Tetrazole-Functionalized Organoboranes Exhibiting Dynamic Intramolecular N→B-Coordination and Cyanide-Selective Anion Binding.

Starting from two different cyano-functionalized organoboranes, we demonstrate that 1,3-dipolar [3+2] azide-nitrile cycloaddition can serve to generate libraries of alkyl-tetrazole-functionalized compounds capable of intramolecular N→B-Lewis adduct formation. Due to the relatively low basicity of tetrazoles, structures can be generated that exhibit weak and labile N→B-coordination. The reaction furnishes 1- and 2-alkylated regio-isomers that exhibit different effective Lewis-acidities at the boron centers, and vary in their optical absorption and fluorescence properties. Indeed, we identified derivatives capable of selectively binding cyanide over fluoride, as confirmed by 11B NMR. This finding demonstrates the potentialities of this synthetic strategy to systematically fine-tune the properties of lead structures that are of interest as chemical sensors.

1,3,4,5-Tetrasubstituted Poly(1,2,3-triazolium) Obtained through Metal-Free AA+BB Polyaddition of a Diazide and an Activated Internal Dialkyne.

A tetra(ethylene glycol)-based 1,3,4,5-tetrasubstituted poly(1,2,3-triazolium) is synthesized in two steps including: i) the catalyst-free polyaddition of a diazide and an activated internal dialkyne and ii) the N-alkylation of the resulting 1,2,3-triazole groups. In order to provide detailed structure/properties correlations different analogs are also synthesized. First, parent poly(1,2,3-triazole)s are obtained via AA+BB polyaddition using copper(I)-catalyzed alkyne-azide cycloaddition or metal-free thermal alkyne-azide cycloaddition (TAAC). Poly(1,2,3-triazole)s with higher molar masses are obtained in higher yields by TAAC polyaddition. A 1,3,4-trisubstituted poly(1,2,3-triazolium) structural analog obtained by TAAC polyaddition using a terminal activated dialkyne and subsequent N-alkylation of the 1,2,3-triazole groups enables discussing the influence of the methyl group in the C-4 or C-5 position on thermal and ion conducting properties. Obtained polymers are characterized by 1H, 13C, and 19F NMR spectroscopy, differential scanning calorimetry, thermogravimetric analysis, size exclusion chromatography, and broadband dielectric spectroscopy. The targeted 1,3,4,5-tetrasubstituted poly(1,2,3-triazolium) exhibits a glass transition temperature of -23 °C and a direct current ionic conductivity of 2.0 × 10-6 S cm-1 at 30 °C under anhydrous conditions. The developed strategy offers opportunities to further tune the electron delocalization of the 1,2,3-triazolium cation and the properties of poly(1,2,3-triazolium)s using this additional substituent as structural handle.

A facile synthesis of chromeno[3,4-c]spiropyrrolidine indenoquinoxalines via 1,3-dipolar cycloadditions.

A one-pot, four-component reaction for the synthesis of novel chromeno[3,4-c]spiropyrrolidine-indenoquinoxalines is described via a 1,3-dipolar cycloaddition of 3-acetyl-coumarins with the azomethine ylides followed by deacetylation and protonation (deuteration). The products were obtained in moderate to high yields, and their structures were confirmed by 1H NMR, 13C NMR, FT-IR, and MS spectroscopy.

Exploration and Development of Nitrone Chemistry.

Nitrones are widely used as 1,3-dipoles in organic synthesis, but control of their reactions is not always easy. This review outlines our efforts to make the reactions of nitrones more predictable and easier to use. These efforts can be categorized into (1) 1,3-nucleophilic addition reaction of ketene silyl acetals to nitrones, (2) geometry-controlled cycloaddition of C-alkoxycarbonyl nitrones, (3) stereo-controlled cycloaddition using double asymmetric induction, and (4) generation of nitrones by N-selective modification of oximes.

Facile Synthesis of Some New Peptidomimetic ß3 -and ß2,3 -Amino Alcohols Possessing Pyridyl Moiety via Reductive Ring Opening of Pyridyl-isoxazolidines.

Regio- and stereoselective 1,3-dipolar cycloadditions of C-(3-pyridyl)-N-phenylnitrone (2) with variedly substituted dipolarophiles (3, 4) were carried out to obtain substituted pyridyl-isoxazolidines (5-8). Reductive cleavage of pyridyl-isoxazolidines (5-8) with ammonium formate, methanol-THF solvents, at ambient temperature, in the presence of Pd/C provided a facile route for the synthesis of ß3 -and ß2,3 -amino alcohols (9-12), with a substitution pattern having pronounced influence on torsional angles. The obtained compounds (9-12) are valuable scaffolds which can be utilized for peptidomimetics. Thus, the present methodology for reductive opening of isoxazolidine ring avoids the disadvantages of using expensive apparatus and hazards involved in the use of hydrogen gas. The preferential formation of amino-alcohols in case of bicyclic isoxazolidines (8a-c), which precludes any recyclization is rationalized by DFT calculations.

Synthesis of New Isoxazolidine Derivatives Utilizing the Functionality of N-Carbonylpyrazol-Linked Isoxazolidines.

Using Ni(II) as the catalyst, electron-deficient 3,5-dimethylacryloylpyrazole olefin was reacted with C,N-diarylnitrones alone for 10 min to prepare novel five-member heterocyclic products, 4-3,5-dimethylacryloylpyrazole isoxazolidines with 100% regioselectivity and up to 99% yield. And then, taking these cycloadducts as substrates, six kinds of derivatization reactions, like ring-opening, nucleophilic substitution, addition-elimination and reduction, were studied. Experimental results showed that all kinds of transformations could obtain the target products at a high conversion rate under mild conditions, a finding which provided the basic methods for organic synthesis methodology research based on an isoxazolidine skeleton.

Diastereoselective Three-Component 1,3-Dipolar Cycloaddition to Access Functionalized ß-Tetrahydrocarboline- and Tetrahydroisoquinoline-Fused Spirooxindoles.

A chemselective catalyst-free three-component 1,3-dipolar cycloaddition has been described. The unique polycyclic THPI and THIQs were creatively employed as dipolarophiles, which led to the formation of functionalized ß-tetrahydrocarboline- and tetrahydroisoquinoline-fused spirooxindoles in 60-94% of yields with excellent diastereoselectivities (10: 1->99: 1 dr). This reaction not only realizes a concise THPI- or THIQs-based 1,3-dipolar cycloaddition, but also provides a practical strategy for the construction of two distinctive spirooxindole skeletons.

2,5-Di-tert-butyl-2,5-diethylpyrrolidine-1-oxyls: Where Is a Reasonable Limit of Sterical Loading for Higher Resistance to Reduction?

The pyrrolidine nitroxides with four bulky alkyl substituents adjacent to the N-O∙ group demonstrate very high resistance to reduction with biogenic antioxidants and enzymatic systems. This makes them valuable molecular tools for studying the structure and functions of biomolecules directly in a living cell and for functional EPR and NMR tomography in vivo. The first example of highly strained pyrrolidine nitroxides with both ethyl and tert-butyl groups at each of the α-carbon atoms of the nitroxide moiety with cis-configuration of the tert-butyl groups was prepared using a three-component domino reaction of tert-leucine and 2,2-dimethylpentan-3-one with dimethyl fumarate with subsequent conversion of the resulting strained pyrrolidine into 1-pyrroline-1-oxide and addition of EtLi. The nitroxide has demonstrated unexpectedly fast reduction with ascorbate, the rate constant k2 = (2.0 ± 0.1) × 10-3 M-1s-1. This effect was explained by destabilization of the planar nitroxide moiety due to repulsion with the two neighboring tert-butyl groups cis to each other.

Synthesis and In Silico Analysis of New Polyheterocyclic Molecules Derived from [1,4]-Benzoxazin-3-one and Their Inhibitory Effect against Pancreatic α-Amylase and Intestinal α-Glucosidase.

This study focuses on synthesizing a new series of isoxazolinyl-1,2,3-triazolyl-[1,4]-benzoxazin-3-one derivatives 5a-5o. The synthesis method involves a double 1,3-dipolar cycloaddition reaction following a "click chemistry" approach, starting from the respective [1,4]-benzoxazin-3-ones. Additionally, the study aims to evaluate the antidiabetic potential of these newly synthesized compounds through in silico methods. This synthesis approach allows for the combination of three heterocyclic components: [1,4]-benzoxazin-3-one, 1,2,3-triazole, and isoxazoline, known for their diverse biological activities. The synthesis procedure involved a two-step process. Firstly, a 1,3-dipolar cycloaddition reaction was performed involving the propargylic moiety linked to the [1,4]-benzoxazin-3-one and the allylic azide. Secondly, a second cycloaddition reaction was conducted using the product from the first step, containing the allylic part and an oxime. The synthesized compounds were thoroughly characterized using spectroscopic methods, including 1H NMR, 13C NMR, DEPT-135, and IR. This molecular docking method revealed a promising antidiabetic potential of the synthesized compounds, particularly against two key diabetes-related enzymes: pancreatic α-amylase, with the two synthetic molecules 5a and 5o showing the highest affinity values of 9.2 and 9.1 kcal/mol, respectively, and intestinal α-glucosidase, with the two synthetic molecules 5n and 5e showing the highest affinity values of -9.9 and -9.6 kcal/mol, respectively. Indeed, the synthesized compounds have shown significant potential as antidiabetic agents, as indicated by molecular docking studies against the enzymes α-amylase and α-glucosidase. Additionally, ADME analyses have revealed that all the synthetic compounds examined in our study demonstrate high intestinal absorption, meet Lipinski's criteria, and fall within the required range for oral bioavailability, indicating their potential suitability for oral drug development.

Synthesis and Properties of Azahomocorannulenyl Cations and Radicals.

Cycloheptatrienyl (tropyl) molecules are representative non-alternant hydrocarbons that offer interesting chemistry because of their unique structures and properties. However, there have been a limited number of polycyclic aromatic tropyl cations and radicals reported in the literature. Herein, we report the synthesis of a series of azahomocorannulene derivatives, where the key reactions are a 1,3-dipolar cycloaddition of polycyclic aromatic azomethine ylides with dibenzotropone and a subsequent palladium-catalyzed cyclization. X-ray diffraction analysis revealed that the obtained azahomocorannulenyl cation and radical adopt planar structures and exhibit unique packing structures. Their electronic and optical properties were investigated experimentally and theoretically to reveal their aromatic character.

Dipolarophile-Steered Formal Stereodivergent Synthesis of 2,5-cis/trans-Pyrrolidines Based on Asymmetric 1,3-Dipolar Cycloaddition of Imino Lactones.

The stereodivergent asymmetric synthesis of 2,5-trans/cis pyrrolidines by 1,3-dipolar cycloaddition using two different types of activated alkenes is described. When ylidene-isoxazolones were employed as dipolarophiles, the Ag/(S,Sp )-iPr-FcPHOX-catalyzed asymmetric [3+2] cycloaddition of imino lactones proceeded with 2,5-trans selectivity. Subsequent decarboxylation of the isoxazolone rings produced pyrrolidines with 2,5-trans stereoretention. In the reaction using acyclic enones as activated alkenes, the Ag/(R,Sp )-ThioClickFerrophos complex-catalyzed asymmetric [3+2] cycloaddition afforded 2,5-cis substituted pyrrolidines in high yields and enantioselectivities. Therefore, these methods can be considered as a formal stereodivergent synthesis of 2,5-cis/trans pyrrolidines.

Catalytic Enantioselective [3+2] Cycloaddition of N-Metalated Azomethine Ylides.

Asymmetric [3+2] cycloaddition reactions are fascinating and powerful methods for the synthesis of enantioenriched pyrrolidines up to four stereocentres. Pyrrolidines are important compounds for both biology and organocatalytic applications. This review summarizes the most recent advances in the enantioselective synthesis of pyrrolidines by [3+2] cycloadditions of azomethine ylides using metal catalysis. It has been organized by the type of metal catalysis used and further arranged by the complexity nature of dipolarophile. The presentation of each reaction type highlights their advantages and limitations.

Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3-Dipolar Cycloaddition of 3-Oxidopyridinium Betaines and Dienamines.

Tropane alkaloids constitute a compound-class which is structurally defined by a central 8-azabicyclo[3.2.1]octane core. A diverse bioactivity profile combined with an unusual aza-bridged bicyclic framework has made tropanes molecules-of-interest within organic chemistry. Enantioselective examples of (5+2) cycloadditions between 3-oxidopyridinium betaines and olefins remain unexplored, despite 3-oxidopyridinium betaines being useful reagents in organic synthesis. The first asymmetric (5+2) cycloaddition of 3-oxidopyridinium betaines is reported, affording tropane derivatives in up to quantitative yield and with excellent control of peri-, regio-, diastereo-, and enantioselectivity. The reactivity is enabled by dienamine-activation of α,ß-unsaturated aldehydes combined with in situ formation of the pyridinium reaction-partner. A simple N-deprotection protocol allows for liberation of the tropane alkaloid motif, and synthetic elaborations of the cycloadducts demonstrate their synthetic utility to achieve highly diastereoselective modification around the bicyclic framework. DFT computations suggest a stepwise mechanism where regio- and stereoselectivity are defined during the first bond-forming step in which the pyridinium dipole exerts critical conformational control over its dienamine partner. In the second bond-forming step, a kinetic preference toward an initial (5+4) cycloadduct was identified; however, a lack of catalyst turn-over, reversibility, and thermodynamic bias favoring a (5+2) cycloadduct rendered the reaction fully periselective.

Is DFT Accurate Enough to Calculate Regioselectivity? The Case of 1,3-Dipolar Cycloaddition of Azide to Alkynes and Alkenes.

The importance of regioselectivity in 1,3-dipolar cycloadditions (DCs) makes it surprising that no benchmarking study on this problem has appeared. We investigated whether DFT calculations are an accurate tool to predict the regioselectivity of uncatalyzed thermal azide 1,3-DCs. We considered the reaction between HN3 and 12 dipolarophiles, comprising ethynes HC≡C-R and ethenes H2 C=CH-R (R=F, OH, NH2 , Me, CN, CHO), which cover a broad range of electron demand and conjugation ability. We established benchmark data by the W3X protocol [complete-basis-set-extrapolated CCSD(T)-F12 energy with T-(T) and (Q) corrections and MP2-calculated core/valence and relativistic effects] and showed that core/valence effects and high-order excitations are important for accurate regioselectivity. Regioselectivities calculated using an extensive set of density functional approximations (DFAs) were compared with benchmark data. Range-separated and meta-GGA hybrids gave the best results. Good treatment of self-interaction and electron exchange are the key features for accurate regioselectivity. Dispersion correction slightly improves agreement with W3X results. The best DFAs provide the isomeric TS energy difference with an expected error ≈0.7 mh and errors ≈2 mh can occur. The isomer yield provided by the best DFA has an expected error of ±5 %, though errors up to 20 % are not rare. At present, an accuracy of 1-2 % is unfeasible but it seems that we are not far from achieving this goal.

1,3-Dipolar cycloaddition reactions of isatin-derived azomethine ylides for the synthesis of spirooxindole and indole-derived scaffolds: recent developments.

The unique therapeutic and biological characteristics of spirooxindole have led to the presentation of numerous reactions for the synthesis of spirooxindoles through 1,3-Dipolar cycloaddition of highly reactive isatin-derived azomethine ylides with activated olefins as the main tool for the formation of spirocyclic oxindoles during the last 4 years. Therefore, there is a need to highlight the recent developments in this area, along with the representative synthetic methods and relevant reaction mechanisms from 2018 to 2021. The representative synthetic methodologies were listed in four sections based on the procedure to form the azomethine ylide species including isatins and amino acids, isatin-derived α-(trifluoromethyl)imine, isatins and benzylamines, and from isatin-derived cyclic imine 1,3-dipoles.

An efficient one-pot synthesis and docking studies of bioactive new antiproliferative dispiro[oxindole/acenaphthylenone‒benzofuranone] pyrrolidine scaffolds.

A new and efficient method has been developed to synthesize dispiro[oxindole/acenaphthylenone-benzofuranone]pyrrolidine compounds. This is done by triggering the 1,3-dipolar cycloaddition reaction of azomethine ylides by reacting isatin/acenaphthoquinone with L-picolinic acid/L-proline/sarcosine/L-thioproline/tetrahydroisoquinolines, in a highly regioselective manner in an ionic liquid [DBU][Ac] with 4'-chloro-auron[2-(4-chlorobenzylidene)benzofuran-3(2H)-one]. Single-crystal X-ray diffraction data support the proposed structures of the new compounds. The heterocycles derived from amino acids such as L-picolinic acid, L-proline, and L-thioproline showed significant inhibitory effects against six human solid tumors, including lung, breast, cervix, colon, and others. These new structures were also tested in the active sites of the MDM2 receptor to further study their antiproliferative effects.

Regioselective Cycloaddition of Nitrile Imines to 5-Methylidene-3-phenyl-hydantoin: Synthesis and DFT Calculations.

Nitrile imine cycloaddition to hydantoins containing an exocyclic C=C double bond has been previously described in a very limited number of examples. In this work, regioselective synthesis of spiro-pyrazoline-imidazolidine-2,4-diones based on a 1,3-dipolar cycloaddition reaction of nitrile imines to 5-methylidene-3-phenyl-hydantoin have been proposed. It was found that, regardless of the nature of the aryl substituents at the terminal C and N atoms of the C-N-N fragment of nitrile imine (electron donor or electron acceptor), cycloaddition to the 5-methylidenhydantoin exocyclic C=C bond proceeds regioselectively, and the terminal nitrogen atom of the nitrile imine connects to the more sterically hindered carbon atom of the double bond, which leads to the formation of a 5-disubstituted pyrazoline ring. The observed cycloaddition regioselectivity was rationalized using DFT calculations of frontier molecular orbital interactions, global CDFT reactivity indices, and minimum energy paths.

[3+2]-Cycloaddition of Nitrile Imines to Parabanic Acid Derivatives-An Approach to Novel Spiroimidazolidinediones.

Approximately 1,3-Dipolar cycloaddition of imidazolidine derivatives containing exocyclic double bonds is a convenient method of creating spiro-conjugated molecules with promising anticancer activity. In this work, the derivatives of parabanic acid (2-thioxoimidazolidine-4,5-diones and 5-aryliminoimidazolidine-2,4-diones) were first investigated as dipolarophiles in the reactions with nitrile imines. The generation of nitrile imines was carried out either by the addition of tertiary amine to hydrazonoyl chlorides «drop by drop¼ or using the recently proposed diffusion mixing technique, which led to ~5-15% increases in target compound yields. It was found that the addition of nitrile imines to C=S or C=N exocyclic double bonds led to 1,2,4-thiazolines or triazolines and occurred regioselectively in accordance with the ratio of FMO coefficients of reactants. The yield of the resulting spiro-compound depended on the presence of alkyl substituents in the nitrile imine structure and was significantly decreased in reactions with imines with strong electron donor or electron-withdrawing groups. Some of the obtained compounds showed reasonable in vitro cytotoxicity. IC50 values were calculated for HCT116 (colon cancer) cells using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) test.

Dipolarophile-Controlled Regioselective 1,3-Dipolar Cycloaddition: A Switchable Divergent Access to Functionalized N-Fused Pyrrolidinyl Spirooxindoles.

N-fused pyrrolidinyl spirooxindole belongs to a class of privileged heterocyclic scaffolds and is prevalent in natural alkaloids and synthetic pharmaceutical molecules. To realize the switchable synthesis of divergent N-fused pyrrolidinyl spirooxindoles for further biological activity evaluation via a substrate-controlled strategy, a chemically sustainable, catalysis-free, and dipolarophile-controlled three-component 1,3-dipolar cycloaddition of isatin-derived azomethine ylides with diverse dipolarophiles is described in this work. A total of 40 functionalized N-fused pyrrolidinyl spirooxindoles were synthesized in 76-95% yields with excellent diastereoselectivities (up to >99:1 dr). The scaffolds of these products can be well-controlled by employing different 1,4-enedione derivatives as dipolarophiles in EtOH at room temperature. This study provides an efficient strategy to afford a spectrum of natural-like and potentially bioactive N-fused pyrrolidinyl spirooxindoles.

Synthesis and Properties of (1R(S),5R(S),7R(S),8R(S))-1,8-Bis(hydroxymethyl)-6-azadispiro[4.1.4.2]tridecane-6-oxyl: Reduction-Resistant Spin Labels with High Spin Relaxation Times.

Site-directed spin labeling followed by investigation using Electron Paramagnetic Resonance spectroscopy is a rapidly expanding powerful biophysical technique to study structure, local dynamics and functions of biomolecules using pulsed EPR techniques and nitroxides are the most widely used spin labels. Modern trends of this method include measurements directly inside a living cell, as well as measurements without deep freezing (below 70 K), which provide information that is more consistent with the behavior of the molecules under study in natural conditions. Such studies require nitroxides, which are resistant to the action of biogenic reductants and have high spin relaxation (dephasing) times, Tm. (1R(S),5R(S),7R(S),8R(S))-1,8-bis(hydroxymethyl)-6-azadispiro[4.1.4.2]tridecane-6-oxyl is a unique nitroxide that combines these features. We have developed a convenient method for the synthesis of this radical and studied the ways of its functionalization. Promising spin labels have been obtained, the parameters of their spin relaxation T1 and Tm have been measured, and the kinetics of reduction with ascorbate have been studied.