Intramolecular Migration Research Articles

Alkylcyanation of Unactivated Alkenes with Protic C(sp3)−H Feedstocks via Radical‐Initiated Intramolecular Cyano Group Migration Enabled by Photoredox/Brønsted Base Dual Catalysis

AbstractCyanofunctionalization of alkenes via radical‐initiated cyano migration was a straightforward pathway to access alkyl nitriles. Herein, By the synergistic merger of photoredox catalysis and Brønsted base catalysis, a mild protocol of alkylcyanation of unactivated alkenes with protic C(sp3)−H feedstocks via intramolecular 1,4‐cyano group migration was reported. This method was enabled in an atom‐, and step‐economy manner, delivering a series of γ‐cyanoester derivatives in moderate to excellent yields.

Base‐Mediated Cascade Reaction of CF3‐Imidoyl Sulfoxonium Ylides and Diimides for the Synthesis of Functionalized Amidines

AbstractA base‐mediated cascade reaction of CF3‐imidoyl sulfoxonium ylides (TFISYs) and diimides has been developed for the preparation of functionalized amidines. In the transformation, a cascade nucleophilic addition and subsequent [2,3]‐sigmatropic rearrangement of sulfoxonium ylide occur to enable an intramolecular migration of dimethyl sulfoxide (DMSO). The unexpected result of the developed protocol demonstrates the chameleonic reactivity of TFISYs.

N-Substituted Iminothiolane (NIT): A Promising Strategy for Protecting Lysine Side Chains for Solid-Phase Peptide Chemistry.

In this study, we introduce N-substituted iminothiolane (NIT) as a robust protecting group for lysine side chains. NIT is compatible with Fmoc-SPPS and can be efficiently removed under mild nucleophilic conditions. Notably, NIT offers enhanced hydrophilicity compared to traditional orthogonal lysine-protecting groups and does not undergo intramolecular migration. Additionally, the synthesis of NIT in aqueous media highlights its eco-friendly nature, positioning it as a promising alternative to protect lysine side chains.

Ferrocenyl conjugated oxazepines/quinolines: multiyne coupling and ring-expanding or rearrangement.

Ferrocenyl conjugated oxazepine/quinoline derivatives were presented through the reaction of hexadehydro-Diels-Alder (HDDA) generated arynes with ferrocenyl oxazolines under mild conditions via ring-expanding or rearrangement processes. Water molecule participated in this unexpected rearrangement process to produce quinoline skeletons, and DFT calculations supported a ring-expanding and intramolecular hydrogen migration process for the formation of oxazepine derivatives. Two variants of this chemistry, expanded the reactivity between ferrocenyl conjugated substances and arynes, further providing an innovative approach for the synthesis of ferrocene derivatives.

Fluoride-Mediated Aryne 1,2-Difunctionalization Involving C═S Bond Heterolysis.

We have successfully synthesized a series of bidentate ligands by utilizing 2-(trimethylsilyl)phenyl trifluorosulfonate as a precursor for the benzyl group. This method proceeded by inserting a polythiourea into the C═S π-bond, intramolecular ring proton migration, and ring opening. Salient features of this strategy are mild reaction conditions, a novel product structure, excellent stereochemistry, and a good functional group tolerance. Furthermore, a series of density functional theory calculations were performed to gain insights into the transfer mechanism.

Applications of Baker-venkataraman Rearrangement in the Synthesis of Promising Organic Molecules

Abstract:: In organic synthesis, carbon-carbon bond formation is the fundamental transformation to create the carbon backbone of organic molecules and this key reaction is very popular in the improvement of organic chemistry, which exists at the bottom of the heart of the chemical sciences. The Baker- Venkataraman rearrangement has received great attention in the formation of 1,3-diketones through the regioselective construction of carboncarbon bonds. This rearrangement is an important type of chemical transformation in which the intramolecular migration of the ester acyl group takes place to provide 1,3-diketones in the presence of the base. Generally, 1,3-diketones or ortho-hydroxydibenzoylmethane derivatives undergo cyclization to provide the corresponding flavones in the presence of concentrated sulfuric acid. The Baker-Venkataraman rearrangement is frequently employed in the preparation of flavones and chromones. Besides, anthrapyran and anthracyclin antibiotics, benzopyrans, coumarins, xanthones, etc., are also synthesized with the help of these reactions. This review deals with the brilliant application of the Baker-Venkataraman rearrangement in the synthesis of promising organic compounds.

Site-selective synthesis of indanyl-substituted indole derivatives via 1,3-dithiane induced Nazarov cyclization.

We report an efficient site-selective synthetic method to C2 and C3 indanyl-substituted indole derivatives via 1,3-dithianyl induced Nazarov-type cyclization. In particular, C2-selective indanyl-substituted indoles were directly obtained by a BF3·Et2O-promoted sequence of intramolecular C3-C2 migration and Nazarov-type cyclization process.

Graphitic Carbon Nitride as a Metal‐Free Heterogeneous Semiconductor Photocatalyst for Fluoroalkylation Reactions

AbstractThe increasing use of fluorine‐containing bioactive molecules necessitates efficient strategies for fluorinated group installation. Despite the impressive development of photoinduced radical fluoroalkylation as a powerful tool for introducing fluorine, the persistent issues, including the recyclability and reaction specificity of homogeneous photocatalysts, still leave great room for further advancement in a sustainable and general fashion. Herein, we report a conceptually different approach toward multiple types of fluoroalkylations by using recoverable and versatile graphitic carbon nitride (g‐CN) nanosheets as a heterogeneous photocatalyst. This photocatalytic system enables diverse intermolecular fluoroalkylations of alkenes with fluoroalkanesulfinates and intramolecular fluoroalkyl migrations of alkenyl triflates. Detailed characterizations and mechanism studies substantiate the stability of this organic semiconductor and the crucial role of photogenerated electron‐hole pairs.

C3-Symmetric Luminescent Diketone with Amido-Linkage as a Polymorphic Fluorescence Emitter.

The study introduces a novel C3-symmetric β-diketone compound, BTA-D3, and its monomeric counterpart, D, with a focus on their synthetic procedure, photophysical properties and aggregation behavior. Both compounds exhibit characteristic absorption and weak fluorescence in solution, with BTA-D3 displaying higher absorption coefficients due to its larger number of diketone units. Density Functional Theory (DFT) calculations suggest increased co-planarity of diketone groups in BTA-D3. A significant finding is the Aggregation-Induced Emission (AIE) property of BTA-D3, as its fluorescence intensity increases dramatically when exposed to specific solvent ratios. The AIE behavior is attributed to intermolecular excitonic interaction between BTA-D3 molecules in self-organized aggregates. We also studied fluorescence anisotropy of BTA-D3 and D. Despite its larger size, BTA-D3 showed reduced anisotropy values because of efficient intramolecular energy migration among three diketone units. Furthermore, BTA-D3 demonstrates unique polymorphism, yielding different emission colors and structures depending on the solvent used. A unique approach is presented for promoting the growth of self-organized aggregate structures via solvent evaporation, leading to distinct fluorescence properties. This research contributes to the understanding of C3-symmetric structural molecules and provides insights into strategies for controlling molecular alignment to achieve diverse fluorescence coloration in molecular materials.

Experimental and Theoretical Studies on Stereomutation Through gem‐Difluorocyclopropanylide Intermediates

AbstractA desilylation process of optically active silyl‐substituted gem‐difluorocyclopropanes with tetrabutylammonium fluoride (TBAF) showed a substantial reduction of enantiopurity of the resultant gem‐difluorocyclopropanes even at ambient temperatures. The electron‐withdrawing aryl substituent at the 3‐position in the 1‐silyl‐2,2‐difluorocyclopropane system accelerated the racemization, indicating a correlation with the stability of the anionic intermediates. The plausible racemization pathway through homolytic cleavage of the distal bond in gem‐difluorocyclopropane is inconsistent with the experimental results because the high energy of >34 kcal/mol is required for generating the open‐shell 2,2‐difluoropropane‐1,3‐diyl skeleton. The DFT studies using the anionic 2,2‐difluoromethyl‐3‐phenylcyclopropanylide intermediate supported the alternative isomerization pathway through the intramolecular migration of hydrogen and the resultant thermodynamically stable 2,2‐difluoromethyl‐1‐phenylcyclopropanylide anion could facilitate the racemization process at the stereocenter. Although the transition state indicated considerable activation energies, the high frequency of imaginary vibration should correlate with a barrier of a very narrow width enabling quantum tunneling under the H‐migration step. The observed isotope effect is compatible with the proposed mechanism through the intramolecular H‐migration.

Selective S-arylation of thiols with o-OTf-substituted diaryliodonium salts toward diarylsulfides.

In contrast to the previously reported intramolecular aryl migration, we present the selective sulfenylation of ortho-trifluoromethanesulfonate (OTf) substituted diaryliodonium salts with thiols. As such, diarylsulfides bearing vicinal OTf groups were synthesized in good yields. The unique reactivity of the vicinal OTf group and the sulfur atom in arylsulfides offers further transformations.

Synthesis of phosphate stabilised iodanes and their application in intramolecular aryl migrations.

A diverse set of hydroxy-benzo[e]iodadioxaphosphinine oxides and derived diaryl iodonium salts are prepared and two examples are characterized by X-ray crystallography, featuring an out-of-plane geometry of the hypervalent bond for both compound classes. Treatment of the phosphate-stabilized diaryliodonium salts with Ca(OH)2 results in an efficient base-induced intramolecular aryl migration under aqueous conditions, yielding iodo-substituted diaryl ethers with yields up to 94%. Our findings highlight the synthetic potential of this previously underexplored compound class in organic transformations.

Theoretical kinetic studies on intramolecular H-migration reactions of peroxy radicals of diethoxymethane.

Diethoxymethane (DEM), a promising carbon-neutral fuel, has high reactivity at low temperatures. The intramolecular hydrogen migration reaction of the DEM peroxy radicals can be viewed as a critical step in the low temperature oxidation mechanism of DEM. In this work, multistructural transition state theory (MS-TST) was utilized to calculate the high-pressure limit rate constants of 1,5, 1,6 and 1,7 H-migration reactions for DEM peroxy radicals. In addition to the tunneling effects and anharmonic effects, the intramolecular effects, including steric hindrance, intramolecular hydrogen bonding and conformational changes in reactants and transition states, are also considered in the rate constant calculations. The calculated energy barriers and rate constants demonstrated the substantial impact of intramolecular effects on the kinetics of H-migration reactions in DEM peroxy radicals. Specifically, the distinct configurations of transition states could potentially influence the reaction kinetics. The pressure-dependent rate constants are computed using system-specific quantum RRK theory. The calculated results show that the falloff effect of 1,5 and 1,6 H-migration reactions is more pronounced than that of the 1,7 H-migration reaction. The thermodynamics and kinetics presented in this study could be instrumental in understanding the low-temperature oxidation mechanism of DEM and might prove crucial for future research on comprehensively analyzing the autoignition behavior.

Steglich Esterification of Activated Cinnamyl Cinnamate Derivatives and Computational Studies of Intramolecular Diels-Alder for Lignan Synthesis

A ryltetralin and arylnaphthalene lignans consisting of methylenedioxy or trimethoxy groups, such as podophyllotoxin and phyllanthusmin C, are known to have effective anticancer properties. The synthesis of these compounds can be achieved through intramolecular Diels-Alder reactions on cinnamyl cinnamate ester derivatives. Furthermore, this ester is commonly synthesized through an esterification reaction between cinnamoyl halide and cinnamyl alcohol. In this study, cinnamyl cinnamate only produced a 41% yield, while a nearly quantitative yield of 98% was obtained using the Steglich reaction with N,N’-dicyclohexylcarbodiimide and 4-dimethylaminopyridine. This reaction was used to synthesize eight cinnamyl cinnamate ester derivatives, which consisted of methylenedioxy and trimethoxy groups, following a combinatorial synthesis. 3,4-Methylenedioxy- and 3,4,5-trimethoxycinnamyl alcohols were obtained by reducing methyl 3,4-methylenedioxycinnamate and 3,4,5-trimethoxycinnamic acid, respectively. The results showed that the ester yields were excellent, except for the ester derivatives of 3,4,5-trimethoxycinnamyl alcohol. This alcohol was unstable during column chromatography, leading to the direct esterification of the crude reduction products. A side product with Rf adjacent to the ester was obtained, thereby reducing the ester yield. The identification of this by-product and the intramolecular Diels-Alder reaction on the products obtained were described in this study. Computational studies showed that transforming reactants into products led to the production of one intermediate compound and two transition states (TS). Each TS represented the intramolecular Diels-Alder cycloaddition reaction and migration of [1,3]-hydrogen. Thermodynamic studies consistently revealed that a solvent environment could effectively reduce the activation energy associated with a chemical process.

Copper(II)/DBU Relay Catalyzed Annulation of α-Carbonyl-γ-alkynyl Sulfoxonium Ylides for Accessing N-Sulfonamido 2H-Isoindoles.

A copper(II)/DBU relay catalyzed annulation of α-carbonyl-γ-alkynyl sulfoxonium ylides as a new class of sulfoxonium ylide reagents with sulfonyl hydrazides is reported, enabling intramolecular oxygen migration to produce a series of N-sulfonamido 2H-isoindoles with good yields. The present annulation proceeded readily by combining the Cu(II)-catalyzed 6-endo-dig oxo-cyclization with the DBU-catalyzed isochromene skeletal rearrangement, resulting in the formation of multiple new chemical bonds.

Mass spectrometry-based gas phase intramolecular benzyl migration in sparsentan, a novel endothelin and angiotensin II receptor antagonist.

We report a collision-induced dissociation (CID) based gas phase rearrangement study using quadrupole time-of-flight mass spectrometry coupled with liquid chromatography on a novel endothelin and angiotensin II receptor antagonist, sparsentan. We performed tandem mass spectrometry to identify precursor and fragment ion relationships and assigned structures for major fragment ions. We propose a benzyl migration mechanism based on bond length measurements in density functional theory (B3LYP/6-31+G*) optimized geometries of protonated sparsentan and its m/z 547 fragment. Protonated sparsentan undergoes loss of ethanol, which yields a resonance-stabilized benzylic cation with m/z 547, which further fragments into m/z 353 via benzyl migration, where the benzylic cation migrates to one of the nucleophilic nitrogen atoms followed by proton transfer from the sulfonamide nitrogen to a carbonyl oxygen, resulting in a neutral loss of mass 194. Further fragmentation of m/z 353 results in m/z 258, which undergoes radical and neutral loss to yield m/z 193 and 194, respectively. The proposed mechanism of generation of m/z 353 was confirmed by CID of deuterated sparsentan. Considering the importance of gas phase rearrangements of organic molecules in structural identifications as well as the novelty of the molecule, these findings will be helpful for future studies to predict gas phase benzyl migration in sparsentan analogs and for degradation product and metabolite identification of sparsentan and its analogs using LC-MS.

Circumambulatory migrations of arylazo groups in the systems of pentamethoxycarbonyland pentamethylcyclopentadiene

According to quantum chemical calculations CAM-B3LYP/6-311++G(d,p) intramolecular migrations of arylazo groups in 5-arylazo-1,2,3,4,5-pentamethoxycarbonylcyclopentadienes occur by a dissociative mechanism through the intermediate formation of tight ionic pairs with low energy barriers: Δ E ≠ZPE, benzonitrile, 14.0 (Ar = C6H4NO2-4) and 16.5 [Ar = C6H3(NO2)2-2,4] kcal/mol. In 5-arylazo-1,2,3,4,5-pentamethylcyclopentadienes, 1,5-sigmatropic shifts of arylazo groups occur along the perimeter of the five-membered ring in conformers with the exo position of the azo group relative to the cyclopentadiene ring with significantly higher activation barriers: Δ E ≠ZPE, benzonitrile, 30.3 (Ar = C6H4NO2-4) and 27.5 [Ar = C6H3(NO2)2-2,4] kcal/mol. The calculations are in good agreement with the data for these compounds obtained by us earlier by dynamic NMR.

H2 formation via non-Born-Oppenheimer hydrogen migration in photoionized ethane

Neutral H2 formation via intramolecular hydrogen migration in hydrocarbon molecules plays a vital role in many chemical and biological processes. Here, employing cold target recoil ion momentum spectroscopy (COLTRIMS) and pump-probe technique, we find that the non-adiabatic coupling between the ground and excited ionic states of ethane through conical intersection leads to a significantly high yield of neutral H2 fragment. Based on the analysis of fingerprints that are sensitive to orbital symmetry and electronic state energies in the photoelectron momentum distributions, we tag the initial electronic population of both the ground and excited ionic states and determine the branching ratios of H2 formation channel from those two states. Incorporating theoretical simulation, we established the timescale of the H2 formation to be ~1300 fs. We provide a comprehensive characterization of H2 formation in ionic states of ethane mediated by conical intersection and reveals the significance of non-adiabatic coupling dynamics in the intramolecular hydrogen migration.

Application of Silver Compounds in Fluoroorganic Synthesis: A Minireview

AbstractThe mini‐review is focused on application of silver and its compounds in fluoroorganic synthesis, and it reflects immense progress in this field which took place during the last two decades, with additional examples of reactivity of historical importance. Reactions of C−H, C−F, N−H and O−H bond functionalization, as well as catalysis of cycloaddition reactions and intramolecular rearrangement, retro‐rearrangement, and functional group migrations, have been described. Whenever available in original works, the reaction mechanisms were discussed. Since silver may be catalytically active in each of its available oxidation states from (0), via (I) and (II) to (III) with their immensely diverse properties, the organofluorine part is preceded by a brief overview of chemistry of silver in general. Uniqueness of silver among Group 11 elements is highlighted.

Rhodium(I)-Catalyzed Enantioselective Ring-Opening and Isomerization of Cyclobutanols through a (Z)-Unsaturated Ketone Intermediate.

A rhodium(I)-catalyzed highly enantioselective ring-opening and isomerization of cyclobutanols has been developed. The reaction provides a mild, atom-economical, and redox-neutral approach for the synthesis of chiral acyclic ketones bearing a β-tertiary stereocenter. Excellent enantioselectivities and high yields can be achieved using cyclobutanols with alkoxy substituents at the C3 position. Mechanistic studies reveal that cyclobutanol only undergoes intramolecular hydrogen migration, and the formation of a (Z)-unsaturated ketone intermediate is crucial for achieving high enantioselectivity.