SNAr Reaction Research Articles

Synthesis and biological evaluation of benzoxepinoindol‐1‐one analogs as Brd4 bromodomain inhibitors

AbstractA novel series of benzo[6,7]oxepino[4,3,2‐cd]indol‐1(2H)‐one derivatives were synthesized via a one‐pot aldol condensation and SNAr reaction by coupling indolin‐2‐ones with 2‐fluorobenzaldehydes. In addition, molecular docking studies of the designed compound 2 revealed strong hydrogen bonds in the hot binding pocket of Brd4. All compounds were evaluated for their enzymatic activity in Brd4 bromodomain inhibition.

SnAr Reactions of 2,4-Diazidopyrido[3,2-d]pyrimidine and Azide-Tetrazole Equilibrium Studies of the Obtained 5-Substituted Tetrazolo[1,5-a]pyrido[2,3-e]pyrimidines.

A straightforward method for the synthesis of 5-substituted tetrazolo[1,5-a]pyrido[2,3-e]pyrimidines from 2,4-diazidopyrido[3,2-d]pyrimidine in SnAr reactions with N-, O-, and S- nucleophiles has been developed. The various N- and S-substituted products were obtained with yields from 47% to 98%, but the substitution with O-nucleophiles gave lower yields (20-32%). Furthermore, the fused tetrazolo[1,5-a]pyrimidine derivatives can be regarded as 2-azidopyrimidines and functionalized in copper(I)-catalyzed azide-alkyne dipolar cycloaddition (CuAAC) and Staudinger reactions due to the presence of a sufficient concentration of the reactive azide tautomer in solution. In total, seven products were fully characterized by their single crystal X-ray studies, while five of them were representatives of the tetrazolo[1,5-a]pyrido[2,3-e]pyrimidine heterocyclic system. Equilibrium constants and thermodynamic values were determined using variable temperature 1H NMR and are in agreement of favoring the tetrazole tautomeric form (ΔG298 = -3.33 to -7.52 (kJ/mol), ΔH = -19.92 to -48.02 (kJ/mol) and ΔS = -43.74 to -143.27 (J/mol·K)). The key starting material 2,4-diazidopyrido[3,2-d]pyrimidine presents a high degree of tautomerization in different solvents.

9-Phenyl-9-phosphafluorene oxide based organic ligands synthesized via successive SNAr reactions and their symmetric phosphorescent Ir(III) complexes for highly efficient solution-processed OLEDs

Three organic ligands with 9-phenyl-9-phosphafluorene oxide (PhFlPO) group have been synthesized via successive nucleophilic aromatic substitution (SNAr) reactions between dibenzothiophene dioxides and PhPH2-KOH under mild reaction conditions at room temperature. In this way, the novel PhFlPO-type organic ligands can be easily obtained without either highly sensitive Grignard or organolithium reagents of noble metal catalysts. Using these PhFlPO-type organic ligands, cyclometalated Ir(III) phosphorescent complexes with PhFlPO groups have been developed through well-accepted two-step strategy. To the best of our knowledge, these complexes represent the unprecedented examples of symmetric cyclometalated Ir(III) phosphorescent complexes bearing PhFlPO group. It has been found that electron-density on the coordinated carbon atom in the PhFlPO unit can exert a significant influence on the metal-to-ligand charge transfer transition (MLCT) processes and phosphorescent emission behavior of these cyclometalated Ir(III) phosphorescent complexes. In addition, the electroluminescent potential of these new cyclometalated Ir(III) phosphorescent complexes with PhFlPO groups has been characterized in solution-processed organic light-emitting diodes (OLEDs). They can show very impressively high external quantum efficiency (ηext), current efficiency (ηL) and power efficiency (ηP) of 20.0%, 71.7 cd A−1 and 56.1 lm W−1, respectively. These encouraging research results can furnish critical information for developing new PhFlPO-based Ir(III) phosphorescent emitters.

Domino Aza-Michael-SNAr-Heteroaromatization Route to C5-Substituted 1-Alkyl-1H-Indole-3-Carboxylic Esters.

A new synthesis of C5-substituted 1-alkyl-1H-indole-3-carboxylic esters is reported. A series of methyl 2-arylacrylate aza-Michael acceptors were prepared with aromatic substitution to activate them towards SNAr reaction. Subsequent reaction with a series of primary amines generated the title compounds. Initially, the sequence was expected to produce indoline products, but oxidative heteroaromatization intervened to generate the indoles. The reaction proceeded under anhydrous conditions in DMF at 23–90 °C using equimolar quantities of the acrylate and the amine with 2 equiv. of K2CO3 to give 61–92% of the indole products. The reaction involves an aza-Michael addition, followed by SNAr ring closure and heteroaromatization. Since the reactions were run under nitrogen, the final oxidation to the indole likely results from reaction with dissolved oxygen in the DMF. Substrates incorporating a 2-arylacrylonitrile proved too reactive to prepare using our protocol. The synthesis of the reaction substrates, their relative reactivities, and mechanistic details of the conversion are discussed.

Reaction Kinetic Model Considering the Solvation Effect Based on the FMO Theory and Deep Learning

Reaction solvents are capable of significantly enhancing the kinetic rate and selectivity of chemical reactions through the solvation effects. However, the commonly used reaction kinetic models considering the solvation effects are based on the transition state theory, which is generally limited to the demanding exploration of transition states. In this paper, a reaction solvent screen framework is established for screening potential reaction solvents, where a novel reaction kinetic model is proposed based on the frontier molecular orbital theory correlating the reaction rate constants with the numbers of hydrogen bond donors/acceptors of solvents and the solvation HOMO/LUMO energies of reactants, which quantify the solvation effects on reaction systems independent of transition states and are calculated through the implicit solvation model using the solvent dielectric constants. To facilitate high-throughput screening of reaction solvents in a wide search space, a tailor-made text-based deep learning model is then developed for fast and accurate predictions of dielectric constants. Finally, two case studies, namely, SNAr and Menschutkin reactions, are presented to demonstrate the feasibility and effectiveness of the proposed reaction solvent screen framework.

Effective synthesis of regular ladder-type oligo(p-phenol)s via intramolecular SNAr O-arylation reaction

A series of novel ladder-type O-heteroarenes containing benzofuran units were effectively synthesized from the precursors via intramolecular SNAr reaction between F and OH groups in the backbone. The key intramolecular SNAr reaction was catalyst-free and highly efficient, moreover, the accurate annulation of fluorine atom ensured the regularity of the structure. We could smoothly obtain the ladder-type oligomer with seven oxygen bridges. The successes of the ladder-type oligomers also demonstrated the feasibility for preparing other regular oligomers and polymers with oxygen bridges.

Selective nucleophilic aromatic substitution of 2-(polyfluorophenyl)-4H-chromen-4-ones with pyrazole

The formation of various fluorine atoms substitution products in Cs2CO3-promoted SNAr reactions of 2-(polyfluoroaryl)-4H-chromen-4-ones with pyrazole in refluxing MeCN was shown. Selective synthesis of mono(1H-pyrazol-1-yl)- and per(1H-pyrazol-1-yl)flavones was performed in the presence of NaOBut at room temperature using different pyrazole and base equivalents. A mechanism for fluorine atoms substitution in 2-(pentafluorophenyl)-4H-chromen-4-one by sodium pyrazolide was proposed. The structures of pyrazolyl-substituted flavones were established based on the combined analysis of NMR and XRD data.

Charge-Transfer Transitions Govern the Reactivity and Photophysics of Vicinally Diphosphanyl-Substituted Diborapentacenes.

2,3-Difluoro-5,14-dihydro-5,14-diborapentacene (DBP) was endowed with two vicinal Ph2 P groups by an SN Ar reaction at both CF sites using Ph2 PSiMe3 . Computations reveal the ambipolar product P to undergo P-to-B charge transfer under ambient light irradiation. Consequently, P is prone to photooxidation by air, yielding the Ph2 P(O) species PO. With S8 or [Me3 O][BF4 ], P furnishes the Ph2 P(S) or Ph2 P(Me)+ derivatives PS or [PMe][BF4 ]2 . Along the series P, PO, PS, and [PMe][BF4 ]2 , the redox potentials shift anodically from E1/2 =-1.89 V to -1.02 V (CH2 Cl2 ). Thus, derivatization of the Ph2 P group allows late-stage modulation of the LUMO-energy level of the DBP. Derivatization also influences the emission properties of the compounds, as PO shows green (521 nm) and [PMe][BF4 ]2 red (622 nm) fluorescence in C6 H6 , while P and PS are dark. With CuBr and AgBr, P forms dimeric [M(μ-Br)]2 complexes [PCu]2 and [PAg]2 , which show pronounced metal-to-ligand charge transfer (MLCT), making P a promising ligand for photocatalysts.

4,7-Bis(2,3,3a,8b-tetrahydrocyclopenta[b]indol-4(1H)-yl)-[1,2,5]thiadiazolo[3,4-c]pyridine

Donor-acceptor-donor (D-A-D) type molecules are of interest as components in organic light emitting diodes (OLEDs). In this communication, 4,7-bis(2,3,3a,8b-tetrahydrocyclopenta[b]indol-4(1H)-yl)-[1,2,5]thiadiazolo[3,4-c]pyridine was obtained by two successive reactions—aromatic nucleophilic substitution SNAr and Buchwald-Hartwig cross-coupling reaction. The structure of newly synthesized compounds was established by elemental analysis, high resolution mass-spectrometry, 1H, 13C NMR, IR and UV spectroscopy and mass-spectrometry. The luminescent properties of the title compound were studied.

Structural study of azide-tetrazole equilibrium in pyrido[2,3-d]pyrimidines

C-5 Substituted pyrido[3,2-e]tetrazolo[1,5-a]pyrimidines were obtained by simple azidation of 2,4-dichloropyrido[2,3-d]pyrimidine followed by SNAr reactions with S-, N- and O-nucleophiles. Their NMR and IR studies revealed that the mono-azido products undergo azide-tetrazole equilibrium, whereas 2,4-diazidopyrido[2,3-d]pyrimidine exists in four tautomeric forms in various solutions, and its solid phase tautomer was established by the X-ray analysis. In total, nine of the obtained products are fully characterized by their single crystal X-ray structures and seven of them revealed a novel annulated pyrido[3,2-e]tetrazolo[1,5-a]pyrimidine skeleton. Among the studied products the amino derivatives - 5-aminopyrido[3,2-e]tetrazolo[1,5-a]pyrimidines - exist mainly in their tetrazole form both in the solid phase and in the solutions. However, also the latter enter the tautomeric equilibrium and the liberated azido group is able to undergo copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and form the corresponding 1,2,3-triazole derivatives. Free Gibbs energies of the tautomerization of C-5 substituted cyclohexylmercapto-, isopropyloxy- and phenoxy-pyrido[3,2-e]tetrazolo[1,5-a]pyrimidines were found to be -21.30, -23.19 and -17.02 kJ/mol, respectively.

Discovery and Characterization of a Novel Series of Chloropyrimidines as Covalent Inhibitors of the Kinase MSK1.

We describe the identification and characterization of a series of covalent inhibitors of the C-terminal kinase domain (CTKD) of MSK1. The initial hit was identified via a high-throughput screening and represents a rare example of a covalent inhibitor which acts via an SNAr reaction of a 2,5-dichloropyrimidine with a cysteine residue (Cys440). The covalent mechanism of action was supported by in vitro biochemical experiments and was confirmed by mass spectrometry. Ultimately, the displacement of the 2-chloro moiety was confirmed by crystallization of an inhibitor with the CTKD. We also disclose the crystal structures of three compounds from this series bound to the CTKD of MSK1, in addition to the crystal structures of two unrelated RSK2 covalent inhibitors bound to the CTKD of MSK1.

NHC-Catalyzed Intramolecular SNAr Reaction of Styrenes for the Synthesis of Polyaromatic Compounds

NHC-Catalyzed Intramolecular SNAr Reaction of Styrenes for the Synthesis of Polyaromatic Compounds

Kinetics and Reaction Mechanism of Biothiols Involved in SNAr Reactions: An Experimental Study

Few kinetic parameters, or reaction rates, are known up to date in detail about 1-chloro and 1-fluoro-2,4-dinitrobenzene (ClDNB and FDNB, respectively) with a series of biothiols in aqueous media. These biological nucleophiles with thiol groups have been widely used as a reference in nucleophile reactivity assays due to their prevalence and cellular abundance. The main aim of this study was to elucidate the reaction mechanism based on Brönsted-type plots and reactivity patterns of the electrophile/nucleophile pairs. A complete kinetic study was performed in terms of the comparison of Brönsted-type slope parameters (β nuc) for the reactions and was used for assigning the mechanism and the rate-determining step associated with the reaction route. A mass spectrometry analysis demonstrated that the nucleophilic center of the biothiols is the -SH group and there is only one kinetic product. The kinetic study suggests that the reaction mechanism might be the borderline between concerted and stepwise pathways. An amine–enol equilibrium for the most reactive nucleophiles appears to be the main determining factor controlling the nucleophilic attack in the nucleophilic aromatic substitution reactions investigated, highlighting the anionic form for these nucleophiles. This amine–enol equilibrium involves a hydrogen bond which stabilizes the intermediate species in the reaction pathway. Thus, intramolecular bonds are formed and enhance the nucleophilic strength through the contribution of the solvent surrounding the electrophile/nucleophile pairs. Finally, we highlight the importance of the formation of electrophile/nucleophile adducts that could modify structures and/or functions of biological systems with potential toxic effects. Therefore, it is essential to know all these kinetic and reactivity patterns and their incidence on other studies.

C(sp3)-Arylation by Conformationally Accelerated Intramolecular Nucleophilic Aromatic Substitution (SNAr).

ConspectusThe asymmetric synthesis of heavily substituted benzylic stereogenic centers, prevalent in natural products, therapeutics, agrochemicals, and catalysts, is an ongoing challenge. In this Account, we outline our contribution to this endeavor, describing our discovery of a series of new reactions that not only have synthetic applicability but also present significant mechanistic intrigue. The story originated from our longstanding interest in the stereochemistry and reactivity of functionalized organolithiums. While investigating the lithiation chemistry of ureas (a “Cinderella” sister of the more established amides and carbamates), we noted an unexpected Truce–Smiles (T-S) rearrangement involving the 1,4-N → C transposition of a urea N′-aryl group to the α-carbanion of an adjacent N-benzyl group. Despite this reaction formally constituting an SNAr substitution, we found it to be remarkably tolerant of the electronic properties of the migrating aryl substituent and the degree of substitution at the carbanion. Moreover, in contrast to classical SNAr reactions, the rearrangement was sufficiently rapid that it took place under conditions compatible with configurational stability in an organolithium intermediate, enabling enantiospecific arylation at benzylic stereogenic centers. Experimental and computational studies confirmed a low kinetic barrier to the aryl migration arising from the strong preference for a trans arrangement of the urea N′-aryl and carbonyl groups, populating a reactive conformer in which spatial proximity was enforced between the carbanion and N′-aryl group, hugely accelerating ipso-substitution.This discovery led us to uncover a whole series of conformationally accelerated intramolecular N → C aryl transfers using different anilide-based functional groups, including a diverse range of urea, carbamate, and thiocarbamate-substituted anions. Products included enantioenriched α-tertiary amines (including α-arylated N-heterocycles) and alcohols, as well as rare α-tertiary thiols. Synthetically challenging diarylated centers with differentiated aryl groups featured heavily in all product sets. The absolute enantiospecificity (retention versus inversion) of the reaction was dependent on the heteroatom α to the lithiation site: the origin of this stereodivergence was probed both experimentally and computationally. Asymmetric variants of the rearrangement were realized by enantioselective deprotonation, and connective strategies were developed in which an intermolecular C–C bond-forming event preceded the anionic rearrangement. Substrates where the N′-nucleofuge (at the aryl ipso position) was tethered to the migrating arene allowed us to use the rearrangement as a ring expansion method to generate 8- to 12-membered medium-ring N-heterocycles from very simple precursors. Stabilized carbon nucleophiles such as alkali metal enolates also readily promoted intramolecular N → C aryl transfer in N′-arylureas, opening up access to biologically relevant hydantoins, and enabling a “chiral memory” approach for the (hetero)arylation of chiral α-amino acids with programmable retention or inversion of configuration. Collectively, our studies of electronically versatile T-S rearrangements in anilide-based systems have culminated in a practical and general strategy for transition metal-free C(sp3)-arylation. More broadly, our results highlight the power of conformational activation to achieve unprecedented reactivity in the construction of challenging C–C bonds.

Poly(arylene sulfide)s via nucleophilic aromatic substitution reactions of halogenated pyromellitic diimides

AbstractNucleophilic aromatic substitution (SNAr) reactions are exploited to prepare poly(arylene sulfide)s (PAS's) via the reaction of bis‐thiolates and dibrominated pyromellitic diimide (PMDI) derivatives. Small‐molecule model studies reveal the reaction is well‐defined and proceeds in quantitative yield in practical times at room temperature. Variation in comonomer feed ratios allowed some control over target polymer molecular weights in the step polymerization, but control was likely limited by the relatively poor polymer solubility in the dipolar aprotic solvents typically employed to promote SNAr reactions. One substitution pattern produces a steric “pocket” around the PMDI units, inducing a peculiar solubility trend in halogenated solvents; that is, greatly reduced solubility in CHCl3 relative to CH2Cl2 and C2H2Cl4. One example small‐molecule readily dissolves in CHCl3 at room temperature, then rapidly grows poorly soluble crystals revealed by single‐crystal XRD to contain CHCl3 molecules in the steric pockets. Finally, the recently demonstrated depolymerization of phthalonitrile‐based PAS's via ipso substitution with monothiolates as chain scission agents yields quantitative molecular weight reduction to monomeric species from the polymers reported here.

SNAr reactions of 5-bromo-2-chloro-4-fluoro-3-iodopyridine and its 3-substituted analogs

We have previously demonstrated that 5-bromo-2-chloro-4-fluoro-3-iodopyridine (6) can serve as a versatile intermediate to penta-substituted pyridines. This work describes regioselective SNAr reactions of 6 and its 3-substituted analogs with a variety of nucleophiles to deliver highly functionalized pyridines as valuable building blocks in medicinal chemistry and drug design.

Toward Novel [18F]Fluorine-Labeled Radiotracers for the Imaging of α-Synuclein Fibrils.

The accumulation of α-synuclein aggregates (α-syn) in the human brain is an occurrence common to all α-synucleinopathies. Non-invasive detection of these aggregates in a living brain with a target-specific radiotracer is not yet possible. We have recently discovered that the inclusion of a methylenedioxy group in the structure of diarylbisthiazole (DABTA)-based tracers improves binding affinity and selectivity to α-syn. Subsequently, complementary in silico modeling and machine learning (ML) of tracer–protein interactions were employed to predict surface sites and structure–property relations for the binding of the ligands. Based on this observation, we developed a small focused library of DABTAs from which 4-(benzo[d][1,3]dioxol-5-yl)-4′-(3-[18F]fluoro-4-methoxyphenyl)-2,2′-bithiazole [18F]d2, 6-(4′-(3-[18F]fluoro-4-methoxyphenyl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d4, 4-(benzo [d][1,3]dioxol-5-yl)-4′-(6-[18F]fluoropyridin-3-yl)-2,2′-bithiazole [18F]d6, and 6-(4′-(6-[18F]fluoropyridin-3-yl)-[2,2′-bithiazol]-4-yl)-[1,3]dioxolo[4,5-b]pyridine [18F]d8 were selected based on their high binding affinity to α-syn and were further evaluated. Binding assay experiments carried out with the non-radioactive versions of the above tracers d2, d4, d6, and d8 showed high binding affinity of the ligands to α-syn: 1.22, 0.66, 1.21, and 0.10 nM, respectively, as well as excellent selectivity over β-amyloid plaques (Aβ) and microtubular tau aggregates (>200-fold selectivity). To obtain the tracers, their precursors were radiolabeled either via an innovative ruthenium-mediated (SNAr) reaction ([18F]d2 and [18F]d4) or typical SNAr reaction ([18F]d6 and [18F]d8) with moderate-to-high radiochemical yields (13% – 40%), and high molar activity > 60 GBq/μmol. Biodistribution experiments carried out with the tracers in healthy mice revealed that [18F]d2 and [18F]d4 showed suboptimal brain pharmacokinetics: 1.58 and 4.63 %ID/g at 5 min post-injection (p.i.), and 1.93 and 3.86 %ID/g at 60 min p.i., respectively. However, [18F]d6 and [18F]d8 showed improved brain pharmacokinetics: 5.79 and 5.13 %ID/g at 5 min p.i.; 1.75 and 1.07 %ID/g at 60 min p.i.; and 1.04 and 0.58 %ID/g at 120 min p.i., respectively. The brain uptake kinetics of [18F]d6 and [18F]d8 were confirmed in a dynamic PET study. Both tracers also showed no brain radiometabolites at 20 min p.i. in initial in vivo stability experiments carried out in healthy mice. [18F]d8 seems very promising based on its binding properties and in vivo stability, thus encouraging further validation of its usefulness as a radiotracer for the in vivo visualization of α-syn in preclinical and clinical settings. Additionally, in silico and ML-predicted values correlated with the experimental binding affinity of the ligands.

Lignin‐Inspired Polybenzylethersulfone Synthesis via SNAr Reaction

AbstractA new type of lignin‐inspired polybenzylethersulfone (PBES) is synthesized by SNAr reaction in 75% yield. Success of the polymerization is confirmed by ATR‐IR, 1H, 13C NMR spectroscopy and MALDI‐TOF MS. The obtained polysulfone is solvent casted into a film which displays high thermal and chemical stability. Treatment with 33% HBr in acetic acid leads to degradation of the material. The isolated degradation products are identified and repolymerized back into PBES demonstrating the opportunity for chemical recycling of this new polymer.

Thermal Stability and Utility of Dienes as Protecting Groups for Acrylamides.

Acrylamides are privileged electrophiles used in targeted covalent therapies, often installed at the end of a synthetic sequence due to their reactive nature. Herein, we report several diene-acrylamide adducts with a range of thermal stabilities toward retro-Diels-Alder deprotection of the acrylamide, enabling this masked functionality to be introduced early in a synthetic route and deprotected in a specific temperature range. Through kinetic studies, we identify solvent and structural trends that impact the stability of trimethylsilyl cyclopentadiene (TMS-CP) acrylamide adducts. TMS-CP protected acrylamides were installed on several amine-containing drugs, whose acrylamides were thermally unveiled (T = 160 °C, time ≤ 1 h) in moderate to high yields. We also showcase the potential utility of this protection strategy by improving the yield of a base-promoted SNAr reaction when the acrylamide is masked.

Meso‐Monoaryl‐Substituted Neo‐confused Calixsmaragdyrins and Meso‐monoaryl Substituted Smaragdyrins: Synthesis, Structures and Properties

AbstractWhile SNAr reaction of 3,5‐dibromo‐8‐mesityl BODIPY 1 with a 5,10‐diaryltripyrrane with Cs2CO3 was reported to provide 5,10,19‐triaryl[22]smaragdyrin as the first synthetic method of all‐aza smaragdyrin, the reaction of 1 with meso‐free tripyrrane 6 took a different course to give a doubly Neo‐confused calixsmaragdyrin 7. On the other hand, the SNAr reaction of 2,3,5,6‐tetrabromo‐8‐mesityl BODIPY 9 with 6 provided 16,22‐dibromo‐19‐mesitylsmaragdyrin BF2 complex 10. In addition, calixsmaragdyirn 7 has been shown to serve as a ligand for RhI and BIII metals, and oxidation of 10 with MnO2 gave meso‐oxidized smaragdyrin 11 that was shown to be weakly antiaromatic.