Regioselective Synthesis of 1,2,3,4-Tetrasubstituted Arenes by Vicinal Functionalization of Arynes Derived from Aryl(Mes)iodonium Salts**

Herein, the synthesis of 1,2,3,4-tetrasubstituted benzenoid rings, motifs found in pharmaceutical, agrochemical, and natural products, is described.^[1] In the past, the regioselective syntheses of such compounds have been a significant challenge. This work reports a method using substituted arynes derived from aryl(Mes)iodonium salts to access a range of densely functionalized 1,2,3,4-tetrasubstituted benzenoid rings. Significantly, it was found that halide substituents are compatible under these conditions, enabling post-synthetic elaboration via palladium-catalyzed coupling. This concise strategy is predicated on two regioselective events: 1) ortho- deprotonation of aryl(Mes)iodonium salts to generate a substituted aryne intermediate, and 2) regioselective trapping of said arynes, thereby improving previously reported reaction conditions to generate arynes at room temperature and in shorter reaction times. Density functional theory (DFT) computations and linear free energy relationship (LFER) analysis suggest the regioselectivity of deprotonation is influenced by both proximal and distal ring substituents on the aryne precursor. A competition experiment further reveals the role of arene substituents on relative reactivity of aryl(Mes)iodoniums as aryne precursors.     

Regioselective Synthesis of New Bibracchial Lariat Ethers

A practical and regioselective synthetic method for the synthesis of cis‐diastereomers of bibracchial lariat ethers (BiBLEs) bearing ester and amide groups is reported. The novel BiBLEs 3a and 4a–e with neutral side arms were prepared by reaction of the corresponding aza‐crown macrocycles 1a – c with ethylchlroacetate and chloroacetamide. The structures of the new compounds have been confirmed by FTIR, ¹H, ¹³C, DEPT, and MS spectroscopy.     

A concise and simple click reaction catalyzed by immobilized Cu(I) in an ionic liquid leading to the synthesis of β-hydroxy triazoles

This study describes an ecocompatible, concise, and practically reliable approach for the regioselective synthesis of β-hydroxy triazoles via Huisgen's click coupling reaction among varied epoxides, NaN₃, and suitable acetylenes catalysed by immobilized Cu(I) in ionic liquid (IL). This one-pot, atom-economic, efficient, and highly regioselective green protocol ensures higher yield of β-hydroxy triazole scaffolds (85–95%). To make the process ecofriendly, this study emphasizes on the catalyst immobilization technique along with its possible recycling that gave a high reaction yield in up to three runs. The structures of all synthesized compounds have been characterized by comparing ¹H nuclear magnetic resonance (NMR), ¹³C NMR, and mass spectroscopic data with those reported in the literature.     

Efficient Regioselective Synthesis of Mono-2-O-Sulfonyl-cyclodextrins by the Combination of Sulfonyl Imidazole and Molecular Sieves

Abstract

Cyclodextrins are cyclic oligosaccharides consisting of six or more α-1,4-linked D-glucopyranose units, which possess primary hydroxyl groups at the C-6 positions and secondary hydroxyl groups at the C-2 and C-3 positions. Because cyclodextrins have a hydrophobic and optically active interior, they have been utilized as transporters of hydrophobic molecules and small molecular mimics of enzymes. The chemical modification of cyclodextrins has been investigated in order to improve these characteristics. Sulfonations of the primary or secondary hydroxyl groups of cyclodextrin have been applied for further functionalization of cyclodextrin, and several methods for regioselective sulfonations have been developed. Among these strategies, selective monotosylation of the C-6 hydroxyl group is done relatively easily by reaction of α or β-cyclodextrin and p-toluenesulfonyl chloride in pyridine^1,2 or in alkaline aqueous solution.^3,4 However, sulfonation of the secondary hydroxyl groups is more difficult and new sulfonation methods must be developed to provide precursors for cyclodextrin analogues such as amino and sulfide analogues. Several strategies for the sulfonation of one C-2 hydroxyl group have been reported. However, because reaction conditions can require specific sulfonation reagent,⁵ alkaline condition,^3-7 strict anhydrous conditions,^8,9 or use of protected C-6 hydroxyl groups,^10,11 the methodology is not convenient to employ.     

One‐pot Synthesis of Novel 2,8‐dithioxopyrano[2,3‐d:6,5‐d′]dipyrimidine‐4,6(1H)‐dione Catalyzed by p‐Toluenesulfonic Acid

Novel 2,8‐dithioxopyrano[2,3‐d:6,5‐d′]dipyrimidine‐4,6(1H)‐dione derivatives were synthesized by a clean and efficient methodologies involving one‐pot regioselective and chemoselective reactions between two moles substituted thiobarbituric acid and 1 mol various aromatic aldehydes in the presence of p‐toluenesulfonic acid as a catalyst in EtOH with good yields in compression with alternative conditions such as microwave and promoted ultrasound. All of the compounds have been characterized by IR, ¹H NMR, ¹³C NMR spectral data, and elemental analyses.     

Discovery of a Fungal Multicopper Oxidase That Catalyzes the Regioselective Coupling of a Tricyclic Naphthopyranone To Produce Atropisomers

Atropisomeric dinapinones A1 and A2 (DPA1 and DPA2) were isolated from a culture of Talaromyces pinophilus FKI‐3864. Monapinone coupling enzyme (MCE), which dimerizes naphthopyranone monapinone A (MPA), was purified from a cell‐free extract of T. pinophilus FKI‐3864. MCE regioselectively dimerizes MPA at the 8,8′‐positions to synthesize the atropisomers DPA1 and DPA2 in a ratio of approximately 1:2.5 without a cofactor. The optimal pH value and temperature for MCE were 4.0 and 50 °C, and the apparent K_m and V_max values for MPA were (72.7±23.2) μm and (1.21±0.170) μmol min⁻¹ mg⁻¹ protein. The MCE polypeptide is significantly homologous with multicopper oxidases. Heterologous expression of MCE and functional analysis confirmed that MCE catalyzes the regioselective coupling reaction of MPA to produce DPA. No fungal multicopper oxidase has previously been reported to catalyze regioselective intermolecular oxidative phenol coupling to produce naphthopyranone atropisomers.     

Preparation of 1-Alkynyl (Trimethyl) Silanes from Trimethylsilylpropargyl Phenyl Ether and Organoboranes

Organoboranes have been recently demonstrated to be highly versatile reagents and intermediates for organic synthesis.¹ Several papers have been reported dealing with allenic or propargylic boranes for such purposes.² On the other hand, organosilicon compounds have become increasingly important in synthetic chemistry.³ In search of finding novel synthetic applications by combination of organoboranes and organosilanes, we examined a synthesis of 1-alkynyl (trimethyl) silanes from trimethylsilylpropargyl phenyl ether and trialkylboranes.     

The Origin of Anti‐Markovnikov Regioselectivity in Alkene Hydroamination Reactions Catalyzed by [Rh(DPEphos)]+

The development of regioselective anti‐Markovnikov alkene's hydroamination is a long‐standing goal in catalysis. The [Rh(COD)(DPEphos)]⁺ complex is the most general and regioselective group 9 catalyst for such a process. The reaction mechanism for intermolecular hydroamination of alkenes catalyzed by [Rh(DPEphos)]⁺ complex is analyzed by means of DFT calculations. Hydroamination (alkene vs. amine activation routes) as well as oxidative amination pathways are analyzed. According to the computational results the operating mechanism can be generally described by alkene coordination, amine nucleophilic addition, proton transfer through the metal center and reductive elimination steps. The mechanism for the formation of the oxidative amination side product goes via a β‐elimination after the nucleophilic addition and metal center protonation steps. The origin of the regioselectivity for the addition process (Markovnikov vs. anti‐Markovnikov additions) is shown to be not charge but orbitally driven. Remarkably, η² to η¹ slippage degree on the alkene coordination mode is directly related to the regioselective outcome.     

Regioselective Substitutions of Unsymmetrical 1,2-Diols using Dioxaphospholanes: Applications to Carbohydrates

Abstract

For several years, the method employing 1,3,2λ⁵dioxaphospholanes to effect regioselective substitution of unsymmetrical 1,2-diols has been investigated.^[1] As carbohydrates are an abundant source of diols, this study has been extended to the use of 1,2-O-isopropylidene- D-ghCOfuranOSe 1. We have synthesized a single dioxaphospholane 2 and subsequently treated it with trimethylsilyltriflate to form oxyphosphonium ions 3 and 4.     

Synthesis and Derivatization of 1,1‐[18F]Difluorinated Alkenes

A general method for the synthesis of 1,1‐[¹⁸F]difluorinated alkenes from [¹⁸F]fluoride is reported. This transformation is highly regioselective giving the desired ¹⁸F‐fluoroalkenes with radiochemical purities of up to 77 % within 20 minutes and a molar activity (A_m) of 1 GBq μmol^?1. The transformations are operationally simple to perform and were readily translated onto a commercial automated synthesis unit. The resultant 1,1‐[¹⁸F]difluorinated alkene motif is prevalent in numerous drug molecules, and this is the first general method to synthesize this motif with fluorine‐18. ¹⁸F‐fluorinated alkenes are excellent building blocks and participate in a number of post‐labeling transformations to access a range of ¹⁸F‐perfluorinated functional groups that have never before been radiolabeled with non‐carrier‐added [¹⁸F]fluoride. This method considerably expands the range of ¹⁸F‐motifs accessible to radiochemists.     

New Route for the Synthesis of Four‐Membered Cyclic Ketene Dithioacetals

Novel ketene dithioacetals have been synthesized by a one‐pot condensation reaction of active methylene compounds with CS₂ in the presence of alkyl acetylenecarboxylates. This reaction proceeds in a regioselective manner and provides products in good yields. The structures of the ketene dithioacetals were characterized by IR, ¹H‐ and ¹³C‐NMR, and MS data, and elemental analyses.     

1,3-Dipolar Cycloadditions to Strained Olefins

The Bredt olefins bicyclo [3.3.1]non-1-ene (2) , bicyclo [4.2.1]non-1 (8)-ene (3) , and bicyclo [4.2.1]non-1 (2)-ene (4) react rapidly with 1,3-dipoles such as diazomethane, phenyl azide, and mesitonitrile oxide to yield mixtures of two regioisomeric cycloadducts 10, 11 and 12 , respectively. On the contrary, cycloaddition to the comparable monocyclic 1-methyl-(E)-cyclooctene (5) is fairly regioselective. 2-Methylnorborn-2-ene (6) gives one isomer with mesitonitrile oxide (as do less strained olefins), but mixtures with diazomethane and phenyl azide. ¹H-NMR. and ¹³C-NMR. spectra of the cycloadducts are reported. The results are discussed in the light of frontier molecular orbital theory.     

An Easy Access to Spiroisoxazoline [5,31] Flavan-41-one Through 1,3-Dipolar Cycloaddition Reaction of Nitrile Oxide to Unusual Dipolarophiles

Abstract

Synthesis of a series of novel spiro[3,4-diaryl-4,5-dihydroisoxazole-5,3¹-flavan-4¹-one] has been accomplished in good yields by the regioselective 1,3-dipolar cycloaddition reaction of nitrile oxide to 3-arylmethylidene flavan-4-ones.     

Amino acids as selective acylating agents: regioselective N-acylation of imidazolidin-4-one derivatives of the antimalarial drug primaquine

The acylation of bioactive primaquine-based imidazolidin-4-ones was studied using N^α-Boc-protected glycine as acylating agent. Two synthesis routes, eight different coupling methods and seven distinct solvents were compared. Mild carbodiimide-based couplings on high dielectric constant solvents such as DMF or MeCN increased acylation yields, whereas alcohols inhibited carbodiimide-mediated acylations to take place. Achievement of the synthetic goals was limited by the size of the imidazolidin-4-one ring substituents R¹, R² and R³, but resort to MW-assisted synthesis allowed overcoming such obstacle, though with very modest reaction yields. All reactions involving a Boc-protected amino acid were regioselective, independent of reaction conditions employed. In contrast, regioselective acetylation of the imidazolidin-4-ones could only be achieved by resort to very mild coupling procedures.     

Regioselective deprotection of the monosaccharide‐bearing thiocyanomethyl group at the anomeric position monitored by reversed‐phase HPLC method

In the current work, the investigation and development of a chemo‐enzymatic approach for the synthesis of neo‐glycoproteins have been studied. This strategy is based on the regioselective enzymatic hydrolysis of peracetylated monosaccharide, functionalized at the anomeric position (C1) as 1‐thio‐(S‐cyanomethyl) group, a precursor of the 2‐ iminomethoxyethyl thioglycosides‐linker for protein glycosylation, catalyzed by immobilized enzymes to obtain selectively monodeprotected compounds. The use of this activation in C1 is the most frequently used strategy for glycoprotein preparation. The selected biocatalysts are the lipase from Candida rugosa and the acetyl xylan esterase from Bacillus pumilus. A reversed‐phase high‐performance liquid‐chromatographic (HPLC) method for monitoring the regioselective deprotection reaction has been developed. The developed HPLC method was used as a fingerprint to follow the hydrolysis of substrate 1 to substrate 1a and to determine its purity and yield. Moreover, the obtained compound was further purified by flash chromatography. The obtained compound 1a was further characterized using ¹H, ¹³C NMR, correlation spectroscopy (COSY) and heteronuclear multiple bond correlation. The resulting product can be used as an intermediate for the preparation of di‐ and more complex oligosaccharides aimed at protein conjugation. Copyright © 2016 John Wiley & Sons, Ltd.     

NMR analyses of two isomeric cyclobutanes from a [2 + 2] photocycloaddition

Complete ¹H and ¹³C NMR assignments are reported for two isomeric cyclobutanes generated from the photochemical [2 + 2] cycloaddition of N‐methylisocarbostyril and 4‐methoxy‐3‐buten‐2‐one. The reaction is 100% regioselective and demonstrates the potential synthetic utility of de Mayo type reactions using an isocarbostyril and a stable β‐dicarbonyl enol derivative. Copyright © 2002 John Wiley & Sons, Ltd.     

Novel erythromycin A 9-tritylhydrazone: selective 6-O-methylation and conformational analysis

The straightforward synthesis of the novel 9-tritylhydrazone erythromycin A and its highly regioselective O-methylation at C(6)-OH are described. Preliminary conformational data based on X-ray diffraction, ¹H NMR and molecular mechanics is also presented with the aim of understanding the observed high regioselectivity. The facile synthesis of 6,12-O-dimethylerythromycin A, a standard to assess clarithromycin purity in quality control processes, is reported as well.     

Amino acids as selective sulfonamide acylating agents

Acylation of antimalarial and bacteriostatic sulfonamides with N-protected amino acids and peptides was carried out using standard peptide coupling methods. These acylation reactions are regioselective for the N⁴ nitrogen atom of diazine-containing sulfonamides. In contrast, only N¹ coupling was found for sulfisoxazole, an isoxazole-based sulfonamide. Computational studies suggest that a combination of geometrical, thermodynamic and electronic factors are responsible for the different reactivities reported.     

A concise and optimized four-step approach toward 2-(aryl-)alkylsulfanyl-, 4(5)-aryl-, 5(4)-heteroaryl-substituted imidazoles using alkyl- or arylalkyl thiocyanates

A convenient cyclization method leading to trisubstituted imidazoles in up to 84% yield is reported. Diverse 1-aryl-, 2-heteroaryl-substituted ethanones are converted into the corresponding α-oximino derivatives which are reduced under regioselective conditions. The obtained α-amino carbonyl intermediates are reacted with alkyl- or arylalkyl thiocyanates to directly yield C²-S-substituted imidazoles.     

An Efficient Steric Controlled Photo-Fries Rearrangement in the Naphthalene Series

For the work on the synthesis of 2-acyl-5-methoxynaphthoquinones as tricyclic analogues of daunomycinone¹, we wanted to develop an efficient regioselective synthesis of 5-methoxy-2-acyl-1-naphthols without using Lewis acids. This requirement precluded the use of the thermal Fries but not the photo-Fries rearrangement. Although the mechanistic aspects of the photo reaction have received much study², the reaction has been little used preparatively³ because it usually gives poor yields of hydroxy ketones even when only one product is possible.