Fluorine in Flow

Science

A Unified Flow Strategy for the Preparation and Use of Trifluoromethyl-Heteroatom Anions

M. Spennacchio,^† M. Bernús,^† J. Stanić,^† D. Mazzarella, M. Colella, J. J. Douglas, O. Boutureira & T. Noël*

Science 2024, 385, 991–996 (DOI: 10.1126/science.adq2954)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-3bqt6) 🔓

The trifluoromethyl group (CF₃) is a key functionality in pharmaceutical and agrochemical development, greatly enhancing the efficacy and properties of resulting compounds. However, attaching the CF₃ group to heteroatoms such as sulfur, oxygen, and nitrogen poses challenges because of the lack of general synthetic methods and reliance on bespoke reagents. Here, the authors present a modular flow platform that streamlines the synthesis of heteroatom-CF₃ motifs. The method uses readily available organic precursors in combination with cesium fluoride as the primary fluorine source, facilitating the rapid generation of N-trifluoromethyl(R) [NCF₃(R)], SCF₃ (trifluoromethylthio), and OCF₃ (trifluoromethoxy) anions on demand without reliance on perfluoroalkyl precursor reagents. This strategy offers a more environmentally friendly synthesis of trifluoromethyl(heteroatom)–containing molecules, with the potential for scalability in manufacturing processes facilitated by flow technology.

Stereodivergent Access to Non-Natural α-Amino Acids via Enantio- and Z/E-Selective Catalysis

P. Li, E. Zheng, G. Li, Y. Luo, X. Huo, S. Ma* & W. Zhang*

Science 2024, 385, 972–979 (DOI: 10.1126/science.ado4936)

The precise control of Z and E configurations of the carbon-carbon double bond in alkene synthesis has long been a fundamental challenge in synthetic chemistry, even more pronounced when simultaneously striving to achieve enantioselectivity [(Z,R), (Z,S), (E,R), (E,S)]. Moreover, enantiopure non-natural α-amino acids are highly sought after in organic and medicinal chemistry. In this study, the authors report a ligand-controlled stereodivergent synthesis of non-natural α-quaternary amino acids bearing trisubstituted alkene moieties in high yields with excellent enantioselectivity and Z/E selectivities. This success is achieved through a palladium/copper–cocatalyzed three-component assembly of readily available aryl iodides, allenes, and aldimine esters by simply tuning the chiral ligands of the palladium and copper catalysts.

Nature

Reductive Alkyl-Alkyl Coupling from Isolable Nickel-Alkyl Complexes

S. Al Zubaydi, S. Waske,^‡ V. Akyildiz,^‡ H. F. Starbuck, M. Majumder, C. E. Moore, D. Kalyani* & C. S. Sevov*

Nature 2024 (DOI: 10.1038/s41586-024-07987-9)

The selective cross-coupling of two alkyl electrophiles to construct complex molecules remains a challenge in organic synthesis. Known reactions are optimized for specific electrophiles and are not amenable to interchangeably varying electrophilic substrates that are sourced from common alkyl building blocks, such as amines, carboxylic acids, and halides. These limitations restrict the types of alkyl substrates that can be modified and, ultimately, the chemical space that can be explored. Here, the authors report a general solution to these limitations that enables a combinatorial approach to alkyl-alkyl cross-coupling reactions. This methodology relies on the discovery of unusually persistent Ni(alkyl) complexes that can be formed directly by oxidative addition of alkyl halides, redox-active esters, or pyridinium salts. The resulting alkyl complexes can be isolated or directly telescoped to couple with a second alkyl electrophile, which represent cross-selective reactions that were previously unknown.

Synthesis of Non-Canonical Amino Acids through Dehydrogenative Tailoring

X. Gu,^† Y.-A. Zhang,^† S. Zhang, L. Wang, X. Ye, G. Occhialini, J. Barbour, B. L. Pentelute & A. E. Wendlandt*

Nature 2024 (DOI: 10.1038/s41586-024-07988-8)

Amino acids are essential building blocks in biology and chemistry. While nature relies on a small number of amino acid structures, chemists desire access to a vast scope of structurally diverse analogs. The selective modification of amino acid side-chain residues represents an efficient strategy to access non-canonical derivatives of value in chemistry and biology. While semi-synthetic methods leveraging the functional groups found in polar and aromatic amino acids have been extensively explored, highly selective and general approaches to transform unactivated C–H bonds in aliphatic amino acids remain less developed. Here, the authors disclose a stepwise dehydrogenative method to convert aliphatic amino acids into structurally diverse analogs. The key to the success of this approach lies in the development of a selective catalytic acceptorless dehydrogenation method driven by photochemical irradiation, which provides access to terminal alkene intermediates for downstream functionalization.

Nature Chemistry

A Metalloenzyme Platform for Catalytic Asymmetric Radical Dearomatization

W. Fu, Y. Fu,^‡ Y. Zhao,^‡ H. Wang, P. Liu* & Y. Yang*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01608-8)

Catalytic asymmetric dearomatization represents a powerful means to convert flat aromatic compounds into stereochemically well-defined three-dimensional molecular scaffolds. Using new-to-nature metalloredox biocatalysis, the authors describe an enzymatic strategy for catalytic asymmetric dearomatization via a challenging radical mechanism that has eluded small-molecule catalysts. Enabled by directed evolution, new-to-nature radical dearomatases P450_rad1–P450_rad5 facilitated asymmetric dearomatization of a broad spectrum of aromatic substrates, including indoles, pyrroles and phenols, allowing both enantioconvergent and enantiodivergent radical dearomatization reactions to be accomplished with excellent enzymatic control.

Nature Synthesis

Suzuki–Miyaura Coupling of Arylthianthrenium Tetrafluoroborate Salts Under Acidic Conditions

L. Zhang, Y. Xie, Z. Bai & T. Ritter*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00631-4) 🔓

The palladium-catalysed Suzuki–Miyaura cross-coupling (SMC) is currently the most commonly used reaction to construct carbon–carbon bonds in the pharmaceutical industry. Typical methods require the use of a base, which limits the substrate scope. To mitigate this shortcoming, substantial effort has been made to develop base-tolerant organoboron reagents, efficient catalysts and reaction conditions that do not require external bases. Still, many boronic acids cannot be used or must be independently protected, and many Lewis-basic functional groups poison the catalyst. Here, the authors report a conceptually different SMC reaction that can proceed even under acidic conditions, with a broad substrate scope. Key to this advance is the formation of an acid-stable, palladium-based ion pair between the reaction partners that does not require base for subsequent productive transmetallation. Boronic acids that cannot be used directly in other SMC reactions, such as 2-pyridylboronic acid and boronic acids with strong Lewis bases, can now be used successfully.

Nature Communications

Leveraging Long-Lived Arenium Ions in Superacid for meta-Selective Methylation

P. Bourbon, K. Vitse, A. Martin-Mingot, H. Geindre, F. Guégan, B. Michelet* & S. Thibaudeau*

Nat. Commun. 2024, 15, 7435 (DOI: 10.1038/s41467-024-49421-8) 🔓

Electrophilic aromatic substitution is one of the most mechanistically studied reactions in organic chemistry. However, precluded by innate substituent effects, the access to certain substitution patterns remains elusive. While selective C–H alkylation of biorelevant molecules is eagerly awaited, especially for the insertion of a methyl group whose magic effect can boost lead molecules potency, one of the most obvious strategies would rely on electrophilic aromatic substitution. Yet, the historical Friedel-Crafts methylation remains to date poorly selective and limited to activated simple aromatics. Here, the authors report the development of a selective electrophilic methylation enabling the direct access to highly desirable 1,3-disubstituted arenes. The reaction is driven by the generation of long-lived arenium intermediates produced by protonation in superacid and can be applied to a large variety of functionalized (hetero)aromatics going from standard building blocks to active pharmaceutical ingredients.

Journal of the American Chemical Society

Iron-Catalyzed Primary Amination of C(sp³)–H Bonds

Y. Liu,^† Y. Chen,^† Y.-J. Zhao, G.-Q. Zhang, Y. Zheng, P. Yu,* P. Chen* & Z.-J. Jia*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05407)

Primary amines are privileged molecules in drug development. Yet, there is a noticeable scarcity of methods for directly introducing a primary amine group into the ubiquitous C(sp³ )–H bonds within organic compounds. Here, the authors report an iron-based catalytic system that enables direct primary amination of C(sp³ )–H bonds under aqueous conditions and air. Various types of C(sp³ )–H bonds, including benzylic, allylic, and aliphatic ones, can be readily functionalized with high selectivity and efficiency. The broad utility of this method has been further verified by late-stage amination of 11 complex bioactive molecules. Mechanistic studies unveil a protonated iron-nitrene complex as the key intermediate for the C–H bond activation.

Enantioselective Total Synthesis of (−)-Cyathin B₂: A Desymmetric Double-Allylboration Approach

J. Wang, J. Yin, H. Imtiaz, H. Wang & Y. Li*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08042)

A powerful Pt-catalyzed asymmetric diboration/desymmetric double-allylboration cascade reaction has been developed for the construction of synthetically useful, densely functionalized hydrindanes with five stereocenters, including three quaternary ones, in good yields and excellent enantiomeric excess (e.e.) values within a single synthetic operation. A unified strategy utilizing this key tandem methodology enabled the concise asymmetric total synthesis of cyathane diterpene (−)-Cyathin B₂ in 14 steps from commercially available starting materials, thereby demonstrating its remarkable potential in the synthesis of hydrindane-containing natural products and pharmaceuticals.

Synthesis of Bridged Five-Membered Ring Systems by Type II [3+2] Annulation of Allenylsilane-ene

L.-Z. Li, Y.-R. Huang, Z.-X. Xu, H.-S. He, H.-W. Ran, K.-Y. Zhu, J.-C. Han* & C.-C. Li*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09384)

The first type II intramolecular [3+2] annulation of allenylsilane-ene has been achieved, enabling diastereoselective and efficient construction of synthetically challenging bridged five-membered ring systems such as bicyclo[3.2.1]. The process shows a broad substrate scope, is highly stereospecific and represents the first stereoselective method for the direct synthesis of bicyclo[3.2.1] ring systems from acyclic precursors. Additionally, the first asymmetric total syntheses of (+)- and (−)-strepsesquitriol, and the efficient formation of the synthetically challenging tetracyclic core of pierisjaponol D are achieved by this type II [3+2] annulation reaction.

ACS Catalysis

Unveiling the Stereoselectivity Aspects of Metallaphotoredox Decarboxylative Arylation

R. Nallagonda,* R. Quan, L. Grant, C. Jorge, S. Yip, D.-R. Wu, T. G. M. Dhar, J. Kempson, A. Mathur & M. S. Oderinde*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c03818)

Decarboxylative cross-coupling methodologies are now widely employed in pharmaceutical drug discovery research, forming the basis of strategic retrosynthetic analysis and radical-based bond disconnections. Herein, the authors unveil the diastereoselectivity aspects of metallaphotoredox decarboxylative arylation of substituted cyclic carboxylic acids. Through judicious screening of conditions, a photoredox-promoted Ni-catalyzed decarboxylative arylation was rendered highly diastereoselective, enabling modular access to complex cyclic architectures. Computational DFT structural and energetic studies of L₂ArXNi(III)R complexes revealed a conformational preference for all equatorial over equatorial/axial conformations. To showcase the robustness and scalability of this methodology for drug discovery and process development, a 200 mmol (51.5 g) reaction was successfully carried out in flow. Finally, to demonstrate the simplifying power of this coupling approach, it was employed to truncate the synthesis of Iptacopan (LNP023) from the previously reported 12-steps (racemic route) to 4-steps (enantioselective route).

Angewandte Chemie International Edition

Carbenoids with Sulfinate as Nucleofuge for Matteson-Type Homologation: Direct Insertion of Oxygen- and Nitrogen-Substituted Units into Carbon‒Boron Bonds

Q. Liu & G. Dong*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202411980)

Carbenoid insertion into boronate carbon−boron bonds, namely the Matteson-type homologation, has been recognized as a powerful tool for constructing carbon−carbon bonds. However, some limitations and inconvenience still exist with the carbenoids currently employed, such as the use of highly cryogenic and basic conditions. Herein, the authors report a new class of stable carbenoids with sulfinate as nucleofuge for Matteson-type homologations, which directly introduce O- and N-substituted methylenes into carbon−boron bonds. Enabled by oxazaborolidines as the boronic substrates, the reaction is operable at 0 °C or room temperature with weaker bases. Broad functional groups, including acidic C−H bonds, can be tolerated. The synthetic utility of this method has been demonstrated in the gram-scale synthesis and iterative insertion of various carbenoids.

ChemRxiv

Oxoammonium-Catalyzed Oxidation of N-Substituted Amines

J. Rein,^† B. Górski,^† Y. Cheng,^‡ Z. Lei,^‡ F. Buono & S. Lin*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-brd62) 🔓

The authors report the development of an oxoammonium-catalyzed oxidation of N-substituted amines via a hydride transfer mechanism. Steric and electronic tuning of catalyst led to complementary sets of conditions that can oxidize a broad scope of carbamates, sulfonamides, ureas, and amides into the corresponding imides. The reaction was further demonstrated on a 100-g scale using a continuous flow setup.

Oxoammonium-Catalyzed Ether Oxidation via Hydride Abstraction: Methodology Development and Mechanistic Investigation using Paramagnetic Relaxation Enhancement NMR

Y. Cheng, J. Rein, N. Le & S. Lin*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-gzx7t) 🔓

Hydride abstraction represents a promising yet underexplored approach in the functionalization of C–H bonds. In this work, the authors report the oxidation of α-C–H bonds of ethers via oxoammonium catalysis using 3-chloroperbenzoic acid (m-CPBA) as the terminal chemical oxidant or by means of electrochemistry. Mechanistic studies revealed intricate equilibria and interconversion events between various catalytic intermediates in the presence of m-CPBA, which alone was incompetent to drive catalytic turnover. The addition of a small amount of strong acid HNTf₂ or weakly coordinating salt NaSbF₆ turned on catalytic turnover and promoted ether oxidation with excellent efficiency. NMR experiments leveraging paramagnetic relaxation enhancement effect allowed for quantification of open-shell catalytic intermediates in real time during the reaction course, which aided the identification of catalyst resting states and elucidation of reaction mechanisms.

A Divergent Synthesis of Numerous Pyrroloiminoquinone Alkaloids Identifies Promising Antiprotozoal Agents

G. L. Barnes,^† N. L. Magann,^† D. Perrotta, F. M. Hörmann, S. Fernandez, P. Vydyam, J.-Y. Choi, J. Prudhomme, A. Neal, K. Le Roch, C. B. Mamoun & C. D. Vanderwal*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-9tvnq) 🔓

On the basis of a streamlined route to the pyrroloiminoquinone (PIQ) core, the authors made 16 natural products spread across four classes of biosynthetically related alkaloid natural products, and multiple structural analogues, all in ≤8 steps longest linear sequence (LLS). The strategy features a Larock indole synthesis as the key operation in a five-step synthesis of a key methoxy-PIQ intermediate. Critically, this compound was readily diverged via selective methylation of either (or both) of the imine-like or the pyrrole nitrogens, which then permitted further divergence by either O-demethylation to o-quinone natural products or displacement of the methoxy group with a range of amine nucleophiles. Based on a single, early report of their potential utility against the malaria parasite, these compounds were assayed against several strains of Plasmodium falciparum, as well as two species of the related protozoan parasite Babesia. In combination with evaluations of their human cytotoxicity, several compounds were identified with potent (low-nM IC₅₀) antimalarial and antibabesial activities that are much less toxic toward mammalian cells and therefore are promising lead compounds for antiprotozoal drug discovery.

Green Synthesis of Morpholines via Selective Monoalkylation of Amines

K. G. Ortiz, A. T. Brusoe*, J. An, E. Chong & L. Wu

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-5vwkp) 🔓

Morpholines are common heterocycles in pharmaceutical and agricultural products, yet methods to synthesize them from 1,2-amino alcohols are inefficient. The authors report the simple, high yielding, one or two-step, redox neutral protocol using inexpensive reagents (ethylene sulfate and t-BuOK) for the conversion of 1,2-amino alcohols to morpholines. Key to this methodology is the identification of general conditions that allow for the clean isolation of monoalkylation products derived from a simple S_N2 reaction between an amine and ethylene sulfate. This method can be used for the synthesis of a variety of morpholines containing substituents at various positions, including 28 examples derived from primary amines and several examples contained in known active pharmaceutical ingredients. Multiple examples have been conducted on >50 g scale and while this new methodology has many environmental and safety benefits relative to the traditional methods used to prepare morpholines from 1,2-amino alcohols, the most striking feature is the facile selective monoalkylation of a variety of primary amines.

Expedited Aminoglutarimide C-N Cross-Coupling Enabled by High-Throughput Experimentation

J. W. Gu, M. S. Oderinde, H. Li, F. Roberts, J. M. Ganley* & M. D. Palkowitz*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-1skr0) 🔓

A simple protocol for the direct Buchwald-Hartwig cross-coupling of (hetero)aryl halides with unprotected aminoglutarimide to afford diverse Cereblon Binding Motifs is disclosed. This C-N cross-coupling method development was enabled by high throughput combinatory screening of key reaction parameters namely solvents, temperatures and ligands. Scope studies revealed generality across various heteroaryl and aryl halides, with the reaction proceeding under mild conditions. In comparison, this method demonstrated strategic superiority over previously reported approaches, as evidenced by a significant step count reduction from known syntheses in the patent literature.

Chemical Science

Nitrogen-to-Functionalized Carbon Atom Transmutation of Pyridine

F.-P. Wu, M. Lenz, A. Suresh, A. R. Gogoi, J. L. Tyler, C. G. Daniliuc, O. Gutierrez* & F. Glorius*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC04413D) 🔓

The targeted and selective replacement of a single atom in an aromatic system represents a powerful strategy for the rapid interconversion of molecular scaffolds. Herein, the authors report a pyridine-to-benzene transformation via nitrogen-to-carbon skeletal editing. This approach proceeds via a sequence of pyridine ring-opening, imine hydrolysis, olefination, electrocyclization, and aromatization to achieve the desired transmutation. The most notable features of this transformation are the ability to directly install a wide variety of versatile functional groups in the benzene scaffolding, including ester, ketone, amide, nitrile, and phosphate ester fragments, as well as the inclusion of meta-substituted pyridines which have thus far been elusive for related strategies.

Organic Letters

Aryne Aminohalogenation Using Protic Amines Enabled by Halogen Transfer

J. T. Gavin, L. W. Anderson & C. C. Roberts*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c02407)

Methods for aryne difunctionalization have been the focus of recent research, but one limitation is the use of nucleophiles with proton sources. Herein, the authors demonstrate the use of halogen transfer reagents to enable protic amines in aryne aminohalogenation difunctionalizations in up to 86% yield. This method uses amines and arynes with a variety of N-heterocyclic scaffolds. Through a variety of derivatizations, the synthetic utility of these products is demonstrated.

Journal of Organic Chemistry

Direct C4 and C2 C–H Amination of Heteroarenes Using I(III) Reagents via a Cross Azine Coupling

B. J. Motsch, A. H. Quach, J. L. Dutton,* D. J. D. Wilson* & S. E. Wengryniuk*

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c01593)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-n14xq) 🔓

Aminated nitrogen heterocycles are valuable motifs across numerous chemical industries, perhaps most notably in small molecule drug discovery. While numerous strategies for installing nitrogen atoms onto azaarenes exist, most require prefunctionalization and methods for direct C–H amination are almost entirely limited to position C2. Herein, the authors report a method for the direct C2 and C4 C–H amination of fused azaarenes via in situ activation with a bispyridine-ligated I(III) reagent, [(Py)₂IPh]₂OTf, or Py-HVI. Unlike commonly used N-oxide chemistry, the method requires no preoxidation of the azaarene and provides unprecedented direct access to C4 amination products. The resulting N-heterocyclic pyridinium salts can be isolated via simple trituration. The free amine can be liberated under mild Zincke aminolysis, or the amination and cleavage can be telescoped to a one-pot process.

That’s all for this issue! Have a great week and we’ll see you next Monday.