Cyclobutane Derivatives Research Articles

Visible-Light Organic Photosensitizers Based on 2-(2-Aminophenyl)benzothiazoles for Photocycloaddition Reactions.

We have studied 2-(2-aminophenyl)benzothiazole and related derivatives for their photophysical properties in view of employing them as new and readily tunable organic photocatalysts. Their triplet energies were estimated by DFT calculations to be in the range of 52-57 kcal mol-1, suggesting their suitability for the [2+2] photocycloaddition of unsaturated acyl imidazoles with styrene derivatives. Experimental studies have shown that 2-(2-aminophenyl)benzothiazoles comprising alkylamino groups (NHMe, NHiPr) or the native amino group provide the best photocatalytic results in these visible-light mediated [2+2] reactions without the need of any additives, yielding a range of cyclobutane derivatives. A combined experimental and theoretical approach has provided insights into the underlying triplet-triplet energy transfer process.

Access to Alkenyl Cyclobutanols by Ni‐Catalyzed Regio‐ and Enantio‐Selective syn‐Hydrometalative 4‐exo‐trig Cyclization of Alkynones

AbstractEnantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel‐catalyzed asymmetric syn‐hydrometalative 4‐exo‐trig cyclization of 1,4‐alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl‐containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni−H species, with carbonyl‐directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.

Access to Alkenyl Cyclobutanols by Ni-Catalyzed Regio- and Enantio-Selective syn-Hydrometalative 4-exo-trig Cyclization of Alkynones.

Enantioselective synthesis of (spiro)cyclobutane derivatives poses significant challenges yet holds promising applications for both synthetic and medicinal chemistry. We report here a nickel-catalyzed asymmetric syn-hydrometalative 4-exo-trig cyclization of 1,4-alkynones to synthesize alkenyl cyclobutanols with a tetrasubstituted stereocenter. This strategy features a broad substrate scope, delivering a variety of trifluoromethyl-containing rigid (spiro)carbocycle skeletons in good yields with high enantioselectivities (up to 84 % yield and 98.5 : 1.5 er). The synthetic utility is demonstrated through stereospecific transformations into fused spiro molecules. Experimental and computational mechanistic studies indicate that the reaction is initiated by an active Ni-H species, with carbonyl-directed hydrometalation as the key for regioselective control. This catalytic method provides a general solution for regioselective hydrofunctionalization of alkynes and represents an efficient reaction pattern for assembling highly strained enantioenriched bioisosteres.

Ligand-controlled regiodivergent aminocarbonylation of cyclobutanols toward 1,1- and 1,2-substituted cyclobutanecarboxamides

Four-membered carbocycles are among the most sought-after backbones which are commonly found in biologically active molecules. However, difficulties on their producing are existing due to its highly strained ring system. On the other hand, cyclobutanols can be straightforwardly prepared and can serves as precursors for synthesizing cyclobutane derivatives. Here we report an example of regioselective aminocarbonylation of cyclobutanols in which the cyclobutane core remained intact. The method exhibits good functional group compatibility, as well as high regio- and stereoselectivity, offering new pathways for synthesizing several pharmaceuticals. Furthermore, this strategy enables the rapid installation of cyclobutane as a conformational restricted skeleton, greatly facilitating direct access to valuable drug molecules that require conformational restriction.

High‐Pressure‐Mediated Fragment Library Synthesis of 1,2‐Disubsituted Cyclobutane Derivatives

AbstractCyclobutanes have attracted significant interest in medicinal chemistry because of their unique structure and potential advantages in pharmacological properties. Nevertheless, 1,2‐disubstituted cyclobutanes remain underrepresented, both in the general chemical space and in fragment‐based drug discovery libraries. In this study, a two‐diversification‐point library of cyclobutanesulfonamides was synthesized through a hyperbaric [2+2] cycloaddition reaction between ethenesulfonyl fluoride and tert‐butyl vinyl ether as the key step. The sulfonyl fluoride was subsequently transformed into various sulfonamides, whereas the tert‐butyl ether was converted into carbamates and triazoles to synthesize a fragment library. Overall, this synthesis contributes to addressing the underrepresentation of 1,2‐disubstituted cyclobutane fragments, making a valuable addition to the field of fragment‐based drug discovery.

Catalytic Asymmetric Conjugate Addition and Allylic Substitution of Cyclobutenones with Arylzinc Halides

Comprehensive SummaryConjugate addition and allylic substitution are two essential chemical transformations, and they could be competitive for substrates with multiple reactive sites. Herein, we report the diversified enantioselective synthesis of cyclobutenes via the functionalization of cyclobutenones. The conjugate addition of cyclobutenones with arylzinc halides provided enantioenriched cyclobutenes with all‐carbon quaternary centers. On the other hand, when cyclobutenones with gem‐dichloro groups were employed, a chemo‐ and enantioselective allylic substitution occurred. Further synthetic utility was demonstrated for synthesizing versatile cyclobutane derivatives, together with ring‐opening and expansion products.

Enantioselective Synthesis of Cyclobutylboronates

AbstractCyclobutane derivatives are important motifs in natural products and bioactive compounds. Owing to their inherent strain, the asymmetric synthesis of cyclobutanes remains a formidable challenge. With the development of various stereospecific transformations of alkylboronic esters, chiral cyclobutylboronates are expected to serve as promising synthetic intermediates for accessing chiral cyclobutane derivatives. However, obtaining highly enantioenriched cyclobutylboronates poses a daunting task in the field of organic synthesis. In this context, we highlight recent significant advances in the synthesis of chiral cyclobutylboronates.1 Introduction2 Enantioselective Borylation of Cyclobutenes3 Enantioselective Borylation of Cyclobutanes4 Other Methods5 Conclusions

Two new cyclobutane derivatives of thiazolidin-4-ones: Synthesis, spectroscopic characterization, DFT quantum chemical calculations and determination of protonation constants

In the first stage of this study, 2-((4-(4-(3-methyl-3-phenylcyclobutyl)thiazol-2-yl)imino)thiazolidin-4-one (compound 1) and 2-((4-(3-(2,5-dimethylphenyl)-3-methylcyclobutyl)thiazol-2-yl)imino)thiazolidin-4-one (compound 2) were synthesized, characterized using FT-IR and NMR methods, and a combination of experimental and theoretical studies of the title compounds was performed. With the aid of the 6-311+G(d,p) basis set, all theoretical computations were performed using the density functional theory (DFT) B3LYP approach. The GIAO approximation was used to compute the chemical shifts of 1H and 13C-NMR. Theoretical calculations provide detailed information on chemical activity and molecular properties by determining electrophilic and nucleophilic properties. Accordingly, global chemical activity descriptors (FMOs, hardness, and softness parameters) were investigated, natural bond orbital (NBO) analyses were performed, thermodynamic properties at different temperatures were calculated, and the related relationships with temperature were obtained. The experimental and calculated NMR data presented consistent results for both compounds. R2 values for the 1H-NMR and 13C-NMR of compound 1 are 0.9914 and 0.9988, respectively. For the second compound, 2, these values are 0.9957 and 0.9962, respectively.In the second stage, the acid-base equilibria of title compounds containing cyclobutane, thiazole, and thiazolidinone functional groups were investigated potentiometrically in 60% dioxane-water media at room temperature and constant ionic strength. The values of the protonation constants determined in this study, logKNH(1) and logKNH(2), are related to the protonation of the azomethine nitrogen atom and the nitrogen atom on the thiazole ring, respectively. The sum of these values is the total protonation value of title compounds. The total protonation constants for compounds 1 and 2 are 10.59 and 10.58, respectively.

Synthesis of 1,1,3-Polyfunctionalized Cyclobutane Derivatives from the Reaction of Sulfur Ylides with Bicyclo[1.1.0]butanes.

1,1,3-Polyfunctionalized cyclobutane derivatives have been synthesized from sulfur ylides and bicyclo[1.1.0]butanes (BCBs). This protocol operates under mild reaction conditions without the need for catalysts, generally producing moderate to good yields of syn-addition derivatives with structural diversity. An unexpected intramolecular rearrangement mechanism has also been proposed.

Flash vacuum pyrolysis of steroid propargyl ethers

Owing to its unique rearrangement and cyclization processes via flash vacuum pyrolysis (FVP), the acetylenic moiety has attracted considerable attention by organic chemists as a key building block in the construction of innovative organic architects. Herein, a series of seven steroid propargyl ether precursors have been successfully synthesized and pyrolyzed. Analysis and characterization of the FVP products revealed that the propargyl ethers of phenolic steroids undergo Claisen-rearrangement to give 2-indanone and benzo cyclobutene derivatives, while propargyl ethers of non-aromatic steroids resulted in the corresponding α, β-unsaturated ketones.

Diversified Synthesis of Chiral Fluorinated Cyclobutane Derivatives Enabled by Regio- and Enantioselective Hydroboration.

The diversified synthesis of chiral fluorinated cyclobutane derivatives has remained a difficult task in synthetic chemistry. Herein, we present an approach for asymmetric hydroboration and formal hydrodefluorination of gem-difluorinated cyclobutenes through rhodium catalysis, providing chiral gem-difluorinated α-boryl cyclobutanes and monofluorinated cyclobutenes with excellent regio- and enantioselectivity, respectively. The key to the success of the two transformations relies on an efficient, mild and highly selective rhodium-catalyzed asymmetric hydroboration with HBPin (pinacolborane), in which the subsequent addition of a base, and a catalytic amount of palladium in some cases, results in the formation of formal hydrodefluorination products with the four-membered ring retained. The obtained chiral gem-difluorinated α-boryl cyclobutanes are versatile building blocks that provide a platform for the synthesis of enantioenriched fluorinated cyclobutane derivatives to a great diversity.

Diversified Synthesis of Chiral Fluorinated Cyclobutane Derivatives Enabled by Regio‐ and Enantioselective Hydroboration

AbstractThe diversified synthesis of chiral fluorinated cyclobutane derivatives has remained a difficult task in synthetic chemistry. Herein, we present an approach for asymmetric hydroboration and formal hydrodefluorination of gem‐difluorinated cyclobutenes through rhodium catalysis, providing chiral gem‐difluorinated α‐boryl cyclobutanes and monofluorinated cyclobutenes with excellent regio‐ and enantioselectivity, respectively. The key to the success of the two transformations relies on an efficient, mild and highly selective rhodium‐catalyzed asymmetric hydroboration with HBPin (pinacolborane), in which the subsequent addition of a base, and a catalytic amount of palladium in some cases, results in the formation of formal hydrodefluorination products with the four‐membered ring retained. The obtained chiral gem‐difluorinated α‐boryl cyclobutanes are versatile building blocks that provide a platform for the synthesis of enantioenriched fluorinated cyclobutane derivatives to a great diversity.

Palladium-Catalyzed Divergent Enantioselective Functionalization of Cyclobutenes.

Aliphatic strained rings have been increasingly applied in medicinal chemistry due to their beneficial physicochemical and pharmacokinetic properties. However, the divergent synthesis of enantioenriched cyclobutane derivatives with various structural patterns continues to be a significant challenge. Here, we disclose a palladium-catalyzed enantioselective desymmetrization of cyclobutenes, resulting in a series of hydroarylation and 1,2- and 1,3-diarylation products via the interceptions of a common Heck intermediate. Mechanistic investigations provide valuable insights into understanding the catalytic mode of the palladium catalysts and the observed variations in the deuterium-responsive behavior during reactions. Furthermore, the synthetic utility is demonstrated in the syntheses of deuterated drug candidate belaperidone skeletons and pseudosymmetrical truxinic acid-type derivatives.

Ligand Field Sensitive Spin Acceleration in the Iron-Catalyzed [2 + 2] Cycloaddition of Unactivated Alkenes and Dienes.

Redox-active pyridine(diimine) (PDI) iron catalysts promote the reversible [2 + 2] cycloaddition of alkenes and dienes to cyclobutane derivatives that have applications ranging from fuels to chemically recyclable polymers. Metallacycles were identified as key intermediates, and spin crossover from the singlet to the triplet surface was calculated to facilitate the reductive coupling step responsible for the formation of the four-membered ring. In this work, a series of sterically and electronically differentiated PDI ligands was studied for the [2 + 2] cycloaddition of ethylene and butadiene to vinylcyclobutane. Kinetic studies revealed that the fastest and slowest turnover were observed with equally electron-deficient supporting ligands that either feature phenyl-substituted imine carbon atoms (MeBPDI) or a pyrazine core (MePZDI). While the oxidative cyclization was comparatively slow for both catalysts, the rate of reductive coupling─determined by stoichiometric 13C2H4 labeling studies─correlated with the turnover frequencies. Two-state density functional theory studies and the distinct electronic structures of related (iPrBPDI) and (iPrPZDI) iron methyl complexes revealed significantly different ligand field strengths due to either diminished ligand σ-donation (MeBPDI) or promoted metal π-backbonding (MePZDI). Spin acceleration, leading to fast reductive coupling and catalytic turnover, was promoted in the case of the weaker ligand field and depends on both the nature and position of the electron-withdrawing group. This study provides strong evidence for the role of two-state reactivity in C(sp3)-C(sp3) bond formation and insights on how ligand design either promotes or inhibits spin acceleration in earth-abundant metal catalysis.

Entry into Lithium Ynolates from α,α,α-Tribromomethyl Ketones: Synthesis of Cyclobutenes via the [2 + 2] Cycloaddition with α,β-Unsaturated Carbonyls.

This study reports the synthesis of cyclobutene derivatives in good yields via the [2 + 2] cycloaddition between lithium ynolates and α,β-unsaturated carbonyls. The ynolates are generated from α,α,α-tribromomethyl ketones and tert-butyl lithium via a simple and novel method, which does not produce any harmful byproducts, such as lithium alkoxide, which induces a polymerization reaction with α,β-unsaturated carbonyls.

Back Cover

Oxyallyl cations, as powerful electrophilic intermediates, have shown versatile utilities in organic synthesis. Modular synthesis of multi‐substituted cyclobutanones enabled by oxyallyl cations provides facile access to multi‐substituted cyclobutanones via direct nucleophilic substitution of (di)chlorocyclobutanones under mild basic conditions. Both aryl or alkyl substituents could be efficiently introduced on the four‐membered ring skeleton. Further transformation leads to tetrasubstituted cyclobutane derivatives in a stereoselective manner, demonstrating potential synthetic utility. More details are discussed in the article by Lu et al. on page 459—463.image

Design of Cyclobut-3-Ene-1,2 Dione Derivatives as Anti-tubercular Agents

Introduction: Recent studies have shown modified cyclobutene derivatives as potent anti- tubercular agents, and the discovery of drugs against strains of Mycobacterium tuberculosis is still a crucial challenge in the modern world. Objective: The objective of the present study is to design and perform molecular docking studies and in-silico analysis of some novel cyclobut-3-ene-1,2 Dione derivatives with the aim of creating new, potential Mtb ATP synthase inhibitors. Materials and Methods: The structures of 24 compounds of diamino-substituted cyclobut-3-ene-1,2 Dione derivatives against Mtb ATP synthase were drawn using ChemSketch. Further, molecular docking and in-silico studies for the prediction of drug-likeness and pharmacokinetic parameters were carried out. Results: The docking studies of the novel compounds were done, and they had a better docking score with a good binding affinity towards the protein molecule. The synthesized compounds also comply with the in-silico prediction of drug-likeness and pharmacokinetic parameters and have shown good activity against Mtb ATP synthase. Conclusion: The current study shows that the cyclobut-3-ene-1,2 Dione derivatives can serve as a better lead molecule against Mtb ATP synthase and can be involved in further drug discovery

Synthesis of the MN Ring of Caribbean Ciguatoxin C-CTX-1 via Desymmetrization by Acetal Formation.

The MN ring of Caribbean ciguatoxin C-CTX-1 was synthesized from a meso-syn-2,7-dimethyloxepane derivative corresponding to the M ring via desymmetrization by acetal formation with a camphor derivative, followed by construction of the N ring via the Horner-Wadsworth-Emmons reaction and acetal formation. The meso-syn-2,7-dimethyloxepane derivative was synthesized via photoinduced electrocyclization of a conjugated exo-diene under flow conditions, giving a cyclobutene derivative, followed by ring expansion via oxidative cleavage and diastereoselective reduction of a β-hydroxy ketone.

Recent Advances in Asymmetric Synthesis of Chiral Cyclobutenes

AbstractCyclobutene scaffolds occur in natural products and bioactive compounds. Their unique structural features and intrinsic ring strain make cyclobutene a type of important building block in synthetic chemistry. In recent years, considerable efforts have been dedicated to the synthesis of chiral cyclobutenes. Enantioselective [2+2] cycloadditions and functionalization of cyclobutene derivatives have emerged as powerful and reliable protocols for achieving this goal, resulting in significant progress in this field. This review provides a comprehensive summary of the recent advancements in the asymmetric synthesis of chiral cyclobutenes, and the discussion is logically divided into four parts according to the reaction mode.

Solid-State [2+2] Photoreaction of Isostructural Cd(II) Metal Complexes and Solid-State Fluorescence.

A green method to synthesize cyclobutane derivatives has been developed over the past three decades in the form of solid-state [2+2] photochemical reactions. These solid-state reactions also play a major role in the structural transformation of hybrid materials. In this regard, crystal engineering has played a major role in designing photoreactive molecular systems. Here, we report three novel binuclear Cd(II) complexes with the molecular formula [Cd2(4spy)4L4], where 4spy = 4-styryl pyridine and L = p-toluate (1); 4-fluorobenzoate (2); and 3-fluorobenzoate (3). Although three different benzoates are used, all three complexes are isostructural, as corroborated through SCXRD experiments. Structural analysis also helped in identifying two potential photoreactions. These are both intra- and intermolecular in nature and are driven by the head-to-head (HH) and head-to-tail (HT) alignment of 4spy linkers within these metal complexes. 1H NMR spectroscopy studies showed evidence of a quantitative head-to-head photoreaction in all these three complexes, and SCXRD analysis of the recrystallization of the photoproducts also provided confirmation. TGA studies of these photoreactive complexes showed an increase in the thermal stability of the complexes due to the solid-state photoreaction. Photoluminescence studies of these complexes have been conducted, showing a blue shift in emission spectra across all three cases after the photoreaction.