Dehydrative Reaction Research Articles

Preparation of 2-Aminoimidazole-Activated Substrates for the Study of Nonenzymatic Genome Replication.

Nonenzymatic genome replication is thought to be an important process for primitive lifeforms, but this has yet to be demonstrated experimentally. Recent studies on the nonenzymatic primer extension mechanism mediated by nucleoside 5'-monophosphates (NMPs) activated with 2-aminoimidazole have revealed that imidazolium-bridged dinucleotide intermediates (N*N) account for the majority of the chemical copying process. As a result, an efficacious synthetic pathway for producing substrates activated with an imidazoyl moiety is desirable. This article provides a detailed protocol for the standard dehydrative redox reaction between NMPs and 2-aminoimidazole to produce nucleotide phosphoroimidazolides. In addition, we describe a similar synthetic pathway to produce N*N in high yields for homodimers. Finally, a simple reversed-phase cation exchange step is described to increase NMP solubility, which significantly increases yields for certain substrates. This approach allows for an efficient and cost-effective methodology to prepare high-quality substrates utilized in origins-of-life studies. © 2024 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol 1: Synthesis of 2-aminoimidazolephosphoroimidazolide-activated cytidine Basic Protocol 2: Synthesis of 2-aminoimidazolium-bridged dicytidyl intermediate Basic Protocol 3: Cation exchange of guanosine 5'-monophosphate disodium salt Alternate Protocol: Synthesis of cytidine 5'-phosphoroimidazolide or 2-aminoimidazolium-bridged dicytidyl from cytidine 5'-monophosphate disodium salt.

Efficient synthesis of the 2-aminoimidazolium-bridged diguanosyl intermediate for nonenzymatic primer extension

Nonenzymatic genome replication has yet to be demonstrated experimentally. Recently, studies on the nonenzymatic primer extension mechanism mediated by nucleoside 5′-monophosphates (NMPs) activated with 2-aminoimidazole (2AI) have revealed that imidazolium-bridged dinucleotide intermediates (N*N) are responsible for the bulk of the chemical copying process. As a result, an efficacious synthetic pathway for producing these substrates is desirable. Standard dehydrative redox reaction between NMPs and 2AI can produce N*N in high yields for all homodimers, apart from riboguanosine 5′-monophosphate. Here, we report a vastly improved methodology for the preparation of G*G, by the introduction of a simple reverse-phase cation exchange step to increase the solubility of the mononucleotide. Our approach is more efficient, cost-effective, less time-consuming, and has better atom economy than the currently established methodology for this important molecule in primer extension studies.

Direct Intramolecular Coupling of Primary/Secondary Alcohols with Secondary Alcohols for Macrocyclic Alkenylation Using Ni‐Zeolite Catalyst Under Continuous‐Flow Conditions

AbstractHerein, we report the direct intramolecular coupling of primary and secondary alcohols for the selective synthesis of macrocyclic olefins in the presence of Ni‐zeolite catalyst under continuous flow. This reaction proceeds via dehydration of secondary alcohols to alkenes, which subsequently undergo intramolecular dehydrative coupling reaction with a primary alcohol to obtain moderate yields of macrocyclic olefins. This reaction is also effective for the coupling of secondary‐secondary alcohols and alkene‐alcohols to produce diverse macrocyclic olefin products. This unique approach has various advantages including step‐economy, no additives and pre‐functionalization required, inexpensive and reusable catalyst, and exemplification with 23 macrocycles in different ring sizes. The continuous flow macrocyclisation afforded higher productivity and space‐time yield than the batch reaction conditions.

Chemoselective direct amidation of fatty acids with furfurylamine without coupling reagents in reversed micellar microenvironment

AbstractFuran heterocyclic compounds derived from renewable sources are popular versatile candidates for the production of multifunctional macromolecular materials. These compounds are also used as hydrophobilization monomers for reversible polyadducts or as versatile building blocks in Diels‐Alder reactions. In the present study, an efficient approach to chemoselective acylation of furfurylamine with a series of non‐preactivated monocarboxylic or dicarboxylic long‐chain fatty acids and some of their functionalized derivatives has been achieved via catalytic direct amidation in reversed micellar medium. A convenient and environmentally friendly method has been developed for furfurylamides via a dehydrative coupling reaction. For this purpose, a new cationic Brønsted‐type sulfonic acid catalyst containing a hexadecyl alkyl chain was synthesized and fully characterized. The present catalytic reaction produced the respective N‐furfurylamides materials in good to excellent yields. This study also confirms that the direct amidation of carboxylic acids with selected amine compounds can be successfully catalyzed by Brønsted acids. Its simplicity and high atom economy are the main advantages of this method.

Route to Functionalized Tetrahydrobenzo[d]azepines via Re2O7-Mediated Intramolecular Friedel-Crafts Reaction.

We describe a Re2O7-mediated intramolecular dehydrative Friedel-Crafts reaction for the efficient synthesis of various benzo-fused heterocycles such as benzazepines and benzazocines. This process is characterized by a broad substrate scope, mild reaction conditions, high efficiency, and high atom economy. The potential application of this methodology was exemplified by the facile preparation of a NMDA antagonist as well as a key intermediate en route to SKF 38393.

Organo‐Catalyzed Intermolecular Dehydrative Coupling Reaction to Prepare Arylacetic Acid Derivatives

AbstractHerein, the use of triphenylmethylium tetrakis(pentafluorophenyl)borate as an efficient catalyst for the intermolecular dehydrative coupling of p‐hydroxymandelic acid hydrate with substituted aromatic amines and (thio)phenols was developed, which allows for the preparation of arylacetic acid derivatives in a convenient manner. Notably, this method offers several advantages, including being prefunctionalization free, high atom efficiency, and high regioselectivity. Additionally, it exhibits a broad substrate scope, enabling the synthesis of a range of arylacetic acid derivatives. Furthermore, this method can also be applied to the etherification of arylthiol derivatives, facilitating the preparation of various thiolated products, which would enhance the applicability and potential utility of this method in organic synthesis.

High-performance pyramid-SiNWs biosensor for NH3 gas detection

NH3 is widely existed in the environment and is closely associated with various health issues. Additionally, detecting the small amounts of NH3 exhaled by patients with liver and kidney diseases offers potential opportunities for painless early disease diagnosis. Therefore, there is an urgent need for a convenient, rapid, and highly sensitive real-time NH3 monitoring method. This work presents a high-performance NH3 sensor based on olfactory receptor-derived peptides (ORPs) on a pyramid silicon nanowires (SiNWs) structure substrate. First, we successfully fabricated the pyramid-SiNWs structure on a silicon substrate using a chemical etching method. Subsequently, by dehydrative condensation reaction between the amino groups on APTES and the carboxyl groups of ORPs, ORPs were successfully immobilized onto the pyramid-SiNWs structure. This methodology allows the ORPs sensor on the pyramid-SiNWs substrate to detect NH3 as low as 1 ppb, which was the reported lowest limit of detection, with a higher response rate compared to ORPs sensors on flat SiNWs substrates. The sensors also exhibit good sensitivity and stability for NH3 gas detection. The results show the feasibility and potential applications of ORPs-pyramid-SiNWs structure sensors, in the fields of food safety, disease monitoring, and environmental protection, etc.

Cationic indium catalysis as a powerful tool for generating α-alkyl propargyl cations for SN1 reactions

Dehydration is an abundant and promising process in chemical, biochemical, and industrial fields. Dehydration methods can contribute to building a modern and sustainable society with minimal environmental impact. Breakthrough advances in the dehydrative SN1 reaction can be achieved through the discovery of new cationic indium catalysts. Here we show that the breakthrough advances in the dehydrative SN1 reaction can be achieved using the cationic indium catalysts. The dehydrative carbon–carbon bond formation of α-alkyl propargyl alcohols afforded a wide variety of α-aryl- and heteroaryl-propargyl compounds. Mechanistic investigations into this process revealed that the InCl3/AgClO4/Bu4NPF6/1,1’-binaphthol catalytic system generated a powerful cationic indium catalyst that could promote the dehydration of alcohols. Labile α-alkyl propargyl cations were found to self-condense, and the catalyst system efficiently regenerated propargyl cations for reaction with nucleophiles. This propargylation reaction directly proceeded from the corresponding alcohols under mild and open-air conditions and tolerated a broad scope of functional groups. Furthermore, a wide variety of nucleophiles, including aromatic and heteroaromatic compounds, phenols, alcohols, and sulfonamides, reacted with the corresponding cations to afford the propargyl compounds in good to high yields. Finally, the synthetic utility of this reaction was demonstrated by the synthesis of colchicine and allocolchicine analogues. The dehydration process could help create new compounds that were previously impossible to synthesize and is more eco-friendly and efficient than conventional methods.

Montmorillonite K‐10 Clay Promoted Direct Dehydrative Nucleophilic Substitution of Pyrrole and Indole with 4‐Chromanols

AbstractA mild and inexpensive method of alkylation of pyrrole and indole with substituted 4chromanols and 3‐arylidene‐4‐chromanols mediated by montmorillonite K‐10 is reported. Indole and pyrrole upon treatment with 4‐chromanols in the presence of activated montmorillonite K‐10 undergo facile nucleophilic substitution under ambient condition to afford 2‐(chroman‐4‐yl)‐1H‐pyrrole and 3‐(chroman‐4‐yl)‐1H‐indole in moderate to good yields. In the case of 3‐arylidene‐4‐chromanols, this direct dehydrative substitution reaction is found to be highly regioselective affording only the respective C‐4 substituted (arylidene‐chroman‐4‐yl)‐ pyrrole/indole derivatives.

Lipase/H2SO4‐Cocatalyzed Dynamic Kinetic Resolution of Alcohols in Pickering Emulsion

AbstractThis study reports the first chemoenzymatic dynamic kinetic resolution (DKR) of racemic sec‐alcohols by simultaneously using immobilized lipase and aqueous sulfuric acid as catalysts for kinetic resolution and racemization, respectively. The nanoparticle‐stabilized phase separation in a Pickering emulsion enabled the use of these inherently incompatible catalysts in a single vessel. The racemization reaction in the aqueous sulfuric acid solution significantly suppressed the dehydrative side reactions that form alkenes and dimeric ethers, which are often observed in racemization using Brønsted/Lewis acids or oxovanadium compounds in organic solvents. The efficacy of the Pickering emulsion was confirmed by the significantly lower catalytic performance in DKR without emulsification. This method achieved high yields and high optical purities in the production of a wide range of sec‐alcohols.

Imidazo[1,2-a]pyridine derivatives synthesis from lignin β-O-4 segments via a one-pot multicomponent reaction

The catalytic conversion of lignin into N-containing chemicals is of great significance for the realization of value-added biorefinery concept. In this article, a one-pot strategy was designed for the transformation of lignin β-O-4 model compounds to imidazo[1,2-a]pyridines in yields up to 95% using 2-aminopyridine as a nitrogen source. This transformation involves highly coupled cleavage of C-O bonds, sp3C-H bond oxidative activation, and intramolecular dehydrative coupling reaction to construction of N-heterobicyclic ring. With this protocol, a wide range of functionalized imidazo[1,2-a]pyridines sharing the same structure skeleton as those commercial drug molecules, such as Zolimidine, Alpidem, Saripidem, etc., were synthesized from different lignin β-O-4 model compounds and one β-O-4 polymer, emphasizing the application feasibility of lignin derivatives in N-heterobicyclic pharmaceutical synthesis.

N–N Bond Formation by a Small-Ring Phosphine Catalyst via the PIII/PV Cycle: Mechanistic Study and Guidelines to Obtain a Good Catalyst

The mechanism of the N–N cross-coupling of nitroarene and aniline catalyzed by 1,2,2,3,4,4-hexamethylphosphetane oxide (1PO) as well as the prediction of a better catalyst was theoretically investigated using DFT and DLPNO-CCSD(T) calculations. An active species 1P is generated through deoxygenation of 1PO by diphenylsilane. Then, 1P extracts one oxygen atom from nitroarene to produce nitrosoarene. In this deoxygenation step, the [3 + 1] cheletropic addition is a rate-determining step with the ΔG0≠ and ΔG0 values of 28.8 and −7.3 kcal/mol, respectively. Next, nitrosoarene exclusively undergoes a dehydrative condensation reaction with aniline to form an azo-cation intermediate, which is the origin of the high selectivity in this cross-coupling reaction. In this step, 2,4,6-trimethylbenzoic acid plays an essential role to significantly reduce the ΔG0≠ value from 41.1 to 14.8 kcal/mol. Subsequently, 1P reacts with the azo cation to form a stable hydrazinylphosphonium species through the nucleophilic attack of the phosphorus atom to the cationic nitrogen atom. The phosphonium center preferably accepts a hydroxyl group from water to ensure the formation of hydrazine in the subsequent step. In the [3 + 1] cheletropic addition step, the highest occupied molecular orbital (HOMO) of 1P plays an important role. The small-ring scaffold of 1P raises the HOMO energy compared to acyclic phosphorus compounds to achieve high activity of 1P. Substitution of a dimethylamino group for the methyl group in 1P was theoretically predicted to improve the activity by further increasing the HOMO energy.

Trichloroisocyanuric acid (TCCA): A Suitable Reagent for Direct Glycosylations of C1‐Hemiacetals with Different Nucleophiles

AbstractTrichloroisocyanuric acid (TCCA), a readily accessible, inexpensive, shelf‐stable, and non‐toxic reagent in combination with PPh3, has been used for dehydrative glycosylation reactions with furanose, pyranose, and deoxy‐sugar hemiacetals. The methodology provides a mild reaction condition, good functional group tolerance, featuring a wide variety of substrate scope using O‐, C‐, N‐, and S‐based nucleophiles with good to excellent yields and majority α‐selectivity in case of O‐glycosides while the stereoselectivity in case of C‐, N‐ and S‐ glycosides depends upon the nature of nucleophiles. Notably, this mild dehydrative glycosylation system also provides a reliable method for the synthesis of challenging phenolic glycosides. The progress of the dehydrative glycosylation reaction was monitored by mass and NMR spectroscopy and it is hypothesized that alkoxyphosphonium ions might be the reactive intermediate formed in this process, supported by 31P nuclear magnetic resonance studies.

Tf2O-Promoted Morgan–Walls Reaction: From a Flexible Approach to Functionalized Phenanthridines and Quinazolines to the Short and Divergent Total Syntheses of Alkaloids

AbstractA new protocol for the direct transformation of secondary amides (N-acyl-o-xenylamines) to phenanthridines under mild conditions is reported. The method features trifluoromethanesulfonic anhydride (Tf2O)/2-fluoropyridine as the efficient amide activation system and MeCN or CH2Cl2 as the solvent. For some substrates, MeCN participated in the reaction, which affords a mild access to polysubstituted quinazolines. By employing a Tf2O/2,4,6-tri-tert-butylpyrimidine (TTBP) combination, the method was extended to an N-formyl-o-xenylamine, which represents a recalcitrant amide substrate type for the dehydrative cyclization reaction. More importantly, a one-pot method was established for the direct and divergent synthesis of four types of phenanthridinoids from o-xenylamines, which features both a tert-N-formyl-o-xenylamine and phenanthridinium salt as key and versatile intermediates. The investigation has resulted in one of the shortest and the most efficient total syntheses of the three natural products trisphaeridine, 5,6-dihydrobicolorine, and N-methylcrinasiadine, and in the formal total syntheses of three other ones: 3-hydroxytrisphaeridine, bicolorine, and zephycandidine A.

Pincer‐Ruthenium Catalyzed Oxygen Mediated Dehydrative Etherification of Alcohols and Ortho‐Alkylation of Phenols

AbstractIn the current report, a dehydration strategy has been formulated for the selective etherification of secondary alcohols catalyzed by NNN pincer‐ruthenium(II) carbonyl complexes based on bis(imino)pyridine ligands in the presence of molecular oxygen under solvent‐free and base‐free conditions at 140 °C. Under these conditions, very high yields (up to 92%, ca. 6133 TON) of the corresponding ethers are obtained at a very low catalyst loading (ca. 0.015 mol%). Mechanistic studies provide key evidence for the various events that occur during the catalytic cycle. While iodometric titration gives quantitative proof for the liberation of hydrogen peroxide in catalytic amounts and hence confirms the role of oxygen as a co‐catalyst, DFT, HRMS, IR and 13C NMR analysis are indicative of the non‐labile nature of the ancillary CO ligand. On the other hand, DFT, NMR and HRMS studies reveal the hemi‐labile nature of the pincer‐ligand in the presence of oxygen. EPR analysis provide conclusive evidence for generation of Ru(III) species via single electron transfer (SET) from O2. Apparently the Ru(III) species (Ph2NN)RuCl2(CO)(OH) is the resting‐state of the etherification reaction and several of its derivatives have been detected by HRMS analysis. The pincer‐ruthenium catalyzed etherification of 1‐phenyl ethanol has been successfully extended not only to various aromatic secondary alcohols but also to the cross‐etherification and/or o‐alkylation of 1‐phenyl ethanols with a variety of phenols. Readily available oxygen and tiny amounts (0.015 mol%) of pincer‐Ru catalyst are the only requirement for this atom‐economical and environmentally benign dehydrative etherification reaction which apparently has not been reported thus far.magnified image

Cyclopropenium Ions in Catalysis.

Cyclopropenium ions are the smallest class of aromatic compounds, satisfying Hückel's rules of aromaticity with two π electrons within a three-membered ring. First prepared by Breslow in 1957, cyclopropenium ions have been found to possess extraordinary stability despite being both cationic and highly strained. In the 65 years since their first preparation, cyclopropenium ions have been the subject of innumerable studies concerning their synthesis, physical properties, and reactivity. However, prior to our work, the reactivity of these unique carbocations had not been exploited for reaction promotion or catalysis.Over the past 13 years, we have been exploring aromatic ions as unique and versatile building blocks for the development of catalysts for organic chemistry. A major portion of this work has been focused on leveraging the remarkable properties of the smallest of the aromatic ions─cyclopropeniums─as a design element in the invention of highly reactive catalysts. Indeed, because of its unique profile of hydrolytic stability, compact geometry, and relatively easy oxidizability, the cyclopropenium ring has proven to be a highly advantageous construction module for catalyst invention.In this Account, we describe some of our work using cyclopropenium ions as a key element in the design of novel catalysts. First, we discuss our early work aimed at promoting dehydrative reactions, starting with Appel-type chlorodehydrations of alcohols and carboxylic acids, cyclic ether formations, and Beckmann rearrangements and culminating in the realization of catalytic chlorodehydrations of alcohols and a catalytic Mitsunobu-type reaction. Next, we describe the development of cyclopropenimines as strong, neutral organic Brønsted bases and, in particular, the use of chiral cyclopropenimines for enantioselective Brønsted catalysis. We also describe the development of higher-order cyclopropenimine superbases. The use of tris(amino)cyclopropenium (TAC) ions as a novel class of phase-transfer catalysts is discussed for the reaction of epoxides with carbon dioxide. Next, we describe the formation of a cyclopropenone radical cation that has a portion of its spin density on the oxygen atom, leading to some peculiar metal ligand behavior. Finally, we discuss recent work that employs TAC electrophotocatalysts for oxidation reactions. The key intermediate for this chemistry is a TAC radical dication, which as an open-shell photocatalyst has remarkably strong excited-state oxidizing power. We describe the application of this strategy to transformations ranging from the oxidative functionalization of unactivated arenes to the regioselective derivatization of ethers, C-H aminations, vicinal C-H diaminations, and finally aryl olefin dioxygenations. Collectively, these catalytic platforms demonstrate the utility of charged aromatic rings, and cyclopropenium ions in particular, to enable unique advances in catalysis.

Successive Cleavage and Reconstruction of Lignin β‐O‐4 Models and Polymer to Access Quinoxalines

The construction of N-heterocyclic compounds from lignin remains a great challenge due to the complex lignin structure and the involvement of multiple steps, including the cleavage of lignin C-O linkages and the formation of heterocyclic aromatic rings. Herein, the first example of KOH mediated sustainable synthesis of quinoxaline derivatives from lignin β-O-4 model compounds in a one-pot fashion under transition-metal-free conditions has been achieved. Mechanistic studies suggested that this transformation includes highly coupled cascade steps of cleavage of C-O bonds, dehydrative condensation, sp3 C-H bond oxidative activation, and intramolecular dehydrative coupling reaction. With this protocol, a wide range of functionalized quinoxalines, including an important drug compound AG1295, were synthesized from lignin β-O-4 model compounds and β-O-4 polymer, showcasing the application potential of lignin in pharmaceutical synthesis.

Dehydrative Substitution Reaction in Water for the Preparation of Unsymmetrically Substituted Triarylmethanes: Synthesis, Aggregation-Enhanced Emission, and Mechanofluorochromism.

Water as a reaction media in chemical transformations has several advantages in terms of safety and non-toxicity. However, dehydrative substitution reaction in water is a highly challenging operation. In this paper, we have reported a sulfamic acid-mediated dehydrative substitution reaction of benzofuryl alcohols with several nucleophiles in water towards the scalable, easily isolable, synthesis of unsymmetrically substituted triarylmethanes (TRAMs) in good to excellent yields (up to 92 %). Moreover, we have demonstrated that rationally designed propellor-shaped triarylmethanes promote aggregation-induced emission (AIE) through restricted intramolecular rotation with irreversible mechanoflurochromic property.

Regioselective Cycloaddition and Substitution Reaction of Tertiary Propargylic Alcohols and Heteroareneboronic Acids via Acid Catalysis.

We report an acid-catalyzed formal cycloaddition and dehydrative substitution reaction of tertiary propargylic alcohols and heteroareneboronic acids. The properties of the substituents on the alkynyl moiety determines the regioselectivity of the reaction, which could selectively construct fused heterocycles, tetrasubstituted allenes, or 1,3-dienes. This reaction proceeds efficiently with a wide array of substrate scope in up to 89% yield. A significant advantage of this protocol is the transition-metal-free and mild conditions needed.

Synthesis and Antioxidant/Anti-Inflammatory Activity of 3-Arylphthalides.

Phthalides are a group of compounds with relevant biological activities in different areas such as cytotoxicity, anti-stroke activity, neuroprotection, and inflammation, among others. In this study we designed and synthesized a series of 3-arylphthalide derivatives in order to identify their antioxidant and anti-inflammatory activities. The synthetic methodology was established in terms of atom and step economy through a dehydrative coupling reaction between 3-hydroxyphthalide and different properly functionalized arene rings. The evaluation of the antioxidant activity was performed by the ABTS assay and for the anti-inflammatory activity the inhibition of LPS-induced nitric oxide (NO) production in microglial cells Bv.2 and macrophage cells RAW 264.7 was measured. The synthesized compound 3-(2,4-dihydroxyphenyl)phthalide (5a) showed better antioxidant activity than the Trolox standard and caused strong inhibition of NO production in LPS-stimulated Bv.2 and RAW 264.7 cells. In addition, compound 5a reduced the expression of the pro-inflammatory cytokines Il1b and Il6 in RAW 264.7 cells. These results, which are the first account of the anti-inflammatory activity of 3-arylphthalides, suggest that compound 5a could be a promising candidate for more advanced anti-inflammatory studies.