Cyclobutane Products Research Articles

Ligand‐Controlled Regioselective Hydroacylation Reactions of Methylenecyclobutanes under Rhodium Catalysis

AbstractIn this study, we report a Rh(I)/dppf catalytic system that can tune the regioselectivity of methylenecyclobutanes. Under the optimal reaction conditions, a series of 1,3‐disubstituted cyclobutanes were prepared in high yields (up to 95%) with excellent regioselectivity (>20:1 r.r.). Scale‐up synthesis of the cyclobutane product at a low catalyst loading (2 mol%) demonstrates the robustness of this dppf‐controlled hydroacylation.

Construction of olefinic coordination polymer single crystal platforms: precise organic synthesis, in situ exploration of reaction mechanisms and beyond.

Olefin [2+2] photocycloaddition reactions based on coordination-bond templates provide numerous advantages for the selective synthesis of cyclobutane compounds. This review outlines the recent advances in the design and construction of single crystal platforms of olefinic coordination polymers for precise organic synthesis, in situ exploration of reaction mechanisms, and possible developments as comprehensively as possible. Numerous examples are presented to illustrate how the arrangements of the olefin pairs influence the solid-state photoreactivity and examine the types of cyclobutane products. Furthermore, the photocycloaddition reaction mechanisms are investigated by combining advanced techniques such as single crystal X-ray diffraction, powder X-ray diffraction, nuclear magnetic resonance, infrared spectroscopy, fluorescence spectroscopy, laser scanning confocal microscopy and theoretical calculations. Finally, potential applications resulting from promising physicochemical properties before and after photoreactions are discussed, and existing challenges and possible solutions are also proposed.

Divergent Synthesis of 1,2,3,4‐Tetrasubstituted Cyclobutenes from a Common Scaffold: Enantioselective Desymmetrization by Dual‐Catalyzed Photoredox Cross‐Coupling

AbstractFour‐membered carbocycles are important structural motifs found in several natural products and drugs. Amongst those, cyclobutenes are attractive intermediates because the residual olefin can be manipulated selectively into various saturated and unsaturated analogs. Few methods exist to access chiral tri‐ and tetra‐C‐substituted cyclobutenes and they are generally limited in terms of diversification. Herein, a divergent synthetic strategy was developed where a single optically enriched scaffold is diversified into a variety of derivatives with different substitution patterns. To this end, the enantioselective desymmetrization of prochiral 1,2‐dibromocyclobutene imides was enabled by a dual Ir/Ni‐catalyzed photoredox C(sp2)−C(sp3) cross‐coupling with an alkyltrifluoroborate salt to install a convertible carbon fragment in good yields and >90 % enantiomeric excess. Exceptional mono‐coupling selectivity is observed and the resulting chiral bromocyclobutene serves as a common scaffold that can be transformed in a divergent manner into several valuable 1,2,3,4‐tetra‐C‐substituted cyclobutane products while maintaining optical purity.

Divergent Synthesis of 1,2,3,4-Tetrasubstituted Cyclobutenes from a Common Scaffold: Enantioselective Desymmetrization by Dual-Catalyzed Photoredox Cross-Coupling.

Four-membered carbocycles are important structural motifs found in several natural products and drugs. Amongst those, cyclobutenes are attractive intermediates because the residual olefin can be manipulated selectively into various saturated and unsaturated analogs. Few methods exist to access chiral tri- and tetra-C-substituted cyclobutenes and they are generally limited in terms of diversification. Herein, a divergent synthetic strategy was developed where a single optically enriched scaffold is diversified into a variety of derivatives with different substitution patterns. To this end, the enantioselective desymmetrization of prochiral 1,2-dibromocyclobutene imides was enabled by a dual Ir/Ni-catalyzed photoredox C(sp2 )-C(sp3 ) cross-coupling with an alkyltrifluoroborate salt to install a convertible carbon fragment in good yields and >90 % enantiomeric excess. Exceptional mono-coupling selectivity is observed and the resulting chiral bromocyclobutene serves as a common scaffold that can be transformed in a divergent manner into several valuable 1,2,3,4-tetra-C-substituted cyclobutane products while maintaining optical purity.

Access to Symmetrical and Unsymmetrical Cyclobutanes via Template-Directed [2+2]-Photodimerization Reactions of Cinnamic Acids

AbstractIn this work, we have developed a general and broadly applicable template-directed photochemical [2+2]-cycloaddition reaction which provides access to a wide range of symmetrical and unsymmetrical cyclobutane products. The use of 1,8-dihydroxynaphthalene as a covalent template paved the way for successful and highly selective photochemical homodimerization and heterodimerization reactions in the solid state between cinnamic acid derivatives. Notably, the method works equally well with aryl- and heteroaryl-containing substrates leading to the formation of β-truxinic acid analogues as single diastereomers and in high yields (up to 99%).

Iridium-Catalyzed Asymmetric Difunctionalization of C-C σ-Bonds Enabled by Ring-Strained Boronate Complexes.

Enantioenriched organoboron intermediates are important building blocks in organic synthesis and drug discovery. Recently, transition metal-catalyzed enantioselective 1,2-metalate rearrangements of alkenylboronates have emerged as an attractive protocol to access these valuable reagents by installing two different carbon fragments across C═C π-bonds. Herein, we report the development of an iridium-catalyzed asymmetric allylation-induced 1,2-metalate rearrangement of bicyclo[1.1.0]butyl (BCB) boronate complexes enabled by strain release, which allows asymmetric difunctionalization of C-C σ-bonds, including dicarbonation and carboboration. This protocol provides a variety of enantioenriched three-dimensional 1,1,3-trisubstituted cyclobutane products bearing a boronic ester that can be readily derivatized. Notably, the reaction gives trans diastereoisomers that result from an anti-addition across the C-C σ-bond, which is in contrast to the syn-additions observed for reactions promoted by PdII-aryl complexes and other electrophiles in our previous works. The diastereoselectivity has been rationalized based on a combination of experimental data and density functional theory calculations, which suggest that the BCB boronate complexes are highly nucleophilic and react via early transition states with low activation barriers.

C(sp2)-H cyclobutylation of hydroxyarenes enabled by silver-π-acid catalysis: diastereocontrolled synthesis of 1,3-difunctionalized cyclobutanes.

Ring-opening of bicyclo[1.1.0]butanes (BCBs) is emerging as a powerful strategy for 1,3-difunctionalized cyclobutane synthesis. However, reported radical strain-release reactions are typically plagued with diastereoselectivity issues. Herein, an atom-economic protocol for the highly chemo- and diastereoselective polar strain-release ring-opening of BCBs with hydroxyarenes catalyzed by a π-acid catalyst AgBF4 has been developed. The use of readily available starting materials, low catalyst loading, high selectivity (up to >98 : 2 d.r.), a broad substrate scope, ease of scale-up, and versatile functionalizations of the cyclobutane products make this approach very attractive for the synthesis of 1,1,3-trisubstituted cyclobutanes. Moreover, control experiments and theoretical calculations were performed to illustrate the reaction mechanism and selectivity.

Organophotocatalytic [2+2] Cycloaddition of Electron-Deficient Styrenes.

A visible-light organophotocatalytic [2+2] cycloaddition of electron-deficient styrenes is described. Photocatalytic [2+2] cycloadditions are typically performed with electron-rich styrene derivatives or α,β-unsaturated carbonyl compounds, and with transition-metal-based catalysts. We have discovered that an organic cyanoarene photocatalyst is able to deliver high-value cyclobutane products bearing electron-deficient aryl substituents in good yields. A range of electron-deficient substituents are tolerated, and both homodimerisations and intramolecular [2+2] cycloadditions to fused bicyclic systems are available by using this methodology.

Pore-Directed Solid-State Selective Photoinduced E – Z Isomerization and Dimerization within Metal–Organic Frameworks

Pore-Directed Solid-State Selective Photoinduced <i>E</i> – <i>Z</i> Isomerization and Dimerization within Metal–Organic Frameworks

Supramolecular Template-Assisted Catalytic [2+2] Photocycloaddition in Homogeneous Solution

Supramolecular Template-Assisted Catalytic [2+2] Photocycloaddition in Homogeneous Solution

Rhodium‐Catalyzed Tandem Addition–Cyclization of 1,5‐Enynes with Organoboronic Acids for the Synthesis of Alkylidene‐Cyclobutanes

AbstractDescribed here is the rhodium(I)‐catalyzed tandem addition–cyclization of 1,5‐enynes with aryl‐ and alkenylboronic acids. In the presence of triethylamine and catalytic [Rh(OH)(COD)]2 in methanol, both the terminal and internal alkyne substrates possessing an electron‐deficient alkene undergo inter‐ and intramolecular C−C bond formations to yield alkylidene–cyclobutane products. The reaction proceeds through a series of processes involving generation of an aryl or alkenyl rhodium from the organoboronic acid, 1,2‐syn‐carbometalation of the alkyne and 4‐exo‐type‐cyclization of the resulting alkenyl rhodium intermediate with the tethered, carbonyl‐conjugated alkene. Thus, the reaction enables a net R,H‐addition across the 1,5‐enyne π‐system – hydroarylation and hydroalkenylation – under mild rhodium catalysis while achieving 4‐membered ring formation. Preliminary studies show that the reaction can also be rendered enantioselective by employing a chiral diene ligand for the rhodium catalyst.

Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds

Nickel-Catalyzed Regiodivergent Asymmetric Cycloadditions of α,β-Unsaturated Carbonyl Compounds

Chiral Br\xf8nsted acid-controlled intermolecular asymmetric [2\u2009+\u20092] photocycloadditions

Control over the stereochemistry of excited-state photoreactions remains a significant challenge in organic synthesis. Recently, it has become recognized that the photophysical properties of simple organic substrates can be altered upon coordination to Lewis acid catalysts, and that these changes can be exploited in the design of highly enantioselective catalytic photoreactions. Chromophore activation strategies, wherein simple organic substrates are activated towards photoexcitation upon binding to a Lewis acid catalyst, rank among the most successful asymmetric photoreactions. Herein, we show that chiral Brønsted acids can also catalyze asymmetric excited-state photoreactions by chromophore activation. This principle is demonstrated in the context of a highly enantio- and diastereoselective [2+2] photocycloaddition catalyzed by a chiral phosphoramide organocatalyst. Notably, the cyclobutane products arising from this method feature a trans-cis stereochemistry that is complementary to other enantioselective catalytic [2+2] photocycloadditions reported to date.

Chemo- and stereoselective intermolecular [2 + 2] photocycloaddition of conjugated dienes using colloidal nanocrystal photocatalysts

The use of visible-light photosensitizers to power [2+2] photocycloadditions that produce complex tetrasubstituted cyclobutanes is a true success of photochemistry, but the scope of this reaction has been limited to activated α, β-unsaturated carbonyls. This paper describes selective intermolecular homo- and hetero-[2+2] photocycloadditions of terminal and internal aryl conjugated dienes - substrates historically unsuited for this reaction because of their multiple possible reaction pathways and product configurations - through triplet-triplet energy transfer from CdSe nanocrystal photocatalysts, to generate valuable and elusive syn-trans aryl vinylcyclobutanes. The negligible singlet-triplet splitting of nanocrystals' excited states allows them to drive the [2+2] pathway over the competing [4+2] photoredox pathway, a chemoselectivity not achievable with any known molecular photosensitizer. Reversible tethering of the cyclobutane product to the nanocrystal surface results in near quantitative yield of the syn-trans product. Flat colloidal CdSe nanoplatelets produce cyclobutanes coupled at the terminal alkenes of component dienes with up to 89% regioselectivity.

Understanding the Difference between Electrochemical and Photochemical Single Electron Transfer: Investigation of Radical Cation [2 + 2] Cycloadditions

Chemical synthesis by electrocatalysis and photocatalysis has been developed as a new energy conversion system and it can realize sustainable production processes for various products. Electron transfer is driven by electrical energy and solar energy under ambient temperature and pressure. In the case of electrocatalysis, voltage and current are tunable, and it can realize easy control of reaction conditions. In photocatalysis with semiconductor nanoparticles, one particle can work as both oxidant and reductant, and it would be beneficial toward redox neutral reactions. To understand mechanistic details of both electrocatalysis and photocatalysis is important to develop new processes with high efficiency. We reported oxidative single electron transfer (SET) triggered radical cation cycloaddition reactions in lithium perchlorate (LiClO4)/nitromethane (CH3NO2) by electrolysis and TiO2 semiconductor photocatalysis. These reactions start by substrate activation to form radical cation species, which is derived from anodic oxidation (in electrolysis) or hole oxidation (in photocatalysis). In this research, the [2+2] cycloaddition reactions in LiClO4/CH3NO2 solution were used as model reactions to study mechanistic details of three different SET catalysis, including electrocatalysis TiO2 photocatalysis with and without Pt loading. TiO2 and Pt loaded TiO2 (Pt-TiO2) were selected as photocatalyst in this work. Commercially available TiO2 nanoparticles (P25, 20–40 nm) were used. Pt-TiO2 was synthesized from the TiO2 (P25) and H2PtCl6 as a Pt precursor. H2PtCl6 was reduced by NaBH4 in the presence of TiO2 in H2O to give Pt-TiO2. From TEM observations and EDS measurement, Pt nanoparticles were located on the surface of TiO2 with 3.8 wt% of loading ratio and the size was 2.9 nm. Two types of model [2+2] cycloaddition reactions were used in this research. One is reaction between enol ether and olefin, the other is reaction between enyloxy benzene and olefin. All reactions were carried out in 1 mol/L LiClO4/CH3NO2 solution. For electrocatalysis, constant potential (1.2 V, 1.0 F/mol) was used with carbon felt electrodes as both anode and cathode. For photocatalysis, TiO2 or Pt-TiO2 nanoparticles were dispersed in the solution with 10 mg/mL and the solution was irradiated by 15 W UV lamp. From cyclic voltammetry (CV) of substrate, it was indicated these reactions were driven by SET of enol ether or enyloxy benzene. In the case of enol ether model reaction under air, yield of cyclobutane product was similar to electrocatalysis (78%) and TiO2 photocatalysis (79%), however, Pt-TiO2 photocatalysis showed relatively low yield (46%). Previously, it was proposed that Pt can function as an electron trap to alter the mechanism of reductive SET. It could be explained that the reductive SET from Pt was not involved in the reaction, decreasing the yield of the product. In the case of enyloxy benzene model reaction under air, electrocatalysis realized high yield of cyclobutane product (81%), however, TiO2 and Pt-TiO2 photocatalysis showed low yields (53% and 17%, receptively). We found that O2 bubbling to solution improved the yield of the product when TiO2 photocatalysis (80%) was used, in contrast, it was not the case for the reaction using Pt-TiO2 photocatalysis (trace). It was indicated that O2 can work as a mediator or an oxidant and this role is important for the [2+2] cycloaddition between enyloxy benzene and olefin when TiO2 photocatalysis was used, however, it was not observed under Pt-TiO2 condition. One possibility is that, O2 functions as a reductive redox mediator. Specifically, O2 was reduced by excited electron in TiO2 conduction band via single electron reduction and superoxide species were generated. Since these species have high reducing ability, they can reduce cyclobutane intermediate radical cation to form cyclobutane product. In the case of Pt-TiO2, excited electron could be trapped by Pt, which altered the reductive SET from one-electron mechanism to two- or four-electron pathways that produced H2O2 or H2O from O2. Since these species cannot reduce the radical cation, cyclobutane product was not formed. In addition, H2O2 can change to OH radical species that have high oxidative potential and they potentially decomposed substrate and/or product. In conclusion, we demonstrated the mechanistic differences among electrocatalysis and TiO2 in the presence or absence of Pt by using SET triggered [2+2] cycloaddition reactions as models. Pt-TiO2 might decrease the reduction ability of TiO2. O2 bubbling can increase yield of product in enyloxy benzene reaction because superoxide species might be generated by excited electron in TiO2 and they function as a redox mediator to reduce radical cation intermediate. This O2 mediated system cannot be realized when Pt-TiO2 was used, probably because Pt can reduce O2 into H2O2 or H2O. Figure 1

Thermodynamics and Mechanism of a Photocatalyzed Stereoselective [2 + 2] Cycloaddition on a CdSe Quantum Dot.

Colloidal quantum dots (QDs) have shown promise over the last few decades for a range of applications including single photon emission, in vivo imaging, and photocatalysis. Recent experiments demonstrated that QDs impart stereoselectivity to triplet excited-state [2 + 2] cycloaddition reactions of alkenes photocatalyzed by the QD through self-assembly of the reagent molecules on the QD surface, but these experiments did not reveal the precise geometries of surface-bound molecules or their interactions with surface atoms. Here, a theoretical mechanistic approach is used to study such interactions for [2 + 2] cycloadditions of 4-vinylbenzoic acid derivatives on CdSe QDs. Spin-polarized periodic density functional theory (DFT) and nonperiodic DFT calculations are deployed to determine the origin of the selectivity for the syn diastereomer of the resultant tetrasubstituted cyclobutane product via atomistic modeling of the CdSe surface and substrates, determination of the thermodynamic energies of reactions for each step, the intermolecular interactions between the substrates, and the triplet state reaction paths. The calculations indicate that reaction selectivity arises from preferred binding of pairs through intermolecular interactions of substrate molecules on the QD surface in a syn-precursor structure followed by dimerization after triplet excitation. These mechanisms are generalizable to other metal-enriched QD surfaces that have a similar surface structure as that of CdSe, such as InSe or CdTe. Design principles for anti diastereomer derivatives are also discussed.

Investigations into the Mechanism of Inter- and Intramolecular Iron-Catalyzed [2 + 2] Cycloaddition of Alkenes.

Mechanistic studies are reported on the inter- and intramolecular [2 + 2] alkene cycloadditions to form cyclobutanes promoted by (tricPDI)Fe(N2) (tricPDI = 2,6-(2,4,6-tricyclopentyl)C6H2N = CMe)2C5H3N). A combination of kinetic measurements, freeze-quench 57Fe Mössbauer and infrared spectroscopic measurements, deuterium labeling studies, natural abundance 13C KIE studies, and isolation and characterization of catalytically relevant intermediates were used to gain insight into the mechanism of both inter- and intramolecular [2 + 2] cycloaddition reactions. For the stereo- and regioselective [2 + 2] cycloaddition of 1-octene to form trans-1,2-dihexylcyclobutane, a first-order dependence on both iron complex and alkene was measured as well as an inverse dependence on N2 pressure. Both 57Fe Mössbauer and infrared spectroscopic measurements identified (tricPDI)Fe(N2)(η2-1-octene) as the catalyst resting state. Rate-determining association of 1-octene to (tricPDI)Fe(η2-1-octene) accounts for the first order dependence of alkene and the inverse dependence on N2. Heavy atom 13C/12C kinetic isotope effects near unity also support post rate-determining C-C bond formation. By contrast, the intramolecular iron-catalyzed [2 + 2] cycloaddition of 1,7-octadiene yielded cis-bicyclo[4.2.0]octane in 92:8 d.r. and a first order dependence on the iron precursor and zeroth order behavior in both diene and N2 pressure were measured. A pyridine(diimine) iron trans-bimetallacycle was identified as the catalyst resting state and was isolated and characterized by X-ray diffraction and 1H NMR and 57Fe Mössbauer spectroscopies. Dissolution of the iron trans-bimetallacycle in benzene-d6 produced predominantly the cis-cyclobutane product, establishing interconversion between the trans and cis metallacycles during the catalytic reaction and consistent with a Curtin-Hammett kinetic regime. A primary 13C/12C kinetic isotope effect of 1.022(4) was measured at 23 °C, consistent with irreversible unimolecular reductive elimination to form the cyclobutane product. Despite complications from competing cyclometalation of chelate aryl substituents, deuterium labeling experiments were consistent with unimolecular C-C reductive elimination that occurred either by a concerted pathway or a radical rebound sequence that is faster than C-C bond rotation.

2+2] Photocycloaddition of 3-Alkoxycoumarins with C60

The [2+2] cycloaddition of 3-alkoxycoumarins with C60 proceeded stereoselectively under photoirradiation conditions to produce a new class of fullerene fused oligocyclic cyclobutane products. This reaction seems to progress via radical ion pair intermediates that arise from the SET processing of 3-alkoxycoumarins with the excited form of C60.

Diversifying molecular and topological space via a supramolecular solid-state synthesis: a purely organic mok net sustained by hydrogen bonds.

A three-dimensional hydrogen-bonded network based on a rare mok topology has been constructed using an organic molecule synthesized in the solid state. The molecule is obtained using a supramolecular protecting-group strategy that is applied to a solid-state [2+2] photodimerization. The photodimerization affords a novel head-to-head cyclo-butane product. The cyclo-butane possesses tetrahedrally disposed cis-hydrogen-bond donor (phenolic) and cis-hydrogen-bond acceptor (pyridyl) groups. The product self-assembles in the solid state to form a mok network that exhibits twofold interpenetration. The cyclo-butane adopts different conformations to provide combinations of hydrogen-bond donor and acceptor sites to conform to the structural requirements of the mok net.

Metal‐Free Carbocyclization of Homoallylic Silyl Ethers Leading to Cyclopropanes and Cyclobutanes

AbstractWe have developed a Hosomi‐Sakurai type carbocyclization of homoallylic silyl ethers in reaction with silyl nucleophiles, catalyzed by Lewis acidic silylium salt. It offers cyclopropane and cyclobutane products with high efficiency and selectivity. A range of silyl nucleophiles could be engaged in this transformation to give small‐sized carbocycles incorporating allyl, allenyl, carbonyl, indole or thioether groups. Diastereoselectivity in the cyclobutane formation was observed to be dependent on the steric bulkiness of incoming nucleophiles.