Anomeric Amides Enable Heteroaryl Halogenation

Nature

Stereospecific Alkenylidene Homologation of Organoboronates by S_NV Reaction

M. Chen, C. D. Knox, M. C. Madhusudhanan, T. H. Tugwell, C. Liu, P. Liu* & G. Dong*

Nature 2024 (DOI: 10.1038/s41586-024-07579-7)

Concerted nucleophilic substitution, known as S_N2 reaction, is a fundamental organic transformation used in synthesis to introduce new functional groups and construct carbon−carbon and carbon−heteroatom bonds. S_N2 reactions typically involve backside attack of a nucleophile to the σ* orbital of a C(sp³ )−X bond (X= halogen or other leaving group), resulting in complete inversion of a stereocenter. In contrast, the corresponding stereoinvertive nucleophilic substitution on electronically unbiased sp² vinyl electrophiles, namely concerted S_NV(σ) reaction, is much rarer and so far, limited to carefully designed substrates mostly in ring-forming processes. Here, the authors show that concerted S_NV reactions can be accelerated by a proposed strain-release mechanism in metallated complexes, leading to the development of a general and stereospecific alkenylidene homologation of diverse organoboronates. This method enables the iterative incorporation of multiple alkenylidene units, giving cross-conjugated polyenes that are challenging to prepare otherwise.

Nature Chemistry

Discovery of N–X Anomeric Amides as Electrophilic Halogenation Reagents

Y. Wang, C. Bi, Y. Kawamata, L. N. Grant, L. Samp, P. F. Richardson, S. Zhang, K. C. Harper, M. D. Palkowitz, A. Vasilopoulos, M. R. Collins, M. S. Oderinde, C. C. Tyrol, D. Chen, E. A. LaChapelle, J. B. Bailey, J. X. Qiao & P. S. Baran*

Nat. Chem. 2024 (DOI: 10.1038/s41557-024-01539-4)

Previously: ChemRxiv (DOI: 10.26434/chemrxiv-2023-z15zd) 🔓

Electrophilic halogenation is a widely used tool employed by medicinal chemists to either pre-functionalize molecules for further diversity or incorporate a halogen atom into drugs or drug-like compounds to solve metabolic problems or modulate off-target effects. Current methods to increase the power of halogenation rely on either the invention of new reagents or activating commercially available reagents with various additives such as Lewis or Brønsted acids, Lewis bases and hydrogen-bonding activators. There is a high demand for new reagents that can halogenate otherwise unreactive compounds under mild conditions. Here, the authors report the invention of a class of halogenating reagents based on anomeric amides, taking advantage of the energy stored in the pyramidalized nitrogen of N–X anomeric amides as a driving force. These robust halogenating methods are compatible with a variety of functional groups and heterocycles, as exemplified on over 50 compounds (including 13 gram-scale examples and 1 flow chemistry scale-up).

Journal of the American Chemical Society

A General Synthetic Strategy toward the Truxillate Natural Products via Solid-State Photocycloadditions

E. F. Plachinski, H. J. Kim, M. J. Genzink, K. M. Sanders, R. M. Kelch, I. A. Guzei & T. P. Yoon*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04706)

The truxillates constitute a large class of dimeric natural products featuring a central, highly substituted cyclobutane core. In principle, these structures could be efficiently synthesized via [2+2] photocycloaddition. However, the difficulty in controlling the high-energy electronically excited reactive intermediates in the solution state can lead to poor regio- and diastereocontrol. This has limited the use of photocycloaddition methodology toward the synthesis of this important class of natural products. Herein, the authors demonstrate that acid-controlled precipitation of C-acyl imidazoles promotes a highly selective solid-state photocycloaddition, and the products of this reaction can be quickly transformed into truxillate natural products.

Copper-Mediated Cyanodifluoromethylation of (hetero)Aryl Iodides and Activated (hetero)Aryl Bromides with TMSCF₂CN

J. Nicolai, T. Fantoni, T. W. Butcher, S. Arlow, S. V. Ryabukhin, D. M. Volochnyuk* & J. F. Hartwig*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03618)

Molecules bearing fluorine are increasingly prevalent in pharmaceuticals, agrochemicals, and functional materials. The cyanodifluoromethyl group is unique because its size is closer than that of any other substituted difluoromethyl group to the size of the trifluoromethyl group, but its electronic properties are distinct from those of the trifluoromethyl group. In addition, the presence of the cyano group provides synthetic entry to a wide range of substituted difluoromethyl groups. However, the synthesis of cyanodifluoromethyl compounds requires multiple steps, highly reactive reagents or specialized starting materials. Herein, the authors report a copper-mediated cyanodifluoromethylation of hetero(aryl) iodides and activated (hetero)aryl bromides with TMSCF₂CN. This cyanodifluoromethylation tolerates an array of functional groups, is applicable to late-stage functionalization of complex molecules, yields analogues of FDA-approved pharmaceuticals and fine chemicals, and enables the synthesis of a range of complex molecules bearing a difluoromethylene unit by transformations of the electron-poor CN unit.

Practical Synthesis of Chiral α-Aminophosphonates with Weak Bonding Organocatalysis at ppm Loading

J. Lu,^† Y. Yu,^† Z. Li, J. Luo & L. Deng*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c04129)

α-Aminophosphonic acids as an important class of bioisosteres of α-amino acids demonstrate various biologically important activities. Here, the authors report the development of a highly enantioselective isomerization of α-iminophosphonates enabled by an extraordinarily efficient organocatalyst. This organocatalyst afforded a total turnover number (TON) of 20,000–1,000,000 for a wide range of α-alkyl iminophosphonates. Even at a parts-per-million (ppm) loading, this catalyst achieved a complete reaction in greater than 93% enantiomeric excess (e.e.). Computational studies revealed that this small-molecule catalyst achieved enzyme-like efficiency via a network of weak bonding interactions that effectively preorganized the substrate and catalyst toward a transition-state-like complex.

Regioselective and Enantioselective Nickel-Catalyzed Intermolecular Reductive Coupling of Aliphatic Alkenes with Imines

Z.-H. Chen, L.-J. Gu, B. Wang*, L.-J. Xiao*, M. Ye & Q.-L. Zhou*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c00463)

Unactivated aliphatic alkenes are particularly desirable as starting materials because they are readily accessible in large quantities, but the enantioselective intermolecular reductive coupling of unactivated alkenes with imines is challenging. In this paper, the authors report a method for nickel-catalyzed intermolecular reductive coupling reactions between aliphatic alkenes and imines to yield chiral amines with excellent enantioselectivities and good linear selectivities. The reaction conditions are compatible with a broad range of aliphatic alkenes, including those derived from bioactive molecules. The success of this method can be attributed to the use of newly developed monodentate chiral spiro phosphine ligands.

Access to Complex Scaffolds Through [2+2] Cycloadditions of Strained Cyclic Allenes

M. S. McVeigh, J. P. Sorrentino, A. T. Hands & N. K. Garg*

J. Am. Chem. Soc. 2024, ASAP (DOI: 10.1021/jacs.4c03369)

The authors report the strain-induced [2+2] cycloadditions of cyclic allenes for the assembly of highly substituted cyclobutanes. By judicious choice of trapping agent, complex scaffolds bearing heteroatoms, fused rings, contiguous stereocenters, spirocycles, and quaternary centers are ultimately accessible. Moreover, they show that the resulting cycloadducts can undergo thermal isomerization. This study provides an alternative strategy to photochemical [2+2] cycloadditions for accessing highly functionalized cyclobutanes, while validating the use of underexplored strained intermediates for the assembly of complex architectures.

Angewandte Chemie International Edition

Copper-Catalyzed Dearomative 1,2-Hydroamination

C. W. Davis,^† Y. Zhang,^† Y. Li, M. Martinelli, J. Zhang, C. Ungarean, P. Galer, P. Liu* & D. Sarlah*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202407281)

Catalytic olefin hydroamination reactions are some of the most atom-economical transformations that bridge readily available starting materials–olefins and high-value-added amines. Despite significant advances in this field over the last two decades, the formal hydroamination of nonactivated aromatic compounds remains an unsolved challenge. Herein, the authors report the extension of olefin hydroamination to aromatic π-systems by using arenophile-mediated dearomatization and Cu-catalysis to perform 1,2-hydroamination on nonactivated arenes. This strategy was applied to a variety of substituted arenes and heteroarenes to provide general access to structurally complex amines. The authors also developed a practical, scalable desymmetrization to deliver enantioenriched dearomatized products and enable downstream synthetic applications.

Site-Selective Distal C(sp³)–H Bromination of Aliphatic Amines as a Gateway for Forging Nitrogen-Containing sp³ Architectures

J. Chen, T. K. Clarence,^‡ J. Rodrigalvarez,^‡ S. Zhang & R. Martin*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202406485)

The authors disclose a new strategy that rapidly and reliably incorporates bromine atoms at distal, secondary C(sp³ )–H sites in aliphatic amines with excellent and predictable site-selectivity pattern. The resulting halogenated building blocks serve as versatile linchpins to enable a series of carbon-carbon and carbon-heteroatom bond-formations at remote C(sp³ ) sites, thus offering a new modular and unified platform that expedites the access to advanced sp³ architectures possessing valuable nitrogen-containing saturated heterocycles of interest in medicinal chemistry settings.

Nickel-Catalyzed Highly Selective Radical C-C Coupling from Carboxylic Acids with Photoredox Catalysis

B. Ling, S. Yao, S. Ouyang, H. Bai, X. Zhai, C. Zhu,* W. Li* & J. Xie*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202405866)

The selective coupling of two different radicals is a long-standing challenge due to the process occurring statistically. Generally, the cross-coupling selectivity is achieved by the persistent radical effect (PRE), resulting in limited radical precursors. In this paper, a highly selective cross-coupling of alkyl radicals with acyl radicals to construct C(sp² )-C(sp³ ) bonds, or with alkyl radicals to construct C(sp³ )-C(sp³ ) bonds have been achieved with the readily available carboxylic acids and their derivatives (NHPI ester) as coupling partners. This protocol offers a facile and flexible access to structurally diverse ketones (up to 90% yield), and also a new solution for the challenging double decarboxylative C(sp³ )-C(sp³ ) coupling.

Chemoselective and Stereoselective Allylation of Bis(alkenyl)boronates

M.-K. Tran & J. M. Ready*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202407824)

Bis(alkenyl)boronates react with optically active Ir(π-allyl) species in a process that involves allylation of the more substituted olefin and 1,2-metalate shift of the less substituted olefin. The method constructs valuable enantioenriched tertiary allylic boronic esters with high chemoselectivity, enantioselectivity and diastereoselectivity. Allylic functionalization reactions transform the 1,3-stereodiad to 1,5- and 1,6-stereochemical relationships.

A Rationally Designed Iron(II) Catalyst for C(sp³)−C(sp²) and C(sp³)−C(sp³) Suzuki−Miyaura Cross-Coupling

D. Chen, C. Lepori, R. Guillot, R. Gil, S. Bezzenine & J. Hannedouche*

Angew. Chem. Int. Ed. 2024, Accepted (DOI: 10.1002/anie.202408419) 🔓

Despite the paramount importance of the Suzuki-Miyaura coupling (SMC) in academia and industry, and the great promise of iron to offer sustainable catalysis, iron-catalyzed SMC involving sp³ -hybridized partners is still in its infancy. The authors report the development of a versatile, well-defined electron-deficient anilido-aldimine iron(II) catalyst. This catalyst effectively performed C(sp³ )-C(sp² ) and C(sp³ )-C(sp³ ) SMC of alkyl halide electrophiles and (hetero)aryl boronic ester and alkyl borane nucleophiles respectively, in the presence of a lithium amide base. These couplings operated under mild reaction conditions and displayed wide functional group compatibility including various medicinally relevant N-, O- and S-based heterocycles. They also tolerated primary, secondary and tertiary alkyl halides (Br, Cl, I), electron-neutral, -rich and -poor boronic esters and primary and secondary alkyl boranes. The methodology could be directly and efficiently applied to synthesize key intermediates relevant to pharmaceuticals and a potential drug candidate.

ChemRxiv

Oxidative Amination of Unactivated Alkenes via Nitrogen Atom Insertion into Carbon-Carbon Double Bonds

Y. Brägger,^† A.-S. K. Paschke,^† N. Nasiri, B. B. Botlik, F. Felician, B. Morandi*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-6r5wn) 🔓

The synthesis of nitrogen-containing molecules through C–N bond formation is critical for the discovery and preparation of medicines, agrochemicals and materials. Traditional synthetic methods using alkenes as ubiquitous substrates leverage the reactivity of the C(sp² )–C(sp² ) π-bond for C–N bond formation. In contrast, methods that can form C–N bonds through complete cleavage of the double bond are scarce, despite the considerable synthetic potential of such a strategy. Here, the authors report the direct insertion of a nitrogen atom into unactivated carbon-carbon double bonds to access aza-allenium intermediates which can be converted either into nitriles or amidine products, depending on the initial alkene substitution pattern. This operationally simple and highly functional group tolerant reaction works on a wide range of unactivated alkenes.

Oxidative Nitrogen Insertion into Silyl Enol Ether C=C Bonds

A. Lin, A. Ghosh,^‡ S. Yellen,^‡ Z. T. Ball* & L. Kürti*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-2k2g0) 🔓

The authors demonstrate a fundamentally new reactivity of the silyl enol ether functionality utilizing an in situ-generated “iodonitrene”-like species. The present transformation inserts a single nitrogen atom between the silyl enol ether olefinic carbons with concomitant cleavage of the C=C bond without fragmentation. Overall, this facile transformation converts a C-nucleophilic silyl enol ether to the corresponding C-electrophilic N-acyl-N,O-acetal. This unprecedented access to alpha-amidoalkylating agents enables facile and modular derivatization, allowing deep exploration of unchartered chemical space. Applications presented herein include late-stage nitrogen insertion into carbon skeletons of complex natural products with previously unattainable regioselectivity, as well as modified conditions for ¹⁵ N labeling of amides and lactams.

Formate-Mediated Aryl Halide Reductive Cross-Coupling Catalyzed by Iodide-Bridged Palladium(I) Dimers: Experimental and Computational Studies

Y. Cho,^† Y.-H. Chang,^† Z. H. Strong,^† K. P. Quirion,^† Z. J. Dubey, N. Nguyen, S. Lee, N. A. White,* P. Liu* & M. J. Krische*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-fmc1n) 🔓

The first efficient reductive cross-couplings of aryl halides mediated by an abundant feedstock, sodium formate, are described. These processes, which exploit air-stable Pd(I) iodide dimers, are especially effective for challenging 2-pyridyl systems due to intervention of chelated intermediates. Furthermore, orthogonality with respect to Suzuki and Buchwald-Hartwig coupling processes is displayed, as pinacol boronates and anilines are tolerated. Although palladium-catalyzed transfer hydrogenolyses of aryl halides mediated by formate are longstanding, it is not a major competing pathway under the present conditions. Experimental and computational studies corroborate a novel catalytic cycle for cross-coupling where the Pd(I) precatalyst, [Pd(I)(P^tBu₃)]₂, is converted to the active dianionic catalyst, [Pd₂I₄][NBu₄]₂, from which aryl halide oxidative addition is more facile. Rapid, reversible Pd-to-Pd transmetalation delivers iodide-bridged diarylpalladium dimers. The hetero-diarylpalladium dimers are more stable than the homodimers and have lower barriers to reductive elimination, resulting in high cross-selectivity.

Defluorinative Multicomponent Cascade Reaction of Trifluoromethylarenes via Palladium Photoredox Catalysis

Z. Li, L. Bao, K. Wei, B. Zhan, P. Lu & X. Zhang*

ChemRxiv 2024 (DOI: 10.26434/chemrxiv-2024-9m6sx) 🔓

The incorporation of aromatic difluoromethyl motifs has proven to be a fruitful strategy for enhancing the therapeutic profiles of modern pharmaceutical candidates. While the defluorofunctionalization of trifluoromethylarenes offers a promising pathway towards diverse aromatic difluoromethyl compounds, current methods are predominantly limited to two-component reactions. Multicomponent cascade reactions (MCRs) involving a transient aromatic difluoromethyl radical are still uncommon and highly sought after owing to their capacity to rapidly generate challenging molecular structures. In this study, the authors present a photocatalytic manifold that combines commercially available trifluoromethylarenes, feedstock dienes and various nucleophiles to achieve a modular defluorinative MCR. This method features mild reaction conditions and a broad substrate scope with excellent functional group compatibility.

Organic Letters

Expanding Natural Diversity: Tailored Enrichment of the 8,12-Sesquiterpenoid Lactone Chemical Space through Divergent Synthesis

V. P. Demertzidou,^† M. Kourgiantaki^† & A. L. Zografos*

Org. Lett. 2024, ASAP (DOI: 10.1021/acs.orglett.4c01374)

The divergent synthesis of a non-natural 8,12-sesquiterpenoid lactone collection is described. The synthesis relies on a rationally designed guaianolide scaffold bearing a tertiary hydroxyl as the pinpoint for inducing its selective diversification. Key reactions include an unprecedented Suarez-type CH lactonization and a highly diastereoselective oxy-Cope/ene cascade that allows the introduction of three stereocenters in a single operation. Selective oxidative/reductive and redox neutral transformations follow to highlight the synthesis of naturally unpresented highly substituted 8,12-guaianolides.

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