HFIP-Mediated Desulfinative Friedel-Crafts Cyclobutenylation Reaction.

In 1,1,1,3,3,3-hexafluoroisopropyl alcohol (HFIP), gem-bis(triflyl)cyclobutenes, which can be prepared by the (2+2) cycloaddition reaction of Tf2C=CH2 with alkynes, underwent desulfination to generate the corresponding cyclobutenyl cation. This unique reactivity was successfully applied to the Friedel-Crafts type cyclobutenylation reaction of several (hetero)aromatic compounds.

Ficini Reaction with Acrylates for the Stereoselective Synthesis of Aminocyclobutanes.

The first Ficini reaction between ynamides and acrylates is reported herein. The reaction is catalyzed by B(C6F5)3 acting as a Lewis acid and is giving access to stable tri-substituted aminocyclobutenes in high yield. The resulting products can be hydrogenated and epimerized under basic conditions or in presence of a Lewis acid, providing two distinct trans- aminocyclobutane monoester stereoisomers in high yield and diastereoisomeric ratio (up to quantitative yield and >99:1 dr).

Determining the Factors Accounting for Reaction Selectivity: A Relative Energy Gradient - Interacting Quantum Atoms and Natural Bonding Orbitals Study.

Identifying the main physicochemical properties accounting for the course of a reaction is of utmost importance to rationalize chemical syntheses. To this aim, the relative energy gradient (REG) method is an appealing approach because it is an unbiased and automatic process to extract the most relevant pieces of energy information. Initially formulated within the interacting quantum atoms (IQA) framework for a single reaction, here we extend the REG method to natural bond orbitals (NBO) analysis and to the case of two competitive processes. This development enables the determination of the driving forces of any chemical selectivity. We illustrate the extended REG method on the case study of ring opening in cyclobutenes, which is an important instance of the so-called torquoselectivity.

Hydrazine-Catalysed Ring-Opening Metathesis Polymerization Of Cyclobutenes.

Materials formed by the ring-opening metathesis polymerization (ROMP) of cyclic olefins are highly valued for industrial and academic applications but are difficult to prepare free of metal contaminants. Here we describe a highly efficient metal-free ROMP of cyclobutenes using hydrazine catalysis. Reactions can be initiated via in situ condensation of a [2.2.2]-bicyclic hydrazine catalyst with an aliphatic or aromatic aldehyde initiator. The polymerizations show living characteristics, achieving excellent control over molecular weight, low dispersity values, and high chain-end fidelity. Additionally, the hydrazine can be used in substoichiometric amounts relative to the aldehyde chain-end while maintaining good control over molecular weight and low dispersity values, indicating that a highly efficient chain transfer mechanism is occurring.

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.

Nickel-Catalyzed Tunable Enantioconvergence and Kinetic Resolution in the Coupling of Tertiary Cyclobutenols with Arylboroxines.

We report that a nickel catalyst system with a modified 1,1'-spirobiindane-7,7'-diol-phosphoramidite (SPINOL) as the chiral ligand can enable the coupling of tertiary cyclobutenols and arylboroxines in an enantioconvergent manner, providing cyclobutenes with an all-carbon quaternary stereocenter in good yields (up to 84 % yield) with excellent enantioselectivities (up to >99 % ee). Moreover, the catalytic system can be applied in the kinetic resolution of cyclobutenols under slightly modified conditions, giving enantioenriched tertiary cyclobutenols with an s factor of up to >200. The reaction uses free hydroxyl groups as the leaving group without additional activation while the strained ring remains untouched. Preliminary mechanistic studies reveal that the inherent discrepant reactivity of the two enantiomers is the key to the controllable enantioconvergent and kinetic resolution process.

Ethene-1,1-disulfonyl Difluoride (EDSF) for SuFEx Click Chemistry: Synthesis of SuFExable 1,1-Bissulfonylfluoride Substituted Cyclobutene Hubs.

We present the synthesis of 1,1-bis(fluorosulfonyl)-2-(pyridin-1-ium-1-yl)ethan-1-ide, a bench-stable precursor to ethene-1,1-disulfonyl difluoride (EDSF). The novel SuFEx reagent, EDSF, is demonstrated in the preparation of 26 unique 1,1-bissulfonylfluoride substituted cyclobutenes via a cycloaddition reaction. The regioselective click cycloaddition reaction is rapid, straightforward, and highly efficient, enabling the generation of highly functionalized 4-membered ring (4MR) carbocycles. These carbocycles are valuable structural motifs found in numerous bioactive natural products and pharmaceutically relevant small molecules. Additionally, we showcase diversification of the novel cyclobutene cores through selective Cs2 CO3 -activated SuFEx click chemistry between a single S-F group and an aryl alcohol, yielding the corresponding sulfonate ester products with high efficiency. Finally, density functional theory calculations offer mechanistic insights about the reaction pathway.

Enantioselective [2+2] Cycloaddition of Allenyl Imide with Mono- or Disubstituted Alkenes.

An efficient catalytic asymmetric [2+2] cycloaddition of allenyl imide and mono- or disubstituted alkenes is disclosed. The key feature of this method is the use of bidentate allenyl imide and weakly activated and less steric hindered alkene pair by utilizing chiral magnesium(II) complex of N,N'-dioxide, which could provide through-space dispersion interactions to orientate the arrangement of the alkene. This protocol allows the generation of a series of axially chiral cyclobutenes and four-membered ring-containing spirocycles (80 examples) in high yield (up to 99 %) with excellent enantioselectivity (up to >99 % ee), and the late-stage modification of biologically active molecules as well. Experimental studies and DFT calculations revealed that this [2+2] cycloaddition proceeded via a stepwise mechanism involving a short-lived zwitterionic intermediate. The π-π interaction between the alkenes and the amide moiety in the ligand was crucial for the enantiocontrol.

Uncommon Four-Membered Building Blocks - Cyclobutenes, Azetines and Thietes.

Strained ring systems have gained considerable importance over the last few years for their implication in natural product syntheses or in drug discovery programs. We present herein a recollection of our work on the construction and functionalization of unsaturated four-membered carbo- and heterocycles in the context of the literature, as well as their applications in further reactions.

Daylight LED promotes photochemical ring contraction of 2-amine-4H-pyran-3-carbonitriles with consequent loss of their antifungal activity.

The initial objective of our work was to synthesize a series of 2-amino-4H-pyran-3-carbonitriles to be tested for their antifungal activities against economically relevant phytopathogenic fungi. Fourteen compounds were prepared in up to 94% yield and shown percentages of Botrytis cinerea inhibition above 70%. Despite the promising biological results, we observed that stock solutions prepared for biological tests showed color changing when kept for a few days on the laboratory bench, under room conditions, illuminated by common LED daylight tubes (4500-6000 k). This prompted us to investigate the possible photo-induced degradation of our compounds. FT-IR ATR experiments evidenced variations in the expected bands for functional of -amino-4H-pyran-3-carbonitriles stored under LED daylight. Following, HPLC-UV analysis showed reductions in the intensity of chromatographic peaks of 2-amino-4H-pyran-3-carbonitriles, and but not for solutions kept in the dark. A solution of (E)-2-amino-8-(4-nitrobenzylidene)-4-(4-nitrophenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile underwent 84.4% of conversion after 72 h of exposure to continuous LED daylight in a BOD chamber, and the reaction product was isolated in 36% yield and characterized as (E)-7-cyano-5-(4-nitrobenzylidene)-8-(4-nitrophenyl)bicyclo[4.2.0]oct-1(6)-ene-7-carboxamide (7*). Despite freshly prepared solutions of 2-amino-4H-pyran-3-carbonitriles produced antifungal activities, these solutions lost biological activity when left on the bench for a week. Besides, compound 7* formed from photo-induced degradation of 7 also showed no antifungal activity. With this, we hope to bring two contributions: (1) production of cyclobutenes through photochemical reactions of 2-amino-4H-pyran-3-carbonitriles can be carried out through exposure to simple white LED daylight; (2) biological applications of such 2-amino-4H-pyran-3-carbonitriles may be impaired by their poor photostability.

Stereoselective Diboration of Spirocyclobutenes: A Platform for the Synthesis of Spirocycles with Orthogonal Exit Vectors.

The diastereo- and enantioselective diboration of spirocyclobutenes provides a platform for the rapid preparation of a wide variety of chiral spirocyclic building blocks. The chemoselective functionalization of the carbon-boron bond in the products, including a stereospecific sp3 -sp2 Suzuki-Miyaura cross-coupling reaction, provides a powerful tool to control the directionality and the nature of the exit vectors in the spirocyclic framework.

Effect of Remote Substituents on the Torquoselectivity of 3-Silyl Cyclobutene-Derivatives Ring-Opening Reactions.

We have quantum chemically studied the structure and nature of 1-substituted 3-trimethylsilyl cyclobutenes and 2,2-disubstituted-7-trimethylsilyl bycyclo[4.2.0]octa-1(6),3-dienes comparing their reactivity to archetypal 3-substituted cyclobutene systems using density functional theory at M06-2X(PCM)/TZ2P level. We wish to understand how the ring opening reaction is affected by a substituent not directly connected to the σ Carbon-Carbon breaking bond. To this end, we have analyzed the reaction profiles considering second order perturbation energies and natural steric analysis within NBO framework.

On the Stability of Disubstituted Cyclobutenes - A Computational Study.

A computational study of the electrocyclic ring-opening of 2-substituted cyclobutenecarboxylic acids is presented. Detailed calculations suggest a model to predict whether the product of nucleophilic alkylation of a bicyclic lactone electrophile will be a cyclobutenecarboxylic acid or its dienoic acid isomer, based on the used nucleophile.

Preparation of Cyclobutene Acetals and Tricyclic Oxetanes through Photochemical Tandem and Cascade Reactions.

We describe a photochemical reaction using two starting materials, a cyclopent-2-enone and an alkene, which are transformed in a controlled manner via the initial [2+2]-photocycloaddition adducts into cyclobutene aldehydes (conveniently trapped as stable acetals) or unprecedented angular tricyclic 4:4:4 oxetane-containing skeletons. These compounds are formed through tandem or triple cascade photochemical reaction processes, respectively. Small libraries of each compound class were prepared, thus suggesting that this photochemistry approach opens new opportunities for synthesis design and for widening molecular diversity.

Unsaturated Four-Membered Rings: Efficient Strategies for the Construction of Cyclobutenes and Alkylidenecyclobutanes.

Our recent studies of the diastereo- and enantioselective formation of strained alkylidenecycloalkanes drove us to more-thoroughly investigate the formation of four-membered rings for which only few efficient methods are described. We first developed a strategy to diversify the saturated part of the four-membered ring and applied it to a highly diastereoselective synthesis of more-elaborate alkylidenecyclobutanes, which completed our precedent studies. In parallel, cyclobutene structures were built employing simple organometallic methods and further functionalized to give a diverse range of new substitution patterns, which consequently enriched the pool of cyclobutene-based building blocks.

Catalytic Asymmetric [3+1]-Cycloaddition Reaction of Ylides with Electrophilic Metallo-enolcarbene Intermediates.

The first asymmetric [3+1]-cycloaddition was successfully achieved by copper(I) triflate/double-sidearmed bisoxazoline complex catalyzed reactions of ß-triisopropylsilyl-substituted enoldiazo compounds with sulfur ylides. This methodology delivered a series of chiral cyclobutenes in good yields with high enantio- and diastereoselectivities (up to 99 % ee, and >20:1 d.r.). Additionally, the [3+1]-cycloaddition of catalytically generated metallo-enolcarbenes was successfully extended to reaction with a stable benzylidene dichlororuthenium complex.

Enantioselective Synthesis of Cyclobutylboronates via a Copper-Catalyzed Desymmetrization Approach.

The first catalytic enantioselective synthesis of cyclobutylboronates, by using a chiral copper(I) complex, is reported. A broad variety of cyclobutanes have been prepared with consistently high levels of diastereo- and enantiocontrol. Moreover, this method constitutes the first report of an enantioselective desymmetrization of meso-cyclobutenes to prepare chiral cyclobutanes.

Palladium-Catalyzed Oxidative Carbocyclization-Borylation of Enallenes to Cyclobutenes.

A highly efficient palladium-catalyzed oxidative borylation of enallenes was developed for the selective formation of cyclobutene derivatives and fully-substituted alkenylboron compounds. Cyclobutenes are formed as the exclusive products in MeOH in the presence of H2 O and Et3 N, whereas the use of AcOH leads to alkenylboron compounds. Both reactions showed a broad substrate scope and good tolerance for various functional groups, including carboxylic acid ester, free hydroxy, imide, and alkyl groups. Furthermore, transformations of the borylated products were conducted to show their potential applications.

The profound effect of the ring size in the electrocyclic opening of cyclobutene-fused bicyclic systems.

Fused cyclobutenes, prepared by the photocycloaddition of propargyl alcohols to cyclic anhydride chromophores, undergo facile thermochemical ring opening to fused γ-lactones. The size of the fused ring profoundly influences the temperature that is required to facilitate the ring opening (from 50 °C to 180 °C) and the nature of the product that is formed. Our studies provide new insights into the mechanistic course of these reactions and have been extended to facilitate the preparation of lactams fused to medium-sized rings.

Cyclobutene formation in PtCl2-catalyzed cycloisomerizations of heteroatom-tethered 1,6-enynes.

Aza(oxa)bicyclo[3.2.0]heptenes are accessed through the PtCl2 -catalyzed cycloisomerizations of heteroatom-tethered 1,6-enynes featuring a terminal alkyne and amide as the solvent. It is shown that the weak coordinating properties of the solvent and alkyl substituent(s) at the propargylic carbon atom favor the formation of cyclobutenes instead of other possible cycloisomerization products such as 1,3-diene derivatives or cyclopropane-fused heterocycles.