Selective Deprotonation Research Articles

Recent Advances in the Preparation of Air Stable Organozinc Pivalates and their Applications in Organic Synthesis

AbstractThis review discusses various methods for the preparation of air and water‐stable organozinc pivalates containing aryl, heteroaryl, alkyl, alkenyl, benzyl and alkynyl scaffolds achieved via i) selective metalation (DoM) in the presence of a directing group (DG) in the aromatic core, ii) direct oxidative Zn metal insertion/or X/M exchange reaction followed by transmetalation with Zn(Opiv)2, which are then further functionalized by Negishi cross‐coupling reactions, or trapping with different aryl, heteroaryl, alkenyl, alkynyl electrophiles used by transition metal catalysts (Pd, Co, Ni, Cu). Selective deprotonation of aryl or heteroaryl derivatives can be performed using LDA, TMP−Mg and TMP−Zn reagents in the presence of a directing group on the aromatic system. Different organozinc reagents based on aromatic and non‐aromatic structures with electron‐rich and electron‐deficient substituents undergo transition metal‐catalyzed C(sp2)−C(sp2), C(sp2)−C(sp) and C(sp2)−C(sp3) types of cross‐coupling reactions with aryl and heteroaryl halides and diaryl disulfides under mild conditions with the sustainable catalytic process. The literature report shows that the polyfunctionalized nitrogen, oxygen and sulfur‐based bioactive pharmaceutical scaffolds, natural products and target organic molecules are accessible using highly air and moisture‐stable organozinc pivalates under sustainable coupling reaction conditions. Importantly, the sensitive functional groups are tolerable, and the commercially available substrates and inexpensive low toxic reagents can be employed with organozinc pivalates. In this context, this review article provides a detailed summary of the numerous synthetic strategies and practical methods for the preparation of aryl, alkenyl, benzyl and alkynyl organozinc reagents that can be isolated in the pure solid form. Additionally, some recently published examples demonstrating their catalytic application in organic synthesis are discussed.

A (C5Me5)/enolamido lutetium dinitrogen complex promoted by deprotonation on the amidinate ligand.

Selective deprotonation of the amidinate ligand in lutetium dinitrogen complex [{Cp*{MeC(NiPr)2}Lu}2(μ2-η2:η2-N2)][K(crypt)] (Cp* = (C5Me5)-, crypt = 2,2,2-cryptand) afforded the novel Cp*/enolamido lutetium dinitrogen complex [{Cp*{H2CC(NiPr)2}Lu}2(μ2-η2:η2-N2)K][K(crypt)]. Due to the skeleton tension, a further rearrangement was confirmed with the formation of [{Cp*K{H2CC(NiPr)2}Cp*Lu}2(μ2-η2:η2-N2)][K(crypt)]2.

Functionalization of Pyridine and Quinoline Scaffolds by Using Organometallic Li‐, Mg‐ and Zn‐Reagents

AbstractThis Review discusses the various methods for functionalizing pyridine and quinoline scaffolds, including direct selective metalation (DoM), halogen/metal exchange reactions, Li, Mg, and Zn insertion, and trans‐metalation approaches, which are then followed by cross‐coupling reactions of the Kumada or Negishi types. Selective deprotonation of aryl or pyridyl/quinolinyl derivatives can be performed using n‐BuLi, LDA, and TMP‐based different organolithium, ‐magnesium, and ‐zinc reagents. The functionalized pyridine and quinoline‐based heterocyclic compounds were prepared by selectively deprotonating with presenting a directing functional group substituted pyridine/quinoline analogues in the presence of TMP‐bases (TMP−Li, Mg, Zn reagents). Different aryl or alkyl Li, Mg, and Zn reagents with electron‐donating and electron‐withdrawing substituents undergo transition metal‐catalyzed C(sp2)−C(sp2) and C(sp2)−C(sp3) types of cross‐coupling reactions with pyridine/quinoline halides under mild conditions with the sustainable process producing complex N‐heterocycles. Using moderate and sustainable reaction conditions, sensitive functional group tolerance, and inexpensive and low toxic chemicals, highly functionalization of pyridine and quinoline‐based bioactive therapeutic scaffolds and natural products was accomplished. Therefore, in this article, we provide a succinct overview of the numerous synthetic strategies and practical methods used by various authors between 2010 and 2023 to functionalize pyridine and quinoline analogues using diverse Li, Mg, and Zn organometallic reagents.

Stereoselective Synthesis of 1,1’,2,2’‐Tetrasubstituted Ferrocenes by Double Lithiation of a 1,1’‐Disubstituted Ferrocenyl Pyrroloimidazolone

AbstractA 1,1’‐disubstituted ferrocenyl pyrroloimidazolone with syn stereochemistry undergoes double lithiation–electrophile quench in a one‐pot procedure to give C2‐symmetric 1,1’,2,2’‐tetrasubstituted products in >95 : 5 diastereomeric ratio (dr). These results represent an extension of double lithiation to access tetrasubstituted planar chiral ferrocenes for the first time to a nitrogen‐linked (pyrroloimidazolone) chiral directing group. The stereochemistry of the products was determined by X‐ray crystallography of distannane and dibromide adducts in combination with deuteration, elimination, and transmetalation experiments. Results support that products arise from selective deprotonation of the pro‐Sp position of each cyclopentadienyl (Cp) ring.

Tropane and related alkaloid skeletons via a radical [3+3]-annulation process

Tropanes and related bicyclic alkaloids are highly attractive compounds possessing a broad biological activity. Here we report a mild and simple protocol for the synthesis of N-arylated 8-azabicyclo[3.2.1]octane and 9-azabicyclo[3.3.1]nonane derivatives. It provides these valuable bicyclic alkaloid skeletons in good yields and high levels of diastereoselectivity from simple and readily available starting materials using visible-light photoredox catalysis. These bicyclic aniline derivatives are hardly accessible via the classical Robinson tropane synthesis and represent a particularly attractive scaffold for medicinal chemistry. This unprecedented annulation process takes advantage of the unique reactivity of ethyl 2-(acetoxymethyl)acrylate as a 1,3-bis radical acceptor and of cyclic N,N-dialkylanilines as radical 1,3-bis radical donors. The success of this process relies on efficient electron transfer processes and highly selective deprotonation of aminium radical cations leading to the key α-amino radical intermediates.

The selective deprotonation of carbon quantum dots for fluorescence detection of phosphate and visualization of latent fingerprints.

We developed a water-soluble, stable and selective "turn-on" fluorescence sensing platform based on carbon quantum dots (CQDs) for rapid determination of phosphate (Pi) in aqueous solutions and for visualization of latent fingerprints on paper. The hydroxyl groups on the surface of the synthesized CQDs can be deprotonated by Pi to trigger the intramolecular charge transfer (ICT) process and the inhibition of excited-state proton transfer (ESPT), achieving a turn-on emission response. CQDs demonstrated the capability to selectively detect Pi over other common ions and biomolecules with the linear fluorescence intensity change in the range from 0 to 100 μM. Moreover, the paper sprayed with the CQD solution showed a remarkable blue emission speckle and a fingerprint upon addition of Pi solution and finger touching, respectively. Notably, the fingerprint images including level 3 details (crossover, bifurcation, termination, and island and sweat pores) are also clearly identified and distinguished, indicating their potential application in document security. We believe that the as-synthesized CQDs will provide a new tool for Pi detection in aqueous media and paper document security.

Electrochemistry as a surrogate for protein phosphorylation: voltage-controlled assembly of reflectin A1.

Phosphorylation is among the most widely distributed mechanisms regulating the tunable structure and function of proteins in response to neuronal, hormonal and environmental signals. We demonstrate here that the low-voltage electrochemical reduction of histidine residues in reflectin A1, a protein that mediates the neuronal fine-tuning of colour reflected from skin cells for camouflage and communication in squids, acts as an in vitro surrogate for phosphorylation in vivo, driving the assembly previously shown to regulate its function. Using micro-drop voltammetry and a newly designed electrochemical cell integrated with an instrument measuring dynamic light scattering, we demonstrate selective reduction of the imidazolium side chains of histidine in monomers, oligopeptides and this complex protein in solution. The formal reduction potential of imidazolium proves readily distinguishable from those of hydronium and primary amines, allowing unequivocal confirmation of the direct and energetically selective deprotonation of histidine in the protein. The resulting 'electro-assembly' provides a new approach to probe, understand, and control the mechanisms that dynamically tune protein structure and function in normal physiology and disease. With its abilities to serve as a surrogate for phosphorylation and other mechanisms of charge neutralization, and to potentially isolate early intermediates in protein assembly, this method may be useful for analysing never-before-seen early intermediates in the phosphorylation-driven assembly of other proteins in normal physiology and disease.

Lithium-mediated Ferration of Fluoroarenes.

While fluoroaryl fragments are ubiquitous in many pharmaceuticals, the deprotonation of fluoroarenes using organolithium bases constitutes an important challenge in polar organometallic chemistry. This has been widely attributed to the low stability of the in situ generated aryl lithium intermediates that even at -78 °C can undergo unwanted side reactions. Herein, pairing lithium amide LiHMDS (HMDS = N{SiMe₃}₂) with FeII(HMDS)₂ enables the selective deprotonation at room temperature of pentafluorobenzene and 1,3,5-trifluorobenzene via the mixed-metal base [(dioxane)LiFe(HMDS)₃] (1) (dioxane = 1,4-dioxane). Structural elucidation of the organometallic intermediates [(dioxane)Li(HMDS)₂Fe(ArF)] (ArF = C6F5, 2; 1,3,5-F₃-C6H₂, 3) prior electrophilic interception demonstrates that these deprotonations are actually ferrations, with Fe occupying the position previously filled by a hydrogen atom. Notwithstanding, the presence of lithium is essential for the reactions to take place as Fe II (HMDS)₂ on its own is completely inert towards the metallation of these substrates. Interestingly 2 and 3 are thermally stable and they do not undergo benzyne formation via LiF elimination.

Organocatalytic Selective [3 + 2] Cycloadditions: Synthesis of Functionalized 5-Arylthiomethyl-1,2,3-triazoles and 4-Arylthio-1,2,3-triazoles.

An organocatalytic azide-ketone [3 + 2] cycloaddition (OrgAKC) of a variety of 1-aryl-3-(arylthio)propan-2-ones and 1-alkyl-3-(arylthio)propan-2-ones with different aryl/vinyl/alkyl azides is reported under ambient conditions to furnish the medicinally important 1,4-disubstituted-5-arylthiomethyl-1,2,3-triazoles and 1,5-disubstituted-4-arylthio-1,2,3-triazoles, respectively, in a regioselective manner with high yields/rates. With controlled and online NMR experiments, we proved that the reaction path is following the organocatalytic enolization through selective deprotonation followed by a [1,3]-H shift. Surprisingly, the [3 + 2] cycloaddition of aryl/vinyl/alkyl azides with the in situ-generated equilibrated thermodynamic ↔ kinetic enolates furnished the highly regioselective functionally rich 1,2,3-triazoles by discriminating their reactivities. This is the first report on the investigation of a selective OrgAKC with the regiomers of enolates generated in situ from the unsymmetrical carbonyl compounds. The reaction sustainability is explained with a few controlled experiments, mechanistic studies, and applications.

Metalated Ir–CNP Complexes Containing Imidazolin‐2‐ylidene and Imidazolidin‐2‐ylidene Donors – Synthesis, Structure, Luminescence, and Metal–Ligand Cooperative Reactivity

The iridium complex 1 based on a metalated CNP ligand containing an imidazolin‐2‐ylidene fragment has been prepared by treatment of the ligand precursor 4 with Ag2O followed by reaction with [IrCl(COE)2]2. The chlorohydride imidazolidin‐2‐ylidene complex 6, which is isostructural to 1, was synthetized by reaction of the previously reported dihydride derivative 3 with CH2Cl2. Complexes 1 and 6 exhibit luminescence arising from a 3MLCT/ILCT state involving the metalated CNP ligand, which is particularly intense for 1 in the solid state at 298 K. Furthermore, the reactivity of complexes 1 and 6 towards bases was compared. Deprotonation of 1 with KOtBu produced the selective formation of the dinuclear complex 7; meanwhile, the reaction of 6 led to a complex mixture of products. The same reactions carried out in the presence of PPh3 produced the selective deprotonation of the P‐bonded methylene bridges of 1 and 6, yielding the isostructural derivatives 9 and 10. DFT calculations performed on the uNHC‐containing tautomers I and II, and the sNHC‐based isomers III and IV, showed that the NHC‐deprotonated derivatives II and IV are more stable by 3.20 and 2.73 kcal mol–1, respectively, than their P‐deprotonated counterparts (I and III). However, a reverse stability order was observed for hexacoordinated tautomers I·L and II·L, and III·L and IV·L (L = PPh3, CO, MeCN). Finally, the catalytic activity of complex 3 in the transfer hydrogenation of ketones has been assessed.

Negative Charge as a Lens for Concentrating Antiaromaticity: Using a Pentagonal “Defect” and Helicene Strain for Cyclizations

AbstractIncorporation of a five‐membered ring into a helicene framework disrupts aromatic conjugation and provides a site for selective deprotonation. The deprotonation creates an anionic cyclopentadienyl unit, switches on conjugation, leads to a >200 nm red‐shift in the absorbance spectrum and injects a charge into a helical conjugated π‐system without injecting a spin. Structural consequences of deprotonation were revealed via analysis of a monoanionic helicene co‐crystallized with {K+(18‐crown‐6)(THF)} and {Cs+2(18‐crown‐6)3}. UV/Vis‐monitoring of these systems shows a time‐dependent formation of mono‐ and dianionic species, and the latter was isolated and crystallographically characterized. The ability of the twisted helicene frame to delocalize the negative charge was probed as a perturbation of aromaticity using NICS scans. Relief of strain, avoidance of antiaromaticity, and increase in charge delocalization assist in the additional dehydrogenative ring closures that yield a new planarized decacyclic dianion.

All-Thiophene-Based Double Helix: Synthesis, Crystal Structure, Chiroptical Property and Arylation.

The all-thiophene-based double helix DH-1 was designed and prepared originally from the selective deprotonation of cyclooctatetrathiophene (tetra[3,4]thienylene, COTh) and following the Negishi coupling reaction with 3,3′-bithiophene. The X-ray crystallographic studies revealed that DH-1 has a double-helical scaffold. The arylations including tetraphenylation and tetrathienylation were efficiently employed to replace the four α-protons of the central COTh of DH-1 with phenyl and thiophenyl groups via cross-coupling reactions. The chiral resolution of rac-DH-1 was fulfilled via chiral high-performance liquid chromatography, and the chiroptical properties were characterized by circular dichroism spectra and optical rotation. Ultraviolet–visible absorption and fluorescence behaviors of DH-1 and its arylation products were also characterized to describe the extended conjugated scaffold.

Regiocontrolled Halogen Dance of Bromothiophenes and Bromofurans.

The LDA (lithium diisopropylamide)-promoted regiocontrolled halogen dance of α-bromothiophenes and α-bromofurans is described. Bromothiophenes bearing a diethyl acetal moiety undergo selective deprotonation at the β-position adjacent to the bromo group. In contrast, oxazoline, ester, and amide groups act as directing groups in the initial lithiation step to generate a carbanion at the β-position neighboring the directing group to exclusively give the other regioisomer. These results can be applied to the regiocontrolled halogen dance of bromofuran derivatives.

An Experimental Validated Computational Method for pKa Determination of Substituted 1,2-Dihydroxybenzenes

1,2-dihydroxybenzenes (DHBs) are organic compounds which are widely studied as they are applied to advanced oxidation processes (AOPs). These compounds are also related to the development of oxidative stress, wood biodegradation, and neuronal disease in humans. DHBs are metal ligands with pro-oxidant and antioxidant properties. These activities are related to their chelation properties and a consequence of the deprotonation of their hydroxyl groups. In literature, there are several pKa values for the hydroxyl groups of DHBs. These values vary depending on the experimental conditions or the algorithm used for calculation. In this work, an experimentally validated computational method was implemented in aqueous solution for pKa determination of 24 DHBs. The deprotonation order of the hydroxyl groups in DHB was determined observing a selective deprotonation, which depended on the ability of the substituent to donate or withdraw electron density over the ring.

Alkylimidazole‐Based Phosphines as Efficient Ligands for Palladium‐Catalyzed Suzuki Reactions

Two series of alkylimidazole‐based phosphines were conveniently synthesized in one step from the corresponding alkylimidazole by selective deprotonation and quenching with chlorodiphenylphosphine. The novel ligands are easily tunable and exhibit good‐to‐excellent performance in the palladium‐catalyzed Suzuki coupling reaction.

Coupling N-H Deprotonation, C-H Activation, and Oxidation: Metal-Free C(sp3)-H Aminations with Unprotected Anilines.

An intramolecular oxidative C(sp3)-H amination from unprotected anilines and C(sp3)-H bonds readily occurs under mild conditions using t-BuOK, molecular oxygen and N,N-dimethylformamide (DMF). Success of this process, which requires mildly acidic N-H bonds and an activated C(sp3)-H bond (BDE < 85 kcal/mol), stems from synergy between basic, radical, and oxidizing species working together to promote a coordinated sequence of deprotonation: H atom transfer and oxidation that forges a new C-N bond. This process is applicable for the synthesis of a wide variety of N-heterocycles, ranging from small molecules to extended aromatics without the need for transition metals or strong oxidants. Computational results reveal the mechanistic details and energy landscape for the sequence of individual steps that comprise this reaction cascade. The importance of base in this process stems from the much greater acidity of transition state and product for the 2c,3e C-N bond formation relative to the reactant. In this scenario, selective deprotonation provides the driving force for the process.

Bridged N-Heterocyclic/Mesoionic (NHC/MIC) Heterodicarbenes as Ligands for Transition Metal Complexes.

Following a copper catalyzed alkyne azide cycloaddition (CuAAC) and N-alkylation protocols, we report the preparation of a hybrid N-heterocyclic/mesoionic [NHC(H+)-MIC(H+)][2I]2- salt (1) in high yields. The treatment of salt 1 with Cu2O and KI yields a second hybrid NHC/MIC proligand featuring a tetraiodocuprate anion [NHC(H+)-MIC(H+)][Cu2I4]2- (2). Through selective deprotonation and metalation, both salts 1 and 2 can generate either the chelate heterodicarbene complexes (3) with the rare [NHC·(M)·MIC]+[MX2]- general formula (M = PdII, RhI) or NHC-anchored/pendent triazolium species (4) [NHC·(M)-MIC(H+)]. If the triazolium moiety of type 4 complexes is deprotonated with KHMDS in the presence of a second metal center, a series of heterobimetallic complexes of the type [NHC·(M)-MIC·(M')] (5) are achieved. Interestingly, the reaction of salt 2 with KHMDS yields the bimetallic copper heterodicarbene (6) which can be a useful transfer reagent for the preparation of type 3 complexes. A variety of synthetic routes for the preparation of complexes 3-5 and their full characterization in solution and in the solid state will be discussed.

Selective deprotonation of tetra[3,4]thienylene in the presence of n-BuLi

The sequential lithiation mechanism for the selective deprotonation of tetra[3,4]thienylene (1) to form Li4-1 in the present of n-BuLi in THF is investigated.

Diastereoselective Ortho Lithiation of Phosphinimidic Amides: A Multinuclear Magnetic Resonance and Computational Study

The structure of the dianion (SP,RC)-10 formed in the diastereoselective N,Cortho dilithiation of the phosphinimidic amide (RC)-Ph2P(═NCO2Me)NHCH(Me)Ph (5; dr of 95:5) with tert-butyllithium in THF has been elucidated using multinuclear magnetic resonance methods, including 2D 7Li,nX-HMQC (nX = 15N, 31P) correlations. (SP,RC)-10 consists of a monomer in which C,N and N,O chelation of the lithium cations generates a system containing a five- and a six-membered metallacycle, respectively, sharing a P-N bond with the lithium atoms connected through the NCO moiety of the phosphazenyl group. Selective deprotonation of the pro-S P-phenyl ring of 5 was ascertained through NOE measurements. DFT computations at the M06-2X(SMD,THF)/6-311+G(d,p)//M06-2X/6-31G(d) level showed that the stereoselective ortho deprotonation process fulfills the features of the CIPE model. The P═N linkage of the N-lithiated species (RC)-8 acts as a directing metalation group via N···LitBu coordination. The mixed complex that is formed evolves to a more stabilized species due to the intramolecular coordination of the OMe group to the lithium cation of the base. Abstraction of the ortho proton proceeds with energy barriers of 12.4 and 13.3 kcal/mol for the pro-R and pro-S phenyl rings. The preference for the latter is explained in terms of the Curtin-Hammett principle.

Deprotonation effect of tetrahydrofuran‐2‐carbonitrile buffer gas dopant in ion mobility spectrometry

When dopants are introduced into the buffer gas of an ion mobility spectrometer, spectra are simplified due to charge competition. We used electrospray ionization to inject tetrahydrofuran-2-carbonitrile (F, 2-furonitrile or 2-furancarbonitrile) as a buffer gas dopant into an ion mobility spectrometer coupled to a quadrupole mass spectrometer. Density functional theory was used for theoretical calculations of dopant-ion interaction energies and proton affinities, using the hybrid functional X3LYP/6-311++(d,p) with the Gaussian 09 program that accounts for the basis set superposition error; analytes structures and theoretical calculations with Gaussian were used to explain the behavior of the analytes upon interaction with F. When F was used as a dopant at concentrations below 1.5mmolm(-3) in the buffer gas, ions were not observed for α-amino acids due to charge competition with the dopant; this deprotonation capability arises from the production of a dimer with a high formation energy that stabilized the positive charge and created steric hindrance that deterred the equilibrium with analyte ions. F could not completely strip other compounds of their charge because they either showed steric hindrance at the charge site that deterred the approach of the dopant (2,4-lutidine, and DTBP), formed intramolecular bonds that stabilized the positive charge (atenolol), had high proton affinity (2,4-lutidine, DTBP, valinol and atenolol), or were inherently ionic (tetraalkylammonium ions). This selective deprotonation suggests the use of F to simplify spectra of complex mixtures in ion mobility and mass spectrometry in metabolomics, proteomics and other studies that generate complex spectra with thousands of peaks. Copyright © 2016 John Wiley & Sons, Ltd.