Intermediate Salts Research Articles

An Interrupted Pummerer/Nickel-Catalysed Cross-Coupling Sequence.

An interrupted Pummerer/nickel-catalysed cross-coupling strategy has been developed and used in the elaboration of styrenes. The operationally simple method can be carried out as a one-pot process, involves the direct formation of stable alkenyl sulfonium salt intermediates, utilises a commercially available sulfoxide, catalyst, and ligand, operates at ambient temperature, accommodates sp-, sp2 -, and sp3 -hybridised organozinc coupling partners, and delivers functionalised styrene products in high yields over two steps. An interrupted Pummerer/cyclisation approach has also been used to access carbo- and heterocyclic alkenyl sulfonium salts for cross-coupling.

Three-Component Reactions of Arynes, Amines, and Nucleophiles via a One-Pot Process.

An unprecedented three-component reaction of arynes, tertiary amines, and nucleophiles has been demonstrated through ammonium salt intermediates. This protocol allows access to tertiary aniline derivatives containing the piperazine motif in good-to-excellent yields. Expansively, this reaction can produce biologically important 2-(4-phenylpiperazin-1-yl)ethyl-containing molecules using arynes, 1,4-diazabicyclo(2.2.2)octane (DABCO), and nucleophiles via a one-pot process.

Novel derivatives of the antibiotic NHC–Ag(I) drug candidate SBC3: Synthesis, biological evaluation and 109Ag NMR studies

The synthesis of six novel N-heterocyclic carbene silver(I) acetate complexes, three symmetrical and three non-symmetrical, were achieved using 4,5-diphenylimidazole to produce intermediate imidazolium salts and then obtain the corresponding silver(I) complexes through complexation with silver acetate via the Youngs’ method. In vitro biological testing, using the Kirby–Bauer disk diffusion method, was conducted against Methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli, with a NHC–silver(I) acetate compound, SBC3, and Tetracycline as standards. Silver(I) acetate complex 7 resulted in a 4 mm clearance against MRSA, showing the highest antibiotic activity of the novel derivatives. Crystallographic data revealed similar bond lengths and angles to previously reported NHC–silver(I) acetate complexes, with complex 8 showing interesting η2-coordination between the silver atom and acetate oxygens. 109Ag NMR studies were conducted, highlighting the effects of the substituents of the imidazole ring on the silver atom shown by the corresponding shifts in the 109Ag NMR spectra. The incorporation of isopropyl groups to several of the novel complexes resulted in larger upfield 109Ag NMR shift values compared to all other substituents.

Metal‐Free Multicomponent Reaction for Synthesis of 4,5‐Disubstituted 1,2,3‐(NH)‐Triazoles

AbstractA metal‐free domino reaction was developed for efficient synthesis of 4,5‐disubstituted 1,2,3‐(NH)‐triazoles by sequentially coupling sulfur salts with aldehydes and sodium azide. In the presence of L‐proline, olefinic sulfur salt intermediates rather than epoxides are formed in situ via the coupling of sulfur salts with aldehydes and cyclize with azide ion. This process features mild conditions, high efficiency, commercially available starting materials, and wide substrate scope.magnified image

Rapid, Selective, Ambient Growth and Optimization of Copper Benzene-1,3,5-Tricarboxylate (Cu–BTC) Metal–Organic Framework Thin Films on a Conductive Metal Oxide

Metal–organic frameworks (MOFs) are useful for thin film-based device integration as they show high adsorption capacity for selected gases. However, optimized device integration of MOFs for various platforms requires high-quality, well controlled thin film growth techniques that are flexible, scalable, and manufacturable. For this reason, there is a critical need for the ability to grow MOFs in the form of dense and uniform thin films efficiently on a wide range of substrates. In this work, copper benzene-1,3,5-tricarboxylate (Cu–BTC) MOF thin films are rapidly produced at room temperature by using a conductive aluminum-doped zinc oxide (AZO) as a seed layer to template Cu–BTC growth, with growth only occurring on the AZO layer via a hydroxy double salt intermediate. The formation pathway of the Cu–BTC films was investigated in detail because of the significant importance of improving the Cu–BTC film growth from the perspective of optimized device integration. We demonstrate that the structure of the resu...

One-Pot Synthesis of Deuterated Aldehydes from Arylmethyl Halides.

A facile, one-pot approach for synthesizing deuterated aldehydes from arylmethyl halides was developed using D2O as the deuterium source. The efficient process is realized by a sequence of formation, H/D exchange, and oxidation of pyridinium salt intermediates. The mild and air-compatible reaction conditions enable efficient synthesis of diverse deuterated aldehydes with high deuterium incorporation.

Synthesis of Triazolodiazepinium Salts: Sequential [3++2] Cycloaddition/Rearrangement Reaction of 1-Aza-2-azoniaallenium Cation Intermediates Generated from Piperidin-4-ones.

The bicyclic 1-aza-2-azoniaallenium salt intermediates, generated from the azoester species upon treatment with a Lewis acid, have been demonstrated to participate in Huisgen-type cycloaddition with nitriles to result in the formation of fused 6,7,8,9-tetrahydro-5 H-[1,2,4]triazolo[1,5- d][1,4]diazepinium salts. This transformation is interpreted as a regular [3++2] cycloaddition between intermediates as the reactive 1,3-monopole reactants and nitriles as the nucleophilic reagents followed by spontaneous [1,2]-cationic rearrangement. The azoester precursors were easily accessible via oxidation of the corresponding hydrazones using hypervalent iodine oxidant PhI(OAc)2 under mild conditions. The [1,2,4]triazolodiazepine compounds represent a class of N-containing biologically important heterocycles with a new type of scaffold.

Renaissance of Sandmeyer-Type Reactions: Conversion of Aromatic C-N Bonds into C-X Bonds (X = B, Sn, P, or CF3).

The Sandmeyer reaction represents an important organic transformation that converts an arylamine to an aryl halide using Cu(I) halide via a diazonium salt intermediate. The reaction was first reported by Sandmeyer in 1884, and a number of named reactions closely related to it have been developed and widely applied in organic synthesis throughout the 20th century. These include the Pschorr reaction for the synthesis of biaryl tricycles, the Gomberg-Bachmann reaction for biaryl formations, the Balz-Schiemann reaction for C-F bond formations, and the Meerwein reaction for arylation of α,β-unsaturated carbonyl compounds. However, all these reactions were discovered before 1940. In 1977, Doyle and co-workers reported an organic phase diazotization process, and Kikukawa and Matsuda used aryldiazonium salts in transition metal-catalyzed cross-coupling reactions. However, completely new processes involving diazonium salts have been seldom reported since then, although aryldiazonium salts are widely utilized in modern organic synthesis. In the past few years, diazonium salt chemistry has been revisited and become a fast-growing research topic. Several novel transformations based on diazonium salts have been developed and have been practiced in organic synthesis. In 2010, we reported a direct conversion of arylamines to pinacol boronates through the reaction of in situ generated aryl diazonium salts with B2pin2. This new strategy is under metal-free conditions and thus completely avoids contamination by transition metals in the boron products. From readily available arylamines various functionalized arylboronates, some of which are difficult to access by other methods, can be easily obtained with this reaction. Mechanistic investigations indicate the reaction likely follows a radical mechanism, which is similar to traditional Sandmeyer-type reactions. Subsequently, modified reaction conditions for this transformation appeared in the literature, which include light-induced reactions, aqueous-phase diazotization methods, and reactions with aryltriazenes as the arene diazonium salt surrogates. In addition to the borylation, we have also demonstrated the corresponding stannylation and phosphorylation of arylamines with similar Sandmeyer-type approaches. The stannylation of arylamines was achieved by the reaction of in situ generated diazonium salts with a distannane reagent, while phosphorylation is the reaction of arylamines with trimethyl phosphite in the presence of tert-butyl nitrite (t-BuONO). With the sequential borylation and stannylation approaches, the aromatic compounds bearing two amino groups are easily converted into trimethylstannyl arylboronates, which can be further used in consecutive Stille and Suzuki-Miyaura cross-couplings. Finally, direct conversion of the amino group of arylamines to the trifluoromethyl group has been developed through aryl diazonium salts almost simultaneously by several groups. These reactions represent a novel strategy to achieve trifluoromethylation of aromatic compounds. These developments show the revivification of this age-old chemistry, and this Account will summarize the Sandmeyer reaction-related transformations that have been developed since 2010.

Acetic Anhydride Mediated Retro-Ene Reaction via a [4.4.3]Propel­lane Skeleton Intermediate Containing a Quaternary Ammonium Linkage

A novel retro-ene reaction via a [4.4.3]propellane intermediate containing a quaternary ammonium linkage was developed. The feature of this acetic anhydride mediated rearrangement includes the elimination of an acetoxy group at the C14 position and subsequent intramolecular nucleophilic addition of a nitrogen functional group to form an isolable ammonium salt intermediate. We clarified the reaction mechanism utilizing the deuterated derivative.

CeCl3-mediated addition of acetylenic bis-lithium salts to aldehydes and ketones: An efficient route to bis-substituted alkyne diols

An efficient, chemoselective protocol to access propargylic diols via a CeCl3-mediated addition reaction is reported. Propargylic alcohols were transformed into the corresponding acetylenic bis-lithium salt intermediates, which react with aldehydes and ketones in the presence of dry CeCl3 to furnish the corresponding bis-substituted alkyne diols. This protocol does not involve protection-deprotection or transmetallation steps, and allows the use of poorly reactive or highly enolizable substrates.

Versatile and chemoselective synthesis of fluorinated methyl ethers from methoxymethyl ethers

A versatile and chemoselective route has been developed for the synthesis of aliphatic fluorinated methyl ethers (ROCH2RF), specifically monofluoromethyl ethers (ROCH2F) and trifluoromethylthiomethyl ethers (ROCH2SCF3), through pyridinium-type salt intermediates derived from methoxymethyl (MOM) ethers. The addition of a fluorine source (F− or SCF3−) to the pyridinium-type salts afforded the corresponding fluorinated methyl ethers in good yields under mild conditions. Notably, the synthesis of monofluoromethyl ethers proceeded within just 5min.

Synthesis of 4-membered ring alkaloid analogues via intramolecular [2+2] cycloaddition involving keteniminium salt intermediates

We have developed a very straightforward method for the synthesis of 4-membered ring alkaloid analogues via intramolecular [2+2] cycloadditions. This involves the cyclization of a keteniminium salt in which an alkene is linked by the nitrogen atom, and where, the resulting cyclobutane iminium is reduced in a diastereoselective manner. Competition reactions have been performed to fully understand the features of this sequence. Moreover, DFT calculations have verified that the [2+2] cycloaddition step is driven by kinetic and not thermodynamic factors confirming all the experimental observations.

Synthesis of Water-Sensitive Metal–Organic Frameworks within Fiber Sorbent Modules

We report a synthetic route for the production of water-sensitive metal–organic frameworks (MOFs) in polymer fiber sorbents by use of metal oxides as seeding intermediates. Cellulose acetate/ZnO (48 wt %) fibers were spun via a dry-jet wet-quench method and converted through hydroxy double salt (HDS) intermediates into HKUST-1 and ZIF-8. MOF loadings within the fiber sorbent reached 85 and 66 wt %, respectively. We demonstrate this process on module-packaged fibers, in which ready-to-use fiber sorbents are synthesized in a moisture-free environment. Modules are then employed in proof-of-concept CO2/N2 breakthrough experiments.

Concise Synthesis of 3-(Aminomethyl)pyrrolizidines via an In(OTf)3-Mediated Ring Rearrangement of 2-[2-(1-Pyrrolin-2-yl)-alkyl]aziridines

In this study, an efficient ring rearrangement of 2-[2-(1-pyrrolin-2-yl)alkyl]aziridines, prepared from 2-(bromomethyl)aziridines, toward novel trans- and cis-3-aminomethyl-substituted pyrrolizidines was developed. To that end, addition of In(OTf)3 as an appropriate Lewis acid catalyst resulted in the formation of intermediate pyrrolizidinium salts via regioselective aziridine ring opening, which were then trapped by a hydride or cyanide nucleophile. Column chromatographic purification allowed the isolation of the major trans-isomers, exclusively.

ChemInform Abstract: Intramolecular [4 + 2] Cycloaddition of Aryl‐1‐aza‐2‐azoniaallene Salts: A Practical Approach to Highly Sterically‐Congested Polycyclic Protonated Azomethine Imines.

We report an improved two-step reaction sequence that gives tricyclic protonated azomethine imine products containing a 1,2,3,4-tetrahydrocinnoline scaffold in high yield. This sequence involves the oxidation of aryl hydrazones with TFAA-activated DMSO to give the corresponding α-trifluoroacetoxyazo products, which react readily with TMSOTf to give 1-aza-2-azoniaallene salt intermediates that undergo intramolecular (4+2) cycloadditions with pendent alkenes. This reaction sequence is more general, more practical and more environmentally friendly than our initially reported method. The cycloaddition provides exceptionally sterically-hindered products in high yield.

ChemInform Abstract: Site‐Selective N‐Dealkylation of 1,2,3‐Triazolium Salts: A Metal‐Free Route to 1,5‐Substituted 1,2,3‐Triazoles and Related Bistriazoles.

N3-Alkylation of 1-(pivaloyloxymethyl)-1,2,3-triazoles with alkyl triflates carrying latent “click” functionality, followed by a nucleophile-promoted N1-dealkylation of the resulting strongly electrophilic intermediate triazolium salts, provides an efficient route to 1,5-disubstituted 1,2,3-triazoles. The azide and alkyne groups incorporated by N-alkylation can be submitted to further copper-catalyzed azide–alkyne and Huisgen cycloadditions to provide bis(1,2,3-triazoles) with unprecedented 1,5/1,4 substitution patterns.

Preparation of P-heterocyclic phosphine boranes and optically active phosphine oxides via phosphonium salts

GRAPHICAL ABSTRACT

ChemInform Abstract: Synthesis of β‐Substituted Cyclic Enones via Phosphonium Salt‐Activated, Palladium‐Catalyzed Cross‐Coupling of Cyclic 1,3‐Diones.

AbstractActivation of cyclic 1,3‐diones with PyBroP generates phosphonium salt intermediates which readily undergo Pd‐catalyzed Suzuki—Miyaura coupling with boronic acids and pinacol esters as well as Pd/Cu‐catalyzed Sonogashira coupling with terminal alkynes.

ChemInform Abstract: Visible‐Light Photocatalytic α‐Amino C(sp3)—H Activation Through Radical Translocation: A Novel and Metal‐Free Approach to α‐Alkoxybenzamides.

Abstracto‐Aminobenzamides are converted into diazonium salt intermediates, which can be reduced to generate aryl radicals.

Novel Armed Pyrazolobenzothiazine Derivatives: Synthesis, X-Ray Crystal Structure and POM analyses of Biological Activity Against Drug Resistant Clinical Isolate of Staphylococcus aureus

Novel structural hybrids of pyrazolobenzothiazine and triazole ring systems have been prepared to observe a synergistic effect of the two ring systems. The methodology involves condensation of pyrazolobenzothiazine rings with methyl chloroacetate, followed by hydrazide formation. The hydrazides were converted to triazoles through the formation of intermediate potassium salts of dithiocarbazate. The final compounds as well as intermediates were screened for their antibacterial activity against a multidrug resistant strain of Staphylococcus aureus. It was interesting to observe that dithiocarbazates (7a, 7b) and target triazoles (8a, 8b) exhibited antibacterial activity.