A Modular Approach for Accessing 3D Heterocycles via 1,2-Dicyanation of Planar N-Heteroarenes.

The rapid construction of three-dimensional (3D) heterocyclic frameworks is a key challenge in contemporary medicinal chemistry. The molecules with three-dimensional complexity hold a greater probability to improve clinical outcomes, solubility, selectivity for target proteins, and metabolic stability. However, the prevalence of flat molecules persists among new drug candidates, primarily owing to the multitude of chemical methods available for their synthesis. In principle, the dearomative functionalization of N-heteroarene allows for the conversion of readily available planar molecules into partially or fully saturated nitrogen heterocycles, which are most significant structural motifs of pharmaceuticals and natural products. Unfortunately, these reactions are very rare because of the inherent challenge imposed by heteroarenes' poor reactivity, rendering the process thermodynamically unfavorable. Herein, we report a modular approach for accessing 3D chemical space in translating planar heteroarenes into valuable 3D heterocycles via the installation of a highly versatile cyano group as a new vector. This approach is enabled by the in situ generation of reactive, non-symmetric iodane by combining cyanide anion and bench-stable PhI(OAc)2. This reaction represents a rare example of 1,2-dicyanation of N-heteroarenes that meets the numerous requirements for broad implementation in drug and agrochemical discovery.

Hydrogen bonding template enables remote meta-C-H alkenylation of nitroarenes with electron-deficient alkenes.

Regioselective distal C-H functionalization of nitroarenes by overriding proximal C-H activation has remained an unsolved challenge. Herein, we present a palladium-catalyzed meta-C-H alkenylation of nitroarene substrate, achieved through leveraging the non-covalent hydrogen bonding interactions. Urea-based templates comprising an elongated biphenyl linker designed in such a way that it interacts with nitro group via strong hydrogen bonding interaction, while a cyano based directing group is attached along the template to coordinate with the palladium center, thereby facilitating the activation of the remote meta-C-H bond of nitrobenzene. Computational mechanistic investigation and the analysis of non-covalent interaction deciphers the crucial role of H-bonding in regulating the regioselectivity.

Deuteration and Tritiation of Pharmaceuticals by Non-Directed Palladium-Catalyzed C-H Activation in Heavy and Super-Heavy Water.

Deuterated and tritiated analogs of drugs are valuable compounds for pharmaceutical and medicinal chemistry. In this work, we present a novel hydrogen isotope exchange reaction of drugs using non-directed homogeneous Pd-catalysis. Aromatic C-H activation is achieved by a commercially available pyridine ligand. Using the most convenient and cheapest deuterium source, D2O, as the only solvent 39 pharmaceuticals were labelled with clean reaction profiles and high deuterium uptakes. Additionally, we describe the first application of non-directed homogeneous Pd catalysis for H/T exchange on three different pharmaceuticals by using T2O as isotopic source, demonstrating the applicability to the synthesis of radiotracers.

Impact of the Hydrophilicity of Poly(sarcosine) on Poly(ethylene glycol) (PEG) for the Suppression of Anti-PEG Antibody Binding.

A method of poly(ethylene glycol) (PEG) conjugation is known as PEGylation, which has been employed to deliver therapeutic drugs, proteins, or nanoparticles by considering the intrinsic non- or very low immunogenic property of PEG. However, PEG has its weaknesses, and one major concern is the potential immunogenicity of PEGylated proteins. Because of its hydrophilicity, poly(sarcosine) (P(Sar)) may be an attractive-and superior-substitute for PEG. In the present study, we designed a double hydrophilic diblock copolymer, methoxy-PEG-b-P(Sar) m (m = 5-55) (mPEG-P(Sar) m ), and synthesized a triblock copolymer with hydrophobic poly(l-isoleucine) (P(Ile)). We validated that double hydrophilic mPEG-P(Sar) block copolymers suppressed the specific binding of three monoclonal anti-PEG antibodies (anti-PEG mAbs) to PEG. The results of our indirect ELISAs indicate that P(Sar) significantly helps to reduce the binding of anti-PEG mAbs to PEG. Importantly, the steady suppression of this binding was made possible, in part, thanks to the maximum number of sarcosine units in the triblock copolymer, as evidenced by sandwich ELISA and biolayer interferometry assay (BLI): the intrinsic hydrophilicity of P(Sar) had a clear supportive effect on PEG. Finally, because we used P(Ile) as a hydrophobic block, PEG-P(Sar) might be an attractive alternative to PEG in the search for protein shields that minimize the immunogenicity of PEGylated proteins.

Pd-catalyzed regioselective activation of C(sp2)-H and C(sp3)-H bonds.

Differentiating between two highly similar C-H bonds in a given molecule remains a fundamental challenge in synthetic organic chemistry. Directing group assisted strategies for the functionalisation of proximal C-H bonds has been known for the last few decades. However, distal C-H bond functionalisation is strenuous and requires distinctly specialised techniques. In this review, we summarise the advancement in Pd-catalysed distal C(sp2)-H and C(sp3)-H bond activation through various redox manifolds including Pd(0)/Pd(II), Pd(II)/Pd(IV) and Pd(II)/Pd(0). Distal C-H functionalisation, where a Pd-catalyst is directly involved in the C-H activation step, either through assistance of an external directing group or directed by an inherent functionality or functional group incorporated at the site of the Pd-C bond is covered. The purpose of this review is to portray the current state of art in Pd-catalysed distal C(sp2)-H and C(sp3)-H functionalisation reactions, their mechanism and application in the late-stage functionalisation of medicinal compounds along with highlighting its limitations, thus leaving the field open for further synthetic adjustment.

Expedited Proton Relay in Enzyme-Inspired Cobaloximes Facilitate Organic Transformations.

Developing a water-soluble, oxygen-tolerant, and acid-stable synthetic H2 production catalyst is vital for renewable energy infrastructure. To access such an effective catalyst, we strategically incorporated enzyme-inspired, multicomponent outer coordination sphere elements around the cobaloxime (Cl-Co-X) core with suitable axial coordination (X). Our cobaloximes with axial imidazole or L-histidine coordination in photocatalytic HAT including the construction of anilines via a non-canonical cross-coupling approach is found superior compared to commonly used cobaloxime catalysts. The reversible Co(II)/Co(I) process is influenced by the axial N ligand's nature. Imidazole/L-histidine with a higher pKa promptly produces H2 upon irradiation, leading to the improved reactivity compared to previously employed axial (di)chloride or pyridine analogue.

Palladium-Catalyzed Remote C-H Functionalization: Non-Covalent Interactions and Reversibly Bound Templates.

Pd-catalysis has stood as a pivotal force in synthetic transformations for decades, maintaining its status as a paramount tool in the realm of C-H bond activation. While functionalization at proximal positions has become commonplace, achieving selective and sustainable access to distal positions continues to captivate scientific endeavors. Recently, a noteworthy trend has emerged, focusing on the utilization of non-covalent interactions to address the challenges associated with remote functionalization. The integration of these non-covalent interactions into palladium catalysis stands as a justified response to the demands of achieving selective transformations at distal positions. This review delves into the latest advancements and trends surrounding the incorporation of non-covalent interactions within the field of palladium catalysis. Furthermore, it is noteworthy to emphasize that multifunctional templates, particularly those harnessing hydrogen bonding, present an elegant and sophisticated approach to activate C-H bonds in a highly directed fashion. These templates showcase versatility and demonstrate potential applications across diverse contexts within the area of remote functionalization.

Tandem dehydrogenation-olefination-decarboxylation of cycloalkyl carboxylic acids via multifold C-H activation.

Dehydrogenation chemistry has long been established as a fundamental aspect of organic synthesis, commonly encountered in carbonyl compounds. Transition metal catalysis revolutionized it, with strategies like transfer-dehydrogenation, single electron transfer and C-H activation. These approaches, extended to multiple dehydrogenations, can lead to aromatization. Dehydrogenative transformations of aliphatic carboxylic acids pose challenges, yet engineered ligands and metal catalysis can initiate dehydrogenation via C-H activation, though outcomes vary based on substrate structures. Herein, we have developed a catalytic system enabling cyclohexane carboxylic acids to undergo multifold C-H activation to furnish olefinated arenes, bypassing lactone formation. This showcases unique reactivity in aliphatic carboxylic acids, involving tandem dehydrogenation-olefination-decarboxylation-aromatization sequences, validated by control experiments and key intermediate isolation. For cyclopentane carboxylic acids, reluctant to aromatization, the catalytic system facilitates controlled dehydrogenation, providing difunctionalized cyclopentenes through tandem dehydrogenation-olefination-decarboxylation-allylic acyloxylation sequences. This transformation expands carboxylic acids into diverse molecular entities with wide applications, underscoring its importance.

Combinatorial Ligand Assisted Simultaneous Control of Axial and Central Chirality in Highly Stereoselective C-H Allylation.

The significance of stereoselective C-H bond functionalization thrives on its direct application potential to pharmaceuticals or complex chiral molecule synthesis. Complication arises when there are multiple stereogenic elements such as a center and an axis of chirality to control. Over the years cooperative assistance of multiple chiral ligands has been applied to control only chiral centers. In this work, we harness the essence of cooperative ligand approach to control two different stereogenic elements in the same molecule by atroposelective allylation to synthesize axially chiral biaryls from its racemic precursor. The crucial roles played by chiral phosphoric acid and chiral amino acid ligand in concert helped us to obtain one major stereoisomer out of four distinct possibilities.

Urea-Promoted Neat Synthesis of Fused Dihydroisoquinolines and Disubstituted Pyridines: A Mechanistic Observation with Molecular-Sensing Studies.

An efficient and short synthesis of fused dihydroisoquinolines, diaryl substituted pyridine derivatives in good to high yields has been established by using an environmentally safe, solvent-metal-oxidant-free tandem approach. In this article, we discuss how the electrocyclic reaction is more pronounced in the solid phase in the presence of urea, whereas the typical aza-Michael addition is more prominent in presence of arylamine in the solution phase for 3-(2-formylcycloalkenyl)acrylic ester derivative substrates. The wide range of substrates and urea-promoted neat synthesis made our approach more significant in medical and also analytical science. Moreover, an isoquinoline alkaloid decumbenine B analogue has been synthesized by using our newly developed neat methodology. We have also investigated the photophysical properties of the synthesized fused dihydroisoquinoline derivatives. One of the synthesized molecules was used as a sensor for the selective detection of toxic picric acid. Therefore, the effective neat synthesis and molecular sensing applications of these compounds made our approach more exciting in the field of heterocyclic chemistry.

Photo-Catalyzed Acyl Azolium Promoted Selective α-C(sp3 )-H Acylation of Acetone via HAT: Access to Thermodynamically Less Favoured (Z)-α,ß-Unsaturated Ketones.

Mono α-acylation of acetone has been achieved for the first time by reacting with bench-stable acyl azolium salts under violet-LED light at room temperature. The intermolecular hydrogen atom transfer (HAT) from acetone to triplet state of azolium salts under violet LED irradiation resulted in thermodynamically less favourable (Z)-α,ß-unsaturated ketones with up to 99 : 1 selectivity via C-C bond formation. This compelling protocol access the desired α-C(sp3 )-H acylation product under metal-, ligand- and oxidant-free conditions on a wide range of substrates.

Highly scalable photoinduced synthesis of silanols via untraversed pathway for chlorine radical (Cl•) generation.

The emergence of visible light-mediated synthetic transformations has transpired as a promising approach to redefine traditional organic synthesis in a sustainable way. In this genre, transition metal-mediated photoredox catalysis has led the way and recreated a plethora of organic transformations. However, the use of photochemical energy solely to initiate the reaction is underexplored. With the direct utilization of photochemical energy herein, we have established a general and practical protocol for the synthesis of diversely functionalized organosilanols, silanediols, and polymeric siloxanol engaging a wide spectrum of hydrosilanes under ambient reaction conditions. Streamlined synthesis of bio-active silanols via late-stage functionalization underscores the importance of this sustainable protocol. Interestingly, this work also reveals photoinduced non-classical chlorine radical (Cl•) generation from a readily available chlorinated solvent under aerobic conditions. The intriguing factors of the proposed mechanism involving chlorine and silyl radicals as intermediates were supported by a series of mechanistic investigations.

Electro-oxidative Synthesis of Unsymmetrical Alkyne-1,4-diones via Sequential Ring Formation and Cleavage.

Synthesis of unsymmetrical but-2-yne-1,4-diones is reported through oxidative alkyne translocation of readily accessible homopropargylic alcohols. The developed method consists of an unprecedented one-pot sequential electro-oxidative annulation-fragmentation-chemical selenoxide elimination process. Excellent functional group compatibility was observed, and an array of yne-1,4-diones were synthesized. Derivatization of the alkyne gave access to other valuable scaffolds. Detailed mechanistic studies through the isolation of key intermediates clarified the cascade transformation.

Base Metal Catalyst for Indirect Hydrogenation of CO2.

We herein report a novel Mn-SNS-based catalyst, which is capable of performing indirect hydrogenation of CO2 to methanol via formylation. In this domain of CO2 hydrogenation, pincer ligands have shown a clear predominance. Our catalyst is based on the SNS-type tridentate ligand, which is quite stable and cheap as compared to the pincer type ligands. The catalyst can also be recycled effectively after the formylation reaction without any significant change in efficiency. Various amines including both primary and secondary amines worked well under the protocol to provide the desired formylated product in good yields. The formed formylated amines can also be reduced further at higher pressures of hydrogen. As a whole, we have developed a protocol that involves indirect CO2 hydrogenation to methanol that proceeds via formylation of amines.

Transition-metal catalyzed C-H activation as a means of synthesizing complex natural products.

Over the past few decades, the advent of C-H activation has led to a rethink among chemists about the synthetic strategies employed for multi-step transformations. Indeed, deploying innovative and masterful tricks against the numerous classical organic transformations has been the need of the hour. Despite this, the immense importance of C-H activation remains unfulfilled unless the methodology can be deployed for large-scale industrial processes and towards the concise, step-economic synthesis of prodigious natural products and pharmaceutical drugs. Lately, the growing potential of C-H activation methodology has indeed driven the pioneers of synthetic organic chemists into finding more efficient methods to accelerate the synthesis of such complex molecular scaffolds. This review aims to draw a general overview of the various C-H activation procedures that have been adopted for synthesizing these vast majority of structurally complicated natural products. Our objective lies in drawing a complete picture and taking the readers through the synthesis of a series of such complex organic compounds by simplified techniques, making it step-economic on a larger scale and thus instigating the readers to trigger the use of such methodology and uncover new, unique patterns for future synthesis of such natural products.

Directing group assisted para-selective C-H alkynylation of unbiased arenes enabled by rhodium catalysis.

Regioselective C-H alkynylation of arenes via C-H activation is challenging yet a highly desirable transformation. In this regard, directing group assisted C(sp2)-H alkynylation of arenes offers a unique opportunity to ensure precise regioselectivity. While the existing methods are mainly centered around ortho-C-H alkynylation and a few for meta-C-H alkynylation, the DG-assisted para-selective C-H alkynylation is yet to be reported. Herein we disclose the first report on Rh-catalyzed para-C-H alkynylation of sterically and electronically unbiased arenes. The para-selectivity is achieved with the assistance of a cyano-based directing template and the selectivity remained unaltered irrespective of the steric and electronic influence of the substituents. The post-synthetic modification of synthesized para-alkynylated arenes is also demonstrated. The mechanistic intricacies of the developed protocol are elucidated through experimental and computational studies.

Energy-efficient CO2/CO interconversion by homogeneous copper-based molecular catalysts.

Facile conversion of CO2 to commercially viable carbon feedstocks offer a unique way to adopt a net-zero carbon scenario. Synthetic CO2-reducing catalysts have rarely exhibited energy-efficient and selective CO2 conversion. Here, the carbon monoxide dehydrogenase (CODH) enzyme blueprint is imitated by a molecular copper complex coordinated by redox-active ligands. This strategy has unveiled one of the rarest examples of synthetic molecular complex-driven reversible CO2 reduction/CO oxidation catalysis under regulated conditions, a hallmark of natural enzymes. The inclusion of a proton-exchanging amine groups in the periphery of the copper complex provides the leeway to modulate the biases of catalysts toward CO2 reduction and CO oxidation in organic and aqueous media. The detailed spectroelectrochemical analysis confirms the synchronous participation of copper and redox-active ligands along with the peripheral amines during this energy-efficient CO2 reduction/CO oxidation. This finding can be vital in abating the carbon footprint-free in multiple industrial processes.

Photoinduced [3+2] Cycloaddition of Carbenes and Nitriles: A Versatile Approach to Oxazole Synthesis.

We have developed a photoinduced protocol for the synthesis of pharmaceutically important oxazole molecules using diazo- and nitrile-containing reactants. The process involves the initial photolysis of the diazo compound to afford singlet carbenes, which are tapped by nitriles in a [3+2] cycloaddition fashion to give substituted oxazoles. With di-nitrile compounds, useful bis-oxazoles were obtained. The applicability of the transformation is showcased through the expedient synthesis of small-molecule drugs and biologically relevant molecules such as felbinac, pimprinine, texamine, ugnenenazole etc. The protocol is also useful for the generation of 2 H and 13 C isotope labelled oxazoles. Merging photolysis with continuous-flow chemistry was demonstrated for scaling up the reaction. The non-requirement of metal catalysis or photosensitizers to harness the light energy with blue light sufficing the execution of the reaction makes it a versatile and general protocol for the synthesis of structurally diverse oxazoles.

Design of Water-Soluble Rotaxane-Capped Superparamagnetic, Ultrasmall Fe3O4 Nanoparticles for Targeted NIR Fluorescence Imaging in Combination with Magnetic Resonance Imaging.

Integrating an NIR fluorescent probe with a magnetic resonance imaging (MRI) agent to harvest complementary imaging information is challenging. Here, we have designed water-soluble, biocompatible, noncytotoxic, bright-NIR-emitting, sugar-functionalized, mechanically interlocked molecules (MIMs)-capped superparamagnetic ultrasmall Fe3O4 NPs for targeted multimodal imaging. Dual-functional stoppers containing an unsymmetrical NIR squaraine dye interlocked within a macrocycle to construct multifunctional MIMs are developed with enhanced NIR fluorescence efficiency and durability. One of the stoppers of the axle is composed of a lipophilic cationic TPP+ functionality to target mitochondria, and the other stopper comprises a dopamine-containing catechol group to anchor at the surface of the synthesized Fe3O4 NPs. Fe3O4 NPs surface-coated with targeted NIR rotaxanes help to deliver ultrasmall magnetic NPs specifically inside the mitochondria. Two carbohydrate moieties are conjugated with the macrocycle of the rotaxane via click chemistry to improve the water solubility of MitoSQRot-(Carb-OH)2-DOPA-Fe3O4 NPs. Water-soluble, rotaxane-capped Fe3O4 NPs are used for live-cell mitochondria-targeted NIR fluorescence confocal imaging, 3D and multicolor imaging in combination with T2-weighted MRI on a 9.4 T MR scanner with a high relaxation rate (r2) of 180.7 mM-1 s-1. Biocompatible, noncytotoxic, ultrabright NIR rotaxane-capped superparamagnetic ultrasmall monodisperse Fe3O4 NPs could be a promising agent for targeted multimodal imaging applications.

Access to unsaturated bicyclic lactones by overriding conventional C(sp3)-H site selectivity.

Transition metal catalysis plays a pivotal role in transforming unreactive C-H bonds. However, regioselective activation of distal aliphatic C-H bonds poses a tremendous challenge, particularly in the absence of directing templates. Activation of a methylene C-H bond in the presence of methyl C-H is underexplored. Here we show activation of a methylene C-H bond in the presence of methyl C-H bonds to form unsaturated bicyclic lactones. The protocol allows the reversal of the general selectivity in aliphatic C-H bond activation. Computational studies suggest that reversible C-H activation is followed by ß-hydride elimination to generate the Pd-coordinated cycloalkene that undergoes stereoselective C-O cyclization, and subsequent ß-hydride elimination to provide bicyclic unsaturated lactones. The broad generality of this reaction has been highlighted via dehydrogenative lactonization of mid to macro ring containing acids along with the C-H olefination reaction with olefin and allyl alcohol. The method substantially simplifies the synthesis of important bicyclic lactones that are important features of natural products as well as pharmacoactive molecules.