Intramolecular SNAr Research Articles

Synthesis of Spirocyclic Diarylfluorenes by One-Pot Twofold SNAr Reactions of Diaryl Sulfones with Diarylmethanes.

Treatment of dibenzothiophene dioxides with cyclic diarylmethanes in the presence of KN(SiMe3)2 results in the formation of fluorene-based spirocyclic tetraarylmethanes in a single operation. The transformation would proceed via an intermolecular SNAr reaction of the dioxides with cyclic diarylmethylpotassium followed by intramolecular SNAr cyclization. This straightforward strategy provides a wide range of spirocyclic diarylfluorenes including unusual ones that are otherwise difficult to synthesize.

Microwave-assisted synthesis in water: first one-pot synthesis of a novel class of polysubstituted benzo[4,5]imidazo[1,2-b]pyridazines via intramolecular SNAr

A novel and straightforward one-pot synthesis protocol has been developed for the synthesis of benzo[4,5]imidazo[1,2-b]pyridazines through intramolecular SNAr, utilizing water as a green solvent and microwaves as an efficient green energy source.

Total synthesis of plagiochin G and derivatives as potential cancer chemopreventive agents

A new and efficient total synthesis has been developed to obtain plagiochin G (22), a macrocyclic bisbibenzyl, and four derivatives. The key 16-membered ring containing biphenyl ether and biaryl units was closed via an intramolecular SNAr reaction. All synthesized macrocyclic bisbibenzyls inhibited Epstein–Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cells and, thus, are potential cancer chemopreventive agents.

New Short Strategy for the Synthesis of the Dibenz[b,f]oxepin Scaffold

In this report a short and efficient synthesis of the dibenz[b,f]oxepin framework through intramolecular SNAr and McMurry reactions is described. The diaryl ethers required for the McMurry reaction have been obtained in good yields under microwave-assisted conditions of the reaction of salicylaldehydes with fluorobenzaldehydes without catalysts. Application of an intramolecular McMurry reaction to the synthesized diarylethers using TiCl4/Zn in THF gave the target dibenzo[b,f]oxepin system in 53%–55% yields.

Synthesis of Dibenzothiophene, Dibenzofuran and Carbazole Donor-Acceptor Chromophores

We present efficient synthetic protocols for functionalizing dibenzothiophene, dibenzofuran, and carbazole with hydroxy and nitro or cyano groups. The synthesis of these donor–acceptor chromophores is based on a key Suzuki–Miyaura coupling using an appropriately substituted aromatic boronic acid. Subsequent intramolecular SNAr reaction allows formation of the dibenzothiophene and dibenzofuran scaffolds, while a carbon–hydrogen activation reaction is employed to afford the carbazole. A final demethylation step unmasks the phenol moiety of the tricyclic chromophores. The UV/Vis absorption properties of the phenol and phenolate forms of these chromophores are also studied.

Enantioselective Total Synthesis of (−)-Δ8-THC and (−)-Δ9-THC via Catalytic Asymmetric Hydrogenation and SNAr Cyclization

The highly efficient asymmetric total syntheses of (-)-Δ(8)-tetrahydrocannabinol ((-)-Δ(8)-THC) (13 steps, 35%) and (-)-Δ(9)-tetrahydrocannabinol ((-)-Δ(9)-THC) (14 steps, 30%) have been developed by using ruthenium-catalyzed asymmetric hydrogenation of racemic α-aryl cyclic ketones via dynamic kinetic resolution and intramolecular S(N)Ar cyclization.

Quick access to the core of mersicarpine through an SNAr strategy

A quick access to the core of dihydroindole alkaloid mersicarpine was developed based on straightforward transformations from readily available and inexpensive starting materials. The synthetic route features an aldol reaction, a Beckmann rearrangement for the synthesis of the δ-lactam, an intramolecular SNAr strategy for indoxyl heterocycle formation, and in situ autoxidation of indoxyl intermediate. The new strategy offered an alternative approach for the formation of an oxidized indoxyl moiety, which could potentially have a wider application in the total synthesis of indole alkaloids containing apparent or masked indoxyl moieties.

Enantioselective Synthesis of (−)‐(R)‐Cordiachromene and (−)‐(R)‐Dictyochromenol Utilizing Intramolecular SNAr Reaction

AbstractA simple and efficient enantioselective synthesis of chromene, (−)‐(R)‐cordiachromene (1), and (−)‐(R)‐dictyochromenol (2) has been accomplished. This convergent synthesis utilizes intramolecular SNAr reaction for the formation of chroman ring, and Seebach's method of ‘self‐reproduction of chirality’ should establish the (R)‐configuration of the C(2) side chain as key steps.

ChemInform Abstract: Concise Synthesis of Riccardin C, Macrocyclic Bisbibenzyl Natural Product.

AbstractThe key step for the title synthesis is the intramolecular SNAr reaction of the compound (II), which is the product of a diimide reduction keeping the sulfinyl group intact.

Synthesis and Crystal Structure of 1-(3-Fluorophenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one

The base catalyzed intramolecular nucleophilic cyclization of 1-(2-bromobenzoyl)-3-(2-fluorophenyl)thiourea (1) in the presence of N,N-dimethyl formamide (DMF) afforded the 1-(3-fluorophenyl)-2-thioxo-2,3-dihydroquinazolin-4(1H)-one (2) by an intramolecular nucleophilic substitution SNAr mechanism. The structure was supported by the spectroscopic data and unambiguously confirmed by the single crystal X-ray diffraction data. It crystallizes in the orthorhombic space group P na21 with unit cell dimensions a = 22.430(4), b = 8.1478(16), c = 13.522(3) Å, V = 2471.2(9) Å3. There are two independent molecules per asymmetric unit that are linked to centrosymmetric AB-dimers via intermolecular N-H…S bonds.

Concise Synthesis of Riccardin C, Macrocyclic Bisbibenzyl Natural Product

Abstract Riccardin C (1) has been synthesized by exploiting an intramolecular SNAr reaction of α-sulfinylfluorobenzene by an internal phenolate, providing the key 18-membered ring closure in excellent yield.

ChemInform Abstract: Access to Macrocycles with an endo Aryl Ether and an endo Aryl—Aryl Bond: Development and Application

AbstractReview: 103 refs.

ChemInform Abstract: Application of 2‐(2‐Chloroaroyl)methyleneimidazolidines in Domino and Multicomponent Reaction: New Entries to Imidazo[1,2‐a]pyridines and Benzo[b]imidazo[1,2,3‐ij][1,8]naphthyridines.

Abstract A new strategy for the synthesis of tetrahydroimidazo[1,2-a]pyridines and unusual tetrahydrobenzo[b]imidazo[1,2,3-ij][1,8]naphthyridines has been successfully developed by cascade reactions including Knoevenagel condensation, aza–ene reaction, imine–enamine tautomerization, cyclocondensation/oxidation, and intramolecular SNAr of precursors 2-(2-chloroaroyl)methyleneimidazolidines as new heterocyclic ketene aminals (HKA), which represent a class of polyfunctional scaffolds with four active reaction sites with aromatic aldehydes and malononitrile or ethyl 2-cyanoacetate under mild conditions. In this domino reaction, nine different active sites are involved, and two C–C bonds, two C–N bonds, and two new rings are constructed with all reactants efficiently utilized in the chemical transformation.

Total Synthesis of Plagiochin D by an Intramolecular SNAr Reaction

AbstractThe total synthesis of plagiochin D, a macrocyclic bis(bibenzyl) compound isolated from the liverwort plagiochila acanthophylla, has been accomplished. Closure of the key 16‐membered ring, which contained biphenyl ether and biaryl units, was achieved in good yield by an intramolecular SNAr reaction. The Suzuki and Wittig protocols proved to be powerful tools for the construction of a linear precursor that was crucial for ring cyclization.

Access to Macrocycles with an endo Aryl Ether and an endo Aryl-Aryl Bond, Development and Application

Macrocyclization methodologies allowing access to macrocycles having an endo aryl ether and an endo aryl-aryl bond, especially those based on an intramolecular S(N)Ar reaction and the Suzuki-Miyaura reaction, are summarized. Total synthesis of complestatin, a bis-macrocyclic natural product, featuring these two technologies are presented.

Reactivity of Functionalized N,S-Ketene Acetal: Regioselective Construction of Tetrahydrobenzo[b]pyran and Chromeno[2,3-b]quinoline Derivatives

Regioselective synthesis of functionalized tetrahydrobenzo[b]pyrans has been developed by multicomponent reactions (MCRs) and tandem [3 + 3] annulations of β-benzoylthioacetanilides or β-(2-haloaroyl)thioacetanilides as valuable sources with aromatic aldehydes and 5,5-dimethyl-1,3-cyclohexanedione catalyzed by triethylamine. This MCR followed by a postcondensation cyclization via an intramolecular S(N)Ar in the presence of K(2)CO(3) led to an unprecedented novel chromeno[2,3-b]quinoline framework containing an important chromene moiety in good yields. The reactions were very mild, convenient, and o-selective to form new fused tetracyclic target molecules.

Scaling Out by Microwave‐Assisted, Continuous Flow Organic Synthesis (MACOS): Multi‐Gram Synthesis of Bromo‐ and Fluoro‐benzofused Sultams Benzthiaoxazepine‐1,1‐dioxides

Scaling Out by Microwave‐Assisted, Continuous Flow Organic Synthesis (MACOS): Multi‐Gram Synthesis of Bromo‐ and Fluoro‐benzofused Sultams Benzthiaoxazepine‐1,1‐dioxides

Parallel synthesis of 19-membered ring macro-heterocycles via intramolecular thioether formation

Abstract Starting from resin-bound orthogonally protected lysine, the generation of 19-membered ring macro-heterocycles via intramolecular thioether formation is described. The on resin cyclization occurred by the coupling of p-fluoro-m-nitro benzoic acid or bromo acetic acid followed by intramolecular substitution SNAr or SN2 displacement of the fluoro and bromo groups, respectively. The described approaches present versatile synthetic routes toward the synthesis of libraries of macro-heterocycles in an attempt to establish lead drug candidates. The desired cyclic products were obtained in good yields and good purities.

A concise formal synthesis of diazonamide A by the stereoselective construction of the C10 quaternary center.

Protecting groups are overrated! A formal total synthesis of diazonamide A is described. The key step in this synthesis is an intramolecular SNAr reaction between an oxindole and a bromooxazole. Interestingly, this reaction proceeds best using the mild base Na2CO3, and with no protecting groups on the oxindole nitrogen atom or phenol groups of the cyclization precursor.

Stable Spirocyclic Meisenheimer Complexes

Meisenheimer complexes are important intermediates in Nucleophilic Aromatic Substitution Reactions (SNAr). They are formed by the addition of electron rich species to polynitro aromatic compounds or aromatic compounds with strong electron withdrawing groups. It is possible to distinguish two types of Meisenheimer or σ-complexes, the σH-complex or σX-complex (also named ipso), depending on the aromatic ring position attacked by the nucleophile (a non-substituted or substituted one, respectively). Special examples of σX- or ipso-complexes are formed through intermediate spiro adducts, via intramolecular SNAr. Some of these spirocyclic Meisenheimer complexes, a type of σX-complex, are exceptionally stable in solution and/or as solids. They can be isolated and characterized using X-ray, and various spectroscopic techniques such as NMR, UV-Vis, IR, and fluorescence. A few of these stable spirocyclic Meisenheimer complexes are zwitterionic and exhibit interesting photophysical and redox properties. We will review recent advances, synthesis and potential applications of these stable spirocyclic Meisenheimer complexes.