Benzenesulfonyl Azide Research Articles

Amphiphilic Block Copolymers Containing Benzenesulfonyl Azide Groups as Visible Light-Responsive Drug Carriers for Image-Guided Delivery.

Nanoparticles (NPs) containing light-responsive polymers and imaging agents show great promise for controlled drug delivery. However, most light-responsive NPs rely on short-wavelength excitation, resulting in poor tissue penetration and potential cytotoxicity. Moreover, excessively sensitive NPs may prematurely release drugs during storage and circulation, diminishing their efficacy and causing off-target toxicity. Herein, we report visible-light-responsive NPs composed of an amphiphilic block copolymer containing responsive 4-acrylamide benzenesulfonyl azide (ABSA) and hydrophilic N,N'-dimethylacrylamide (DMA) units. The polymer pDMA-ABSA was loaded with the chemotherapy drug dasatinib and zinc tetraphenylporphyrin (ZnTPP). ZnTPP acted as an imaging reagent and a photosensitizer to reduce ABSA upon visible light irradiation, converting hydrophobic units to hydrophilic units and disrupting NPs to trigger drug release. These NPs enabled real-time fluorescence imaging in cells and exhibited synergistic chemophotodynamic therapy against multiple cancer cell lines. Our light-responsive NP platform holds great promise for controlled drug delivery and cancer theranostics, circumventing the limitations of traditional photosensitive nanosystems.

Ethynyl-substituted benzosiloxaboroles: the role of C(π)⋯B interactions in their crystal packing and use in Cu(i)-catalyzed 1,3-dipolar cycloaddition.

The synthesis and characterization of two novel 6-ethynyl-7-halogen substituted benzosiloxaboroles (Hal = F, Cl) is reported. The crystal structures of these compounds show a unique type of supramolecular assembly dictated by distinctive C(π)⋯B interactions resulting in the formation of columnar networks involving alternating ethynyl groups and boron atoms. The QTAIM, NBO and NCI analyses were performed in order to obtain a deeper quantitative insight into the nature of these interactions including energy and charge density distribution. The fluoro derivative 1c was used as a starting material in Cu-catalyzed 1,3-dipolar cycloaddition reactions with substituted benzenesulfonyl azides giving rise to benzosiloxaboroles with pendant 1-(arylsulfonyl)-1,2,3-triazole-4-yl functionalities or analogous ionic species, i.e., 1,2,3-triazolium arylsulfonates. Screening of antimicrobial activity of obtained derivatives against a wide selection of Gram-positive and Gram-negative bacteria as well as fungi strains was performed and the obtained results were compared with the data obtained previously for related benzosiloxaborole derivatives.

Base-Mediated Coupling Reactions of Benzenesulfonyl Azides with Proline: Synthesis of Proline-Derived Benzenesulfonamides.

Sulfonamides and lipids are widely found in natural products, bioactive substances, and pharmaceuticals. Here, we report N-sulfonylation and esterification of carboxylic acids in an environment-friendly one-pot tandem protocol involving 1,2-dichloroethane (DCE). Moreover, 1,8-diazabicyclo (5.4.0) undec-7-ene was necessary for this reaction as a strong base, which drives the reaction to completion. Although DCE is a very low activity reagent, it acts not only as a solvent but also as a reactant in the reaction. The β-chloroester contained in the reaction product can be easily dissociated to react with N, S, and O atoms, increasing the possibility for subsequent synthesis.

Computational study on the mechanism of the reaction of benzenesulfonyl azides with oxabicyclic alkenes.

The reaction of benzenesulfonyl azides with oxabicyclic alkenes to form aziridines could either proceed via initial [3 + 2] cycloaddition to form triazoline intermediates which then leads to aziridines, or via initial dinitrogen cleavage of the benzenesulfonyl azide to afford a nitrene intermediate followed by addition of this nitrene species across the olefinic C-C bond of the oxabicyclic alkene. Calculations at the DFT M06-2X/6-311G(d,p) level indicate that the initial [3 + 2] cycloaddition reaction of benzenesulfonyl azide and oxabicyclic alkene has barriers of 15.0kcal/mol (endo) and 10.3kcal/mol (exo) and rate constants of 5.23 × 103s-1 (endo) and 3.86 × 106s-1 (exo) whereas the pathway involving initial formation of nitrene species has a high activation barrier of 39.2kcal/mol and rate constant of 8.92 × 10-12s-1, indicating that the reaction will go through the former route to form an exo triazoline intermediate. The exo triazoline can either undergo a concerted C-C, N-N bond cleavage to form a ring-opened intermediate, a reaction that has a barrier of 23.4kcal/mol, followed by dinitrogen extrusion and C-C, C-N bond regeneration with barriers of 29.1 and 23.5kcal/mol respectively to form endo aziridines, or it can undergo direct nitrogen extrusion to form the exo product, a reaction with a barrier of 38.3kcal/mol. Since the rate-determining step of the former route is 9.2kcal/mol more favored than the latter, the former route rate is favored. The rate constants of the rate-determining steps are 1.30 × 10-5s-1 (endo) and 3.16 × 10-11s-1 (exo), indicating that endo aziridine would be formed as the major product and this is in conformity with the experimental observations of Chen et al. (J. Org. Chem. 18:11863-11872, 2019). The position of substituents on the benzene group of the benzenesulfonyl azide affects the endo/exo diastereoselectivity.Graphical abstract.

Enantioselective Hydroazidation of Trisubstituted Non‐Activated Alkenes

AbstractA one‐pot procedure for the enantioselective hydroazidation of non‐activated trisubstituted alkenes is described. Hydroboration with monoisopinocampheylborane (IpcBH2) provides dialkylboranes that are in situ selectively converted into monoalkyl‐substituted catecholboranes; these undergo radical azidation upon treatment with benzenesulfonyl azide and a radical initiator. Enantiomerically enriched azides were thus obtained in yields of 59–81 % and enantioselectivities of up to 94:6 e.r. (98:2 e.r. if the intermediate dialkylborane is purified by crystallization). A rapid access to enantiomerically pure (+)‐rodocaine is also described. The use of other arenesulfonyl radical traps enables enantioselective hydroallylation, hydrosulfanylation, and hydrobromination reactions with yields of 71–86 %.

Enantioselective Hydroazidation of Trisubstituted Non‐Activated Alkenes

A one-pot procedure for the enantioselective hydroazidation of non-activated trisubstituted alkenes is described. Hydroboration with monoisopinocampheylborane (IpcBH2 ) provides dialkylboranes that are in situ selectively converted into monoalkyl-substituted catecholboranes; these undergo radical azidation upon treatment with benzenesulfonyl azide and a radical initiator. Enantiomerically enriched azides were thus obtained in yields of 59-81 % and enantioselectivities of up to 94:6 e.r. (98:2 e.r. if the intermediate dialkylborane is purified by crystallization). A rapid access to enantiomerically pure (+)-rodocaine is also described. The use of other arenesulfonyl radical traps enables enantioselective hydroallylation, hydrosulfanylation, and hydrobromination reactions with yields of 71-86 %.

Development and Application of a Recyclable High-Load Magnetic Co/C Hybrid ROMP-Derived Benzenesulfonyl Chloride Reagent and Utility of Corresponding Analogues.

The development and application of high-load, recyclable magnetic Co/C hybrid ROMP-derived benzenesulfonyl chloride and analogues is reported. The regeneration and utility of these reagents in the methylation/alkylation of various carboxylic acids is demonstrated via efficient retrieval of the magnetic reagent with a neodymium magnet. Additional reactions employing the analogue sulfonic acid and in situ generated magnetic benzenesulfonyl azide are also reported.

The decomposition of benzenesulfonyl azide: a matrix isolation and computational study.

The thermal-decomposition and photo-decomposition of benzenesulfonyl azide, PhS(O)2N3, have been studied by combining matrix-isolation IR spectroscopy and quantum chemical calculations. Upon flash vacuum pyrolysis at 800 K, the azide splits off molecular nitrogen and exclusively furnishes phenylnitrene (PhN) and SO2 in the gas phase. In contrast, the azide favors stepwise photodecomposition in solid Ar and Ne matrices at 2.8 K. Specifically, the UV laser photolysis (193 and 266 nm) of PhS(O)2N3 results in the formation of the key nitrene intermediate PhS(O)2N in the triplet ground state, which undergoes pseudo-Curtius rearrangement into N-sulfonyl imine PhNSO2 under subsequent visible light irradiation (380-450 nm). Further fragmentation of PhNSO2 into SO2 and PhN followed by ring-expansion to didehydroazepine also occurs upon visible light irradiation. The preference of the stepwise mechanism for the decomposition of PhS(O)2N3 is supported by quantum chemical calculations using DFT B3LYP/6-311++G(3df,3pd) and CBS-QB3 methods.

Studies towards a greener diazo transfer methodology

A mild, efficient and green method has been developed for diazo transfer to β-ketoesters using polystyrene-supported benzenesulfonyl azide, water as solvent and catalytic base.

Enzyme-Controlled Regiodivergent C–H Amination

Significance: Arnold and co-workers report an enzyme-catalyzed asymmetric and regiodivergent C–H amination. By modifying the active site of P411BM3, a cytochrome P450BM3 variant in which the axial position of the iron-heme prosthetic group is ligated by serine instead of cysteine, two variants enabling different regioselectivity were obtained. One allowed the selective amination of the energetically more favored benzylic position, while the other was selective for the homobenzylic position of 2,5-disubstituted benzenesulfonyl azides. Comment: Due to the availability of a weaker benzylic C–H bond, direct C–H amination of homobenzylic positions are a challenge in small-molecule catalysis. Breaking the C–H bond is kinetically controlled, and therefore, this can in some cases be overcome by variation of the steric properties of the used ligands. However, genetically engineered enzymes are an attractive alternative for regiodivergent C–H amination, enabling access to the desired products in good to excellent regioand enantioselectivities. R1

Synthesis of Novel Aliphatic N-sulfonylamidino Thymine Derivatives by Cu(I)-catalyzed Three-component Coupling Reaction

A series of new aliphatic N-sulfonylamidino thymine derivatives containing nucleobase, N-sulfonyl and amidine pharmacophores in the structure were synthesized by Cu(I)-catalyzed three-component coupling of 1-propargyl thymine, benzenesulfonyl azides and amines or ammonium salts. Preliminary in vitro antitumor screening (human cervix adenocarcinoma -HeLa and leukemia cells - Jurkat) revealed promising activities of N,N-diethyl- (2) and N-4-cyanobenzyl- (6) derivatives of 4-acetamido-benzenesulfonyl amidine.

A Radical Procedure for the Anti-Markovnikov Hydroazidation of Alkenes

A one-pot procedure for the efficient hydroazidation of alkenes involving hydroboration with catecholborane followed by reaction with benzenesulfonyl azide in the presence of a radical initiator is described. The regioselectivity is controlled by the hydroboration step and corresponds in most cases to an anti-Markovnikov regioselectivity. This procedure is applicable to a wide range of alkenes and gives excellent results with 1,2-disubstituted and trisubstituted alkenes.

Stereoselective Synthesis of (Z)‐4‐(2‐Bromovinyl)benzene‐sulfonyl Azide and Its Synthetic Utility for the Transformation to (Z)‐N‐[4‐(2‐Bromovinyl)benzenesulfonyl]imidates

AbstractA novel method for the stereoselective synthesis of (Z)‐4‐(2‐bromovinyl)benzenesulfonyl azide by simultaneous azidation and debrominative decarboxylation of anti‐2,3‐dibromo‐3‐(4‐chlorosulfonylphenyl)propanoic acid using NaN3 only was developed. Facile transformation of (Z)‐4‐(2‐bromovinyl)benzenesulfonyl azide to (Z)‐N‐[4‐ (2‐bromovinyl)benzenesulfonyl]imidates was also achieved by Cu‐catalyzed three‐component coulping of (Z)‐4‐(2‐bromovinyl)benzenesulfonyl azide, terminal alkynes and alcohols/phenols.

Azidosulfonylation of alkenes, dienes, and enynes

The radical mediated azidosulfonylation of various alkenes and alkynes that are able to undergo a rapid radical rearrangement is reported. For instance, treatment of 1,6-dienes or 1-en-6-ynes with benzenesulfonyl azide affords cyclic azidosulfones. High yields are observed when tertiary alkyl radicals are azidated in the last step of the cascade process. The azidosulfonylation of β-pinene involving ring opening of the bicyclic skeleton is also reported.

Insertion reaction of azidosulfonyl azo dye with model alicyclic and heterocyclic compounds

Thermal reactions of 4-(2-hydroxynaphthalen-1-yldiazenyl)benzenesulfonyl azide with cyclohexane, benzene, toluene, anisole, p-xylene, mesitylene, dihydropyran, and pyridine were studied. Structures of the resulting azo dyes were confirmed by FT-IR, UV, 1H and 13C NMR, and mass spectra and elemental analyses, and their solvatochromic properties were examined. Probable mechanisms of nitrene insertion were discussed.

High-load, soluble oligomeric benzenesulfonyl azide: application to facile diazo-transfer reactions

The development of a high-load, soluble oligomeric sulfonyl azide using ROM polymerization is reported. The utility in diazo transfer reactions with active methylene compounds is demonstrated using an efficient protocol, with most reactions showing completion in 30 min. The sulfonamide byproduct, being insoluble in the reaction solvent, can be completely removed by simple filtration through a silica gel SPE cartridge.

3‐Pyridinesulfonyl Azide: A Useful Reagent for Radical Azidation

AbstractRadical azidations and carboazidations have been achieved using 3‐pyridinesulfonyl azide as azidating agent. Due to its base properties and its polarity, the excess of reagent is readily removed at the end of the reaction by filtration through silica gel or by extraction with either aqueous 1 M HCl or 1 M CuSO4. The use of this reagent greatly facilitates the tedious purifications of the final azides frequently encountered when reactions are run according to the original procedure involving benzenesulfonyl azide.

Tin-Free Radical Carboazidation

The radical carboazidation of alkenes could be achieved in water using triethylborane as initiator. This efficient process is complete in one hour at room temperature in an open system. These new tin-free azidation and carboazidation conditions are environmentally friendly and enable reactions to be run with an excess of either the alkene or the radical precursor. Furthermore, 3-pyridinesulfonyl azide could be used in order to avoid tedious purifications, especially when the reaction product has a similar chromatographic behavior to benzenesulfonyl azide, our original azidation reagent.

Design and synthesis of novel celecoxib analogues as selective cyclooxygenase-2 (COX-2) inhibitors: replacement of the sulfonamide pharmacophore by a sulfonylazide bioisostere

A group of celecoxib analogues in which the para-SO2NH2 substituent on the N1-phenyl ring was replaced by a para-sulfonylazido (SO2N3) 4, or a meta-SO2N38, substituent were designed for evaluation as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 inhibition studies showed that 4-[5-(4-methylphenyl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonyl azide (4) with a para-SO2N3 substituent was a selective COX-1 inhibitor. In contrast, 3-[5-(4-methylphenyl)-3-trifluoromethylpyrazol-1-yl]benzenesulfonyl azide (8a) having a meta-SO2N3 substituent (COX-1 IC50 >100μM; COX-2 IC50=5.16μM; COX-2 selectivity index >19.3) is a selective COX-2 inhibitor. A molecular modeling (docking) study showed that the SO2N3 group of 8a inserts deep inside the secondary pocket of the COX-2 binding site. The SO2N3 moiety of 8a can undergo a dual H-bonding interaction via one of its SO2 oxygen-atoms, and an electrostatic (ion–ion) interaction via the terminal azido (N3) nitrogen-atom, to the guanidino NH2 of Arg513 in the secondary pocket of COX-2. These observations indicate that an appropriately positioned SO2N3 moiety is a novel alternative bioisostere to the traditional SO2NH2 and SO2Me pharmacophores present in selective COX-2 inhibitors, that are only capable of H-bonding interactions with the COX-2 isozyme, for use in drug design.

A novel approach for the formation of carbon-nitrogen bonds: azidation of alkyl radicals with sulfonyl azides.

Two preparatively attractive methods for the azidation of alkyl radicals are described. Secondary and tertiary alkyl iodides and dithiocarbonates are easily converted into the corresponding azides, either by reaction with ethanesulfonyl azide in the presence of dilauroyl peroxide, or by treatment with benzenesulfonyl azide and hexabutylditin in the presence of a radical initiator. Interestingly, intramolecular tandem radical cyclization-azidation processes can be performed in high yields.