Bismuth Makes Light Work of Cyclopropane Formation

Nature Chemistry

Enantiospecific Cross-Coupling of Cyclic Alkyl Sulfones

R. Nolla-Saltiel,^† Z. T. Ariki,^† S. Schiele, J. Alpin, Y. Tahara, D. Yokogawa, M. Nambo & C. M. Crudden*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01594-x)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-rqhmz) 🔓

Methods to form carbon–carbon bonds efficiently and with control of stereochemistry are critical for the construction of complex molecules. Cross-coupling reactions are among the most efficient and widely used reactions to construct molecules, with reactions enabling the retention or installation of chirality as recent additions to this powerful toolbox. Sulfones are robust, accessible organic electrophiles that have many attractive features as cross-coupling partners; however, since the first example of their use in 1979, there have been no examples of their use in enantioselective, enantiospecific or entantioconvergent cross-couplings. The high acidity of sulfones makes it unclear whether this transformation is even possible outside tertiary systems. Here, the authors report the enantiospecific cross-coupling of cyclic sulfones and Grignard reagents. Up to 99% chirality transfer is observed despite the strong basicity of the Grignard components. In situ monitoring reveals that the cross-coupling is kinetically competitive with competing deprotonation, resulting in a highly enantioselective transformation.

Journal of the American Chemical Society

Reductive Cyclopropanation through Bismuth Photocatalysis

S. Ni, D. Spinnato & J. Cornella*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07262) 🔓

The authors present a catalytic method based on a low-valent Bi complex capable of cyclopropanation of double bonds under blue LED irradiation. The catalysis features various unusual Bi-based organometallic steps, namely, (1) two-electron inner sphere oxidative addition of Bi(I) complex to CH₂I₂, (2) light-induced homolysis of the Bi(III)–CH₂I bond, (3) subsequent iodine abstraction-ring-closing, and (4) reduction of Bi(III) to Bi(I) with an external reducing agent to close the cycle. Stoichiometric organometallic experiments support the proposed mechanism. This protocol represents a unique example of a reductive photocatalytic process based on low-valent bismuth radical catalysis.

Total Synthesis of Ganoapplanin Enabled by a Radical Addition/Aldol Reaction Cascade

N. Müller,^† O. Kováč,^† A. Rode, D. Atzl & T. Magauer*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08291) 🔓

The total synthesis of the Ganoderma meroterpenoid ganoapplanin, an inhibitor of T-type voltage-gated calcium channels, is reported. The synthetic approach is based on the convergent coupling of a readily available aromatic polyketide scaffold with a bicyclic terpenoid fragment. The three contiguous stereocenters of the terpenoid fragment, two of which are quaternary, were constructed by a diastereoselective, titanium-mediated iodolactonization. For the fusion of the two fragments and to simultaneously install the crucial biaryl bond, the authors devised a highly effective two-component coupling strategy. This event involves an intramolecular 6-exo-trig radical addition of a quinone monoacetal followed by an intermolecular aldol reaction. A strategic late-stage oxidation sequence allowed the selective installation of the remaining oxygen functionalities and the introduction of the characteristic spiro bisacetal structure of ganoapplanin.

An Aza-Enolate Strategy Enables Iridium-Catalyzed Enantioselective Hydroalkenylations of Minimally Polarized Alkenes en Route to Complex N-Aryl β²-Amino Acids

F. Hong, C. M. Robertson & John F. Bower*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07519) 🔓

Cationic Ir(I)-complexes modified with homochiral diphosphines promote the hydroalkenylative cross-coupling of β-(arylamino)acrylates with monosubstituted styrenes and α-olefins. The processes are dependent on the presence of an NH unit, and it is postulated that metalation of this generates an iridium aza-enolate that engages the alkene during the C–C bond forming event. The method offers high branched selectivity and enantioselectivity and occurs with complete atom economy. Diastereocontrolled reduction of the products provides β² -amino acids that possess contiguous stereocenters.

Amination of Aminopyridines via η⁶-Coordination Catalysis

J. Chen, Y. Lin, W.-Q. Wu, W.-Q. Hu, J. Xu & H. Shi*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07306)

Pyridine, a widespread aromatic heterocycle, features an sp² -hybridized nitrogen atom that can readily coordinate to metals. In stark contrast, π-coordination of pyridine and derivatives with transition metals is notably scarce, and the involvement of such activation mode in catalysis remains to be developed. Herein, the authors present amination reactions of aminopyridines that leverages the reversible π coordination with a ruthenium catalyst as the arenophilic π acid, rather than relying on the conventional κ-N coordination. Specifically, a transient η⁶ -pyridine complex functions as the electrophile in the nucleophilic aromatic substitution with amines, providing a diverse array of products via the cleavage of the pyridyl C–N bond. In addition, this method can be employed to incorporate chiral amines and ¹⁵ N-labeled amines.

Iridium-Catalyzed Oxidant-Free Transfer Dehydrogenation of Carboxylic Acids

Y. Xu, R. Zhang, B. Zhou & G. Dong*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07115)

Direct dehydrogenation of carboxylic acids to their unsaturated counterparts represents a valuable transformation for complex molecule synthesis, which, however, has been challenging to achieve. In addition, the current carbonyl desaturation methods are almost all based on oxidative conditions. Here, the authors report an Ir-catalyzed redox-neutral transfer dehydrogenation approach to directly convert carboxylic acids to either α,β- or β,γ-unsaturated counterparts. These reactions avoid using oxidants or strong bases, thus, tolerating various functional groups. The combined experimental and computational mechanistic studies suggest that this transfer hydrogenation reaction involves directed C–H oxidative addition, β-H elimination, and dihydride transfer to an alkene acceptor with C(sp³ )–H reductive elimination as the turnover-limiting step.

Angewandte Chemie International Edition

Organocatalyzed Carbonylation of Alkyl Halides Driven by Visible Light

X. Liu,^† B. S. Portela,^† A. Wiedenbeck, C. H. Chrisman, R. S. Paton* & G. Miyake*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202410928)

The authors describe a new strategy for the carbonylation of alkyl halides with different nucleophiles to generate valuable carbonyl derivatives under visible light irradiation. This method is mild, robust, highly selective, and proceeds under metal-free conditions to prepare a range of structurally diverse esters and amides in good to excellent yields. In addition, they highlight the application of this activation strategy for ¹³ C isotopic incorporation. The reaction is proposed to proceed by a photoinduced reduction to afford radical anions from alkyl halides, which undergo subsequent single electron-oxidation to form a carbocationic intermediate. Carbon monoxide is trapped by the carbocation to generate an acylium cation, which can be attacked by a series of nucleophiles to give a range of carbonyl products.

Insight into C4 Selectivity in the Light-Driven C–H Fluoroalkylation of Pyridines and Quinolines

L. Kim,^† W. Lee^† & S. Hong*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202410408)

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

Given the prevalence of pyridine motifs in FDA-approved drugs, selective fluoroalkylation of pyridines and quinolines is essential for preparing diverse bioisosteres. However, conventional Minisci reactions often face challenges in achieving precise regioselectivity due to competing reaction sites of pyridine and the limited availability of fluoroalkyl radical sources. Herein, the authors present a light-driven, C4-selective fluoroalkylation of azines utilizing N-aminopyridinium salts and readily available sulfinates. The approach employs electron donor-acceptor complexes, achieving highly C4-selective fluoroalkylation under mild conditions without an external photocatalyst. This practical method not only enables the installation of CF₂H groups but also allows for the incorporation of CF₂-alkyl groups with diverse functional entities, surpassing the limitations of previous methods. The versatility of the radical pathway is further demonstrated through straightforward three-component reactions involving alkenes and [1.1.1]propellane.

Traceless Nucleophile Strategy for C5-Selective C–H Sulfonylation of Pyridines

J. Kim, Y.-E. Kim & S. Hong*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202409561)

The functionalization of pyridines is crucial for the rapid construction and derivatization of agrochemicals, pharmaceuticals, and materials. Conventional functionalization approaches have primarily focused on the ortho- and para-positions, while achieving precise meta-selective functionalization, particularly at the C5 position in substituted pyridines, remains a formidable challenge due to the intrinsic electronic properties of pyridines. Herein, the authors present a new strategy for meta- and C5-selective C–H sulfonylation of N-amidopyridinium salts, which employs a transient enamine-type intermediate generated through a nucleophilic addition to N-amidopyridinium salts. This process harnesses the power of electron donor-acceptor complexes, enabling high selectivity and broad applicability, including the construction of complex pyridines bearing valuable sulfonyl functionalities under mild conditions without the need for an external photocatalyst. The remarkable C5 selectivity, combined with the broad applicability to late-stage functionalization, significantly expands the toolbox for pyridine functionalization, unlocking access to previously unattainable meta-sulfonylated pyridines.

ChemRxiv

A Broadly Applicable Strategy to Aminate Azines Enabled by Electronically Tuned Phosphine Reagents

R.-R. Liu, J. N. Levy & A. McNally*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-qrh6d) 🔓

The authors describe a strategy for aminating pyridines and other azines via phosphonium salt intermediates. Precisely tuning the electronic properties of the phosphonium ion was key for C–N bond formation via an S_NAr-halogenation, S_NAr-amination sequence. The process accommodates a wide range of amine classes and pyridine coupling partners and is viable for applications such as late-stage amination of complex pharmaceuticals and fragment-fragment coupling reactions. The capacity to rapidly modify the structure of the phosphine reagent was decisive and is a valuable feature in pseudohalide design.

Generation of Stereocenters via Single-Carbon-Atom Doping Using N-Isocyanides

H. Fujimoto,* T. Nishioka, K. Imachi, R. Nishimura & M. Tobisu*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-666ll) 🔓

Among the electronically unsaturated carbon species, atomic carbon is the most challenging to use for the synthesis of organic molecules, despite its potential to forge four distinct covalent bonds at a carbon center in a single process. Single-carbon-atom doping (SCAD) into organic molecules without loss of atoms in the reactant is highly attractive because it allows for a remarkable increase in molecular complexity in a single process. The authors have previously reported that N-heterocyclic carbenes can serve as an atomic carbon equivalent suitable for SCAD reactions. However, that method is limited to the formation of methylene carbons, leaving the full potential of the concept unrealized. Here, the authors report an SCAD reaction that results in the formation of stereocenters by unlocking the reactivity of (N-isocyanoimino)triphenylphosphorane as an atomic carbon equivalent. This reagent enables the single-step conversion of a range of acyl chlorides into homologated α-chloro cyclic ketones, which proceeds via the generation of four different bonds, i.e., one C-Cl, one C-H, and two C-C bonds at the incorporated carbon atom.

Strategies and Tactics for Site Specific Deuterium Incorporation at Each Available Carbon Atom of α-Pinene

J. Luo, M. A. Upshur, M. M. Vega, N. A. Doering, J. G. Varelas, Z. Ren, F. M. Geiger, R. Sarpong & R. J. Thomson*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-q0ng5) 🔓

The development of several unique strategies and tactics for the synthesis of α-pinene isotopologues that has culminated in access to all eight possible isomers with deuterium incorporated selectively at each available carbon atom is described. Access to this library of isotopologues provides new tools to more fully investigate the atmospheric autoxidation of a-pinene, a complex process that plays a major role in the formation of secondary organic aerosol (SOA) in the Earth’s atmosphere.

Palladium Bisphosphine Mono-Oxide Complexes: Synthesis, Scope, Mechanism, and Catalytic Relevance

S. Yang, M. Deng, R. A. Daley, A. Darù, W. J. Wolf, D. T. George, S. Ma, B. K. Werley, E. Samolova, J. B. Bailey, M. Gembicky, J. Marshall, S. R. Wisniewski, D. G. Blackmond* & K. M. Engle*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-8qcg4) 🔓

Recent studies in transition metal catalysis employing chelating phosphines have suggested a role for partial ligand oxidation in formation of the catalytically active species, with potentially widespread relevance in a number of catalytic systems. The authors examine the internal redox reaction of Pd^II (bisphosphine)X₂ (X = Cl, OAc, etc.) complexes to reveal previously underexplored aspects of bisphosphine mono-oxides (BPMOs), including evaluation of ligand structure and development of general reaction conditions to access a collection of structurally diverse BPMO precatalysts based on organopalladium oxidative addition complexes. In particular, a series of Pd^II (BPMO)(R)(X) (R=Aryl, Alkyl; X=I, Br) oxidative addition complexes bearing 24 different BPMO ligands were characterized by NMR and X-ray crystallography. Comparison of the catalytic performance of the oxidative addition complexes of phosphine versus bisphosphine mono-oxides as precatalysts is demonstrated to be an enabling diagnostic tool in Pd catalytic reaction development. Finally, the differences in catalytic behavior between bisphosphine and bisphosphine mono-oxide complexes were rationalized through solid-state parametrization and stoichiometric experiments.

High-Throughput enabled Iridium-Catalyzed C-H Borylation Platform for Late-Stage Functionalization

J. M. Zakis, R. A. Lipina, S. Bell, S. R. Williams, M. Mathis, M. J. Johansson J. Wencel-Delord & T. Smejkal*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-cs5vg) 🔓

In this work, the authors present an automated platform designed to facilitate the expedited use of late-stage C-H borylation in fast-moving discovery chemistry projects. Their microscale reaction optimization panel emphasizes the regiodivergent nature of different borylation protocols and provides a rapid assessment of all accessible positions with minimal starting material consumption. The approach taken provides a rapid and sustainable tool to evaluate reaction conditions targeting multiple C-H bonds. They illustrate the workflow by screening numerous fragment-like compounds, drugs and agrochemicals and demonstrate its practicality by successfully isolating 36 derivatives of bioactive compounds. Additionally, a systematic comparison of various catalytic methods using an informer library approach provides valuable insights regarding the desirable future direction of C-H borylation research.

Late-Stage Functionalization using a Popular Titrating Agent: Aryl-Chlorides and -Fluorides Activation by the Diphenylacetic Acid Dianion

A. Cerveri,* G. Russo, S. Sparascio, D. Merli, R. Maggi, N. D. Ca', M. Lanzi & G. Maestri*

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

Aryl-chlorides and -fluorides are common building blocks, but their use in synthesis is limited by the high stability of the Ar-X bond. The generation of aryl radicals via activation of strong Ar-X bonds is possible through the irradiation of tailor-made organic anions, which become reductants stronger than lithium metal. The authors report that the combination of visible light with the cheap diphenylacetic acid dianion is an even better tool, showing excellent activity across a variety of complex substrates and providing opportunities for late-stage drug modification.

Chemical Science

Trityl Isocyanide as a General Reagent for Visible Light Mediated Photoredox-Catalyzed Cyanations

I. Quirós, M. Martín, C. Pérez-Sánchez, T. Rigotti* & M. Tortosa*

Chem. Sci. 2024, Accepted (DOI: 10.1039/D4SC04199B) 🔓

A photoredox catalytic strategy has been developed to enable the functionalization of a variety of commercially available, structurally different radical precursors by the use of a bench-stable isonitrile as an efficient cyanating reagent. Specifically, a radical-based reaction has provided a mild and convenient procedure for the cyanation of primary, secondary and tertiary radicals derived from widely accessible sp³ -hybridized carboxylic acids, alcohols and halides under visible light irradiation. The reaction tolerates a variety of functional groups and it represents a complementary method for the cyanation of structurally different scaffolds that show diverse native functionalities, expanding the scope of previously reported methodologies.

Organic Letters

Scalable Synthesis of an Acid Stable Analogue of Hippuristanol

E. MacDonald,^† P. Blencowe,^† J. Baker, C. Bennett, S. Boyd, K. Fowler, L. Rigoreau, E. Stanway, M. Watson, H. Mao, H. Gao, C. Zhao, F. Zhang & H. Abas*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c02615)

Hippuristanol is a marine derived steroidal natural product with promising anticancer activity. However, instability at low pH has precluded its development as an efficient therapy. The authors addressed this limitation by replacing one of the oxygen atoms of the spiroketal moiety with a carbon atom. Key steps in the synthesis include a Meyer–Schuster/Nazarov cascade, a hypoiodite mediated oxyfunctionalization, and the late-stage installation of a hydroxyl group on the C-ring of the steroid.

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