Cross-(−CO)upling

Welcome to this week’s Organic Synthesis Newsletter.

You’ll notice a slightly different format to the newsletter this week in an attempt to improve reading experience; further changes will be implemented as the newsletter continues.

—Steve

Monday 16^th September – Sunday 22^nd September 2024

SCIENCE

A Decarbonylative Approach to Alkylnickel Intermediates and C(sp³)-C(sp³) Bond Formation

Z. Huang, M. E. Akana, K. M. Sanders, D. J. Weix*

Science 2024, 385, 1331–1337 (DOI: 10.1126/science.abi4860)

The myriad nickel-catalyzed cross-coupling reactions rely on the formation of an organonickel intermediate, but limitations in forming monoalkylnickel species have limited options for C(sp³) cross-coupling. The formation of monoalkylnickel(II) species from abundant carboxylic acid esters would be valuable, but carboxylic acid derivatives are primarily decarboxylated to form alkyl radicals that lack the correct reactivity. In this work, the authors disclose a facile oxidative addition and decarbonylation sequence that forms monoalkylnickel(II) intermediates through a nonradical process. The key ligand, bis(4-methylpyrazole)pyridine, accelerates decarbonylation, stabilizes the alkylnickel(II) intermediate, and destabilizes off-cycle nickel(0) carbonyl species. The utility of this new reactivity in C(sp³)-C(sp³) bond formation is demonstrated in a reaction that is challenging by purely radical methods—the selective cross-coupling of primary carboxylic acid esters with primary alkyl iodides.

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Aldehyde–Olefin Couplings via Sulfoxylate-Mediated Oxidative Generation of Ketyl Radical Anions

Z. Li, J. A. Tate & A. Noble*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10093) 🔓

Ketyl radicals are valuable reactive intermediates because they allow carbonyl chemistry to be extended beyond traditional electrophilic reactivity through simple single-electron reduction to a nucleophilic radical. However, this pathway is challenging due to the large negative reduction potentials of carbonyls, thus requiring highly reducing conditions. Herein, the authors describe the development of an alternative strategy to access ketyl radicals from aldehydes, which avoids the reduction pathway by instead proceeding via single-electron oxidation and desulfination of α-hydroxy sulfinates. These redox-active aldehyde adducts are generated in situ through the addition of sulfoxylate (SO₂^2–) to aldehydes and possess low oxidation potentials, thereby facilitating ketyl radical formation and circumventing the need for strongly reducing conditions. The application of this sulfoxylate-mediated ketyl radical formation has been demonstrated in ketyl–olefin coupling reactions.

Silyl Radicals as Single-Electron Reductants: α-Aminoalkyl Radical Formation via a Photocatalytic Oxidatively Initiated Radical Chain Process

H. C. Waller & M. J. Gaunt*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08230) 🔓

The α-amino-radical constitutes a versatile reactive intermediate that has been used to great effect in the synthesis of complex amine-containing products. Here, the authors report the development of a multicomponent photocatalytic platform enabling access to all-alkyl α-amino-radicals, exploiting the oxidative formation of silyl-radicals from commercially available tris(trimethylsilyl)silane. A key design element of the new process involves the role of silyl-radicals in generating α-amino-radicals from iminium ions as part of an oxidatively initiated photocatalytic radical chain process. This distinct activation mode is showcased by engaging the ensuing radicals in cross-radical coupling with persistent arene radical anions, enabling the arylation of in situ-generated all-alkyl iminium ions to furnish alkyl-substituted benzylamines.

Copper-Catalyzed Amination of Aryl Chlorides under Mild Reaction Conditions

H.-J. Ai,^† S.-T. Kim,^† C. Liu & S. L. Buchwald*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c10237)

The authors report a mild method for the copper-catalyzed amination of aryl chlorides. Key to the success of the method was the use of highly sterically encumbered N¹,N²-diaryl diamine ligands which resist catalyst deactivation, allowing reactions to proceed at significantly lower temperatures and with a broader scope than current protocols. A sequence of highly chemoselective C–N and C–O cross-coupling reactions were demonstrated, and mechanistic studies indicate that oxidative addition of the Cu catalyst to the aryl chlorides is rate-limiting.

Development of a Deactivation-Resistant Dialkylbiarylphosphine Ligand for Pd-Catalyzed Arylation of Secondary Amines

K. Feng,^† E. R. Raguram,^† J. R. Howard, E. Peters, C. Liu, M. S. Sigman* & S. L. Buchwald*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09667)

Despite the prevalence of N-heteroarenes in small-molecule pharmaceuticals, Pd-catalyzed C–N cross-coupling reactions of aryl halides and amines containing these rings remain challenging due to their ability to displace the supporting ligand via coordination to the metal center. To address this limitation, the authors report the development of a highly robust Pd catalyst supported by a new dialkylbiarylphosphine ligand, FPhos. The FPhos-supported catalyst effectively resists N-heteroarene-mediated catalyst deactivation to readily promote C–N coupling between a wide variety of Lewis-basic aryl halides and secondary amines, including densely functionalized pharmaceuticals. Mechanistic investigations elucidated two key features that enable FPhos to overcome the limitations of previous ligands. First, the ligated Pd complex is stabilized through its conformational preference for the O-bound isomer, which likely resists coordination by N-heteroarenes. Second, 3′,5′-disubstitution on the non-phosphorus-containing ring of FPhos creates the ideal steric environment around the Pd center, which facilitates binding by larger secondary amines while mitigating the formation of off-cycle palladacycle species.

Enantioselective Decarboxylative C(sp³)-C(sp³) Cross-Coupling of Aliphatic Redox-Active Esters with gem-Borazirconocene Alkanes

J. Wang, S. Bai, C. Yang & X. Qi*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c09245)

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

Asymmetric decarboxylative cross-coupling of carboxylic acids is a powerful method for synthesizing chiral building blocks essential in medicinal chemistry and materials science. Despite their potential, creating versatile chiral alkylboron derivatives through asymmetric decarboxylative C(sp³)-C(sp³) cross-coupling from readily available primary aliphatic acids and mild organometallic reagents remains challenging. In this study, the authors present a visible light-induced Ni-catalyzed enantioconvergent C(sp³)-C(sp³) cross-coupling of unactivated primary aliphatic acid NHPI esters with gem-borazirconocene alkanes, producing a diverse array of valuable chiral alkylboron building blocks. The method boasts a broad substrate scope, high functional group tolerance, and the ability for late-stage modification of complex drug molecules and natural products with high enantioselectivity, showcasing its synthetic potential.

Adaptive Photochemical Amination via Co(II) Catalysis

G. Song, J. Song, Q. Li, T. Kang, J. Dong, G. Li, J. Fan, C. Wang & D. Xue*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c08130)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2024-8pn7s) 🔓

Transition-metal-catalyzed amination of aryl halides is one of the most employed methods for constructing N-arylation adducts. However, the broad success of these reactions largely relies on the screening of precatalysts, elaborated ligands, and case-by-case optimization of reaction conditions (solvent, base, additive, temperature, etc.) for electronically or structurally diverse nucleophiles. Herein, the authors report an adaptive photochemical C–N coupling of aryl halides with various nitrogen nucleophiles by Co(II) catalysis under the same reaction conditions without the addition of any exogenous photocatalyst. This photochemical amination features a wide substrate scope (>130 examples, up to 95% yield) with excellent functional group tolerance.

Formal [2σ+2σ]-Cycloaddition of Aziridines with Bicyclo[1.1.0]butanes: Access to Enantiopure 2-Azabicyclo[3.1.1]heptane Derivatives

S. Dutta, C. G. Daniliuc, C. Mück-Lichtenfeld & A. Studer*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c11296)

Saturated nitrogen heterocycles are among the most significant structural components in small-molecule pharmaceuticals. Herein, a protocol for the construction of enantiopure 2-azabicyclo[3.1.1]heptane derivatives by a stereospecific intermolecular formal cycloaddition of aziridines with bicyclo[1.1.0]butanes is described. The reaction is run by using B(C₆F₅)₃ as a catalytic additive to give access to a library of enantiopure 2-azabicyclo[3.1.1]heptane derivatives (37 examples) under mild and operationally simple conditions. Successful scale-up reactions, mechanistic experiments, density functional theory (DFT) calculations and synthetic applications are presented.

ACS CATALYSIS

Acridine/Lewis Acid Complexes as Powerful Photocatalysts: A Combined Experimental and Mechanistic Study

D. R. L. Rickertsen,^† J. D. Crow,^† T. Das, I. Ghiviriga, J. S. Hirschi* & D. Seidel*

ACS Catal. 2024, ASAP (DOI: 10.1021/acscatal.4c04897)

A class of in situ generated Lewis acid (LA) activated acridine complexes is reported, which act as potent photochemical catalysts for the oxidation of a variety of protected secondary amines. Acridine/LA complexes exhibit tunable excited state reduction potentials ranging from +2.07 to 2.38 V vs. SCE. The ytterbium triflate complex of 3,6-di-tert-butyl-9-mesitylacridine catalyzes a photochemical Giese-type reaction of Boc-protected secondary amines with challenging conjugate acceptors such as acrylates, that are inaccessible to the analogous acridinium (t-Bu-Mes-Acr^⊕) catalyzed reaction. The mechanism of this reaction was investigated using a suite of physical organic probes including intramolecular ¹³C kinetic isotope effects (KIEs), variable time normalization analysis (VTNA) kinetics, determination of redox potentials, and computational studies.

ANGEWANDTE CHEMIE INTERNATIONAL EDITION

Photoinduced Pd-Catalyzed Direct Sulfonylation of Allylic C–H Bonds

K. Mukherjee, K. P. S. Cheung & V. Gevorgyan*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202413646)

Allylic sulfones are valuable motifs due to their medicinal and biological significance and their versatile chemical reactivities. While direct allylic C–H sulfonylation represents a straightforward and desirable approach, these methods are primarily restricted to terminal alkenes, leaving the engagement of the internal counterparts a formidable challenge. Herein, the authors report a photocatalytic approach that accommodates both cyclic and acyclic internal alkenes with diverse substitution patterns and electronic properties. Importantly, the obtained allylic sulfones can be readily diversified into a wide range of products, thus enabling formal alkene transposition and all-carbon quaternary center formation through the sequential C–H functionalization.

CHEMRXIV

Selective Ni-Catalyzed Cross-Electrophile Coupling of Heteroaryl Chlorides and Aryl Bromides at 1:1 Substrate Ratio

Z.-M. Su, D. L. Poole, M. Rafiee, R. S. Paton, D. J. Weix & S. S. Stahl*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-3q21n) 🔓

Nickel-catalyzed cross-electrophile coupling (XEC) reactions of (hetero)aryl electrophiles represent appealing alternatives to palladium-catalyzed methods for biaryl synthesis, but they often generate significant quantities of homocoupling and/or proto-dehalogenation side products. In this study, an informer library of heteroaryl chloride and aryl bromide coupling partners is used to identify Ni-catalyzed XEC conditions that access high selectivity for the cross-product when using equimolar quantities of the two substrates. Two different catalyst systems are identified that show complementary scope and broad functional-group tolerance, and time-course data suggest the two methods follow different mechanisms.

Cross-Coupling Reactions with Nickel, Visible Light, and tert-Butylamine as a Bifunctional Additive

J. Düker, M. Philipp, T. Lentner, J. Cadge, J. E. A. Lavarda, R. M. Gschwind, M. S. Sigman, I. Ghosh* & B. König*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-43xbn) 🔓

Transition metal catalysis is crucial for the synthesis of complex molecules, with ligands and bases playing a pivotal role in optimizing cross-coupling reactions. Despite advancements in ligand design and base selection, achieving effective synergy between these components remains challenging. Here, the authors present a general approach to nickel-catalyzed photoredox reactions employing tert-butylamine as a cost-effective bifunctional additive, acting as the base and ligand. This method proves effective for C–O and C–N bond-forming reactions with a diverse array of nucleophiles, including phenols, aliphatic alcohols, anilines, sulfonamides, sulfoximines, and imines. Notably, the protocol demonstrates significant applicability in biomolecule derivatization and facilitates sequential one-pot functionalizations.

Saturated F₂-Rings from Alkenes

Y. Li, X.-B. Liu, V. Sham, I. Logvinenko, J.-H. Xue, J.-Y. Wu, J.-L. Fu, S. Lin, Y. Liu, Q. Li*, P. K. Mykhailiuk* & H. Wang*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-0wf3l-v2) 🔓

A general method to convert simple exocyclic alkenes (no Ar-substituents) into saturated F₂-rings has been developed. The reaction involves the I^III-reagent C₆F₅I(OAc)₂ (F₅-PIDA). The reaction efficiently works on a mg-, g-, and even multigram scale.

Reversing the Chemoselectivity in Photocatalytic C–F Bond Cleavage Enabled by Zirconocene and Photoredox Catalysis

H. Takimoto, K. Aida, Y. Nishimoto,* D. Yokogawa, E. Ota* & J. Yamaguchi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-ssj00) 🔓

The development of chemoselective defluorination reactions is highly desirable due to the exceptional stability of the C–F bond compared to other functional groups. Recent advances in photocatalysis have enabled cataytic single-electron transfer (SET) processes, offering an alternative to stoichiometric methods that rely on strong reducing agents. However, these strategies have primarily focused on trifluoromethyl substrates, with limited success for compounds containing fewer fluorine atoms, which are inherently more resistant to SET. Herein, the authors report a novel defluorination strategy for α-fluorocarbonyl compounds, employing zirconocene and photoredox catalysis. The method leverages the strong fluorine affinity of zirconocene and bypassed reliance on reduction potential, focusing instead on the bond dissociation energy of the fluorinated molecules.

Scalable Electrocatalyzed Formation of C–O Bonds using Flow Reactor Technology

M. Prieschl, D. Cantillo, C. O. Kappe & G. Laudadio*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-2npx7) 🔓

The development of modular and robust synthetic routes that can serve in both medicinal and process chemistry settings is rare. Generally, highly modular medicinal chemistry routes are too hazardous and expensive to be translated into a process chemistry environment. Taking the case study of delamanid, a pharmaceutical compound used for multidrug-resistant tuberculosis treatment, the development of a sustainable, modular and scalable C–O bond formation via electrocatalysis is reported. In this work, the electrochemical batch reaction was studied, addressing critical reproducibility issues and the reaction was successfully translated to a flow electrochemical reactor design, which allowed the use of carbon felt electrodes. The high modularity of the protocol was demonstrated by the synthesis of 11 different examples, while the scalability of the reaction was proven by a gram scale preparation of a key intermediate for the synthesis of delamanid.

ORGANIC LETTERS

Organocatalytic Asymmetric Allylic Benzylborylation via Fluoride-Assisted Catalytic Generation of α-Boryl Carbanionic Intermediates

J. Duran, P. Rodríguez, W. Vermeer & X. Companyó*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c03242) 🔓

The authors describe the organocatalytic asymmetric allylic benzylborylation of allyl fluorides with α-silyl benzylboronic esters. The catalytic protocol leverages the singular features of fluoride as an unconventional leaving group, enabling the catalytic generation of reactive α-boryl carbanion species through desilylative activation. It allows the construction of a wide set of homoallylic benzylated organoboronates bearing two contiguous stereocenters. The chiral boronate installed in the products serves as a synthetic lynchpin to construct complex chemical architectures in a stereospecific manner.

JOURNAL OF ORGANIC CHEMISTRY

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

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

J. Org. Chem. 2024, ASAP (DOI: 10.1021/acs.joc.4c01702)

Previously: ChemRxiv (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 α-pinene, a complex process that plays a major role in the formation of secondary organic aerosol in the Earth’s atmosphere.

OUTSIDE OF SYNTHESIS, INSIDE OF SCIENCE:

• According to an in-depth study of antimicrobial resistance, antibiotic-resistant infections will be responsible for 40 million deaths between now and 2050 with deaths in those aged 70 and over expected to rise by 70%.