Buchwald–Hartwig Amination with Aqueous Ammonia

Nature Chemistry

Diastereodivergent Nucleophile–Nucleophile Alkene Chlorofluorination

S. Doobary,^† A. J. D. Lacey,^† S. G. Sweeting, S. B. Coppock, H. P. Caldora, D. L. Poole & A. J. J. Lennox*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01561-6) 🔓

The selective hetero-dihalogenation of alkenes provides useful building blocks for a broad range of chemical applications. Unlike homo-dihalogenation, selective hetero-dihalogenation reactions, especially fluorohalogenation, are underdeveloped. Current approaches combine an electrophilic halogen source with a nucleophilic halogen source, which necessarily leads to anti-addition, and regioselectivity has only been achieved using highly activated alkenes. Here, the authors describe an alternative, nucleophile–nucleophile approach that adds chloride and fluoride ions over unactivated alkenes in a highly regio-, chemo- and diastereoselective manner. A curious switch in the reaction mechanism was discovered, which triggers a complete reversal of the diastereoselectivity to promote either anti- or syn-addition. The conditions are demonstrated on an array of pharmaceutically relevant compounds, and detailed mechanistic studies reveal the selectivity and the switch between the syn- and anti-diastereomers are based on different active iodanes and which of the two halides adds first.

Nature Catalysis

Enantioselective Alkylation of α-Amino C(sp³)−H Bonds via Photoredox and Nickel Catalysis

J. Li,^† B. Cheng,^† X. Shu, Z. Xu, C. Li & H. Huo*

Nat. Catal. 2024 (DOI: 10.1038/s41929-024-01192-7)

The catalytic enantioselective construction of C(sp³ )−C(sp³ ) bonds remains a substantial challenge in organic synthesis. One particularly promising approach is the use of transition-metal-catalysed C(sp³ )−H functionalization. However, a general strategy for the enantioselective alkylation of non-acidic C(sp³ )−H bonds has yet to be developed. Here, the authors present a unified platform for the enantioselective (trideutero)methylation and alkylation of α-amino C(sp³ )–H bonds, using a combination of photoredox and nickel catalysis with widely available redox-active esters. This technique activates two coupling agents to form carbon-centred radicals, which are then asymmetrically coupled by a chiral nickel catalyst. This strategy is unique in its ability to separately control radical generation and cross-coupling, facilitating the use of transiently generated alkyl radicals, including highly reactive methyl radicals, in asymmetric catalysis, and thereby expediting the synthesis of enantioenriched bioactive alkaloids and offering a promising method for advancing asymmetric C(sp³ )−C(sp³ ) bond formation.

Nature Synthesis

Boryl Radical-Mediated Halogen-Atom Transfer enables Arylation of Alkyl Halides with Electrophilic and Nucleophilic Coupling Partners

Z. Zhang, M. J. Tilby & D. Leonori*

Nat. Synth. 2024 (DOI: 10.1038/s44160-024-00587-5)

Traditional metal-catalysed cross-couplings of alkyl halides for C(sp³ )–C(sp² ) bond formation are often challenging to achieve. Processes where the alkyl halide is initially converted into a radical species can provide valuable complementarity. So far, these strategies are almost exclusively orchestrated by silicon-based reagents, which can be expensive, have low atom economy and are sensitive to steric factors. Here, the authors report the use of the stable Lewis acid–Lewis base complex Me₃N–BH₃, which, upon conversion into its corresponding amine-ligated boryl radical, enables nickel- and copper-catalysed cross-coupling of alkyl iodides and bromides with electrophilic aryl bromides and nucleophilic aryl boronic acids. Mechanistically, this method uses the amine borane radical’s propensity to activate halides via halogen-atom transfer through highly polarized transition states. This reactivity features mild conditions and broad tolerability of functional groups and engages sterically hindered alkyl halides.

Journal of the American Chemical Society

Palladium-Catalyzed Amination of Aryl Halides with Aqueous Ammonia and Hydroxide Base Enabled by Ligand Development

K. Choi,^† J. N. Brunn,^† K. Borate, R. Kaduskar, C. L. Pueyo, H. Shinde, R. Goetz & J. F. Hartwig*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05768)

The conversion of aryl halides to primary arylamines with a convenient and inexpensive source of ammonia has been a long-standing synthetic challenge. Aqueous ammonia would be the most convenient and least expensive form of ammonia, but such a palladium-catalyzed amination reaction with a high concentration of water faces challenges concerning catalyst stability and competing hydroxylation, and palladium-catalyzed reactions with this practical reagent are rare. Further, most reactions with ammonia to form primary amines are conducted with tert-butoxide base, but reactions with ammonium hydroxide would contain hydroxide as base. Thus, ammonia surrogates, ammonia in organic solvents, and ammonium salts have been used under anhydrous conditions instead with varying levels of selectivity for the primary amine. The authors report the palladium-catalyzed amination of aryl and heteroaryl chlorides and bromides with aqueous ammonia and a hydroxide base to form the primary arylamine with high selectivity. The palladium catalyst containing a new dialkyl biheteroaryl phosphine ligand (KPhos) suppresses both the formation of aryl alcohol and diarylamine side products.

Total Synthesis of Hypersampsone M

A. E. Samkian, S. C. Virgil* & B. M. Stoltz*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c07007) 🔓

The authors report the first total synthesis of hypersampsone M, an archetypal member of the homoadamantane polycyclic polyprenylated acylphloroglucinols (PPAPs). Commencing from cyclohexenone, a key cyclopentene annulation followed by ring-expansion results in an elusive hydrazulene that undergoes a series of unexpected late-stage transformations, ultimately enabling completion of the synthesis. The route detailed herein represents a potentially general strategy for the synthesis of related homoadamantane PPAPs.

Stereospecific Enzymatic Conversion of Boronic Acids to Amines

D. Hanley,^† Z.-Q. Li,^† S. Gao, S. C. Virgil, F. H. Arnold* & E. Alfonzo*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04190)

Boronic acids and esters are highly regarded for their safety, unique reactivity, and versatility in synthesizing a wide range of small molecules, bioconjugates, and materials. They are not exploited in biocatalytic synthesis, however, because enzymes that can make, break, or modify carbon–boron bonds are rare. Here, the authors introduce an engineered protoglobin nitrene transferase that catalyzes the new-to-nature amination of boronic acids using hydroxylamine. Initially targeting aryl boronic acids, they show that the engineered enzyme can produce a wide array of anilines with high yields and total turnover numbers (up to 99% yield and >4000 TTN), with water and boric acid as the only byproducts. Exploring the enzyme’s capacity for enantioselective catalysis, the authors found that a racemic alkyl boronic ester affords an enantioenriched alkyl amine, a transformation not achieved with chemocatalysts. The formation of an exclusively unrearranged product during the amination of a boronic ester radical clock and the reaction’s stereospecificity support a two-electron process akin to a 1,2-metallate shift mechanism. The developed transformation enables new biocatalytic routes for synthesizing chiral amines.

Threonine Aldolase-Catalyzed Enantioselective α-Alkylation of Amino Acids through Unconventional Photoinduced Radical Initiation

T.-C. Wang, Z. Zhang, G. Rao, J. Li, J. Shirah, R. D. Britt, Q. Zhu* & Y. Yang*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c05949)

Visible light-driven pyridoxal radical biocatalysis has emerged as a promising strategy for the stereoselective synthesis of valuable noncanonical amino acids (ncAAs). Previously, the use of well-tailored photoredox catalysts represented the key to enable efficient pyridoxal phosphate (PLP) enzyme-catalyzed radical reactions. Here, the authors report a PLP-dependent threonine aldolase-catalyzed asymmetric α-C–H alkylation of abundant amino acids using Katritzky pyridinium salts as alkylating agents. The use of engineered threonine aldolases allowed for this redox-neutral radical alkylation to proceed efficiently, giving rise to challenging α-trisubstituted and -tetrasubstituted ncAA products in a protecting-group-free fashion with excellent enantiocontrol. Mechanistically, this enantioselective α-alkylation capitalizes on the unique reactivity of the persistent enzymatic quinonoid intermediate derived from the PLP cofactor and the amino acid substrate to allow for novel radical C–C coupling. Surprisingly, this photobiocatalytic process does not require the use of well-established photoredox catalysts and operates through an unconventional photoinduced radical generation involving a PLP-derived aldimine.

Removing Neighboring Ring Influence in Monocyclic B–OH Diazaborines: Properties and Reactivity as Phenolic Bioisosteres with Dynamic Hydroxy Exchange

J. J. Blackner, O. M. Schneider, W. O. Wong & D. G. Hall*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06360)

The design of small molecules with unique geometric profiles or molecular connectivity represents an intriguing yet neglected challenge in modern organic synthesis. To expand the structural diversity of boron-containing heterocycles, the authors report the preparation of novel monocyclic hemiboronic acids, diazaborines. These compounds have enabled the study of a pseudoaromatic boranol-containing (B–OH) ring free of influence from an appended aromatic system. Synthetic and spectroscopic studies have provided insight into the aromatic character, Lewis acidic nature, chemical reactivity, and unique ability of the exocyclic B–OH unit to participate in hydroxy exchange, suggesting their use in organocatalysis and as reversible covalent inhibitors. Moreover, density functional theory and nucleus-independent chemical shift calculations reveal that the aromatic character of the boroheterocyclic ring is increased significantly in comparison to known bicyclic benzodiazaborines (naphthoid congeners), consequently leading to attenuated Lewis acidity. Direct structural comparison to a well-established biaryl isostere, 2-phenylphenol, through X-ray crystallographic analysis reveals that N-aryl derivatives are strikingly similar in size and conformation, with attenuated logP values underscoring the value of the polar BNN unit. Their potential application as low-molecular-weight scaffolds in drug discovery is demonstrated through orthogonal diversification and preliminary antifungal evaluation (Candida albicans), which unveiled analogs with low micromolar inhibitory concentration.

Stereospecific Phosphination and Thioetherification of Organoboronic Esters

H. Liang, M. R. Berwanger & J. P. Morken*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06526)

Alkyllithium-activated organoboronic esters are found to undergo stereospecific phosphination with copper chloride and chlorophosphines. They also react with thiolsulfonate electrophiles under copper catalysis. These reactions enable stereospecific phosphination and thiolation of organoboronic esters, which are further applied in preparation of chiral ligands and biologically active molecules.

Diverse Synthesis of C-Glycosides by Stereoselective Ni-Catalyzed Carboboration of Glycals

M.-Y. Lyu, S. A. Jacobo & M. K. Brown*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c06246)

C-Glycosides are important structures that are common to natural products and pharmaceutical agents. Established methods for their synthesis involve the reaction of an activated anomeric carbon. In this study, the authors report a conceptually new approach that involves the stereoselective Ni-catalyzed carboboration of glycals. In these reactions, not only is a C–C bond formed at the anomeric carbon, but a synthetically useful C–B bond is also installed. Upon C–B oxidation, differentially protected C-glycosides to be formed. In addition, stereospecific manipulation of the C–B bond leads to diverse C-glycosides. Finally, the authors report the application of this method in the synthesis of established C-glycosides, such as C-glycosyl amino acids, as well as a strategy to make all possible diastereomers at C1 and C2.

Enantioselective Carbon Isotope Exchange

M. G. J. Doyle,^† O. Bsharat,^† A. Sib, V. Derdau* & R. J. Lundgren*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03685)

The synthesis of isotopically labeled organic molecules is vital for drug and agrochemical discovery and development. Carbon isotope exchange is emerging as a leading method to generate carbon-labeled targets, which are sought over hydrogen-based labels due to their enhanced stability in biological systems. While many bioactive small molecules bear carbon-containing stereocenters, direct enantioselective carbon isotope exchange reactions have not been established. The authors describe the first example of an enantioselective carbon isotope exchange reaction, where (radio)labeled α-amino acids can be generated from their unlabeled precursors using a stoichiometric chiral aldehyde receptor with isotopically labeled CO₂ followed by imine hydrolysis. Many proteinogenic and non-natural derivatives undergo enantioselective labeling, including the late-stage radiolabeling of complex drug targets.

Angewandte Chemie International Edition

Electrophilic C(sp²)–H Cyanation with Inorganic Cyanate (OCN^–) by P^III/P^V=O-Catalyzed Phase Transfer Activation

S. Hu & A. T. Radosevich*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202409854) 🔓

An organophosphorus redox-catalyzed method for the direct electrophilic cyanation of C(sp² )–H nucleophiles with sodium cyanate (NaOCN) is reported. The catalytic deoxyfunctionalization of the OCN^– anion is enabled by the use of a small-ring phosphacyclic (phosphetane) catalyst in combination with a terminal hydrosilane O-atom acceptor and a malonate-derived bromenium donor. In situ spectroscopy under single-turnover conditions demonstrate that insoluble inorganic cyanate anion is activated by bromide displacement on a bromophosphonium catalytic intermediate to give a reactive N-bound isocyanatophosphonium ion, which delivers electrophilic “CN⁺ ” equivalents to nucleophilic (hetero)arenes and alkenes with loss of a phosphine oxide. These results demonstrate the feasibility of deoxyfunctionalization of insoluble inorganic salts by P^III /P^V =O catalyzed phase transfer activation.

Ring Contraction of Saturated Cyclic Amines and Rearrangement of Acyclic Amines Through Their Corresponding Hydroxylamines

Y. Peng, G. Wang,* H. F. T. Klare & M. Oestreich*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202410483) 🔓

Compared to modifications at the molecular periphery, skeletal adjustments present greater challenges. Within this context, skeletal rearrangement technology stands out for its significant advantages in rapidly achieving structural diversity. Yet, the development of this technology for ring contraction of saturated cyclic amines remains exceedingly rare. While most existing methods rely on specific substitution patterns to achieve ring contraction, there is a persistent demand for a more general strategy for substitution-free cyclic amines. To address this issue, the authors report a B(C₆F₅)₃-catalyzed skeletal rearrangement of hydroxylamines with hydrosilanes. This methodology, when combined with the N-hydroxylation of amines, enables the regioselective ring contraction of cyclic amines and proves equally effective for rapid reorganization of acyclic amine skeletons. By this, the direct scaffold hopping of drug molecules and the strategic deletion of carbon atoms are achieved in a mild manner.

Electrochemical Skeletal Indole Editing via Nitrogen Atom Insertion by Sustainable Oxygen Reduction Reaction

B.-S. Zhang,^† S. L. Homölle,^† T. Bauch, J. C. A. Oliveira, S. Warratz, B. Yuan, X.-Y. Gou & L. Ackermann*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202407384) 🔓

Skeletal molecular editing gained considerable recent momentum and emerged as a uniquely powerful tool for late-stage diversifications. Thus far, superstoichiometric amounts of costly hypervalent iodine(III) reagents were largely required for skeletal indole editing. In contrast, the authors show that electricity enables sustainable nitrogen atom insertion reactions to give bio-relevant quinazoline scaffolds without stoichiometric chemical redox-waste product. The transition metal-free electro-editing was enabled by the oxygen reduction reaction (ORR) and proved robust on scale, while tolerating a variety of valuable functional groups.

Exploiting Trans-Sulfinylation for the Synthesis of Diverse N-Alkyl Sulfinamides via Decarboxylative Sulfinamidation

J. A. Andrews,^† R. G. Woodger,^† C. F. Palmer, D. L Poole & M. C. Willis*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202407970) 🔓

Combining simple amines with the bench-stable sulfinylamine Tr-NSO allows in situ preparation of reactive alkyl sulfinylamines, which when combined with alkyl radicals generated by photocatalytic decarboxylation, provides N-alkyl sulfinamides. The reactions are broad in scope and tolerate a wide variety of functional groups on both the acid and amine components. The sulfinamide products are used to prepare a selection of challenging S(VI) products. The method provides a convenient way to use reactive and unstable alkyl sulfinylamines.

A Modified Arbuzov-Michalis Reaction for Selective Alkylation of Nucleophiles

J.-X. Wang,^† M.-Q. Chen,^† Y. Zhang,* B. Han,* Z.-D. Mou, X. Feng, X. Zhang & D. Niu*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202409931)

The alkylation of nucleophiles is among the most fundamental and well-developed transformations in chemistry. However, to achieve selective alkylation of complex substrates remains a non-trivial task. The authors report a general and selective alkylation method without using strong acids, bases, or metals. In this method, the readily available phosphinites/phosphites, in combination with ethyl acrylate, function as effective alkylating agents. Various nucleophilic groups, including alcohols, phenols, carboxylic acids, imides, and thiols can be alkylated. This method can be applied in the late-stage alkylation of natural products and pharmaceutical agents, achieving chemo- and site-selective modification of complex substrates.

ChemRxiv

Biocatalytic C–H Oxidation Meets Radical Cross-Coupling: Simplifying Complex Piperidine Synthesis

J. He^† , K. Yokoi^† , B. Wixted, B. Zhang, Y. Kawamata*, H. Renata* & P. S. Baran*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-9ks60) 🔓

Medicinal chemists in the modern era are targeting molecules with greater complexity to address increasingly challenging biological targets, a drive to enhance on-target specificity as well as physiochemical properties. As such, structures with greater fraction sp³ (Fsp³ ) character, reminiscent to those found in nature, are being synthesized. Many decades of synthetic methodology development have democratized access to flat, high sp² (for example biaryl linkages) which has led to the commercialization of innumerable medicines. Those approaches rely heavily on electrophilic aromatic substitution (such as halogenation) followed by Pd-based cross coupling. In contrast, methods and strategies that allow for similarly modular and rapid construction of three-dimensional saturated molecules are less well developed. Here, the authors exemplify a new approach for the rapid, modular, enantioselective construction of piperidine frameworks (the saturated analog of pyridine) that combines robust, tunable, and scalable biocatalytic methods with the logic of radical cross coupling. Thus, a set of reliable enzymatic systems (analogous to site-selective aromatic functionalization) provides scalable access to enantiopure hydroxyacid- containing piperidine derivatives that can be utilized to dramatically simplify routes to medicinally important molecules and natural products by employing recently developed electrocatalytic couplings (analogous to Pd-based cross couplings in aromatic systems).

Decarboxylative Cross-Coupling Enabled by Fe and Ni Metallaphotoredox Catalysis

R. Nsouli, S. Nayak^‡ , V. Balakrishnan^‡ , J.-Y. Lin^‡ , B. K. Chi, H. G. Ford, A. V. Tran, I. A. Guzei, J. Bacsa, N. R. Armada, F. Zenov, D. J. Weix* & L. K. G. Ackerman-Biegasiewicz*

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

Decarboxylative cross-coupling of carboxylic acids and aryl halides has become a key transformation in organic synthesis to form C(sp² )–C(sp³ ) bonds. In this report, a base metal pairing between Fe and Ni has been developed with complementary reactivity to the well-established Ir and Ni metallaphotoredox reactions. Utilizing an inexpensive FeCl₃ co-catalyst along with a pyridine carboxamidine Ni catalyst, a range of aryl iodides can be preferentially coupled to carboxylic acids over boronic acid esters, triflates, chlorides, and even bromides in high yields. Additionally, carboxylic acid derivatives containing heterocycles, N-protected amino acids, electron-rich amines, and protic functionality can be coupled in 23-96% yield with a range of sterically hindered, electron-rich, and electron-deficient aryl iodides.

Arylthianthrenium Salts for Triplet Energy Transfer Catalysis

Y. Cai, T. K. Roy, T. J. B. Zähringer, B. Lansbergen, C. Kerzig* & T. Ritter*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-gq4gf) 🔓

Sigma bond cleavage through electronically excited states allows synthetically useful transformations with two radical species. Direct excitation of simple aryl halides to form both aryl and halogen radicals necessitates UV-C light, so undesired side reactions are often observed, and specific equipment is required. Moreover, only aryl halides with extended pi systems and comparatively low triplet energy are applicable to synthetically useful energy transfer catalysis with visible light. Here, the authors show the conceptual advantages of arylthianthrenium salts (ArTTs) for energy transfer catalysis with visible light in high quantum yield as compared to conventional aryl(pseudo)halides, and their utility in arylation reactions of ethylene. The fundamental advance is enabled by the low triplet energy of ArTTs that may originate in large part from the electronic interplay between the distinct sulfur atoms in the tricyclic thianthrene scaffold, which is neither accessible in simple (pseudo)halides nor other conventional sulfonium salts.

Organic Letters

“Naked Nickel”-Catalyzed Amination of Heteroaryl Bromides

R. Saeb, B. Boulenger & J. Cornella*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01738) 🔓

The authors report that the air-stable “naked nickel” [Ni(^4-tBu stb)₃] is a competent catalyst in thermal C–N bond formation between (hetero)aryl bromides and N-based nucleophiles. The catalytic system is characterized by a “naked nickel” complex and Zn and by the absence of external light sources, photocatalysts, exogenous ligands, and electrical setups. Upon application of this method, various heteroaryls bearing Lewis-basic heteroatoms can be accommodated and directly aminated with a set of primary and secondary amines.

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