Metal‐Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing

Kloß, Florian; Neuwirth, Toni; Haensch, Veit G.; Hertweck, Christian

doi:10.1002/ange.201805961

Cited by 17 publications

(7 citation statements)

References 39 publications

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“…138.13, 137.10, 130.10, 129.67, 128.60, 127.12, 126.81, 52.11, 21.18. The spectral data matched those reported in the literature (Kloss et al, 2018). 151.36, 145.49, 137.06, 130.09, 128.63, 126.94, 126.85, 125.92, 52.11, 34.65, 31.34.…”

Section: Nicotinic Acid and 3-methoxyphenylboronic Acid (3as Figure 4 Entry 45)supporting

confidence: 85%

Synthesis of Biaryls via Decarbonylative Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of Carboxylic Acids

Li¹,

Ji²,

Qin³

et al. 2019

iScience

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Summary The biaryl motif is a building block in many drugs, agrochemicals, and materials, and as such it is highly desirable as a synthesis target. The state-of-the-art process for biaryl synthesis from ubiquitous carboxylic acids is decarboxylative cross-coupling involving loss of carbon dioxide (CO 2 ). However, the scope of these methods is severely limited, mainly due to specific substitution required to promote decarboxylation. The present report implements a decarbonylative version with loss of carbon monoxide (CO) that enables to directly engage carboxylic acids in a Suzuki-Miyaura cross-coupling to produce biaryls as a general method with high cross-coupling selectivity using a well-defined Pd(0)/(II) catalytic cycle. This protocol shows a remarkably broad scope (>80 examples) and is performed in the absence of exogenous inorganic bases. In a broader context, the approach shows promise for routine applications in the synthesis of biaryls by carefully controlled decarbonylation of prevalent carboxylic acids.

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Section: Nicotinic Acid and 3-methoxyphenylboronic Acid (3as Figure 4 Entry 45)supporting

confidence: 85%

Synthesis of Biaryls via Decarbonylative Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of Carboxylic Acids

Li¹,

Ji²,

Qin³

et al. 2019

iScience

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“…To gain more insight into the structure of the photoproduct, we scaled up the photoreaction in a flow reactor (Figure 2 A). [25a] Compared to the 1 H NMR spectrum of the educt ( 6 a ), the spectrum of the purified photoproduct lacks the signals of both methyl groups. Instead, a signal at δ=3.75 ppm indicates the presence of a new methylene group (Figure 2 B).…”

Section: Resultsmentioning

confidence: 98%

“…Moreover, MSMS experiments indicated that the resulting photoproduct has an unusually high stability, fragmenting only at very high energies (see Supporting Information). To gain more insight into the structure of the photoproduct, we scaled up the photoreaction in a flow reactor (Figure 2A) [25a] . Compared to the 1 H NMR spectrum of the educt ( 6 a ), the spectrum of the purified photoproduct lacks the signals of both methyl groups.…”

Section: Resultsmentioning

confidence: 99%

“…While investigating the suitability of various linker systems for a directed photochemical aryl coupling, [25] we noted an irregular behavior of an ether-linked bis-aryl substrate. Although methyl 4-(4-methylphenethoxy)benzoate (6 a) quickly lost its fluorescence on a thin-layer chromatography (TLC) plate upon irradiation (λ = 254 nm), a change that is indicative of a lightinduced conversion, [25c] high-resolution mass spectrometry (HRMS) revealed that the new compound differs from the expected biphenyl.…”

Section: Resultsmentioning

confidence: 99%

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A Photochemical Macrocyclization Route to Asymmetric Strained [3.2] Paracyclophanes

Haensch

Görls

Hertweck

2022

Chemistry A European J

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The intricate frameworks of paracyclophanes are an important target for synthesis since they are found in various chiral auxiliaries, solar cells, high-performance plastics, pharmaceuticals, and molecular machines. Whereas numerous methods exist for the preparation of symmetric paracyclophanes, protocols for the efficient synthesis of strained asymmetric scaffolds are limited. Here we report a remarkably simple photochemical route to strained [3.2]paracyclophanes starting from readily available educts. By way of NMR and Xray analyses, we discovered that UV-irradiation of an aromatic carboxylic ester tethered to a toluene moiety leads to the intramolecular formation of a new CÀ C bond, with loss of an alcohol. A systematic evaluation of the reaction conditions and substituents, as well as radical starter and triplet quenching experiments, point to a reaction mechanism involving an excited triplet state and hydrogen atom transfer. The new method proved to be robust and versatile enabling the synthesis of a range of cyclophanes with different substitutions, including an unusual diastereoisomer with two planar chiral centers, and thus proved to be a valuable addition to the synthetic toolbox.

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“…[157][158][159][160][161][162][163][164][165][166] Kloss recently reported a novel metal-free cross-coupling reaction, where two phenyl groups tethered by a sulfonamide linker can be fused in a single coupling product through irradiation by ultraviolet light with high regio-and chemoselectivity. [167,168] Haensch proposed an intramolecular photochemical mechanism involving a five-membered TS. Here, we present the calculation of a GS reaction coordinate for this photoreaction using pysisyphus as it is an example for a complex and computationally challenging reaction where three bonds are broken and one bond is formed.…”

Section: Intrinsic Reaction Coordinatementioning

confidence: 99%

pysisyphus: Exploring potential energy surfaces in ground and excited states

Steinmetzer

Kupfer

Gräfe

2020

Int J of Quantum Chemistry

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Predicting the energetics of chemical transformations requires localizing stationary points on a potential energy surface. While educts and products of a chemical reaction may be known, transition state optimization is challenging as good guesses may be unavailable. Extending stationary point searches to the excited state leads to additional difficulties as several states may be close in energy, requiring efficient state tracking. Here, we report the implementation of pysisyphus, an external optimizer, that allows localization of stationary points not only in the ground state but also for excited state by providing several state-tracking algorithms. pysisyphus offers all necessary tools for calculating reaction paths, starting from the optimization of the reactants, running chain-of-states methods such as the nudged elastic band or the growing string method with subsequent transition state optimization, and a concluding intrinsic reaction coordinate calculation.

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Metal‐Free Synthesis of Pharmaceutically Important Biaryls by Photosplicing

Abstract: A patent application on the synthetic method has been submitted.

Cited by 17 publications

References 39 publications

Synthesis of Biaryls via Decarbonylative Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of Carboxylic Acids

Synthesis of Biaryls via Decarbonylative Palladium-Catalyzed Suzuki-Miyaura Cross-Coupling of Carboxylic Acids

A Photochemical Macrocyclization Route to Asymmetric Strained [3.2] Paracyclophanes

pysisyphus: Exploring potential energy surfaces in ground and excited states

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