method presented by the research team not only improves the overall synthetic process but also offers a pathway to access a wider range of drug molecules in a more cost-effective manner. By comparing their reimagined Mizoroki–Heck reaction with existing methodologies utilizing protected amine substrates and aryl iodides, the researchers highlighted the numerous advantages of their approach. With improved atom and step economy, higher selectivity, and broader substrate scope, their method represents a significant advancement in the field of organic synthesis.

Scheme 2. Substrate scope of aryl boronic acid coupling partners in the E-selective Mizoroki–Heck reaction on cinnamylamines. Reactions were performed using amine (0.15 mmol) and aryl boronic acid (0.30 mmol) under air atmosphere. All reactions were performed in triplicate and the average isolated yields reported. E/Z ratios were determined from the crude ¹H NMR using 1,1,2,2-tetrachloroethane as internal standard. ^a Solvent was 0.9 mL HFIP:0.3 mL AcOH. ^b Solvent was 4.0 mL AcOH. ^c Reaction was performed under 1 atm of O₂.

The researchers examined electron-deficient carbonyl-containing compounds with various functional groups, such as esters, ketones, aldehydes, amides, and nitriles (Scheme 2). The reaction proceeded successfully for all these compounds, and the nitrile group remained intact without undergoing hydrolysis, unlike in previous harsher conditions using a different coupling partner. The reactions generally exhibited high E-selectivity, with the Z-product undetectable in several cases. The researchers also explored electron-poor substrates containing fluorides and bromides, although the bromide compound had a lower yield. The recovery of the starting amine was reasonably high, and analysis revealed that the low yield of the bromide compound was due to a complex mixture of products resulting from Suzuki-Miyaura cross-coupling. Conjugated systems and electron-rich groups on the arene were also compatible with the reaction. Additionally, a coupling partner with both electron-withdrawing and donating groups yielded the desired product without the formation of the Z-isomer.

Scheme 3. Substrate scope of cinnamylamine coupling partners in the E-selective Mizoroki–Heck reaction on cinnamylamines. Reactions were performed using amine (0.15 mmol) and phenyl boronic acid (0.30 mmol) under air atmosphere. All reactions were performed in triplicate and the average isolated yields reported. E/Z ratios were determined from the crude ¹H NMR using 1,1,2,2-tetrachloroethane as internal standard. ^a Solvent was 0.9 mL HFIP:0.3 mL AcOH. ^b Solvent was 4.0 mL AcOH. ^c Reaction was performed under 1 atm of O₂.

In the investigation of amine substrate scope, various secondary amines were found to be viable substrates (Scheme 3). This included secondary amines with α-tertiary, α-secondary, and α-primary aliphatic substituents. Although cyclopropylamine showed low reactivity, introducing a methylene spacer enabled the generation of a reactive substrate. When targeting the addition of phenyl groups to the substrate, a spot check revealed a strong preference for the E-product over the Z-product (>20:1 ratio) when using 4-ethoxycarbonyl phenylboronic acid as the coupling partner. Sterically congested bornylamine derivatives, aliphatic amines with aromatic or heteroaromatic groups, and saturated heterocycles such as tetrahydrofurfuryl could also be successfully converted to the desired products. Similar E/Z-selectivity was observed when using 4-ethoxycarbonyl phenylboronic acid as the coupling partner for these substrates. Amino acid-derived substrates yielded good yields of the product, with complete E-selectivity observed based on the crude reaction mixture’s 1H NMR. The stereochemistry of the amino ester was confirmed to have >99% enantiomeric excess (ee) based on Mosher amide analysis. Electron-rich furfurylamine-derived substrates were viable, whereas pyridines did not show reactivity. N-tert-butyl-(4,4-dimethylamino)cinnamylamine, which decomposed under previous harsh conditions, could be converted to the desired product under the milder conditions, albeit with decreased Z/E-selectivity. Furthermore, an amine derived from podophyllotoxin, containing several oxygen-based functional groups, successfully participated in the reaction. Control of β-hydride elimination was achieved when a 3-(phenethyl)-substituted allylamine was used, resulting in the formation of the β,γ-unsaturated allylamine product. Expanding the scope to less and more-substituted substrates, primary cinnamylamine was functionalized with the desired product in 68% yield. The need for CO₂ to prevent amine decomposition during the reaction, as in previous work, was not necessary under the milder conditions. Acyclic and cyclic amine substrates could be functionalized with good yields, demonstrating the versatility of this modified approach to amine functionalization. Trans-selectivity was observed when unsymmetrical 3,3-diarylallylamines were used as substrates.

Figure 1. Proposed catalytic cycle.

Young and his coworkers propose a preliminary mechanistic understanding of the Mizoroki-Heck reaction using aryl boronic acids as coupling partners (Figure 1). They suggest that the active catalyst is formed through the incomplete reduction of Pd(OAc)₂ to Pd nanoparticles (NPs) ligated by allylamine. Transmetallation with activated aryl boronic acid occurs through ligand exchange, followed by C–Pd bond insertion across the alkene. This forms an organic metallic intermediate, which undergoes β-hydride elimination to yield the desired product coordinated to the nanoparticle. The catalyst is regenerated through oxidation of the metal-hydride in the presence of molecular oxygen and acetic acid, while the functionalized amine is exchanged for unfunctionalized substrate. Further investigations are needed to confirm and refine this proposed mechanism.

The developed method not only demonstrates compatibility with 1°, 2°, and 3° amines but also showcases its ability to facilitate chain walking reactions. Moreover, it provides practical and scalable solutions to address longstanding challenges in drug synthesis. The implications of this research extend far beyond the laboratory, as it opens up new possibilities for pharmaceutical development. By harnessing the power of the Mizoroki–Heck reaction with aryl boronic acids, researchers can now expedite the synthesis of 3,3-diarylallylamines, ultimately accelerating the discovery and development of novel drugs targeting G protein-coupled receptors. This breakthrough has the potential to revolutionize the pharmaceutical industry, improving drug accessibility and affordability for patients worldwide. Its impact on drug synthesis and the potential for transforming the pharmaceutical landscape cannot be overstated. This innovative approach sets the stage for further advancements in the field and offers hope for the discovery of new and more effective medications.

Prof. Michael Christopher Young

Michael Young was born in King, N.C. (approximately where Mayberry of Andy Griffith fame would be if it were real). He always knew he wanted to be a scientist, and while studying at Western Carolina University decided that chemistry was a better career choice than trying to genetically engineer Pokémon. He began his independent career after a PhD (2014) at UC – Riverside with Prof. Richard Hooley and a postdoc (2014 – 2016) at UT – Austin with Prof. Guangbin Dong. His group is interested in developing more sustainable routes to biologically relevant compounds, with a particular interest in G-protein coupled receptor-agonists and antagonists.

Olutayo Nathanael Farinde

Olutayo Nathanael Farinde is a PhD student currently working in the Young lab at The University of Toledo. He holds a BS degree in Analytical and Environmental Chemistry from the University of Ibadan, Nigeria, which he completed in 2019. At The University of Toledo, Nate’s research focuses on the area of C–H functionalization and alkene functionalization of amines. He is interested in developing novel synthetic methods which can be used to synthesize biologically-active molecules. When he’s not at the bench, Nate enjoys learning new computational methods.

Dr. Satheesh Vanaparthi

Satheesh Vanaparthi was born and raised in Telangana, India. He obtained his BSc and MSc from Osmania University and later received his PhD from Indian Institute of Technology – Guwahati, India (Prof. T. Punniyamurthy, 2019). After a postdoc at the Technion-Israel Institute of Technology, Israel (Prof. Graham de Ruiter), Satheesh moved to The University of Toledo, USA to work with the Young lab where he is currently working on rhodium and palladium-catalysed transformations.

Kendra Kumar Shrestha

Kendra hails from Nepal. He obtained his BSc and MSc from Tribhuvan University. In 2019, he moved to The University of Toledo to pursue his Ph.D. with Prof. Michael C. Young where he is working on palladium-catalysed selective functionalisations of aminees as wel as cycloaddition reactions exploiting organo-supramolecular catalysis.

Carmen Rose Rhinehalt

Carmen is a chemistry major with a passion for how and why the world works. She is currently working on the deuteration of benzoic acid derivatives and would like to transfer everything she has learned in the lab and chemistry to the development of cosmetic products. In her free time, Carmen likes to try new recipes and bake all kinds of sweets!

Dr. Vinod Gokulkrishna Landge

Vinod obtained his PhD from the National Chemical Laboratory in Pune, India, in 2019, where worked with Prof. Ekambaram Balaraman. He then joined the Young lab where he worked extensively on Pd and organocatalysis. He current works as a Process Development Scientists at Piramal Pharma Solutions.

Cycloisomerization of 1,n-enynes provides a variety of cyclic compounds via multiple bond cleavage and formation. Since these processes are generally induced by alkyne π-bond activation, transition metal catalysts have been well studied for the selective construction of these cyclic products (Scheme 1A). However, transition metal catalysts can be hardly applied to electron-deficient alkynes having acyl groups or other relative strong electron-withdrawing groups. Since acyl groups can be converted to various functional groups, it is desirable to develop catalyst systems applicable to such starting materials. In addition, the activation of alkynes via carbonyl groups can lead to the construction of new skeletons and thus systematic studies on the cycloisomerization of enynones is an important research project.

Recently, as a further expansion of BF₃·MeCN-catalyzed cycloisomerization of 7-en-2-ynones into six-membered cyclic dienes (Org. Lett., 2020, 22, 4063), the group of Prof. Akio Saito from Tokyo University of Agriculture and Technology have developed the aluminum halide-mediated formation of the halogenated bicyclo[3.1.0]hexanes from the same substrates (Scheme 1B).

Scheme 1: Cycloisomerization of enynes and enynones.

The aluminum halide-mediated cycloisomerization of 7-en-2-ynones proceeded at room temperature to give the corresponding the halogenated bicyclo[3.1.0]hexanes in 45-96% yields. Furthermore, quenching with NCS (N-chlorosuccinimide) before the usual work-up afforded the dichloroketone product in good yield through the chlorination of the aluminum enolate intermediate (Scheme 2).

On the basis of DFT calculations and experimental data, we proposed the mechanism including the common zwitterionic intermediate with six-membered cyclic dienes (Scheme 1B), and concluded that different bond lengths between group 13 elements and halogens lead to cycloisomerization into different products.

Scheme 2: Aluminum halide-mediated cycloisomerization of 7-en-2-ynones into the halogenated bicyclo[3.1.0]hexanes

Corresponding author:

Akio SAITO Professor

Akio SAITO received his Ph.D. degrees from Tokyo University of Pharmacy and Life Sciences in 2003. From 2001 to 2005, he joined as a Research Associate in the group of Professor Takeo Taguchi at the same university. From 2005 to 2012, he worked as an Assistant Professor with Professor Yuji Hanzawa at Showa Pharmaceutical University. In 2012, he moved to the present university as an Associate Professor. Since 2021, he was appointed to the present position. His current research interests include the development of domino reactions and multicomponent reactions based on iodine and other non-metallic elements chemistry. He is the author of more than 96 articles indexed by WoS and cited more than 2400 times with an h-index = 31.

https://www.webofscience.com/wos/author/record/C-1270-2013

Carbon–phosphorus (C–P) bond cleavage reactions are one of the most important transformations because organophosphorus compounds are widely utilized as pharmaceuticals, phosphine ligands, organocatalysts, and functional materials. Therefore, C–P bond cleavage reactions have been developed using various approaches such as radicals produced using photolysis or peroxides, reduction using transition metal catalysts and alkali metals, and via P(V) intermediates (Scheme 1A). However, these synthetic methodologies require relatively harsh conditions, leading to low functional group tolerance. In addition, they require the use of precious transition metals and the formation of highly polarized C–P bonds in activated species.

Recently, the group of Prof. Shinobu Takizawa and Mohamed S. H. Salem as a collaborator from SANKEN, Osaka University have developed a metal-free C(aryl)–P bond cleavage reaction starting via the reaction of triarylphosphines and alkynyl esters using water as a nucleophile and electrophile to yield propanoic acid/phosphine oxide derivatives (Scheme 1B), which have applications in pharmaceuticals and catalysis.

Scheme 1: Methods of C(aryl)–P bond cleavage.

The reaction proceeded under mild and neutral conditions (10 °C, 24 h, H₂O as a nucleophile) without using any metal catalyst, which is consistent with the concepts of green chemistry. In addition, they have carried out the full optimization of the reaction system to obtain high yields (up to 98%). The scopes of phosphine reagents and activated alkynes were investigated under the optimal conditions to disclose a broad spectrum with high yields in most of the cases.

Takizawa, Salem and coworkers have complemented their experimental work with computational calculations to understand and verify their proposed reaction mechanism. DFT calculations and some control experiments using (allenic esters, or vinyl ketone instead of propiolate esters), and (D₂O, or H₂¹⁸O instead of water) indicated that the rapid formation of hydroxy-λ⁵-phosphane as a key intermediate plays a crucial role in smooth C(aryl)–P bond cleavage (Scheme 2).

Scheme 2: The proposed reaction mechanism of rapid C(aryl)–P bond cleavage and 1,2-aryl migration to the Michael acceptor via a hydroxyl-λ5-phosphane intermediate.

The development of this new synthetic method using metal-free conditions is crucial for the development of greener chemical practices. Further, the understanding of the mechanism of these synthetic reactions has a key value in expanding their applications, as well as the synthesis of industrially important phosphorus-containing molecules.

Author:

Mohamed S. H. SALEM
Osaka University

Mohamed Salem is a Ph.D. student in the SANKEN at Osaka University (Japan). He received his M.Sc. in Medicinal Chemistry at the Faculty of Pharmacy, Suez Canal University in 2017. Subsequently, he received a Japanese Government Scholarship (MEXT) to study for a Ph.D. in 2019 with Professor Hiroaki SASAI and Shinobu TAKIZAWA. The research field of Mohamed Salem is asymmetric catalysis using first-row organometallic complexes such as Cobalt and Vanadium and the study and development of new green and cutting edge electrochemical transformations.

https://orcid.org/0000-0002-8919-095X
https://www.researchgate.net/profile/Mohamed-Salem-39

Corresponding Author:

Shinobu TAKIZAWA 滝澤　忍
Osaka University

Shinobu TAKIZAWA is an associate professor in the Institute of Scientific and Industrial Research (SANKEN) and AI Research Center at Osaka University (Japan). He received his Ph.D. in chemistry at the Graduate School of Pharmaceutical Science, Osaka University in 2000. From 2006 to 2008 he did postdoctoral studies at The Scripps Research Institute (USA) with Professor Dale L. Boger. The research field of Professor Shinobu TAKIZAWA is asymmetric catalysis using either organo-or organometallic catalysts and the study and development of new green and cutting edge chemical transformations either electrochemically or photochemically guided by AI and ML. He is the author of more than 118 articles indexed by SCI and cited more than 4000 times with an index H = 38.

https://orcid.org/0000-0002-9668-1888

Moving from single molecules to dynamic molecular systems and responsive materials requires control of molecules that can induce motion and enable machine-like functions. Light-driven rotary molecular motors are compounds that can undergo unidirectional rotational motion, using light as a power source. Their 360° rotation cycle is driven by the successive interconversion of four unique isomers of the motor, undergoing two energetically uphill photochemical E-Z isomerisation (PEZ) steps and two downhill thermal helix inversion (THI) steps. Thanks to this unidirectional rotational behaviour, molecular motors can be used to produce useful physical work on the nanoscale – finding a multitude of applications in fields of catalysis, smart materials, and nanotechnology. 

The physical characteristics governing the rotational motion of molecular motors include their rotational speed, the wavelength of light which the motors can consume to power their motion, and their photochemical efficiency (or quantum yield). Investigating these characteristics will allow us to understand the dynamic behaviour of molecular motors – and ultimately how to tune this behaviour – will allow molecular motors to be used as tuneable actuators and  molecular machines. 

Figure 1: A) Oxindole-based molecular motors functionalised on the upper half or lower half of the motor scaffold, with either cyano or methoxy groups; B) Unidirectional rotation cycle of the molecular motors, consisting of two photochemical E-Z isomersations (PEZ) and two thermal helix inversions (THI).

Molecular motors containing the heterocyclic oxindole moiety were discovered in 2019 and it was found that they have desirable rotational properties – they can be driven with benign visible light, and they can be synthesised easily and quickly, relative to traditional hydrocarbon-based molecular motors. Due to these advantages, more research into the functionalisation of oxindole-based motors could help to further improve these promising motors.

Recently, researchers in the group of Ben Feringa have carried out a systematic benchmark study on oxindole-based molecular motors; through functionalisation with cyano or methoxy groups at three different positions along the motor backbone, the rotational properties of oxindole-based molecular motors can be fine-tuned (Figure 1).

By functionalising the motors at these positions (Figure 1, R¹, R² and R³), the wavelength of light used to power the molecular motors can be further red-shifted into the visible region of the electromagnetic spectrum, which is a lower energy source of light. In some cases, the use of longer wavelengths even improved the photochemical efficiency of the motors. In addition, the photochemical quantum yields of the motors could be tuned, with electron withdrawing cyano groups improving the quantum yields of the photochemical isomerisation steps of the motor rotation cycle.

The favourable properties fulfilled by the oxindole-based molecular motors investigated in this work show the great potential of these molecules to be used as viable visible light-driven actuators, which can be fine-tuned to accurately control nanoscale motion in light responsive systems.

Corresponding author:

Professor Ben Feringa

Ben Feringa obtained his PhD degree in 1978 at the University of Groningen in the Netherlands under the guidance of Prof. Hans Wynberg. After working as a research scientist at Shell he was appointed full professor at the University of Groningen in 1988 and named the distinguished Jacobus H. van’t Hoff Professor of Molecular Sciences in 2004. He was elected foreign member of the American Academy of Arts and Sciences, and the Royal Society and is member of the Royal Netherlands Academy of Sciences. His research interests include stereochemistry, organic synthesis, asymmetric catalysis, molecular switches and motors, photopharmacology, self-assembly and nanosystems.

Indian scientist, Dr Harapriya Rath and her collaborator Dr. Dandamudi Usharani experimentally isolated and theoretically supported the first ever s-aromatic doubly N-confused porphyrinoid. Unique π-reconstructions owing to sequential C-oxygenation of N-confused N-methyl pyrrole rings leading to the genesis of 18π aromatic doubly N-confused monooxo porphyrinoid, 16π antiaromatic doubly N-confused diioxo porphyrinoid and σ-aromatic doubly N-confused tetraoxo isophlorinoid via chemical transformation(s) of doubly N-confused porphodimethene.

Corresponding Author:

Harapriya Rath received her PhD degree from the Indian Institute of Technology, Kanpur, India on the Nonlinear Optical studies of Core-modified Aromatic Expanded porphyrinoids under the supervision of Prof. T. K. Chandrashekar in 2006. In 2007, she joined the group of Prof. Hiroshi Shinokubo at the Kyoto University, Japan as JSPS Postdoctoral fellow and focused on the subject of Möbius aromaticity (antiaromaticity) and excited state aromaticity of metallated all-aza expanded porphyrinoids. In 2009, she moved to Prof. Richard EP Winpenny’s lab at the University of Manchester, United Kingdom as a Royal Society Newton International postdoctoral fellow focusing on hybrid Organic-Inorganic Rotaxanes. In 2012, she started an independent academic career at Indian Association for the Cultivation of Science, Kolkata, India as an Assistant professor and Ramanujan Fellow. Since 2017, she is Associate Professor in the School of Chemical Sciences, IACS, Kolkata, India.