Search

This review describes the most recent developments in materials design and the advanced features of ionogels, as well as their emerging biomedical applications.

A metal-free strategy regarding iodine catalysis to achieve ortho-aminomethylation of phenols in aqueous media has been developed, which is highlighted by the late-stage functionalization of drug molecules containing phenolic structures.

A Pd/Ca catalytic system to promote the unsymmetrical bis-allylation of malononitrile was developed by selecting conjugated dienes and allylic alcohols as allylic reagents. This catalytic system suppressed the competitive symmetrical bis-allylation process and guaranteed the desired unsymmetrical bis-allylation with high chemoselectivity. A wide range of conjugated dienes and allylic alcohols were tolerated well in this transformation, and diverse 1,6-dienes were obtained with high efficiency. We gratefully acknowledge financial support from the National Natural Science Foundation of China (21702108); the Natural Science Foundation of Jiangsu Province, China (BK20211257 and BK20160977); and the Six Talent Peaks Project in Jiangsu Province (YY-033).

Amine-targeting reactions that work under biocompatible conditions or in water are green processes that are extremely useful for the synthesis of functional materials and biotherapeutics. Unfortunately, despite the usefulness of this reaction, there are very few good amine-specific click methods reported thus far. Here, we report an amine-specific click reagent using alkynone β-trifluoroborates as the electrophiles. These boron-containing alkynyl reagents exhibit extremely high chemoselectivity toward amines even in the presence of thiols. The resulting oxaboracycle products are bench-stable, displaying the reactivities of both organoborates and enaminones. Intrinsic advantages of this methodology include benign reaction conditions, operational simplicity, remarkable product stability, and excellent chemoselectivity, which satisfy the criteria of click chemistry and demonstrate the high potential in bioconjugation. Hence, this water-based chemical approach is also applicable to the modification of native amino acids, peptides, and proteins. Ultimately, the essential role of water during the reaction was elucidated. Ministry of Education (MOE) Nanyang Technological University Published version We gratefully acknowledge the financial support from Distinguished University Professor grant (Nanyang Technological University); AcRF Tier 1 grant from the Ministry of Education of Singapore (RT14/20); and the Agency for Science, Technology, and Research (A*STAR) under its MTC Individual Research grant (M21K2c0114) and RIE2025 MTC Programmatic Fund (M22K9b0049) for T.-P.L. We also thank a Changjiang Scholarship, a university development fund (UDF01001996) from the Chinese University of Hong Kong, Shenzhen and a Warshel Institute for Computational Biology fund (C10120180043) for H.H.

We described an efficient catalytic species generated from Ph3C+[B(C6F5)4]− by the water mediated Friedel–Crafts type reaction of indoles with carbonyl compounds to access 3,3′-bisindolylmethanes (BIMs).

An efficient BF3-promoted cyclization of α-amino acetals with alkynes for the assembly of substituted pyrroles has been developed. This cascade process can be easily achieved through a simple metal-free operation under mild conditions.

Catalyst-free biocompatible reactions are a class of green chemical processes that are also applicable to the field of chemical biology. In this account, we detail our journey in this exciting area of research since 2000. Various types of catalyst-free biocompatible reactions, such as the Mukaiyama aldol reactions and thiol-specific click reactions, and their applications to the functionalization of proteins are described. These reactions work well without destroying the three-dimensional structures of the proteins. Other reactions, including the C–SO2 and C–N bond-forming reactions, are also discussed. These reactions work in a truly green manner in which the use of organic solvents can be totally avoided. This toolbox of green chemical processes will certainly facilitate the work of researchers in the pharmaceutical industries.1 Introduction2 C–C Bond-Formation Reactions: The Mukaiyama Aldol Reaction3 C–S Bond-Formation Reactions: Allenic Amide as the Electrophiles4 C–SO2R Bond-Formation Reactions4.1 Allylic Alcohols as the Electrophiles4.2 Allenic Carbonyl Compounds as the Electrophiles5 C–N Bond-Formation Reactions6 Conclusions and Outlook

Many fields in chemical biology and synthetic biology require effective bioconjugation methods to achieve their desired functions and activities. Among such biomolecule conjugates, antibody–drug conjugates (ADCs) need a linker that provides a stable linkage between cytotoxic drugs and antibodies, whilst conjugating in a biologically benign, fast and selective fashion. This review focuses on how the development of novel organic synthesis can solve the problems of traditional linker technology. The review shall introduce and analyse the current developments in the modification of native amino acids on peptides or proteins and their applicability to ADC linker. Thereafter, the review shall discuss in detail each endogenous amino acid's intrinsic reactivity and selectivity aspects, and address the research effort to construct an ADC using each conjugation method., The review shall introduce and analyse the current developments in the chemical modification of native amino acids on peptides or proteins and their applicability to ADC linkers.

An organic photoredox-catalyzed dehydroxylative trifluoromethylation of allylic alcohols was developed in an environmentally benign manner. In this reaction, the readily available CF3SO2Na was selected as the trifluoromethylation reagent. The in situ generated byproduct SO2 was reutilized to activate C-OH bond, which enabled this dehydroxylative trifluoromethylation to be performed conveniently. A variety of multifunctionalized CF3-allylic compounds were obtained in high yields and excellent stereoselectivity. We gratefully acknowledge financial support from the National Natural Science Foundation of China (21702108), the Natural Science Foundation of Jiangsu Province, China (BK20160977), and the Six Talent Peaks Project in Jiangsu Province (YY-033).

A transition-metal-free catalytic system was designed to address the dehydrative cross-coupling of unactivated primary/secondary alcohols with amines/amides under environmentally benign conditions. Mg

Achieving selective meta-functionalization of phenols is a significant challenge. Accessing such compounds generally needs elevated temperature or incorporation of complex templates. Here, we report a general approach to achieve meta-arylated phenols with a simple and common directing group. This coppercatalyzed protocol proceeds with complete meta-selectivity and tolerates a variety of functional groups in both coupling partners. Computational studies have revealed that the reaction proceeded via a Heck-like pathway. Ministry of Education (MOE) Nanyang Technological University We gratefully acknowledge the financial support from Northwestern Polytechnical University (NPU), China, Tier 1 grant M4012045.110 (RG12/18-S) from the Ministry of Education of Singapore and Distinguished University Professor grant, Nanyang Technological University, Singapore.

A green method for the sulfination of allenic carbonyl compounds to access a wide variety of vinylic sulfones is developed. This reaction works in aqueous media under very mild conditions. This reaction is atom economic. A wide variety of vinylic sulfones could be obtained in moderate to excellent yields with wide functional group tolerance. The efficiency of this method is demonstrated in some reactions where the desired products can be isolated by filtration.

An environmentally benign protocol for C–P bond construction was developed under metal- and solvent-free conditions. In the presence of B(C6F5)3, wide-spectrum P–H species, including dialkylphosphite, hypophosphite ester, and secondary phosphine oxides, can be successfully incorporated into the dehydrative cross-coupling process with allylic alcohols delivering the corresponding allylic organophosphorus compounds in high yields.

With the increasing awareness of sustainable chemistry principles, the development of an efficient and mild strategy for C(sp3)–H bond activation of nitrogen-containing compounds without the utilization of any oxidant and metal is still highly desired and challenging. Herein, we present a metal-free reaction system that enables C–H bond functionalization of aliphatic sulfonamides using DABCO as a promoter under mild conditions, affording a series of α,β-unsaturated imines in good yields with high selectivities. This protocol tolerates a broad range of functionalities and can serve as a powerful synthetic tool for the late-stage modification of complex compounds. More importantly, control experiments and detailed DFT calculations suggest that this process involves [2 + 2] cyclization/ring-cleavage reorganization, which opens up a new platform for the establishment of other related reorganization reactions., The mild base-promoted C−H bonds functionalization of amides to obtain α,β-unsaturated imines in good yields with high chemoselectivities was achieved. Control experiments show this process involves [2 + 2] cyclization/ring-cleavage reorganization.

Redox-active covalent organic frameworks (COFs) with dense redox sites are promising electrical energy storage materials with robust architectures, high surface areas, insolubility in electrolytes, and open pores for electrolyte transportation. However, low redox potentials and poor electrical conductivity of pristine COFs often result in low accessibilities of redox-active sites and slow redox kinetics, greatly limiting their practical applications. Herein, we report the design and synthesis of two novel p-type phenoxazine-based COFs (DAPO-COFs) with high redox potentials (∼3.6 V vs. Li/Li+) and excellent electrical conductivities. Simply blended with conductive additives (CAs) and binders, pristine bulk DAPO-COFs without pre-composition with CAs or extra exfoliation are readily useable as cathode materials for lithium-ion batteries. Both as-synthesized DAPO-COF powders displayed superior active-site accessibility, ultrafast redox kinetics, and remarkable cycling stability. This work provides new perspectives on the development of readily useable COF-based cathode materials, and contributes to the advancement of eco-friendly and sustainable organic-based energy storage devices.

A highly efficient and regioselective bromination of electron-rich arenes and heteroarenes using commercially available BrCCl3 as a “Br” source has been developed. The reaction was performed in air under mild conditions with photocatalyst Ru(bpy)3Cl2·6H2O, avoiding the usage of strong acids and strong oxidants. Mono-brominated products were obtained with medium to excellent yields (up to 94%). This strategy has shown good compatibility and high para-selectivity, which will facilitate the complicated synthesis.

A practical palladium/calcium catalytic system was developed for dehydrative allylation with unactivated allylic alcohols. EtOH solvent with a H2O additive was identified as powerful medium to accelerate proton transfer. This catalytic system and environmentally benign medium enabled a variety of soft carbonic nucleophiles and allylic alcohols to react smoothly at room temperature with water as the only byproduct. A wide spectrum of allylic compounds bearing a variety of functional groups can be obtained with high to excellent yields.

An efficient and versatile zinc oxide-supported iridium (Ir/ZnO) catalyst was developed to catalyze the additive-free N-methylation of amines with methanol. Mechanistic studies suggested that the high catalytic reactivity is rooted in the small sizes (1.4 nm) of Ir nanoparticles and the high ratio (93%) of oxidized iridium species (IrOx, Ir3+ and Ir4+) on the catalyst. Moreover, the delicate cooperation between the IrOx and ZnO support also promoted its high reactivity. The selectivity of this catalytic N-methylation was controllable between dimethylation and monomethylation by carefully tuning the catalyst loading and reaction solvent. Specifically, neat methanol with high catalyst loading (2 mol% Ir) favored the formation of N,N-dimethylated amine, while the mesitylene/methanol mixture with low catalyst loading (0.5 mol% Ir) was prone to producing mono-N-methylated amines. An environmentally benign continuous flow system with a recycled mode was also developed for the efficient production of N-methylated amines. With optimal flow rates and amine concentrations, a variety of N-methylamines were produced with good to excellent yields in this Ir/ZnO-based flow system, providing a starting point for the clean and efficient production of N-methylamines with this cost-effective chemical process.

A photoinitiated perfluoroalkylative coupling of enamides with perfluoroalkyl iodides and a visible-light-induced difluoroacetylation of enamides with ethyl bromodifluoroacetate have been developed, respectively. These transformations allow the efficacious and straightforward incorporation of biologically and physiologically privileged fluoro-containing moieties into synthetically eminent enamide scaffolds with excellent regio- and stereoselectivities under mild and environmentally friendly conditions.

Searching for membrane-active synthetic analogues that are structurally simple yet functionally comparable to natural channel proteins has been of central research interest in the past four decades, yet custom design of the ion transport selectivity still remains a grand challenge. Here we report on a suite of buckyball-based molecular balls (MBs), enabling transmembrane ion transport selectivity to be custom designable. The modularly tunable MBm-Cn (m = 4-7; n = 6-12) structures consist of a C60-fullerene core, flexible alkyl linkers Cn (i.e., C6 for n-C6H12 group), and peripherally aligned benzo-3m-crown-m ethers (i.e., m = 4 for benzo-12-crown-4) as ion-transporting units. Screening a matrix of 16 such MBs, combinatorially derived from four different crown units and four different Cn linkers, intriguingly revealed that their transport selectivity well resembles the intrinsic ion binding affinity of the respective benzo-crown units present, making custom design of the transport selectivity possible. Specifically, MB4s, containing benzo-12-crown-4 units, all are Li+-selective in transmembrane ion transport, with the most active MB4-C10 exhibiting an EC50(Li+) value of 0.13 μM (corresponding to 0.13 mol % of the lipid present) while excluding all other monovalent alkali-metal ions. Likewise, the most Na+ selective MB5-C8 and K+ selective MB6-C8 demonstrate high Na+/K+ and K+/Na+ selectivity values of 13.7 and 7.8, respectively. For selectivity to Rb+ and Cs+ ions, the most active MB7-C8 displays exceptionally high transport efficiencies, with an EC50(Rb+) value of 105 nM (0.11 mol %) and an EC50(Cs+) value of 77 nM (0.079 mol %).

Reported herein is a practical method for macrolactam synthesis via a Rh(III)-catalyzed ring closing alkene-alkene cross-coupling reaction. The reaction proceeded via a Rh-catalyzed alkenyl sp2 C-H activation process, which allows access to macrocyclic molecules of different ring sizes. Macrolactams containing a conjugated diene framework could be easily prepared in high chemoselectivities and Z,E stereoselectivities. Ministry of Education (MOE) Nanyang Technological University The authors gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21702108), the Natural Science Foundation of Jiangsu Province, China (No. BK20160977), the Six Talent Peaks Project in Jiangsu Province (No. YY-033), Tier 1 grant M4012045.110 (No. RG12/18-S) from the Ministry of Education of Singapore and Distinguished University Professor grant, Nanyang Technological University, Singapore.

The Mukaiyama-aldol reaction is probably one of the most efficient strategies to prepare synthetically useful β-hydroxy carbonyl compounds. However, only several reported methods were concerned with the accesses to α-fluoro-β-hydroxy esters. Herein, we report a protocol for a fluoride anion-mediated Mukaiyama aldol reaction with low catalytic loading in a short reaction time to incorporate fluorine at the α position into β-hydroxy esters. The method shows good functional-group tolerance and scale-up potential, moreover, is applicable to the late-stage modification of natural products and small molecular drugs.

A palladium-catalyzed intermolecular polarity-mismatched addition of unactivated alkyl radicals to unactivated alkenes was developed for the first time. In the two-component dicarbofunctionalizatio...

A photoredox-catalyzed regio- and stereoselective trifluoroethylation reaction of enamides using commercially available 2,2,2-trifluoroethyl iodide as trifluoroethylating agents has been developed,...

This paper reports a highly site-selective alkylation of heteroarene N-oxides using hypervalent iodine(III) carboxylates to serve as an alkylating agent in the presence of a cheap copper catalyst under visible light conditions. This mild method proceeds at room temperature in an air atmosphere and can withstand various heteroarene N-oxides as well as various primary, secondary, and tertiary alkyl carboxylic acids. It also provides a practical method for enabling the rapid conversion of commercially available raw materials into medically relevant "drug-like" molecules.

Facile preparation of secondary amines from alcohols or aldehydes is achieved by using the hydrazine (N2H4) as an easy-to-handle nitrogen source. The anatase titania-supported Pt (Pt/TiO2-A) is dis...

A mild rhodium catalytic system has been developed to synthesize vinylcyclopropa[b]indolines through cyclopropanation of indoles with vinyl carbenoids generated from ring opening of cyclopropenes in situ. By employing a Rh-migration strategy, the products can be obtained with good to excellent E:Z ratios (≤99:1) and complete diastereoselectivity (≤99:1). This method is easy, has a low catalyst loading, and works for a broad range of functionalities.

A general intermolecular anti-Michael reductive Heck reaction of α,β-unsaturated esters with organobromides has been developed. Most topical classes of aryl, heteroaryl, and vinyl bromides were found to efficiently react with a variety of internal conjugated alkenes. This protocol set up a platform toward diverse α-arylated 1,6-dicarbonyl frameworks found in natural products and drugs, which are still highly challenging targets in traditional α-arylation protocols because of competitive selectivity of enolation. A removable directing group, gram-scale reaction, and modification of complex molecules have additionally demonstrated that the anti-Michael reductive Heck reaction is a powerful complementary strategy to the classical α-arylation approaches. Preliminary mechanistic studies are consistent with our proposed mechanistic design. We gratefully acknowledge funding from the National Natural Science Foundation of China (21602104), Natural Science Foundation of Jiangsu Province, China (BK 20160986), the Starting Funding of Research (3983500176) from Nanjing Tech University. We thank Dr. Victor Gray and Dr. Sanyang Han (from Cavendish Laboratory, University of Cambridge) for proofreading.

We report a chelation-assisted C-H arylation of various indoles with sterically and electronically diverse (hetero)arylsilanes enabled by cost-effective Cp*-free cobalt catalysis. Key to the success of this strategy is the judicious choice of copper(II) fluoride as a bifunctional sliane activator and catalyst reoxidant. This methodology features a broad substrate scope and good functional group compatibility. The synthetic versatility of this protocol has been highlighted by the gram-scale synthesis and late-stage diversification of biologically active molecules.

An economical strategy has been designed to formally cleave CC bonds of ynones through copper-catalyzed carbene chemistry. It proceeds under mild reaction conditions in a step-economy process by simultaneously cleaving the CC bonds and constructing C-C bonds. Depending on the substitution of the ynones, the reactions can proceed efficiently to generate synthetically useful 1,4-ketoaldehydes and cyclopentenone compounds. A plausible pathway is proposed that involves an active cyclopropane intermediate that consequently undergoes a cascade ring-opening reaction. The method works for a spectrum of ynones and N-tosylhydrazones that give good to excellent yields using a cheap copper catalytic system. We gratefully acknowledge funding from the National Natural Science Foundation of China (21971112), Jiangsu Province Funds Surface Project (BK 20161541), and the Starting Funding of Research (39837107) from Nanjing Tech University and Jiangsu Students’ Platform for Innovation and Entrepreneurship Training Program (201910291140Y). Dr. Li Yan Chan and Dr. Juha Siitonen are thanked for proofreading the manuscript.

2H-Azirine-2-caboxamides have been designed to perform as a new type of bifunctional thiol linker under very mild reaction conditions. The cleavage of a C-N double bond of 2H-azirine furnishes an amino amide functional group in situ through a thiol addition and ring-opening process. It works with a broad scope of thiols and 2H-azirines in the absence of any catalysts at room temperature. Cysteine-containing peptides have also been demonstrated to work efficiently in a completely water solution. We gratefully acknowledge funding from the National Natural Science Foundation of China (21971112), Jiangsu Province Funds Surface Project (BK 20161541), and the Starting Funding of Research (39837107) from Nanjing Tech University

A highly efficient Pd/Ca catalytic system for the directly dehydrative cross-coupling of allylic alcohols with terminal alkynes was developed. This calcium salt cocatalyst facilitates the oxidative addition of the palladium catalyst (1 mol %) to the C-OH bond. Then, the in situ-generated hydroxide ion deprotonates the terminal alkynes to promote the formation of the allylalkynylpalladium intermediate, liberating water as the only byproduct. This proposed mechanism is also supported by density functional theory calculations. An anticancer agent was prepared from inexpensive starting materials on a 10 g scale.

We have presented a unique example of dehydrogenative acylation of enamides with aldehydes enabled by an earth-abundant iron catalyst. The protocol provides the straightforward access to valuable β-ketoenamides with ample substrate scope and excellent functional group tolerance. Notably, distinct C-H acylation of enamide rather than at N-H moiety site occurs with absolute Z-selectivity was observed. Late-stage modifications of complex molecules and versatile synthetic utility of β-ketoenamides further highlight the practicability of this transformation.

A simple and practical method to access N-substituted 2-pyridones via a formal [3+3] annulation of enaminones with acrylates based on RhIII-catalyzed C-H functionalization was developed. Control and deuterated experiments led to a plausible mechanism involving C-H bond cross-coupling and aminolysis cyclization. This strategy provides a short synthesis of structural motifs of N-substituted 2-pyridones.

A C-N bond formation reaction under biocompatible conditions for the amination of allenic ketone compounds to access a diversity of β-keto enamines is developed. This reaction is atom economical, green, and highly regioselective and works well with many structurally important amines such as amino sugar and amino acid esters or peptides. A wide array of β-keto enamines was obtained in modest to excellent yields with wide functional group tolerance using this protocol. A gram-scale synthesis of an anti-microbial agent was also realized using this strategy under green reaction conditions. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University Published version The authors gratefully acknowledge the financial support from the Distinguished University Professor grant (Nanyang Technological University, Singapore), AcRF Tier 1 grants from the Ministry of Education of Singapore (RG107/19, RG11/20 and RT14/20), and the Agency for Science, Technology and Research (A*Star) under its MTC Individual Research Grant (IRG).

The unprecedented triarylcarbonium ion-pair-catalyzed Pictet-Spengler reaction of tryptamines with aromatic aldehydes and cyclic ketones in water was disclosed. Under metal-free conditions, diverse tetrahydro-β-carbolines and spirocyclic tetrahydro-β-carbolines were obtained in good yields with excellent functional group tolerance, including late-stage modification of natural products and small molecular drugs. The practicability of this protocol is also characterized in the gram-scale synthesis of Komavine and several other functional compounds. Preliminary mechanistic studies indicated that in aqueous media the in situ-generated superacidic species from the carbonium ion pair with water was crucial to promote the Pictet-Spengler reaction. Nanyang Technological University We thank the financial support from the Start-up Grant of Nanjing Tech University (No. 38274017103, 38037037). T.P.L. thanks Nanyang Technological University Tier-1 grant support. We also acknowledge the Donors of the Science and Technology Innovation Research Fellowship in Nanjing for partial support of this research (No. 51237024) and the Postgraduate Research & Practice Innovation Program of Jiangsu Province (No. KYCX20_1031).

The β-carboline moiety exists in a wide range of drugs and natural products, but synthesis often relies on noble metals and stochiometric oxidants. Here, we develop a metal-free strategy using a triaryl carbenium ion pair as a catalyst to access β-carbolines from tryptamines and aromatic aldehydes. This protocol exhibits excellent functional group tolerance, and its practicality is demonstrated with the preparation of Eudistomin U and fluorescent compounds on gram scales. Mechanistic studies reveal that the trityl radical is generated via a single-electron transfer process and subsequently trapped by an oxygen molecule. In addition, the in-situ-generated reactive oxygen-centered radical is also found to be essential for the efficient dehydroaromatization process to afford the desired products. Agency for Science, Technology and Research (A*STAR) Ministry of Education (MOE) Nanyang Technological University Published version We are thankful for the financial support from the Start-up Grant of Nanjing Tech University (nos. 38274017103 and 38037037). T.-P.L. is thankful for the financial support from the Distinguished University Professor grant (Nanyang Technological University), AcRF Tier 1 grants from the Ministry of Education of Singapore (RG107/19, RG11/20, and RT14/20), and the Agency for Science, Technology and Research (A*STAR) under its MTC Individual Research Grants (M21K2c0114). Acknowledgment is also made to the Donors of the Science and Technology Innovation Research Fellowship in Nanjing for partial support of this research (no. 51237024) and Postgraduate Research & Practice Innovation Program of Jiangsu Province (nos. KYCX20_1031 and KYCX21_1081).

An alkaline-earth metal catalytic system for environmentally benign allylic alkylation was developed. Allylic alcohols can be utilized directly at room temperature in this transition-metal-free process, producing water as the only byproduct. A variety of allylic compounds, including the ones containing all-carbonyl quaternary centers, can be obtained with high yields. Ministry of Education (MOE) We gratefully acknowledge the financial support from the National Natural Science Foundation of China (21702108), the Natural Science Foundation of Jiangsu Province, China (BK20160977), the Six Talent Peaks Project in Jiangsu Province (YY-033), the grant from Ministry of Education of Singapore MOE2016-T1-002-043 (RG111/16), and Nanjing Tech University (39837101).

A metal-free, water-tolerant, and one-pot process for