Lossen Rearrangement Research Articles

Deprotective Lossen rearrangement: a direct and general transformation of Nms-amides to unsymmetrical ureas.

Ureas stand out as potent pharmacophores in drug development, rendering them a prime focus for synthesis. Herein, we present an appealing entry point for urea synthesis from protected amines (Nms-amides) and relying on a Lossen-type rearrangement process as an elegant example of deprotective functionalisation. The method developed exhibits an exceptionally broad tolerance towards various protected amines, encompassing numerous drug derivatives, and delivers high reaction yields.

Synthesis of Cyclic β-Amino Acid Derivatives by Desymmetrization and Lossen Rearrangement of N-Sulfoxy Meso-Succinimides.

Bifunctional thiourea-based organocatalysts facilitate an enantioselective desymmetrization and Lossen rearrangement cascade reaction of N-sulfoxy meso-succinimides, resulting in the synthesis of cyclic β-amino acid derivatives. This catalytic system was optimized for bicyclic and tricyclic succinimide substrates affording yields from 61-91% and up to 96:4 er. This reaction proceeds via the group selective addition of the primary alcohol nucleophile to an enantiotopic carbonyl group with sequential rearrangement of the intermediate O-sulfonyl hydroxamate ester.

Late-Stage Formation of a Sactionine Linkage Enabled by Lossen Rearrangement of Glycyl Hydroxamic Acid.

Late-stage formation of a sactionine thioether bond connecting a Gly α-carbon and Cys thiol was achieved by Lossen rearrangement of a glycyl hydroxamic acid (GlyHA) residue in a peptide. Lossen rearrangement allowed conversion of GlyHA within a peptide to an N-acyl iminium equivalent, which subsequently reacted with S-acetamidomethyl Cys (Cys(Acm)) in TFA in the presence of guanidine hydrochloride (Gn·HCl) to yield the desired thioether linkage in the final stage.

4 + 2] Cyclization or Lossen Rearrangement: Rhodium-Catalyzed Divergent Synthesis of Carboline Derivatives with Anticancer Activity.

An unusual rhodium-catalyzed C-H activation/Lossen rearrangement/oxa-Michael addition tandem cyclization has been achieved along with a tunable well-known C-H activation/[4 + 2] annulation, leading to regio-, chemo-, and diastereoselective access to diverse pentacyclic α-carbolines and β-carboline-1-one derivatives in moderate to good yields with significant anticancer activity.

Synthesis of N-Glyoxylyl Peptides Enabled by a Lossen Rearrangement-Induced Intramolecular Redox Reaction of N-Terminal Glycyl Hydroxamic Acid.

An oxidant-free approach to the synthesis of N-glyoxylyl peptides has been developed that utilizes the Lossen rearrangement of the N-terminal glycyl hydroxamic acid residue. The synthesis proceeds via an intramolecular redox mechanism to yield the glyoxylyl peptides, which are then subjected to various peptide cyclization procedures. The reaction scheme is suitable for oxidation-sensitive moieties including amino acids.

Tf2O‐Promoted Synthesis of Ureas, Carbamates and Thiocarbamate via Lossen Rearrangement: A Mechanistic Insight

AbstractHerein, we report triflic anhydride mediated synthesis of ureas starting from hydroxamic acids. The scope of triflic anhydride was also expanded to encompass carbamates. In addition, this reaction is applicable to activation of hydroxamic acid derivative of dipeptide giving α‐uriedopeptidomimetics in good yield. The mechanistic study of reaction was carried out by DFT. This study is important because it demonstrates that Tf2O has the potential to be effective when used on a substrate that possesses amide bond. A broad substrate scope and mild conditions render this protocol a promising approach to the synthesis of diverse types of ureas.

3+2] Cycloaddition of Vinyl Cyclopropane and Hydroxylamines via Isocynate Intermediate to γ‐Lactams

Comprehensive SummaryA general and efficient strategy for the synthesis of γ‐lactams has been reported. The hydroxylamines form Lossen rearrangement products of electron‐deficient group migration with base and then undergo [3+2] cycloaddition reaction with vinyl cyclopropane, which could be performed with broad substrate scope, excellent functional group tolerance and high efficiency to produce the desired products. It also allowed further modification to other derivatives of these γ‐lactams.

Synthesis and characterizations of polystyrene materials with low dielectric constant and low dielectric loss at high frequency

AbstractIn this article, a facile and efficient approach to the modification of polystyrene (PS) materials with low dielectric properties at high frequency is reported. A series of N‐acetoxy amide (AA)‐containing polystyrenes (PSAAs) synthesized by free‐radical polymerization can be transformed into NCO‐containing polymers (rPSAAs) via Lossen rearrangement reaction of the AA group. The modified PS materials were then obtained by reacting the rPSAAs with hydroxyl‐terminated poly(phenylene oxide) (PPOD), polybutadiene, and amino‐terminated polysiloxane, respectively. The thermal stability, mechanical, and dielectric properties of PPOD‐modified PS materials were improved with increase of PPOD content. The PPOD (20 wt%)‐modified PS had a dielectric constant of 2.22 and dissipation factor of 1.65 × 10−3 at 10 GHz. This work provides an easy and effective method to prepare high performance modified PS materials by introducing poly(phenylene oxide), which could meet the requirement of new‐generation communication technology.

Role of cyanuric chloride in organic synthesis: A concise overview

AbstractCyanuric chloride, a chlorinated analog of 1,3,5‐triazine, is used as a catalyst, promoter, and activator to catalyze and initiate several reactions like Beckmann rearrangement, Lossen rearrangement, Biginelli reaction, Suzuki coupling reaction, Pictet Spengler reaction, Mannich reaction, etc. It is employed in several reactions due to its several properties like stable, non‐volatile, cost‐efficient, easy to handle, and easy commercial availability. Moreover, it is a very renowned precursor for the synthesis of triazine‐class pesticide atrazine, dyes, and crosslinking agents. Herein in this review article, the reactions initiated, catalyzed, and promoted by cyanuric chloride from 2010 to 2022 have been elaborated.

Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles

AbstractOxindoles and iso‐oxindoles are natural product‐derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso‐oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective RhIII‐catalyzed scaffold‐divergent synthesis of spirooxindole–isooxindoles and spirooxindole–oxindoles from differently protected diazooxindoles and N‐pivaloyloxy aryl amides which includes a functional group‐controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype.

Morphological Profiling Identifies the Motor Protein Eg5 as Cellular Target of Spirooxindoles.

Oxindoles and iso-oxindoles are natural product-derived scaffolds that provide inspiration for the design and synthesis of novel biologically relevant compound classes. Notably, the spirocyclic connection of oxindoles with iso-oxindoles has not been explored by nature but promises to provide structurally related compounds endowed with novel bioactivity. Therefore, methods for their efficient synthesis and the conclusive discovery of their cellular targets are highly desirable. We describe a selective RhIII -catalyzed scaffold-divergent synthesis of spirooxindole-isooxindoles and spirooxindole-oxindoles from differently protected diazooxindoles and N-pivaloyloxy aryl amides which includes a functional group-controlled Lossen rearrangement as key step. Unbiased morphological profiling of a corresponding compound collection in the Cell Painting assay efficiently identified the mitotic kinesin Eg5 as the cellular target of the spirooxindoles, defining a unique Eg5 inhibitor chemotype.

Catalyst-Free Decarboxylative Amination of Carboxylic Acids in Water Microdroplets.

Previous studies have shown that hydroxyl radicals can be formed at the water-gas surface of water microdroplets. We report the use of in situ generated hydroxyl radicals to carry out an organic transformation in one step, namely, the formation of anilines from aryl acids as well as both ammonia and primary/secondary amines via decarboxylation. Benzoic acids and amines are dissolved in water, and the solution is sprayed to form microdroplets whose chemical contents are analyzed mass spectrometrically. All intermediates and products are determined using mass spectrometry (MS) as well as in some cases tandem mass spectrometry (MS2). These results support the following reaction mechanism: NR2OH, formed via reaction of the amine with •OH, reacts with benzoic acid to form an isocyanate via a Lossen rearrangement. Hydrolysis followed by liberation of CO2 then delivers the aniline product. Notably, the scope of this transformation includes a variety of amines and aromatic acids and enables their conversion into aniline and N-substituted anilines, all in a single step. Additionally, this reaction occurs at room temperature and does not require metal catalysts or organic solvents.

Synthesis of Nε-acetyl-L-homolysine by the Lossen rearrangement and its application for probing deacetylases and binding modules of acetyl-lysine.

Lysine acetylation is a posttranslational protein modification mediating protein-protein interactions by recruitment of bromodomains. Investigations of bromodomains have focused so far on the sequence context of the modification site and acyl-modifications installed at lysine side chains. In contrast, there is only little information about the impact of the lysine residue that carries the modification on bromodomain binding. Here, we report a synthesis strategy for L-acetyl-homolysine from L-2-aminosuberic acid by the Lossen rearrangement. Peptide probes containing acetylated homolysine, lysine, and ornithine were generated and used for probing the binding preferences of four bromodomains from three different families. Tested bromodomains showed distinct binding patterns, and one of them bound acetylated homolysine with similar efficiency as the native substrate containing acetyl-lysine. Deacetylation assays with a bacterial sirtuin showed a strong preference for acetylated lysine, despite a broad specificity for N-acyl modifications.

Incorporation of Rhodamine into a Host Polymer via In-Situ Generated Isocyanato Group and Application for the Detection of Cu2+ Ion

A rhodamine-based fluorescent polymer P(MMA-co-RB) has been synthesized via an intermediate NCO-containing polymer generated by the Lossen rearrangement reaction. The fluorescent property of P(MMA-co-RB) with regard to metal ions, such as Cu2+, Fe3+, Cr3+, Al3+, Zn2+, Co2+, Sn2+ and Ag+, was studied by fluorescence emission spectroscopy. The results demonstrate that the fluorescence intensity of P(MMA-co-RB) decreased gradually with an increase of the concentration of Cu2+ ion. Furthermore, a test strip made of P(MMA-co-RB) can be used for fast and quantitative determination of Cu2+ ion. In the presence of Cu2+ ion, the sensory tester undergoes distinct changes in fluorescence intensity and visible color.

Synthesis of carbamoyl azides via the Lossen rearrangement utilizing diphenyl phosphorazidate

A novel method was developed for the synthesis of carbamoyl azides from hydroxamic acids via the Lossen rearrangement using diphenyl phosphorazidate, which acts as both the activator and azide source to produce the azides via an isocyanate intermediate. Using this method, various hydroxamic acids were converted into the corresponding carbamoyl azides, enabling their preparation without the use of highly explosive reagents.

Formation of reactive isocyanate group-containing polymers via Lossen rearrangement

We report an efficient and phosgene-free method for the synthesis of isocyanate group (NCO)-containing polymers via Lossen rearrangement. The key monomer of N-acetoxymethacrylamide (AMAA), possessing N-acetoxy amide (AA) group was synthesized from the reaction of N-hydroxymethacrylamide (MHA) with acetic anhydride. By adjusting the feed ratio of methyl methacrylate (MMA) and AMAA, a series of AA-containing polymers (P1-P3) were prepared by free-radical polymerization. Fourier transform infrared spectroscopy (FTIR) and thermogravimetric analysis (TGA) revealed that the AA groups in polymers P1-P3 can be readily converted to isocyanate groups by heating at 130 ℃ to afford the NCO-containing polymers P4-P6 with conversion percent of 60, 77 and 78, respectively. Furthermore, the AA-containing polymers can be used as a latent NCO-containing polymer for further chemical modification, such as in-situ grafting reaction with hydroxyl compounds. The spectroscopic analyses confirmed that the dye functional group of disperse red 1 (DR1) was successfully grafted on either NCO- or AA-containing polymers.

Synthesis and application of thiocarbamates via thiol-dioxazolone modified Lossen rearrangement.

Thiocarbamates could be synthesized in green solvents via thiol-dioxazolone modified Lossen rearrangement under transition-metal free, additive free, and mild conditions. Polythiocarbamates were further prepared with excellent self-healing and shape-memory properties, showing great potential in the development of functional materials.

Lossen Rearrangement of p-Toluenesulfonates of N-Oxyimides in Basic Condition, Theoretical Study, and Molecular Docking.

The sulfonic esters of N-oxyimides are a group of compounds with a wide range of biological activities, as well as a unique reactivity toward amines. They undergo this reaction with primary amines and other nucleophilic reagents according to a Lossen-like rearrangement. The reaction is initiated by nucleophilic attack on a carbonyl group in the succinimide ring followed by isocyanate formation, which next interacts with another nucleophile molecule forming an addition product (e.g., ureido or urethane derivative). However, the secondary amines are also susceptible to other reactions leading to products containing the maleimide ring formed by sulphonic acid elimination. In the case of tertiary amines, this reaction is predominant. To explain the phenomenon of the reactivity of the N- oxyimides toward different types of amines, we employed various spectroscopic and X-ray approaches as well as DFT calculation. Results suggest that the basicity of the amine used for the reaction plays a crucial role in the reaction mechanism that eventually dominates the entire chemical process. Moreover, we applied molecular docking to investigate the ability of the products to act as serine protease inhibitors using human leukocyte elastase (HLE).

Lossen rearrangement by Rh(III)-catalyzed C-H activation/annulation of aryl hydroxamates with alkynes: access to quinolone-containing amino acid derivatives.

A convenient and robust method for the preparation of new CF3-containing 2-quinolones has been developed via a Rh(III)-catalyzed C-H activation/Lossen rearrangement/annulation cascade of N-pivaloyloxy-arylamides with internal alkynes bearing an α-CF3-α-amino acid moiety on the triple bond. This work expands the scope of valuable products that are available through C-H activation/annulation reactions of arylamides in organic synthesis.

Lossen Rearrangement vs C-N Reductive Elimination Enabled by Rh(III)-Catalyzed C-H Activation/Selective Lactone Ring-Opening: Chemodivergent Synthesis of Quinolinones and Dihydroisoquinolinones.

An unprecedented Rh(III)-catalyzed cascade C-H activation/Lossen rearrangement of aromatic amides with methyleneoxetanones has been realized along with a tunable C-N bond reductive elimination/trans esterification, giving divergent access to quinolinones and dihydroisoquinolinones via selective ring-opening of the four-membered lactone unit. Combined computational and experimental mechanistic studies defined the solvent-involved distinguished reaction paths, the origin of the observed chemodivergence, as well as the role of the substituent attached at the oxidizing directing group in tuning the reaction outcomes.