Electrooxidative C(sp3)‒H Cyanation of Sparteine and Lupanine in Undivided Batch and Continuous-Flow Cells.

Sparteine is widely used as a chiral ligand in asymmetric synthesis, but methods for providing efficient access to functionalized sparteine derivatives are still limited. Herein, we describe an electrochemical α-cyanation of sparteine-type bis-quinolizidine alkaloids. This method features commercially available setups for batch and single-pass continuous flow conditions, enabling easy gram scale synthesis of valuable racemic and enantiopure products. Moreover, insights into the selectivity of the reaction and overoxidation mechanisms are disclosed. This allows for the development of divergent oxidation pathways depending on the electrolysis conditions.

Enantioconvergent Cross-Nucleophile Coupling: Copper-Catalyzed Deborylative Cyanation.

Organoboron compounds are widely utilized in organic synthesis for their diverse reactivity, modular preparation, and stability compared to other classes of organometallic reagents. While organoboron species are commonly employed as nucleophiles in cross-coupling reactions, their potential as racemic building blocks in enantioconvergent transformations remains largely untapped. Herein, we demonstrate the direct utilization of alkylboronic pinacol esters in intermolecular enantioconvergent transformations. Specifically, this work describes the development and mechanistic study of an enantioconvergent deborylative cyanation enabled by Cu catalysis. This method imparts a high degree of enantioselectivity and tolerates a wide range of common functional groups and heterocycles. The reaction is proposed to proceed through a radical-relay mechanism. Aniline-assisted homolysis of the carbon-boron bond results in prochiral alkyl radicals that are functionalized by in situ generated Cu(II)(CN)2 species in an enantioselective fashion. The Cu(II)(CN)2 intermediate was characterized by electron paramagnetic resonance (EPR) spectroscopy, and its electronic structure was probed using density functional theory (DFT) calculations. Computational studies were carried out to corroborate the proposed radical-relay mechanism.

Copper-Catalyzed Trifunctionalization of Heteroaryl-Substituted 1-Hexenes via Remote Heteroaryl Migration.

A copper-catalyzed trifunctionalization (trifluoromethylation, heteroarylation, and cyanation) of heteroaryl-substituted 1-hexenes via remote heteroaryl migration is reported. A variety of CF3 and heteroaryl-containing nitriles were readily constructed under mild conditions. The reaction features high chemo- and regioselectivities and represents a convenient method for the synthesis of multifunctionalized molecules in organic synthesis.

Formation of a diiron-(µ-η1:η1-CN) complex from acetonitrile solution.

The activation of C-C bonds by transition-metal complexes is of continuing interest and acetonitrile (MeCN) has attracted attention as a cyanide source with comparatively low toxicity for organic cyanation reactions. A diiron end-on µ-η1:η1-CN-bridged complex was obtained from a crystallization experiment of an open-chain iron-NHC complex, namely, µ-cyanido-κ2C:N-bis{[(acetonitrile-κN)[3,3'-bis(pyridin-2-yl)-1,1'-(methylidene)bis(benzimidazol-2-ylidene)]iron(II)} tris(hexafluorophosphate), [Fe2(CN)(C2H3N)2(C25H18N6)2](PF6)3. The cyanide appears to originate from the MeCN solvent by C-C bond cleavage or through carbon-hydrogen oxidation.

Electrophilic C(sp2)-H Cyanation with Inorganic Cyanate (OCN-) by PIII/PV=O-Catalyzed Phase Transfer Activation.

An organophosphorus -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 PIII/PV=O catalyzed phase transfer activation.

High-Voltage Single-Ion Covalent Organic Framework Electrolytes Enabled by Nitrile Migration Ladders for Lithium Metal Batteries.

The poor electrochemical stability window and low ionic conductivity in solid-state electrolytes hinder the development of safe, high-voltage, and energy-dense lithium metal batteries. Herein, taking advantage of the unique electronic effect of nitrile groups, we designed a novel azanide-based single-ion covalent organic framework (CN-iCOF) structure that possesses effective Li+ transport and high-voltage stability in lithium metal batteries. Density functional theory (DFT) calculations and molecular dynamics (MD) revealed that electron-withdrawing nitrile groups not only resulted in an ultralow HOMO energy orbital but also enhanced Li+ dissociation through charge delocalization, leading to a high tLi+ of 0.93 and remarkable oxidative stability up to 5.6 V (vs. Li+/Li) simultaneously. Moreover, cyanation leveraging Strecker reaction transformed reversible imine-linkage to a stable sp3-carbon-containing azanide anion, which facilitated contorted alignment of transport "ladders" along the one-dimensional anionic channels and the ionic conductivity could reach 1.33×10-5 S cm-1 at ambient temperature without any additives. As a result, CN-iCOF allowed operation of solid-state lithium metal batteries with high-voltage cathodes such as LiNi0.8Mn0.1Co0.1O2 (NCM811), demonstrating stable lithium deposition up to 1,100 h and reversible battery cycling at ambient temperature up to 4.5 V, shedding light on the importance of discovering new functionality for forthcoming high-performance batteries.

Copper-Catalyzed Radical Allene C(sp2 )-H Cyanation.

While the hydrogen atom abstraction (HAA) from C(sp3 )-H bond has been well explored, the radical-mediated chemo- and regio-selective functionalization of allenic C(sp2 )-H bond via direct HAA from C(sp2 )-H bond of allene remains an unsolved challenge in synthetic chemistry. This is primarily due to inherent challenges with addition of radical intermediates to allenes, regioselectivity of HAA process, instability of allenyl radical toward propargyl radical et al. Herein, we report a copper catalyzed allenic C(sp2 )-H cyanation of an array of tri- and di-substituted allenes with exceptional site-selectivity, while mono-substituted allene was successfully cyanated, albeit with a low yield. In the developed strategy, steric N-fluoro-N-alkylsulfonamide, serving as precursor of hydrogen atom abstractor, plays a crucial role in achieving the desired regioselectivity and avoiding addition of N-centered radical to allene.

DWL-4-140: A allene small molecule targeting STING that alleviates lupus-like phenotype in Trex1-/- mice.

The innate immune system plays a critical role in the host response against pathogenic microbial infection. However, aberrant activation of the innate immune pathways is a characteristic feature of various diseases. Thus, targeted drugs must be developed based on the understanding of the innate immune signaling pathways. This study demonstrated that an allene small molecule (DWL-4-140) can efficiently and selectively exert regulatory effects on the stimulator of interferon genes (STING), resulting in the downregulation of DNA-induced interferon responses. Mechanistically, DWL-4-140 targeted the cyclized nucleotide-binding domain (CBD) of STING, inhibiting the assembly of the STING multimeric complex and the recruitment of downstream signaling mediators. In addition to downregulating the 10-carboxymethyl-9-acridanone-induced production of inflammatory factors, DWL-4-140 alleviated the pathological features of Trex1 deletion-induced lupus in mice. Thus, this study demonstrated that DWL-4-140 pharmacologically inhibits STING with potential therapeutic applications in auto-inflammatory diseases.

Pairing Electrocarboxylation of Unsaturated Bonds with Oxidative Transformation of Alcohol and Amine.

A parallel paired electrosynthetic method, coupling electrocarboxylation incorporating CO2 into ketone, imine, and alkene with alcohol oxidation or oxidative cyanation of amine, was developed for the first time. Various carboxylic acids as well as aldehyde/ketone or α-nitrile amine were prepared at the cathode and anode respectively in a divided cell. Its utility and merits on simultaneously achieving high atom-economic CO2 utilization, elevated faradaic efficiency (FE, total FE of up to 166 %), and broad substrate scope were demonstrated. The preparation of pharmaceutical intermediates for Naproxen and Ibuprofen via this approach proved its potential application in green organic electrosynthesis.

Nitrilase mediated mild hydrolysis of a carbon-14 nitrile for the radiosynthesis of 4-(7-hydroxycarbamoyl-[1-14 C-heptanoyl]-oxy)-benzoic acid methyl ester, [14 C]-SHP-141: A novel class I/II histone deacetylase (HDAC) inhibitor.

A strategy has been developed for the carbon-14 radiosynthesis of [14 C]-SHP-141, a 4-(7-hydroxycarbamoyl-heptanoyloxy)-benzoic acid methyl ester derivative containing a terminal hydroxamic acid. The synthesis involved four radiochemical transformations. The key step in the radiosynthesis was the conversion of the 7-[14 C]-cyano-heptanoic acid benzyloxyamide [14 C]-4 directly into the carboxylic acid derivative, 7-benzyloxycarbamoyl-[14 C]-heptanoic acid [14 C]-8 using nitrilase-113 biocatalyst. The final step involved deprotection of the benzyloxy group using catalytic hydrogenation to facilitate the release of the hydroxamic acid without cleaving the phenoxy ester. [14 C]-SHP-141 was isolated with a radiochemical purity of 90% and a specific activity of 190 µCi/mg from four radiochemical steps starting from potassium [14 C]-cyanide in a radiochemical yield of 45%.

11 C-Cyanation of Aryl Fluorides via Nickel and Lithium Chloride-Mediated C-F Bond Activation.

Aryl fluorides are expected to be useful as radiolabeling precursors due to their chemical stability and ready availability. However, direct radiolabeling via carbon-fluorine (C-F) bond cleavage is a challenging issue due to its significant inertness. Herein, we report a two-phase radiosynthetic method for the ipso-11 C-cyanation of aryl fluorides to obtain [11 C]aryl nitriles via nickel-mediated C-F bond activation. We also established a practical protocol that avoids the use of a glovebox, except for the initial preparation of a nickel/phosphine mixture, rendering the method applicable for general PET centers. This method enabled the efficient synthesis of diverse [11 C]aryl nitriles from the corresponding aryl fluorides, including pharmaceutical drugs. Stoichiometric reactions and theoretical studies indicated a significant promotion effect of lithium chloride on the oxidative addition, affording an aryl(chloro)nickel(II) complex, which serves as a precursor for rapid 11 C-cyanation.

Boron Lewis Acid Catalysis Enables the Direct Cyanation of Benzyl Alcohols by Means of Isonitrile as Cyanide Source.

The development of an efficient and straightforward method for cyanation of alcohols is of great value. However, the cyanation of alcohols always requires toxic cyanide sources. Herein, an unprecedented synthetic application of an isonitrile as a safer cyanide source in B(C6F5)3-catalyzed direct cyanation of alcohols is reported. With this approach, a wide range of valuable α-aryl nitriles was synthesized in good to excellent yields (up to 98%). The reaction can be scaled up and the practicability of this approach is further manifested in the synthesis of an anti-inflammatory drug, naproxen. Moreover, experimental studies were performed to illustrate the reaction mechanism.

Terminal Cyano-Functionalized Fused Bithiophene Imide Dimer-Based n-Type Small Molecular Semiconductors: Synthesis, Structure-Property Correlations, and Thermoelectric Performances.

n-Doped small molecular organic thermoelectric materials (OTMs) hold advantages of high Seebeck coefficient and better performance reproducibility over their polymeric analogues; however, high-performance n-type small molecular OTMs are severely lacking. We report here a class of small molecular OTMs based on terminal cyanation of a bithiophene imide-based ladder-type heteroarene BTI2. It was found that the cyanation could effectively lower the lowest unoccupied molecular orbital (LUMO) level from -2.90 eV (BTI2) to -4.14 eV (BTI2-4CN) and thus lead to significantly improved n-doping efficiency. Additionally, terminal cyano-functionalization can maintain the close packing and efficient intermolecular charge transfer between these cyanated molecules, thus yielding high electron mobilities of up to 0.40 cm2 V-1 s-1. Benefiting from its low LUMO-enabled efficient n-doping and high electron mobility, an encouraging n-type electrical conductivity of 0.43 S cm-1 and power factor (PF) of 6.34 µW m-1 K-2 were achieved for tetracyanated BTI2-4CN, significantly outperforming those of its noncynated BTI2 (<10-7 S cm-1, PF undetectable) and dicyanated BTI2-2CN (0.24 S cm-1, 1.78 µW m-1 K-2). These results suggest the great potential of the terminal cyanation strategy of ladder-type heteroarenes for developing high-performance small molecular OTMs.

11C, 12C and 13C-Cyanation of Electron-Rich Arenes via Organic Photoredox Catalysis.

As a non-invasive imaging technology, positron emission tomography (PET) plays a crucial role in personalized medicine, including early diagnosis, patient screening, and treatment monitoring. The advancement of PET research depends on the discovery of new PET agents, which requires the development of simple and efficient radiolabeling methods in many cases. As bioisosteres for halogen and carbonyl moieties, nitriles are important functional groups in pharmaceutical and agrochemical compounds. Here, we disclose a mild organophotoredox-catalyzed method for efficient cyanation of a broad spectrum of electron-rich arenes, including abundant and readily available veratroles and pyrogallol trimethyl ethers. Notably, the transformations not only are compatible with various affordable 12C and 13C-cyanide sources, but also could be applied to carbon-11 synthons to incorporate [11C]nitriles into arenes. The aryl [11C]nitriles can be further derivatized to [11C]carboxylic acids, [11C]amides, and [11C]alkyl amines. The newly developed reaction can serve as a powerful tool for generating new PET agents.

Direct Regioselective C-H Cyanation of Purines.

A direct regioselective C-H cyanation of purines was developed through a sequential triflic anhydride activation, nucleophilic cyanation with TMSCN, followed by a process of base-mediated elimination of triflous acid (CF3SO2H). In most cases, the direct C-H cyanation occurred on the electron-rich imidazole motif of purines, affording 8-cyanated purine derivatives in moderate to excellent yields. Various functional groups, including allyl, alkynyl, ketone, ester, nitro et al. were tolerated and acted as a C8 directing group. The electron-donating 6-diethylamino, as C2-directing group substituent, can switch the regioselectivity of purine from 8- to 2-position, enabling the synthesis of 8- and 2-cyano 6-dialkylaminopurines from corresponding 6-chloropurine in different reaction order. Further functional manipulations of the cyano group allow the conversions of 8-cyanopurines to corresponding purine amides, imidates, imidothioates, imidamides, oxazolines, and isothiazoles.

Polyaromatic Group Embedded Cd(II)-Coordination Polymers for Microwave-Assisted Solvent-Free Strecker-Type Cyanation of Acetals.

In this work, two new 1D Cd(II) coordination polymers (CPs), [Cd(L1)(NMF)2]n (1) and [Cd(L2)(DMF)(H2O)2]n·n(H2O) (2), have been synthesized, characterized and employed as catalysts for the microwave-assisted solvent-free Strecker-type cyanation of different acetals. Solvothermal reaction between the pro-ligand, 5-{(pyren-1-ylmethyl)amino}isophthalic acid (H2L1) or 5-{(anthracen-9-ylmethyl)amino}isophthalic acid (H2L2), and Cd(NO3)2.6H2O in the presence of NMF or DMF:THF solvent, produces the coordination polymer 1 or 2, respectively. These frameworks were characterized by single-crystal and powder X-ray diffraction analyses, ATR-FTIR, elemental and thermogravimetry analysis. Their structural analysis revealed that both CPs show one-dimensional structures, but CP 1 has a 1D double chain type structure whereas CP 2 is a simple one-dimensional network. In CP 1, the dinuclear {Cd2(COO)4} unit acts as a secondary building unit (SBU) and the assembly of dinuclear SBUs with deprotonated ligand (L12-) led to the formation of a 1D double chain framework. In contrast, no SBU was observed in CP 2. To test the catalytic effectiveness of these 1D compounds, the solvent-free Strecker-type cyanation reactions of different acetals in presence of trimethylsilyl cyanide (TMSCN) was studied with CPs 1 and 2 as heterogenous catalysts. CP 1 displays a higher activity (yield 95%) compared to CP 2 (yield 84%) after the same reaction time. This is accounted for by the strong hydrogen bonding packing network in CP 2 that hampers the accessibility of the metal centers, and the presence of the dinuclear Cd(II) SBU in CP 1 which can promote the catalytic process in comparison with the mononuclear Cd(II) center in CP 2. Moreover, the recyclability and heterogeneity of both CPs were tested, demonstrating that they can be recyclable for at least for four cycles without losing their structural integrity and catalytic activity.

Paired Electrolysis Enabled Cyanation of Diaryl Diselenides with KSCN Leading to Aryl Selenocyanates.

The first example of paired electrolysis-enabled cyanation of diaryl diselenides, with KSCN as the green cyanating agent, has been developed. A broad range of aryl selenocyanates can be efficiently synthesized under chemical-oxidant- and additive-free, energy-saving and mild conditions.

Electrophotochemical Metal-Catalyzed Enantioselective Decarboxylative Cyanation.

In contrast to the rapid growth of electrophotocatalysis in recent years, enantioselective catalytic reactions powered by this unique methodology remain rare. In this work, we report an electrophotochemical metal-catalyzed protocol for direct asymmetric decarboxylative cyanation of aliphatic carboxylic acids. The synergistic merging of electrophotochemical cerium catalysis and asymmetric electrochemical copper catalysis permits mild reaction conditions for the formation and utilization of the key carbon centered radicals by combining the power of light and electrical energy. Electrophotochemical cerium catalysis enables radical decarboxylation to produce alkyl radicals, which could be effectively intercepted by asymmetric electrochemical copper catalysis for the construction of C-CN bonds in a highly stereoselective fashion. This environmentally benign method smoothly converts a diverse array of arylacetic acids into the corresponding alkyl nitriles in good yields and enantioselectivities without using chemical oxidants or pre-functionalization of the acid substrates and can be readily scaled up.

Organocatalytic Access to Tetrasubstituted Chiral Carbons Integrating Functional Groups.

Three-dimensional organic structures containing sp3 carbons bearing four non-hydrogen substituents can provide drug-like molecules. Although such complex structures are challenging targets in synthetic organic chemistry, efficient synthetic approaches will open a new chemical space for pharmaceutical candidates. This review provides an account of our recent achievements in developing organocatalytic approaches to attractive molecular platforms based on optically active sp3 carbons integrating four different functional groups. These methodologies include asymmetric cycloetherification and cyanation of multifunctional ketones, both of which take advantage of the mild characteristics of organocatalytic activation. Enzyme-like but non-enzymatic organocatalytic systems can be used to precisely manufacture molecules containing complex chiral structures without substrate specificity problems. In addition, these catalytic systems control not only stereoselectivity but also site-selectivity and do not induce side reactions even from substrates with rich functionality.

C3-Cyanation of Pyridines: Constraints on Electrophiles and Determinants of Regioselectivity.

Methods for C-H cyanation of pyridines are rare. Here, we report a method for C3-selective cyanation of pyridines by a tandem process with the reaction of an in situ generated dihydropyridine with a cyano electrophile as the key step. The method is suitable for late-stage functionalization of pyridine drugs. The low reduction potential of the electrophile and effective transfer of the nitrile group were found to be essential for the success of this method. We studied the reaction mechanism in detail by means of control experiments and theoretical calculations and found that a combination of electronic and steric factors determined the regioselectivity of reactions involving C2-substituted pyridines.