1233032-09-1

Basic information

• Product Name: 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-ethoxycyclobut-3-ene-1,2-dione
• Synonyms: 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-ethoxycyclobut-3-ene-1,2-dione
• CAS NO: 1233032-09-1
• Molecular Weight: 353.221
• Mol File: 1233032-09-1.mol

Chemical Properties

• CAS DataBase Reference: 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-ethoxycyclobut-3-ene-1,2-dione(CAS DataBase Reference)
• NIST Chemistry Reference: 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-ethoxycyclobut-3-ene-1,2-dione(1233032-09-1)
• EPA Substance Registry System: 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-ethoxycyclobut-3-ene-1,2-dione(1233032-09-1)

Safety Data

• Hazardous Substances Data: 1233032-09-1(Hazardous Substances Data)

Upstream product

• 5231-87-8 3,4-diethoxy-3-cyclobuten-1,2-dione 
• 328-74-5 3,5-Bis-(trifluoromethyl)aniline 

Downstream Products

• 1570357-01-5 C₁₈H₁₀F₆N₂O₂ 
• 1570357-04-8 C₃₀H₂₀F₁₂N₄O₄ 
• 1570357-05-9 C₂₅H₂₅F₆N₃O₂ 
• 1233032-32-0 3-(3,5-bis(trifluoromethyl)phenylamino)-4-(4-nitrophenylamino)cyclobut-3-ene-1,2-dione 
• 1454257-29-4 3-((S)-3-phenyl-1-(piperidin-1-yl)propan-2-ylamino)-4-(3,5-bis(trifluoromethyl)phenylamino)cyclobut-3-ene-1,2-dione 
• 1346683-42-8 3-((3,5-bis(trifluoromethyl)phenyl)amino)-4-(((1R,2R)-2-(pyrrolidin-1-yl)cyclohexyl)amino)cyclobut-3-ene-1,2-dione 

Relevant articles and documents

Colorimetric and luminescent sensors for chloride: Hydrogen bonding vs deprotonation

The synthesis and photophysical properties of four squaramide based fluorescent anion sensors (1-4) are described. These luminescent compounds showed selectivity for Cl- over various other anions with concomitant changes in both their UV/visible and fluorescence properties upon Cl - addition, attributed to initial H-bonding followed by NH deprotonation in the presence of excess Cl-, signaled by a color change. The nature of the electron withdrawing aryl substituents is directly related to the H-bonding ability/acidity of the squaramide protons and can be used to tune the deprotonation behavior.

Supramolecular Hydrogels Based on Minimalist Amphiphilic Squaramide–Squaramates for Controlled Release of Zwitterionic Biomolecules

Supramolecular hydrogels with tunable properties have innovative applications in biomedicine, catalysis, and materials chemistry. Minimalist low-molecular-weight hydrogelators based on squaramide and squaramic acid motifs have been designed. This approach benefits from the high acidity of squaramic acids and the aromaticity of squaramides. Moreover, substituents on the aryl ring tune the π density of the arylsquaramide motif. Thus, materials featuring distinct thermal and mechanical properties have been successfully prepared. The hydrogel (G′≈400 Pa, G′′≈57 Pa; at 1.0 % w/v; 1 Hz) obtained from 4-nitrophenylsquaramide motif 1 is thermoreversible (T=57 °C at 0.2 % w/v), thixotropic, self-healable, and undergoes irreversible shrinking in response to saline stress. Furthermore, the hydrogel is injectable and can be loaded with substantial amounts (5:1 excess molar ratio) of zwitterionic biomolecules, such as l-carnitine, γ-aminobutyric acid (GABA), or d,l-Ala-d,l-Ala, without any loss of structural integrity. Then, the release of these molecules can be modulated by saline solutions.

Synthesis and biological effect of lysosome-targeting fluorescent anion transporters with enhanced anionophoric activity

Two lysosome-targeting fluorescent anion transporters derived from coumarins, trifluoromethylated arylsquaramides and morpholines were synthesized, and their specificity and efficiency to target and alkalize lysosomes were investigated. They are able to target lysosomes specifically. Compared with the previous analogue without trifluoromethyl substituents, these two conjugates, in particular the one having a 3,5-bis(trifluoromethyl) substituent, exhibit significantly higher ability to facilitate the transport of chloride anions, alkalize lysosomes and reduce the activity of lysosomal Cathepsin B enzyme. The present finding suggests that improving the anionophoric activity of lysosome-targeting fluorescent anion transporters is favorable to the efficiency to alkalize lysosomes and deactivate lysosomal Cathepsin B enzyme.

Tripodal squaramide conjugates as highly effective transmembrane anion transporters

Two tripodal squaramide conjugates having 4-(trifluoromethyl)phenyl and 3,5-bis(trifluoromethyl)phenyl substituents were synthesized and found to exhibit highly efficient transmembrane anion transport with the EC50 values being 0.14 and 0.75?mol%, respectively. Though one of them has been reported to act as a strong anion receptor, in particular for sulfate anions, these two compounds exhibit no significant selectivity with respect to the tested monovalent anions and a very low level of activity in the presence of sulfate anions.

Self-assembly of amphiphilic aryl-squaramides in water driven by dipolar π-π interactions

Squaramides are versatile compounds with a great capacity to interact via non-covalent interactions and therefore of interest for the development of supramolecular systems and functional materials. In the present work, a new series of aryl-squaramide amphiphiles (1-5) were prepared to form supramolecular polymers in water. Interestingly, only compounds 1 and 2 that contain electron-deficient aryl groups are capable of forming hydrogels (～10-2 M) upon treatment with a base (NaOH or PBS). The aggregation behaviour of 1 and 2 was studied by static light scattering, UV-Vis, 1H NMR, FT-IR, and atomic force microscopy, and it was found that these compounds aggregate forming well-defined 1D nanofibers below the critical gelation concentration (-3 M). Moreover, the combination of these experiments with 1D and 2D NMR studies and theoretical calculations revealed that 1 and 2 self-assemble via an unprecedented interaction motif showing dipolar π-π interactions between the squaramide rings and the 4-nitrophenyl or 3,5-bis(trifluoromethyl)phenyl rings of 1 and 2, respectively. Such kinds of assemblies are stabilized by the compensation of the dipole moments of the stacked molecules. This interaction mode contrasts with those typically driving squaramide-based assemblies based on either hydrogen bonds or antiparallel stacking. We believe that this interaction motif is of interest for the design and development of new squaramide nanomaterials with free hydrogen bonding groups, which might be useful in drug delivery applications.

Highly enantioselective one-pot sequential synthesis of valerolactones and pyrazolones bearing all-carbon quaternary stereocentres

Highly enantiopure and bioactive δ-valerolactones and pyrazolones, bearing α-all-carbon quaternary stereocentres, were successfully and sequentially preparedviaa one-pot procedure starting from readily available, inexpensive materials, catalysed by a new chiral squaramide under mild reaction conditions. An organocatalytic Michael reaction afforded the valerolactones, while a one-pot Michael-hydrazinolysis-imidization cascade yielded the pyrazolones. This procedure is economically efficient and environmentally benign.

A novel dual organocatalyst for the asymmetric pinder reaction and a mechanistic proposal consistent with the isoinversion effect thereof

In general, the Pinder reaction concerns the reaction between an enolisable anhydride and an aldehyde proceeding initially through a Knoevenagel reaction followed by the ring closing process generating lactones with at least two chiral centers. These scaffolds are frequently present in natural products and synthetic bioactive molecules, hence it has attracted intense interest in organic synthesis and medicinal chemistry, particularly with respect to controlling the diastereo-and enantioselectivity. To the best of our knowledge, there has been only one attempt prior to this work towards the development of a catalytic enantioselective Pinder reaction. In our approach, we designed, synthesized, and tested dual chiral organocatalysts by combining BIMAH amines, (2‐(α‐ (alkyl)methanamine)‐1H‐benzimidazoles, and a Lewis acid motif, such as squaramides, ureas and thioureas. The optimum catalyst was the derivative of isopropyl BIMAH bearing a bis(3,5‐ trifluoromethyl) thiourea, which afforded the Pinder products from various aromatic aldehydes with diastereomeric ratio >98:2 and enatioselectivity up to 92 ee%. Interestingly, the enantioselectivity of this catalyzed process is increased at higher concentrations and exhibits an isoinversion effect, namely an inverted ?U? shaped dependency with respect to the temperature. Mechanistically, these features, point to a transition state involving an entropy‐favored heterodimer interaction between a catalyst/anhydride and a catalyst/aldehyde complex when all other processes leading to this are much faster in comparison above the isoinversion temperature.

Squaramide–Quaternary Ammonium Salt as an Effective Binary Organocatalytic System for Oxazolidinone Synthesis from Isocyanates and Epoxides

Squaramide–quaternary ammonium salt is illustrated as a simple, tunable, and competent metal-free binary catalytic platform for the atom-economic conversion of epoxides and isocyanates into oxazolidinones. Although, various metal catalysts have been employed for the title reaction, application of organocatalysis is scarce. At first, a rational survey of catalytic activity of several air-stable and architecturally distinct squaramides was undertaken. Thereafter, the impact on catalytic capability of different parameters, such as temperature, catalyst loading, and nature of nucleophiles, was examined. This binary organocatalytic system for the oxazolidinone synthesis, composed of a squaramide entity along with a suitable halide anion, was applied to the challenging conversion of a plethora of alkyl- and aryl-substituted epoxides– including disubstituted and enantioenriched ones– and isocyanates into the corresponding oxazolidinones in high-to-excellent yields. The time-dependent formation of oxazolidinone from epoxide and isocyanate was monitored by FTIR-ATR and 1H NMR spectroscopy and the scalability of this process was also described. In light of 1H NMR experiment, a hydrogen-bonding/anion-binding mechanism was proposed wherein the nucleophilic ring-opening operation, and oxo- and carbamate-anions stabilization occur cooperatively towards isocyanate fixation.

ω-Quinazolinonylalkyl aryl ureas as reversible inhibitors of monoacylglycerol lipase

The serine hydrolase monoacylglycerol lipase (MAGL) is involved in a plethora of pathological conditions, in particular pain and inflammation, various types of cancer, metabolic, neurological and cardiovascular disorders, and is therefore a promising target for drug development. Although a large number of irreversible-acting MAGL inhibitors have been discovered over the past years, there are only few compounds known so far which inhibit the enzyme in a reversible manner. Therefore, much effort is put into the development of novel chemical entities showing reversible inhibitory behavior, which is thought to cause less undesired side effects. To explore a wide range of chemical structures as MAGL binders, we have applied a virtual screening approach by docking small molecules into the crystal structure of human MAGL (hMAGL) and envisaged a library of 45 selected compounds which were then synthesized. Biochemical investigations included the determination of the inhibitory potency on hMAGL and two related hydrolases, i.e. human fatty acid amide hydrolase (hFAAH) and murine cholesterol esterase (mCEase). The most promising candidates from theses analyses, i.e. three ω-quinazolinonylalkyl aryl ureas bearing alkyl spacers of three to five methylene groups, exhibited IC50 values of 20–41 μM and reversible, detergent-insensitive behavior towards hMAGL. Among these compounds, the inhibitor 1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(4-oxo-3,4-dihydroquinazolin-2-yl)butyl)urea (96) was selected for further kinetic characterization, yielding a dissociation constant Ki = 15.4 μM and a mixed-type inhibition with a pronounced competitive component (α = 8.94). This mode of inhibition was further supported by a docking experiment, which suggested that the inhibitor occupies the substrate binding pocket of hMAGL.

Hydrogen-Bond Catalysis of Imine Exchange in Dynamic Covalent Systems

The reversibility of imine bonds has been exploited to great effect in the field of dynamic covalent chemistry, with applications such as preparation of functional systems, dynamic materials, molecular machines, and covalent organic frameworks. However, acid catalysis is commonly needed for efficient equilibration of imine mixtures. Herein, it is demonstrated that hydrogen bond donors such as thioureas and squaramides can catalyze the equilibration of dynamic imine systems under unprecedentedly mild conditions. Catalysis occurs in a range of solvents and in the presence of many sensitive additives, showing moderate to good rate accelerations for both imine metathesis and transimination with amines, hydrazines, and hydroxylamines. Furthermore, the catalyst proved simple to immobilize, introducing both reusability and extended control of the equilibration process.