Jason Williams

Synlett
DOI: 10.1055/s-0037-1611527

Pyridines are valuable motifs in a number of bioactive and functional molecules. The chemoselective functionalization of these structures from stable and widely available starting materials is a meaningful goal. We have demonstrated selective formation of pyridyl radicals at any position (2-, 3-, 4-pyridyl), through the action of a reducing photoredox catalyst. These radicals readily engage alkenes to deliver high-value products. Alteration of the reaction medium has enabled the use of a diverse range of alkene subtypes in a highly divergent and chemoselective manner.1 Introduction2 Minisci-Type Pyridine Alkylation3 An Alternate Approach – Reductive Radical Formation4 Conjugate Addition of Pyridyl Radicals5 Radical Hydroarylation of Neutral and Rich Olefins6 Solvent-Based Chemoselectivity7 Summary and Outlook
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© Georg Thieme Verlag Stuttgart · New York

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Practical and regioselective amination of arenes using alkyl amines

Practical and regioselective amination of arenes using alkyl amines, Published online: 22 April 2019; doi:10.1038/s41557-019-0254-5

The blockbuster antibacterial drug linezolid is synthesized in 73 % yield from simple starting blocks by a convergent continuous flow sequence involving seven (7) chemical transformations.

Abstract

Herein, the blockbuster antibacterial drug linezolid is synthesized from simple starting blocks by a convergent continuous flow sequence involving seven (7) chemical transformations. This is the highest total number of distinct reaction steps ever performed in continuous flow without conducting solvent exchanges or intermediate purification. Linezolid was obtained in 73 % isolated yield in a total residence time of 27 minutes, corresponding to a throughput of 816 mg h⁻¹.

Goldilocks and the sensitivity screen: This work introduces a standardized, systematic, and user‐friendly tool to gain valuable information on the sensitivity of a reaction, with the aim of enhancing reproducibility and supporting troubleshooting.

Abstract

A systematic, user‐friendly assessment tool that delivers a clear overview of the sensitivity of reactions to key parameters is highly desirable. Herein, the development of such a method is described. The intuitive, standardized presentation of the results in a radar diagram enables the sensitivity of a protocol to be rapidly assessed. This method was applied to five different visible‐light‐mediated photochemical reactions, and the results were correlated to the underlying mechanism. Ultimately, we believe that this assessment will help to increase the uptake of new synthetic methods and their reproducibility.

The science publishing struggles are not calming down – just the opposite. As of yesterday, the entire University of California system is no longer subscribing to Elsevier journals. That’s a mighty big university system and a mighty big publisher; this is Godzilla vs. Megalon. The dispute is around two mighty big issues as well.

The first one, naturally, is cost. Subscribing to scientific journals has always been expensive (as in, for decades) but the prices have been climbing with great speed and vigor, to the point that many subscribers (especially academic ones) have been feeling the financial pain. Elsevier has been especially notable over the years (since they have so many journals under their umbrella) for pushing subscription plans that require institutions to take a wide range of journals simultaneously rather than a more a-la-carte model. The second issue is open access (OA). The business model of for-profit scientific publishing is the charge money to subscribe to the journal and for access to the archives. Some publishers make older papers open-access, but some don’t, and the definition of “older” varies widely. What the UC system wants to do is have all papers published out of their system be open-access, regardless of the journal they appear in. That’s a laudable goal, but it bangs right into the business model of the Elseviers of the world.

Open-access, of course, can only work if the authors pay costs up front, rather than having the subscribers pay to read the papers when they’re published. (And its that author-pays model that’s left the door open to a lot of shady operators at the low end of the business). The UC folks have apparently been trying to negotiate a deal on what those OA fees would be as part of a subscription agreement, and have been unable to come to terms. So they’ve walked away. Science says that negotiations were underway for eight months, which should have given everyone plenty of time to get their proposals on the table and play all the chicken anyone could want.

This is a big move. The California system accounts for about 10 per cent of all the scientific publications in the US, and they are definitely the largest US academic defection from Elsevier journals. Add this to the ongoing saga of Plan S in Europe, where several national funding agencies are going at the open-access issue with not only Elsevier, but every other for-profit scientific publisher, and it’s clear that begun, these OA wars have.

Benzophenone resurrected: The inherent reactivity of benzophenone upon photochemical excitation is used for the aliphatic C−H arylation reaction. The conditions are tolerant to a broad range of functional groups. Mechanistic experiments shed light on the dual role of the new photocatalyst of the metallaphotoredox family.

Abstract

A dual catalytic protocol for the direct arylation of non‐activated C(sp³)−H bonds has been developed. Upon photochemical excitation, the excited triplet state of a diaryl ketone photosensitizer abstracts a hydrogen atom from an aliphatic C−H bond. This inherent reactivity was exploited for the generation of benzylic radicals which subsequently enter a nickel catalytic cycle, accomplishing the benzylic arylation.

Photochemistry’s rise over the last ten years or so has been one of the big stories in organic chemistry, but there are still some difficulties with using it. The use of photoredox catalysts has brought blue light into a lot of fume hoods, which is certainly more selective and easier to use than than old ultraviolet sources – I will not miss mercury lamps, I can tell you. But the physical problem remains of getting enough photons poured into the reaction. It’s been demonstrated that with any of these sources that you only tend to get photoreactions in the outer few millimeters of the solution. Thus the flow photochemistry rigs that people have used, which are attempts to turn the entire reaction into a 2mm-deep layer around the light source – otherwise, you have to stir vigorously and just keep beaming away until things are finally done.

But physics to the rescue: there are other possibilities. Here’s a paper on one, triplet upconversion. Near-infrared light has far better ability to penetrate solutions (and tissue, for that matter). But taking advantage of that isn’t always easy. One of the reasons it’s penetrating is that it’s not be absorbed by anything along the way, and even when it is, light of those wavelengths isn’t packing enough energy to do a lot of work. It’s definitely not going to break or form any bonds by itself – absorption at those frequencies all goes into things like rotational or vibrational energy, so you’re just going to warm things up. And it’s not enough to send any of your favorite photoredox catalysts into an electronically excited state, either.

Triplet upconversion, though, is a way of pooling this energy and making something out of it. A sensitizer species is chosen that can usefully absorb the NIR light to provide a singlet excited state, and this decays to a triplet form. That interacts with another species (the “annihilator”), turning it into an excited triplet, and then two of those react with each other. One falls back to the ground state, and the other ends up boosted to yet a higher energy state, and then emits a photon with some oomph to it – you’ve upconverted near-IR light into the visible or even UV range by doing a two-for-one exchange. This is a big topic in many fields, not least solar energy production.

You have to pick your species carefully – the sensitizer, the annihilator, and eventual photoredox catalyst that absorbs that last photon – but what’s organic chemistry for if we can’t tune the properties of our molecules by changing their structures? This latest paper has gotten things to line up with a palladium octabutoxyphthalocyanine complex that absorbs down at 730nM, furanyldiketopyrrolopyrrole as the annhilator, and eosin as the eventual catalyst. Eosin is known to (for example) catalyze dehalogenation under blue-light conditions, and in this system it’ll do so under near-IR illumination. But you get comparable yields with the triplet-upconversion system while using a light source that’s only one-thousandth the power (!)

That’s because, physically, this would seem to be equivalent to setting off photochemical illumination sources, molecule-by-molecule, throughout most of the solution. Absorption tests showed that the NIR light was penetrating typical reaction solutions hundreds of times better than blue LED light, so that’s quite an improvement over trying to beat in the photons from the outside. Switching to a different (tetraphenyltetranaphthoporphyrin) palladium complex and a tetra-t-butylperylene annihilator (which emits up into the blue range), they were able to use the popular Ru(bpy)₃ catalyst. Interestingly, in one of the systems tried (a cyclobutane-forming reaction), the catalyzed system gave a 48% yield, while leaving out the Ru catalyst still gave a 38% one, so it appears that the excited singlet perylene species is enough by itself to get the reaction to go in some cases.

This idea would seem to have real applications for photochemical scaleup. The higher penetration is a great feature, as is the lower power consumption, and the excess heat of whole setup would be a lot easier to deal with (it’s a major problem as you go to larger rigs). Getting your photons this way might be the photochemistry of the future, if enough good absorber/annihilator pairs can be identified.

Mirror mirror on the wall, where has the other enantiomer gone? Catalyst 2 establishes an equilibrium between the two enantiomers 1 and ent‐1 in which one enantiomer prevails (up to 55 % ee). The deracemization is responsible for the enantioselective formation of 3‐cyclopropylquinolones from 3‐allyl‐substituted quinolones.

Abstract

3‐Allyl‐substituted quinolones undergo a triplet‐sensitized di‐π‐methane rearrangement reaction to the corresponding 3‐cyclopropylquinolones upon irradiation with visible light (λ=420 nm). A chiral hydrogen‐bonding sensitizer (10 mol %) was shown to promote the reaction enantioselectively (88–96 % yield, 32–55 % ee). Surprisingly, it was found that the enantiodifferentiation does not occur at the state of initial product formation but that it is the result of a deracemization event. The individual parameters that control the distribution of enantiomers in the photostationary state have been identified.

Lighting the (reaction) path: Photoredox and photocatalysis have recently provided fresh opportunities to expand the potential of organic synthesis. So far, innovation has mainly been driven by the quest for novel reactivities, often at the expense of a thorough mechanistic understanding. But these fields are now entering a more mature phase where the combination of experimental and mechanistic studies will play a dominant role in sustaining further innovation.

Abstract

The fast‐moving fields of photoredox and photocatalysis have recently provided fresh opportunities to expand the potential of synthetic organic chemistry. Advances in light‐mediated processes have mainly been guided so far by empirical findings and the quest for reaction invention. The general perception, however, is that photocatalysis is entering a more mature phase where the combination of experimental and mechanistic studies will play a dominant role in sustaining further innovation. This Review outlines the key mechanistic studies to consider when developing a photochemical process, and the best techniques available for acquiring relevant information. The discussion will use selected case studies to highlight how mechanistic investigations can be instrumental in guiding the invention and development of synthetically useful photocatalytic transformations.

Achieving the ‘flow’: The development of a continuous‐flow protocol for a Pd‐catalyzed formylation of (hetero)aryl bromides using carbon monoxide and hydrogen is described. The applicability of the continuous‐flow protocol is demonstrated on several (hetero)aryl bromide substrates. The intensified continuous‐flow process enables safe and scalable Pd‐catalyzed formylation using gases.

Abstract

A continuous‐flow protocol utilizing syngas (CO and H₂) was developed for the palladium‐catalyzed reductive carbonylation of (hetero)aryl bromides to their corresponding (hetero)aryl aldehydes. The optimization of temperature, pressure, catalyst and ligand loading, and residence time resulted in process‐intensified flow conditions for the transformation. In addition, a key benefit of investigating the reaction in flow is the ability to precisely control the CO‐to‐H₂ stoichiometric ratio, which was identified as having a critical influence on yield. The protocol proceeds with low catalyst and ligand loadings: palladium acetate (1 mol % or below) and cataCXium A (3 mol % or below). A variety of (hetero)aryl bromides at a 3 mmol scale were converted to their corresponding (hetero)aryl aldehydes at 12 bar pressure (CO/H₂=1:3) and 120 °C reaction temperature within 45 min residence time to afford products mostly in good‐to‐excellent yields (17 examples). In particular, a successful scale‐up was achieved over 415 min operation time for the reductive carbonylation of 2‐bromo‐6‐methoxynaphthalene to synthesize 3.8 g of 6‐methoxy‐2‐naphthaldehyde in 85 % isolated yield. Studies were conducted to understand catalyst decomposition within the reactor by using inductively coupled plasma–mass spectrometry (ICP–MS) analysis. The palladium could easily be recovered using an aqueous nitric acid wash post reaction. Mechanistic aspects and the scope of the transformation are discussed.