Versatile Electrophiles Research Articles

Amide Synthesis from Decarboxylative Coupling of Isocyanates and Carboxylic Acids.

Isocyanates are versatile electrophiles that can react with a wide range of nucleophiles to afford important organic structures. Although the reactions between isocyanates and alcohols, amines and organometallic reagents have been well established, the synthesis of amides through the decarboxylative condensation of carboxylic acids and isocyanates is less appreciated. In this review, the synthesis of isocyanates and its application on amide synthesis through the condensation with carboxylic acids are summarized and discussed. It is our hope that this review will attract more attention to this less mentioned transformation and inspire new developments in the fields of organic synthesis, polymer synthesis and chemical biology.

Aziridines as Versatile C(sp3) Precursors in Transition-Metal Catalyzed Cross-Coupling Strategies

Aziridines, which serve as valuable scaffolds in numerous pharmaceuticals and bioactive molecules, have emerged as highly efficient C(sp3) precursors in the realm of organic chemistry. Particularly, employing aziridines as versatile electrophiles in transition metal-catalyzed cross-coupling has enabled precise control over the regiochemistry in the formation of new C(sp3)-C, Si, B bonds. This review explores recent innovative aziridine cross-coupling approaches using Ni or Pd catalysis, highlighting initial findings of new mechanistic approaches and delineating distinct catalytic pathways.

Photoelectrochemical Fe/Ni cocatalyzed C−C functionalization of alcohols

The simultaneous activation of reactants on the anode and cathode via paired electrocatalysis has not been extensively demonstrated. This report presents a paired oxidative and reductive catalysis based on earth-abundant iron/nickel cocatalyzed C–C functionalization of ubiquitous alcohols. A variety of alcohols (i.e., primary, secondary, tertiary, or unstrained cyclic alcohols) can be activated at very low oxidation potential of (~0.30 V vs. Ag/AgCl) via photoelectrocatalysis coupled with versatile electrophiles. This reactivity yields a wide range of structurally diverse molecules with broad functional group compatibility (more than 50 examples).

Discovery of an Azabicyclo[2.1.1]hexane Piperazinium Salt and Its Application in Medicinal Chemistry via a Rearrangement.

Herein we report the discovery of an azabicyclo[2.1.1]hexane piperazinium methanesulfonate salt from an unexpected rearrangement reaction in the preparation of ligand-directed degraders (LDDs). This bench-stable compound was found to be a versatile electrophile in a ring-opening reaction with various types of nucleophiles. Its utility as a versatile medicinal chemistry building block is further demonstrated in the synthesis of an LDD compound targeting degradation of the androgen receptor.

Controlled semi‐Pinacol rearrangement on a strained ring: Efficient access to multi‐substituted cyclopropanes by group migration strategy

We describe a versatile electrophile addition/SPR sequence of readily available cyclopropyl carbinols that affords multi-substituted carbonylated cyclopropanes with high stereo-fidelity. This approach tolerates various heteroatom electrophiles, migration of carbon moiety of all possible hybridization states, facile ring reorganization and natural compound valorization. The examples represent an unprecedented version of SPR wherein migration to a non-benzylic bulky tertiary carbo-cation is realized with promising enantiocontrol.

Distinguishing Competing Mechanistic Manifolds for C(acyl)-N Functionalization by a Ni/N-Heterocyclic Carbene Catalyst System.

Carboxylic acid derivatives are appealing alternatives to organohalides as cross-coupling electrophiles for fine chemical synthesis due to their prevalence in biomass and bioactive small molecules as well as their ease of preparation and handling. Within this family, carboxamides comprise a versatile electrophile class for nickel-catalyzed coupling with carbon and heteroatom nucleophiles. However, even state-of-the-art C(acyl)-N functionalization and cross-coupling reactions typically require high catalyst loadings and specific substitution patterns. These challenges have proven difficult to overcome, in large part due to limited experimental mechanistic insight. In this work, we describe a detailed mechanistic case study of acylative coupling reactions catalyzed by the commonly employed Ni/SIPr catalyst system (SIPr = 1,3-bis(2,6-di-isopropylphenyl)-4,5-dihydroimidazol-2-ylidine). Stoichiometric organometallic studies, in situ spectroscopic measurements, and crossover experiments demonstrate the accessibility of Ni(0), Ni(I), and Ni(II) resting states. Although in situ precatalyst activation limits reaction efficiency, the low concentrations of active, SIPr-supported Ni(0) select for electrophile-first (closed-shell) over competing nucleophile-first (open-shell) mechanistic manifolds. We anticipate that the experimental insights into the nature and controlling features of these distinct pathways will accelerate rational improvements to cross-coupling methodologies involving pervasive carboxamide substrate motifs.

OxSTEF Reagents Are Tunable and Versatile Electrophiles for Selective Disulfide-Rebridging of Native Proteins.

Site-selective disulfide rebridging has emerged as a powerful strategy to modulate the structural and functional properties of proteins. Here, we introduce a novel class of electrophilic reagents, designated oxSTEF, that demonstrate excellent efficiency in disulfide rebridging via double thiol exchange. The oxSTEF reagents are prepared using an efficient synthetic sequence which may be diverted to obtain a range of derivatives allowing for tuning of reactivity or steric bulk. We demonstrate highly selective rebridging of cyclic peptides and native proteins, such as human growth hormone, and the absence of cross-reactivity with other nucleophilic amino acid residues. The oxSTEF conjugates undergo glutathione-mediated disintegration under tumor-relevant glutathione concentrations, which highlights their potential for use in targeted drug delivery. Finally, the α-dicarbonyl motif of the oxSTEF reagents enables "second phase" oxime ligation, which furthermore increases the thiol stability of the conjugates significantly.

Iodine(III)-Based Hypervalent Iodine Electrophiles in Organic Synthesis

Abstract: The chemistry of hypervalent iodine reagents is now developed as an important tool of synthetic organic chemistry. These reagents play a key role in replacing the toxic heavy metal reagent because of their mild reaction condition and environmentally friendly nature. Mainly, these reagents were known for oxidative properties, but the scope of these reagents is not limited to oxidation reactions. In the past two decades, they have been used as versatile electrophiles in various key organic transformations. Recently, the demand for these reagents has increased drastically for green chemistry, mainly due to their application in catalysis. Hypervalent iodine reagents have been successfully used to develop various oxidative transformations such as the oxidation of different organic species, α-functionalization of carbonyl compounds, cyclization reactions, C-H activation reactions, lactonization and oxidative rearrangements. Moreover, the use of these reagents is not limited to general organic reactions but is successfully used to develop several stereoselective transformations by using chiral hypervalent iodine reagents. This review article highlights various acyclic and cyclic reactions where the hypervalent iodine reagents have been used as electrophiles.

Photo-induced trifunctionalization of bromostyrenes via remote radical migration reactions of tetracoordinate boron species

Tetracoordinate boron species have emerged as radical precursors via deboronation by photo-induced single electron transfer (SET) pathway. These reactions usually produce an alkyl radical and boron-bound species, and the valuable boron species are always discarded as a by-product. Given the importance of boron species, it will be very attractive if the two parts could be incorporated into the eventual products. Herein we report a photo-catalyzed strategy in which in situ generated tetracoordinated boron species decomposed into both alkyl radicals and boron species under visible light irradiation, due to the pre-installation of a vinyl group on the aromatic ring, the newly generated alkyl radical attacks the vinyl group while leaving the boron species on ipso-position, then both radical part and boron moiety are safely incorporated into the final product. Tertiary borons, secondary borons, gem-diborons as well as 1,2-diborons, and versatile electrophiles are all well tolerated under this transformation, of note, ortho-, meta- and para-bromostyrenes all demonstrated good capabilities. The reaction portraits high atom economy, broad substrate scope, and diversified valuable products with tertiary or quaternary carbon center generated, with diborons as substrates, Csp2-B and Csp3-B are established simultaneously, which are precious synthetic building blocks in chemical synthesis.

Unusual graphite fluoride hydrolysis toward unconventional graphene oxide for high-performance supercapacitors and Li-ion batteries

Graphene oxide was universally acknowledged to be a very important precursor to prepare graphene or the relative derivatives, but it was criticized sharply due to its quite inferior electrical properties and many structural defects arising out of strong oxidation process. Non-oxidation synthetic strategy of graphene oxide was expected a good solution to mitigate the disadvantages. Inspired by this concept, we attained a totally new, well-defined graphene oxide, that is, G(C4)–OH, in which hydroxyl was the unique oxygen-containing group and the hexagonal honeycomb carbon lattice was less-defective, by successfully challenging the hydrolysis of ultra-inert, commercially-available graphite fluoride feedstock. An advantaged structure made G(C4)–OH greatly outperforming traditional graphene oxide both in fundamental electrical properties, such as conductivity, carrier mobility, and in electrochemical performances when applied in supercapacitors and lithium-ion batteries. As convenient as traditional graphene oxide, G(C4)–OH was pretty reactive to versatile electrophiles and allowed tremendous post-functionalization opportunities to customize graphene functions and orientate its applications.

Enhanced Suppression of a Protein–Protein Interaction in Cells Using Small-Molecule Covalent Inhibitors Based on an N-Acyl-N-alkyl Sulfonamide Warhead

Protein-protein interactions (PPIs) intimately govern various biological processes and disease states and therefore have been identified as attractive therapeutic targets for small-molecule drug discovery. However, the development of highly potent inhibitors for PPIs has proven to be extremely challenging with limited clinical success stories. Herein, we report irreversible inhibitors of the human double minute 2 (HDM2)/p53 PPI, which employ a reactive N-acyl-N-alkyl sulfonamide (NASA) group as a warhead. Mass-based analysis successfully revealed the kinetics of covalent inhibition and the modification sites on HDM2 to be the N-terminal α-amine and Tyr67, both rarely seen in traditional covalent inhibitors. Finally, we demonstrated prolonged p53-pathway activation and more effective induction of the p53-mediated cell death in comparison to a noncovalent inhibitor. This study highlights the potential of the NASA warhead as a versatile electrophile for the covalent inhibition of PPIs and opens new avenues for the rational design of potent covalent PPI inhibitors.

Solution-Phase DNA-Compatible Pictet-Spengler Reaction Aided by Machine Learning Building Block Filtering.

SummaryThe application of machine learning toward DNA encoded library (DEL) technology is lacking despite obvious synergy between these two advancing technologies. Herein, a machine learning algorithm has been developed that predicts the conversion rate for the DNA-compatible reaction of a building block with a model DNA-conjugate. We exemplify the value of this technique with a challenging reaction, the Pictet-Spengler, where acidic conditions are normally required to achieve the desired cyclization between tryptophan and aldehydes to provide tryptolines. This is the first demonstration of using a machine learning algorithm to cull potential building blocks prior to their purchase and testing for DNA-encoded library synthesis. Importantly, this allows for a challenging reaction, with an otherwise very low building block pass rate in the test reaction, to still be used in DEL synthesis. Furthermore, because our protocol is solution phase it is directly applicable to standard plate-based DEL synthesis.

DNA-Encoded Libraries: Aryl Fluorosulfonates as Versatile Electrophiles Enabling Facile On-DNA Suzuki, Sonogashira, and Buchwald Reactions.

Using (hetero)aryl fluorosulfonates as versatile electrophiles, facile on‐DNA cross‐coupling reactions of Suzuki, Sonogashira, and Buchwald are reported here. Notably, all of these reactions show excellent functional group tolerance, mild reaction conditions (relative low temperature and open to air), rich heterocyclic coupling partners, and more importantly, DNA‐compatibility. Thus, these new reactions based on efficient formation of C(sp2)‐C(sp2), C(sp2)‐C(sp), and C(sp2)‐N bonds are highly amenable to synthesis of DNA‐encoded libraries with great molecular diversity.

Basicity‐Engineered Graphite Fluoride Functionalization and Beyond: An Unusual Reaction between Ultraweak Nucleophile and Ultrastrong CF Bonds

AbstractGraphite fluoride‐launched graphene functionalization has attracted increasing interest in recent years. Highly basic nucleophiles are normally employed for ultrastrong CF bonding. However, frequently, an appreciable majority of C–F units of graphite fluoride are reductively eliminated, leading to low functionalization degrees. It is hypothesized that graphite fluoride could likely be functionalized to a larger degree by lowering the basicity of the nucleophiles. Herein, ultraweakly basic NH3·H2O is adopted as a nucleophile to react with extremely inert graphite fluoride, and the resulting reaction affords amino/hydroxyl cofunctionalized graphene (NH2–G–OH). As expected, the NH2/OH functionalization degree and the ratio of substituted C–F units to reduced ones reach high values of 0.34 and 1.62, respectively. Due to the dual energy‐storage mechanisms of the electrochemical double‐layer capacitance coupled with Faradaic pseudocapacitance, the NH2–G8–OH‐based all‐solid‐state supercapacitors are flexible and robust and deliver state‐of‐the‐art capacitive characteristics, while exhibiting high rate capability and electrochemical cycling stability. In addition, NH2/OH moieties remain highly reactive to be post‐functionalized by versatile electrophiles, not only achieving an umpolung of graphite fluoride, but also enabling NH2–G8–OH a competitive alternative to monopolistic GO, and opening up an innovative pathway for development of high‐performance graphene derivatives amenable to multifarious applications.

Safe, Metal‐Free, and Direct Synthesis of Dialkyl Acylmethylidenehydrazine‐1,1‐dicarboxylates from Dimethylsulfoxonium Acylmethylides and Dialkyl Azodicarboxylates

AbstractN‐Acylhydrazones are versatile electrophiles for the synthesis of nitrogen‐containing compounds. Dialkyl acylmethylidenehydrazine‐1,1‐dicarboxylates are a class of N‐acylhydrazones and were prepared efficiently from dimethylsulfoxonium acylmethylides and dialkyl azodicarboxylates. The reaction is temperature‐controlled, generating tetraalkyl 3,6‐diacyl‐1,2,4,5‐tetrazinane‐1,2,4,5‐tetracarboxylates as major products accompanied by dialkyl acylmethylidenehydrazine‐1,1‐dicarboxylates as byproducts at low temperature, or dialkyl acylmethylidenehydrazine‐1,1‐dicarboxylates only at high temperature. The current direct synthetic method is a safe and transition‐metal‐free route for the synthesis of dialkyl acylmethylidenehydrazine‐1,1‐dicarboxylates.magnified image

Direct Access to Versatile Electrophiles via Catalytic Oxidative Cyanation of Alkenes.

Nucleophilic attack on carbon-based electrophiles is a central reactivity paradigm in chemistry and biology. The steric and electronic properties of the electrophile dictate its reactivity with different nucleophiles of interest, allowing the opportunity to fine-tune electrophiles for use as coupling partners in multistep organic synthesis or for covalent modification of proteins in drug discovery. Reactions that directly transform inexpensive chemical feedstocks into versatile carbon electrophiles would therefore be highly enabling. Herein, we report the catalytic, regioselective oxidative cyanation of conjugated and nonconjugated alkenes using a homogeneous copper catalyst and a bystanding N-F oxidant to furnish branched alkenyl nitriles that are difficult to prepare using existing methods. We show that the alkenyl nitrile products serve as electrophilic reaction partners for both organic synthesis and the chemical proteomic discovery of covalent protein ligands.

Mechanistic Insights into Aerobic Oxidative Methyl Esterification of Primary Alcohols with Heterogeneous PdBiTe Catalysts

Aerobic oxidative methyl esterification of primary alcohols is an important chemical transformation that converts a nucleophile (alcohol) into a versatile electrophile (methyl ester). We recently discovered a heterogeneous PdBiTe/C catalyst that exhibits the highest activity yet reported for this transformation. Bi and Te serve as synergistic promoters that enhance both the rate and yield of the reactions relative to reactions employing Pd alone or Pd in combination with Bi or with Te as the sole promoter. Here, we report a mechanistic study of the oxidative methyl esterification of benzyl alcohol and 1-octanol to provide insights into the overall multistep transformation as well as the role of the Bi and Te in the reaction. The catalytic rates of the oxidative esterification of benzyl alcohol and octanol with Pd, PdBi, PdTe, and PdBiTe catalysts exhibit a saturation dependence on [alcohol] and [K2CO3] and a first-order dependence on pO2. Hammett studies of benzyl alcohol oxidation reveal opposing electro...

Development of Versatile Sulfone Electrophiles for Suzuki–Miyaura Cross-Coupling Reactions

The development of fluorinated sulfone derivatives as versatile electrophiles for Suzuki–Miyaura cross-coupling reactions is described. Introducing electron-withdrawing groups on the aryl ring of the sulfone facilitates the Pd-catalyzed activation of C–SO2 bonds. Cross-coupling reactions with fluorinated sulfone electrophiles are reported, leading to a variety of multiply arylated products in good yields. The reactivity of this unusual electrophile is benchmarked versus common electrophiles and its use in iterative cross-couplings for concise synthesis of biologically active molecules is described.

ChemInform Abstract: Preparation of Novel 3‐Fluorophenyl Triazolothiadiazoles and of Triazolothiadiazines.

AbstractThe title compounds are prepared by cyclization of amino(fluorophenyl)triazolethione (I) with versatile electrophiles under microwave irradiation conditions.

ChemInform Abstract: Alkyl Halide‐Free Heteroatom Alkylation and Epoxidation Facilitated by a Recyclable Polymer‐Supported Oxidant for the In‐Flow Preparation of Diazo Compounds.

Highly reactive metal carbenes, generated from simple ketones via diazo compounds, including diazo-amides and -phosphonates, using a recyclable reagent in-flow, are transient but versatile electrophiles for heteroatom alkylation reactions and for epoxide formation. The method produces no organic waste, with the only by-products being water, KI and nitrogen, without the attendant hazards of isolation of intermediate diazo compounds.