Nucleophilic Activation Research Articles

Carbene‐Catalyzed N,N‐Nucleophilic Activation of Thioureas for Access to Pyrimidinthione Derivatives

AbstractAn N‐heterocyclic carbene‐catalyzed [3+3] cycloaddition reaction of acylthioureas with ynals is reported. Both N atoms in the thiourea substrate are activated as nucleophiles and incorporated inside the ring system of the product. Pyrimidinthione derivatives bearing various substituents and substitution patterns are afforded as the products in moderate to good yields.

Enantioselective Desymmetrization of 2-Aryl-1,3-propanediols by Direct O-Alkylation with a Rationally Designed Chiral Hemiboronic Acid Catalyst That Mitigates Substrate Conformational Poisoning.

Enantioselective desymmetrization by direct monofunctionalization of prochiral diols is a powerful strategy to prepare valuable synthetic intermediates in high optical purity. Boron acids can activate diols toward nucleophilic additions; however, the design of stable chiral catalysts remains a challenge and highlights the need to identify new chemotypes for this purpose. Herein, the discovery and optimization of a bench-stable chiral 9-hydroxy-9,10-boroxarophenanthrene catalyst is described and applied in the highly enantioselective desymmetrization of 2-aryl-1,3-diols using benzylic electrophiles under operationally simple, ambient conditions. Nucleophilic activation and discrimination of the enantiotopic hydroxy groups on the diol substrate occurs via a defined chairlike six-membered anionic complex with the hemiboronic heterocycle. The optimal binaphthyl-based catalyst 1g features a large aryloxytrityl group to effectively shield one of the two prochiral hydroxy groups on the diol complex, whereas a strategically placed "methyl blocker" on the boroxarophenanthrene unit mitigates the deleterious effect of a competing conformation of the complexed diol that compromised the overall efficiency of the desymmetrization process. This methodology affords monoalkylated products in enantiomeric ratios equal or over 95:5 for a wide range of 1,3-propanediols with various 2-aryl/heteroaryl groups.

Nucleophilic Activation of Hydrosilanes via a Strain-Imposing Strategy Leading to Functional Sila-aromatics.

Carefully designed cyclic hydrosilanes enable trans-selective hydrosilylation of unactivated alkynes without transition metal catalysts via silicate formation. Employment of sterically demanding bidentate ligands of silicon increases steric congestion upon silicate formation, and this strain-imposing strategy facilitates hydride transfer. This hydrosilylation provides efficient access to diverse benzosiloles, silaphenalenes, and related silacycles.

Facile preparation of pH/redox dual-responsive biodegradable polyphosphazene prodrugs for effective cancer chemotherapy

In order to maximize the therapeutic effect and and minimize the systemtic side effect of the small molecule anticancer drugs, biodegradable drug delivery systems (DDSs) that respond to tumor microenvironment (TME) have attracted significant attention. Herein, a novel redox/pH dual-responsive and biodegradable polyphosphazene (PPZ) nano-prodrugs have been prepared via one-pot crosslinking of vanillin modified DOX (VMD, acid-sensitive) and 4,4′-dihydroxydiphenyl disulfide (HPS, GSH-responsive) with hexachlorocyclotriphosphazene (HCCP). The phenol groups of the as-synthesized VMD and HPS have high nucleophilic substitution activity towards HCCP under base catalyst and afforded PPZ nano-prodrugs, denoted as HCCP-VMD-HPS, with a high drug loading ratio of up to 56.4 %. As expected, the skeleton of the PPZ consisting of imine bonds in VMD and the disulfide bonds in HPS and cyclotriphosphazenes inclined to be decomposed in low pH conditions and high level of GSH environments. The antitumor drug DOX was found to be controlled released in TME conditions (extracellular, pH∼6.8 and endosomes, lysosomes pH∼5.0 with ∼10 mM GSH), rather than neutral physiological conditions (pH 7.4 with ∼20 μM GSH). Moreover, the resulting HCCP-VMD-HPS nano-prodrug have obvious cytotoxicity to cancer cells while a negligible side effect to normal cells. We therefore believe that the prepared redox/pH dual-responsive and biodegradable PPZ DDSs have great potential in various field.

Enantioselective vinylogous aldol reaction of acylphosphonates with 3-alkylidene oxindoles.

A simple strategy for yielding chiral tertiary α-hydroxy phosphonates that integrates two highly biologically relevant scaffolds namely 3-alkylidene-2-oxindoles and phosphonates has been described. The hydrogen bonding ability of the bifunctional thiourea catalyst allows simultaneous dual activation of a vinylogous oxindole nucleophile and an acylphosphonate electrophile, affording hydroxyphosphonato-3-alkylidene-2-oxindoles as aldol adducts in high yields (up to 92%) with excellent stereocontrol (up to 99% ee).

Defluorinative Functionalization of Pd(II) Fluoroalkyl Complexes.

When subjected to arylboranes, anionic trifluoromethyl and difluorobenzyl palladium(II) complexes undergo fluoride abstraction followed by 1,1-migratory insertion. The resulting intermediate fluoroalkyl species can be induced to undergo a subsequent transmetalation and reductive elimination from either an in situ formed fluoroboronate (FB(Ar3)-) or an exogenous boronic acid/ester (ArB(OR)2) and nucleophilic activator, representing a net defluorinative arylation reaction. The latter method enabled a structurally diverse substrate scope to be prepared from either an isolated palladium-CF3 complex, or from Pd(PPh3)4 and other commercially available reagents.

The Vinylogous Michael Addition of 3‐Alkylidene‐2‐oxindoles to β,γ‐Unsaturated α‐Keto Esters by Bifunctional Cinchona Alkaloids

A highly enantioselective vinylogous Michael addition of 3‐alkylidene‐2‐oxindoles with β,γ‐unsaturated α‐keto esters using a bifunctional tertiary‐amine thiourea catalyst is demontsrated. The challenging Michael reaction with the β,γ‐unsaturated α‐keto esters has been accomplished due to the synchronized H‐bond guided dual activation of vinylogous nucleophile and electrophile by catalyst. The reaction afforded product in high yield while resulting in excellent stereocontrol (> 19:1 E/Z and upto 99 % ee).

Synthesis of propylene glycol methyl ether catalyzed by imidazole polymer catalyst: Performance evaluation, kinetics study, and process simulation

An imidazole polymer (divinylbenzene-vinylimidazole) catalyst (P-DVB-VIM) was developed for production of the eco-friendly solvent propylene glycol methyl ether (PGME) by the propoxylation reaction of propylene oxide (PO) with methanol (ME). The catalyst was characterized in detail by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR), and Brunauer-Emmett-Teller (BET) analysis. 1H NMR was used to characterize the structural features of the catalyst precursor, i.e., the linear polymer of vinylimidazole (PVIM). An “electrophile nucleophile dual activation” ring-opening mechanism was proposed based on the “cooperative effect” of the reactant and PVIM. The catalytic performance was investigated and optimized at 100–130 ℃ using an autoclave batch reactor. The results reveal that the P-DVB-VIM shows excellent catalytic performance, exhibiting the highest turnover frequency (TOF) number at 120 °C within 45 min. The reaction kinetics was systematically studied using the pseudohomogeneous (PH) kinetic model. The kinetic parameters were determined by non-linear regression analysis of the experimental data. Validation of the model showed that the experimental data were in good agreement with the predicted outcomes. Moreover, based on the proposed kinetic model, steady-state simulations of the production of PGME in a fixed-bed reactor were carried out to determine the optimal design parameters, thus providing a useful guide for the design and production of PGME on the industrial scale.

Nucleophilic versus Electrophilic Activation of Hydrogen Peroxide over Zr-Based Metal-Organic Frameworks.

Zr-based metal-organic frameworks (Zr-MOF) UiO-66 and UiO-67 catalyze thioether oxidation in nonprotic solvents with unprecedentedly high selectivity toward corresponding sulfones (96-99% at ca. 50% sulfide conversion with only 1 equiv of H2O2). The reaction mechanism has been investigated using test substrates, kinetic, adsorption, isotopic (18O) labeling, and spectroscopic tools. The following facts point out a nucleophilic character of the peroxo species responsible for the superior formation of sulfones: (1) nucleophilic parameter XNu = 0.92 in the oxidation of thianthrene 5-oxide and its decrease upon addition of acid; (2) sulfone to sulfoxide ratio of 24 in the competitive oxidation of methyl phenyl sulfoxide and p-Br-methyl phenyl sulfide; (3) significantly lower initial rates of methyl phenyl sulfide oxidation relative to methyl phenyl sulfoxide (kS/kSO = 0.05); and (4) positive slope ρ = +0.42 of the Hammett plot for competitive oxidation of p-substituted aryl methyl sulfoxides. Nucleophilic activation of H2O2 on Zr-MOF is also manifested by their capability of catalyzing epoxidation of electron-deficient C═C bonds in α,β-unsaturated ketones accompanied by oxidation of acetonitrile solvent. Kinetic modeling on methyl phenyl sulfoxide oxidation coupled with adsorption studies supports a mechanism that involves the interaction of H2O2 with Zr sites with the formation of a nucleophilic oxidizing species and release of water followed by oxygen atom transfer from the nucleophilic oxidant to sulfoxide that competes with water for Zr sites. The nucleophilic peroxo species coexists with an electrophilic one, ZrOOH, capable of oxygen atom transfer to nucleophilic sulfides. The predominance of nucleophilic activation of H2O2 over electrophilic one is, most likely, ensured by the presence of weak basic sites in Zr-MOFs identified by FTIR spectroscopy of adsorbed CDCl3 and quantified by adsorption of isobutyric acid.

Transition-metal-free formal cross-coupling of aryl methyl sulfoxides and alcohols via nucleophilic activation of C-S bond

Employment of sulfoxides as electrophiles in cross-coupling reactions remains underexplored. Herein we report a transition-metal-free cross-coupling strategy utilizing aryl(heteroaryl) methyl sulfoxides and alcohols to afford alkyl aryl(heteroaryl) ethers. Two drug molecules were successfully prepared using this protocol as a key step, emphasizing its potential utility in medicinal chemistry. A DFT computational study suggests that the reaction proceeds via initial addition of the alkoxide to the sulfoxide. This adduct facilitates further intramolecular addition of the alkoxide to the aromatic ring wherein charge on the aromatic system is stabilized by the nearby potassium cation. Rate-determining fragmentation then delivers methyl sulfenate and the aryl or heteroaryl ether. This study establishes the feasibility of nucleophilic addition to an appended sulfoxide as a means to form a bond to aryl(heteroaryl) systems and this modality is expected to find use with many other electrophiles and nucleophiles leading to new cross-coupling processes.

Catalytic Intramolecular Conjugate Additions of Aldehyde-Derived Enamines to α,β-Unsaturated Esters

We report a pairing of known catalysts that enables intramolecular conjugate additions of aldehyde-derived enamines to α,β-unsaturated esters. Despite extensive prior exploration of conjugate additions of aldehyde-derived enamines, catalytic conjugate additions to unactivated enoate esters are unprecedented. Achieving enantioselective and diastereoselective six-membered ring formation requires the coordinated action of a chiral pyrrolidine, for nucleophilic activation of the aldehyde via enamine formation, and a hydrogen bond donor, for electrophilic activation of the enoate ester. Proper selection of the hydrogen bond donor is essential for chemoselectivity, which requires minimizing competition from homoaldol reaction. Utility is demonstrated in a six-step synthesis of (-)-yohimbane from cycloheptene.

Dinitrosyl Iron Complex [K‐18‐crown‐6‐ether][(NO)2Fe(MePyrCO2)]: Intermediate for Capture and Reduction of Carbon Dioxide

AbstractContinued efforts are made for the utilization of CO2 as a C1 feedstock for regeneration of valuable chemicals and fuels. Mechanistic study of molecular (electro‐/photo‐)catalysts disclosed that initial step for CO2 activation involves either nucleophilic insertion or direct reduction of CO2. In this study, nucleophilic activation of CO2 by complex [(NO)2Fe(μ‐MePyr)2Fe(NO)2]2− (2, MePyr=3‐methylpyrazolate) results in the formation of CO2‐captured complex [(NO)2Fe(MePyrCO2)]− (2‐CO2, MePyrCO2=3‐methyl‐pyrazole‐1‐carboxylate). Single‐crystal structure, spectroscopic, reactivity, and computational study unravels 2‐CO2 as a unique intermediate for reductive transformation of CO2 promoted by Ca2+. Moreover, sequential reaction of 2 with CO2, Ca(OTf)2, and KC8 established a synthetic cycle, 2 → 2‐CO2 → [(NO)2Fe(μ‐MePyr)2Fe(NO)2] (1) → 2, for selective conversion of CO2 into oxalate. Presumably, characterization of the unprecedented intermediate 2‐CO2 may open an avenue for systematic evaluation of the effects of alternative Lewis acids on reduction of CO2.

Dinitrosyl Iron Complex [K-18-crown-6-ether][(NO)2 Fe(Me PyrCO2 )]: Intermediate for Capture and Reduction of Carbon Dioxide.

Continued efforts are made for the utilization of CO2 as a C1 feedstock for regeneration of valuable chemicals and fuels. Mechanistic study of molecular (electro-/photo-)catalysts disclosed that initial step for CO2 activation involves either nucleophilic insertion or direct reduction of CO2 . In this study, nucleophilic activation of CO2 by complex [(NO)2 Fe(μ-Me Pyr)2 Fe(NO)2 ]2- (2, Me Pyr=3-methylpyrazolate) results in the formation of CO2 -captured complex [(NO)2 Fe(Me PyrCO2 )]- (2-CO2 , Me PyrCO2 =3-methyl-pyrazole-1-carboxylate). Single-crystal structure, spectroscopic, reactivity, and computational study unravels 2-CO2 as a unique intermediate for reductive transformation of CO2 promoted by Ca2+ . Moreover, sequential reaction of 2 with CO2 , Ca(OTf)2 , and KC8 established a synthetic cycle, 2 → 2-CO2 → [(NO)2 Fe(μ-Me Pyr)2 Fe(NO)2 ] (1) → 2, for selective conversion of CO2 into oxalate. Presumably, characterization of the unprecedented intermediate 2-CO2 may open an avenue for systematic evaluation of the effects of alternative Lewis acids on reduction of CO2 .

Mild and Chemoselective Thioacylation of Amines Enabled by the Nucleophilic Activation of Elemental Sulfur.

A mild and chemoselective method for the thioacylation of amines using α-keto acids and elemental sulfur has been developed. The key to the success of this transformation is the nucleophilic activation of elemental sulfur by thiols such as 1-dodecanethiol. A variety of functional groups, including unprotected hydroxyl, carboxyl, amide, sulfide, and tertiary amine moieties, are tolerated under the applied reaction conditions. To demonstrate the advantages of this method compared with conventional O-S exchange reactions using Lawesson's reagent or P2S5, thioamide moieties were introduced site-specifically into biologically active compounds.

Nucleophilic Activation of Red Phosphorus for Controlled Synthesis of Polyphosphides.

Reactions between red phosphorus (Pred) and potassium ethoxide in various organic solvents under reflux convert this rather inert form of the element to soluble polyphosphides. The activation is hypothesized to proceed via a nucleophilic attack by ethoxide on the polymeric structure of Pred, leading to disproportionation of the latter, as judged from observation of P(OEt)3 in the reaction products. A range of solvents has been probed, revealing that different polyphosphide anions (P73-, P162-, P213-, and P5-) can be stabilized depending on the combination of the boiling point and dielectric constant (polarity) of the solvent. The effectiveness of activation also depends on the nature of nucleophile, with the rate of reaction between Pred and KOR increasing in the order t-Bu < n-Hex < Et < Me, which is in agreement with the increasing order of nucleophilic strength. Thiolates and amides were also examined as potential activators, but the reaction with these nucleophiles were substantially slower; nonetheless, all reactions between Pred and NaSR yielded exclusively P162- as a soluble polyphosphide product.

A Computational Chemistry Approach for the Hydrolysis of DNA Molecule by Hydrated Transition Metal Complexes as Artificial Metallonuclease

인공 핵산분해효소로 작용하는 10종의 수화된 (배위수: 6) 단일 리간드 전이금속 착 화합물([M(H₂O)&#8326;]z&#8314; 및 [M(OH)&#8326;]z&#8315;)과 DNA분자의 해리반응(pKa)전 후 조건에서, 전산화학적인 경계분자궤도(FMO) 이론에 따른 이들 화합물의 반응성을 정량적으로 검토하였다. 그리고 분자 간 FMO에너지 차이(ΔE)로부터, Lewis acid 촉매로서 금속 착 화합물의 친핵성 리간드 활성화(A)에 따른 궤도조절(orbital control) 반응과 금속 착 화합물의 활성화(B)로 인한 전하조절(charge control) 반응이 각각 예측되었다. 모든 경우에 반응성은 물 분자 리간드 금속 착 화합물([M(H₂O)&#8326;]z&#8314;)보다 hydroxo 리간드 금속 착 화합물([M(OH)&#8326;]z&#8315;)이 높았으며, 그리고 2가 화합물([M(H₂O)&#8326;]²&#8314; 및 [M(OH)&#8326;]⁴&#8315;)이 3가 화합물([M(H₂O)&#8326;]³&#8314; 및 [M(OH)&#8326;]³&#8315;)보다 빠른 반응성을 나타내었다. 이들의 반응성은 주로 [M(OH)6]z&#8315;과 해리 후 DNA분자 사이의 음 이온성 반발력이나 착 이온의 입체효과와 전하크기에 의존적이었다. 그러므로 이 같은 리간드 효과로부터 가장 빠른 반응조건에서(6M) HOMO에너지에 의존적인 주 반응(A)에 따른 [M(OH)&#8326;]z&#8315;에 의한 DNA 분자의 가수분해 전환과정(turnover process)을 제시하였다.The acting as artificial metallonucleases under the condition at before and after dissociation (pKa) of DNA molecule and 10 hydrated (coordination number: 6) homoleptic transition metal complexes ([M(H₂O)&#8326;]z&#8314; & [M(OH)&#8326;]z&#8315;) are reviewed quantitatively based on the frontier molecule orbital (FMO) theory in computational chemistry. In additions, from the FMO energy difference (ΔE) between the complexes and DNA molecule, the orbital control reaction by nucleophilic ligand activation (A) of the metal complexes as Lewis acid catalyst, and the charge control reaction by activation (B) of the metal complexes are predicted, respectively. Hence, the reactivity of [M(OH)&#8326;]z&#8315; was higher than that of [M(H₂O)&#8326;]z&#8314; in all cases. Moreover, divalent ([M(H₂O)&#8326;]²&#8314; and [M(OH)&#8326;]⁴&#8315;) show rapid responses comparing to the trivalent compounds ([M(H₂O)&#8326;]³&#8314; and [M(OH)&#8326;]³&#8315;). Their reactivity was mainly dependent on the anionic repulsive force between hydroxo ligand metal complex and dissociated DNA molecule, or steric effect and charge size of complexe ions. Therefore, from these results of ligand effect, the turnover process on the hydrolytic decomposition of contaminated DNA molecule by homoleptic hydroxo metal complexes ([M(OH)&#8326;]z&#8315;) in the fastest reaction condition (6M) was proposed as the major reaction (A) depend upon the HOMO energy.

A simple and general approach for the synthesis of biodegradable triblock copolymers by organocatalytic ROP from poly(lactide) macroinitiators

To overcome the present limitations in the synthesis of biodegradable triblock copolymers with PLA as central building block, three different reactional mechanisms (coordination-insertion, anionic and cationic) have been involved, while employing the transition from organometallic to organic catalysis. Even though activated chain-end mechanism with stannous octanoate is well known for the successful ROP catalytic reactivity, the synthesis of PLA based triblock copolymers according to this route revealed not negligible transesterification reactions. In the same way, the activated chain-end mechanism through nucleophilic activation (TBD) presented either no reactivity or weak control over the anionic polymerization process. Herein, we therefore propose an activated monomer mechanism as general and simple route for obtaining controlled PTMC-b-PDLLA-b-PTMC and PCL-b-PDLLA-b-PCL triblock copolymers by using cationic organocatalysis (MSA). 1H, 13C NMR and DOSY-NMR spectra confirmed the well-controlled polymer architecture of the B-A-B triblock copolymer.

Carbonyl-Stabilized Phosphorus Ylide as an Organocatalyst for Cyanosilylation Reactions Using TMSCN

We report carbonyl-stabilized phosphorus ylides as general and efficient catalysts for the cyanosilylation of ketones. The N,N-diethylacetamide derived phosphorane is identified as an extremely efficient catalyst for the cyanosilylation of dialkyl ketones, alkyl aryl ketones, diaryl ketones, and α,β-unsaturated enones with catalyst loading down to 0.005 mol %, the lowest ever known for ketone cyanosilylation. Aldehydes, aldimines, and ketimines are also viable substrates. By NMR and React IR analysis, as well as electrical conductivity experiments, it is proposed that the phosphorane acts as a Lewis base in order to mediate the reaction via the desilylative nucleophilic activation of TMSCN.

Harnessing Ionic Interactions and Hydrogen Bonding for Nucleophilic Fluorination.

We review recent works for nucleophilic fluorination of organic compounds in which the Coulombic interactions between ionic species and/or hydrogen bonding affect the outcome of the reaction. SN2 fluorination of aliphatic compounds promoted by ionic liquids is first discussed, focusing on the mechanistic features for reaction using alkali metal fluorides. The influence of the interplay of ionic liquid cation, anion, nucleophile and counter-cation is treated in detail. The role of ionic liquid as bifunctional (both electrophilic and nucleophilic) activator is envisaged. We also review the SNAr fluorination of diaryliodonium salts from the same perspective. Nucleophilic fluorination of guanidine-containing of diaryliodonium salts, which are capable of forming hydrogen bonds with the nucleophile, is exemplified as an excellent case where ionic interactions and hydrogen bonding significantly affect the efficiency of reaction. The origin of experimental observation for the strong dependence of fluorination yields on the positions of -Boc protection is understood in terms of the location of the nucleophile with respect to the reaction center, being either close to far from it. Recent advances in the synthesis of [18F]F-dopa are also cited in relation to SNAr fluorination of diaryliodonium salts. Discussions are made with a focus on tailor-making promoters and solvent engineering based on ionic interactions and hydrogen bonding.

Hydrogen-Bonding Catalysis of Alkyl-Onium Salts.

The synthetic utility of alkyl-onium salt compounds is widely recognized in the field of organic chemistry. Among the wide variety of onium salts, quaternary ammonium, phosphonium, and tertiary sulfonium salts have been the most useful compounds in organic syntheses. These compounds have been very useful reagents in the construction of organic building blocks. In addition, onium salts are known as reliable catalysts, which are used to promote important organic transformations by serving as phase-transfer and ion-pair catalysts through the activation of nucleophiles. Although phase-transfer catalysis is a major direction for onium salt catalysis, hydrogen-bonding catalysis of alkyl-onium salts, which is promoted via the activation of electrophiles, has recently become a relevant topic in the field of onium salt chemistry. This Minireview introduces new possibilities and future directions for alkyl-onium salt chemistry based on its use in hydrogen-bonding catalysis and on its overall utility.