Intramolecular Nucleophilic Substitution Reaction Research Articles

Base‐Induced Annulation of Glycal‐Derived α‐iodopyranone with 2‐Aminopyrimidinones: Access to Chiral Imidazopyrimidinones

AbstractA simple, environmentally benign and catalyst‐free method for the synthesis of chirally enriched imidazo[1,2‐a]pyrimidinone glycohybrids has been successfully developed. The protocol is based on a base‐induced annulation of α‐iodo‐pyranone with Michael addition of 2‐aminopyrimidinones followed by intramolecular nucleophilic substitution reaction. The privilege of this method includes mild reaction conditions, eco‐friendly solvent and a transition‐metal‐free approach. Moreover, using straightforward simple methods, this reaction method exhibits a broad range of substrate scope and remarkable tolerance toward various functional groups.

De novo synthesis of inherently chiral heteracalix[4]aromatics from enantioselective macrocyclization enabled by chiral phosphoric acid-catalyzed intramolecular SNAr reaction

N3,O-calix[2]arene[2]triazines, whose inherent chirality arises from one different heteroatom linkage, were synthesized enantioselectively in ee up to 95% from macrocyclization via chiral monophosphoric acid-catalyzed intramolecular SNAr reaction.

Highly Novel Diastereoselective Synthesis of (E)-1-Aryl-1-alkenes

A convenient, novel synthesis of (E)-1-phenyl-1-alkenes based on (Z)-1-bromo-1-alkenylboronate esters will be developed. α-Bromo-(Z)-1-alkenylboronate esters readily available from literature procedures will undergo a reaction with phenyllithium in tetrahydrofuran to provide the corresponding “ate” complexes. These “ate” complexes will then undergo intramolecular nucleophilic substitution reactions to provide the corresponding (E)-1-alkenylboronate esters containing a phenyl moiety which upon protonolysis with acetic acid will afford the corresponding (E)-1-phenyl-1-alkenes. All (E)-1-phenyl-1-alkenes were characterized by PMR and CMR spectral data successfully.

Diverse Synthesis of 2H-Isoindole-Based Polycyclic Aromatic Compounds.

1,3-Disubstituted N-aryl-2H-isoindoles have been synthesized by a cascade reaction of divinyl ethers, which are derived from easily available 4-bromoisocoumarins, with substituted anilines in HFIP. This cascade reaction consists of a ring-opening step through addition-elimination mechanism and the following 5-exo-tet type ring-closing step via the intramolecular nucleophilic substitution reaction. Thus obtained 2H-isoindoles have been derivatized to high-order nitrogen-containing polycycles including less accessible benzo[a]ullazines.

Highly Strained Oxygen-Doped Chiral Molecular Belts of the Zigzag-Type with Strong Circularly Polarized Luminescence.

Herein we report a two-directional cyclization strategy for the synthesis of highly strained depth-expanded oxygen-doped chiral molecular belts of the zigzag-type. From the easily accessible resorcin[4]arenes, an unprecedented cyclization cascade generating fused 2,3-dihydro-1H-phenalenes has been developed to access expanded molecular belts. Stitching up the fjords through intramolecular nucleophilic aromatic substitution and ring-closing olefin metathesis reactions furnished a highly strained O-doped C2 -symmetric belt. The enantiomers of the acquired compounds exhibited excellent chiroptical properties. The calculated parallelly aligned electric (μ) and magnetic (m) transition dipole moments are translated to the high dissymmetry factor (|glum | up to 0.022). This study provides not only an appealing and useful strategy for the synthesis of strained molecular belts but also a new paradigm for the fabrication of belt-derived chiroptical materials with high CPL activities.

Base-Promoted Decarboxylative Annulation of Methyl 2-(2-Bromophenyl)acetates and Ynones to Access Benzoxepines

A simple and efficient base-mediated decarboxylative annulation of ynones with methyl 2-(2-bromophenyl)acetates has been developed. A broad range of benzoxepines were prepared with a broad substrate scope and high regioselectivity in moderate to excellent yields under transition-metal-free conditions. This method proceeds through a tandem [2 + 4] annulation, ring-opening decarboxylative reaction, and the intramolecular nucleophilic aromatic substitution reaction. Additionally, the key intermediates were successfully obtained and characterized unambiguously by single-crystal X-ray crystallography, which could favorably support a decarboxylative annulation mechanism. Furthermore, gram-scale reaction and synthetic applications for the further functionalization are also studied.

Non-Stabilized Vinyl Anion Equivalents from Styrenes by N-Heterocyclic Carbene Catalysis and Its Use in Catalytic Nucleophilic Aromatic Substitution.

A protocol for the catalytic nucleophilic activation of unactivated styrenes is reported, which enables the generation of a non-stabilized alkenyl anion equivalent as a transient intermediate. In the reaction, N-heterocyclic carbenes add across styrenes to generate ylide intermediates, which can then be used in intramolecular nucleophilic aromatic substitution reactions of aryl fluorides, chlorides, and methyl ethers. The method allows for straightforward access to complex polyaromatic compounds.

A TICS-fluorophore based probe for dual-color GSH imaging

Cascading reactions in fluorophores accompanied by the replacement of different fluorescence wavelengths can be used to develop luminescent materials and reactive fluorescent probes. Based on multiple signal channels, the selectivity of probes can be improved and the range of response to guest molecule recognition can be expanded. By regulating the position, number, and activity of active sites in fluorophores, fluorescent probes that successively react with thiol and amino groups in cysteine (Cys), homocysteine (Hcy) have been developed, which can only react with the thiol group of GSH. In this paper, we report the first probe capable of cascading nucleophilic substitution reaction with the thiol group and amino group of GSH at a single reaction site, and showed the dual-color recognition of GSH, which improved the selectivity of GSH also was an extension of GSH probes. The probe Rho-DEA was based on a TICS fluorophore, and the intramolecular cascade nucleophilic substitution reaction occurs with Cys/Hcy. The thiol substitution of the first step reaction with Cys/Hcy was quenched due to intersystem crossing to triplet state, so GSH can be selectively recognized from the fluorescence signal. Rho-DEA has the ability of mitochondrial localization, and finally realized in situ dual-color fluorescence recognition of GSH in mitochondria.

Boron-Templated Synthesis of B(III)-Submonoazaporphyrins: The Hybrids of B(III)-Subporphyrins and B(III)-Subporphyrazines.

A new class of hybridized and core-contracted porphyrinoids, B(III)-submonoazaporphyrins, which may be viewed as the hybrids of B(III)-subporphyrins and B(III)-subporphyrazines, was reported. The versatile single-step synthesis was based on an efficient intramolecular nucleophilic substitution reaction on readily available α-amino-α'-bromotripyrromethenes, while boronic acids, trifluoroborate salts, or trimethoxyborate simultaneously acted as the template and provider of apical substituent. Those new hybrids, as robust and photostable compounds, were fully characterized by NMR, mass spectrometry, and X-ray crystallography. They showed intense absorption and emission in the visible region, and their electrochemical properties and computational calculation are also discussed.

Synthesis of Carbohydrate Based Macrolactones and Their Applications as Receptors for Ion Recognition and Catalysis.

Glycomacrolactones exhibit many interesting biological properties, and they are also important in molecular recognitions and for supramolecular chemistry. Therefore, it is important to be able to access glycomacrocycles with different sizes and functionality. A new series of carbohydrate-based macrocycles containing triazole and lactone moieties have been designed and synthesized. The synthesis features an intramolecular nucleophilic substitution reaction for the macrocyclization step. In this article, the effect of some common sulfonate leaving groups is evaluated for macrolactonization. Using tosylate gave good selectivity for monolactonization products with good yields. Fourteen different macrocycles have been synthesized and characterized, of which eleven macrocycles are from cyclization of the C1 to C6 positions of N-acetyl D-glucosamine derivatives and three others from C2 to C6 cyclization of functionalized D-glucosamine derivatives. These novel macrolactones have unique structures and demonstrate interesting anion binding properties, especially for chloride. The macrocycles containing two triazoles form complexes with copper sulfate, and they are effective ligands for copper sulfate mediated azide-alkyne cycloaddition reactions (CuAAC). In addition, several macrocycles show some selectivity for different alkynes.

Early Steps of Glycolonitrile Oligomerization: A Free-Energy Map.

Building on our previous free-energy map (J. Phys. Chem. A 2018, 122, 6769-6779) examining the reactions of monomeric glycolonitrile, we explore the formation of its dimers and trimers in aqueous solution under neutral conditions. While 5-membered rings are kinetically favored, open-chain oligomers with ester or amide linkages are thermodynamically favored. Accessing the 5-membered rings also provides a potential route to glyoxal that bypasses preforming glycolamide, the thermodynamic sink for monomers. However, finding a kinetically accessible route to glycine starting from glycolonitrile in the absence of added ammonia at room temperature proved challenging; the best case involved an intramolecular nucleophilic substitution reaction in a dimer containing neighboring imine and amide groups. Our free-energy map also examines routes to experimentally proposed moieties, explaining why some are observed in low yield or not at all.

Oxygen- and Nitrogen-Embedded Zigzag Hydrocarbon Belts.

Despite the aesthetically appealing structures and tantalizing physical and chemical properties, zigzag hydrocarbon belts and their heteroatom-embedded analogues remain challenging synthetic targets. We report herein the synthesis of diverse O/N-doped zigzag hydrocarbon belts based on selective bridging of the fjords of resorcin[4]arene derivatives through intramolecular SN Ar and palladium-catalyzed intermolecular C-N bond formation reactions. Preorganized conformations of mono-macrocyclic, half-belt and quasi-belt compounds were revealed to facilitate cyclization reactions to construct heteroatom-linked octahydrobelt[8]arenes. The acquired products had strained square-prism-shaped belt structures in which all six-membered heterocyclic rings adopted an unusual boat conformation with equatorially configured alkyl groups. The unprecedented heteroatom-bearing belts also exhibited different photophysical and redox properties to those of octahydrobelt[8]arene analogues.

Base-mediated synthesis of benzimidazole-fused 1,4-benzoxazepines via sequential intermolecular epoxide ring-opening/intramolecular SNAr reactions

We have developed a transition-metal-free, practical route to benzimidazole-fused 1,4-benzoxazepines. Operationally, the protocol involves a K2CO3-mediated intermolecular ring opening of terminal epoxides by 2-(2-fluorophenyl)benzimidazole, followed by an intramolecular nucleophilic aromatic substitution (SNAr) reaction of the resulting products in the presence of NaH. We have also achieved an 11-step synthesis of a chroman-linked benzimidazole-fused 1,4-benzoxazepine using a phenoxide-ion induced 6-exo intramolecular epoxide ring-opening and an alkoxide-ion induced intramolecular SNAr reaction as key steps.

Synthesis of a conjugated polymer with ring-fused pyridinium units via a postpolymerization intramolecular cyclization reaction

The synthesis of a novel conjugated polymer containing fused pyridinium units in its main chain is reported. A precursor polymer possessing pyridine and tetrafluorophenylene moieties was reacted in the presence of Lewis acid additives to promote the intramolecular nucleophilic aromatic substitution (SNAr) reaction. The polymer reaction with BE3-OEt2 gave a product polymer soluble in polar organic solvents, and the successful formation of fused pyridinium ring structures was spectroscopically confirmed. The electrochemical and optical properties of the synthesized polymers were also investigated, suggesting that the polymer product has a narrower band gap than the precursor polymer. The synthesis of a novel conjugated polymer containing fused pyridinium units in its main chain is reported. A precursor polymer possessing pyridine and tetrafluorophenylene moieties was reacted in the presence of Lewis acid additives to promote the intramolecular nucleophilic aromatic substitution (SNAr) reaction. The polymer reaction with BE3-OEt2 gave a product polymer soluble in polar organic solvents, and the successful formation of fused pyridinium ring structures was spectroscopically confirmed. The electrochemical and optical properties of the synthesized polymers were also investigated.

Novel Synthesis of β-Keto Cycloacetals via Organoboranes

(Z)-1-Bromo-1-alkenylboronate esters were easily synthesized from the hydroboration of terminal alkynes with dibromoborane dimethyl complex under nitrogen atmosphere followed by treatment with propne-1,3-diol. These boronate esters are readily reacted with 1,3-dioxan-2-ylethyl)magnesium bromide in ether and tetrahydrofuran at -78 ºC for 1 h. The resulting "ate" complex upon addition of sodium methoxide in methanol undergo intramolecular nucleophilic substitution reactions to produce the corresponding (E)-alkenylboronate esters containing (1,3-dioxan-2-ylethyl) moiety in 70-82% isolated yields. The resulting intermediates are oxidized with sodium acetate and hydrogen peroxide to provide the corresponding β-keto cycloacetals in good yields (68-84%).

A simple and efficient approach for the synthesis of a novel class aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives via intramolecular nucleophilic substitution reaction

In this study, we synthesized a new series of substituted aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives (6-24) in yields ranging from 42 to 70% with an interesting mechanism that involves internal nucleophilic substitution followed by an SN2-type nucleophilic substitution. First, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanone (3) was synthesized from the reaction of 5-methyl-1,3,4-thiadiazole-2-thiol (1) with 2-bromo-1-(4-chlorophenyl)ethanone (2) in the presence of potassium hydroxide. Then, 1-(4-chlorophenyl)-2-((5-methyl-1,3,4-thiadiazol-2-yl)thio)ethanol (4) was synthesized by a reduction reaction of this compound using NaBH4. Finally, 5-methyl-3-alkyl-1,3,4-thiadiazol-2(3H)-one derivatives (6-24), which are the target compounds, were synthesized from the reaction of this compound (4), which is a secondary alcohol with various alkyl halides (5a-n) in the presence of sodium hydride (NaH). This study presents an interesting reaction mechanism related to the synthesis of aliphatic 1,3,4-thiadiazol-2(3H)-one derivatives that is not recorded in the literature.

Concise Synthesis of a New Chiral Cyclopentenone Building Block for Prostaglandins and their Derivatives

(4R,5R)‐4,5‐O‐isopropylidene‐2‐(dimethoxyphosphoryl)cyclopen‐2‐enone was obtained in enantiomerically pure form in four steps starting from commercially available 2,3‐O‐isopropylidene‐D‐erythronolactone. The key steps involved are diastereoselective lactone ring opening leading in a one‐pot procedure to the ε‐silyloxy Weinreb‐type amide, and the cyclopentenone ring formation by the rhodium catalyzed carbenoid cyclization of the corresponding ε‐silyloxy‐α‐diazo‐β‐ketophosphonate followed by the elimination of tert‐butyldimethylsilanol. During the synthetic study on the construction of the cyclopentanone ring by the intramolecular nucleophilic substitution reaction of an anion generated from ε‐bromo‐β‐ketophosphonate, the formation of cyclopropane derivative was observed. This stereochemical outcome was rationalized using quantum chemical calculations.

Asymmetric Total Synthesis and Evaluation of Antitumor Activity of Ophiorrhisine A and Its Derivatives.

The first asymmetric total synthesis of ophiorrhisine A (1), a new cyclic tetrapeptide isolated from Ophiorrhiza nutans, was accomplished via an intramolecular aromatic nucleophilic substitution reaction (IMSNAr) of a linear tripeptide to construct a 14-membered paracyclophane ring, resulting in confirmation of its structure and absolute configuration. The structure-activity relationship study of 1 and its derivatives demonstrated that some derivatives possessed cytotoxicity toward human cancer cell lines A549, HT29, and HCT116.

An Expedient Synthesis of Ketocalix[6]arene Hexamethyl Ether

p-tert-Butylcalix[6]arene hexamethyl ether was oxidized in one step to the corresponding ketocalix[6]arene via photochemical bromination (100 W spot lamp) with NBS in a chloroform/water mixture. A pentamethyl ketocalix[6]arene derivative was obtained by reaction of the ketocalix[6]arene hexamethyl ether with boron tribromide dimethyl sulfide complex, and characterized by X-ray crystallography. In the presence of base, the compound undergoes an intramolecular nucleophilic aromatic substitution reaction.

Microwave-Assisted, Asymmetric Synthesis of 3-Amino-2,3-Dihydrobenzofuran Flavonoid Derivatives from Chalcones.

A route to access 3-amino-2,3-dihydrobenzofurans that utilizes microwave-assisted organic synthesis to rapidly generate analogues has been developed. The route begins with an acid-catalyzed, microwave-assisted aldol condensation to generate chalcone intermediates, followed by a Corey-Bakshi-Shibata reduction and subsequent Sharpless asymmetric epoxidation to access stereoisomeric epoxyalcohols. The final step is a one-pot, microwave-assisted, regioselective, acid-catalyzed epoxide opening with various amines followed by an intramolecular nucleophilic aromatic substitution reaction to generate the 3-amino-2,3-dihydrobenzofurans. This route provides ready access to stereochemically and structurally diverse analogues of these flavonoid scaffolds. Additionally, a pilot library was synthesized, and the biological activity diversity of the chalcones and dihydrobenzofurans was explored in human carcinoma cell lines.